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ffefa398-de0d-4481-a8ce-0276e7d09a9c.5	About the Editors Ermina Begovic graduated from Zagreb University, where she also finished her MSc degree. She completed her PhD at University of Naples Federico II, where, at present, she holds the position of Associate Professor of Ship Seakeeping. Her main research interests are high speed and planing craft seakeeping, safety and comfort on board of high speed ships, experimental hydrodynamics, hydrodynamic loads acting on intact and damaged ships, and high speed hull form design and optimization. Ermina Begovic is the author of more than 90 papers published in international journals, conference proceedings, and book chapters, and a member of the ISSC Specialist Committee on Special Craft and of Stability Research and Development Committee. Simone Mancini, since 2020, has been the numerical team leader at the Department of Hydro and Aerodynamics at the FORCE Technology, Denmark. Furthermore, he was, for 15 years, a technical officer of the Italian Navy and, after periods of experience on board, he served as a project manager at the Ship Design Office of the Italian Navy General Staff. In 2012, he completed his MSc in Naval Architect and Marine Engineering at the University of Naples "Federico II", where he also completed his PhD in Computational Fluid Dynamics, in 2016. He is the author of more than 40 papers published in international journals, conference proceedings, and book chapters. He has served as a reviewer for more than 30 journals, and he is a member of the editorial board of two international journals. Since 2015, he has been a Contract Professor at the University "Giustino Fortunato". He is a SNAME member.	doab	2025-04-07T04:13:04.611249	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 5 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.6	Preface to "Stability and Seakeeping of Marine Vessels" Stability has always been the first safety issue for any marine vessel and static stability evaluation has been adequate for ship service. Recently, research interests have focused on ship dynamics and stability failure modes in rough sea for higher safety. Seakeeping assessment is today one of the most important design features to establish operational limits for both speed and comfort since the early design stage, thanks to the increasing of numerical and simulation capabilities. The new requirements on safety and comfort regulations make this analysis even more relevant. This book is based on the research papers of many scientists and engineers, showing the recent developments, especially in the application of numerical techniques in hull motions and added resistance evaluation and second generation intact stability criteria assessment. > Ermina Begovic, Simone Mancini Editors ### Editorial Stability and Seakeeping of Marine Vessels *Ermina Begovic 1,\ and Simone Mancini <sup>2</sup>** Stability has always been the main safety issue for all marine vessels, and static stability evaluation is adequate for ship service. Recently, research interests have focused on ship dynamics and stability failure modes in rough seas for higher safety. Hence, seakeeping assessment today is one of the most important design features to establish operational limits for both speed and comfort. The book Stability and Seakeeping of Marine Vessels includes nine contributions [1–9] to this Special Issue published during 2020. The overall aim of the collection is to improve knowledge about the most relevant and recent topics in ship stability and seakeeping. Specifically, the articles cover a wide range of topics regarding ship stability and seakeeping and reflect the recent scientific efforts in second-generation intact stability criteria evaluation and modelling of ship dynamics assessment in intact or damaged conditions. These topics are investigated mainly through direct assessments performed both via numerical methods and tools, such as boundary element methods (BEM) and computational fluid dynamics (CFD), and via EFD (experimental fluid dynamics). A brief overview of all the contributions, emphasizing the main investigation topic and the outcomes of the analysis, follows. Zhang et al. (2019) [1] focus on the analysis of the effect of damage openings, specifically side and bottom damage openings, on the ship flooding process. The investigation is carried out numerically using the commercial CFD code CD Adapco Star CCM+, and the damaged hull investigated is the DTMB 5415 ship at zero speed. The URANS (Unsteady Reynolds average Navier–Stokes) simulation results indicate that the flooding process and the hull motion responses are strongly sensitive to the damaged opening positions and the internal compartment arrangement. Furthermore, the visualization of the flooding process efficiently explains the causes of the motion responses and can improve the analysis of ship survivability. Mei et al. (2020) [2] propose an improved potential flow model for the hydrodynamic analysis of ships advancing in waves. This advanced potential flow method is based on the desingularized Rankine panel method, which is improved with the added effect of nonlinear steady wave-making (NSWM) flow in the frequency domain. The method is validated with results of simple geometry and a modified Wigley hull. A comparison of the results indicates that the improved model using the NSWM flow can give results in better agreement with the experimental results than those obtained using different potential flow approaches. Pennino et al. (2020) [3] investigate a new adaptive weather routing model based on the Dijkstra shortest path algorithm with the aim of selecting the optimal route that maximizes the ship performances in a seaway. The model is based on a set of ship motionlimiting criteria and the weather forecast maps, providing the sea state conditions that the ship is expected to encounter along the scheduled route. The new adaptive weather routing model is applied to optimize the scheduled route of a containership in the northern Atlantic Ocean. The results show that it is possible to achieve appreciable improvements, up to 50% of the ship seakeeping performances, without excessively increasing the route length and the voyage duration. Begovic et al. (2020) [4] present an experimental validation of the hybrid frequency– time domain method for vertical motions assessment for the hard-chine "low-drag" dis- Citation: Begovic, E.; Mancini, S. Stability and Seakeeping of Marine Vessels. J. Mar. Sci. Eng. 2021, 9, 222. https://doi.org/10.3390/jmse9020222 Received: 16 February 2021 Accepted: 16 February 2021 Published: 19 February 2021 Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). placement hull. Currently, for a warped hard-chine hull operating in displacement and semi-displacement regimes, there is no adequate numerical tool available. Thorough validation of the applied method is performed in irregular head and following seas at Froude numbers Fr = 0.2, 0.4, and 0.6. Simulations are performed with the time step equal to the frequency of sampling, and an identical analysis of the numerical and experimental time series is performed, giving reliable results in head and following waves. Petacco and Gualeni (2020) [5] give an overview of the development process that leads to the finalized version of second-generation intact stability criteria (SGIS), providing for each of the five stability failure modes a brief description of the vulnerability level requirements. Operational measures, categorized into two typologies—operational guidance and operational limitations—are analyzed through the application for a Ro-Ro Pax Ferry ship and finally provide guidance and limitations during navigation. Ljulj and Slapnicar (2020) [6] present full-scale seakeeping tests conducted on a coastal patrol ship (CPS) during ship trials. Coast guards around the world have numerous challenges related to peacetime tasks, such as preventing human and drug tracking, fighting terrorism, controlling immigration, and protecting the marine environment, and, therefore, excellent seakeeping is of paramount importance. All relevant seakeeping criteria in different sea states are analyzed, including CPS behavior at high speed in severe sea states as well as the stern vertical displacement at the low speed required for launch and recovery tasks. The authors report a comparison of measured motions on sea against numerical calculations and model tests, and they review the set of seakeeping criteria to be used at the design stage. Jing et al. (2020) [7] perform a study on the optimization of the motion response in waves of a barge platform using a zero-pressurized air cushion incorporated into the barge platform. The pressure of the zero-pressurized air cushion is equal to atmospheric pressure. Compared to the conventional pressurized air cushion, the zero-pressurized one has the advantage of less air leakage risk. The numerical results, based on the boundary element method, show that in regular and irregular waves, the air cushion could significantly reduce the amplitude of motions response close to the resonance condition. Martic et al. (2020) [8] study the effect of ship characteristics on added resistance in regular waves and irregular head sea in relation to the IMO (International Maritime Organization) goal of reducing CO2 emission by ships. Hydrodynamic calculations of added resistance of the KCS (Kriso container ship) are performed by the 3D panel method based on potential flow theory. The obtained numerical results are corrected for the direction component of added resistance in short waves and validated against the experimental data available in the literature. Numerical uncertainty is evaluated for the results in regular waves, whereas monotonic convergence is achieved and for the mean value of added resistance in irregular waves for certain sea states. The obtained results provide an overview of the effect ship characteristics variation on added resistance. Finally, Pacuraru et al. (2020) [9] carry out a fully numerical analysis of the seakeeping performance of the KCS vessel. Several hydrodynamic methods, in-house code based on linear strip theory, the 3D fully nonlinear time-domain boundary element method (BEM), and the commercial CFD code NUMECA are employed to obtain accurate results of ship hydrodynamic response in regular head waves. The results obtained using these methods are presented and discussed to establish a methodology for estimating the ship response in regular waves with accurate results and to determine the sensitivity of hydrodynamical models. Author Contributions: Conceptualization, E.B. and S.M.; resources, E.B. and S.M.; writing—original draft preparation, E.B. and S.M.; writing—review and editing, E.B. and S.M.; supervision, E.B. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. #### References	doab	2025-04-07T04:13:04.611374	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 6 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.7	Article Numerical Investigation into the Effect of Damage Openings on Ship Hydrodynamics by the Overset Mesh Technique *Xinlong Zhang 1, Zhuang Lin 1,\, Simone Mancini 2, Ping Li 1, Dengke Liu 1, Fei Liu <sup>1</sup> and Zhanwei Pang <sup>1</sup> Received: 8 November 2019; Accepted: 19 December 2019; Published: 23 December 2019 Abstract: Damage stability is difficult to assess due to the complex hydrodynamic phenomena regarding interactions between fluid and structures. Therefore, a detailed analysis of the flooding progression and motion responses is important for improving ship safety. In this paper, numerical simulations are performed on the damaged DTMB 5415 ship at zero speed. All calculation are carried out using CD Adapco Star CCM + software, investigating the effect of damage openings on ship hydrodynamics, including the side damage and the bottom damage. The computational domain is modelled by the overset mesh and solved using the unsteady Reynold-average Navier-Stokes (URANS) solver. An implicit solver is used to find the field of all hydrodynamics unknown quantities, in conjunction with an iterative solver to solve each time step. The Volume of Fluid (VOF) method is applied to visualize the flooding process and capture the complex hydrodynamics behaviors. The simulation results indicated that two damage locations produce the characteristic flooding processes, and the motion responses corresponding to the hydrodynamic behaviors are different. Through comparative analysis, due to the difference between the horizontal impact on the longitudinal bulkhead and the vertical impact on the bottom plate, the bottom damage scenario always has a larger heel angle than the side damage scenario in the same period. However, the pitch motions are basically consistent. Generally, the visualization of the flooding process is efficient to explain the causes of the motion responses. Also, when the damage occurs, regardless of the bottom damage or the side damage, the excessive heel angle due to asymmetric flooding is often a threat to ship survivability with respect to the pitch angle. Keywords: URANS; VOF; overset mesh; side damage; bottom damage; flooding process; motion response #### 1. Introduction Nowadays, ship safety is of high priority to the maritime industry. However, despite many efforts being to improve ship design in recent years, damage accidents continue to occur due to collision, grounding, or the unpredictable sea environment (wind, current and waves). The loss of hull integrity leading to damage flooding can be a severe risk to ship stability [1], even making the damaged ship sink or capsize. For a damaged ship, different damage scenarios correspond to the special opening locations. The resulting flooding processes and ship motion responses are also characteristic. In the flooding process, the ship motions impact the water flooding and sloshing in the flooded compartments. Simultaneously, the liquid loads acting on the compartments also influence the ship motions [2]. Therefore, the accurate prediction of the hydrodynamic behavior coupled with the ship motions is crucial to assess the remaining survivability of the damaged ship. Also, the complex hydrodynamic behaviors caused by the coupled motion has attracted significant attention at several recent International Towing Tank Conferences [3,4]. In order to enhance the understanding of the flooding process and motion responses of the damaged ship, a series of model experiments were performed while various numerical simulation methods were developed and implemented. An experimental campaign was carried out on a passenger ferry hull to underline the effects of the damage opening on the ship roll response. The damaged ship was placed in still water and beam regular waves at zero speed [5]. Lim et al. [6] used a course-keeping model ship to measure the advance speed and motion response of the damaged ship in head and following seas. Through the free-running tests, the motion characteristics under safe return to port (SRTP) regulations were identified. Siddiqui et al. [7] performed a detailed series of experiments in a wave flume on a thin walled prismatic hull form. The obtained results demonstrate the occurrence of sloshing and piston mode resonance in the tests and their influence on the hydrodynamics load of a damaged ship. The effect of air compressibility in the airtight compartment on local floodwater behavior was also investigated. Rodrigues, et al. [8] presented an experimental procedure to measure progressive flooding on a small-scale damaged floating body. Their focus was on the estimation of the discharge coefficient at different opening geometries in still water. Additionally, a numerical simulation based on the Reynolds averaged Navier-Stokes (RANS) solver was applied to validate its capability to reasonably reproduce the physical experiments. Korkut et al. [9] carried out six degrees of freedom motion responses tests in regular waves for intact and damaged conditions. The effect of the damage opening and waves with different wave heights and wave frequencies on the motion responses of the damaged model was explored. The obtained experimental results indicated that the damage opening has an adverse influence depending on the directionality of the waves and the applied wave frequency. Generally, the applied experimental models above are created on the simplified assumption that the damaged compartment is empty, not considering the effect of permeability on the flooding and motion responses. In the real compartment layout, obstacles in the compartment and inner subdivision may affect the flooding path and quantity. Therefore, accounting for more realistic modeling of the damage flooding, Acanfora et al. [10] carried out an experimental investigation on the dynamic response of a damaged ship with a realistic arrangement of the flooded compartment. The results presented the effects of obstacles in the engine room compartment, such as decks and engine, on the roll responses. Similarly, Domesh et al. [11] used a damaged segmented ship model to study the effect of permeability and the internal arrangement of the damaged compartment on the pitch and heave responses. When the effect of the internal structures on the flooding process and motion responses is taken into account, the bearing capacity of different components will determine whether the secondary water ingress will occur. When the flooding water pressure exceeds the bearing limitation of components, the components will leak or collapse. Based on this aspect, Risto et al. [12] conducted unique full-scale tests to determine the leakage and collapse characteristics of various typical non-watertight structures, when subjected to the flooding water pressure. The obtained results can provide guideline values to determine when the structure may collapse with the accumulation of the flooding water. These well-designed model tests can accurately assess the damaged stability with complicated physical phenomena, establishing a database for the motion responses of the damaged ship. Although the experimental tests can well investigate damaged ships, their flexibility and economic efficiency are very limited. In most cases, full-scale experiments are impossible, and model experiments are associated with problems of the scale effect. In the last decade, owing to the development of high-performance computers, there has been an increasing interest in the application of computational fluid dynamics (CFD) to investigate the multi-phenomena hydrodynamic problem of the damaged ship. A Navier-Stokes (NS) solver with a free surface capturing technique, i.e., the volume of fluid method, was developed to numerically simulate water flooding into a damaged vessel. The proposed method can be used to predict the dynamic behavior of the flooding water and its impact forces on the flooded compartment [13]. Sadat-Hosseini et al. [14] performed unsteady Reynold averaged Navier-Stokes (URANS) simulations for zero-speed damaged passenger ships in calm water and waves. The flooding procedure and roll decay in calm water were studied, and the motions in regular beam waves for various wavelength were analyzed. Even though the simulation demands a larger computation costs, the predicted results coincide better with the experiment results than those reported for potential flow solver. Santos et al. [15] described a mathematical model in the time domain of the motions and flooding of ships in a seaway. Different factors affecting the survivability of the damaged ships were assessed. Ming et al. [16] applied the weakly compressible smoothed particle hydrodynamics (SPH) method to explore the influences of transversal waves on the dynamic flooding process of a damaged compartment. The simulation results indicate that when the waves slam against the damaged ship, the relative position between the damage opening and the free surface will be changed. Further, different wave directions will result in different flooding processes. This method has the advantage of dealing with large deformation problems of free surface flow and fluid–structure interaction. In addition, Manderbacka et al. [17] and Acanfora et al. [18] presented a non-linear time domain simulation method for damaged ships. The flooding water motion is based on the lumped mass method with a moving free surface, and the ship's transient response to an abrupt flooding is simulated. It has been proven that these numerical methods have been an alternative approach to study the damage flooding. In this paper, the URANS method combining the overset mesh technique in conjunction with the 6 Degree-of-Freedom (DOF) solver is applied to investigate the effect of side damage and bottom damage on the flooding process and motion responses. The paper is organized as follows. The overset mesh methodology is depicted in Section 2, including the definition of the overset mesh and the interpolation options. Section 3 introduces the utilized 5415 scale model. Section 4 underlies the whole simulation process and the critical settings, including the creation of the simulation domain, the boundary conditions, the choice of mesh types and the relevant solver settings. The captured flooding process and measured motion responses are presented and discussed in Section 5. Finally, conclusions and future research directions are taken in Section 6. #### 2. Overset Mesh Methodology** #### 2.1. Definition of the Overset Mesh With the development of computational fluid dynamics, time-domain simulation approaches based on the finite volume method (FOM) have been constantly evolving. However, for unstructured grids, the mesh-partitioning stage can be challenging due to the memory limitations of the massively parallel architectures. In this case, in order to run a simulation with increasingly fine grids and increasingly complex physics modelling, the high-performance computing represents a crucial capability to solve this problem [19]. Moreover, among the different motion-mesh techniques, the overset mesh (also known as Chimera or overlapping grids) has been considered as an efficient way to accurately describe the rotation motion of the damaged ship. Taking the simulation case as an example, as illustrated in Figure 1, when the overset mesh is activated, two individual regions are created: a background region and an overset region surrounding the damaged ship. The motion specification can be assigned to the overset region, rather than the background region. Because when the overset mesh is not applied, the motion specification can only be assigned to the background region. The background region will rotate relative to the stationary hull under the influence of the flooding water, monitoring the roll and pitch motion of the damaged hull. This will make the free surface out of the original mesh refinement block, resulting in poor simulation accuracy. However, the overset mesh can avoid this problem well. When the motion specification is assigned to the overset region, the background region is always stationary. The limited overset region will follow the movement of the damaged ship. Even if the damaged ship has a large roll or pitch motion, good overset mesh quality will ensure the accuracy of the simulation results. In addition, two regions are meshed separately, and the overset interface is created between them. For implicitly coupling the background region and the overset region, the interface is set to the overset mesh boundary condition. In this case, as the damaged ship moves within the background region, the overset region will correspondingly change. Simultaneously, the data information between the regions is exchanged through the overlapping cells. As illustrated in Figure 2, once the overset mesh is performed, the hole-cutting process in STAR-CCM + automatically couples the overset region with the background region through the overset interface. Four types of cells from the hole-cutting process are created. Active cells (cyan and yellow): Discretizing governing equations are solved here. Passive cells (dark blue). Donor cells (green): These provide interpolation information to the mesh acceptor cells. Acceptor cells (red): The boundary cells that receive information from the donor cells [20]. Figure 1. Sketch of the simulation domain. Figure 2. Four types of cells. #### 2.2. Interpolation Option For the overset mesh, the interpolation function determines the data transfer relationship between the acceptor cells and the donor cells, ensuring implicit coupling of the background region and the overset region. In this case, a solution is computed on all grids simultaneously, leading to improved robustness and convergence. Of the specified interpolation options, the alternative interpolation options include distance-weighted interpolation, linear interpolation, and least-squares interpolation [21]. For the distance–weight interpolation, the interpolation factors are inversely proportional to the distance from the acceptor to the donor cell center, resulting in the closest cell giving the largest contribution. If the simulation involves moving mesh without great motion, the linear interpolation will be a better choice as it can ensure that interpolation elements do not overlap. This choice is more accurate but also more expensive due to the computational effort required. Finally, the least-squares interpolation transfers data from source to target meshes by data mappers. This method is suitable where there is a large variation of the moving grid with respect to the background mesh, as indicated in CD Adapco User's Guide [21] and De Luca et al. [22]. Based on the features of the simulation cases, linear interpolation is adopted to obtain an accurate solution. #### 3. Model Description Numerical simulations have been performed using the well-known benchmark US Navy Destroyer Hull DTMB 5415 with a corresponding scale ratio of 1:25. Figures 3 and 4 respectively show the side view and body lines of the ship model, and Table 1 presents the principal dimensions of the ship model [23]. The created damaged compartment is located near the bow. The damaged compartment is assumed to be empty, not considering the influence of permeability and internal arrangements on the flooding water motion and damaged stability. However, in the real damage scenario, compartments could be full of equipment and obstacles that modify the flow of the water ingress. The simulation results will visualize the flooding process and measure the motion responses of the damaged ship in still water. The influence of the forward speed and external wave conditions on the coupled motion of the damaged ship and flooding water is not taken into account. Figure 3. The schematic diagram of the damaged ship. Figure 4. Body lines of DTMB 5415 model (Unit: inch). As shown in Figure 5, two comparative damage scenarios are modeled separately. It can be found that the scenarios are specific to the location of the damage opening. Side damage and bottom damage will cause different types of flooding, while the corresponding motion responses are different. In the simulation process, in order to eliminate the composite influence arising from the air compressibility, an appropriate ventilation hole is constructed on the upper deck. In [24–27], it has been elaborated that the air compression in the flooded compartments will delay the flooding process and affect the dynamic behaviors of the damaged ship. According to the much-simplified assumption in MSC.362 (92) [28], if the total ventilation hole sectional area is 10% or more of the damage opening, the air compression may be neglected and the flooded compartment can be considered to be fully ventilated. Therefore, in order to ensure the adequate ventilation condition, a relatively large ventilation hole is set in the damage scenarios. The detailed dimensions of the damage opening and ventilation hole are shown in Table 2. It is worth noting that, except for the location of the damage opening, the other properties of the hull in the two scenarios are completely consistent, including the size and location of the ventilation hole, the size of the damage opening, the weight, the center of the gravity, and the inertia moments. In this case, it is meaningful to investigate the effect of the damage location on the flooding process and motion responses of the damaged ship. For the characteristics of the hull, a preliminary analysis was conducted by the means of a fine CAD (Computer aided design) model using CATIA CAD software. The density of the low carbon steel is assigned to each part in the CAD environment. Subsequently, the total weight of the hull, the center of mass, and moments of inertia can be accurately calculated, as presented in Table 2. Figure 5. The schematic diagram of damage scenarios. Table 2. Characteristics of the hull and details of the damage opening and the ventilation hole. After determining the characteristics of the damaged hull and ensuring that the damage location is the single variation, the actual draft of the damaged hull at the corresponding weight needs to be calculated. In the simulation setup, the height of the free surface needs to be consistent with the actual draft height calculated above. Specifying an accurate draft value will ensure that the damaged hull does not instantaneously heave due to the difference between weight and displacement at the moment of release, which also reproduces the actual physical process to some extent. Therefore, before carrying out the damage simulations, it is necessary to specify the weight of the damaged hull for the intact hull, calculating the actual draft in the case of the 665.64 kg displacement. As shown in Figure 6, the initial draft specified by the simulation is 0.3 m. Under the action of gravity and buoyancy, the final actual draft is stable at 0.269737 m. However, in the process of calculating the draft, only the vertical Z-axis motion is released, and other degrees of freedom are restrained. Such simplification will result in the transient pitch motion of the damaged hull due to the difference in bow and stern weight distribution. The specific simulation results will be analyzed in Section 5. Figure 6. The actual initial draft of the damaged hull. #### 4. Numerical Setup #### 4.1. Simulation Domain and Physical Models The applied overset mesh technique requires two different regions, including the background region and the overset region, as shown in Figure 7. The overset region is obtained by Boolean operation (subtraction) between the cylinder block and the damaged hull. The overset region will rotate and translate with the movements of the damaged ship. The background region is stationary, only providing the external flow field information. The background region and the overset region are implicit through the interface, while the connectivity between them takes place through the interpolation scheme specified for the interface. The interface mentioned here is the surface of the cylinder block. According to the Mancini et al. [29], Handschel et al. [30], and the available ITTC recommended procedure and guidelines [31], the dimensions of the background region and the overset region are summarized in Table 3. The background region is usually designed in compliance with the "Practical Guidelines for Ship CFD Application" [31]. However, there is no clear specification for the dimension of the overset region, as indicated by Tezdogan et al. [32]. It is worth mentioning that in the process of generating grids, the two regions use their individual mesh continuum to generate grids respectively, and the parameter properties of the two mesh continuums are independent of each other. However, in order to ensure the consistency of the external physical field, one identical physical continuum is applied to define the physical models in two regions. Table 3. Presentation of domain dimensions. Figure 7. Region representations and domain dimensions. In the simulations, the behaviors of two fluids (liquid and air) are modelled in the same physical continuum by the volume of fluid (VOF) approach. Due to the presence of two fluids, the Euler multiphase flow model is activated, and the gravity model is used to consider the gravitational effects of two fluids. The liquid phase is modeled with constant density water. In order to reproduce the real physical process, although the air compression is not considered, the air phase is still characterized by an ideal gas model. The necessary user defined field function (UDFF) model is needed to distribute the water and air [33]. Finally, a realizable k-ε two-Layer turbulence model is applied to solve the Reynolds stress problem, which can provide a good compromise between robustness, computational cost, and accuracy [34]. #### 4.2. Boundary Conditions and Solver Settings According to Zhang et al. [33] and Begovic et al. [35], the boundaries of the simulation domain are represented in Figure 8. The chosen boundary conditions and optimal solver settings are presented in Table 4. For a clear description of the internal arrangement of the simulation domain, the boundaries on both sides are not shown. It can be found that by creating isospheric surfaces, the entire simulation domain is divided into two parts by the free surface, including the air part above and the water part below. In order to obtain the sharp interfaces between the air and water, the second-order convection term is recommended. In this case, the high-resolution interface capturing (HRIC) scheme is designed to mimic the convective transport of immiscible fluid components, forming a scheme that is suited for tracking sharp interfaces. Figure 8. Boundaries representation of the simulation domain. Table 4. Boundary conditions and solver settings. The mass conservation equation and the momentum conservation equations including the turbulence model were calculated in the incompressible based unsteady state. For the coupling of velocity and pressure, a semi-implicit method for pressure linked equations (SIMPLE) method was used [36]. In order to increase the convergence performance of the linear algebraic equation, AMG (Algebraic Multi-Grid) method [37] was used and, using the Gauss-Seidel method, the simultaneous linear equation was solved. The URANS (unsteady Reynolds-averaged Navier-Stokes) equations have been applied to control the update at each physical time for the calculation. In order to converge the solution for that given instant of time, each physical time is set to involve some number of inner iterations. Considering the compromise between the computational accuracy and the computational cost, the simulation program in this paper used a constant time step of 0.002 s, while the maximum number of the inner iteration steps is 10. The numbers determined are also consistent with the related recommendations of practical guidelines for ship CFD applications [31]. In addition, the second-order temporal discretization is activated to perform the transient calculations, which uses the current time level and the solutions from the previous two-time levels. Therefore, when the solver performs first-step calculation utilizing the second-order temporal discretization, the first-order temporal discretization is temporarily activated to provide the solutions of the first two inner iteration steps. #### 4.3. Mesh Type and Mesh Size For the mesh type, the trimmed hexahedral type is used to generate the mesh. In Begovic et al. [35], detailed sensitivity analysis of the mesh types has been performed on the roll damping assessments of the damaged ship with two hybrid meshes (polyhedral and trimmed) and two trimmed meshes. The simulation results indicate that the hybrid meshes are prohibitive due to the high time consumption and poor simulation accuracy, while the trimmed meshes are recommended. Based on this conclusion, the generated mesh in this paper is shown in Figure 5. It can be found that the entire domain is divided into three regions with different mesh densities, including the background region, the cylindrical overset region, and the overlapping region. In order to optimize the discretization of the overset region, the mesh density of the overset region is denser than the other two regions. To minimize the errors that occur when interpolating variables between two meshes, the same mesh density order of magnitude is used in the overlapping region and the background region. Therefore, it can be seen from Figure 9 that the mesh density of the overlapping region is denser than the background region and coarser than the overset region. However, fundamentally, the overlapping region is still part of the background area. It is just a refinement block extracted from the background region. In addition, the meshes around the free surface are also locally refined, which can prevent the floating-point exception due to the free surface fluctuation or breakage. Finally, in order to avoid large computational costs, the free surface of the overset region is finer than that of the background region. The mesh sizes in different parts are summarized in Table 5. Figure 9. Visualization of the hexahedral mesh. In addition to optimizing the mesh sizes of the different regions described above, the mesh quality of the damaged ship also determines the calculation accuracy. As shown in Table 5, the wrapper model, the remesh model and the trim model are activated in the mesh continuum. The appropriate wrapper and remesh sizes will restore the original geometry of the damaged ship. It can also be found that the wrapper model is not activated in the mesh continuum of the background region. This is because the damaged ship is located in the overset region, and only the wrapper characteristics in the mesh continuum of the overset region can be defined to the damaged ship. The setting of a mesh size requires a comprehensive combination of mesh quality and the mesh number. Too fine meshes will cause a longer computation time, while too coarse meshes will result in poor computation convergence. Taking the mesh size of the overlapping region as an example, when the trim size is set to 0.100 m, the mesh number will be much larger than when the mesh size is set to 0.110 m. Consequently, the time consumption is very high. So, in order to achieve the balance between the simulation accuracy and the time consumption, the final trim size is to set 0.110 m. Similarly, the mesh sizes of other parts are determined after repeated attempts. Especially for the damage opening, the ventilation hole, and the bulbous bow, since their outer contours display a large curvature, the wrapper and remesh sizes need to be modified repeatedly to ensure the real opening shape. For the flooded compartment, the trim size is locally refined. Because only when the mesh is fine enough, the complex hydrodynamics phenomena in the flooding process can be accurately captured. The generated surface of the volume mesh is shown in Figure 10. It can be seen from the figure that the original surface of the damaged ship is restored well, and the necessary block is correspondingly refined. Figure 10. Volume mesh of the hull and refinement details of the local blocks. #### 4.4. Near-Wall Treatment The wall function approach is used for the near-wall treatment, in particular, the All wall Y + model. This approach is formulated to assure reasonable answers for meshes of intermediate resolution and is considered as the best compromise between description of the boundary layer with acceptable quality and the time required for the calculation [29]. The wall y + is a non-dimensional distance similar to the local Reynolds number, often used in CFD to describe how coarse or fine a mesh is for a particular flow [38]. As indicated in the User's Guide [21], values of y+ ≈ 30 are most desirable for wall functions, whereas values of y+ ≈ 1 are most desirable for near-wall modeling. The values of wall y + on the hull surface is shown in Figure 11. It can be found that the y + values on the hull are very close to 1. For this reason, the realizable k-ε two layers turbulence model is applied. This turbulence model represents an improved treatment of the near-wall region for turbulent flows at low Reynolds numbers. This model is characterized for the layer next to the wall, where the turbulent dissipation rate and the turbulent viscosity are specified as functions of wall distance. More details about this model are available in Rodi [39]. Figure 11. Wall Y + visualization on the hull. #### 5. Simulation Results and Discussion Based on the appropriate solver settings and the optimized mesh generation, the simulation results respectively analyze the effect of damage locations on the flooding process and the motion responses. The complex hydrodynamic behaviors in the flooding process are visualized. The corresponding motion responses are compared and discussed, including the roll and pitch motion. #### 5.1. The Analysis of the Flooding Process in the Side Damage Scenario Figure 12 presents the distribution of the flooding water at different time points. In the early stage of the damage flooding, due to large pressure difference between inside and outside of the damaged opening, the water ingress flows into the flooded compartment with a jet form in the opening section. The water ingress impacts the bottom plate and the longitudinal bulkhead, resulting in the splashing of the flooding water. Since the flooding water is violent, the compressed air in the damaged compartment cannot smoothly escape from the ventilation hole, and the complex hydrodynamic behavior such as a bubble is formed in the flooding water. This stage is complex but short, which is often defined as the transient flooding stage. As shown in Figure 12, the period from 0 s to 4.9 s can be roughly referred to as the transient flooding stage. With the effect of asymmetric water ingress, the damaged ship heels towards the starboard side, causing the pressure at the opening section to become larger. From the four graphs corresponding to 1, 2.9, 4, and 4.9 s, it can be found that the increased pressure at the opening section makes the slamming point (1, 2, 3, 4) on the longitude move upward. Such a slamming effect will produce a restoring moment that makes the damaged ship heel towards the port side. When the flooding water develops to a certain extent, the pressure difference between the inside and outside of the damaged compartment will gradually smaller, the flooding will become slower. This stage is often referred to as the progressive flooding stage, as shown in Figure 12 for the period from 4.9 s to 20 s. In this stage, the flooding water continuously flooded the damaged compartment. The free surface exhibits a wave-propagating form, producing a reflective behavior when it touches the longitudinal bulkhead. Although the flooding process is almost completed in about 20 s, from the capture of the flooding process at 30 s, the free surface is still sloshing due to the roll motion of the damaged ship. Conversely, the sloshing of the free surface also affects the motion response of the damaged ship. Finally, if the damaged ship can keep afloat, not capsizing or sinking due to the added flooding water, the final equilibrium state will be characterized. This stage is often referred to as the steady stage. Such detailed descriptions of the hydrodynamic behaviors in the flooding process can be applied to explain the causes of the damaged ship's motion responses. The specific and comprehensive explanation is elaborated in the motion response analysis in Section 5.3.1. Figure 12. Visualization of the side flooding process. #### 5.2. The Analysis of the Flooding Process in the Bottom Damage Scenario After comparison, there are both similarities and differences between the side flooding process illustrated in Figure 12 and the bottom flooding process illustrated in Figure 13. The overall similarity is that the bottom flooding process also experiences three flooding stages, including the transient stage, the progressing stage, and the steady stage. In the transient flooding stage (0–2.0 s), due to the large pressure difference between the inside and outside of the damaged opening, the violent seawater flooded the damaged compartment in a short time. Then, with the accumulation of the flooding water, the pressure difference gradually reduces while the flooding water occupied the damaged compartment at a slow rate (2.0–15.2 s). Finally, under the coupled influence of the tank sloshing, the damaged ship tends to be stable in the roll decay motion (15.2 s–30.0 s). At 24.6 s and 30.0 s, the internal wave propagation caused by the sloshing of the free surface can be clearly seen in the damaged compartment. At the same time, the flooding characteristics in the bottom damage scenario are also evident. Corresponding to the normal direction of the bottom opening section, the flooding water is sprayed from the ship bottom in the form of a water column. When the flooding water slams the longitudinal bulkhead and reaches the highest point at 0.3 s, the flooding waterfalls under the influence of gravity. Complex dynamic behaviors can be observed when the falling flooding water touches the ship bottom from 0.5 to 1.2 s, including splashing and bubble phenomena. In addition, in contrast to the side damage scenario, the damage opening in the bottom damage scenario is located deeper below the waterline. In this case, the hydrostatic pressure at the bottom opening section is much greater than that at the side bottom opening section. This also explains why under the premise of the same damage opening size, the bottom flooding process is completed in about 15 s, however, the side damage flooding takes about 20 s. Although the extra 5 s is relatively short, according to the Froude law, the converted flooding time for the real ship longer is than on the scale model. All simulation cases in this paper were carried out on the scale model (1/25). Therefore, the extra 5 s is about 25 s when converted to the full-scale ship. Once the damage accident occurs, 25 s can provide more rescue options. Therefore, accurately predicting the flooding time in different damage scenarios is meaningful for the emergency crew to take appropriate rescue managements. Generally, this detailed visualization of the hydrodynamic behaviors is helpful to enhance the understanding of the entire flooding process among the crew and ship designers. Figure 13. Visualization of the bottom flooding process. #### 5.3. The Analysis of the Coupled Motion Responses #### 5.3.1. Description of the Roll Motion Response Based on the hydrodynamic behavior in Section 5.1. and Section 5.2, the resulting motion responses are elaborated in this section. As shown in Figure 14, although the damage locations of the two damage scenarios are different, the asymmetric flooding occurs in both damage scenarios. The asymmetric moment generated by the flooding water causes the damaged ship to heel only in the starboard. There is no periodic reciprocating roll motion between the portside and starboard. According to the right-hand rule, the value of the heel angle is negative. The heel angle can reach 15 degrees or more, indicating that the asymmetric flooding in a damaged ship is a dangerous situation. Therefore, efficient and feasible cross-flooding arrangements are needed to provide the necessary equalization across the ship in order to decrease the heel angle [40]. After a separate analysis of the roll motion curves in the two damage scenarios, it can be found that the damaged ship does not always heel towards the starboard, but gradually heels during left and right shaking. On the one hand, this is due to the inherent restoring moment of the hull itself. On the other hand, the flooding water causes a leftward impact on the longitudinal bulkhead, which also causes the damaged ship to have a tendency to heel towards the portside. As can be seen from Figure 12, the side flooding water continuously impacts the longitudinal bulkhead from the starboard. However, the horizontal impact effect due to side flooding is small compared to the vertical effect of the flooding water accumulation on the starboard bottom plate. In this case, the damaged ship only has a slight tendency to heel towards the portside, and never has a positive heel angle. At the same time, since the normal direction of the bottom opening section points to the longitudinal bulkhead, the water column in Figure 13 inevitably have an impact effect on the longitudinal bulkhead, so that the same shaking phenomenon as the side damage scenario occurs in the roll motion curve of the bottom damage scenario. In addition, the roll motion of the damaged ship and the flooding water affect each other. The roll motion makes the flooding water slosh in the flooded compartment. Conversely, the water sloshing has an impact effect on the internal bulkhead, including the longitudinal bulkhead and hull plate. Such coupled motion can present a risk to the ship survivability, even making the damaged ship capsize due to the parametric roll motion. This coupled analysis also explains why the damage scenarios still have a roll motion, even though the flooding water is no longer increased. However, due to the dissipation of energy, the entire roll motion will gradually decay. Figure 14. Comparison of heel angles in different damage scenarios. Finally, by comprehensively comparing and analyzing the roll motion of the two damage scenarios, it can be found that different hydrodynamic behaviors produce distinct motion responses. The roll motion curves of the two damaged scenarios follow the similar periodic variation rule. However, there are certain differences in the peak and trough values for the same period. In Figure 14, the peaks and troughs in the same periods are connected by the black line segments and the yellow line segments. The magnitude of the peak value represents the extent to which the damaged ship heels towards the portside (the intact side), and the magnitude of the trough value represents the extent to which the damaged ship heels towards the starboard (the damaged side). It can be seen that the bottom damage flooding in the same period produces a larger heel angle with respect to the side damage flooding, regardless of the peak value or trough value. The reason for this difference is close to the hydrodynamic behaviors of the specified damage scenario. For the bottom damage flooding, the vertical effect of the upward flooding on the bottom plate is much larger than the horizontal effect of the water column on the longitudinal bulkhead. In this case, in comparison with the side damage scenario, the damaged ship with the bottom opening has a greater inclination towards the starboard. This also corresponds to the fact that the trough values of the bottom damage scenario are below those of the side damage scenario. For the side damage flooding, the flooding water strikes the longitudinal bulkhead from the starboard to the portside. The horizontal impact drives the damaged ship heel towards the portside. This explains why the peak values of the side damage scenario in the same period are above the bottom damage scenario. In general, the visualization of the flooding process is very helpful and meaningful for analyzing the causes of motion responses. #### 5.3.2. Description of the Pitch Motion Response For analyzing the influence of the damage location on the pitch motion, Figure 15 presents the pitch motion curves of the two damage scenarios. From the overall analysis, the maximum values of the pitch angle for the two damage scenarios are only about 2 degrees in the flooding process. Conversely, the maximum value of the heel angle can reach about 15 degrees. This validates a basic conclusion that the damaged ships rarely lose stability due to the excessive pitch angle. The damaged ships often capsized due to the excessive heel angle caused by the additional flooding water. Therefore, this also provides an empirical reference for the ship designers and the emergency personnel onboard. When the damage occurs, especially for asymmetric flooding, in order to reduce the risk of capsizing or sinking, appropriate countermeasures should be taken to equalize the heel angle. Figure 15. Comparison of pitch angles in different damage scenarios. Although the pitch angle caused by the flooding water does not pose a threat to the safety of the damaged ship, its relevant effect deserves enough attention. Especially for the military ships, even if the ship is in a damaged situation, the ship must guarantee the corresponding operational missions and has to able to recover functionality following an incident (recoverability). Hence, the resulting 2 degree pitch angle is likely to affect the accuracy of the weapon strikes. So, the way to eliminate the extra pitch angle is of research significance. By comparing the pitch motion curves of the two damage scenarios, it can be found that the two pitch motion curves maintain the same variation rule, and the differences of the peak and trough values are small. This shows that the effect of the damage location on the pitch motion is small, even can be negligible. For analyzing the tendency of the pitch motion curves, it can be divided into two parts. The first part is that the damaged ship will have a transient head-pitching process at the beginning of the calculation. Because in the simulation settings, the damaged ship is placed horizontally by default. When the simulation runs, the damaged ship firstly have the initial pitch motion due to the uneven distribution of the fore and bow weights. Therefore, it can be seen from the Figure 15 that the pitch motion curves of the two damage scenarios are basically consistent at the beginning of the damage flooding, which is caused by the ship's own weight distribution described above and has little to do with the hydrodynamic behavior. The second part is that, as the flooding continues to develop, the flooding water gradually flooded the damaged compartment. Due to the strong nonlinear phenomenon of the flooding water, the flooding water spread irregularly in the damaged compartment. This is why the predicting pitch motion curves fluctuate up and down. However, the amplitude of the peak and trough values are very small. In this case, the crew onboard will not have the sloshing feeling caused by the pitch motion. Therefore, from the perspective of ensuring the survivability of the hull and the safety of human life, the threat posed by the roll motion is the problem that should be solved first. #### 6. Conclusion and Future Researches The paper demonstrated the feasibility of CFD simulations to investigate complex flooding phenomena. The developed numerical approach in this paper can well capture the complex hydrodynamic behavior in the flooding process, including splash, jet, water column, and bubble. The URANS solver involving the overset mesh technique is applied to monitor the motion responses of the damaged ship with different damage locations. Through analysis, the visualization of the flooding process can be efficient to explain the cause of the resulting motion response. Comparing the bottom damage and the side damage, the upward flooding in the bottom damage scenario causes a larger vertical impact on the bottom plate while the flooding water from starboard to portside in the side damage scenario causes a larger horizontal impact on the longitudinal bulkhead. This detailed visualization description explains why the bottom damage flooding in the same period produces a larger heel angle with respect to the side damage flooding, regardless of the peak value or trough value. In addition, due to the coupled motion between the damaged ship and the flooding water, the tank sloshing makes the damaged ship still roll even if the flooding water is not increased. And, the wave propagation in the flooded is seen clearly. After comparing the roll motion and pitch motion, it can be found that the symmetric flooding is a dangerous situation, even making the damaged ship capsize. Though the damage locations are different, the asymmetric flooding produces an excessive heel angle. However, asymmetric flooding has little effect on the pitch angle. Based on these summaries, the final suggestion is that when the damage flooding takes place, especially asymmetric flooding, appropriate counter measures should be taken first to equalize the heel angel. In this case, the damaged ship can keep a good floating state, which is helpful to improve the survivability of the damaged ship and ensure the safety of human life. From the perspective of the simulation validation, only numerical simulation results are introduced, without validation with experimental results. Subsequently, the specified model tests will be carried out to prove the reliability of the applied numerical simulation approach. In the future, a more realistic compartment arrangement will be created, considering the effect of the permeability on the flooding process and motion responses. Also, more sea conditions will be included, including wind, wave, and forward speed. This gradual improvement process will also present new challenges to the current simulation approach. Author Contributions: X.Z. performed the numerical simulation and wrote the paper. Z.L. gave the investigating idea and revised the manuscript. S.M. optimized the numerical program and revised the manuscript. P.L. provided the detailed model information. D.L. established the damaged 5415 model. F.L., and Z.P. post-processed the simulation results. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the National Natural Science Foundation of China (NSFC Grants 51709063). Acknowledgments: This research was supported by the College of Shipbuilding Engineering, Harbin Engineering University. Conflicts of Interest: The authors declare no conflict of interest. #### References © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).	doab	2025-04-07T04:13:04.611986	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 7 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.8	Article Numerical Study on Hydrodynamics of Ships with Forward Speed Based on Nonlinear Steady Wave Tianlong Mei 1,2, Maxim Candries 2, Evert Lataire <sup>2</sup> and Zaojian Zou 1,3,\* Received: 31 December 2019; Accepted: 7 February 2020; Published: 10 February 2020 Abstract: In this paper, an improved potential flow model is proposed for the hydrodynamic analysis of ships advancing in waves. A desingularized Rankine panel method, which has been improved with the added effect of nonlinear steady wave-making (NSWM) flow in frequency domain, is employed for 3D diffraction and radiation problems. Non-uniform rational B-splines (NURBS) are used to describe the body and free surfaces. The NSWM potential is computed by linear superposition of the first-order and second-order steady wave-making potentials which are determined by solving the corresponding boundary value problems (BVPs). The so-called mj terms in the body boundary condition of the radiation problem are evaluated with nonlinear steady flow. The free surface boundary conditions in the diffraction and radiation problems are also derived by considering nonlinear steady flow. To verify the improved model and the numerical method adopted in the present study, the nonlinear wave-making problem of a submerged moving sphere is first studied, and the computed results are compared with the analytical results of linear steady flow. Subsequently, the diffraction and radiation problems of a submerged moving sphere and a modified Wigley hull are solved. The numerical results of the wave exciting forces, added masses, and damping coefficients are compared with those obtained by using Neumann–Kelvin (NK) flow and double-body (DB) flow. A comparison of the results indicates that the improved model using the NSWM flow can generally give results in better agreement with the test data and other published results than those by using NK and DB flows, especially for the hydrodynamic coefficients in relatively low frequency ranges. Keywords: nonlinear steady flow; desingularized Rankine panel method; forward speed; radiation and diffraction #### 1. Introduction Over the last decades, the rapid development of computing power and the emergence of more sophisticated numerical methods have promoted the applications of numerical methods in ship hydrodynamics problems. Nevertheless, these problems still need to be simplified due to the complexity behind the physical models. It becomes even more complicated when different models need to be coupled, which is for example the case when ship maneuvering in waves is considered. In the early stage, two-dimensional strip theory was developed as a practical way to evaluate ship hydrodynamic performances [1,2]. However, relying on the assumption that the ship is a slender body, strip theory is only suitable for low speed and high encounter wave frequency cases. In order to consider more realistic three-dimensional (3D) effects, it is not appropriate to assume that the ship is slender. In the study of ship hydrodynamics problems, 3D potential flow theory has focused mainly on linear analysis [3]. The theory assumes that the disturbance due to the presence of a ship in waves is relatively small. When using Rankine panel methods, two linearization methods can be distinguished: the Neumann–Kelvin (NK) linearization and the double-body (DB) linearization. The former considers uniform flow as basic flow to linearize the free surface boundary conditions. The latter is essentially based on a slow-ship assumption which obtains the double-body velocity potential by treating the free surface as a rigid horizontal plane and takes the DB flow as basic flow to linearize the free surface boundary conditions. Numerous studies have been published using these two methods. For instance, Kim and Kim [3] presented a study on ship hydrodynamics comparing the NK and DB linearization methods. Similar researches discussing the advantages and disadvantages of these two methods can be found in Zhang et al. [4], Zhang and Beck [5], Zhang and Zou [6]. Attempts have also been made to include ship maneuvering in waves in the analysis, e.g., Seo and Kim [7], Zhang et al. [8]. In their studies, the mean second-order wave force was evaluated by Rankine panel method using NK or DB linearization, which was then treated as the input force in the equations for predicting maneuvering behavior. However, these two linearization methods, as described in [4], can be justified in the case of a slender ship, but they are not suitable for blunt bodies or ships moving at high speeds [9]. In light of the limitations of the NK and DB linearizations, works addressing ship hydrodynamics by using steady wave-making flow as basic flow for linearization were carried out; e.g., Gao and Zou [10] computed the linear steady wave-making flow beforehand and then applied the results to solve the diffraction and radiation problems. Recently, researchers have considered nonlinear steady flow to study the interactions between the linear periodic wave-induced flow and the nonlinear steady flow caused by the ship's forward speed in calm water, such as the studies by Bunnik [11], Söding et al. [12] and Chillcce and el Moctar [13] in frequency domain. As for the time domain method, studies can be found in Riesner et al. [14], Riesner and el Moctar [15] and Chen et al. [9]. Though the transient effect of flow can be investigated in time domain, the boundary integral equation should be solved at each time step, which is more computationally expensive than that with frequency domain method. In this study, a new model is proposed to compute the ship hydrodynamic forces in the frequency domain. In contrast to other methods, nonlinear steady flow is considered and the interaction between nonlinear steady flow and unsteady flow is considered not only in the body boundary condition, but also in the free surface boundary conditions in the corresponding diffraction and radiation problems. The main objective of this method is to capture the coupling factors as accurately as possible. The boundary value problems (BVPs) for the first-order and second-order steady wave-making potentials are first derived and solved, and the nonlinear steady wave-making (NSWM) potential is then approximated by linear superposition of the first-order and second-order steady wave-making potentials. Subsequently, the wave exciting forces and the radiation forces are evaluated based on the obtained NSWM flow. A desingularized Rankine panel method with distributed sources at a small distance inside the body and above the free surface [16,17] is applied to numerically solve the problems. This method has the advantage over conventional boundary integral methods in that it separates the integration surface and the collocation surface, which in turn results in a boundary integral equation with non-singular kernels. In addition, the second-order or even higher-order derivatives of the velocity potential can be directly evaluated without complicated numerical treatments to eliminate the singularities in the integral equation; thus, the method is faster and easier to implement. In recent years, this method has been extended and applied in the analysis of 2D wave-body interaction problems, such as Feng et al. [18–20]. To verify the proposed model, non-uniform rational B-splines (NURBS) are used to generate the mesh both on the body surface and the free surface. The desingularized Rankine panel method is then employed to discretize and solve the boundary integral equation. The mj terms in the body boundary condition are evaluated with nonlinear steady flow, and the free surface boundary conditions in the diffraction and radiation problems are also derived by taking the nonlinear steady flow into account. In order to identify the effects of steady flow on the unsteady flow, the present method is compared with those based on NK and DB linearizations. The computations are carried out for a submerged moving sphere and a modified Wigley hull advancing in head waves. The numerical results including the wave exciting forces, added masses and damping coefficients with the effects of different steady flows are presented. #### 2. Mathematical Formulations Figure 1 shows the two coordinate systems that are used: an earth-fixed coordinate system o<sup>0</sup> − x<sup>0</sup> y0z<sup>0</sup> and a coordinate system o − xyz moving along with the ship at a constant speed U with ox positive to the bow, oy positive to the port side and oz directing upwards. Figure 1. Coordinate systems. In o<sup>0</sup> − x<sup>0</sup> y0z0, based on the assumptions of ideal fluid and irrotational flow, the total velocity potential Ψ( x 0, t) should satisfy the following equations: Laplace's equation in fluid domain: $$ \nabla^2 \Psi = 0 \tag{1} $$ The kinematic and dynamic boundary conditions on the free surface SF: $$\left[\frac{\partial}{\partial t} + \nabla \Psi \cdot \nabla \right] [z\_0 - \eta(\mathbf{x}\_0, \mathbf{y}\_0, t)] = 0 \tag{2}$$ $$ \delta\_t \mathbf{g} \eta + \Psi\_t + \frac{1}{2} \nabla \Psi \cdot \nabla \Psi = 0 \tag{3} $$ where η is the free surface elevation, g is the gravitational acceleration. The subscripts (i.e., t, x0, y0) denote the derivatives with respect to the corresponding variables. By combining Equation (2) and Equation (3), the following boundary condition on SF is derived: $$ \Psi\_{tt} + \nabla \Psi \cdot \nabla \Psi\_t + \Psi\_{x0} \Psi\_{x0} + \Psi\_{y0} \Psi\_{y0t} + \Psi\_{x0} \nabla \Psi \cdot \nabla \Psi\_{x0} + \Psi\_{y0} \nabla \Psi \cdot \nabla \Psi\_{y0} + \mathcal{g} \Psi\_{z0} = 0 \tag{4} $$ The boundary condition on the body surface SB: $$ \nabla \Psi \cdot \overrightarrow{n} = \overrightarrow{V}\_B \cdot \overrightarrow{n} \tag{5} $$ where <sup>n</sup> is the unit normal vector directed inward of the body surface with (n1, <sup>n</sup>2, <sup>n</sup>3) <sup>=</sup> n,(n4, n5, n6) = <sup>x</sup> <sup>×</sup> n; VB is instantaneous velocity of the body surface SB Moreover, a radiation condition should be satisfied. The details for implementing the numerical radiation condition will be introduced in Section 3. By using the Galilean transformation, the relation from o<sup>0</sup> − x<sup>0</sup> y0z<sup>0</sup> to o − xyz can be transformed as: $$\frac{d}{dt} = \frac{\partial}{\partial t} - \mathcal{U}\frac{\partial}{\partial \mathbf{x}}\tag{6}$$ where <sup>d</sup> dt is the time derivative in coordinate system <sup>o</sup><sup>0</sup> <sup>−</sup> <sup>x</sup><sup>0</sup> <sup>y</sup>0z<sup>0</sup> and <sup>∂</sup> <sup>∂</sup><sup>t</sup> is the time derivative in the moving coordinate system o − xyz. In o − xyz, assuming that the velocity potential Ψ( x , t) can be written as: $$\Psi(\overrightarrow{\mathbf{x}},t) = -l\mathbf{l}\mathbf{x} + \Phi^S(\overrightarrow{\mathbf{x}}) + \text{Re}\Big[A\boldsymbol{\rho}^I(\overrightarrow{\mathbf{x}})\boldsymbol{\epsilon}^{i\omega t} + A\boldsymbol{\rho}^D(\overrightarrow{\mathbf{x}})\boldsymbol{\epsilon}^{i\omega t}\Big] + \text{Re}\Big[\sum\_{j=1}^6 \left[\overline{\xi}\_j \boldsymbol{\epsilon} \boldsymbol{p}\_j^R(\overrightarrow{\mathbf{x}})\boldsymbol{\epsilon}^{j\omega t}\right]\Big] \tag{7}$$ where <sup>−</sup>Ux + <sup>Φ</sup>S( x ) is the steady velocity potential; ϕ<sup>I</sup> ( x ), ϕD( x ) and ϕ<sup>R</sup> j ( x ) (j = 1, 2, ··· , 6) are the spatial parts of the incident, diffraction and radiation velocity potentials, respectively; A is the incoming wave amplitude, ξ<sup>j</sup> (j = 1, 2, ··· , 6) is the amplitude of j-th mode of oscillating motion, and ω is the encounter frequency. #### 2.1. Nonlinear Steady Wave-Making (NSWM) Problem Substituting Equation (7) into Equations (1)–(5), using Ψ(x0, y0, z0,t) = Ψ(x + Ut, y, z,t) and Equation (6), and extracting the terms unrelated to time t, the BVP of the steady wave-making velocity potential ΦS( x ) can be expressed in the moving coordinate system o − xyz as: Laplace's equation in fluid domain: $$ \nabla^2 \Phi^S = 0 \tag{8} $$ The boundary condition on the free surface SF: $$\frac{1}{2}\mathbf{U}^{2}\Phi\_{\mathbf{xx}}^{S} - \mathbf{U}\nabla\Phi^{S}\cdot\nabla\Phi\_{\mathbf{x}}^{S} - \mathbf{U}\Phi\_{\mathbf{x}}^{S}\cdot\Phi\_{\mathbf{xx}}^{S} - \mathbf{U}\Phi\_{\mathbf{y}}^{S}\Phi\_{\mathbf{xy}}^{S} + \Phi\_{\mathbf{x}}^{S}\nabla\Phi^{S}\cdot\nabla\Phi\_{\mathbf{x}}^{S} + \Phi\_{\mathbf{y}}^{S}\nabla\Phi^{S}\cdot\nabla\Phi\_{\mathbf{y}}^{S} + \mathbf{g}\Phi\_{\mathbf{z}}^{S} = 0 \tag{9}$$ The boundary condition on the body surface SB: $$-\mathcal{U}\boldsymbol{n}\_1 + \overrightarrow{\boldsymbol{n}} \cdot \nabla \Phi^S = 0 \tag{10}$$ By using Equation (6), the steady hydrodynamic pressure can be obtained from Bernoulli's equation: $$p^S = -\rho \left(\frac{1}{2} \nabla \Phi^S \cdot \nabla \Phi^S - lI \Phi\_\mathbf{x}^S\right) \tag{11}$$ The steady force F<sup>S</sup> <sup>i</sup> (i = 1, 2, ··· , 6) can then be calculated by integrating the pressure over the wetted body surface: $$F\_i^S = \bigcap\_{S\_B} p^S n\_i ds, \quad i = 1, 2, \dots, 6 \tag{12}$$ By using Equation (6), the steady free surface elevation can be obtained from Equation (3): $$ \eta^S = \frac{\mathcal{U}}{\mathcal{g}} \Phi\_\mathbf{x}^S - \frac{1}{2g} \nabla \Phi^S \cdot \nabla \Phi^S \tag{13} $$ The boundary condition Equation (9) is nonlinear. To solve the resulting nonlinear BVP, the velocity potential Φ<sup>S</sup> and the free surface elevation η<sup>S</sup> are expressed by perturbation expansion until second order as: $$\begin{aligned} \Phi^S &\approx \Phi^{S(1)} + \Phi^{S(2)} \\ \eta^S &\approx \eta^{S(1)} + \eta^{S(2)} \end{aligned} \tag{14}$$ Substituting Equation (14) into Equations (8)–(10), the BVPs for the first- and second-order steady velocity potentials can be obtained by Taylor expansion on z = 0 and about the mean wetted body surface Sb. The BVP for the first-order steady velocity potential is given as: $$ \nabla^2 \Phi^{S(1)} = 0,\text{ in fluid domain}\tag{15} $$ $$\frac{\text{d}l^2}{\text{g}}\Phi\_{\text{xx}}^{S(1)} + \Phi\_z^{S(1)} = 0,\text{ on } z = 0\tag{16}$$ $$ \overrightarrow{\alpha} \cdot \nabla \Phi^{S(1)} = l! n\_{1\prime} \text{ on the mean wetted body surface } \overline{\mathcal{S}}\_{\mathbb{b}} \tag{17} $$ The BVP for the second-order steady velocity potential is given as: $$ \nabla^2 \Phi^{S(2)} = 0,\text{ in fluid domain}\tag{18} $$ $$\begin{aligned} \frac{\mathbf{J}^{\rm I}}{\mathcal{S}} \boldsymbol{\Phi}\_{\rm{xx}}^{\rm{S}(2)} + \boldsymbol{\Phi}\_{z}^{\rm{S}(2)} &= -\frac{\partial}{\partial z} \Big( \frac{\mathbf{J}^{\rm I}}{\mathcal{S}} \boldsymbol{\Phi}\_{\rm{xx}}^{\rm{S}(1)} + \boldsymbol{\Phi}\_{z}^{\rm{S}(1)} \Big) \boldsymbol{\eta}^{\rm{S}(1)} + \frac{\mathbf{J}^{\rm I}}{\mathcal{S}} \nabla \boldsymbol{\Phi}\_{\rm{x}}^{\rm{S}(1)} \cdot \nabla \boldsymbol{\Phi}^{\rm{S}(1)} \\ &+ \frac{\mathbf{J}}{\mathcal{S}} \Big( \boldsymbol{\Phi}\_{\rm{x}}^{\rm{S}(1)} \boldsymbol{\Phi}\_{\rm{xx}}^{\rm{S}(1)} + \boldsymbol{\Phi}\_{\rm{y}}^{\rm{S}(1)} \boldsymbol{\Phi}\_{\rm{xy}}^{\rm{S}(1)} \Big) \end{aligned} \quad \text{on } \boldsymbol{z} = \boldsymbol{0} \tag{19}$$ $$ \overrightarrow{n} \cdot \nabla \Phi^{S(2)} = 0,\text{ on the mean wetted body surface } \overleftarrow{S}\_b \tag{20} $$ #### 2.2. Diffraction Problem For the diffraction problem, the ship moves with a constant speed U in waves without oscillations. In deep water, the incident wave velocity potential is given as: $$\varphi^I(\mathbf{x}, \mathbf{y}, \mathbf{z}) = \frac{i\mathcal{G}}{\alpha\wp} e^{k\mathbf{z}} \cdot e^{-i\mathbf{k}(\mathbf{x}\cos\beta + \mathbf{y}\sin\beta)}\tag{21}$$ where ω<sup>0</sup> is the incident wave frequency, k = ω<sup>2</sup> <sup>0</sup>/g is the wave number, β is the wave angle and β = π represents head sea condition. The encounter frequency ω is defined as: $$ \omega = \omega\_0 - klI\cos\beta\tag{22} $$ Substituting Equation (7) into Equations (1)–(5), using Ψ(x0, y0, z0,t) = Ψ(x + Ut, y, z,t) and Equation (6), and extracting the terms related to time t and ϕD(x, y, z), the BVP of the diffraction potential ϕD(x, y, z) can be derived as: Laplace's equation in fluid domain: $$\nabla^2 \boldsymbol{\varphi}^D = 0 \tag{23}$$ The free surface boundary condition on z = 0: $$\begin{array}{cccc} -\omega^2 \boldsymbol{\varrho}^D - 2i\omega \boldsymbol{l} \boldsymbol{l} \boldsymbol{\varrho}^D\_x + \boldsymbol{l} \boldsymbol{l}^2 \boldsymbol{\varrho}^D\_{xx} + \boldsymbol{g} \boldsymbol{q}^D\_z + i\omega \boldsymbol{\nabla} \boldsymbol{\Phi}^S \cdot \boldsymbol{\nabla} \boldsymbol{q}^D + i\omega \boldsymbol{\Phi}^S\_x \boldsymbol{q}^D\_x + i\omega \boldsymbol{\Phi}^S\_y \boldsymbol{q}^D\_y - \boldsymbol{l} \boldsymbol{l} \boldsymbol{\nabla} \boldsymbol{\Phi}^S \cdot \boldsymbol{\nabla} \boldsymbol{q}^D\_x \\\ -\boldsymbol{l} \boldsymbol{\nabla} \boldsymbol{q}^D \cdot \boldsymbol{\nabla} \boldsymbol{\Phi}^S\_x - \boldsymbol{l} \boldsymbol{l} \boldsymbol{\Phi}^S\_x \boldsymbol{q}^D\_{xx} + \boldsymbol{\Phi}^S\_x \boldsymbol{\nabla} \boldsymbol{\Phi}^S \cdot \boldsymbol{\nabla} \boldsymbol{q}^D\_x + \boldsymbol{\Phi}^S\_x \boldsymbol{\nabla} \boldsymbol{q}^D - \boldsymbol{l} \boldsymbol{l} \boldsymbol{q}^D\_x \boldsymbol{\Phi}^S\_{xx} + \boldsymbol{q}^D\_x \boldsymbol{\nabla} \boldsymbol{\Phi}^S \cdot \boldsymbol{\nabla} \boldsymbol{\Phi}^S\_x \\\ -\boldsymbol{l} \boldsymbol{\Phi}^S\_y \boldsymbol{q}^D\_{xy} - \boldsymbol{l} \boldsymbol{l} \boldsymbol{q}^D\_y \boldsymbol{\Phi}^S\_{xy} + \boldsymbol{\Phi}^S\_y \boldsymbol{\nabla} \boldsymbol{\Phi}^S \cdot \boldsymbol{\nabla} \boldsymbol{q}^D\_y + \boldsymbol{\Phi}^S\_y \boldsymbol{\nabla} \boldsymbol{q}^D \cdot \boldsymbol{\nabla} \boldsymbol{\Phi}^S\_y + \boldsymbol{q}^D\_y \boldsymbol{\nabla} \boldsymbol{\Phi}^S \cdot \boldsymbol{\nabla} \boldsymbol{\Phi}^S\_y = RHS{$$ where RHS =ω2ϕ<sup>I</sup> + 2iωUϕ<sup>I</sup> <sup>x</sup> <sup>−</sup> <sup>U</sup>2ϕ<sup>I</sup> xx − gϕ<sup>I</sup> <sup>z</sup> <sup>−</sup> <sup>i</sup>ω∇Φ<sup>S</sup> · ∇ϕ<sup>I</sup> <sup>−</sup> <sup>i</sup>ωΦ<sup>S</sup> xϕ<sup>I</sup> x−iωΦ<sup>S</sup> yϕI <sup>y</sup> + <sup>U</sup>∇Φ<sup>S</sup> · ∇ϕ<sup>I</sup> <sup>x</sup> +U∇ϕ<sup>I</sup> · <sup>∇</sup>Φ<sup>S</sup> <sup>x</sup> + UΦ<sup>S</sup> xϕ<sup>I</sup> xx <sup>−</sup> <sup>Φ</sup><sup>S</sup> x∇Φ<sup>S</sup> · ∇ϕ<sup>I</sup> x−Φ<sup>S</sup> x∇ϕ<sup>I</sup> · ∇Φ<sup>S</sup> <sup>x</sup> + Uϕ<sup>I</sup> xΦ<sup>S</sup> xx −ϕ<sup>I</sup> x∇Φ<sup>S</sup> · ∇Φ<sup>S</sup> x+UΦ<sup>S</sup> yϕI xy+Uϕ<sup>I</sup> yΦ<sup>S</sup> xy <sup>−</sup>Φ<sup>S</sup> <sup>y</sup>∇Φ<sup>S</sup> · ∇ϕ<sup>I</sup> <sup>y</sup> <sup>−</sup> <sup>Φ</sup><sup>S</sup> y∇ϕ<sup>I</sup> · ∇Φ<sup>S</sup> <sup>y</sup> − ϕ<sup>I</sup> y∇Φ<sup>S</sup> · ∇Φ<sup>S</sup> y The boundary condition on the mean wetted body surface Sb: $$ \overrightarrow{n} \cdot \nabla q^D = -\overrightarrow{n} \cdot \nabla q^I \tag{25} $$ It is worth noting that in Equation (24), the nonlinear steady potential Φ<sup>S</sup> is also considered in the free surface boundary condition. Once the diffraction potential ϕ<sup>D</sup> is obtained, the wave exciting forces on the hull can be computed as: $$F\_j = \text{Re}\{Af\_j \varepsilon^{iwt}\}, j = 1, 2, \dots, 6 \tag{26}$$ $$f\_j = -\rho \iiint\_{\overline{S}\_b} \left[ i\omega (q^I + q^D) - \mathcal{U}(q\_x^I + q\_x^D) + \nabla \Phi^S \cdot \nabla (q^I + q^D) \right] \mathfrak{n}\_f ds \tag{27}$$ #### 2.3. Radiation Problem For the radiation problem, it is assumed that the ship undergoes a harmonic oscillation. Similar to the BVP of diffraction potential, the radiation potential ϕ<sup>R</sup> <sup>j</sup> should satisfy the control equation and boundary conditions below: Laplace's equation in fluid domain: $$\nabla^2 \varphi\_j^R = 0, j = 1, 2, \cdots, 6 \tag{28}$$ The free surface boundary condition on z = 0: $$\begin{array}{ll} -\omega^{2}\boldsymbol{\sigma}^{R}\_{j} - 2i\omega\boldsymbol{l}\boldsymbol{L}\boldsymbol{\sigma}^{R}\_{jx} + \boldsymbol{\mathcal{U}}^{2}\boldsymbol{\sigma}^{R}\_{jxx} + g\boldsymbol{\nu}^{R}\_{jx} + i\omega\boldsymbol{\nabla}\boldsymbol{\Phi}^{S}\cdot\boldsymbol{\nabla}\boldsymbol{\eta}^{R}\_{j} + i\omega\boldsymbol{\nabla}\_{x}^{S}\boldsymbol{\eta}^{R}\_{jx} + i\omega\boldsymbol{\nabla}\_{y}^{S}\boldsymbol{\eta}^{R}\_{jx} \\ - \boldsymbol{\Lambda}\boldsymbol{\nabla}\boldsymbol{\Phi}^{S}\cdot\boldsymbol{\nabla}\boldsymbol{\eta}^{R}\_{jx} - \boldsymbol{\Lambda}\boldsymbol{\nabla}\boldsymbol{\eta}^{R}\_{j} \cdot \boldsymbol{\nabla}\boldsymbol{\Phi}^{S}\_{x} - \boldsymbol{\mathcal{U}}\boldsymbol{\Phi}^{S}\_{x}\boldsymbol{\eta}^{R}\_{jxx} + \boldsymbol{\Phi}^{S}\_{x}\boldsymbol{\nabla}\boldsymbol{\Phi}^{S}\cdot\boldsymbol{\nabla}\boldsymbol{\eta}^{R}\_{jx} + \boldsymbol{\Phi}^{S}\_{x}\boldsymbol{\nabla}\boldsymbol{\eta}^{R}\_{j} \cdot \boldsymbol{\nabla}\boldsymbol{\Phi}^{S}\_{x} \\ - \boldsymbol{\Lambda}\boldsymbol{\eta}^{R}\_{jx}\boldsymbol{\Phi}^{S}\_{xx} + \boldsymbol{\eta}^{R}\_{jx}\boldsymbol{\nabla}\boldsymbol{\Phi}^{S}\cdot\boldsymbol{\nabla}\boldsymbol{\Phi}^{S}\_{x} - \boldsymbol{\Lambda}\boldsymbol{\Phi}^{S}\_{y}\boldsymbol{\eta}^{R}\_{jxy} - \boldsymbol{\Lambda}\boldsymbol{\eta}^{R}\_{jy}\boldsymbol{\Phi}^{S}\_{xy} + \boldsymbol{\Phi}^{S}\_{y}\boldsymbol{\nabla}\boldsymbol{\Phi}^{S}\cdot\boldsymbol{\nabla}\boldsymbol{\eta}^{R}\_{jy} \\ + \boldsymbol{\Phi}^{S}\_{y}\boldsymbol{\nabla}\boldsymbol{\eta}^{R}\_{j}\cdot\boldsymbol{\nabla\$$ The boundary condition on the mean wetted body surface Sb: $$ \overrightarrow{m} \cdot \nabla q\_{\vec{j}}^{R} = -i\omega n\_{\vec{j}} + m\_{\vec{j}} \tag{30} $$ where the mj terms representing the coupling effect between the steady and unsteady flows are given as: $$\begin{aligned} (m\_{1\prime}, m\_{2\prime}, m\_3) &= \left(\overrightarrow{n} \cdot \nabla\right) \left(\overrightarrow{l}\overline{l} - \nabla \Phi^S\right) \\ (m\_{4\prime}, m\_5, m\_6) &= \left(\overrightarrow{n} \cdot \nabla\right) \left[\overrightarrow{x} \times \left(\overrightarrow{l}\overline{l} - \nabla \Phi^S\right)\right] \end{aligned} \tag{31}$$ where U = (U, 0, 0) . It is worth noting that the effect of the nonlinear steady potential Φ<sup>S</sup> occurs not only in the so-called mj terms in Equation (30), but also in the free surface boundary condition Equation (29). Once the radiation potential ϕ<sup>R</sup> <sup>j</sup> is determined, the added mass akj and damping coefficient bkj (k, j = 1, 2, ··· , 6) can be obtained as: $$\begin{split} a\_{kj} &= \frac{-\rho}{\omega^2} \text{Re} \underbrace{\iint}\_{\overline{\mathbf{S}}\_b} (i\omega \rho\_j^R - \mathsf{L}l\varphi\_{j\mathbf{x}}^R + \nabla \Phi^S \cdot \nabla \varphi\_j^R) n\_k ds \\ b\_{kj} &= \frac{-\rho}{\omega} \text{Im} \underbrace{\iint}\_{\overline{\mathbf{S}}\_b} (i\omega \rho\_j^R - \mathsf{L}l\varphi\_{j\mathbf{x}}^R + \nabla \Phi^S \cdot \nabla \varphi\_j^R) n\_k ds \end{split} \tag{32}$$ #### 3. Desingularized Rankine Panel Method In this paper, a desingularized Rankine panel method is applied, where the Rankine sources are distributed inside the body and above the free surface at a distance Ld according to the formula Ld = ld(Dm) <sup>υ</sup> proposed by Cao et al. [17], ld and <sup>υ</sup> are equal to 1.0 and 0.5 respectively and Dm is the local mesh size (the square root of the local mesh area), as demonstrated in Figure 2. Figure 2. Desingularized Rankine panel model. A suitable radiation condition should be implemented to ensure a unique solution for the specific BVP when using the Rankine source method. Typically, the numerical techniques can be classified as follows: In this study, the radiation condition is satisfied by using the staggered method for its simple implementation and good stability. The raised source points are moved a distance Δx toward downstream. The recommended parameter in this study is Δx = δ, where δ denotes the average longitudinal value between two adjacent collocation points on the free surface. However, it should be noted that this numerical treatment is only valid for steady wave-making problem and the radiation problem with the Brard number τ = Uω/g > 0.25. By using NURBS, the points (x, y, z) on the body and free surfaces can be described with parameter coordinate (u, v) as: $$\left[\mathbf{x}(\boldsymbol{u},\boldsymbol{v}),\boldsymbol{y}(\boldsymbol{u},\boldsymbol{v}),\boldsymbol{z}(\boldsymbol{u},\boldsymbol{v})\right] = \left[\sum\_{i=0}^{m}\sum\_{j=0}^{n}\boldsymbol{\omega}\_{i\bar{j}}\boldsymbol{D}\_{i\bar{j}}\boldsymbol{N}\_{i\bar{k}}(\boldsymbol{u})\boldsymbol{N}\_{j\bar{l}}(\boldsymbol{v})\right] \left[\left\|\sum\_{i=0}^{m}\sum\_{j=0}^{n}\boldsymbol{\omega}\_{i\bar{j}}\boldsymbol{N}\_{i\bar{k}}(\boldsymbol{u})\boldsymbol{N}\_{j\bar{l}}(\boldsymbol{v})\right\|\right] \tag{33}$$ where Dij are the control points on the body and free surfaces; ωij is the weight; Ni,k(u) and Nj,l(v) are the B-spline basis functions of k(l)-th order for a given knot sequence u = (u0, u1, ··· , un<sup>+</sup>k+1), defined as: $$\begin{cases} N\_{i,0}(u) = \begin{cases} 1, & u\_i \le u < u\_{i+1} \\ 0, & \text{otherwise} \end{cases} \\ N\_{i,k}(u) = \frac{u - u\_i}{u\_{i+k} - u\_i} N\_{i,k-1}(u) + \frac{u\_{i+k+1} - u}{u\_{i+k+1} - u\_{i+1}} N\_{i+1,k-1}(u) \end{cases} \tag{34}$$ According to Green's theorem, the velocity potential ϕ(P) in the flow field can be expressed as: $$\varphi(P) = \iint\_{S} \sigma(Q) \frac{1}{r\_{PQ}} dS = \iint\_{S} \sigma(\overrightarrow{\mathbf{x}\_{s}}) \frac{1}{\left\| \overleftarrow{\mathbf{x}\_{c}} - \overrightarrow{\mathbf{x}\_{s}} \right\|} dS \tag{35}$$ where P is the field point, Q is the source point on the integration surface S, rPQ represents the distance between the field point and the source point; σ(Q) is the source strength distribution over the surface S. <sup>x</sup> <sup>c</sup> and x s represent the coordinates of collocation point and source point, respectively. Applying the corresponding boundary conditions on the free surface Γ<sup>f</sup> and body surface Γb, the integral equations for the unknown source strengths can be established and solved. The velocity potential on Γ<sup>f</sup> and the normal derivative of the velocity potential on Γ<sup>b</sup> are calculated by: $$\bigcup\_{\mathbf{s}\_f} \sigma(\overline{\mathbf{x}}\_s^f) \frac{1}{\left\| \overline{\mathbf{x}}\_c^f - \overline{\mathbf{x}}\_s^f \right\|} ds + \iint\_{\mathbf{s}\_b} \sigma(\overline{\mathbf{x}}\_s^b) \frac{1}{\left\| \overline{\mathbf{x}}\_c^f - \overline{\mathbf{x}}\_s^b \right\|} ds = q\_0(\overline{\mathbf{x}}\_c^f), \ \overline{\mathbf{x}}\_c^f \in \Gamma\_f \tag{36}$$ $$\int\_{S\_f} \overline{\rho} \left( \overline{\mathbf{x}}\_s^f \right) \frac{\partial}{\partial n} \bigg\| \frac{1}{\left\| \overline{\mathbf{x}}\_c^b - \overline{\mathbf{x}}\_s^f \right\|} \bigg\| ds + \iint\_{\mathbf{S}\_b} \sigma(\overline{\mathbf{x}}\_s^b) \frac{\partial}{\partial n} \bigg\| \frac{1}{\left\| \overline{\mathbf{x}}\_c^b - \overline{\mathbf{x}}\_s^b \right\|} \bigg\| dS\_b = \frac{\partial}{\partial n} \rho\_0(\overline{\mathbf{x}}\_c^b), \ \overline{\mathbf{x}}\_c^b \in \Gamma\_b \tag{37}$$ where x f <sup>c</sup> and x b <sup>c</sup> denote the collocation points on the free surface Γ<sup>f</sup> and the body surface Γb; x f s and x b <sup>s</sup> denote the source points on the integration surface.Sf is the integration surface above the free surface Γ<sup>f</sup> , and Sb is the integration surface inside the body surface Γb. ϕ0( x f <sup>c</sup> ) is the given velocity potential at x f <sup>c</sup> and <sup>∂</sup> <sup>∂</sup>nϕ0( x b <sup>c</sup> ) is the given normal derivative of the velocity potential at x b c . Discretizing the body surface and the free surface into Nb and Nf quadrilateral panels respectively, a set of discrete equations can be obtained from the integral equations. From Equations (36) and (37) it follows: $$\sum\_{j=1}^{N\_f} \sigma\_j^f(\overline{\mathbf{x}}\_s^f) \frac{1}{\left\| \overline{\mathbf{x}}\_{ci}^f - \overline{\mathbf{x}}\_{sj}^f \right\|} + \sum\_{j=1}^{N\_b} \sigma\_j^b(\overline{\mathbf{x}}\_s^b) \frac{1}{\left\| \overline{\mathbf{x}}\_{ci}^f - \overline{\mathbf{x}}\_{sj}^b \right\|} = q\_0(\overline{\mathbf{x}}\_{ci}^f) \text{ , } i = 1, 2, \cdots, N\_f \tag{38}$$ $$\sum\_{j=1}^{N\_f} \sigma\_j^f(\overrightarrow{\mathbf{x}}\_s^f) \frac{\partial}{\partial n\_i} \left\| \frac{1}{\left\| \overbrace{\mathbf{x}\_{ci}^b - \overbrace{\mathbf{x}\_{sf}^f}^f \right\|} \right\| + \sum\_{j=1}^{N\_b} \sigma\_j^b(\overrightarrow{\mathbf{x}}\_s^b) \frac{\partial}{\partial n\_i} \left\| \frac{1}{\left\| \overbrace{\mathbf{x}\_{ci}^b - \overbrace{\mathbf{x}\_{sf}^b}^b \right\|} \right\| = \frac{\partial}{\partial n\_i} q \alpha(\overrightarrow{\mathbf{x}}\_{ci}^b) \text{ , } i = 1, 2, \cdots, N\_b \tag{39}$$ As can be seen from the discrete equations of Equations (38) and (39), the total number of equations is equal to the number of unknowns, i.e., N = Nb + Nf . Therefore, by satisfying the corresponding boundary conditions on the body surface and free surface at the collocation points, a set of linear equations for the unknown source strengths can be obtained. By solving these equations, the source strengths can be determined. #### 4. Numerical Results and Discussion Two cases are studied: a sphere given by Equation (40), and a Wigley I ship [26] given by Equation (41): $$x^2 + y^2 + (z - h)^2 = r^2 \tag{40}$$ $$y = \frac{B}{2} \left\{ \left[1 - \left(\frac{z}{T}\right)^2\right] \left[1 - \left(\frac{2x}{L}\right)^2\right] \left[1 + 0.2\left(\frac{2x}{L}\right)^2\right] + \left(\frac{z}{T}\right)^2 \left[1 - \left(\frac{z}{T}\right)^8\right] \left[1 - \left(\frac{2x}{L}\right)^2\right]^4 \right\} \tag{41}$$ where r is the radius of the sphere and h is the submerged depth; L, B and T are the length, the beam and the draft of the hull respectively. The Wigley I ship has the length to beam ratio L/B = 10 and the beam to draft ratio B/T = 1.6. Figure 3 shows the typical panel arrangements of the submerged sphere and the Wigley I ship. In addition, the panel arrangements on the raised plane (cyan) above the free surface are shown. In Figure 3a, the free surface of the computational domain extends to 5.0r upstream, 5.0r sideways and 10.0r downstream. The discretized panels of the sphere and the half width free surface are 21 × 21 and 50 × 16, respectively. In Figure 3b, the free surface of the computational domain extends to 1.0L upstream, 0.75L sideways and 1.5L downstream. The discretized panels of the half Wigley I ship and half width free surface are 30 × 10 and 76 × 19, respectively. Figure 3. Typical panel arrangements of (a) submerged sphere and (b) Wigley I ship. #### 4.1. Results of the NSWM Problem In order to compute the NSWM flow, a submerged moving sphere of r = 1.0 m at three different submerged depths (h = 1.5r, 2.0r, 3.0r) is chosen as the study case, the Froude number is defined as Fr = U/ % gh, so the results at the same Froude number will correspond to different forward speeds when the submerged depth is varied. The numerical results are compared with the analytical results of Wu and Taylor [27]. Figure 4 shows the dimensionless nonlinear wave-making resistance coefficient Cw and lift force coefficient CL of the sphere, where the "linear" results are obtained by solving the BVP of the first-order steady velocity potential, the "nonlinear" results are obtained from the BVPs of the superposition of the first-order and second-order steady velocity potentials; Cw = <sup>−</sup>FS <sup>1</sup>/(ρg<sup>π</sup> <sup>r</sup>3) and CL = F<sup>S</sup> <sup>3</sup>/(ρg<sup>π</sup> <sup>r</sup>3). Figure 4. Coefficients of wave-making resistance (a) and lift force (b) at different Fr. As can be seen from Figure 4, the present results are in good agreement with the analytical results in Wu and Taylor [27] for the linear solution. As can be seen in Figure 4a, the nonlinear results are larger than the linear results when the Froude number is less than a certain threshold value, whereas the situation reverses when it exceeds the threshold. However, a converse trend can be seen for the lift force in Figure 4b. A similar result can also be found in Kim [28]. This may be attributed to the "bow and stern wave-making effect", i.e., when a nonlinear free surface boundary condition is considered, the pressures at the bow and the stern will be different from those when a linear free surface boundary condition is considered. In addition, the differences between the linear and nonlinear results decrease when the submerged depth increases, which demonstrates that the effect of the nonlinear boundary condition on the free surface can be ignored when the submerged depth exceeds a certain value, which is also the case in reality. #### 4.2. mj-Terms The difficulty in solving a radiation problem lies in the accurate calculation of mj terms, which contain the second-order derivatives of the steady velocity potential in the body boundary condition [29]. In order to calculate the mj-terms to verify the calculation accuracy of the derivatives of the velocity potential on the body surface, the desingularized method is applied to a sphere (r = 1.0 m) moving at a speed U = 1.0 m/s in unbounded fluid. The results of the first-order and second-order derivatives of the velocity potential are shown in Figure 5a–c, and the results of m1, m<sup>2</sup> are shown in Figure 5d. It shows that the numerical results virtually coincide with the analytical solutions, which demonstrates that the present method is suitable for calculating the first- and second-order derivatives of the velocity potential on the body surface. Figure 5. Derivatives of the velocity potential and mj terms on the sphere surface along equator line. #### 4.3. Results of the Diffraction Problem Tables 1 and 2 present the non-dimensional real and imaginary parts of the surge and heave wave exciting forces on the submerged sphere (h = 2.0r) moving at Fr = U/ √gr = 0.4 in head waves as function of the non-dimensional wave number obtained by the present method in comparison with the analytical results in [27], where ke = ω2/g. As can be seen in Tables 1 and 2, in general the present results based on the NSWM flow are in better agreement with those in [27] than the results based on the NK flow. Some deviations are observed at low frequencies, especially for the results based on the NK flow. There are two explanations for this larger deviation at low frequencies: firstly, NK flow cannot deal accurately with the relatively high forward speed because the wave disturbance induced by the forward speed of the body is neglected. Secondly, there exists a critical frequency kcr at the Brard number τ = Uω/g = 0.25, which is associated with the radiation condition [10]. Since the critical frequency is kcr= 0.2608 for this case, poor accuracy is resulted when the frequency is near the critical frequency. Table 1. Surge wave exciting forces on the sphere (Fr = 0.4, h = 2.0r, kcr = 0.26808). Table 2. Heave wave exciting forces on the sphere (Fr = 0.4, h = 2.0r, kcr = 0.26808). Figure 6 shows the non−dimensional amplitudes and corresponding phase angles of heave and pitch wave exciting force/moment for the Wigley I ship advancing at Fr = U/ % gL = 0.4 in head waves, where ∇ is the displacement volume. In order to investigate the influence of different steady flow models on wave exciting forces at various wave frequencies, the results based on the NK, DB and NSWM flows are compared in Figure 6. From Figure 6 one can observe that the present results obtained based on the three different steady flow models are in favourable agreement with the results obtained by Kara and Vassalos [30] using a 3D time domain method based on a transient free surface Green function, as well as with the experimental results by Journée [26]. In addition, one can also find that the results based on the NSWM flow and other two methods based on the NK and DB flows do not show evident differences, the reasons can be explained as follows: on one hand, though the effect of nonlinear steady flow is considered in the free surface boundary condition Equation (24), the interaction has no relation with the diffraction potential in the body surface boundary condition Equation (25); on the other hand, the small differences can be attributed to the predominant proportion of the Froude–Krylov force in the wave exciting force. Therefore, it can be concluded that the effect of the NSWM potential contributes unremarkably to the wave exciting force. Figure 6. Amplitudes and phase angles of heave and pitch exciting force/moment on Wigley I ship (Fr = 0.4). Figure 7 shows the real part of the diffraction wave contour for the submerged sphere (Fr = 0.4, kr = 0.5) and the Wigley I ship (Fr = 0.4, kL = 2π) based on the NSWM flow. S) Figure 7. Real part of diffraction wave contour of (a) submerged sphere and (b) Wigley I ship. #### 4.4. Results of the Radiation Problem Tables 3–5 present the added masses and damping coefficients of the submerged sphere (h = 2.0r) moving at Fr = U/ √gr = 0.4 in surge, sway and heave motions respectively, where the added masses and damping coefficients are non-dimensionalized as Aij = aij/(πρr3), Bij = bij/(πρωr3), i, j = 1, 2, 3. The kecr corresponds to the critical frequency ω<sup>c</sup> at the Brard number τ = 0.25. As it can be seen from these tables, the numerical results based on the NSWM flow agree well with the analytical results in [27] and the numerical results in [10]. It should be noted that the linear steady wave-making potential Φ<sup>S</sup> was used to evaluate mj terms in [10], without considering Φ<sup>S</sup> in the free surface boundary condition. From these results, it can be concluded that the effects of the free surface nonlinearities are very weak due to the submerged depth. Table 3. Added masses and damping coefficients of the sphere in surge motion (Fr = 0.4, h = 2.0r, kecr = 0.3906). Table 4. Added masses and damping coefficients of the sphere in sway motion (Fr = 0.4, h = 2.0r, kecr = 0.3906). Table 5. Added masses and damping coefficients of the sphere in heave motion (Fr = 0.4, h = 2.0r, kecr = 0.3906). Table 6 presents the coupling added masses and coefficients. It can be seen that the present results almost show the reverse relations, i.e., (A13, B13)=(−A31, −B31), which is consistent with the results in [27]. Table 6. Coupling added masses and damping coefficients of the sphere (Fr = 0.4, h = 2.0r, kecr = 0.3906). Figure 8 shows the heave and pitch hydrodynamic coefficients of the Wigley I ship at Fr = U/ % gL = 0.4, where the coupling hydrodynamic coefficients are non-dimensionalized as A35(53) = a35(53)/(ρ∇L), B35(53) = b35(53)/(ρ∇L % g/L). As it can be seen in Figure 8, good agreement is achieved among the present numerical results and the results in [30] using NK flow and a transient free surface Green function method, and the experimental results by Journée [26]. The results based on the NSWM flow show in general better agreement with the experimental results than those obtained using DB and NK flows, especially in the low frequency ranges. However, a remarkable deviation can be observed for the heave damping coefficient in Figure 8b. This is because the uniform flow is taken as the basic flow in the method using NK flow, correspondingly the second-order derivatives of the steady potential Φ<sup>S</sup> are neglected in the mj terms. As a result, this treatment cannot accurately reflect the interaction between the steady flow and the unsteady flow in the body surface boundary condition. On the other hand, as explained in [9], the larger contribution of the steady velocity potential in both the body surface and free surface boundary conditions at low frequencies also leads to relatively larger deviations, but these effects are not fully considered in the method using DB flow. Therefore, the coupling effects between the nonlinear steady flow and the unsteady flow, which are reflected in both the free surface boundary condition and the mj terms in the body surface boundary condition, are quite important for the prediction of hydrodynamic coefficients, especially at low frequencies. (e) Heave-pitch coupling added mass (f) Heave-pitch coupling damping coefficient Figure 8. Added masses and damping coefficients of Wigley I ship (Fr = 0.4). Figure <sup>9</sup> shows the real part of the heave radiation wave contour of the sphere (Fr = U/ √gr = 0.4, ker = 2.0) and the Wigley I ship (Fr = 0.4, ω/ % g/L = 3.0) based on the NSWM flow. Figure 9. Real part of the heave radiation wave contour of (a) submerged sphere and (b) Wigley I ship. #### 5. Conclusions In this paper, a desingularized Rankine panel method based on the NSWM flow is applied for analysis of the hydrodynamic problems of a ship advancing in waves. NURBS are used to describe the body surface and the free surface. The wave exciting forces and the hydrodynamic coefficients are computed by solving the diffraction problem and radiation problem, respectively. A numerical study is carried out for a submerged sphere and a modified Wigley hull advancing in head waves. The numerical results are compared with the analytical solutions as well as other numerical results and experimental results available in literature. The following conclusions can be drawn. (1) The numerical results of the wave exciting forces, added masses and damping coefficients computed using the present numerical method show good agreement with the published numerical and experimental results, which verifies the reliability of the present method. A comparison among the results indicates that the method based on the NSWM flow can generally give better agreement with the experimental and other published results than those based on NK and DB flows, especially for the hydrodynamic coefficients in relatively low frequency ranges. (2) The NSWM potential has an influence on the prediction of the wave exciting forces. However, differences among different steady flow models are not very remarkable due to the dominant proportion of the Froude–Krylov force for the considered cases. The coupling effects between the nonlinear steady flow and the linear unsteady flow are important for the prediction of hydrodynamic coefficients, particularly at low frequencies. (3) Compared with the time domain method, considering the NSWM flow as basic flow can be used as a more practical and faster numerical tool for evaluating the hydrodynamic performances of a ship in the early design stage. In the present study, the method based on the NSWM flow is only applied for a submerged sphere and a modified Wigley hull. For reliable verification and application of this numerical method, further study on various ship forms needs to be carried out. Besides, in the numerical study, the squat of the hull (i.e., the trim and sinkage) is neglected. For the cases at larger forward speed, the numerical accuracy could be further improved by taking the effects of trim and sinkage into account. In addition, the desingularized Rankine panel method is only applied for the cases of Brard number τ larger than 0.25, where the radiation condition is satisfied by the staggered method. For τ < 0.25, more robust methods for satisfying the radiation condition, such as the modified Sommerfeld radiation condition in [24,25], should be adopted. These will be the focuses of the future studies. Author Contributions: Methodology, T.M.; formal analysis, T.M. and Z.Z.; Investigation, T.M.; writing—original draft preparation, T.M.; writing—review and editing, M.C., E.L. and Z.Z. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by China Scholarships Council, grant number 201806230196; Lloyd's Register Foundation. Acknowledgments: The first author gratefully acknowledges the financial support from China Scholarship Council (CSC), and from the Lloyd's Register Foundation (LRF) through the joint centre involving University College London, Shanghai Jiao Tong University, and Harbin Engineering University. LRF helps protect life and property by supporting engineering-related education, public engagement, and the application of research. Conflicts of Interest: The authors declare no conflict of interest. #### References © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).	doab	2025-04-07T04:13:04.616190	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 8 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.9	Article Development of a New Ship Adaptive Weather Routing Model Based on Seakeeping Analysis and Optimization #### *Silvia Pennino \, Salvatore Gaglione, Anna Innac, Vincenzo Piscopo and Antonio Scamardella Department of Science and Technology, University of Naples "Parthenope", Centro Direzionale Isola C4, 80143 Naples, Italy; [email protected] (S.G.); [email protected] (A.I.); [email protected] (V.P.); [email protected] (A.S.) \* Correspondence: [email protected]; Tel.: +39-081-547-6686 Received: 17 March 2020; Accepted: 8 April 2020; Published: 10 April 2020 Abstract: This paper provides a new adaptive weather routing model, based on the Dijkstra shortest path algorithm, aiming to select the optimal route that maximizes the ship performances in a seaway. The model is based on a set of ship motion-limiting criteria and on the weather forecast maps, providing the sea state conditions the ship is expected to encounter along the scheduled route. The new adaptive weather routing model is applied to optimize the scheduled route in the Northern Atlantic Ocean of the S175 containership, assumed as a reference vessel, based on the weather forecast data provided by the Global WAve Model (GWAM). In the analysis, both wave and combined wind/swell wave conditions are embodied to investigate the incidence on the optimum route assessment. Furthermore, the effect of the vessel speed on the optimum route detection is also investigated. Current results clearly show that it is possible to achieve appreciable improvements, up to 50% of the ship seakeeping performances, without excessively increasing the route length and the voyage duration. Keywords: adaptive weather routing; Seakeeping Performance Index; route optimization; Dijkstra algorithm #### 1. Introduction Maritime trades are strictly dependent on the weather conditions the ship is expected to encounter along her route, provided that excessive ship motions may cause damage or cargo loss, as well as the decrease of the onboard comfort level, with a negative impact on the safety of navigation for both cargo and passenger ships. In this respect, even if the route selection is entrusted to the ship master, the adaptive weather routing algorithms can provide a significant support to the decision-making process, to ensure the proper balancing between the safety of navigation and the related economic impact, in terms of voyage duration and fuel savings. Nevertheless, as further discussed in Section 2, the impact of weather routing on fuel savings is expected to be marginal, provided that obtained results are not particularly encouraging, as no substantial fuel savings can be gathered if the ship route is varied, as regards the minimum distance route, without reducing the vessel speed. Hence, in the following research, a new adaptive weather routing model is developed to select the best route that maximizes the ship performances in a seaway, based on a set of proper seakeeping criteria. In fact, even if the route selection has a low impact in terms of fuel savings, an appreciable increase of the ship seakeeping performances can be gathered without excessively changing the route, as regards the minimum distance route. The new route optimization procedure, based on the shortest path algorithm, is developed in this paper to detect the best route, based on the weather forecasts the ship is expected to encounter up to the arrival in port. The algorithm is applied to the S715 containership, assumed as a reference vessel, to investigate the effect of the selected seakeeping parameters and vessel speed on the best route selection, as well as on the expected voyage duration and path length. Hence, the main aim of the current research is to develop a new adaptive weather routing model aiming to: (i) maximize the seakeeping performances in a seaway, (ii) investigate the incidence of unimodal/bimodal spectra and vessel speed on the improvement of the seakeeping performances, and (iii) carry out a sensitivity analysis to investigate the effect of each seakeeping parameter on the optimum route selection. #### 2. Literature Review The weather routing problem was addressed by many authors and different approaches were embodied in the past. Following the pioneering works by James [1], Zoppoli [2], and Papadakis and Perakis [3], the first generation of weather routing criteria aimed to minimize the voyage duration, and consequently, the fuel consumption, mainly neglecting the impact of the best route selection on the ship performances in a seaway. Nevertheless, in the last years, the voyage optimization problem was approached in a wide sense, taking into account the ship seakeeping performances, apart from the fuel consumption. In this respect, the second-generation algorithms, developed as general optimization tools and applied to the ship voyage optimization problem, are generally categorized into: dynamic programming, genetic algorithms, and pathfinding methods. The most used techniques include multi-objective genetic algorithms [4–7] that stochastically solve a discretized nonlinear optimization problem [8], based on the ship course and her velocity profile that, in turn, is represented by a set of parametric curves. In this respect, Szłapczynska and Smierzchalski [9] proposed a multi-criteria evolutionary weather-routing algorithm, based on an iterative process of population development, resulting in a Pareto-optimal set of solutions. Shao and Zhou [10] presented a three-dimensional (3D) dynamic-programming based on the original work by De Wit [11], devoted to optimizing the ship speed and the heading angle in the route planning. Zaccone et al. [12] developed a 3D dynamic-programming-based ship voyage optimization method, that attempts to select the optimal path and speed profile, based on the expected weather forecasting along the vessel route. Another technique, devoted to managing the weather routing optimization procedure, is the path-finding method. In this respect, Padhy et al. [13] embodied the Dijkstra [14] algorithm to solve the ship routing problem, while Veneti [15] provided an improved solution based on the exact time-dependent bi-objective shortest path algorithm, to optimize two different conflicting objectives, namely, the fuel consumption and the expected risk along the route. In Reference [16], an overview of weather routing and safe ship handling approaches is presented, addressing the importance of the complementarity between both approaches in such situations and their extensive implementation to achieve optimal and safe navigation conditions in shipping. In Reference [17], some modifications are proposed to find the optimal path in ice-covered waters in order to take into account the possible involvement of an icebreaker. In this view, the icebreaker assistance is considered as an integral part of the overall formulation of the route optimization problem in the frame of graph-based and wave-based numerical routing algorithms. A solution method for a real-life problem of routing and scheduling ships, motivated by the production and logistic activities of an oil company operating in Brazil, is described in Reference [18], where the authors proposed a multi-start heuristic that makes use of intensification and diversification strategies to minimize both transportation and docking costs, as well as avoid consecutive dockings of the same ship in different platforms. In Reference [19], the authors presented a study about a data-driven framework for decision support in the selection of optimal ship routes based on available weather forecasts and the calculation of fuel oil consumption over alternative routes. In detail, a modified version of the Dijkstra algorithm was recursively applied until the optimal route was detected. #### 3. Adaptive Weather Routing Model** #### 3.1. Shortest Path Detection The adaptive weather routing model, developed in Section 3, is based on the Dijkstra algorithm, that allows for the detection of the shortest path between two points of known coordinates, by maximizing a reference non-negative cost-function which is, in the current analysis, the Seakeeping Performance Index (SPI), provided by Equation (1). The Dijkstra algorithm is based on two problems, namely, the construction of the tree of minimum total length between a set of nodes, and the research of the best path between the start and the endpoint by minimizing an assigned cost function. The points, connected by a set of branches, form the required tree, from which a uniquely defined path between two nodes is obtained. In the current analysis, the cost function is the complement to 1 of the SPI provided by Equation (1). Besides, the algorithm is not applied statically but it is iteratively updated by changing the starting point, based on the elapsed time and the path already travelled by the ship. Before assessing the ship performances in a seaway, a network of nodes, between the start and the endpoints of the scheduled route, needs to be preliminarily provided to define a region that constrains the ship route. The network, generated as detailed by Lee et al. [20], is a special form of a Dijkstra graph consisting of nodes and arcs, associated to a set of parameters such as the path length, the cost, or the transit time. The network is generated according to the following steps: (i) the center point C of the great circle, black line in Figure 1a, between S and E, is determined, (ii) around C, a set of center points (red dots), with a fixed step distance, are considered, belonging to the rhumb-line perpendicular to the great circle, and (iii) a network of nodes, blue dots in Figure 1a, are generated, considering, in the first half of the great circle, a set of perpendicular rhumb-lines, as well as in the second half part. On each rhumb-line, a proper step distance between nodes is adopted. Each node is characterized by static information, such as the geographic coordinates, a dynamic grid with the weather data, namely, the significant wave height, the mean wave period, and the prevailing wave direction, which are systematically updated once a new dataset is available. After providing the network of nodes, a set of arcs, connecting two adjacent grid points, is created, and a cost-function, depending on the SPI values at the arc extremities, is assigned to detect the best route, as schematically shown in the flow chart reported in Figure 1b. Each segment of the optimal route corresponds to the maximum of the Seakeeping Performance Index among the set of possible values referenced to the calculation point. Figure 1. Adaptive weather routing algorithm: (a) Grid point network, (b) flow chart. SPI: Seakeeping Performance Index. #### 3.2. Assessment of Ship Seakeeping Performances In the current analysis, the ship seakeeping performances are determined on the basis of five reference criteria, namely: (i) the amplitude of the pitch motion, (ii) the relative vertical acceleration at the ship forward perpendicular, (iii) the probability of slamming occurrence, (iv) the probability of green water on deck, and (v) the Motion Sickness Incidence (MSI), according to the following equation: $$SPI = \max\left\{0; \left(1 - \frac{rms\_p}{rms\_{p,l}}\right) \cdot \left(1 - \frac{rms\_a}{rms\_{a,l}}\right) \cdot \left(1 - \frac{p\_{sl}}{p\_{sl,l}}\right) \cdot \left(1 - \frac{p\_{wd}}{p\_{wd,l}}\right) \cdot \left(1 - \frac{MSI}{MSI\_l}\right)\right\} \tag{1}$$ where rmsp (rmsa) is the RMS, root mean square, of the pitch motion amplitude (relative vertical acceleration), psl (pwd) is the probability of occurrence of slamming (water on deck), MSI is the Motion Sickness Incidence, while the denominators represent the relevant limit values. It is noticed that when any seakeeping index is greater than the limit value, the SPI is null, so satisfying the non-negative condition is required to apply the Dijkstra method. The limit values of the pitch amplitude and the MSI are based on the NATO STANAG, Standardization Agreement, 4154 criteria, while the remaining ones comply with the NORDFORSK 1987 criteria [21,22], as detailed in Table 1. Table 1. General operability limiting criteria for ships. \* at intermediate values, linear interpolation is applied. The RMS of the pitch motion amplitude is determined according to the following equation, based on the ship Response Amplitude Operator [23]: $$rms\_p = \sqrt{\int\_0^\infty \left\| H\_5(\omega\_\varepsilon) \right\|^2 S\_\varepsilon(\omega\_\varepsilon)}\tag{2}$$ where H<sup>5</sup> is the speed-dependent pitch motion transfer function to be determined as detailed in Appendix A, <sup>S</sup><sup>ς</sup> is the wave spectrum, and <sup>ω</sup><sup>e</sup> = <sup>ω</sup> <sup>−</sup> <sup>ω</sup>2<sup>ψ</sup> is the encounter wave frequency that satisfies the Doppler shift equation, depending on the absolute wave frequency ω and the factor ψ = Ucosμ/g, where the vessel speed is denoted by U and μ denotes the heading angle. The RMS of the relative vertical acceleration is obtained by combining the heave and pitch motions at the ship forward perpendicular [23]: $$ \sigma m \mathbf{s}\_{\mathbf{z}} = \sqrt{\int\_{0}^{\infty} \left\| H\_{3}(\omega\_{\varepsilon}) - \overline{\mathbf{x}} H\_{5}(\omega\_{\varepsilon}) - e^{-i\overline{\mathbf{x}}\overline{\mathbf{x}}\cos\mu} \right\|^{2} \omega\_{\varepsilon}^{4} S\_{\zeta}(\omega\_{\varepsilon})} \tag{3} $$ where H<sup>3</sup> is the heave motion transfer function, x is the longitudinal distance (fwd+) of the ship forward perpendicular from its center of mass, and k = ω2/g is the wave number satisfying the deep-water condition. As concerns the slamming occurrence, it is determined according to the formula proposed by Faltinsen [24]: $$p\_{sl} = \varepsilon^{-(\frac{v\_{cr}^2}{2\mathcal{C}\_s^2 m\_{2J}} + \frac{d^2}{2\mathcal{C}\_s^2 m\_{0,r}})}\tag{4}$$ where vcr = 0.093 % gL is the threshold velocity, Cs is the swell up coefficient equal to 1 up to FN = 0.30 [25], and d is the ship draught at the forward perpendicular. In Equation (4), m0,<sup>r</sup> and m2,<sup>r</sup> denote the 0 and second-order spectral moments of the ship relative motion as regards the sea surface. As concerns the probability of green water on forward deck structures, it is determined in a quite similar manner [24]: $$p\_{rad} = e^{-\frac{f\_b^2}{2C\_s^2 m\_{0\varphi}}}\tag{5}$$ where the freeboard at the ship forward perpendicular is denoted by fb. Finally, the Motion Sickness Index is determined according to the formulation developed by O'Hanlon and McCauley [26] and modified by Colwell [27]: $$MSI = 100\Phi(z\_d)\Phi(z'\_T) \tag{6}$$ where Φ is the standard normal cumulative distribution, while za and z <sup>T</sup> are determined by the following equations: $$z\_a = 2.128 \log\_{10} \left( \frac{a\_{MSI}}{g} \right) - 9.277 \log\_{10} (f\_m) - 5.809 [\log\_{10} (f\_m)]^2 - 1.851 \tag{7}$$ $$z\_T' = 1.134z\_d + 1.989 \log\_{10} \left(\frac{T}{60}\right) - 2.904\tag{8}$$ In Equations (7) and (8), T is the exposure time in s, while aMSI and fm are the RMS and the mean frequency in Hz of the ship vertical acceleration [27]. #### 3.3. Assessment of Weather Forecasting Data The availability of daily operational weather forecast data is a key point to assess the reference scenario required in the adaptive weather routing algorithm. In this respect, several software packages, with different resolutions, domains (from regional to global), and quality [28] are available, as proven by the agreements that shipping companies stipulate with one or more meteorological institutes, to obtain updated and reliable weather forecast data. Anyway, nowadays, the community generally follows the standardization established by the World Meteorological Organization (WMO), delivering all information in a self-descripting GRIB (GRIdded Binary) format [29], making the reading of the input data very easy. Among the variety of weather forecast codes, the third-generation Global WAve Model (GWAM), initially developed in the mid-80s by an international group of wave modelers [30], is probably the most embodied one by all research institutions around the world. It explicitly solves the wave transport equation, without any assumptions about the shape of the wave spectrum, therefore properly representing the physics of the wave evolution in compliance with the knowledge about the full set of freedom degrees of two-dimensional wave spectra. The model can be applied to any given regional or global grid, based on a certain topographic dataset. Besides, the grid resolution can be arbitrarily set in both space and time, while the wave propagation can be performed on latitudinal-longitudinal or Cartesian grids. The model outputs, embodied in the route optimization procedure, are the significant wave height and the mean wave period and direction of both wind wave and swell components. #### 4. Input Data #### 4.1. The S175 Containership The S175 containership [31–33] is assumed as a reference vessel in the performed case study. The ship's main dimensions are listed in Table 2, while the zero-speed added mass and radiation damping are determined by the open source code Nemoh [34] and corrected to account for the forward speed effect, as detailed in Appendix A [35]. Table 2. Main particulars of the S175 containership. #### 4.2. Route Selection The reference route falls in the North Atlantic Sea, as this trade lane is one of the most important routes in the global shipping industry and most of the key port infrastructures in Europe are continually upgraded to reflect the demands of shipping across this corridor. Besides, the weather conditions in this area can be rough and vary with seasons, influencing the obtained results. The selected voyage has (34◦ N, 60◦ W) departure and (32◦ N, 20◦ W) arrival coordinates, as depicted in Figure 2, that also provides the great circle or orthodrome (black) and the rhumb-line or loxodrome (red) routes, equal to 2005 and 2018 nm respectively, provided that they are generally combined by the master during the navigation [36,37]. In fact, the great circle or orthodrome is the shortest path route, but it requires to constantly change the vessel heading. On the contrary, the rhumb-line or loxodrome is slightly longer, but it allows the master to keep a constant heading in the absence of wind and sea current, as they are generally combined for practical purposes. The voyage duration is equal to about 7 days, considering a reference vessel speed of 12 knots, corresponding to Froude number FN = 0.15. From Figure 2, it is gathered that the start and the endpoint are slightly far from the departure and arrival ports. This choice is mainly due to the marine traffic congestion the ship experiences when it approaches the coastline, that makes the application of adaptive routing models challenging, as additional restraints, mainly related to neighboring vessels, arise. Figure 2. Great circle (black) and rhumb-line (red) between routes' departure and arrival points. #### 4.3. Weather Forecasting Data In the current analysis, the GRIB files were downloaded for the period from 3 up to 10 January 2020, with 0.25◦ × 0.25◦ grid spacing, 3-hour forecast interval, and two observation periods equal to 1 and 7 days, respectively. The free software XyGrib, able to download and show the meteorological data, was embodied to obtain the GRIB files. An example of the images providing the changes of the environmental conditions in the selected area is reported in Figure 3, that provides a series of GRIB files showing the time trend of the significant wave height, Hs = ) Hs,wind<sup>2</sup> + Hs,swell<sup>2</sup> from 06:00 UTC (Coordinated Universal Time) on 3 January 2020 up to 03:00 UTC on 4 January 2020, where the wind wave (swell) component is denoted by Hs,wind (Hs,swell). Figure 3. Time trend of the significant wave height from 06:00 UTC on 3 January 2020 up to 03:00 UTC on 4 January 2020. #### 5. Case Study #### 5.1. Optimum Route Detection After defining the input data, two GRIB files are embodied in the route optimization procedure. The former, referenced as "Case 1", is a 7-day forecast GRIB file, ranging from 3 up to 10 January 2020. The latter, referenced as "Case 2", is a 1-day GRIB file, updated daily in the same reference period, according to the effective position of the ship during the voyage. The same GRIB files, referenced as "Case 3" and "Case 4", are re-analyzed, including the swell data, apart from the wind-generated waves. In the first two cases, the JONSWAP [38] spectrum is applied in the weather routing optimization procedure, while in the remaining ones, the two-peak Torsethaugen [39] spectrum is embodied, to model weather conditions obtained by combined wind sea and swell components, coming from different directions. In this respect, Figure 4a–d provide the optimal routes with reference to the four selected conditions. In all cases, the great circle route is highlighted in red, the optimum route is depicted in black, while the grey circles represent the starting and the ending points. Besides, Table 3 provides the difference, Δc, between the great circle and optimum route, that maximizes the ship performances, together with the percentage variation, ΔSPI, of the Seakeeping Performance Index (SPI), as regards the values corresponding to the great circle route. Based on the current results, the percentage increase of the route length ranges from 1.1% up to 2.7%, while the SPI increase is much higher and ranges from 10% up to 40%. These results clearly show that the ship seakeeping performances can be highly improved, without significantly increasing the voyage length and, consequently, the fuel consumptions. After carrying out this preliminary analysis, Figure 5a–d and Table 4 provide the same calculations obtained by reversing the travel direction, therefore inverting the departure and arrival coordinates. Also, in this case, the percentage increase of the route length is low and ranges from 3.1% up to 4.9%, while the SPI increase is much higher and ranges from about 10% up to 68%. All calculations were performed based on a reference vessel speed equal to 12 kn, corresponding to FN = 0.15. Figure 4. Minimum distance (great circle) and optimal route detection, FN = 0.15: (a) Case 1; (b) Case 2; (c) Case 3; (d) Case 4. Table 3. Results of optimal route detection, FN = 0.15. Figure 5. Minimum distance (great circle) and optimal route detection, FN = 0.15 (reversed travel direction): (a) Case 1; (b) Case 2; (c) Case 3; (d) Case 4. #### 5.2. Effect of Vessel Speed The incidence of the vessel speed on the optimum route detection is investigated, increasing the Froude number from 0.18 up to 0.24, with 0.03 step. Obviously, the vessel speed increase leads to a corresponding decrease of the travelling time that diminishes up to 138, 119, and 104 h, as well as to a slight variation of the weather conditions that the ship is expected to encounter during the voyage. In this respect, Figure 6a–d, Figures 7a–d and 8a–d provide the optimal routes, while Table 5 summarizes the obtained results. In the first case, corresponding to FN = 0.18, the route length increases from 0.6% up to 2.0%, if compared with the great circle one, while the SPI increases from 3.5% up to 31.5%. In the second condition, corresponding to FN = 0.21, the route length rises up from 0.6% to 6.1%, while the SPI increase ranges from 3.4% up to 39.8%. In the last condition, instead, the route length increases from 0.3% up to 1.6% and the SPI rises from 6.7% up to 32.1%. Based on the current results, it is confirmed that it is possible to achieve considerable improvements of the ship seakeeping performances, without significantly affecting the voyage length. Furthermore, it is verified that the vessel speed plays a fundamental role in the assessment of the optimal route, as well as on the increase of the ship seakeeping performances. Figure 6. Minimum distance (great circle) and optimal route detection, FN = 0.18: (a) Case 1; (b) Case 2; (c) Case 3; (d) Case 4. Figure 7. Minimum distance (great circle) and optimal route detection, FN = 0.21: (a) Case 1; (b) Case 2; (c) Case 3; (d) Case 4. Figure 8. Minimum distance (great circle) and optimal route detection, FN = 0.24: (a) Case 1; (b) Case 2; (c) Case 3; (d) Case 4. Table 5. Incidence of vessel speed on optimal route detection. #### 5.3. Sensitivity Analysis The incidence on the optimum route detection of each seakeeping index provided by Equation (1) is investigated. The optimum routes, corresponding to FN = 0.15, are reported in Figure 9a–j with reference to both JONSWAP (left) and Torsethaugen (right) wave spectra, separately considering the following criteria, namely: (i) the RMS of pitch amplitude (a,b), (ii) the RMS of vertical acceleration (c,d), (iii) the slamming probability (e,f), (iv) the water on deck probability (g,h), and (v) the MSI (i,j). Figure 9. Sensitivity analysis at FN = 0.15 based on JONSWAP (left) and Torsethaugen (right) wave spectra: (a) RMS of pitch amplitude—JONSWAP; (b) RMS of pitch amplitude—Torsethaugen; (c) RMS of vertical acceleration—JONSWAP; (d) RMS of vertical acceleration—Torsethaugen; (e) Slamming probability—JONSWAP; (f) Slamming probability—Torsethaugen; (g) Water on deck probability—JONSWAP; (h) Water on deck probability—Torsethaugen; (i) MSI—JONSWAP; (j) MSI—Torsethaugen. Table 6 provides a comparative analysis between the great circle and the optimum route, together with the percentage variation of the SPI. Based on the current results, the RMS of the vertical acceleration and the Motion Sickness Incidence seem to be the most sensitive parameters. This outcome is confirmed with reference to both JONSWAP and Torsethaugen spectra, even if in the latter case the improvements of the seakeeping performances are slightly lower. #### 6. Discussion The results obtained in Section 5, obtained by a purposely developed code in Matlab, MathWorks, clearly highlight that there is wide space to improve the ship performances in a seaway by properly varying the vessel route, depending on the expected met-ocean conditions. In this respect, the following main outcomes have been achieved: These outcomes clearly suggest that the adaptive weather routing model shall be specialized on a case-by-case basis, depending on the ship type and the key seakeeping performances that need to be monitored and improved. #### 7. Conclusions The Dijkstra shortest path algorithm was applied to detect the optimum route, constrained to maximize a non-negative cost function, namely the SPI index provided by Equation (1), in order to maximize the ship performances in a seaway. Based on the current results, the proposed adaptive weather routing algorithm allows for consistently increasing the ship seakeeping performances up to 50%, without significantly affecting the voyage duration or the route length. Furthermore, it was verified that the vessel speed plays a fundamental role in the assessment of the optimum route, as well as on the improvement of the ship seakeeping performances. Besides, the existence of a swell component, coming from a different direction as regards the wind wave one, can affect the selection of the optimal route. Following these outcomes, the application of an adaptive weather routing criterion, based on ship seakeeping analysis and optimization, seems to be the most suitable way to detect the optimal route, provided that the currently embodied models have an almost negligible impact in terms of fuel savings. Nevertheless, additional fuel savings, also resulting in low gas emissions in the atmosphere, could be gathered by properly varying the ship speed, depending on the estimated time of arrival in port and the availability of the harbor infrastructures. In this respect, if the ship has to wait at anchor, due to the unavailability of the harbor infrastructures for the scheduled loading/unloading operations, it is certainly preferable to reduce the vessel speed, resulting in fuel savings, and delay the time of arrival in port. All these suggestions could be embodied by ship-owners and port authorities, in order to establish a cooperating network between the harbor and the onboard vessel management, resulting in: (i) an increase of the ship performances in a seaway with a positive impact on the safety of navigation, (ii) a reduction of the fuel consumptions, resulting in savings for the ship-owner and in a possible reduction of the gas emissions in the atmosphere, and (iii) optimization of the scheduled loading/unloading operations in port. Based on these outcomes, the current results are encouraging for further research activities, devoted to including additional seakeeping criteria in the adaptive weather routing algorithm. In this respect, the incidence of the selected seakeeping criteria on the optimum route assessment needs to be further investigated. In fact, the SPI index mainly depends on the ship type and mission, which implies that the proposed adaptive weather routing model needs to be properly specialized, on a case-by-case basis. Finally, the current results were obtained in a simulated environment, and therefore, they need to be further verified in real conditions, in order to carry out a comparative analysis between the optimum route, based on the current seakeeping adaptive weather routing model, and previous real ship routes. These topics will be the subject of future works. Author Contributions: Conceptualization, S.G., V.P., and A.S.; Writing—original draft, S.P. and A.I.; Writing—review and editing, S.G., V.P., and A.S.; Methodology, S.P. and A.I.; Software and formal analysis, S.P.; Data curation and visualization, A.I.; Supervision, S.G., V.P., and A.S.; Validation S.G. and V.P.; Funding acquisition, A.S. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Acknowledgments: The work was supported by "DORA—Deployable Optics for Remote Sensing Applications" (ARS01\_00653), a project funded by MIUR-PON "Research & Innovation"/PNR 2015–2020. Conflicts of Interest: The authors declare no conflict of interest. #### Appendix A The heave/pitch motion equations in the encounter wave frequency-domain are provided by the following set of equations: $$\begin{cases} \begin{bmatrix} -\omega\_{\varepsilon}^{2}(\Lambda + A\_{53}) + i\omega\_{\varepsilon}B\_{53} + \mathbb{C}\_{33} \\ -\omega\_{\varepsilon}^{2}A\_{53} + i\omega\_{\varepsilon}B\_{53} + \mathbb{C}\_{53} \end{bmatrix} \mathcal{H}\_{3} + \begin{bmatrix} -\omega\_{\varepsilon}^{2}A\_{55} + i\omega\_{\varepsilon}B\_{55} + \mathbb{C}\_{35} \\ -\omega\_{\varepsilon}^{2}(I\_{55} + A\_{55}) + i\omega\_{\varepsilon}B\_{55} + \mathbb{C}\_{55} \end{bmatrix} \mathcal{H}\_{5} = f\_{5}(\omega) \\ \end{cases} \tag{A1}$$ where Δ and I<sup>55</sup> are the ship displacement and pitch moment of inertia, Aij, Bij, and Cij are the added mass, hydrodynamic damping, and restoring coefficient for the i–jth mode, H<sup>3</sup> and H<sup>5</sup> are the heave and pitch motion transfer functions, while f<sup>3</sup> and f<sup>5</sup> are the heave force and pitch moment per unit wave amplitude. After solving the Equation System (A1), the modulus of the heave and pitch motion transfer functions is derived [23]: $$\left\| H\_{3}(\omega\_{\varepsilon}) \right\| = \left\| \frac{-\omega\_{\varepsilon}^{2}(I\_{\rm BS} + A\_{\rm BS}) + i\omega\_{\varepsilon}B\_{\rm S} + C\_{\rm S} \left\| f\_{3}(\omega) - \left[ -\omega\_{\varepsilon}^{2}A\_{\rm S\rm S} + i\omega\_{\varepsilon}B\_{\rm S\rm S} + C\_{\rm S\rm S} \right] f\_{3}(\omega) \right\|}{\left[ -\omega\_{\varepsilon}^{2}(\Lambda + A\_{\rm S\rm S}) + i\omega\_{\varepsilon}B\_{\rm S\rm S} + C\_{\rm S} \right] \left[ -\omega\_{\varepsilon}^{2}(I\_{\rm BS} + A\_{\rm S\rm S}) + i\omega\_{\varepsilon}B\_{\rm S\rm S} + C\_{\rm S} \right] \left[ -\omega\_{\varepsilon}^{2}A\_{\rm S\rm S} + i\omega\_{\varepsilon}B\_{\rm S\rm S} + C\_{\rm S} \right]} \right\| \quad \text{(A2)}$$ $$\left\| \mathrm{H\_3}(\omega\_{\mathbb{E}}) \right\| \ = \left\| \frac{-\omega\_x^2(\Lambda + A\_{33}) + i\omega\_x B\_{33} + C\_{33} \left[ f\_3(\omega) - \left[ -\omega\_x^2 A\_{33} + i\omega\_x B\_{33} + C\_{33} \right] f\_3(\omega) \right]}{\left[ -\omega\_x^2(\Lambda + A\_{33}) + i\omega\_x B\_{33} + C\_{33} \left[ -\omega\_x^2(I\_{33} + A\_{33}) + i\omega\_x B\_{33} + C\_{33} \right] - \left[ -\omega\_x^2 A\_{33} + i\omega\_x B\_{33} + C\_{33} \right] \left[ -\omega\_x^2 A\_{33} + i\omega\_x B\_{33} + C\_{33} \right] f\_3(\omega) \right] \right\| \ (\Lambda^2 + A^2)^{-1}$$ In Equations (A2) and (A3), the frequency-dependent added masses and radiation dampings combine the zero-speed values with the speed-dependent corrective factors, with no transom correction [35]: $$\begin{aligned} A\_{33} &= A\_{33}^{0}(\omega\_{\varepsilon}); \; B\_{33} = B\_{33}^{0}(\omega\_{\varepsilon}) \\ A\_{35} &= A\_{35}^{0}(\omega\_{\varepsilon}) - \frac{\underline{\iota}\underline{\iota}}{\omega\_{\varepsilon}^{2}} B\_{33}^{0}(\omega\_{\varepsilon}); \; B\_{35} = B\_{35}^{0}(\omega\_{\varepsilon}) + \underline{\iota}\underline{\iota} A\_{33}^{0}(\omega\_{\varepsilon}) \\ A\_{53} &= A\_{53}^{0}(\omega\_{\varepsilon}) + \frac{\underline{\iota}\underline{\iota}}{\omega\_{\varepsilon}^{2}} B\_{33}^{0}(\omega\_{\varepsilon}); \; B\_{53} = B\_{53}^{0}(\omega\_{\varepsilon}) - \underline{\iota}\underline{\iota} A\_{33}^{0}(\omega\_{\varepsilon}) \\ A\_{55} &= A\_{55}^{0}(\omega\_{\varepsilon}) + \frac{\underline{\iota}^{2}}{\omega\_{\varepsilon}^{2}} A\_{33}^{0}(\omega\_{\varepsilon}); \; B\_{55} = B\_{55}^{0}(\omega\_{\varepsilon}) + \frac{\underline{\iota}\underline{\iota}^{2}}{\omega\_{\varepsilon}^{2}} B\_{33}^{0}(\omega\_{\varepsilon}) \end{aligned} \tag{A4}$$ If the 1-to-3 multivalued problem between absolute and encounter wave frequencies occurs, the modulus of heave/pitch motion transfer functions is replaced by the following equation: $$\left\| H\_{\dot{f}}(\omega\_{\varepsilon}) \right\| = \sqrt{\left\| H\_{\dot{f}}^{1}(\omega\_{\varepsilon}) \right\|^{2} + \left\| H\_{\dot{f}}^{2}(\omega\_{\varepsilon}) \right\|^{2} + \left\| H\_{\dot{f}}^{3}(\omega\_{\varepsilon}) \right\|^{2}} \tag{A5}$$ where H<sup>i</sup> j (ωe) is the j-th mode transfer function at the absolute wave frequency ωi, with i = 1, 2, or 3. #### References © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).	doab	2025-04-07T04:13:04.618682	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 9 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.10	Article Vertical Motions Prediction in Irregular Waves Using a Time Domain Approach for Hard Chine Displacement Hull #### *Ermina Begovic 1,\, Carlo Bertorello 1, Ferdi Cakici 2, Emre Kahramanoglu <sup>2</sup> and Barbara Rinauro <sup>1</sup> Received: 23 March 2020; Accepted: 4 May 2020; Published: 9 May 2020 Abstract: In this paper, the validation of the hybrid frequency–time domain method for the assessment of hard chine displacement hull from vertical motions is presented. Excitation and hydrodynamic coefficients in regular waves are obtained from the 3D panel method by Hydrostar® software, while coupled heave and pitch motions are calculated in the time domain by applying the Cummins equations. Experiments using a 1:15 scale model of a "low-drag" small craft are performed in irregular head and following waves at Froude numbers Fr: 0.2, 0.4, and 0.6 at University of Naples Federico II, Italy. Results obtained by hybrid frequency–time domain simulations for heave, pitch, and vertical accelerations at center of gravity and bow are compared with experimental data and showed high accuracy. Keywords: Cummins equations; vertical motions assessment; time domain simulations; experimental seakeeping; hard chine displacement hull form #### 1. Introduction The assessment of ship behavior in an irregular seaway is one of the most difficult hydrodynamic problems. A large variety of different computational methods have been presented in the past three decades and are discussed in Hirdais et al. [1]. They proposed the subdivision into six levels, where each "level" introduces mathematical models closer to the physical models, generally moving from frequency domain calculations to time domain simulations, from linearized to nonlinear boundary conditions, and from small wave amplitudes to breaking waves, spray, and water flowing onto and off the ship's deck. The simplest "Level 1" approach considers the potential flow linearized frequency domain methods, while "Level 6" deals with fully non-linear methods like Reynolds Averaged Navier Stokes (RANS) and Smooth Particle Hydrodynamics (SPH). Significant simplifications have been introduced in mathematical models considering separately vertical and horizontal motions and neglecting the viscous effects and the ship's transversal symmetry. Two main approaches are known—the frequency and time domains. Frequency domain methods have been widely used as strip theories (2D) or as panel methods (3D) with different levels of nonlinearities considered in the mathematical model. They are valid under small wave amplitudes and small ship motions hypothesis, assuming linearized boundary conditions and the linear superposition principle. If the phenomenon involves non-linearities, rising from high wave amplitudes, high advancing speed, or hull forms with strong flare, then the time domain approach should be considered. Today, time domain simulations based on Cummins equation [2] are becoming standard as they can accommodate nonlinearities due to nonlinear wetted surface and steeper waves and are very fast. The original Cummins' equation considers the fluid memory effects for radiation terms that are calculated using the damping and added mass values in the frequency domain. Although the direct calculation of convolution integrals in Cummins equation is possible (so called "full" time domain calculation), as stated in Perez and Fossen [3], this is very time consuming, and for analysis and control system design, the convolutions are not suitable. One of the possible solutions is the introduction of "parametric model identification" since the convolution is a dynamic linear operator and can be represented by a linear ordinary differential equation-state-space model or transfer functions in the Laplace domain [3]. Perez and Fossen [4] schematized works on parametric model identification developed during time as Time Domain Identification (TDI) and Frequency Domain Identification (FDI) and reported the major contributions by different authors. Armesto et al. [5] presented results of time domain simulations for the motion of the water inside an oscillating water column and a free decay test in the heave of a spar buoy by three techniques—the direct solution of convolution integral, an approximation of the convolution integral with state space model, and Prony's estimation of the convolution. The state space method and Prony's approximations are computationally cheaper, and their results are very close to those from the direct solution of convolution integrals. The authors reported different uncertainties seen in the identification of the coefficients in these methods and concluded that, with the increase of computational capabilities given by actual computers, they recommend the use of a direct integration method to compute the radiation term in Cummins' equation. Some of the important works for the "Level 2" methodology validation and application cases presented in the last years are: The present work is further contribution to the validations of the time domain simulations. The 2 DOF time domain simulation code, developed by the authors of this paper and explained in detail in Cakici et al. [8], has been validated for vertical motions in irregular head and following waves of the hard chine displacement boat and compared against experimental data obtained by the authors. The calculation of excitation and radiation terms in the frequency domain has been performed by Hydrostar® software based on the 3D panel methods. Direct computation of the convolution integrals has been used for fluid memory effects. Restoring terms are considered linear and are calculated from the ship main properties. The wave loads in the time domain are obtained by a realization technique from the Hydrostar® frequency domain calculations. The considered ship is representative of actual small craft trends, oriented to the low drag simple hard chine hull form studied in Bertorello and Begovic [11]. Seakeeping characteristics of hard chine and warped hull at high speed are characterized by strong nonlinearities due to the dynamic trim and constant changing of wetted surface. The general approach for planing hulls vertical motions prediction follows time domain simulation by Zarnick's theory [12] based on the potential flow, full planing condition, and constant deadrise angle in regular waves. On the other hand, flow separation and spray formation due to the hard chine present a complex hydrodynamic problem, which can be correctly studied only by RANS methods and sophisticated mesh modelling techniques with high computational efforts. At the moment, for a warped hard chine hull operating in displacement and semi-displacement regimes, there is no adequate numerical tool. Thorough validation of the applied method has been performed considering a very demanding hull form tested in irregular head and following seas at Froude numbers Fr = 0.2, 0.4, and 0.6. Simulations are performed with the time step equal to the frequency of sampling, and an identical analysis of the numerical and experimental time series is performed to obtain the fair comparison. #### 2. Mathematical Model** A brief overview of the fundamental equations used in the mathematical model for vertical motions of ship advancing in irregular waves is given. #### 2.1. Cummins Equation for Coupled Heave and Pitch Motion Starting from the general Cummins' Equation (1), $$\left(\overline{\mathbf{M}} + \mathbf{A}^{\otimes}\right)\bar{\eta}(t) + \int\_{0}^{t} \mathbf{K}(t-\tau)\eta(\tau)d\tau + \mathbf{C}\eta(t) = \mathbf{F}\_{\mathbf{W}}(t) \tag{1}$$ the following parameters can be defined: A∞ is the added mass at infinite frequency, K is the impulse response (retardation) function matrix, defined as $$\mathbf{K}(t) = \frac{2}{\pi} \int\_0^\infty [\mathbf{B}(\omega)] \cos(\omega t) d\omega \tag{2}$$ B(ω) is the damping matrix in frequency domain. C is the restoring matrix. η(t) is the oscillatory response of the ship. Fw(t) is the transient wave force vector that can be created by a linear superposition of frequency domain results for different wave spectra. In this study, the Cummins' equation is solved for the coupled vertical motions of the ship advancing with the constant speed V, as written in Equations (3) and (4). Subscripts 3 and 5 refer to heave and pitch motions, respectively. $$\begin{aligned} \left(\Delta + \mathcal{A}\_{33}^{\text{os}}\right)\ddot{\eta}\_{3}(t) + \mathcal{B}\_{33}(\infty)\eta\_{3}(t) + \int\_{0}^{t} \mathcal{K}\_{33}(t-\tau)\eta\_{3}(\tau)d\tau + \left[\mathcal{C}\_{33} + \mathcal{C}\_{33\gets}\right]\eta\_{3}(t) + \mathcal{A}\_{33}^{\text{os}}\ddot{\eta}\_{5}(t) + \\ \mathcal{B}\_{35}(\infty)\eta\_{5}(t) + \int\_{0}^{t} \mathcal{K}\_{35}(t-\tau)\eta\_{5}(\tau)d\tau + \left[\mathcal{C}\_{35} + \mathcal{C}\_{35\gets}\right]\eta\_{5}(t) = \mathcal{F}\_{3}(t) \end{aligned} \tag{3}$$ $$\begin{aligned} \left(\mathbf{I}\_5 + \mathbf{A}\_{55}^{\text{co}}\right)\ddot{\eta}\_5(t) + B\_{55}(\infty)\eta\_5(t) + \int\_0^t \mathbf{K}\_{55}(t-\tau)\eta\_5(\tau)d\tau + [\mathbf{C}\_{55} + \mathbf{C}\_{55\mathbb{C}}]\eta\_5(t) + \mathbf{A}\_{53}^{\text{co}}\ddot{\eta}\_3(t) \\ \mathbf{I}\_4 + B\_{53}(\infty)\eta\_3(t) + \int\_0^t \mathbf{K}\_{53}(t-\tau)\eta\_3(\tau)d\tau + [\mathbf{C}\mathbf{s} + \mathbf{C}\_{55\mathbb{C}}]\eta\_5(t) = \mathbf{F}\xi(t) \end{aligned} \tag{4}$$ Added mass values at infinite frequency are dependent on the ship geometry only and can be obtained as the convergence value from the frequency domain added mass graphs. Bij(V) term stands for the constant damping arises from forward speed of the ship. According to Riemann–Lesbesque, Lemma Bij(V) can be replaced with B(∞) [4,13,14]. Restoring coefficients C33, C35, C53, and C55 represent the constant values and they are calculated from ship main properties. Convolution term for the restoring coefficients C33C, C35C, C53C, and C55C are also called radiation restoring terms, represent the correction to the hydrodynamic steady forces acting upon the ship surface and can be calculated as follows: $$\mathbf{C\_{ijC}} = \boldsymbol{\omega\_e}^2 \left[ \mathbf{A\_{ij}^{\rm cs}} - \mathbf{A\_{ij}}(\boldsymbol{\omega\_e}) \right] - \boldsymbol{\omega\_e} \cdot \int\_0^\infty \left[ \mathbf{K\_{ij}}(t) \sin \boldsymbol{\omega\_e} t \right] dt, \text{ i. j.}\tag{5}$$ If regular waves are considered, as in Fonseca and Soares [15], then the CijC will be constant and independent of the encounter frequency. While restoring terms are depending on the ship geometry and mass distribution and are independent of wave frequencies, the radiation restoring coefficient is introduced to accommodate for a correction to the hydrostatic buoyancy force/moments due to the unsteady ship motions. In Fonseca and Soares [16–18] and in Vásquez et al. [19], the radiation restoring and the memory functions are obtained by relating the radiation forces in the time domain and in the frequency domain by means of Fourier analysis. Ma et al. [20] theoretically derived a formulation for radiation restoring coefficient by use of strip theory, and for the considered test cases, it seemed the more consistent formulation. Since the irregular waves are considered in the present study, the effects of radiation restoring are neglected. #### 2.2. Calculation of Convolution Terms Kij(t) is the impulse response function, which can be calculated by Equation (6) for the coupled heave and pitch motions as: $$\mathbf{K}\_{\ddot{\mathbb{I}}}(t) = \frac{2}{\pi} \int\_{0}^{\infty} \left[ \mathbf{B}\_{\ddagger \ddot{\mathbb{I}}}(\omega\_{\mathfrak{e}}) - \mathbf{B}\_{\ddot{\mathbb{I}}}(\infty) \right] \cos(\omega\_{\mathfrak{e}}t) d\omega\_{\mathfrak{e}} \tag{6}$$ where i, j = 3, 5. The damping values Bij(ωe) are found using the 3D panel method implemented in Hydrostar® software by Bureau Veritas, France. Bij(∞) can be obtained as the convergence value from the graphs of damping coefficients as function of the wave frequency. In the present study, three forward speeds are considered, and for each speed, the encounter frequencies are calculated in the range of wave frequencies ω = 0.3 rad/s to 2.1 rad/s. The definite integrals for impulse response functions defined by Equation (6) are calculated for head waves since the encounter frequencies range are sufficiently large, and it covers the following wave frequencies as well. It is noted that once the impulse response functions are calculated for three forward speeds for head waves, these values can also be used for the following wave simulations. For calculation of the convolution integrals in Equations (3) and (4), the following approximation is applied. If the convolution integrals are split into two additional parts, one can obtain the following statements: $$\mathbf{X}\_{1} = \int\_{0}^{t} \mathbf{K}\_{33}(t-\tau)\eta\_{5}(\tau)d\tau + \int\_{0}^{t} \mathbf{K}\_{35}(t-\tau)\eta\_{5}(\tau)d\tau \tag{7a}$$ $$\mathbf{X}\_{2} = \int\_{0}^{t} \mathbf{K}\_{53}(t-\tau) \,\eta\_{3}(\tau) d\tau + \int\_{0}^{t} \mathbf{K}\_{55}(t-\tau) \,\eta\_{5}(\tau) d\tau \tag{7b}$$ As noted in Cakici et al. [8], Equations (7a) and (7b) can be approximated as [21–23] $$\mathbf{X}\_{1} = \sum\_{n=0}^{N} \mathbf{K}\_{33}(n\Delta t) \,\eta\_{3}(t - n\Delta t)\Delta t + \sum\_{n=0}^{N} \mathbf{K}\_{35}(n\Delta t) \,\eta\_{5}(t - n\Delta t)\Delta t \tag{7c}$$ J. Mar. Sci. Eng. 2020, 8, 337 $$\mathbf{X}\_{2} = \sum\_{n=0}^{N} \mathbf{K}\_{\mathfrak{F}3}(n\,\Delta t)\eta\_{\mathfrak{F}}(t - n\,\Delta t)\Delta t + \sum\_{n=0}^{N} \mathbf{K}\_{\mathfrak{F}5}(n\,\Delta t)\eta\_{\mathfrak{F}}(t - n\,\Delta t)\Delta t \tag{7d}$$ where N = <sup>t</sup> 1 <sup>Δ</sup>t, Δt is the time step size t <sup>1</sup> maximum time value, The rule of thumb for choosing the time step and the maximum time value is given by the report of McTaggart [24], formulating $$ \Delta t \approx 0.05 \sqrt{\frac{L}{\mathcal{S}}} \text{ and } t^1 \approx 5 \sqrt{\frac{L}{\mathcal{S}}} $$ These formulations suggest that the time interval Δt should be sufficiently small to capture the variation of retardation function, and the maximum time value t <sup>1</sup> should encompass the time when the retardation functions approach zero. In any case, the maximum time value should be determined according to retardation function plots. #### 2.3. Heave Force and Pitch Moment Calculation To obtain randomized time record of heave force F3(x, t) and pitch moment F5(x, t), first the response spectra of heave force and pitch moment SHF/PM(ωE) are calculated, using the linear superposition principle proposed by St Dennis and Pierson [25] as in Equation (8): $$\mathcal{S}\_{\rm HF/PM}(\omega\_E) = \mathcal{S}\_{\zeta}(\omega\_E) \times \left\| TF\_{\rm HF/PM}(\omega\_{E'} \chi) \right\|^2 \tag{8}$$ where Sζ(ωE) is the encounter wave energy spectrum, in this work JONSWAP spectrum was used; TFHF/PM(ωE, χ) is the transfer function (RAO) of heave force or pitch moment; χ denotes the encounter angle; SHF/PM(ωE) is the heave force or pitch moment response spectrum. According to linear random wave theory, unidirectional and long-crested waves can be expressed by the sum of finite regular wave components. The instantaneous heave force amplitude can be stated as follows: $$F\_3(\mathbf{x}, t) = \sum\_{i}^{N} F\_{3i} \cos(\omega\_{i1} t + \varepsilon\_i + \arg[F\_{3i}(\omega\_{i1}, \chi)]) \tag{9}$$ F3<sup>i</sup> = %2SHF(ωei)Δωei represents the amplitude of i-th heave force component, ωei is the i-th encounter wave frequency; ε<sup>i</sup> is the i-th phase lag, randomly assigned between 0 and 2π. It is noted that once random phase lag is chosen, it will be the same for pitch moment; arg[F3i(ωei, χ)] denotes heave force phase angle. #### 2.4. State Space Representation of Mathematical Model of Vertical Ship Motions To solve the system of equations, the state space representation is used as explained in the following Equation: $$\frac{d}{dt}\eta(t) = \mathbf{A}\eta(t) + \mathbf{B}\_1[\mathbf{w}\text{ave}(t) - \text{convo}(t)]\tag{10}$$ where <sup>η</sup>(t) <sup>∈</sup><sup>n</sup> is the differentiable state vector, wave(t) <sup>∈</sup>mW is the wave load input vector, and convo(t) ∈ mC is the convolution vector. A, B1 are known appropriate state space matrices. The system matrices, disturbance inputs and states of the system are defined as $$\mathbf{A} = \begin{bmatrix} 0 & 0 & 1 & 1 \\ 0 & 0 & 1 & 1 \\ -\mathbf{M}^{-1}\mathbf{C} & -\mathbf{M}^{-1}\mathbf{B} \end{bmatrix}, \mathbf{B}\_1 = \begin{bmatrix} 0 & 0 \\ 0 & 0 \\ \mathbf{M}^{-1} \begin{bmatrix} 1 & 0 \\ 0 & 1 \end{bmatrix} \end{bmatrix}'$$ $$\text{wave}(t) = \begin{bmatrix} \mathbf{F}\_3 \\ \mathbf{F}\_5 \end{bmatrix}, \text{conv}(t) = \begin{bmatrix} \mathbf{X}\_1 \\ \mathbf{X}\_2 \end{bmatrix}, \ \eta(t) = \begin{bmatrix} \eta\_3 \\ \eta\_3 \\ \eta\_5 \end{bmatrix}$$ The statements in the state space matrices are defined as follows: $$\mathbf{M} = \begin{bmatrix} \mathbf{A} + \mathbf{A}\mathbf{3}\mathbf{3}^{\mathrm{op}} & \mathbf{A}\mathbf{3}\mathbf{5}^{\mathrm{op}} \\ \mathbf{A}\_{53}\mathbf{3}^{\mathrm{op}} & \mathbf{I}\_{55} + \mathbf{A}\_{55}\mathbf{5}^{\mathrm{op}} \end{bmatrix}, \mathbf{C} = \begin{bmatrix} \mathbf{C}\_{33} & \mathbf{C}\_{35} \\ \mathbf{C}\_{53} & \mathbf{C}\_{55} \end{bmatrix}, \mathbf{B} = \begin{bmatrix} \mathbf{B}\mathbf{3}\mathbf{3}^{\mathrm{op}} & \mathbf{B}\mathbf{3}\mathbf{5}^{\mathrm{op}} \\ \mathbf{B}\mathbf{5}\mathbf{3}^{\mathrm{op}} & \mathbf{B}\mathbf{5}\mathbf{5}^{\mathrm{op}} \end{bmatrix}.$$ #### 3. Experimental Campaign for Hard Chine Displacement Hull Form #### 3.1. Experimental Setup and Model Description The experimental campaign was performed in the Towing Tank of University of Naples Federico II (UNINA), Italy. The towing tank dimensions are 135 × 9 × 4.2 m and it has a wave generator capable of generating waves from 0.20 /hz to 1.25 Hz and towing carriage with maximum speed of 8 m/s. The simulations are performed for the hard chine displacement hull form, studied in Bertorello and Begovic [11] and shown in Figure 1. Figure 1. Hull form from Bertorello and Begovic [11]. A wooden model of 2.00 m LOA was tested at one displacement (342.17 N) in irregular waves, completing the previously performed experimental campaign in calm water and regular waves in Bertorello and Begovic [11]. The values of main characteristics for the tested model are given in Table 1. Table 1. The main characteristics of the tested model. The model has been ballasted again, and the center of gravity position and moments of inertia were measured by the model inertial balance shown in Figure 2. Figure 2. The model on the inertial balance at the Towing Tank of University of Naples Federico II (UNINA). The towing point was at x = 0.87 m from the stern, and the weight of the mechanical arm is the part of the model ballast. The model scale ratio is λ = 15, which corresponds to 30 m LOA. Measurement of pitch and heave motions were performed by the mechanical arm R47, which holds the model restrained to surge, sway, roll, and yaw. Accelerations were measured at the CG and at the bow. Three ultrasonic wave gauges were used for the wave measurements. Two wave gauges were aligned in the front of the model at the distance of 1.93 m from the R47, and one was aligned with the R47 on the tank side. All data are sampled at a frequency of 500 Hz without filtering. The experimental set up is shown in Figure 3. Figure 3. Experimental setup of low drag hard chine hull at UNINA. #### 3.2. Experiments in Irregular Waves The experiments in irregular head and following waves were performed to validate the hybrid frequency–time domain numerical method. The standard JONSWAP theoretical spectra, defined as $$S\_{\subset -\text{JONSWAP}}(\omega) = A\_{\mathcal{V}} S\_{\text{PM}}(\omega) \mathcal{V}^{\exp\left(\frac{-\mathbb{1}}{2} \left(\frac{\omega - \omega \cdot p}{\omega \cdot \omega p}\right)^{2}\right)}\tag{11}$$ where SPM—Pierson-Moskowitz spectrum, as defined by DNV-RP-C205 [26]; γ—non-dimensional peak shape parameter; σ—spectral width parameter, σ = 0.07 for ω ≤ ωP, σ = 0.09 for ω > ωP; Aγ—normalizing factor, defined as A<sup>γ</sup> = 1 − 0.287 ln(γ); were used for the representation of irregular waves. To obtain enough encounters, the runs were repeated 2–10 times, depending on the model speed and heading. For the head sea, the complete time series is 140 s, resulting in a minimum of 120 wave encounters. In the following sea, due to the very low (or negative) encounter frequency, the total time of experimental series is around 200 s, ending up with a minimum of 30 encounters. The JONSWAP spectrum parameters for model and ship scale are reported in Table 2. The example of the measured spectrum is given in Figure 4, together with the ideal wave and encounter spectra. Experimental set up and tested model velocities were identical to those in regular waves. In Table 3, the number of encounters, significant wave height, and m0 are given for the spectra measured at the following three Froude numbers: 0.2, 0.4, and 0.6 in head waves. Table 2. Wave spectrum characteristics. Figure 4. Ideal wave and encounter vs. measured JONSWAP spectra at Froude number Fr = 0.4. Table 3. Measured spectra properties-head waves. Examples of the time series of 140 s registration of the wave, heave, and pitch at Fr = 0.4 in the head and following seas are given in Figures 5a and 6. These show the appreciated different number of wave encounters, and consequently of heave and pitch oscillations for the same registration time in the head and following sea. In Figure 5b, measured accelerations at center of gravity CG and at the bow are given. In the following waves, the measured accelerations were very low, and the signals were noisy, so for the sake of clarity, these data have been neglected for the further comparisons. It can be noted from Figure 5b that the accelerations are normalized by g, so they oscillate around 1g value. (a) Figure 5. Cont. Figure 5. (a) Example of measured wave, heave, and pitch at Fr = 0.4 in head waves; (b) example of measured accelerations at Fr = 0.4 in head waves. Figure 6. Example of measured wave, heave, and pitch at Fr = 0.4 in the following waves. #### 4. Hydrodynamic Coefficients and Exciting Forces Calculation To be able to calculate motions in the time domain, the hydrodynamic coefficients for added mass and damping and exciting forces are needed as input, and they were obtained by the hydrodynamic software HydroSTAR® developed by Bureau Veritas. HydroStar® is a 3D diffraction/radiation potential theory software based on the Green function method for wave–body interactions, and it provides a complete solution of first- and second-order wave loads. Calculations have been performed in ship scale for the following three Froude number cases: 0.2, 0.4, and 0.6, which correspond to ship speed values of 3.385, 6.77, and 10.155 m/s. For each of the Froude number cases, the frequencies of forward incoming regular waves have been considered in the range from 0.3 to rad/s 2.1 rad/s, with the step of 0.05, corresponding to wave periods of 2 s to 20 s. The panelized hull geometry representation of the model in HydroSTAR® is shown in Figure 7. ( \$ NJ P Figure 7. Hull geometry in Hydrostar® software. For the simulation in the time domain, the following hydrodynamic coefficients and transfer functions TF values have been calculated: All diagrams show ship values as a function of wave frequencies ω (rad/s). The model values, used as input for the time domain simulations, are obtained by applying the scaling law as indicated in Table 4 and taking values at the highest wave frequencies. ( ( Figure 8. Added mass coefficients in the range of considered wave frequencies. Figure 9. Damping coefficients in the range of considered wave frequencies. Figure 10. Transfer function (TF) of heave and pitch exciting force. #### 5. Time Domain Simulations #### 5.1. Numerical Results The simulations with the developed code are performed in model scale to be able to compare the time series directly with the measured data. The added mass and restoring coefficients from Hydrostar® are recalculated in model scale as reported in the Table 4. The values of the added mass coefficients at infinity used in further calculations for retardation functions are reported in the last column of the Table 4. While at the sufficiently high frequencies, added mass coefficients are converging to the same value for all Froude numbers, the values of the damping coefficients at infinity are dependent on the forward speed of the model. In Table 4, for the sake of compactness, only the values for Fr = 0.4 are reported. Retardation function has been calculated for 5 s, with the time step equal to 0.002 s, and an example at Fr = 0.4 is reported in Figure 11. Details of the 30 s of time series of heave force and pitch moment acting on the hull surface calculated according to the realization technique, in head and following waves, are given in Figures 12 and 13. Table 4. Scaling of hydrodynamic coefficients from Hydrostar® to model scale. Figure 11. Impulse response functions for the Fr = 0.4. Figure 12. Detail of wave excitations time series for the Fr = 0.4 in head sea. Figure 13. Detail of wave excitation time series for the Fr = 0.4 in following sea. For the solution, The fourth-order Runge Kutta Method is used, where the time step size is taken as 0.002, and the simulation time has been set equal to 140 s for head waves and 280 s for following waves to have a fair comparison with the experimental data. In Figures 14–19, the examples of comparison of 30 s of simulated and measured time histories of motions and accelerations are given. It has to be noted that this comparison has to be seen only as a qualitative control of simulated data. Both time series are random processes and are given for the same interval of time, without trying to overlap signals. Therefore, they can be compared only statistically. Figure 14. Example of simulated and measured heave motion at Fr = 0.4 in head seas. Figure 15. Example of simulated and measured pitch motion at Fr = 0.4. Figure 16. Example of simulated and measured cg accelerations at Fr = 0.4 in head seas. Figure 17. Example of simulated and measured bow accelerations at Fr = 0.4 in head seas. Figure 18. Example of simulated and measured heave motion at Fr = 0.4 in following seas. Figure 19. Example of simulated and measured pitch motion at Fr = 0.4 in following seas. #### 5.2. Results Comparison Both numerical and experimental results have been analyzed in the time domain "peak to peak analysis." The complete set of performed calculations and experiments are summarized in Table 5. Tables 6 and 7 report the number of peaks in each time series, significant height, 1/10th of the highest value, maximum height value, and mean values. The differences among mean values have been expressed in the last column. It can be noted from Table 7 that calculated vertical accelerations in the following waves are very low, in the same order of magnitude as the measured ones. As the analysis of measured accelerations is strongly related to the filtering technique and cut off frequencies for the case of following waves, they have not been considered in the comparison. Table 5. Summary of performed experiments and simulations. Table 6. Head seas results comparison. Table 7. Following seas results comparison. In Tables 6 and 7 the comparison for head and following seas, respectively, are given. As deduced from Table 6, the differences between numerical and experimental heave-pitch motions at head waves in terms of significant mean values remain in the range of 10% for all tested forward speeds, which indicates that the predicted motions have great level of accuracy when it is compared to experimental data. Only for the accelerations at CG at Fr = 0.2 and bow accelerations at Fr = 0.6 differences are 28% and 18%, respectively. As shown in Table 7, in the case of following waves, the differences between numerical and experimental heave-pitch motions are around 10%, except for Fr = 0.4, where the difference is around 24%. It has to be noted that at this Fr, encounter frequencies are close to zero, which is well known situation where there are theoretical restrictions on damping coefficients. Since this Fr also corresponds to the case in which wave celerity and ship speed are the same, it is expected that linear tools might fail to represent this case. As stated previously, in following waves, both measured and calculated vertical accelerations are very low, in the order of magnitude 0.02g, and therefore, this comparison has not been considered. #### 6. Conclusions In the present work, a hybrid frequency–time domain 2 DOF simulations code is presented. The prediction of the wave loads in the time domain was made by a realization technique from the linear frequency domain calculations by HydroStar® software. Direct computation of the convolution integrals was used for the fluid memory effects. The validation of the method was performed comparing the numerical results with the experimental data for a hard chine displacement hull at three model speeds in irregular head and following waves. Results showed that the applied method for the prediction of vertical ship motions in the time domain is reliable for head and following wave cases. The accuracy of the proposed numerical implementation is dependent on the calculation of the impulse response function, which is, in turn, a function of damping values in the frequency domain. As underlined, a 3D panel method is used in this work. If strip theory is used for the evaluation of damping terms, attention must be taken because there are theoretical restrictions at the low-frequency region that directly affect the impulse response function signal. In this situation, filtering for the frequency dependent damping function may help despite the loss of accuracy. Very challenging validation of the developed method has been performed considering hard chine warped displacement hull, relative ship speed corresponding up to Fr = 0.6, and the following sea at the low and negative encounter frequencies. It has to be highlighted that the calculations in HydroStar® have been performed at the static trim, although at the Fr = 0.6 the dynamic trim is around 1.5 deg and this has been neglected in the calculation of the hydrodynamic coefficients. Obtained results in terms of percentage difference of the mean values is at max 15% in all cases, except in following sea at a model speed close to the wave celerity. In that case, the differences are around 25%. For the following sea, the shorter times of the experimental series and the obvious benefit in using the numerical tool, reasonably accurate, and fast to obtain vertical motions in the time domain in the design procedure should all be noted. Future work will consider the implementation and validation of six DOF methodologies. Author Contributions: Conceptualization, data curation, investigation, methodology, validation, writing—original draft, writing—review and editing, supervision: E.B.; Conceptualization, Data Curation, Investigation, Writing—Original Draft: C.B.; Conceptualization, data curation, methodology, software, validation, writing—original draft, writing—review and editing: F.C.; Formal analysis, software, validation, writing—review and editing: E.K.; Data curation, investigation, writing—review and editing: B.R. All authors have read and agreed to the published version of the manuscript. Funding: Ferdi Çakici and Emre Kahramano ˘glu were supported by the Scientific and Technological Research Council of Turkey (TÜB˙ ITAK). Acknowledgments: The calculation by HydroSTAR® software were possible thanks to the cooperation agreement between Bureau Veritas and the Department of Industrial Engineering of University of Naples Federico II (https://www.docenti.unina.it/webdocenti-be/allegati/materiale-didattico/576434). Conflicts of Interest: The authors declare no conflict of interest. #### References © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).	doab	2025-04-07T04:13:04.621157	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 10 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.11	Article IMO Second Generation Intact Stability Criteria: General Overview and Focus on Operational Measures #### *Nicola Petacco \ and Paola Gualeni Department of Electric, Electronic and Telecommunication Engineering and Naval Architecture (DITEN), University of Genova, 16126 Genova, Italy; [email protected] \* Correspondence: [email protected] Received: 10 June 2020; Accepted: 3 July 2020; Published: 5 July 2020 Abstract: At the beginning of 2020, after a long and demanding process, the Second Generation Intact Stability criteria (SGISc) have been finalized at the 7th session of the International Maritime Organization (IMO) sub-committee on Ship Design and Construction (SDC). At present, SGISc are not mandatory, nevertheless IMO endorses their application in order to assess their consistency and validity. It is envisaged that SGISc can support the design of safer ships, nevertheless such a rules framework might have an impact also on the ship operational aspects in a seaway. In fact, within the SGISc framework, Operational Measures have also been implemented providing guidance and limitations during navigation. After a comprehensive overview about SGISc vulnerability levels and direct stability assessment, this paper provides a specific insight into the methodological approach for the Operational Measures extensively addressed as a complementary action to ship design. Keywords: second generation intact stability criteria; operational guidance; operational limitations; vulnerability levels; direct stability assessment; Ro-Ro ferry #### 1. Introduction The so called Second Generation Intact Stability criteria (SGISc) have been finalized during the 7th session of the IMO sub-committee on Ship Design and Construction (SDC) in 2020. Currently, the criteria are intended not to be mandatory but they received the endorsement of IMO, to be extensively applied in the shipping community. It is foreseen that they need further refinement, but it is expected that SGISc will positively influence the ship design process in the next years. The ship stability performance in waves has been addressed by the SGISc, with specific focus on five dynamic phenomena that is, parametric roll, pure loss of stability, dead ship condition, surf-riding and excessive accelerations. An interesting innovation introduced by the SGISc is the multi-layered approach which defines three assessment levels, characterized by different level of accuracy and therefore conservativeness. Adopting this structure, a designer may choose the kind of analysis to be carried out about the ship stability performance. Moreover, within the SGISc framework, ship operational aspects during navigation have been introduced. It is recognized that, in order to get a safer ship performance, addressing only design aspect cannot be enough. Operational measures should be also taken into account and indications should be provided to the master. For this reason, both Operational Limitations and Operational Guidance have been developed in the SGISc framework. In the following sections, an overview of the development process that lead to the finalized version of SGISc is given. Moreover, all the five stability failure modes have been presented with a brief description of the vulnerability level requirements. Finally, a focus on the Operational Measures defined by the SGISc is provided with considerations about the relevant approach and the possible acceptable scenarios. #### 2. From the Intact Stability Code to the Second Generation Intact Stability Criteria** For a long time, through the Rahola criteria [1] and the Weather criterion [2], until the Intact Stability (IS) code issued at the beginning of the 21st Century, the stability of intact ships in calm water has been one of the main topics in the naval architecture field and in the rule making environment. An exhaustive description of the history of intact stability criteria, from the origin up to the IS code, can be found in References [3,4]. During the discussion about the finalization of the IS code, the need to consider more attentively the physics of what may lead to stability failure has been pointed out. This approach, which is less dependant on database of previous incidents, could guarantee criteria in principle applicable regardless the ship typology, adaptable also for new ship projects but above all able to take into account also the dynamic behaviour of ships due to the presence of waves. In the discussion, the new modality has been often named as a physical approach, implying therefore also the possibility to take into consideration the hydrodynamic aspects of a ship in a seaway condition. Adopting such approach requires an enhanced knowledge of the complex behaviour of ship in a rough sea and of the strong non linearities that might entail even the ship capsizing phenomena [5–8]. The IS code has been finalized in 2008 and the need of performance-based criteria addressing ship stability in a seaway condition has been introduced and highlighted in its text, more precisely within the general provisions of its mandatory part [9] (Part A—Section 1.1). The stability failure modes identified by the IS code are the ones addressed within the new intact stability criteria [10–12] and already previously taken into consideration in some IMO Circulars [13,14]: In the early 2008, during the 51st session of the IMO Sub-committee on Stability and Load lines and on Fishing vessels safety (SLF), an inter-sessional correspondence group was established ad hoc [15] (Section 4.27) with the aim to develop a set of criteria for the above identified stability failure modes. At the 53rd session of SLF in 2010 instead of new generation criteria, it has been proposed the current name of criteria, that is, Second Generation Intact Stability criteria (SGISc). Moreover, the excessive acceleration stability problem was added as a further phenomenon to be addressed in the SGISc framework [16,17]. The framework and the relevant terminology have been identified along with the development of the process for the methodology and the criteria identification. Soon, the task appeared to be complex and the required time for its accomplishment long accordingly. #### 2.1. The Multi-Layered Approach The so called multi-layered approach has been an interesting innovation introduced in the SGISc creation. It consists of a set of criteria, defined for each stability failure, characterized by an increasing level of accuracy, in relation with the layer. This approach assumes three assessment levels: the first two levels, namely the vulnerability assessment levels, are meant to identify ships which could be vulnerable to the stability failure under investigation; conversely, the third level is a purely performance-based direct stability assessment. In addition to what above, also the operational aspects of a ship have been considered within the SGISc framework and relevant assessment approaches to identify Operational Measures have been provided as well. The criteria defined at the first vulnerability level (Lv1), for each stability failure mode, are a simplified check to initially separate roughly vulnerable ships from not vulnerable ones. First vulnerability criteria consist of simple assessments, taking into account few ship geometrical data and loading condition parameters, for example, metacentric height and righting moment in calm water. Second vulnerability levels (Lv2) require the knowledge of more details than Lv1; the phenomena are addressed relying on physics-based approaches taking possibly into account the ship dynamic behaviour in a seaway condition. In the criteria of Lv2, the environmental condition are more detailed as well; therefore a wide set of sea states is processed and a sort of long-term analysis is requested to be carried out. The direct stability assessment (DSA) represents the so called third level of the multi-layered approach. It should predict as close as practically possible the actual ship motions in a seaway condition. It should consist of a non-linear time domain numerical simulations considering at least four degrees of freedom and some of their coupling factors. Model tests ensuring the same level of accuracy can be adopted as well. The DSA therefore is the most accurate, but also the most computationally time-consuming level in the SGISc framework. As a supplementary level, the SGISc introduces some measures acting on the environmental conditions and ship operational aspects—such Operational Measure (OM) respectively are named as the Operational Limitations (OL) and Operational Guidance (OG). The latter is a document containing information and recommendation about ship navigation with the aim to reduce the likelihood of failures. Differently, the OL identify restrictions to the ship operability in relation with specific geographical area and environmental conditions, with the aim to avoid stability failures. The multi-layered structure has been introduced in the SGISc framework with the aim of avoiding unnecessary high computational burden when not necessary, that is, when ships are nor likely to be vulnerable. In the framework, the higher is the level, the more complex is the required analysis. On the other hand, as an inherent consequence, a relevant conservative safety margin is introduced at lower levels. Therefore, the sequential application of levels would be desirable—if a ship is deemed vulnerable by Lv1, the second level criteria should be used in order to understand whether it is really an issue or not; in the case where the ship is also considered vulnerable by Lv2, the DSA should be applied as the last level, as the one characterised by the best possible reliability, before the introduction of operational measures. Nevertheless, the finalized version SGISc deem it acceptable that the user can directly apply any design assessment (Lv1, Lv2 or DSA) or operational measures option (OG or OL), without any hierarchy as the one described above. This allow the user to start the design assessment analysis from the DSA or even to directly move to the operational level and apply OL without performing any design assessment. The simplified scheme of the application logic of SGISc is given in Figure 1. Figure 1. Representation of the simplified application scheme of the application logic in the Second Generation Intact Stability criteria (SGISc) framework. Applying the multilayered approach in a sequential logic (from Lv1 to DSA), it is expected that the higher level gives a more reliable answer in confirming the vulnerability of the ship or in rejecting it. On the contrary, a consistency problem between levels can be identified when a lower level considers the ship not vulnerable while a higher level deems the opposite. In this perspective, during the development of the different criteria for the various vulnerability assessments, concerns about consistency of results rose, especially when Lv1 and Lv2 criteria are compared [18–21]. Most of the issues have been fixed during the refinement of the criteria formulation, even if some consistency problem still remains. In this perspective, failure modes have different evidences, for example, Lv1 and Lv2 for dead ship condition may provide non consistent results or Lv2 for pure loss of stability may appear too much conservative for ship with low freeboard. In order to bypass these consistency issues, the sequential application of the multilayered approach is not binding and the user can take advantage of the criteria support in the way it is deemed as the most appropriate. #### 2.2. Toward the Finalization The SGISc development process has been articulated along the years thanks to the intense work of the inter-sessional correspondence groups and the activity during the sessions of the IMO Sub-Committees in charge (the SDC replaced the SLF after 2013). About four years since the beginning of SGISc development, the first structured draft text of the criteria has been presented at IMO [22] (Annex 1 and Annex 2). Meanwhile, a draft text also of explanatory notes has been drawn up, gathering relevant information about the physics background of each stability failure mode and the criteria formulation [23] (Annex 1–5). After this first milestone, the working group proceeded to develop the guidelines identifying the fundamental features of the numerical tool required for an appropriate DSA. The Sub Committee instructed the correspondence group to develop the DSA procedures separately for each stability failure. The first version of the Guidelines for Direct Stability Assessment have been presented at the 1st SDC session in 2014 [24] (Annex 27). Between the 5th and 6th session of SDC, the consolidated version of the vulnerability level criteria has been finalized as well as the DSA guidelines. Also the Operational Measures has been put in the final form in the same very intense period by the inter-sessional correspondence group. Eventually, as an epochal moment, the final version of the Guidelines on the second generation intact stability criteria has been adopted at the 7th session of SDC [25]. A further step still needed is to complete the explanatory notes; this activity is intended to be carried out within the next SDC sessions. The SGISc have been issued as a complementary analysis aside the mandatory criteria defined in the part A of IS code. The Guidelines will be kept under review for a trial period during which the stakeholders are encouraged to provide feedback on SGISc application on existent and new ships. In the Guidelines is clearly stated that SGISc are not intended to be used instead of the existing mandatory criteria. #### 3. Details about Design Assessment As stated above, SGISc address pure loss of stability (PLS), parametric rolling (PR), surf-riding (SR), dead ship condition (DS) and excessive accelerations (EA). In this section, a brief description of the physics behind each phenomenon and the requirements of each criterion is given. The final version of vulnerability levels and DSA for SGISc, as approved at 7th session of SDC, can be found in Reference [25] (Chapters 2–3). #### 3.1. Restoring Arm Variation Due to Waves This phenomenon is related to the interaction between the hull geometry and the encountered wave profile. When a longitudinal wave having a length comparable to the ship length encounters a vessel, variations of waterplane area and immersed volume distribution are registered. This has an effect on the ship restoring capability. The worst case happens when the wave crest is located amidships entailing a righting arm decrease that, in comparison with the one in calm water, can be quite critical. The opposite happens when the wave trough is amidships: in this case the effect is a strengthening of the righting moment. This phenomenon may lead to two different stability failures, that is, pure loss stability and parametric rolling. The typical scenario, that better characterizes PLS, considers a longitudinal wave as long as the vessel, approaching from stern with a celerity just faster than the ship speed. In this situation, the wave takes a long time to pass the vessel and the critical situation, with the wave crest amidship, lasts considerably decreasing the stability performance for a not negligible time. PR can happen when the ship interacts with a train of waves having the length comparable to the ship length and an encounter period that is half of the ship natural roll period. The typical scenario for PR can be depicted as follows: when the ship is far away from its upright position and the wave trough is amidships, the righting arm is "stronger" and therefore the ship is vigorously pushed back to the upright position. When the ship is in the upright position, the wave crest has already moved amidship. In this condition, the righting moment is "weaker" and the ship rolls to an even larger heel angle on the opposite side. If the wave trough moves again amidships when the maximum heel angle on the opposite side is reached, the cycle starts again leading to heel angles larger and larger. #### 3.1.1. First Vulnerability Levels for PLS and PR First levels for PLS and PR assess the metacentric height variation due to the wave profile with a very simplified formulation. Both the levels evaluate an upright hydrostatics at the draft of the specific wave trough. PR requires also an additional hydrostatics at the draft of the wave crest of the same specific wave. The wave characteristics are a length equal to the ship length and a steepness factor of SW = 0.0334 (−) for PLS and SW = 0.0167 (−) for PR. The assessed loading condition of a ship is not judged vulnerable to PLS when condition (1) is verified. $$GM\_{\min} \ge 0.05 \, (\text{m}),\tag{1}$$ where GMmin is the metacentric height calculated for the hydrostatics at the drafts defined above. The assessed loading condition of a ship is not judged vulnerable to PR when condition (2) is verified. $$\frac{\Delta GM\_1}{GM} \le R\_{PR\_1} \tag{2}$$ where GM is the metacentric height in calm water for the considered loading condition; ΔGM<sup>1</sup> is defined as ITH <sup>−</sup>ITL <sup>2</sup>·∇ ; <sup>∇</sup> is the immersed volume; ITH and ITL are the transverse moment of inertia of the waterplane located respectively at the drafts corresponding to the wave crest and the wave trough. The standard RPR is defined as a function of breadth, length, amidship coefficient and the bilge keel projected area; it ranges from 0.17 (−) to 1.87 (−). Moreover, both criteria consider a ship vulnerable if the condition (3) is not verified. $$\frac{\nabla\_D - \nabla}{A\_W \cdot (D - d)} \ge 1.0.\tag{3}$$ #### 3.1.2. Second Vulnerability Levels for PLS and PR The structure of second vulnerability levels is very similar among all the stability failure modes addressed within the SGISc framework. A sort of long-term analysis is undertaken, based on the wave scatter diagram of North-Atlantic ocean, as shown in Equation (4). This analysis implies at first a short-term assessment for each sea state, which is different for the various stability failure modes. $$C = \sum\_{H\_S} \sum\_{T\_Z} C\_S \cdot \mathcal{W}(H\_S; T\_Z). \tag{4}$$ Second vulnerability level for PLS judges a ship not vulnerable if condition (5) is verified. $$\max\{\mathcal{CR}\_1; \mathcal{CR}\_2\} \le R\_{PL0\prime} \tag{5}$$ where RPL<sup>0</sup> = 0.06 (−); CR<sup>1</sup> and CR<sup>2</sup> are the long-term indexes evaluating respectively the capsizing angle in waves and the static equilibrium heel angle under the action of a heeling lever lPL<sup>2</sup> considering the restoring moment in waves. The wave to be considered are obtained by filtering the wave scatter diagram by means of the Grim's wave theory [26,27]. Second vulnerability level for PR considers a ship not vulnerable if condition (6) is verified. $$\mathbb{C}\mathbf{1} \le \mathbb{R}\_{PR1} \quad \text{or} \quad \mathbb{C}\mathbf{2} \le \mathbb{R}\_{PR2} \tag{6}$$ where RPR<sup>1</sup> = 0.06 (−); RPR<sup>2</sup> = 0.025 (−); C1 and C2 are the long-term indexes. The first long-term index takes into account the actual GM variation in waves evaluated for 16 different waves defined within the criterion. The long-term index C2 needs a 1-DoF model able to reproduce roll motions when the ship interacts with longitudinal waves. The waves required by the latter analysis are obtained as specified in the second level criteria for PLS. #### 3.2. Manoeuvring-Related Stability Failure Manoeuvring-related stability problems are those referring to the broaching-to and surf-riding stability failure modes. These phenomena are strictly linked, in fact, broaching is preceded by surf-riding as studied in References [28,29]. Broaching-to can be defined as a sudden and uncontrollable turning despite the opposite action of the rudder to counter act it. This phenomenon may lead to large heel angle and even the capsizing. Instead, the surf-riding happens when a quartering waves with specific characteristics reaches the vessel and accelerates it at the wave celerity. In this condition most of the ships are directionally unstable, thus broaching-to may occur. In light of this relation between broaching and surf-riding, the developed criterion assess ship vulnerability to the latter in order to prevent broaching-to. Surf-riding phenomenon may develop when the ship speed is comparable to the wave celerity and the wave length is about one to three times the ship length, together with a wave steepness great enough to generate a sufficient wave surge force. Surf-riding is characterized by two ship speed thresholds. A ship is affected by the surge motion when the speed is below the first threshold and SR cannot happen. In this condition, a vessel is accelerated by the front part of the approaching wave and then it is decelerated by the back part of the passing wave. Over the first speed threshold surf-riding may occur only under a specific condition. This condition depends mainly on the relative position between the ship and the wave crest. Finally, when the ship speed overreaches the second threshold, SR occurs under any condition. Due to the relative high speed of the vessel, the wave having the above mentioned characteristics trigger the surf-riding regardless the relative position between the ship and the wave crest. #### 3.2.1. First Vulnerability Level for SR First vulnerability levels for SR is made up of a very simple assessment. A ship is judged not vulnerable if relations (7) are verified. $$L \ge 200 \, (\text{m}) \quad \text{or} \quad \text{Fn} \le 0.30 \, (-), \tag{7}$$ where L is the ship length and Fn is the Froude number at the service speed. #### 3.2.2. Second Vulnerability Level for SR The second vulnerability level for SR adopts the same structure defined in condition (4) as a long-term assessment. A ship is judged not vulnerable to SR if condition (8) is verified. $$ \mathbb{C} \le \mathbb{R}\_{SR} \tag{8} $$ with RSR = 0.005 (−). For this stability failure mode the short-term index is evaluated as defined in Equation (9). $$\mathbb{C}\_{\mathcal{S}}(H\_{\mathcal{S}}; T\_{\mathcal{Z}}) = \sum\_{i=0}^{N\_{\lambda}} \sum\_{j=0}^{N\_{\mathfrak{a}}} w\_{ij} \cdot \mathbb{C} \mathbf{2}\_{ij\prime} \tag{9}$$ where wi,<sup>j</sup> is a statistical weighting factor calculated with the joint distribution of local wave steepness and lengths; C2i,<sup>j</sup> is a coefficient as a function of the critical Froude number and the service ship speed. The coefficient C2 is evaluated by an iterative procedure where the equilibrium among ship resistance, propeller thrust and wave surge are pursued. #### 3.3. Dead Ship Condition The stability problem related to the dead ship condition is already addresses by the so called weather criterion included in the IS code. Moreover, the MSC.1 Circular 1200 [30] has been issued by IMO during the IS code revision, introducing alternative assessment procedure for the weather criterion. All the same, it has been decided to address this stability failure mode in the SGISc framework adopting a more precise physical-based analysis. The typical scenario of DS considers a ship which has lost its power and it is rolling under the action of wind and waves, usually turned in beam seas. The ship is assumed to be inclined leeward while rolling under the combined effect of wind and waves. In this situation, a sudden wind gust acts on the vessel when it is at the maximum windward roll angle. The criterion is aimed to assess the acceptable value of the dynamic angle of equilibrium under this circumstances. #### 3.3.1. First Vulnerability Level for DS First vulnerability criterion for DS embeds the Severe wind and rolling criterion known as the weather criterion and defined in Reference [9] (Chapter 2). It differs only for the table of wave steepness factor, which is replaced by the extend version introduced in Reference [30]. The weather criterion is an energy-based model where the energy balance between the wind action and the righting moments is assessed. #### 3.3.2. Second Vulnerability Level for DS The second vulnerability level for DS adopts a different approach with respect to the first level. Often, this is the origin of some inconsistency issues between the two levels. The Lv2 criterion relies on a dynamic-based method where the environmental condition and the ship characteristic parameters are modelled by means of a 1-DoF computational tool. This kind of analysis has to be carried out for each sea state defined in the wave scatter diagram. As a result of this dynamic assessment a short-term index is obtained. Also in this case, a long-term analysis is carried out according to condition (4). A ship is judged not vulnerable if condition (10) is verified. $$C \le R\_{DS0\prime} \tag{10}$$ where C is the long-term index and RDS = 0.06 (−) is the standard threshold. #### 3.4. Excessive Acceleration The EA stability failure mode has been introduced in the SGISc assessments after a list of casualties had been submitted to IMO consideration. In particular, this problem usually involves vessels sailing in ballast condition having high values of metacentric height. The scenario considered in the formulation of EA criteria entails the ship rolling under the action of pure beam seas in the zero-speed condition. Looking at a selected point located on board, the higher is the vertical distance from the roll axis, the longer is the shift to be covered in a half roll period. Since the angular roll velocity is constant along the whole ship, the highest point has the fastest linear velocity in order to cover in the same time a longer distance. Since every half roll period the roll motion changes its direction, also the linear velocity direction changes and this leads to a linear transverse acceleration. The faster is the linear velocity change, the larger is the transverse acceleration due to roll motion. With reference to the close relationship between the roll period and the metacentric height, if the latter is higher the roll period is shorter and in turns this implies that large transverse acceleration may occur during roll motion. Transverse acceleration is very dangerous onboard, both for the cargo and the crew members. Beside seasickness, it may cause loss of balance, fall or even being thrown against bulkheads or furniture. The same for the cargo, which may fall outboard or get damaged. #### 3.4.1. First Vulnerability Level for EA A ship is judged not vulnerable to EA according to Lv1 if condition (11) is verified. $$ \varrho \cdot k\_L \cdot \left( \lg + 4\pi^2 \cdot \frac{h\_r}{T\_{roll}^2} \right) \le R\_{EA1\prime} \tag{11} $$ where REA<sup>1</sup> = 4.64 (m/s2) is the standard; ϕ is the characteristic roll amplitude; kL is a coefficient taking into account simultaneous action of roll, yaw and pitch motions; g is the gravity acceleration; Troll is the roll period and hr is the vertical distance between the roll axis and the highest point where crew or passenger may be present. #### 3.4.2. Second Vulnerability Level for EA The second vulnerability level for EA requires to perform a long-term analysis as defined in condition (4). The short-term index to be considered is given in Equation (12). $$\mathcal{C}\_S = \exp\left(-\frac{R\_2^2}{2\sigma\_{LA}^2}\right),$$ where R<sup>2</sup> = 9.81 (m/s2) and σLA is the standard deviation of the lateral accelerations at zero speed in a beam sea. The short-term index CS represents the probability to exceed a specified lateral acceleration. #### 3.5. Direct Stability Assessment: Requirements & Methodology The DSA can be considered the third level of assessment and it represents the most reliable approach able to evaluate ship stability performances in a seaway condition. Nevertheless, due to the complexity of the investigated phenomenon (i.e., dynamic behaviour of a ship in a seaway), its satisfactory formulation and implementation is challenging. To this regard, significant steps forward have been made in latest years, with promising results [31,32]. The DSA has been conceived to enable the measurement of the level of safety in terms of average stability failure rate, namely the probability that the stability failure event may occur over a specified period of time. As concern the SGISc framework, the failure event is defined as either the exceedance of roll angle or the exceedance of lateral acceleration. The former is defined as the minimum value among 40◦, the capsizing angle or the downfloading angle, all evaluated in calm water. The considered acceleration should be evaluated at the highest point on board the ship where crew members and/or passengers may be present, the threshold should be compliant with 9.81 (m/s2). The procedure for the DSA can be split in two main parts: the methodology able to reproduce reliable ship motions in a seaway, even at very large heel angles, and the post-processing procedure. Detailed specifications and requirements about DSA can be found in the Guidelines for direct stability assessment [25] (Chapter 3). #### 3.5.1. Prediction of Ship Motions The method to adequately model and predict ship motions can be done either by a numerical tool, a model test or a combination of them. Whichever is the selected method, it should be able to reproduce the ship motions in irregular seas. Depending on the investigated stability failure, the direct assessment tool should replicate identified degrees of freedom in the time domain simulation, considering coupling factors among motions. In Table 1, required degrees of freedom to be modelled during the simulation for each stability failure mode are given. In the guidelines, the requirements for the numerical tools are defined as well as how to model the roll damping coefficient, forces and moments acting on the hull. In order to comply with the necessary qualitative and quantitative validations, the numerical tool could be calibrated by means of model tests. The qualitative validation should ensure that the numerical tool is able to reproduce the physics of the stability failure mode considered. The quantitative validation should ensure the degree of accuracy the software is capable to reproduce the stability failure mode. As concern the prediction of ship motions, it is worth mentioning that it is sufficient to be validated only for the phenomenon considered. Therefore, the validation of numerical tool is failure-mode specific. Table1.Degreesoffreedomrequiredinthesimulationofparticularstabilityfailuremodes. thosedegreesoffreedomnotincludedinthedynamic modelling,staticequilibriumshouldbeassumed. Hydrodynamical forces due to vortex shedding should be properly modeled. Surf-Riding/Broaching-to X X For - X - X #### 3.5.2. Post-Processing of Results Within the so called post-processing procedure, the estimation of the likelihood that a stability failure may occur is to be calculated. The Guidelines for DSA define three different approaches for such activity: The first method reproduces as accurately as possible the actual ship operative life, considering every combination of sea states, ship speeds and headings. The criterion is the estimate of the mean long-term stability failure rate, which is calculated as the average over all the combinations that have been simulated. All the stability failures, except for DS, should be simulated considering the heading ranging uniformly from 0◦ to 180◦ as well as the ship forward speed should be distributed from zero to the maximum speed. For the DS stability failure, simulations should be carried out considering beam seas and zero speed condition. Since stability failures may be rare, the full probabilistic method requires additional effort in the solution of the problem of rarity, especially when the mean time to failure is very long with respect to the ship natural roll period. In order to circumvent this issue, methods relying on a selection of assumed design situations have been introduced. The assumed design situations are specifically defined for each stability failure mode, addressing the wave directions, ship speeds and wave periods to be considered in the simulation. Introducing these constrains, the amount of simulations and their duration is notably decreased. The assumed design situation can be assessed with either probabilistic or deterministic criteria. The probabilistic criteria takes into account the maximum stability failure rate over all the simulations for the considered failure mode. To reduce further the simulation time, the deterministic criterion takes into account the greatest mean three-hour maximum roll amplitude or lateral acceleration. Because of the large level of inaccuracy introduced by the deterministic procedure, an additional margin has been added in the selection of the standard: the thresholds have been halved. In addition to the specifications and requirements for the assessment procedures described above, in Reference [25] (Chapter 3) judging criteria are reported as well, to verify whether the failure recorded during a simulation can be considered as the failure mode for which the numerical tool is validated. Since the validation of the numerical tool or model test procedure is failure-mode specific, for each phenomenon a set of different criteria is provided in the Guidelines for DSA. #### 4. An Overview on the Operational Measures It is recognised that safety cannot only be a matter of ship design. To enhance the level of safety of a vessel in a seaway condition, an approach complementary to the ship design is required, as is also recognised in References [33,34]. This can be implemented with operational measures provided to the master, suggesting the safest behaviour in handling ship navigation for specific environmental conditions. It is worth pointing out that, however, when a vessel or a specific loading condition are affected by too many operational restrictions, it means that a refinement of the ship design is needed. Considering the framework of SGISc, the OM have been categorized in two typology — Operational Limitations and Operational Guidance. #### 4.1. Operational Limitations Operational Limitations define operational limits to the navigation, for a specific loading condition, delimiting the environmental condition. The environmental condition may be limited by the OL with two restriction typologies. The first typology is related to the geographical areas where the ship sails (i.e., sheltered water, specific sea area and route) or it can be a seasonal limitation when the likelihood of stability failure is higher. This kind of limitation is called in the IMO document as Operational limitations related to areas or routes and season. The second OL typology is related to the significant wave height that the vessel is able to safely cope with during navigation. It is named Operational Limitations related to maximum significant wave height by IMO document. OL need an assessment tool in order to be identified, for example, vulnerability levels or direct stability assessment. For this reason, OL may be considered a tool able to tune the considered operational profile in the design assessment. This concept is facilitated by the modularity structure of the SGISc which are formulated to easily introduce modifications to selected methodologies or boundary conditions. Therefore, OL should be considered as a complementary instrument to the assessment process and not as a stand-alone assessment tool. A graphical representation of this concept is proposed on Figure 2. Figure 2. Scheme of the logical concept for Operational Limitations (OL). In the SGISc, the environmental conditions can be modified by directly acting on the wave scatter diagram which is considered for the evaluation of the long term stability failure rate for each phenomena. Possible restrictions are aimed to reduce at an acceptable level the risk that a stability failure event occurs in a seaway. As regards the OL related to the geographical area, the whole scatter diagram is replaced accordingly, thus, real time weather forecasts are not required for this restrictions. On the contrary, OL related to the significant wave height modify the wave scatter diagram cutting-off sea states having a significant wave height greater than the selected threshold. The obtained scatter table is named limited scatter table. This limitation implies that detailed weather forecast, including significant wave heights, must be available to the master in real time, in order to avoid the limited sea states. Interesting applications of OL have been presented in References [35,36]. #### 4.2. Operational Guidance The Operational Guidance defines all the situations that are not recommended or should be avoided for each sea state during the navigation. An assumed situation represents the combination of ship operational parameters, such as ship speed and wave encounter heading (i.e., sailing condition) together with the environmental characteristics, that is, significant wave height, zero-crossing wave period, wind direction and gust characteristics. OG defines a set of operative information that support the master in the ship navigation for determined sea states. Following the suggestions of OG, the rate of a stability failure is decreased to an acceptable level. Since the OG is drawn up during the design phase, it is important that guidance addresses all the possible sea states the ship might encounter in relation with the area of navigation. As required for the OL related to the wave height, OG can be fully used only if weather forecast are available on board. In particular, detailed sea state information are beneficial for the master to plan the safest sailing condition (i.e., ship speed and heading) according to the OG. In the SGISc framework, three different approaches have been defined in order to prepare the OG for each loading condition. They differ for the methodology which predicts the stability failure rate. According to their accuracy, an appropriately conservative threshold is introduced in order to guarantee the same level of safety. The three OG approaches are the following: The simplified OG are based on simple methodologies such as those introduced in the vulnerability levels. The other two approaches share the same method adopted in DSA, that is, a model test or a numerical calculation tool able to reproduce ship motions in the time domain with at least three degrees of freedom, considering coupling factors and necessary non linearities in irregular seas. More precise technical requirements for these methodologies are given in Reference [25] (Chapter 4). As a consequence of the requirements briefly described above, OG can be considered an additional assessment level independent from the design assessment (i.e. Lv1, Lv2 and DSA). Although it may share the same methodology, OG can be directly performed without assessing the ship vulnerability for a specific stability failure with another assessment tool. This concept is schematically represented in Figure 3. Figure 3. Scheme of the logical concept for Operational Guidance (OG). #### 4.3. Acceptance of Operational Measures Because of their different concept, OG and OL can be combined together with a multiple choice of combinations. The number of possible cases increases even more when also the design assessments are taken into account. Therefore, a single loading condition can be deemed acceptable according to a set of options defined in Reference [25] (Section 4.4). These configurations have been enumerated below and gathered in Figure 4. geographical area), while the remaining stability failure have been accepted with unrestricted operation, that is, without any kind of restrictions. A schematic representation of all possible cases is proposed in Figure 5. Design assessment made up of vulnerability levels (Lv1 and Lv2) and the DSA is represented. The OG and the OL are evidenced as well. The latter is divided in two sub-domains making reference to the two typologies of limitations (i.e., those related to the significant wave height and to a specific area or route and season). The number in the square stands for the possible configuration, while the arrows indicate which tools are combined in it (i.e., design assessment, operational limitation or operational guidance). Looking at the graph, it is possible to point out that only design assessment and OG may exist alone (configuration 1 and 3) while this is not true for the OL. Figure 4. Summary table of each possible configuration of Operational Measure (OM). (1) Unrestricted operation; (2) Limited operation; (3) operation using onboard OG; (4) operation in a specified area or in a specified route during a specified season; (5) limited operation in a specified area or in a specified route during a specified season; (6) operation using onboard OG in a specified area or in a specified route during a specified season. It is important to highlight that operational guidance may indicate as safe some sailing conditions in relation to the roll motion disregarding other technical aspects, for example, limits of propulsion and steering systems, excessive vertical loads as well as slamming. This should be taken into account in order to avoid misleading OG that can jeopardise vessel navigation because of other problems. For example, sometimes transverse excessive accelerations can be reduced with increasing forward ship, but high speeds cannot be reached in some sea states or may lead to larger vertical motions and slamming. Figure 5. Graphical representation of all configuration of OM. (1) Unrestricted operation; (2) Limited operation; (3) operation using onboard OG; (4) operation in a specified area or in a specified route during a specified season; (5) limited operation in a specified area or in a specified route during a specified season; (6) operation using onboard OG in a specified area or in a specified route during a specified season. #### 5. An Example of Application and Results In order to appreciate the effectiveness of vulnerability levels and operational limitations, an application to a representative Ro-Ro pax ferry is given in this section. In particular, pure loss of stability, dead ship condition and excessive acceleration have been analysed. Principal vessel dimensions are shown in Table 2. In this analysis four drafts have been considered as representative of the most common loading conditions, that is, Departure and Arrival condition considering loaded on board only trucks or only cars. For the EA assessment, the highest point where people may be present is located in x = 169.8 (m) and z = 34.0 (m). For the DS assessment, the considered lateral exposed surface is about AL = 5400 (m2). Table 2. Ro-Ro pax ferry main dimensions. Results are presented in terms of vertical position of center of gravity (KG) limiting curves, as shown in Figures 6–8. It is worth to note that results for EA are given by minimum KG curves. Drafts are presented on the horizontal axis, while the limiting KG are on the vertical axis. In each graph, the limiting curves obtained by the application of Lv1, Lv2, Lv2 with a limitation on the significant wave height and Lv2 with a limitation on the geographical area are shown. The first OL set an admissible significant wave height of HS = 7.5 (m), while in the second limitation the unrestricted navigation has been replaced by a navigation confined in the Mediterranean sea. The design domain is defined as the area below the maximum KG limiting curve (vice-versa for the minimum KG limiting curve due to EA), where the design centre of gravity of the ship may be placed safely. Outcomes point out that there is a significant difference in terms of design domain between first and second vulnerability levels. As expected, this is due to the caution factor inherent with the structure of first levels. Looking at the application of OL, it seems that no noticeable effect of these restrictions are evident on the second vulnerability level of DS. OL increases the design domain for PLS and EA; in particular for this vessel, the restriction on the geographical area gives the greatest improvement in term of KG domain range. Figure 6. Vulnerability assessment in terms of maximum KG limiting curve for the pure loss of stability failure mode. Curves obtained according to the results for the application of Level 1, Level 2, Level 2 for North Atlantic Ocean limited to HS = 7.5 (m) and Level 2 for Mediterranean. Figure 7. Vulnerability assessment in terms of maximum KG limiting curve for the dead ship failure mode. Curves obtained according to the results for the application of Level 1, Level 2, Level 2 for North Atlantic Ocean limited to HS = 7.5 (m) and Level 2 for Mediterranean. Figure 8. Vulnerability assessment in terms of minimum KG limiting curve for the excessive acceleration failure mode. Curves obtained according to the results for the application of Level 1, Level 2, Level 2 for North Atlantic Ocean limited to Hs = 7.5 (m) and Level 2 for Mediterranean. #### 6. Conclusions An overview of the SGISc has been outlined, comprehensive of the first and second vulnerability level criteria (Lv1 and Lv2), the so called direct stability assessment and the Operational Measures that in turn are inclusive of Operational Limitations and Operational Guidance. Graphical representations to better describe the mutual relation among the whole set of different rules have been provided, able to deliver the complex SGISc framework at a glance. The set of rules is the results of a very innovative trade off on different domains: • Physically based modelling and formulation; The point of strength of SGISc is the ability to introduce into the stability assessment the dynamic interactions of the ship with the environment. Nevertheless, it is to be demonstrated now that such set of rules is really and effective asset to design and operate safer ships. The calculation burden and procedure complexity in some cases are really demanding and the sensitivity of results to significant design and operational parameters is to be investigated. Therefore an intensive application campaign of this innovative set of rules is encouraged by IMO in order to possibly improve the SGISc in terms of formulations, procedures and standards. As an example, the vulnerability assessments for pure loss of stability, dead ship condition and excessive acceleration modes have been presented; operational limitations in terms of maximum significant wave height and geographical area have been further investigated as well. Outcomes show how in this case, the consistency of the multilayered philosophy has been respected between levels of the same stability failure mode. Nevertheless, the application of OL for the dead ship failure mode shows how the influence of this option is very limited compared to other stability failure modes. For this case study, SGISc do not imply any severe constrains to the design of the vessel. The application of OL was actually not needed for the analysed vessel, although it shows that introducing restrictions—with a relatively low-impact on the operative life of a ship (i.e., maximum admissible wave height equal to 7.5 (m))—may further enlarge the design domain available to the designer. Furthermore, a proper integration of design modifications with operational measures may lead to an improvement of ship safety without any significant issue on the project. In any case, the study and definition of OG as a support to the master represents a significant aid to the navigation. It becomes an important tool to be complemented with the master experience at sea, with the aim to further improve the ship safety performance. Author Contributions: Conceptualization, N.P. and P.G.; Software, N.P.; Supervision, P.G.; Writing—original draft, N.P.; Writing—review & editing, P.G. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest during preparation and publishing of this work. #### Abbreviations The following abbreviations are used in this manuscript: #### References © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).	doab	2025-04-07T04:13:04.623357	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 11 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.12	Article Seakeeping Performance of a New Coastal Patrol Ship for the Croatian Navy Andrija Ljulj <sup>1</sup> and Vedran Slapniˇcar 2,\* Received: 9 June 2020; Accepted: 12 July 2020; Published: 15 July 2020 Abstract: This paper presents seakeeping test results for a coastal patrol ship (CPS) in the Croatian Navy (CN). The full-scale tests were conducted on a CPS prototype that was accepted by the CN. The seakeeping numerical prediction and model tests were done during preliminary project design. However, these results are not fully comparable with the prototype tests since the ship was lengthened in the last phases of the project. Key numerical calculations are presented. The CPS project aims to renew a part of the Croatian Coast Guard with five ships. After successful prototype acceptance trials, the Croatian Ministry of Defence (MoD) will continue building the first ship in the series in early 2020. Full-scale prototype seakeeping test results could be valuable in the design of similar CPS projects. The main aim of this paper is to publish parts of the sea trial results related to the seakeeping performance of the CPS. Coast guards around the world have numerous challenges related to peacetime tasks such as preventing human and drug trafficking, fighting terrorism, controlling immigration, and protecting the marine environmental. They must have reliable platforms with good seakeeping characteristics that are important for overall ship operations. The scientific purpose of this paper is to contribute to the design process of similar CPS projects in terms of the development of seakeeping requirements and their level of fulfillment on an actual ship. Keywords: coastal patrol ship (CPS); full-scale seakeeping trials; ship design #### 1. Introduction #### 1.1. Literature Review Full-scale ship sea trials are the most important test of a ship's structure, equipment, and crew in order to prove its security, reliability, and operational capability. In principle, a ship's trials should provide the final check of the adequacy of theoretical and experimental predictions of ship behavior [1]. Ship trials are carried out for a variety of reasons, including to: Ship seakeeping design predictions are based on numerical analyses and model tests that are conducted in model tanks. Validation, using full-scale experimental data, is essential to the development of a ship's motion prediction code [2]. Reference [2] presents validations of ship motion predictions using model tank tests and full-scale sea trials for a Canadian naval destroyer. Full-scale trials are considered crucial because they include physical phenomena lacking in model tests due to oversight or scaling effects. The results of full-scale seakeeping trials on several ships, including the Dutch naval destroyer "HM Groningen" are described in [3]. The main goal of these tests was to compare full-scale test results with numerical predictions that had been developed. It was noted that suitable conditions at sea are hard to find, or that the measuring or analyzing methods were not sufficient for correlation purposes. A new experimental methodology to accurately predict wave-induced motions and load responses of ships was proposed in [4]. It is based on self-propelled large-scale model measurements that were conducted in natural environmental conditions. Onboard systems, operated by the crew, were used to measure and record sea waves and the responses of a model. A post-voyage analysis of the measurements, both of the sea waves and the model's responses, was conducted to predict the ship's motion and short term load responses to a corresponding sea state. The results of extensive full-scale seakeeping trials of an all-weather lifeboat, conducted by the Royal National Lifeboat Institution in collaboration with Newcastle University and Lloyd´s Register, are shown in Reference [5]. The trials investigated the seakeeping behavior of the craft in real operational conditions. Patrol vessels must have good performance criteria for seaworthiness, and an analysis of the hydrodynamic aspects of a ship's design is one of the designer's primary tasks [6]. This analysis describes ship motion and ship resistance. The seakeeping tests conducted two variations of a ship loading condition and involved two sea states, namely the World Meteorological Organization (WMO) sea states 3 and 4. In [7], the stern boat deployment system was investigated to evaluate the capability of launching and recovering a rigid hull inflatable boat (RHIB) via the stern ramp. The seakeeping characteristics required for the successful operation of a mother ship and inflatable boat were analyzed. #### 1.2. Paper Content and Main Particulars of the Coastal Partrol Ship This paper presents the seakeeping requirements for a coastal patrol ship (CPS) for the Croatian Navy (CN) and the results of the full-scale seakeeping performance of the ship. The seakeeping requirements are based on Reference [8], which presents the seakeeping criteria for the reference ship, a frigate-size vessel. Because the CPS is a significantly smaller ship, the requirements are downsized accordingly, and presented in Section 2. The seakeeping requirements are composed of: the motion criteria of the ship (roll, pitch); vertical and lateral accelerations at significant positions on the ship; propeller emergence; deck wetness; slamming; and relative vertical motions of the edge of the ship stern. Full-scale trials were conducted during the acceptance of the ship, and the corresponding above-mentioned criteria were applied. After the ship was accepted by the CN, the prototype sea trials were conducted. The purpose of these tests was to check the utmost capabilities of the ship on higher sea states and see how those conditions affect the ship's hull, machinery, other equipment, and the crew. The results of full-scale trials are presented in Section 4. The main CPS particulars are shown in Table 1. The seakeeping numerical prediction and model tests were done during preliminary project design, but these results are not comparable with the full-scale tests since the ship was significantly changed in the last phases of the project (e.g., lengthened). The general arrangement and body plan of the CPS are shown in Figures 1 and 2. The main tasks for the new coastal patrol ship are to conduct: - Low enforcement at sea; - Protection of fishing; - Control and prevention of possible ecology incidents; - Combat against terrorism; - Trafficking of people and narcotics; #### 3. Tasks during wartime [9]. Table 1. The main coastal patrol ship (CPS) particulars. Figure 1. General arrangement of the CPS. Figure 2. Body plan of the CPS. #### 2. Seakeeping Requirements Seakeeping requirements are based on Reference [8], and are reduced to suit the CPS size. Following Reference [9], the CPS should be fully operational at mid sea state 4 (H1/<sup>3</sup> = 1.8 m) following the WMO scale, but not including the launch and recovery of the RHIB. Launch and recovery of the RHIB should be feasible at sea state 3 (H1/<sup>3</sup> = 1.25 m–WMO) and with the CPS sailing at least 5 knots with heading waves. The CPS should be partially operational up to sea state 5 (H1/<sup>3</sup> = 3.1 m–WMO) including sailing in a manner suitable for surveillance, monitoring the operational situation, and reporting. The requirements also include survivability of the CPS on the highest sea state observed on the Adriatic Sea. Other specific seakeeping requirements are shown in Table 2. Table 2. Specific seakeeping requirements for the CPS. #### 3. Test Conditions and Measuring Equipment The trials were conducted with half-full fuel and water tanks, in addition to stocked supplies, at departure. A record sheet captured additional information: sea state; wind speed; wind direction; ship's heading; GPS coordinates; engine RPM; speed over ground; speed through water; draft and displacement of ship at departure; and trial times and duration. The sea states were estimated by three crew members with extensive nautical experience. They were based on sea state descriptions of the Adriatic Sea set by Prof. Tonko Tabain according to experiments conducted during the 1970s [10]. Prof. Tabain also set the relationship between the Adriatic sea state scale and the WMO scale. Sea state estimates were also compared with the sea states provided by the Croatian Meteorological Institute (CMI) to validate the estimates provided by the crew members. The CMI uses a network of buoys for wave measurement and providing related waves statistics. It was difficult to find the required sea state conditions and the trials therefore lasted longer than expected. To record parameters for all seakeeping criteria described in Section 2, the CPS sailed for 20 minutes for each set of criteria. For measuring rolling and pitching angles, a fibro optic gyro (FOG) onboard the CPS was used. The FOG provided raw motion data that were recorded on a laptop and processed later. A typical sequence of maritime courses for seakeeping tests was used as shown in Figure 3. Following Reference [11], root mean square (rms) values of signals were calculated using the expression: $$\sqrt{\left(1/N\right)\sum\_{i=1}^{N}\left(\delta-\overline{\delta}\right)^{2}}\tag{1}$$ where N represents the number of samples, δ is the measured signal value, and δ is the mean value of the signal. The highest expected measured frequency was less than 0.5 Hz and the frequency of FOG data was 4.0 Hz, which assured consistent and well-sampled data. Accelerometers were used to measure vertical and lateral accelerations of specific points on the ship (i.e., the wheelhouse, the control cabin near the engine room, and the stern of the ship). Vertical displacement of the stern was measured using a liquid level sensor that was attached to the stern of the ship. Deck wetness, slamming, and propeller emergence were determined by counting their occurrences during one sailing course of 20 min, and then recalculating at the number of occurrences per hour. Figure 3. Sequence of maritime courses for seakeeping tests [12]. #### 4. Seakeeping Performance Results Seakeeping performance results are presented in Tables 3–5, and were taken from the report by the company hired by the Croatian Ministry of Defence (MoD) to conduct the trials [13]. Table 3 presents the results of the trial at sea state 3–4 (WMO), and at speeds of 0 and 5 knots. The speed of 5 knots was one of the required operational speeds designed for launch and recovery of the RHIB. One of the main goals, in addition to measuring all seakeeping parameters, was to check vertical displacement at the aft perpendicular (AP). This parameter is important for assessing the safe launch and recovery of the RHIB. For the operational sea state 3–4 (WMO), this parameter was 0.6 m, a result below the required limits and signaling the success of this crucial operation. This was born out in practice, with the RHIB successfully being launched and recovered during sea trials. Later on, when the crew had become more experienced, they launched and recovered the RHIB even at sea state 4–5 (WMO). All other parameters were within the required limits. Table 4 presents the results of the trial at sea state 3–4 (WMO), and at a speed of 15 knots, representing the cruising speed of the CPS. As can be seen, all parameters were within required limits, except the angle of pitch (1.9◦ rms) at the heading angle of 90◦, and the number of slammings that were slightly above the allowable limits. Table 5 shows the results of the trial at sea state 3–4 (WMO), and at a speed of 27 knots (i.e., maximum continuous speed). The parameters that exceeded the required thresholds were the angle of pitching at the heading of 45◦ and 135◦, deck wetness (33), and slamming (70). It was expected that the parameters for maximum continuous speed would be exceeded, although there were no requirements to measure these parameters at this speed. Table 3. Results for the trial at sea state 3–4 (WMO), and speed of 0 and 5 knots. Table 4. Results for the trial at sea state 3–4 (WMO), at 15 knots. Table 5. Results for the trial at sea state 3–4 (WMO), and speed of 27 knots. Tables 6 and 7 show the results of numerical calculations, based on strip theory and Jonswap spectra, conducted during the preliminary phase of ship design. Measuring signal examples for the angles of pitching and rolling at v = 15 kn and wave heading = 45◦ are given on Figures 4 and 5 respectively. In further trials, the prototype of the vessel was tested at the higher sea states 4–5 (WMO), and the results obtained were more than satisfactory. Even in these sea state conditions, the RHIB could be successfully launched and recovered, and there was negligible loss of speed. Generally, the vessel demonstrated very good seakeeping characteristics. Table 6. Results of numerical calculations for sea state 3–4 (WMO), and ship speed of 5 knots. Table 7. Results of numerical calculation for sea state 3–4 (WMO), and ship speed of 15 knots. Figure 4. Measuring signal example—the angle of pitching at v = 15 kn and wave heading = 45◦. #### 5. Discussion The presented seakeeping results and performances of the CPS show very good seaworthiness capabilities of the ship. The ship is fully operational at the mid sea state 4 (WMO), which was one of the main seakeeping criteria. When the crew had enough experience manipulating the RHIB, the RHIB could be launched and recovered even at the upper limit of sea state 4. During tests on higher sea states 5 (WMO), the ship showed reasonable seakeeping characteristics, a high level of reliability of all ship subsystems, and a low level of speed loss on waves. Considering some specific criteria that were exceeded (e.g., slamming at maximum continuous speed in a head sea), this was expected and does not mean that ship has unsatisfactory seakeeping performance. There were also some deviations in the angle of pitching at a wave direction of 0 and 45 degrees that were unsurprising due to the size of the ship. Upon increasing ship speed from 5 to 15 knots (cruising speed), the seakeeping parameters changed as follows: Upon raising the ship speed to maximum continuous, it can be observed that all seakeeping parameters rose significantly, and the highest rising rate was related to the vertical acceleration, slamming, and deck wetness, which was expected especially from the heading seas. Comparing numerical calculations and full-scale test results, the following conclusions can be drawn: Seakeeping is one of the most important characteristics of a ship, and there is a need to continuously and rigorously consider it throughout all phases of ship design. This was the case with the CPS; seakeeping was tested through numerical analyses, model tests, and finally, full-scale tests on the ship. Setting seakeeping requirements at an early phase of the project is crucial for successful ship design, and the results presented herein indicate that it is reasonable and useful to set these seakeeping requirements for patrol ships of the CPS' size, as it helps designers to satisfy them. Author Contributions: A.L. contributed to the paper by establishing the concept of paper and definitions of research goals and aims. He participated in conducting the research, control of experiments, and data collection and integration. He wrote an initial paper draft including data and graphics design and presentation. V.S. contributed to the paper through its review, validation, and its final preparation for publication. He participated in the analysis of references dealing with this research area. He also did management and coordination of the research planning. He is responsible for the presentation and interpretation of the work. All authors have read and agree to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. #### Nomenclature #### References © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).	doab	2025-04-07T04:13:04.627174	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 12 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.13	Article A Theoretical Study on the Hydrodynamics of a Zero-Pressurized Air-Cushion-Assisted Barge Platform #### *Fengmei Jing 1, Li Xu 2, Zhiqun Guo 3,\ and Hengxu Liu <sup>3</sup> Received: 8 July 2020; Accepted: 22 August 2020; Published: 27 August 2020 Abstract: Thebarge platform has the advantages of low cost, simple structure, and reliable hydrodynamic performance. In order to further improve the hydrodynamics of the barge platform and to reduce its motion response in waves, a zero-pressurized air cushion is incorporated into the platform in this paper. The pressure of the zero-pressurized air cushion is equal to atmospheric pressure and thus does not provide buoyancy to the platform. As compared to the conventional pressurized air cushion, the zero-pressurized one has advantages of less air leakage risk. However, due to the coupling effect on the interface between water and air cushion, the influence of the gas inside the air cushion on the performance of the floating body has become a difficult problem. Based on the boundary element method, the motion response of the zero-pressurized air-cushion-assisted barge platform under regular and irregular waves is calculated and analyzed in the paper. Compared with the barge platform without air cushion, numerical results from the theoretical method show that in regular waves, the air cushion could significantly reduce the amplitude of heave and pitch (roll) response of the round barge platform in the vicinity of resonance. In irregular waves, the air cushion also observably reduces the pitch (roll) motion, though amplifies the heave motion due to the transfer of heave resonance frequency. Thetheoretical study demonstrates that the zero-pressurized air cushion can reduce the seakeeping motion of barge platforms in high sea states, but might also bring negative effects to heave motion in low sea states. One should carefully design the air cushion for barge platforms according to the operating sea states to achieve satisfactory hydrodynamic performance in engineering application. Keywords: barge platform; zero-pressurized air cushion; hydrodynamic performance; boundary element method #### 1. Introduction The round barge is a common floating platform in ocean engineering. Its structure is simple, the cost is cheaper than other floating platforms, and its life is longer (about 100 years). However, due to the large waterline area of the barge, the motion response under the incident waves is also relatively large. How to improve the seakeeping performance of a barge and reduce its motion response in waves has always been the focus of research in ocean engineering. At present, anti-roll tanks (ARTs), tunedliquid column dampers (TLCDs) and tuned mass dampers (TMDs), air cushions (ACs), heave bottom plates (HBPs), and so forth, can be used to reduce the motion of the offshore floating barge [1]. The principle of the tuned water column damper is the same as the anti-roll water tank, which are considered as one kind in this paper. It was reported that, as compared to other dampers, the air cushion has the most significant anti-rolling effect on the floating platform [1]. Results of studies in other literature also confirm that the air cushion has an obvious effect on improving the hydrodynamic performance of the barge-type offshore platform. The air cushion can significantly reduce the wave bending moment of the floating platform, which is because the air cushion disperses the relatively concentrated wave load [2], and chronic drift forcedue to the existence of the free surface in the air cushion makes waves relatively easy to pass through the platform [3,4]. The application of air cushion technology in the field of ocean engineering has a long history, which can be traced back to the 1970s [3]. Pinkster and Fauzi studied a square air-cushion-supported structure [5]. The Green function method and three-dimensional linear radiation/diffraction theory were used to predict its motion response under waves and the air pressure inside the air cushion, and the numerical results agree well with the experimental ones [6]. Ikoma et al. [7] had studied the elastic floating platform supported by the air cushion based on the potential flow theory and pressure distribution method. The integral equation was used to calculate the movement of the internal air cushion under the regular waves. The results show that the air cushion can effectively reduce the wave drift force and the motion response of the floating platform [7]. For the verylarge floating body supported by the air cushion, Kessel analyzed its motion response based on the three-dimensional linear potential flow theory. The results suggest that this method can accurately solve the motion response of the floating body. It has been improved, and the wave bending moment acting on the structure has been significantly reduced [8]. Lee and Newman studied the wave effects of a super-large floating air cushion support platform in waves based on potential flow theory. They used a series of given Fourier modes to represent the vertical motion on the free surface in the air cushion of the air-supported floating structure, and thus extended the traditional six-freedom rigid body motion equation. The effect of air movement inside the air cushion is expressed by the derived aerodynamic added mass coefficient [9]. Lee and Newman made further improvements using the generated Fourier modals to represent changes in the internal oscillation pressure of the air cushion, which had been applied in WAMIT software [10]. Bie et al. [11] pointed out that the stability of the air-cushion-supported structure was lower than that of the common floating body under the same conditions, while the air cushion compartmentalization can improve the stability. Zhang et al. [12] conducted experimental and theoretical studies on the floating stability of an air-cushion-supported artificial island, whose foundation consists of multiple air cylinder structures. On the other hand, the air cushion has also been applied to the ship field. Yang et al. [13] numerically and experimentally studied the seakeeping performance of a partial air-cushion-supported catamaran (PACSCAT) sailing in regular waves. Yang et al. [14] and Cucinotta et al. [15–17] investigated the air cavity and its evolution under stepped planning hulls. However, the air cushion/cavity under ships generally involves physical processes such as air inflow/generation and air leakage, which are more complicated than thoseunder platforms. Actually, the air cushion under platforms is enclosed by platform structures and free surface, and usually is isolated from atmosphere, so its hydrodynamic performance can be analyzed using simpler theoretical models. In summary, the air cushion possessesa certain amount of displacementin the above literature, which might undergo risk of air pressure loss.On the contrary, the floating platform fitted with a zero-pressurized air cushion has a relatively high safety performance. That is because its static pressure is equal to the atmospheric pressure, and there is no need to worry about the damage or leakage of the air tanks. However, the hydrodynamic performance of the zero-pressurizedaircushion platform is rarely studied. A round barge platform with zero-pressurized air cushion is proposed in this paper, and its hydrodynamic performance is studiedbased on the boundary element method. Firstly, the boundary conditions and control equations are constructed, and the air velocity potential is solved to obtain the air cushion aerodynamic coefficient; secondly, the barge platform motion equations are established and solved, where the hydrodynamic coefficients and wave force are obtained; finally, the influence of the zero-pressurized air cushion on the hydrodynamic performance of the barge platform is studied and the effect of the water depth on the air-cushion-assisted barge platform is analyzed. #### 2. The Zero-Pressurized Air-Cushion-Assisted Barge Platform The three-dimensional model of the zero-pressurized air-cushion-assisted barge platform is shown in Figure 1, and the design parameters are shown in Table 1. Figure 1. 3D model diagram of the zero-pressurized air-cushion-assisted barge platform. (a) Overall model diagram; (b) underwater structure model diagram. Table 1. Parameters of the zero-pressurized air-cushion-assisted barge platform. The zero-pressurized air-cushion-assisted bargeplatform consists of a barge structure main body at the top, a ballast plate at the bottom with the function of heave damping and ballast together, and a connecting truss that connects the above two parts. The main body of the bargeplatform includes a zero-pressurized air cushion tank and a buoyancy tank. The air cushion tank is divided into eightcompartments, which are geometrically equal and symmetrical sector-annular air tanks. These eightcompartments do not provide buoyancy, but they can act as an air spring when the bargeplatform heaves to reduce the motion response of the platform. The buoyancy tank on the periphery of the air tank is a structure that mainly provides buoyancy to the platform. Various materials can also be used to enhance the structural strength of the platform. The bottom of the buoyancy tank has a ring of damping skirt to increase the damping of the platform and thus reduce the motion response in waves. The truss can move up and down through the buoyancy tank to adjust the draft of the ballast tank, which is beneficial for towing the platform through shallow water. The detailed structure of the aircushion floating platform is shown in Figures 2 and 3. Figure 2. Schematic diagram of the zero-pressurized air-cushion-assisted barge platform. (a) Side view; (b) top view. Figure 3. Schematic diagram in 3D of the zero-pressurized air-cushion-assisted barge platform. (a) Top side view; (b) bottom side view. #### 3. Motion Equations of the Air-Cushion-Assisted Barge Platform** Assuming that the fluid is ideal and the flow is irrotational, and the air in the cushion is compressible, the motion of the zero-pressurized air-cushion-assisted barge platform in the waves can be analyzed using potential flow theory. Let Sb be the wetted surface of the barge platform, Sc the inner surface of the platform that surrounds the air cushion, and Si the air–water interface under the air cushion. Then, the complete enclosed surface surrounding the air cushion is expressed as Sa = Sc + Si; the complete boundary between the water and the barge platform can be expressed as Sw = Sb + Si. The free surface outside the float is denoted by Sf . The height of the air tank is h, and the draft is d. #### 3.1. The Definite Problem for the Air Cushion Within the linear frequency domain conditions, the air velocity potential in the cushion can be presented as $$ \Psi = \text{Re}\{\psi \mathbf{e}^{i\omega t}\} \tag{1} $$ Obviously, the air in cushions should obey the law of mass, momentum, and energy conservation [18], from which one gets the control equation (Helmholtz equation) for ψ $$ \nabla^2 \psi + \mathcal{K}\_a^{\;\;2} \psi = 0 \tag{2} $$ where Ka = <sup>ω</sup> c0 , and c<sup>0</sup> = ) dp <sup>d</sup>ρ<sup>a</sup> which is the acoustic velocity under adiabatic conditions, p is the atmospheric pressure, ρ<sup>a</sup> is the air density. Since the air cushion in the platform is fan-shaped (as shown in Figure 4), the cylindrical coordinate system is appropriate to describe the definite problem. Let a, b be the inner and outer diameter of the fan-shaped cushion, respectively. The angle between the boundary of one side and the starting coordinate axis in the positive direction is θ = c, and the angle between the boundary of the other side and the starting coordinate axis in the positive direction is θ = d, the height of air tank is zh − zl = h. The control equation (Helmholtz equation) satisfied by the air velocity potential in the fan-shaped air cushion in the cylindrical coordinate system can be written as $$\frac{1}{r}\frac{\partial}{\partial r}\left(r\frac{\partial \psi}{\partial r}\right) + \frac{1}{r^2}\frac{\partial^2 \psi}{\partial \theta^2} + \frac{\partial^2 \psi}{\partial z^2} + K\_a^2 = 0\tag{3}$$ Figure 4. Top view of single fan-shaped air tank. From the Bernoulli equation, the relationship between the air velocity potential ψ and the pressure p can be obtained. So the pressure on the free surface that is under the air cushion can be expressed as $$p(\mathbf{x}, y, \mathbf{z}\_l) = -\rho g \sum\_{j=\mathcal{T}}^{6+N\_p} \mathbb{1}\_j n\_j(\mathbf{x}, y) \tag{4}$$ where ρ is water density. The free surface condition for the air velocity potential in the air cushion is obtained: $$\psi = \sum\_{j=7}^{6+N\_p} \frac{\rho g}{i\omega \rho\_a} \xi\_j n\_j(\mathbf{x}, y) \tag{5}$$ According to numerical tests in literature [10], if the air cushion is not too large, the uniform pressure can obtain satisfactory results. In this paper, the CFD (Computational Fluid Dynamics) simulation result also suggests that the variation of air pressure in a cushion is no more than 0.2%. Therefore, the pressure on the free surface can be assumed to be evenly distributed, that is, one can set Np = 1, n7(x, y) = 1. The wall conditions for the air velocity potential in the cushion are: $$\frac{\partial \psi}{\partial n} = i\omega \sum\_{j=1}^{6} \xi\_j N\_j \tag{6}$$ Decomposing the air velocity potential yields $$\psi = i\omega \sum\_{j=1}^{6+N\_p} \xi\_j \Phi\_j \tag{7}$$ Then the air velocity potential component Φ<sup>j</sup> also satisfies the control Equation (3), and when j ≤ 6, the following boundary conditions are obtained: $$\begin{cases} \frac{\partial \Phi\_{j}}{\partial \mathbf{n}} = \mathbf{N}\_{j} & \text{on } \mathbf{S}\_{\mathbf{c}} \\\ \boldsymbol{\Phi}\_{\boldsymbol{j}} = \mathbf{0} & \text{on } \mathbf{S}\_{\mathbf{i}} \end{cases} \tag{8}$$ When j ≥ 7, there exist the following relations: $$\begin{cases} \frac{\partial \Phi\_j}{\partial n} = 0 & \text{on } \mathcal{S}\_{\mathbb{C}}\\ \Phi\_j = -\frac{\rho}{\rho\_x} \frac{\mathcal{S}\_x}{a^2} n\_j(x, y) & \text{on } \mathcal{S}\_i \end{cases} \tag{9}$$ Equations (3), (8), and (9) constitute the definite Helmholtz problem for the air velocity potential in the air cushion, which can be solved by analytical or numerical methods. For the rectangular air cushion compartments, the WAMIT software [10] that released by the Massachusetts Institute of Technology can directly give the analytical solution for the air velocity potential [11]. However, for the fan-shaped air cushion, there exists neither analytical solver nor analytical solution given in literature that can directly solve the abovementioned definite problem. To this end, the open-source program BEMHELM [19] that released by the Nantes Central Institute of Technology is employed to numerically solve the definite Helmholtz problem. After obtaining the velocity potential Φj, the air cushion pressure can be written as $$P(x,y,z) = \rho\_{\mathfrak{a}}\omega^2 \sum\_{j=1}^{6+N\_p} \xi\_j \mathfrak{d}\_j \tag{10}$$ #### 3.2. Motion Equations for Air-Cushion-Assisted Barge Platform The air dynamic expression in frequency domain is: $$f\_d = \iint\_{\mathcal{S}\_\varepsilon} P(x, y, z) \cdot N\_i dS = \sum\_{j=1}^{6+N\_P} \left( \omega^2 \mu\_{ij}^a - i\omega \lambda\_{ij}^a - \mathbb{C}\_{ij}^a \right) \xi\_j \qquad (1 \le i \le 6) \tag{11}$$ μa ij, <sup>λ</sup><sup>a</sup> ij, and <sup>C</sup><sup>a</sup> ij are aerodynamic coefficients, where <sup>μ</sup><sup>a</sup> ij is the air added mass matrix; <sup>λ</sup><sup>a</sup> ij is the air damping coefficient matrix; Ca ij is the air restoring coefficient matrix. Combining Equation (11) with Equation (10), the following expression can be obtained: $$\iiint\_{S\_{\mathbb{C}}} P(\xi) N\_{\mathrm{l}} \mathrm{d}S = \rho\_{\mathrm{a}} \omega^{2} \iiint\_{S\_{\mathbb{C}}} (\xi\_{\rangle} \mathcal{O}\_{\overline{\}}) N\_{\mathrm{l}} \mathrm{d}S = \left(\omega^{2} \mu\_{ij}^{a} - i\omega \lambda\_{ij}^{a} - \mathbf{C}\_{ij}^{a}\right) \xi\_{\overline{\}} \tag{12}$$ Based on the above section where the velocity potential Φ<sup>j</sup> is solved, the aerodynamic coefficients can be obtained by the analytical or numerical methods. Thus, the motion equations of the zero-pressurized air-cushion-assisted barge platform can be presented as $$\sum\_{j=1}^{6+N\_p} \left( -\omega^2 \left( M\_{ij} + \mu\_{ij} + \mu\_{ij}^a \right) + i\omega \left( \lambda\_{ij} + \lambda\_{ij}^a \right) + \left( \mathbb{C}\_{ij} + \mathbb{C}\_{ij}^a \right) \right) \xi\_j = X\_i \qquad 1 \le i \le N\_p \tag{13}$$ where Mij, μij, λij represent the mass matrix, added mass matrix, and damping matrix, respectively, which can be solved by using the WAMIT software [10]. #### 4. Motion Response of the Zero-Pressurized Air-Cushion-Assisted Barge Platform in Waves The motion response of the zero-pressurized air-cushion-assisted barge platform is calculated by Equation (13), where the air dynamic and hydrodynamic coefficients are obtained using the BEMHELM [19] solver and WAMIT [10] software, respectively. The principal parameters of the zero-pressurized air-cushion-assisted platform are shown in Table 2. The panel model for the WAMIT calculation was established by Multisurf [10], as shown in Figure 5. Table 2. Parameters of the barge platform with moon pool. Figure 5. Panel model of the air-cushion-supported barge floating platform. #### 4.1. The Influence of the Zero-Pressurized Air Cushion on the Hydrodynamic Performance of the Barge Platform In order to study the impact of the zero-pressurized air cushion on the hydrodynamic performance of the platform, a conventional barge platform (see Figure 6) is selected for comparison that is obtained by reducing the air cushion and its partition plates from the zero-pressurized air-cushion-assisted barge platform. The partition plate is a thin plate whose volume approximately equals to 0. To differentiate the two platforms, the zero-pressurized air-cushion-assisted barge platform is named as "Platform with air cushion", while the conventional barge platform is named as "Platform with moon pool". The platform with moon pool has the same displacement as the one with aircushion. The water depth is set as 60 m, which is 3 times the platform draft. The response amplitude operators (RAOs) of the surge, heave, and pitch of the two platforms in regular waves are shown in Figure 7a–c, respectively, where the solid line denotes the results from the platform with air cushion, and the dashed lines represents those from the platform with moon pool. Figure 6. The platform model with moon pool. Figure 7. Comparison of RAOsbetween platform with air cushion andplatform with moon pool. (a) Surge RAO; (b) heave RAO; (c) pitch RAO. As seen from Figure 7a, the curves of surge response from the two platforms almost coincide with each other. When the frequency is around 0.4 rad/s, the RAO reaches the maximum value, and the platforms resonate in the surge direction. The surge motion resonance range of the floating platform is narrow, which is between 0.4 rad/s and 0.6 rad/s. After the resonance area, the surge motion decreases rapidly with an increase of frequency. It can be found that the air cushion has little effect on the surge of the floating platform, which suggests that the air dynamics do not play an important role in the surge direction. This is because the surge motion does not change the volume of the air cushion. As seen from Figure 7b, the air cushion has significant impact on the heave of the platform. The peak of the heave from the platform with air cushion is reduced about 60%, as compared with the big moon pool one. The heave motion can change the volume of the air cushion and thus excites significant air dynamics. It is worth noting that the resonance frequency of the platform is shifted by the air cushion from a lower frequency (from 0.33 rad/s to 0.36 rad/s) to a higher frequency (from 0.46 rad/s to 0.51 rad/s). The resonance frequency of the platform with air cushion is decided by the natural frequency of both barge platform and air cushion. In the engineering design, the resonance frequency of the platform with air cushion can be adjusted by changing the size of the air cushion to keep away from the classical wave frequencies.However, if the size of the air cushion is not tuned properly, the air cushion might increase the heave RAO of the barge platform at higher frequencies and have a negative effect on the barge platform response, as seen in Section 4.3. As seen from Figure 7c, the pitch amplitude of the platform in the resonance interval can also be greatly reduced by the air cushion. The maximum reduction is about 50%. Obviously, in this case, the air dynamics are also excited by the change of air cushion volume due to the pitch motion. The difference between heave and pitch is that the pitch resonance frequency is not shifted by the air cushion. Except for the resonance interval, the air cushion has little impact on the pitch of the platform. #### 4.2. The Influence of Water Depth on the Hydrodynamic Performance of the Zero-Pressurized Air-Cushion-Assisted Barge Platform The Chinese offshore water depth is around 30 m to 100 m, which is comparable to the draft of the barge platform, so the water depth might have significant influence on the hydrodynamic performance of the platform in the engineering application. To evaluate this effect, the RAO of the zero-pressurized air-cushion-assisted barge platform, with theshape/dimensions of the barge kept the same as in Section 4.1, are calculated in three water depths: 32.5 m, 60 m, and 100 m. The RAOs of the surge, heave, and pitch of the barge platform in the regular waves are given in Figure 8a–c, respectively, where the solid lines, dashed lines, and stippling lines represent the numerical results from 100 m, 60 m, and 32.5 m water depth, respectively. Figure 8. RAO of the platform with air cushion in different water depths. (a) Surge RAO; (b) heave RAO; (c) pitch RAO. As seen from Figure 8a, the maximum surge RAO increases with the water depth, while the resonance frequency interval is barely affected by the water depth. As seen from Figure 8b,c, the maximum heave (pitch) RAO increases with the water depth.Obviously, when the water depth is less than 60 m, the increasing water depth significantly affects the resonance frequency interval by shifting the resonance interval from lower to higher frequency. In contrast, when the water depth is larger than 60 m, the resonance frequency interval is almost not affected by the increasing water depth, though the maximum heave (pitch) RAO increases with water depth. In a word, when the water depth is less than 60 m, both the maximum RAO and the resonance frequency interval will be significantly affected by the water depth. However, with further increasing of the water depth, the influence on the resonance frequency interval can be ignored, while the maximum RAO still increases. The investigating results suggest that the zero-pressurized air-cushion-assisted barge platform has better performance in shallow water. #### 4.3. Motion of the Zero-Pressurized Air-Cushion-Assisted Barge Platform in Irregular Waves To investigate the motion response of the zero-pressurized air-cushion-assisted barge platform in irregular waves, the Chinese offshore wave spectrum [20] was employed for simulating the real wave energy spectra, which is used to describe Chinese coastal waters. The expression of the China Sea spectrum is $$S\_{\zeta}(\omega) = \frac{A}{\omega^5} \exp\left(-\frac{B}{\omega^2}\right) \tag{14}$$ with $$\begin{aligned} A &= 0.74\\ B &= \frac{\text{g}^2}{6.28^2 \cdot \text{H}} \text{\textsuperscript{3}} \end{aligned}$$ where H<sup>1</sup> is the significant wave height. 3 Figure 9 portrays the significant value of surge, heave, and pitch response of the platformwith air cushion in irregular waves of sea states from 2 to 6. Figure 9. Significant value of motion response of the platforms in irregular waves. (a) Surge; (b) heave; (c) pitch. From Figure 9a, one can observe that the surge response of the platform with air cushion is slightly larger than the moon pool one in low sea states (≤ 4), but smaller in high sea states (≥ 5). Similarly, in Figure 9b, the heave response of the platform with air cushion is larger than the moon pool one when sea state is no more than 5, but much smaller when sea state is beyond 6. Finally, from Figure 9c, one finds that the pitch response of the platform with air cushion is always smaller than the moon pool one, and the pitch reduction effect increases with the sea state. Therefore, the air cushion can reduce the overall motions of the barge platform in high sea states, but might bring negative effects to heave motion in low sea states. #### 5. Conclusions In this paper, the hydrodynamic performance of a zero-pressurized air-cushion-assisted barge platform was studied. The definite problem for the air velocity potential in the cushion was firstly proposed and theopen-source Helmholtz solver BEMHELM was employed to solve it. Then the motion equations of the zero-pressurized air-cushion-assisted barge platformwereestablished, in which the hydrodynamic coefficient and wave force of the barge platform were solved by the commercial hydrodynamic software WAMIT. Finally, the motion responses of the barge platform in regular and irregular waves were studied and the following conclusions were obtained. Author Contributions: L.X. developed the theoretical method; Z.G. prepared the study cases; F.J. and H.L. performed the numerical calculation and analysis; and F.J. wrote the paper. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the National Natural Science Foundation of China (grant No.51779063, 51979065), State Key Laboratory of OceanEngineering (Shanghai Jiao Tong University) (Grant No.1913), and the Natural Science Foundation of Heilongjiang Province of China (Grant No. E2018025). Conflicts of Interest: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. #### References © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).	doab	2025-04-07T04:13:04.628488	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 13 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.14	Article Evaluation of the Effect of Container Ship Characteristics on Added Resistance in Waves #### *Ivana Marti´c 1, Nastia Degiuli 1,\, Andrea Farkas <sup>1</sup> and Ivan Gospi´c <sup>2</sup> Received: 7 August 2020; Accepted: 6 September 2020; Published: 9 September 2020 Abstract: Added resistance in waves is one of the main causes of an increase in required power when a ship operates in actual service conditions. The assessment of added resistance in waves is important from both an economic and environmental point of view, owing to increasingly stringent rules set by the International Maritime Organization (IMO) with the aim to reduce CO2 emission by ships. For that reason, it is desirable to evaluate the added resistance in waves already in the preliminary ship design stage both in regular and irregular waves. Ships are traditionally designed and optimized with respect to calm water conditions. Within this research, the effect of prismatic coefficient, longitudinal position of the centre of buoyancy, trim, pitch radius of gyration, and ship speed on added resistance is investigated for the KCS (Kriso Container Ship) container ship in regular head waves and for different sea states. The calculations are performed using the 3D panel method based on Kelvin type Green function. The results for short waves are corrected to adequately take into account the diffraction component. The obtained results provide an insight into the effect of variation of ship characteristics on added resistance in waves. Keywords: container ship; added resistance in waves; sea states; potential flow theory; variation of ship characteristics #### 1. Introduction The ship hull is traditionally designed and optimized for calm water conditions, while an increase in the ship resistance owing to sailing in waves is being taken into account via sea margin. Added resistance in waves, as one of the additional loads acting on the ship in service, affects the attainable ship speed, and causes a change in the performance of the ship propulsion system. Its assessment is of great importance as early as in the preliminary design stage to adequately design and optimize the ship propulsion system. The assessment of added resistance ensures the ability of the ship to sail in severe sea states, as well as the possibility to estimate fuel consumption, with the aim of reducing operating costs and emissions of harmful gases. This is of particular importance from the environmental protection point of view and in accordance with regulations introduced by the International Maritime Organization (IMO). IMO has set a series of measures under the EEDI (Energy Efficiency Design Index) and EEOI (Energy Efficiency Operational Indicator) for new built ships and those already in service [1]. When sailing in waves, the total resistance can increase by 15–30% compared with calm water resistance, and still that increase could be even more pronounced [2]. For that reason, it is of particular importance to analyze the effect of variation of ship characteristics on the added resistance in waves. In that way, it is possible to evaluate a change in added resistance for different hull form characteristics rather than optimizing the hull for calm water conditions only. Moreover, it would enable the estimation of the effect of particular loading conditions on added resistance as early as in the preliminary design stage. The additional power that a ship requires to attain speed when sailing in waves is related to three main components of added resistance. The first and largest one arises owing to the interference of waves generated by the ship response in waves (radiation waves) and incoming waves. It is often called the drift force, although the drift force in the longitudinal direction of the ship is equal to the added resistance in waves only in the case of zero forward speed. The largest contributors to radiation waves are heave and pitch motions and, to a certain extent, roll motion, depending on the phase shift regarding the incoming waves. In short waves, the component of added resistance caused by the ship motions tends to zero, but the second component, called the diffraction force, increases. The wave diffraction is a highly nonlinear phenomenon, thus the accuracy of the methods based on the potential flow theory decreases. The third component of the added resistance is related to the viscous damping of heave and pitch and is negligible compared with the hydrodynamic damping (radiation waves). Therefore, added resistance is considered as an inviscid phenomenon, which allows the application of methods and solvers based on the potential flow theory, as well as an extrapolation of the results from model to full scale, neglecting the scale effects. Added resistance is pressure driven force and can be extrapolated using Froude similarity law. The frictional part of added resistance, subjected to scale effects, is more emphasized in short incoming waves, when it can account for up to 20% of the added resistance. However, it should be emphasized that, in the latter case, added resistance accounts for only up to few percent of calm water resistance [3]. International maritime transport caused an average of 2.6% of global CO2 emission during the period from 2007 to 2015 [4,5]. For example, in 2015, ships burned about 298 million tons of fuel, of which 72% was heavy fuel oil (HFO), which caused the emission of about 932 million tons of CO2 into the atmosphere. Assuming that fossil fuels will remain dominant in the future, CO2 emissions from maritime transport are projected to increase by 50% to 250% by 2050, depending on economic and energy developments [4]. The containerization, which records the most significant increase in cargo transport, is the most energy efficient way to transport cargo and the share of CO2 emitted by ships is relatively low in global CO2 emission. However, there is a tendency to improve the energy efficiency of ships and limit greenhouse gas (GHG) emissions as maritime transport continues to evolve and increase. For this reason, IMO has set a goal in 2011 to reduce GHG emissions of ships by at least 50% by 2050 compared with 2008 by introducing mandatory technical measures for new built ships and operational measures for existing ships, with the aim to increase the energy efficiency of ships and reduce CO2 emissions [1]. EEDI of new built ships is the most important technical measure, aimed at promoting the use of energy efficient equipment and engines, as well as optimization of the propulsion system and ship hull [6]. In the optimization process, it is necessary to take into account the ship response as well as loads acting on the hull in waves. EEDI requires a minimum energy efficiency level per capacity mile for different ship types and sizes. It is expected to encourage innovation and technical development of all components of the ship system that affect fuel consumption, already in the preliminary design phase. Considering the added resistance in waves as an inviscid phenomenon, numerical methods based on the potential flow theory can be successfully applied for its calculation. Bunnik et al. [7] have analyzed and compared the numerical results of motions and added resistance of the container ship and ferry with the available experimental data. Thus, the authors applied a linear potential flow theory based on the Green function with and without forward speed taken into account, that is, with approximate and exact forward speed, a nonlinear method based on Rankine singularities and computational fluid dynamics (CFD) based on the viscous flow theory. The authors concluded that the application of CFD requires incomparably greater computational resources and does not contribute significantly to the accuracy of the results when nonlinear effects are not pronounced. They also concluded that the methods based on a very similar or identical mathematical model give different results depending on the method of implementation, discretization, or boundary conditions, and that it is more demanding to obtained accurate results for heave than for pitch. Hong et al. [8] have divided the added resistance of S175 container ship into a radiation and diffraction part and applied the Green function based on pulsating and translating sources to solve the boundary condition problem. The applied method provided greater accuracy compared with the experimental results at higher Froude numbers than the Rankine panel method. Linear potential flow theory has been applied to calculate added resistance of intact and damaged S175 ships in [9]. For considered sea states, two calculation models, that is, flooding simulated as increased displacement mass and sloshing inside flooded tank, gave very similar results. Riesner and el Moctar [10] have developed a partially nonlinear time domain method for predicting added resistance at a constant forward speed in regular waves. For the calculation of radiation forces in the time domain, the developed method is based on hydrodynamic coefficients obtained in the frequency domain. The pressure is integrated on the instantaneous wetted surface, which enables the determination of nonlinear Froude–Krylov force and restoring forces. Moreover, an additional force is applied to take into account a variation in wetted surface owing to the radiation and diffraction of incident waves. The additional term, added to take into account the viscous component of the added resistance, is in a form of an exponential function depending on the block coefficient, ratio of wavelength to ship length, and constants determined by the least squares method based on the available results from the literature. Yang et al. [11] have improved the Faltinsen asymptotic formula for calculating the added resistance in short waves. The authors took into account the ship draft, the alteration in the flow velocity around the hull, and the shape of the hull above the waterline. Furthermore, the authors introduced a correction factor associated with a variation in the hull cross section below the waterline, and variation in the hull shape above the waterline was taken into account based on the waterline bluntness coefficient. As new built ships are getting larger, the ratio of wavelength to ship length decreases, meaning that it becomes very important to estimate the added resistance in short waves as accurately as possible. Whether based on potential or viscous flow theory, numerical tools for calculating added resistance in short waves require a large number of panels or finite volumes in order to capture alterations in the flow around the fore part of a hull. Liu and Papanikolaou [12] have developed a relatively simple method for the determination of added resistance in accordance with IMO-MEPC.232(65) EEDI recommendations [13] for establishing the so-called level 1 methods for estimating the minimum required power for navigation and maneuverability of ships in severe weather conditions. The developed empirical method requires only main ship and wave characteristics as input values. The proposed method was extended and adapted for a wider speed range and variation of draft and trim at different loading conditions [14]. The authors analyzed the influence of the advancing speed, the pitch radius of gyration, the draft and the trim on the amplitude and position of the peak value of the added resistance in head waves. They concluded that the peak position is closely related to the natural frequency of heave in long waves and that the amplitude depends on the radius of gyration. Seo et al. [15] have numerically calculated added resistance in short waves using methods based on the potential and viscous flow theory for different ship forms. Given that the added resistance in short waves is greatly influenced by the size of the panel or finite volume, especially for full hull forms, the authors concluded that a convergency study is necessary. Liu and Papanikolaou [16] have utilized the 3D panel method to calculate second-order sway force, that is, drift force for various wave headings at low forward speeds, and concluded that the mean sway force is most significant in relatively short waves. Guha and Falzarano [17] have developed a numerical method for the determination of added resistance based on the direct pressure integration along the instantaneous wetted surface, taking into account the angle of bow flare above the linearized free surface. The authors concluded that it is of great importance to take into account the hull immersion angle when calculating the relative wave amplitude along the waterline on the example of container ships S175 and KCS (Kriso Container Ship), while it does not significantly affect the results of the analyzed Ro-Ro ship. Yang and Kim [18] have come to the similar conclusion by analyzing the bow shape of KVLCC2 (Korean Very Large Crude Carrier) above the waterline. Park et al. [19] have investigated the effect of draft on added resistance in waves experimentally and numerically on the example of KVLCC2. On the basis of the experimental results, the authors concluded that, for short wave lengths, the largest added resistance occurs in the ballast condition and that the peak value shifts towards higher frequencies when reducing the draft. The influence of bow flare on added resistance in waves has been investigated by Fang et al. in [20]. The authors performed numerical calculations, based on the potential flow theory in time domain, and concluded that, by increasing the bow flare angle, the ship motion amplitudes decrease, while added resistance in waves increases. Trim optimization has been performed by various authors for calm water conditions [21,22]. However, the literature lacks studies regarding the added resistance in waves for different trim conditions and trim optimization for sailing in waves. Jung and Kim [23] have applied the multi-objective optimization method to minimize the ship resistance and speed loss caused by wind and waves by varying main dimensions and prismatic coefficient of full KVLCC2 hull form. Kim et al. [24] have proposed a reliable methodology for the estimation of speed loss of the S175 container ship for various sea states and wind conditions. The validation study of ship motions and added resistance obtained using 2D and 3D linear potential flow methods and CFD showed reasonably good agreement with the experimental data in regular head and oblique waves. The authors concluded that the estimated sea margin is significantly increased when the initial reference speed is decreased, mainly owing to added resistance in waves, despite the fact that the absolute value of the required increase in power is lower. Within this paper, the effect of hull form characteristics of KCS, that is, prismatic coefficient and longitudinal position of the centre of buoyancy, as well as pitch radius of gyration, trim, and sailing speed on added resistance in regular waves and for different sea states is evaluated. To the best of the authors' knowledge, this problem has not been investigated in such a comprehensive way. Considering that added resistance in waves could cause a significant increase compared with calm water resistance, the obtained results provide a valuable insight into the possibility to reduce the added resistance in waves for actual sea states that the ship will encounter during her service. During the design process, certain ship characteristic could be optimal with respect to the calm water resistance, but could disrupt seakeeping characteristics and cause an increase in motion amplitudes or added resistance in waves. The obtained results show the effect of variation of certain ship characteristics on added resistance in waves, on the example of a typical container ship. Added resistance is calculated utilizing the 3D panel method based on the Kelvin type Green function. The numerically obtained results are validated against the experimental data available in the literature and the convergence study is performed to assess the numerical uncertainty. #### 2. Methodology** #### 2.1. Case Study Calculations of added resistance in regular and irregular waves are performed for the benchmark container ship, KCS, Figure 1. The main particulars of KCS are shown in Table 1. The original hull form is modified in terms of variation of the prismatic coefficient and the position of the longitudinal centre of buoyancy (LCB) by shifting the hull cross sections in the longitudinal direction, while the midship coefficient and main dimensions remain constant. Cross sections of original and modified hull forms have the same shape and area, but different longitudinal positions. The hull modification method can be applied to ships with and without a parallel mid-body, with the aim of adding a parallel mid-body (if the ship does not have one) or changing its length, while keeping the original value of the prismatic coefficient constant or varying its values [25]. The limits for the variation of the prismatic coefficient and position of LCB are defined according to [25–27]. In order to change the prismatic coefficient of the KCS hull form, cross sections are shifted in the longitudinal direction, without affecting the position of LCB. On the other hand, while changing the position of LCB, an original value of the prismatic coefficient is kept constant. Figure 1. 3D model of Kriso Container Ship (KCS). Table 1. The main particulars of Kriso Container Ship (KCS). Cross sections of an example of a modified hull form of KCS with prismatic coefficient equal to 0.688 are shown in Figure 2. In order to analyze the effect of gyration radii on added resistance in waves, the pitch (and yaw) radius of gyration is set as 24%, 25%, and 26% of the length between perpendiculars. The roll radius of gyration is set as 35% of the ship beam. The variation of trim is performed for constant displacement volume with step equal to 0.2◦ with positive trim defined as bow up and negative trim as bow down. Added resistance in waves for the original hull form of KCS is calculated for three different speeds. Figure 2. Cross sections of KCS with CP = 0.661 (black line) and CP = 0.680 (blue line). #### 2.2. Numerical Assessment of Added Resistance in Waves Within this research, added resistance is numerically calculated utilizing the 3D panel method, by satisfying the Kelvin boundary condition on a free surface. The ship hull is discretized by quadrilateral flat panels with sources of constant and unknown strength located in the collocation points. The velocity field in the computational domain is described by a scalar function of the velocity potential Φ and the Green theorem is applied to obtain the velocity potential by distributing the singularities over the domain boundaries. Boundary integral equations (BIEs) are solved to determine the strength of distributed sources, in a way that the Laplace equation and all the necessary boundary conditions are satisfied. By developing the velocity potential above mean free surface and linearizing the equations under the assumption of small amplitudes and wave steepness, that is, excluding the square terms, the boundary value problem (BVP) of the first order is defined as follows [28]: $$ \nabla \mathbf{V} = \nabla^2 \Phi = 0,\tag{1} $$ $$ \delta\_{\mathcal{S}} \Phi\_z + \Phi\_{tt} + \mu \Phi\_t = 0 \text{ for } z = 0,\tag{2} $$ $$ \boldsymbol{\Phi}\_{\boldsymbol{n}} = \mathbf{X}\_{\boldsymbol{t}} \mathbf{n} \quad \text{on wetted surface}\_{\boldsymbol{t}} \tag{3} $$ $$ \Phi\_z = 0 \quad \text{for } z = -h,\tag{4} $$ where X<sup>t</sup> is the velocity vector; n is the normal vector; and indices t and z denote time and space derivatives, respectively. μ represents a positive and small parameter that introduces the energy dissipation into the momentum equation by a fictitious force dependent on the flow velocity without affecting the inviscid and irrotational properties of the fluid. The result is an additional term in the free surface boundary equation in order to prevent an infinite response at resonant frequencies. The radiation boundary condition, which requires the velocity potential to disappear at an infinite distance away from the ship hull, is automatically satisfied in the fairly perfect fluid. All velocity potential components satisfy the radiation condition except for the incoming wave potential. Wave elevation ζ evaluated at mean free surface and pressure p on hull are given as follows: $$ \mathbb{X}\mathbb{g} = -\Phi\_t - \mu\Phi,\tag{5} $$ $$\frac{p}{\rho} = -\mathbf{g}\mathbf{X}\_3 - \Phi\_t - \mu\Phi\_\prime \tag{6}$$ where g is the gravity constant and ρ is the fluid density. The Green function, G, as a fundamental solution of the Laplace equation, is formulated in such way that it satisfies the linearized boundary condition on the free surface, boundary condition on the bottom, and the radiation condition as follows: $$\nabla^2 \mathcal{G}(P, Q, t) = 4\pi \delta(P - Q) \, , \tag{7}$$ $$ \mathcal{g}\mathcal{G}\_z + \mathcal{G}\_{tt} + \mu'\mathcal{G}\_t = 0 \quad \text{for } z = 0,\tag{8} $$ $$\mathcal{G}\_z = 0 \quad \text{for } z = -h,\tag{9}$$ The Green function represents the field of velocity potential in the computational domain at P(x, y, z) created by the source of unit strength located at Q(x , y , z ). δ(P − Q) = δ(x − x )δ(y − y )δ(z − z ) is the Dirac function and μ = μ. The free surface Green function is expressed by the Fourier–Hankel integral and approximated by Chebyschev polynomials. More details can be found in [28]. After applying the Green theorem to the domain boundaries (mean free surface, hull surface, sea bed, and cylindrical surface at infinity) and considering a complementary domain inside the ship limited by hull and interior free surface, the integral equation is defined as follows: $$4\pi\Phi(P) = \iint\limits\_{H} [(\Phi\_{\text{il}} - \Phi\_{\text{il}}')\mathcal{G} - (\Phi - \Phi')\mathcal{G}\_{\text{il}}] \,\text{d}s,\tag{10}$$ where Φ represents the velocity potential in the interior domain. With the velocity potential and the Green function expressed as Φ(P, t) = Re, φ(P)e−iω<sup>t</sup> and <sup>G</sup>(P, <sup>Q</sup>, <sup>t</sup>) <sup>=</sup> Re, G(P, Q)e−iω<sup>t</sup> - , respectively; and velocity potential expressed by radiation φj, diffraction φ7, and incoming wave potential φ<sup>0</sup> as <sup>φ</sup> <sup>=</sup> <sup>−</sup>i<sup>ω</sup> .<sup>6</sup> j=1 ζajφ<sup>j</sup> + ζa0(φ<sup>0</sup> + φ7), with φ = φ and with source strength defined as σ = φ<sup>n</sup> − φ n. Moreover, by satisfying the boundary condition on the hull (derivation of the velocity potential in the normal direction), the strength of distributed sources can be determined as follows: $$2\pi\sigma\_{\hat{\jmath}} + \iint\_{H} \sigma\_{\hat{\jmath}} \mathbf{G}\_{\text{n}} \, \text{ds} = \begin{cases} n\_{\hat{\jmath}} & j = 1 \dots 6 \\ \frac{-\partial \phi\_0}{\partial \mathbf{n}} & j = 7 \end{cases} \tag{11}$$ With the known velocity potential, it is possible to determine the pressure on each panel from the Bernoulli equation. When the point at which the velocity potential is determined is located at a singular point on the hull (P = Q), the gradient of the Green function becomes singular. In that case, the small area around the singular point is excluded from the integration. For this reason, a term 2πσ<sup>j</sup> is added to Equation (11) that contributes to the amount of normal derivative on the hull in the vicinity of the singular point on the hull. Integral Equation (11) has a unique solution except for the frequencies when the determinant disappears. As the Green function satisfies the free surface boundary condition in the entire computational domain, the solution in the exterior domain of the body is obtained simultaneously as a fictitious solution in the complementary domain. That may cause numerical error at so-called irregular frequencies corresponding to the eigenvalues of the homogenous Dirichlet problem. With φ = φ at these frequencies, the interior BVP has a nontrivial solution. One of the possible solutions to this problem is to define a different boundary condition on the interior free surface, and thus achieve a unique solution for all frequencies. The extended BIEM imposes Neumann's "rigid lid" condition on the interior free surface. In that way, an extended boundary condition is introduced without changing or adding any more parameters to the formulation. For this reason, it is necessary to adequately discretize the interior free surface as well, depending on the frequency range in which the occurrence of the first irregular frequency is expected. The integral equations on the hull and interior free surface read as follows: $$2\pi\sigma(P) + \iint\limits\_{H\cup\mathcal{F}'} \sigma(Q)G\_{\mathcal{U}}(P,Q)\mathrm{d}\mathbf{s} = \begin{cases} \begin{array}{c} n\_j \end{array} & j = 1\ldots 6\\ -\partial\phi\_0/\partial\mathbf{n} \text{ j} = 7 \end{array} \tag{12}$$ $$4\pi\sigma(P) - \iint\limits\_{H\cup\mathcal{F}'} \sigma(Q) G\_{\mathcal{U}}(P, Q) \mathrm{d}s = 0,\tag{13}$$ More details on the extended BIEM can be found in [29], where it was shown that the second-order loads are much more sensitive to the irregular frequencies compared with the first-order quantities and that the effects of irregular frequencies should be removed. The second-order wave loads can be determined by integrating the second-order pressure over the mean wetted surface, taking into account the change in the first-order quantities owing to ship motions. In that way, second-order loads can be expressed through one part depending on the variables of the first order and the other part depending on the second-order velocity potential. The ship response to the incoming waves causes a shift from the equilibrium position and a change in the pressure distribution over the wetted surface. Nonlinear forces of a higher order are caused by the change in wetted surface due to the incoming waves, but also as a result of the ship response in waves (especially angular motion), as well as the nonlinear pressure term in the Bernoulli equation. If the force up to the second order is considered, it contains both a constant and an oscillatory part dependent on the square of the wave amplitude. The result of the direct pressure integration along the mean wetted surface and waterline is the quadratic transfer function (QTF) of high-frequency and low-frequency wave loads. The constant drift force, that is, the added resistance, is a time-averaged value of the second-order force, which amounts to about 5% of the first-order wave force and requires only the calculation of the first-order velocity potential. It is represented by the diagonal members of QTF calculated as follows [30,31]: $$\mathbf{F}\_{1} = -\frac{1}{2}\rho g \oint\_{\text{WL}} \zeta\_{r}^{2} \mathbf{n} \,\mathrm{dl} + \frac{1}{2}\rho \iint\_{H} \nabla\Phi \nabla\Phi \,\mathbf{n} \,\mathrm{ds} + \rho \iint\_{H} \mathbf{X} \nabla\Phi\_{l} \mathbf{n} \,\mathrm{ds} + mR\ddot{\mathbf{X}}\_{\text{G}}.\tag{14}$$ where ζ<sup>r</sup> = ζ − X<sup>3</sup> is the relative wave elevation defined as coupled wave elevation and ship vertical motion and X = X<sup>G</sup> + Rx is the motion vector of the first order in the ship coordinate system, where the position vector of the point on the hull is given as x and linearized rotation transformation matrix as R. Equation (14) includes the ship response, the first-order velocity potential, the gradient of the velocity potential, and the wave elevation on mean wetted surface and along the waterline. The first term on the right side of the equation refers to the relative wave elevation, that is, to the integration of the first-order pressure along the variable part of the wetted surface. If the hull emergence angle γ has a non-zero value in the waterline area, that is, the hull surface is not vertical, which is the case for most modern hull forms in the bow and stern area, the normal vector in the integral equation along the waterline needs to be modified according to n = n/ cos <sup>γ</sup> [32]. The second and third term in Equation (14) refer to the integration of the first-order pressure along the mean wetted surface, taking into account pressure correction due to ship displacement. The last term refers to the rotation of the first-order force vector and its horizontal component owing to pitch. Namely, first-order hydrodynamic and hydrostatic forces acting along the vertical axis of ship coordinate system will give a longitudinal second-order force component equal to <sup>x</sup>5F<sup>3</sup> <sup>=</sup> <sup>x</sup>5<sup>m</sup> .. X3G. A commercial software package HydroSTAR [33] based on linear potential flow theory is used to perform hydrodynamic calculations. HydroSTAR provides a solution of the first-order wave diffraction and radiation problem, and second-order wave loads with and without forward speed. The immersed part of the ship hull and interior free surface are discretized by quadrilateral panels. Every panel model has approximately 4000 panels on the hull and 6000 panels on the interior free surface. The size of the panels on the interior free surface is equal to 50% of the panel size on the hull in order to shift irregular frequencies further towards a higher frequency range. The reference coordinate system is located on the mean free surface at the stern with the positive direction of z axis upwards. Within HydroSTAR, mesh is generated using the so-called automatic mesh generator (AMG) based on an adaptive cosine rule, which reduces the panel size from the bottom of the ship towards the waterline, allowing for finer discretization in the area of the waterline. The pressure on the panels closest to the waterline is used to determine the wave elevation using the boundary condition on the free surface. The coordinate system for solving the diffraction and radiation problems is located at the ship centre of buoyancy, and the solution is transformed to the centre of gravity when solving the motion equation. #### 2.2.1. Correction of the Results in Short Waves Generally, added resistance in waves calculated by linear potential flow theory significantly underestimates the experimental results for higher incoming wave frequencies. In short waves, where the diffraction force is dominant, linear potential flow theory fails to properly include the diffraction component owing to highly non-linear effects. The results in short waves are thus corrected according to [34] based on the experimental data. With the correction term included, added resistance is calculated as follows: $$R\_{AW} = R\_{AWm} + R\_{AWr\_{\prime}} \tag{15}$$ where the correction in short waves depends on the bluntness coefficient Bf , draft and incoming wave frequency αd, and forward speed (1 + αU) as follows: $$R\_{AWr} = \frac{1}{2} \rho g \zeta\_a^2 B B\_f \alpha\_d (1 + \alpha\_{lI}) \, \tag{16}$$ $$B\_f = \frac{1}{B} \left\{ \int\_I \sin^2(\alpha + \beta\_w) \sin \beta\_w \mathrm{d}l + \int\_{\mathrm{II}} \sin^2(\alpha - \beta\_w) \sin \beta\_w \mathrm{d}l \right\},\tag{17}$$ $$\alpha\_d = \frac{\pi^2 I\_1^2(k\_\epsilon T)}{\pi^2 I\_1^2(k\_\epsilon T) + K\_1^2(k\_\epsilon T)},\tag{18}$$ $$k\_t = k \left( 1 + \frac{\alpha V}{\mathcal{g}} \cos \alpha \right)^2,\tag{19}$$ $$1 + a\_{\rm II} = 1 + \mathbb{C}\_{\rm II} \text{F} \mathbf{n}\_{\prime} \tag{20}$$ $$\mathcal{C}\_{L}(\alpha) = \max\left[10, -310\mathcal{B}\_f(\alpha) + 68\right],\tag{21}$$ where α is the wave heading, β<sup>w</sup> is the slope of line element along waterline, I and II are the domains of the integration, I<sup>1</sup> is the first-order Bessel function, K<sup>1</sup> is the second-order Bessel function, k is the wave number, ke is the encounter wave number, ω is the wave frequency, and CU is the forward speed coefficient. #### 2.2.2. Added Resistance in Irregular Waves The mean value of added resistance in irregular waves can be determined based on the spectral moment m0<sup>R</sup> or integral of the response spectrum curve. The response spectrum is determined as the product of the added resistance transfer function RAW ζ2 a (ωe) in regular waves and the encounter wave energy spectrum Sζ(ωe) as follows: $$\overline{R\_{AW}} = 2 \int\_0^\infty S\_\zeta(\omega\_\ell) \frac{R\_{AW}}{\zeta\_\pi^2} (\omega\_\ell) \mathrm{d}\omega\_\ell = 2m\_{0\mathcal{R}\_\ell} \tag{22}$$ where ζ<sup>a</sup> is the wave amplitude. In order to cover the wave energy distributed in the range of encounter frequencies, the wave energy spectrum is transformed into the wave encounter spectrum based on the encounter frequency <sup>ω</sup><sup>e</sup> <sup>=</sup> <sup>ω</sup> <sup>−</sup> <sup>ω</sup><sup>2</sup> <sup>g</sup> V cos α as follows: $$S\_{\zeta}(\omega\_{t}) = \frac{S\_{\zeta}(\omega)}{\sqrt{1 - \frac{4\alpha\_{t}V\cos\alpha}{\mathcal{J}}}},\tag{23}$$ It should be noted that Equation (23) is valid only for head and oblique waves. Namely, the following wave encounter spectrum can be double valued because the same encounter frequency corresponds to different incoming wave frequencies. In addition, as the ship speed increases, the wave encounter spectrum extends into the complex solutions range. Within this research, for fully developed sea, a modified two-parameter Pierson–Moskowitz or Bretschneider wave energy spectrum recommended by ITTC (International Towing Tank Conference) is used to calculate added resistance in head waves at different sea states [35]. The Bretschneider wave energy spectrum is defined as follows: $$S\_{\zeta B}(\omega) = \frac{173H\_{S1/3}^2/\overline{T}^4}{\omega^5} \text{e}^{-\frac{602/\overline{T}^4}{\omega^6}},\tag{24}$$ With the characteristic wave period expressed through zero crossing period as T = 1, 086 Tz. HS1/3 is the significant wave height. For limited fetch, the modified JONSWAP (Joint North Sea Wave Project) wave energy spectrum is used: $$S\_{\zeta l}(\omega) = \frac{320H\_{S1/3}^2}{T\_p^4 \alpha^5} \mathbf{e}^{\frac{1050}{T\_p \omega^4}} \boldsymbol{\gamma}^{\left\| - \left( \frac{\omega/\omega\_p - 1}{\omega \sqrt{2}} \right)^2 \right\|}, \quad \boldsymbol{\sigma} = \begin{cases} 0, 07 \text{ za } \omega < \omega\_p \\\ 0, 09 \text{ za } \omega > \omega\_p \end{cases} \tag{25}$$ where ω<sup>p</sup> = <sup>2</sup><sup>π</sup> Tp , γ = 3, 3, and peak wave period is defined as 1, 073Tz = 0, 834Tp. #### 2.3. Validation and Verification Study Numerically obtained results of the added resistance in waves are validated against the available experimental data for KCS [36–38] for Fn = 0.26, which corresponds to a speed of 24 knots. Relative deviation of the numerical results is calculated as follows: $$RD = \frac{\mathbb{C}\_{AW, \text{HSTAR}} - \mathbb{C}\_{AW, \text{EXP}}}{\mathbb{C}\_{AW, \text{EXP}}} 100\%,\tag{26}$$ where added resistance coefficient is defined as follows: $$\mathbb{C}\_{AW} = \frac{R\_{AW}}{\rho g \zeta\_a^2 B^2 / L}. \tag{27}$$ The mesh convergence study, as part of the verification procedure [39], is performed to evaluate the effect of the discretization on the obtained numerical results of added resistance, heave, and pitch amplitudes, as well as to quantify the numerical uncertainty. Although it seems that, using a larger number of panels, with sources of constant strength located in collocation points, a more accurate solution can be achieved, this may not be a case. However, a larger number of panels allows more detailed description of the hull geometry, which is of particular importance in the bow and stern area, where significant changes in pressure occur, Figure 3. Generated panel models have 1048, 4366, and 17,823 panels in total. In order to preserve the geometrical similarity between the panel models, each panel is divided into four panels when creating a model with finer discretization. Figure 3. Panel models of KCS: coarse mesh (upper) and fine mesh (lower) [33]. The numerical uncertainty of the obtained results is performed according to the verification procedure recommended by ITTC [40] to estimate the uncertainty of numerical results obtained by viscous flow theory, but it can also be applied to the results of potential flow theory [41]. The numerical uncertainty is evaluated for added resistance coefficient in regular waves and irregular waves by applying the Bretschneider wave energy spectrum in the frequency range from 0.3 to 0.8 rad/s for sea state defined with Hs = 3.5 m and TZ = 10.5 s. According to [40], the type of convergence is determined based on the change between solutions obtained using medium and fine mesh (φ<sup>2</sup> − φ1) and coarse and medium mesh (φ<sup>3</sup> − φ2) as follows: $$R = \frac{(\phi\_2 - \phi\_1)}{(\phi\_3 - \phi\_2)},\tag{28}$$ Monotonic convergence is achieved when 0 < R < 1, oscillatory convergence when −1 < R < 0, and divergence when \|R\| > 1. Numerical uncertainty can be calculated for monotonic convergence case using generalized Richardson extrapolation (RE). The order of accuracy is calculated as follows: $$p = \frac{\ln\left(\left(\phi\_3 - \phi\_2\right)/\left(\phi\_2 - \phi\_1\right)\right)}{\ln(r)},\tag{29}$$ where r = <sup>h</sup><sup>2</sup> <sup>h</sup><sup>1</sup> h<sup>3</sup> <sup>h</sup><sup>2</sup> is the uniform refinement ratio corresponding to the ratio of panel size determined based on the total number of panels as hi <sup>=</sup> 1/ <sup>√</sup> Ni [42,43]. With safety factor FS equal to 1.25, the normalized numerical uncertainty is calculated as follows: $$ \overline{\mathcal{U}} = \frac{F\_S \left\| \delta\_{RE} \right\|}{\phi\_1 - \delta\_{RE}} \cdot 100,\tag{30} $$ where RE error is defined as follows: $$ \delta\_{RE} = \frac{\phi\_2 - \phi\_1}{\binom{h\_2}{h\_1}^p - 1}. \tag{31} $$ #### 3. Results and Discussion #### 3.1. Validation of the Numerical Results The obtained numerical results show satisfactory accuracy compared with the experimental data, except in the short wave region, Figure 4. After the correction of the results for high wave frequencies has been applied, significantly better agreement with the experimental data is obtained. The correction of the results, which accounts for the diffraction part of added resistance, was applied for the results up to λ/L = 0.85, because it may cause an overestimation of the numerically obtained added resistance values in moderate and long incoming waves. Some discrepancy in the experimental results can be seen as well, especially in the short wave region. By comparing the ship transfer functions of heave and pitch with the experimental data available in the literature, it can be noticed that the pitch transfer function shows much better agreement with the experimental results, with the relative deviation below 5%. The numerically obtained values of heave for moderate and long waves significantly exceed the experimental values. Relative deviation of heave at λ/L = 1474 is equal to 29%, which confirms that ensuring the accuracy of heave is more demanding than pitch, Figure 5. Figure 4. Comparison of the numerically obtained added resistance coefficient with available experimental data [36–38]. Figure 5. Comparison of the numerically obtained heave (left) and pitch (right) transfer functions with available experimental data [36–38]. #### 3.2. Verification of the Numerical Results Table 2 shows the hydrostatic characteristics of KCS obtained using panel models with different mesh density. The differences between the hydrostatic characteristics for different panel models are not significant, even though the displacement volume of the finest discretization is closest to the actual value. It should be noted that the position of the vertical centre of buoyancy is given with the respect to the coordinate system located on the mean free surface. The effect of panel model discretization on the obtained results of heave and pitch motion amplitudes can be seen in Figure 6. Increasing the number of panels does not influence the obtained results, unlike in the case of added resistance. The largest change in the results is obtained for the highest frequency using fine mesh. Without the correction being applied, this value has the lowest relative deviation compared with the experimental results. The numerical uncertainty of the obtained added resistance coefficient in regular waves and coefficient of the mean added resistance in irregular waves can be seen in Table 3. It can be seen that the calculated numerical uncertainty, for the results with monotonic convergence, is below 2.1% for regular and equal to 1.64% for irregular waves. Table 2. Hydrostatic characteristics of KCS obtained using different panel models. Figure 6. Heave (left) and pitch (right) transfer functions obtained using different panel models. Table 3. Convergence study for panel size used to discretize KCS. #### 3.3. Results of the Sensitivity Analysis The effect of the prismatic coefficient of KCS on added resistance in regular and irregular waves (Table 4) is presented by the results in Table 5. The results are given as relative deviations with respect to the results obtained for the original hull form of KCS. It can be seen that, in long and moderate regular waves, except for the wave frequency corresponding to the peak value of added resistance, the increase in prismatic coefficient and block coefficient at the same time causes the decrease in added resistance. Namely, for large wavelengths, without the presence of diffraction component, an increase in the prismatic coefficient leads to smaller amplitudes of the ship motions. The relative motions become large when the length of the ship is approximately equal to the wavelength, causing the largest resistance. In very long waves, the relative motions tend to zero, and the force tends to a Froude–Krylov force that would ideally act on the ship in the absence of a diffraction component. Consequently, in very long waves, the added resistance tends to zero. The peak value of the added resistance decreases with the decrease in the prismatic coefficient. In order to analyze the effect of variation of the prismatic coefficient on added resistance in short waves, a correction for diffraction was applied. It can be noticed that the diffraction part of added resistance in short waves increases as the prismatic coefficient increases, which means that the fore part of ship is fuller. For irregular waves, the mean value of added resistance was calculated for six sea states by means of spectral analysis based on two theoretical wave energy spectra, Table 4. Spectral analysis based on the corrected results showed that added resistance in irregular waves decreases for hull modifications with a lower value of the prismatic coefficient, and vice versa, and that a change in added resistance is more pronounced for lower sea states when wave energy is concentrated in the high frequency range. In that way, the diffraction component of added resistance determines the trend of mean value in irregular waves. At higher sea states, with wave energy distributed along the entire frequency range, the obtained results are mainly within numerical uncertainty and the results in regular waves counteract each other. Table 4. Significant wave height and wave period for considered sea states. Table 5. Influence of the prismatic coefficient on added resistance in regular and irregular waves. JONSWAP, Joint North Sea Wave Project. In Table 6, the obtained results of the effect of the longitudinal centre of buoyancy on added resistance in regular and irregular waves are shown. In order to change the position of LCB, for example, towards the bow, cross sections of the fore part were moved towards bow and cross sections of the aft part towards midship. In that way, the fore prismatic coefficient increases, while the aft one decreases, keeping the original value of the total prismatic coefficient constant. Two LCB positions are analyzed and the obtained numerical results are given as relative deviations with regard to results of the original KCS hull form. On the basis of the obtained numerical results, it is possible to conclude that the position of LCB does not significantly affect added resistance in long regular waves. It can be seen that the peak value of added resistance decreases by almost 6% with LCB shifted towards stern, and increases by over 3% with LCB shifted towards bow. In general, shifting the position of LCB towards the stern allows a fine shape of the fore part of the ship. On the other hand, shifting the position of LCB towards the bow increases the distance between the longitudinal centre of buoyancy and longitudinal centre of floatation, which reduces the ship relative motions, causing the decrease in added resistance in relatively short waves. This can be observed for λ/L = 0.5, where added resistance increases when LCB shifts towards stern. A noticeable effect of LCB on the mean value of added resistance in irregular waves can be observed for higher sea states, when the position of LCB is shifted towards the stern. The decrease in added resistance in that case equals to 3.5–5% for both theoretical wave energy spectra. To perform seakeeping calculations, it is necessary to know the mass characteristics along with the hull form characteristics. As shown in [44], the influence of the vertical position of the centre of gravity on added resistance in head waves is almost negligible when calculated using linear potential flow theory and by keeping the values of gyration radii constant. Changing the position of the centre of gravity does not affect the terms of hydrodynamic mass matrix, given that the coordinate system is placed at the centre of gravity. On the other hand, an insignificant change in terms of hydrodynamic added mass and damping matrix, especially in the case of heave and pitch, is noticed. In the restoring forces matrix, the large value of longitudinal metacentric height changes only slightly by shifting the vertical position of the centre of gravity. Table 6. Influence of the position of the longitudinal centre of buoyancy on added resistance in regular and irregular waves. Pitch gyration radius in head waves has a more significant effect on added resistance in waves. As mentioned before, its value is varied as a percentage of ship length between perpendiculars. The initial value of pitch (and yaw) gyration radius for KCS container ship corresponds to 25% of the length between perpendiculars. Additionally, values corresponding to 24% and 26% of the length between perpendiculars are analyzed, Figure 7. It can be seen that, by increasing and decree asing thpitch gyration radius, added resistance in long and moderate waves increases and decreases, respectively, by approximately 15%, while the change in peak value amounts to about 6%. According to the obtained numerical results in short waves, there is no effect of change on the pitch gyration radius, which is expected considering that the amplitudes of absolute ship motions in that frequency range are small. By changing the pitch radius of gyration, it can be seen from Figure 8 that added resistance in irregular waves decreases or increases by up to 10% for higher sea states. The change in added resistance is more pronounced for the Bretchneider than for the JONSWAP sea spectrum, except for SS6, when the wave energy described by the Bretschneider spectrum shifts towards lower wave frequencies. The narrow banded JONSWAP spectrum has a higher peak value in the range of high wave frequencies, causing a larger change in mean added resistance for SS1, even though the mean value of added resistance in that case equals approximately 20 kN. Figure 9 shows the obtained numerical values of added resistance in regular waves for three speeds: 20, 22, and 24 knots, which correspond to Froude numbers of 0.216, 0.238, and 0.260, respectively. Compared with the design speed equal to 24 knots, at the frequency corresponding to the peak value of added resistance, a decrease of speed by 2 knots causes a decrease in added resistance by 15%, and the decrease by 4 knots causes the decrease by an additional 14%. This decrease is even more pronounced at lower wave frequencies. For example, a decrease in added resistance by decreasing the speed by 2 and 4 knots is about 15% and 28% for λ/L = 1.33 and 22% and 36% for λ/L = 1.5, respectively. It can also be seen that, as the speed increases, the peak value of the added resistance slightly shifts towards lower frequencies. The corrected results in short waves show a significant decrease in added resistance for lower speeds: 25% and 35% for 22 knots and 20 knots, respectively. Figure 7. Influence of pitch gyration radius on added resistance coefficient in regular waves. Figure 8. Influence of pitch gyration radius on added resistance coefficient in irregular waves: ryy/LPP = 0.24 (left), ryy/LPP = 0.26 (right). Figure 9. Influence of speed on added resistance coefficient in regular waves. The decrease in the mean values of added resistance in irregular waves with decrease in speed is shown in Figure 10. It can be seen that, for lower sea states, the decrease in added resistance is more pronounced in the case of the JONSWAP spectrum. Even though a decrease in percentage of added resistance is more pronounced for lower sea states, the absolute differences between the added resistances are much larger at higher sea states. Decreasing the speed for two knots can lead to an approximately 10% reduction in added resistance based on the results obtained using the Bretschneider wave energy spectrum. The obtained numerical results of the effect of ship speed, as well as pitch gyration radius on added resistance in regular waves, show similar trends as in [14]. Figure 10. Influence of speed on added resistance coefficient in irregular waves: 20 knots (left) and 22 knots (right). Figure 11 shows the obtained added resistance coefficients for different trim conditions at the investigated λ/L. Trim can significantly affect the fuel consumption during the operation and is often optimized in the design stage. In that way, finding the optimal trim is enabled, taking into account that the ship's weight distribution affects the trim. As already mentioned, trim is varied from 1◦ to −1◦ with a step equal to 0.2◦. The obtained numerical results are not reliable for a ship with trim equal to 1◦. The values of added resistance for that particular case show unphysical character. Namely, the discretization of the bow, with mean free surface very close to the bulb, in the most prominent trim condition with bow up, leads to almost horizontally positioned flat panels and singularities very close to the free surface, causing the numerical error. With that particular trim condition excluded, it appears that the optimum trim condition in short waves corresponds to 0.8◦, that is, bow up. For λ/L = 1.15, which corresponds to the peak value of added resistance, there is no significant decrease or increase in added resistance for a certain trim condition, except a significant increase equal to 12% for trim of 0.8◦. For trim equal to 0.6◦, the decrease in added resistance equal to 7.3% can be noticed for λ/L = 1.5. For λ/L = 1.33, there is a noticeable decrease in added resistance equal to 6.4% for the same trim as well. Generally speaking, it appears that trim conditions with bow up to certain measure are favorable for added resistance in regular waves despite the contribution of the projected area of flat bottom in the longitudinal direction, which contributes to the added resistance in waves. Figure 11. Influence of trim on added resistance coefficient in regular waves. ¶ The results of sensitivity analysis regarding trim and its influence on mean value of added resistance in irregular waves for six sea states can be seen in Table 7. For the Bretschneider sea spectrum, except for SS1, there is no significant influence of negative trim on added resistance, which increases by 2–3% for trim conditions equal to −0.8◦ and −1◦. For higher sea states, a significant increase in added resistance can be observed for trim of 0.8◦ by stern. On the other hand, for trim equal to 0.6◦, the decrease in added resistance is equal to about 2–3%. In the case of the JONSWAP sea spectrum, the decrease of added resistance is also the largest for trim equal to 0.6◦. In irregular waves, slight trim by the stern seems to be most favorable for added resistance, even though it does not contribute significantly to the decrease in added resistance. The largest change in added resistance calculated by means of both wave energy spectra can be observed for SS1 owing to the diffraction component. It should be noted that some of the obtained numerical results are within the calculated numerical uncertainty. Table 7. Influence of trim on added resistance in regular and irregular waves. The effect of ship characteristics on added resistance in regular head waves depends on the frequency of the incoming wave. By increasing the prismatic coefficient to the highest value considered within this study, added resistance in short waves and the peak value of added resistance increase, while in moderate and long waves, added resistance decreases. In very long waves, the change in the prismatic coefficient as well as the change in the position of the longitudinal centre of buoyancy have a negligible effect. The greatest effect of variation of the LCB position is observed at the peak value of the added resistance. As the speed decreases, the added resistance decreases for all analyzed λ/L values. Finally, as the pitch gyration radius increases, the value of the added resistance increases as well, more significantly at large and moderate wavelengths. Depending on the frequency range covered by spectral energy, for certain sea states, the influence of the pitch gyration radius will be negligible, while for the other sea states with wave energy distributed in the area of lower frequencies, this influence will be significant. A similar trend can be observed in the case of other varied characteristics. It can be concluded that the results are highly dependent on the incoming wave frequencies and characteristics of sea states, as well on the applied theoretical wave energy spectrum. The distribution of wave energy in the frequency range is dependent on the wave period and the intensity of change in added resistance by varying different ship characteristics on the wave height. #### 4. Conclusions Hydrodynamic calculations of added resistance of KCS in regular waves were performed in the frequency range utilizing the 3D panel method based on the potential flow theory. The obtained numerical results were corrected for the diffraction component of added resistance in short waves. The numerical results were validated against the experimental data available in the literature and satisfactory agreement was achieved. Numerical uncertainty was evaluated for those results in regular waves, whereas monotonic convergence was achieved and for the mean value of added resistance in irregular waves for certain sea states. At high wave frequencies, there is a potential problem of the appearance of irregular frequencies when calculating second-order forces and the results are unreliable in this area. In that frequency range, the results depend mostly on the applied correction based on the waterline shape, speed, draft, and wave characteristics. Within this research, the effect of ship characteristics on added resistance in regular waves and for certain sea states was investigated. By increasing the prismatic coefficient, while keeping the main dimensions and midship coefficient constant, the added resistance in long and moderate regular waves decreases, except for the peak value, owing to the smaller amplitudes of ship motions. In short waves, the change in added resistance due to the change in the prismatic coefficient is more pronounced. Namely, with the increase in the prismatic coefficient, added resistance, mostly caused by the diffraction of the waves, increases. Spectral analysis based on the corrected results showed that, despite the decrease in the motion amplitudes, the mean value of added resistance in irregular waves for lower sea states increases with the increase in the prismatic coefficient. On the basis of the results obtained by shifting the LCB position, the largest effect on added resistance in regular waves was observed for the peak value. Shifting LCB towards the bow increases the distance between the longitudinal centre of buoyancy and longitudinal centre of floatation, reducing the amplitudes of relative motions. The mean value of the added resistance in higher sea states decreases by shifting LCB towards the stern. As already known, by decreasing the ship speed, a significant reduction in added resistance can be achieved. A significant influence on added resistance was observed for the pitch gyration radius as well, especially for moderate wavelengths. Additionally, sensitivity analysis of trim was performed considering that optimum trim can lead to higher ship efficiency, not only in calm water, but in waves as well. It was observed that trim by stern up to 0.6◦ reduces added resistance for actual sea states by 2–3%. As the effect of different ship characteristics depends on the distribution of wave energy in the frequency range, the obtained results provide a valuable insight into the effect of the variation of ship characteristics on added resistance for a particular sea state. When designing or optimizing a ship and its propulsion system for calm water conditions, it is important to evaluate the effect of the variation of ship characteristics on added resistance in waves as well, as it is one the main causes of an increase in required power in service. Ship characteristics optimized for calm water performance are not necessarily optimal for real sailing conditions. Considering that a ship in service encounters waves from various directions, it would be beneficial to investigate the effect of variations in ship characteristics for different headings. This will form a part of future research. Author Contributions: Conceptualization, I.M. and N.D.; methodology, I.M., N.D., A.F., and I.G.; software, I.M.; validation, I.M.; formal analysis, I.M.; investigation, I.M., N.D., A.F., and I.G.; resources, I.M.; writing—original draft preparation, I.M., N.D., A.F., and I.G.; writing—review and editing, I.M., N.D., A.F., and I.G.; visualization, I.M; supervision, N.D. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. #### References © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).	doab	2025-04-07T04:13:04.630385	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 14 }
ffefa398-de0d-4481-a8ce-0276e7d09a9c.15	Article On the Comparative Seakeeping Analysis of the Full Scale KCS by Several Hydrodynamic Approaches #### Florin Pacuraru, Leonard Domnisoru and Sandita Pacuraru \* Department of Naval Architecture, "Dunarea de Jos" University of Galati, 800008 Galati, Romania; [email protected] (F.P.); [email protected] (L.D.) \* Correspondence: [email protected] Received: 17 October 2020; Accepted: 19 November 2020; Published: 25 November 2020 Abstract: The main transport channel of the global economy is represented by shipping. Engineers and hull designers are more preoccupied in ensuring fleet safety, the proper operation of the ships, and, more recently, compliance with International Maritime Organization (IMO) regulatory incentives. Considerable efforts have been devoted to in-depth understanding of the hydrodynamics mechanism and prediction of ship behavior in waves. Prediction of seakeeping performances with a certain degree of accuracy is a demanding task for naval architects and researchers. In this paper, a fully numerical approach of the seakeeping performance of a KRISO (Korea Research Institute of Ships and Ocean Engineering, Daejeon, South Korea) container ship (KCS) container vessel is presented. Several hydrodynamic methods have been employed in order to obtain accurate results of ship hydrodynamic response in regular waves. First, an in-house code DYN (Dynamic Ship Analysis, "Dunarea de Jos" University of Galati, Romania), based on linear strip theory (ST) was used. Then, a 3D fully nonlinear time-domain Boundary Element Method (BEM) was implemented, using the commercial code SHIPFLOW (FLOWTECH International AB, Gothenburg, Sweden). Finally, the commercial software NUMECA (NUMECA International, Brussels, Belgium) was used in order to solve the incompressible unsteady Reynolds-averaged Navier–Stokes equation (RANSE) flow at ship motions in head waves. The results obtained using these methods are represented and discussed, in order to establish a methodology for estimating the ship response in regular waves with accurate results and the sensitivity of hydrodynamical models. Keywords: strip theory; BEM; RANS; regular wave; seakeeping #### 1. Introduction Shipping, often considered as the main transport channel of the global economy, is responsible for approximately 80 percent of world trade. An increasing focus on more environmentally friendly shipping pushes hull designers to further ensure fleet safety, proper operation of the ships, and, more recently, compliance with International Maritime Organization (IMO) regulatory incentives regarding the energy efficiency operational indicator (EEOI) and emissions reduction. Considerable efforts have been devoted to an in-depth understanding of the hydrodynamics mechanism and the prediction of ship behavior in waves. In addition to safety, efficiency and operability, the waves' loads may determine structural failure. Prediction of seakeeping performances with a certain degree of accuracy is a demanding task for naval architects and of great practical interest for shipbuilders, owners, operators, as it affects both the ships' design and operation [1]. More recently, the shipping industry has embraced more and more digitalization. Digital twin concept couples physical–numerical modelling and simulation to evolve solutions that improve vessel predictability, behavior control and response. There are several aspects concerning seakeeping that make it one of the most challenging problems in ship hydrodynamics. The nonlinearities induced by the fluid viscosity and hydrodynamic pressure, boundary conditions at free-surface formulation, interference between external waves and ship's body, specific geometry of the hull shape, all require advanced iterative time-domain procedures for the ship's oscillations response analysis, involving significant computational resources [2]. The problem of a moving body interacting with waves has been pursued since the very first Froude and Michel studies. Since then, different approaches, such as experimental fluid dynamics, potential flow and recently computational fluid dynamics, have been developed to estimate the seakeeping performances. Traditionally, the hydrodynamic performances of a full-scale ship are determined by extrapolating the results of model-scale towing tank tests. Another approach commonly adopted in ship hydrodynamics is the employment of numerical techniques to solve the equations' system of ship motions. The prediction of non-linear phenomena specific to ship motions in waves is difficult to be solved numerically, not only due to the complexity of the problem, but also the results are highly dependent on the details of the hull form and the incident wave condition. Due to the development of numerical modelling methods and computing power increase, direct prediction of full-scale ship performance became a practical approach. Most of the available techniques used to predict ship motions rely on assumptions from potential flow theory. Even if the natural trend in ship hydrodynamics is to move from frequency-domain to time-domain approach, from linear 2D strip theory type to fully 3D nonlinear techniques, and from potential to viscous computation, potential flow methods are still highly used in ship design, since they provide robust and quite accurate results in low to moderate sea states [3]. The frequency-domain approach is carried out mainly for linear or weakly nonlinear wave theories, where time dependence can be removed by assuming that solution is harmonic in time, in consequence only steady solutions are solved. Assuming that the ship body is slender, strip theory simplifies the 3D flow problem into a 2D formulation, modelling the ship hull as a set of multiple 2D ship stations [4]. The independent boundary value problem for each station can be solved analytically (Lewis form method) or by boundary element method. For the 2D hydrodynamic formulation, since the 1950s, various strip theories have been developed for the seakeeping problem [5]. The pioneer work of Korvin-Kroukovsky [6] set the principal feature of the strip theory for calculating ship motions based on the slender body assumption. This was the first suitable theory for numerical computations of ship motions that had adequate accuracy for engineering applications [7]. A modified strip theory approach of Gerritsma and Beukelman [8] was shown to obtain a good agreement with experimental tests for head wave case. Ogilvie and Tuck [9] developed a mathematically consistent approach based on short wave-length approximation, conducting a systematic analysis for the slender body problem to determine the added mass and damping for heave and pitch motions. Most of today's strip methods are variations of the approach proposed by Salvesen et al. [7], which is one of the most complete versions, solving five degrees of freedom in ship's motion equations, as the surge component was neglected, being not relevant for a slender body oscillation. Since then, more comprehensive strip theories have been developed for ship design, such as [10–14]. Few comprehensive reviews of strip theory variations have been reported by [4,15,16]. Most recently, a combination of two-dimensional strip theory with the two-dimensional Green function based on the potential theory to solve boundary values and motion responses of a semi-planing craft have been reported by [17]. Despite theoretical shortcomings, strip theory has the advantage of being fast, cheap and sufficiently accurate for a range of hull forms and moderate speeds. However, for higher speed vessels, highly flared hull forms, wave loads or extreme motions, other approaches have to be used. The effort devoted to overcoming the weakness of the strip theory methods and to modelling the non-linear phenomena leads to the development of other potential flow alternatives based on numerical 3D methods that enhance the modelling technique of the physical domain of interest. By the late 1970s, a new treatment of the boundary conditions led to the Neumann–Kelvin approach [2], which supposes that the body boundary condition is applied to the mean position of the exact body surface and linearized free-surface boundary condition [2]. The most efficient way to solve the Neumann–Kelvin problem is to employ boundary integral methods where the solution is formulated in terms of singularities, as sources or dipoles, over the hull and free surface [2]. Two different categories of methods have been developed based on the type of singularities used in integral equations, one relies on Green function [18], which automatically satisfies both the radiation and the linearized free surface condition, and the other one relies on the distribution of the simple Rankine sources [18], not only on the hull surface, but also on the free surface. Some of the weaknesses of strip theory and Green function approach can be overcome by using a 3D time-domain panel method based on Rankine sources, including the fully 3D effects of the flow and forward speeds effects. Hess and Smith [19] proposed in 1964 a method for evaluating velocity and pressure fields around a fully immersed arbitrary three-dimensional body. The method, also called the panel method or the boundary element method allowed, for the first time, to calculate the flow around an arbitrary three-dimensional body imposing the boundary condition exactly on the body surface. Firstly Gadd [20], then Dawson [21], applied the panel method for steady free surface flow distributing Rankine sources on hull and undisturbed free surface. A wide variety of different approaches for solving the nonlinear steady forward motion problem, based on Rankine sources distribution, has been reported by [22–25]. Due to the development of computing capabilities, the panel method has been continuously improved to solve the problems of ship motions in waves considering different modelling of nonlinearities of the hull and free surface boundary conditions. Nakos et al. [26] used a Rankine source method to solve transient wave–body interactions. This method has linearized the solutions about the double body flow. Large ship motion analysis performed by [27] was based on the application of the desingularised source method. Söding et al. [28] applied patch method instead of the collocation method to satisfy boundary conditions on the solid body surface, considering for the free surface a nonlinear condition. Recently, an improved desingularised Rankine method has been proposed by Mei et al. [29] to solve 3D diffraction and radiation problems. Dai and Wu [30] combined a method based on a Rankine panel method for the near-field and a transient Green function method for the far-field to predict large amplitude ship motions. Potential flow solvers for seakeeping prediction have been continuously improved in terms of efficiency and accuracy, but still, the effect of viscosity, turbulence, wave dispersion, wave breaking, green water and slamming impact loading, deck green sea cannot be captured properly using the method based on potential flow assumption [31,32]. Considering the steadily increasing computational power and parallel computing, computational fluid dynamics methods based on the Reynolds-averaged Navier–Stokes (RANS) approach is more frequently applied to solve unsteady seakeeping problems. Most of the commercial solvers adopt a combination of unsteady RANS method, based on finite volume method and multi-phase flow approach, using the volume of fluid method for the treatment of free surface, which is rapidly gaining popularity for ship's motions applications. The advantages of the nonlinear computation techniques without using analytical formulas for added resistance or empirical values for viscous effect are significant for the seakeeping analysis accuracy, but they are considerably more time consuming than potential flow approaches. Therefore, a good balance between accuracy and computational speed is required, especially for the ship design process. The majority of RANS seakeeping simulations have been performed at model scale. The first attempt to solve ship motions in waves was presented in [33]. The results show some problems regarding the accuracy of free-surface due to the limited grid quality. Later, Simonsen et al. [34] carried out motions analysis in heave and pitch motions in regular head waves for KRISO container ship (KCS) hull using the CFDSHIP-IOWA code. Recently, Lungu and Bekhit [35,36] have assessed the seakeeping performances of the KCS and KVLCC (KRISO Very Large Crude Carrier) ship models for regular head wave conditions using NUMECA/FineMarine code. Their results show good agreement with the experiment for model scale. On the other hand, the scale effect seems to be important, as Hochkirch and Mallol [37] presented significant scale effects due to the differences between model-scale flows and full-scale flows. Tezdogan et al. [38] investigate seakeeping behavior and performance of the KCS model at a slow forward speed using Star-CCM+ package (Siemens PLM Software, Plano, TX, USA). Considering the context described above, the present work is focused on a systematic comparison study concerning the analysis of ship's pitch, heave and roll motions in regular waves, for a full-scale ship model. The study was made using three different numerical approaches: the linear strip theory based on the Lewis form shape parameterization developed by Domnisoru [39], as in-house code DYN (module OSC - Oscillations), the non-linear potential flow based on Rankine source distribution using the commercial code SHIPFLOW and, for a limited number of cases, due to it being a highly time consuming solution, the viscous RANS method using NUMECA/FineMarine commercial code. Several series of computations have been performed for the regular wave height of 2 m, heading angle in the range of 0 to 180 deg, with a step of 45 deg. For the BEM model also, a wave height of 8 m has been considered. The computations have been carried out for the full-scale KCS hull numerical model, considering two forward speeds, 12 and, respectively, 24 knots. The authors of this article aim to integrate all the presented methods in the same study in order to achieve a methodology that serves the rapid decision-making process in the case of further studies concerning the choice of the most accurate estimation method for ship motions on waves, depending on the specific requirements of the study and taking into account costs and calculation time. The proposed methodology meant approaching the mentioned methods, globally, with in-house code and commercial software, and the major advantage consisted of a better management of the input data, working conditions, calculation hypotheses, analyzed cases. It is worth mentioning that in the present article, full-scaled ship computations are considered, while most of the literature references reported analyses on model-scaled ship. #### 2. Methods for Ship Motions Prediction As most of the available techniques to predict ship motions for design purposes rely on assumptions of potential flow theory, two different methods from this category have been chosen for comparison. The third approach considered for the present study is based on RANS solver, but, despite the parallel computing, this method does not prove yet to be able to solve the seakeeping problem in reasonable time to be consider in the practical design procedures. Taking into account that the methods involved in the present study rely on well-known mathematical formulation presented in seakeeping references [4,7,22,40–42], in this chapter only a brief presentation for each method is included. The first method is based on a potential flow hydrodynamic linear 2D strip theory, with Lewis ship's stations parameterization and regular wave Airy model excitation, with a frequency-domain solution of the coupled heave–pitch motion equations and uncoupled roll motion equation. This method is implemented by Domnisoru [39]—as in-house code DYN, module OSC—for the linear oscillations response amplitude operator (RAO) response amplitude operator computation. The mathematical formulation of the method used is described in [39]. The DYN code, module OSC, has been validated by experimental tests on scaled models of a fishing vessel [43] and a survey vessel [44], on follow, head, beam and quartering regular wave conditions. For the second set of computations, a 3D fully nonlinear time-domain boundary element method, implemented into the commercial code SHIPFLOW [22,40] has been employed for ship motion estimation, considering only potential flow formulation being suitable for practical use. The method solves the missed boundary value problem for Laplace equation by distributing sources on the hull and free surface. Integrating the kinematic and dynamic boundary conditions with a fourth order Adam–Bashford–Moulton method, the elevation of free surface is obtained at each time step based on a Mixed Euler–Lagrange method. A blending zone based on an analytical solution is introduced in order to avoid the reflection from domain boundaries and in order to generate a certain incident wave. Once the velocity potential is obtained on the hull, using Unsteady Bernoulli formulation, the pressure distribution on the hull can be obtained. Finally, after integrating pressure on the hull, forces, moment and then motions are determined. A full description of the mathematical model and the numerical method may be found in [40,45]. Validation of the above-described method has been reported by Larsson et al. [46] for added resistance, pitch and heave, and by Coslovich et al. [47] mainly for roll. The commercial software NUMECA/FineMarine [41,42] has been used in this study to solve the incompressible unsteady RANSE flow at ship motions in head waves. The solver relies on the finite volume method to build the spatial discretization for the governing equation. Closure to the turbulence is achieved by making use of the k-ω SST model with wall function formulation [41]. Pressure–velocity coupling is enforced through a SIMPLE (Semi-Implicit Method for Pressure Linked Equations)-like approach, where the velocity updates come from the momentum equation and the pressure is extracted from the mass conservation constraints transformed into pressure equation. Convection and diffusion terms in the RANSE are discretized using a second-order up-wind scheme and a central difference scheme, respectively. Free-surface capturing strategy is based on multi-phase flow approach using a volume of fluid method with high-resolution interface schemes [42]. Ship's 6 DOF (Degrees Of Freedom) can be solved by the solver, but also some degree of freedom can be restrained. Mathematical model and the numerical framework are nicely described in [41]. Several validation studies of the solver have been reported by [48] for ship resistance and self-propulsion, and by [31,35,36,49] for ship motions in head waves. Their results show good agreement with the experiment for the scaled model. In the preliminary ship design process, time is an important aspect to be considered due to the fact that naval architect usually cannot afford too long computational time. Considering the present methods comparison for one case (v = 12 Kn, ω = 0.4, hw = 2 m and head wave), by far strip theory is the less time-consuming method, the time spend for a single calculation case was 3 min using a single processor. The nonlinear BEM computations have been performed on 4 processor machines and the physical computational time for the same case was 19 h and 5 min for a number of about 68,000 panels. The RANS computations have been carried out on a high-performance computing (HPC) machine using 120 processors for a grid of about 20 million cells, which led to a 41 h and 47 min computational time. On the other hand, time consuming should be also correlated with the accuracy and with the amount of information received from a specific flow post-processing. The RAO functions for heave, pitch and roll based on the linear strip theory implemented in DYN code have been validated in references [43,44] for heading angles, 0, 90, 180 degrees, proving good results for practical investigations, revealing average differences from 12% to 18%. A validation BEM method in terms of heave and pitch was performed by the authors in [50] and the computed results showed good agreement of 3% to 10% with towing tank measurements. As mentioned before, extensive validation studies may be found in [45,46]. In addition, grid convergence and validations studies based on FineMarine RANS solver have been reported by Lungu and Bekhit [35,36]. Their results revealed good agreement with the towing tank test measurements for model scale, 1–7%. Taking all the above mentioned into consideration, a trade-off between accuracy and computational costs must be counted in order to obtain feasible results for the ship design practical use. In order to compare directly the computational fluid dynamics (CFD) results with those obtained by using linear strip theory, for all numerical analyses, the regular Airy model is considered as excitation source. Both CFD methods are hydrodynamic nonlinear, so that even if the excitation has one harmonic, the time-domain response has several harmonics. For the two CFD methods, heave, pitch and roll time records are spectrally analyzed by using Direct Fourier Transformation Method. Regarding the response amplitude spectra (see Section 6), only the motions amplitudes with encountering wave frequency harmonic are considered. The response amplitude operators (RAO s) for ship motions obtained by the two CFD methods represent the ratio between heave, pitch and roll amplitudes on wave's harmonic and the regular wave amplitude. #### 3. Hull Geometry and Conditions The objective of the present study is to investigate the seakeeping performances of the KRISO container ship (KCS) while sailing in regular wave at two speeds, 12 and 24 Kn, corresponding to Froude numbers of 0.13, and 0.26, respectively. The KCS hull is a benchmark test case for ship hydrodynamics widely used in the marine hydrodynamic scientific community [34]. The hull is a modern commercial container vessel with bulbous bow and flare fore above the waterline. The stern is a typical pram type stern with transom. Bare hull, without rudder, has been considered for the seakeeping calculations. KCS hull geometry is presented in Figure 1 and the main dimensions and conditions used for numerical simulations are presented in Table 1. Figure 1. KRISO container ship (KCS) hull geometry. In Table 2, the test cases for seakeeping analysis are presented. The ship motions are approached considering the ship on regular Airy wave, having the wave height of 2 and 8 m, the wave frequency between 0 and 2 rad/s and heading angle in range of 0 to 180 deg, with a step of 45 deg. Even though the ship response in a regular wave at zero speed was computed, in the following paragraphs the ship motions for only two speed values of 12 and 24 Kn, respectively, are presented. Although, the study was carried out for three values of vertical center of gravity, KG = 7.3, 10.8 and 14.3 m, in the paper, the results for only KG = 10.8 m, which corresponds to a medium loading case of the ship, are presented. Table 2. Test cases. #### 4. Numerical Setup Several details about the computational conditions will be briefly described in the following. For the discretization of the hull used for the linear 2D strip theory calculations, a model of 526 stations has been used. For the BEM method, the boundary value problem modelling the field equation and boundary conditions have been solved, making use of the commercial code SHIPFLOW. The computations carried out with BEM is a fully nonlinear unsteady three-dimensional potential flow method, that takes into account the geometric non-linearities of ship shape and the induced hydrodynamic non-linearities, although the external excitation is kept linear. Wave reflection from domain's boundaries is a pure numerical problem that affects all the simulations with a restricted domain. In order to avoid wave reflection from the free surface truncation boundaries, the flow on the intersection between the outer and inner domain has to be the same. To achieve this condition, a numerical damping zone is located close to the domain's boundaries and such a zone only has to dampen the difference between the velocity potential in the inner and outer domain. This difference in the solution between the inner and the outer domain is mainly due to the presence of the body with radiation and diffraction effects but can also derive from a numerical error. This damping is achieved adding a term in the free surface boundary condition for all those panels that belong to such a zone [51,52]. The fluid domain assumes that the flow is known a priori in the outer domain and the current method uses analytically described waves to represent the flow field in the outer domain. The hull and free surface have been discretized by panels. The calculations have been performed for a surface domain of one ship length upstream, two ship length downstream, the width of the free surface being two ship length. For BEM method, the ship hull is discretized both sides without the request of symmetry condition, so that any heading angle condition can be computed. The number of panels distributed on hull and free surface varied between 60,000 and 90,000 panels function of the wave frequency case studied, which assures a minimum number of 40 panels per wavelength. The computations have been performed on local desktop machines with four cores of 3.1 GHz. For the unsteady RANS simulation of incompressible flow of ship motions in head waves, the commercial solver NUMECA/FineMarine was used. A reference length has been considered Lref = max (LBP, λ). The dimensions of the computation domain have been chosen according to the ship and wavelength, considering 2.0 Lref upstream, 4.0 Lref downstream, 2.0 LBP on the side, 4.0 LBP underneath, and 2.0 LBP above the undisturbed free-surface level. The boundary conditions imposed on the solid wall and domain boundaries, but also the dimensions considered for the computational domain, are depicted in Figure 2. A mirror condition is applied on the centerline plane of the ship and on the side boundary of the domain, to avoid wave reflections at lateral boundary. Considering the head wave case computed by the RANS method, the corresponding wave is generated at the upstream boundary and the inlet boundary is chosen to ensure at least two full waves to be generated before encountering the ship. The free surface is refined for the entire domain using three different refinement boxes, as can be observed in Figure 2. The first starts from the inlet boundary and is extended until it reaches 1.0 Lref behind the ship. The cell size is chosen for this refinement zone in x- and y-direction to provide minimum 60 cells per wavelength, such that Δx1 = Δy1 = λ/60, while in the z-direction the refinement criterion is selected as Δz = hw/16, where hw represents the wave height. The refinement depth in z-direction is extended for 3.0 hw equally distributed above and beneath the non-disturbed free-surface level, which is set at the design draft T = 10.8 m from the ship base line. The second and third boxes are coarsened gradually in x- and y-directions to generate sufficient numerical damping zones to prevent any reflections from the exit boundary. The second box is extended for 1.0 Lref and it is used as an initial damping relaxation zone, in which the cell size is coarsened in x- and y-directions by a factor of 4 (i.e., Δx2 = Δy2 = 4.0 × Δx1). The third refinement zone is used as a final damping zone, having the cell size coarsened in x- and y-directions by a factor of 8.0 (i.e., Δx3 = Δy3 = 8.0 Δx1), while the refinement in the z-direction for the entire domain is maintained unchanged. The effect of damping zone on the RANS solution is clearly seen in Figure 3. Figure 2. RANS Computational domain, dimensions and boundary conditions. Figure 3. RANS damping zone effect. Body-fitted full hexahedral unstructured meshes of about 22 million cells have been generated (Figure 4). The time step Δt has been chosen in order to fulfil the condition of 300-time steps per wave period, with fourth order convergence criteria. All the computations have been performed on a HPC machine with 120 cores of 3.3 GHz. Figure 4. Computational grid. (a) Domain discretization; (b) mesh details in bow area. In general, methodology used in the present paper for the seakeeping performance prediction is based on the practical guidelines recommended by the International Towing Tank Conference (ITTC), by software providers and different sensitivity and validation studies [35,36,49–52], but for some particular cases the recommendations could not be accomplished due to the practical reasons. #### 5. Grid Convergence Test A grid study for SHIPFLOW calculations was conducted for three grids based on the Richardson extrapolation [53] in order to investigate the numerical simulation error and uncertainty. Two calculation cases have been considered for the grid test: ship on regular waves, head waves (μ = 180 deg) and beam sea (μ = 180 deg). For both cases ship speed was v = 12 Kn. The results of grid convergence study for RAO heave, pitch and roll are summarized in Table 3. The convergence ratio is defined as RG = ε21/ε32, where ε<sup>21</sup> = S2 − S1 and ε<sup>32</sup> = S3 − S2 stands for simulation error, S1 represents the solution calculated for fine grid (68,716 panels), S2 for medium grid (32,692 panels) and S3 for coarse grid (16,346 panels), according to Richardson extrapolation approach [53], with the expressions (1) ÷ (4). The grid corresponding to each level of refinement is depicted in Figure 5 for hull and free surface. Table 3. Grid convergence test results. Figure 5. Grid refinement levels used for the grid convergence test. (a1) Coarse grid on hull surface; (a2) Coarse grid on free-surface; (b1) Medium grid on hull surface; (b2) Medium grid on free-surface; (c1) Fine grid on hull surface; (c2) Fine grid on free-surface. Considering the computed values of RG for all variables of grid convergence study, one can observe that monotonic convergence is achieved for all the simulation variable. The order of accuracy pG can be calculated based on the refinement ration rG, as follows: $$p\_G = \frac{\ln\left(\frac{\varepsilon\_{32}}{\varepsilon\_{21}}\right)}{\ln(r\_G)}.\tag{1}$$ The calculated order of accuracy is used further to determine the correction factor CG and the error δG, as follows: $$c\_G = \frac{r\_G^{pc} - 1}{r\_G^{p\_{th}} - 1},\tag{2}$$ $$ \delta\_G = \frac{\pounds\_{21}}{r\_G^{p\_G}} \tag{3} $$ where pth is the theoretical grid convergence order usually considered pth = 2. Finally, the uncertainty is computed by the expression: $$\mathcal{L}I\_{\mathcal{G}} = \|\mathcal{C}\_{\mathcal{G}} \times \delta\_{\mathcal{G}}\| + \|(1 - \mathcal{C}\_{\mathcal{G}}) \times \delta\_{\mathcal{G}}\| \tag{4}$$ Based on this study, bearing in mind that the percentage estimated error with respect to the fine grid is very small, i.e., ε21%S1 << 1, which concludes that the solution computed by SHIPFLOW is grid independent. #### 6. Results and Discussion In this section, the ship hydrodynamic response in regular waves is presented and discussed. The results are represented in the frequency domain, in terms of response amplitude operators (RAO) for heave, pitch and roll motion, respectively. The charts contain the results obtained by linear strip theory method (DYN code) and the boundary element method (SHIPFLOW software), also including a few results obtained using the RANS method (NUMECA/FineMarine). In Figure 6, the ship on regular waves, for the case of top speed v = 12 Kn, μ = 90 deg, ω = 0.4 rad/s and hw = 2 m, is presented. The images represent the hull position at five different fractions of ship motion periods (ΔT) related to free surface topologies. Hydrodynamic forces and moments are determined by integrating pressure over the ship hull based on the quadratic pressure distribution. Pictures on the left, Figure 6a1–e1, present the pressure distribution over the ship hull. One may see that the flow solution for ω = 0.4 rad/s reveals that the wave is fully developed, and artificial damping condition imposed on the boundaries works fine. Moreover, the interference of the wave system generated by the ship and the incident wave is well captured by the boundary element method and some nonlinear effects are expected (see the pictures on the right, Figure 6a2–e2). Figure 6. Cont. Figure 6. Pressure distribution and free surface topology computed for the case μ = 90 deg. (a1) Pressure distribution on the hull, ΔT = 0; (a2) Free-surface topology, ΔT = 0; (b1) Pressure distribution on the hull, ΔT = 0.125; (b2) Free-surface topology, ΔT = 0.125; (c1) Pressure distribution on the hull, ΔT = 0.250; (c2) Free-surface topology, ΔT = 0.250; (d1) Pressure distribution on the hull, ΔT = 0.375; (d2) Fre-surface topology, ΔT = 0.375; (e1) Pressure distribution on the hull, ΔT = 0.500; (e2) Free-surface topology, ΔT = 0.500. In Figures 7–11, the response amplitude operators for heave, pitch and roll motions of KCS ship advancing in regular waves are represented. Heave RAO (m/m), Pitch RAO (rad/m) and Roll RAO (rad/m), respectively, for the speed case of ship speed 12 Kn and the wave height 2 m (amplitude aw = 1 m). In Figure 7, the heave response amplitude operator, Heave RAO (m/m), for the speed case of 12 Kn, obtained using a 2D strip and BEM methods is represented. As a general remark, for both methods, the ship response is significant in the lower frequency domain, while, as the frequency increases, the ship response decreases considerably. The maximum values are recorded for the heading angle μ = 90 deg, at ω = 0.756 rad/s. Once the circular frequency of the regular wave increases, one may observe that both methods are in good agreement. Figure 7. Heave response amplitude operator (RAO) (m/m) for v = 12 Kn, hw = 2 m. (a) μ = 0 deg; (b) μ = 45 deg; (c) μ = 90 deg; (d) μ = 135 deg; (e) μ = 180 deg. Figure 8. Pitch RAO (rad/m), for v = 12 Kn, hw = 2 m. (a) μ = 0 deg; (b) μ = 45 deg; (c) μ = 90 deg; (d) μ = 135 deg; (e) μ = 180 deg. Figure 9. Heave RAO (m/m), DYN–SHIPFLOW–NUMECA comparison, v = 12 Kn, μ = 180 deg, hw = 2 m. Figure 10. Pitch RAO (rad/m), DYN–SHIPFLOW–NUMECA comparison, v = 12 Kn, μ = 180 deg, hw = 2 m. Figure 11. Roll RAO (rad/m), v = 12 Kn, KG = 10.8 m, hw = 2 m. (a) μ = 45 deg; (b) μ = 90 deg; (c) μ = 135 deg. In Figure 8, the response amplitude operator for pitch motion, Pitch RAO (rad/m) is depicted, for ship speed 12 Kn, heading angles from 0 to 180 deg, and wave height of 2 m. For pitch motion at beam sea condition, the response amplitude is the smallest one, recording scattered values between the 2D strip and the BEM hydrodynamic models. In particular, at 90 deg, the variation of BEM results has two peaks, the second one at similar frequency as the DYN results; however, the values obtained by the boundary element method are higher than the strip model results at beam sea. The maximum value is recorded at μ = 135 deg for ω = 0.57 rad/s. A good agreement between both hydrodynamic models is found at a heading angle of 45 and 135 deg. In Figures 9 and 10, the following are presented: numerical results for Heave RAO (m/m) and Pitch RAO (rad/m) obtained with linear 2D strip method (DYN), BEM boundary element method (SHIPFLOW) and RANS method (NUMECA/FineMarine), considering the ship on head regular wave, μ = 180 deg, with 2 m height and a ship speed of 12 Kn. In Figure 11, the following are given: the results for the roll motion in terms of response amplitude operator, Roll RAO (rad/m). The results are represented for the heading angle of 45, 90 and 135 deg, respectively. The maximum value for Roll RAO is recorded for μ = 90 deg and, as long as it moves away from the beam waves, the roll motion of the ship attenuates. Next, a comparison between the results computed with linear 2D strip and BEM hydrodynamic models, for a regular wave height hw = 8m(aw = 4 m) for BEM model, is depicted in Figures 12 and 13. First, one may see the Heave RAO (m/m) values at five different heading angles (Figure 12). The trend of the differences between the two methods remains the same as for the case of wave height hw = 2 m. Very reduced differences occur in the case of the BEM method results at 2 and 8 m wave height, due to the reduced hydrodynamic nonlinearities. Higher differences appear at beam wave condition between 0.4 and 0.6 rad/s. Figure 12. Heave RAO (m/m), v = 12 Kn, hw = 8 m for BEM model. (a) μ = 0 deg; (b) μ = 45 deg; (c) μ = 90 deg; (d) μ = 135 deg; (e) μ = 180 deg. Figure 13. Pitch RAO (rad/m), v = 12 Kn, hw = 8 m for BEM model. (a) μ = 0 deg; (b) μ = 45 deg; (c) μ = 90 deg; (d) μ = 135 deg; (e) μ = 180 deg. In Figure 13, the variation curves of Pitch RAO (rad/m) for wave height hw = 8 m for BEM model, with the peak value for the heading angle of μ = 135 deg around ω = 0.5 rad/s, are depicted. At beam waves, μ = 90 deg, differences between the hydrodynamic approaches are scattered, where the values of Pitch RAO are very reduced. The next results are computed for the second ship speed case, v = 24 Kn, for both wave heights of 2 and 8 m, respectively. There were also considered the same medium loading conditions of the ship. In Figure 14, the RAO heave (m/m) is presented. The differences between the linear 2D strip and BEM hydrodynamic approaches have slightly increased compared to 12 Kn ship speed, especially for wave circular frequency lower than ω = 0.4 rad/s. Figure 14. Heave RAO (m/m), v = 24 Kn, hw = 2 m for BEM model. (a) μ = 0 deg; (b) μ = 45 deg; (c) μ = 90 deg; (d) μ = 135 deg; (e) μ = 180 deg. In Figure 15, the Pitch RAO (rad/m) for 24 Kn ship speed and 2 m wave height are presented. The Pitch RAO has the maximum peak values for the head wave case, around ω = 0.46 rad/s. At the same time, one may observe that the hydrodynamic models provide better agreement for the beam wave case μ = 90 deg. Figure 15. Pitch RAO (rad/m), v = 24 Kn, hw = 2 m. (a) μ = 0 deg; (b) μ = 45 deg; (c) μ = 90 deg; (d) μ = 135 deg; (e) μ = 180 deg. In Figure 16, the Roll RAO (rad/m) for 24 Kn ship speed and 2 m wave height are presented. The trend of results is maintained for the roll motion as for the 12 Kn ship speed case, the boundary element method being in agreement with the strip theory, for all the heading waves considered. The maximum values appear at beam wave, 0.16 rad/m around ω = 0.47 rad/s. At the same time, as long as the ship is in oblique waves, the values of roll motion decrease. Figure 16. Roll RAO (rad/m), v = 24 Kn, KG = 10.8 m, hw = 2 m. (a) μ = 45 deg; (b) μ = 90 deg; (c) μ = 135 deg. At 24 Kn ship speed and 8 m wave height for the BEM model, the Heave RAO (Figure 17) records visible differences to the BEM solution at the same speed, but with 2 m wave height, due to hydrodynamic nonlinearities for the wave's circular frequency up to 0.6 rad/s. Figure 18 presents the pitch RAOs for 24 Kn ship speed and 8 m wave height. The differences between the BEM model, with 8 m wave height, and the linear 2D strip model become more significant in comparison to the case with wave height 2 m, due to the recorded hydrodynamic nonlinearities. Figure 17. Heave RAO (m/m), v = 24 Kn, hw = 8 m for the BEM model. (a) μ = 0 deg; (b) μ = 45 deg; (c) μ = 90 deg; (d) μ = 135 deg; (e) μ = 180 deg. Figure 18. Pitch RAO (rad/m), v = 24 Kn, hw = 8 m for the BEM model. (a) μ = 0 deg; (b) μ = 45 deg; (c) μ = 90 deg; (d) μ = 135 deg; (e) μ = 180 deg. The Heave RAO peak is 1.071 m/m around ω = 0.5 rad/s for μ = 135 deg (as can be seen in Figure 17) while the maximum value of the Pitch RAO is 0.02 rad/m around ω = 0.45 rad/s (shown in Figure 18), when the ship is in head waves μ = 180 deg. In Figure 19, a comparison between heave amplitude spectrum, by DFT (Direct Fourier Transformation) method implemented in DYN code, for the two speed cases (12 and 24 Kn) and wave height hw = 2 m, heading angle μ = 180 deg, wave circular frequency ω = 0.4 rad/s (with ship–wave fe encountering frequencies 0.080 and 0.096 Hz), is made. The same comparison for pitch amplitude spectrum, by DFT method is made. Both diagrams represent the results obtained using the BEM boundary element method by SHIPFLOW. In Figure 20, the same comparison is made for wave height of hw = 8 m. Figure 19. SHIPFLOW—Amplitude Spectrum by DFT method, v = 12 and 24 Kn, hw = 2 m, μ = 180 deg, ω = 0.4 rad/s (fe = 0.080 and 0.096 Hz). (a) Heave Amplitude Spectrum (m); (b) Pitch Amplitude Spectrum (rad). Figure 20. SHIPFLOW— Amplitude Spectrum by DFT method, v = 12 and 24 Kn, hw = 8 m, μ = 180 deg, ω = 0.4 rad/s (fe = 0.080 and 0.096 Hz). (a) Heave Amplitude Spectrum (m); (b) Pitch Amplitude Spectrum (rad). Both heave and pitch amplitude spectra by DFT method, in the case of higher ship speed of 24 Kn, have narrowed frequency bands. Additionally, at hw = 8 m wave height, the heave and pitch amplitude spectra present a series of higher harmonics, with small amplitudes, due to the hydrodynamic nonlinearities. In Figures 21 and 22, a comparison between BEM and RANS hydrodynamic models is performed. A comparison of Heave Time Record and Pitch Time Record computed for the KCS vessel at v = 12 Kn at heading angle μ = 180 deg and circular wave frequency ω = 0.4 rad/s (fe = 0.080 Hz) is presented in Figure 21. Figure 21. NUMECA–SHIPFLOW Time Records comparison v = 12 Kn, hw = 2 m, μ = 180 deg, ω = 0.4 rad/s (fe = 0.080). (a) Heave Time Record (m) (b) Pitch Time Record (rad). Figure 22. Comparison of NUMECA–SHIPFLOW Amplitude Spectrum by DFT method, v = 12 Kn, hw = 2 m, μ = 180 deg, ω = 0.4 rad/s (fe = 0.080). (a) Heave Amplitude Spectrum [m]; (b) Pitch Amplitude Spectrum (rad). A comparison of Heave Amplitude Spectrum and Pitch Amplitude Spectrum computed for the KCS vessel at v = 12 Kn, at heading angle μ = 180 deg and circular wave frequency ω = 0.4 rad/s (fe = 0.080 Hz) is presented in Figure 22. While for the Heave Amplitude Spectrum, SHIPFLOW and NUMECA show good agreement, for the Pitch Amplitude Spectrum some difference occurs between the two models. #### 7. Conclusions In this paper, for the KCS full-scale model (Section 3), several numerical seakeeping analyses have been performed, in order to compare three hydrodynamic methods for the prediction of the dynamic response on heave, pitch and roll oscillations, in terms of response amplitude operators. The selected hydrodynamic methods are the most used approaches for ships motions, linear 2D strip theory, BEM and RANS methods, involving in-house codes and commercial codes. A grid convergence study has been conducted to determine the accuracy of the grid used to compute the flow based on the potential BEM approach (Section 5). The study revealed that solution computed by SHIPFLOW is grid independent and the grid error for the grid used is less than 1%. The BEM and RANS methods, with time-domain solutions, were compared to the linear strip (ST) method, with frequency-domain solution; although the external excitation is a regular wave, the ship's response shows higher harmonics (Figures 19 and 20), due to the hydrodynamic nonlinearities. Therefore, in order to ensure the same reference for all three methods, the nonlinear response amplitude operators (RAOs), obtained using BEM and RANS methods, were computed considering only the main spectral amplitude for the ship-wave encountering frequency, being the only result delivered by the linear 2D strip method. Nevertheless, the BEM and RANS studies have revealed, for the KCS model, reduced nonlinear dynamic response components, even if the regular wave height was up to 8 m and the speed of the ship was 24 Kn (Figures 19, 20 and 22). For a detailed benchmark between the three hydrodynamic models (Section 2), this parametric study developed for the KCS model (Sections 3 and 4), at one loading case, has been focused on the influence of ships speed (12 and 24 Kn), wave heading angle (0, 45, 90, 135, 180 deg) and height (2 and 8 m), on the ship's dynamic response in regular wave, using deterministic analyses (Section 6). Comparing the Heave RAO functions between the three hydrodynamic models' results (Figures 7, 9, 12, 14 and 17) (Section 6), for ship speed of 24 Kn versus 12 Kn and 8 m wave height versus 2 m, the BEM method delivers visible differences due to the hydrodynamic nonlinearities, especially for the wave circular frequencies up to 0.6 rad/s. In the case of beam waves, for wave circular frequency within the range of 0.4 to 0.6 rad/s, the BEM values are quite scattered around the 2D strip model results. In addition, visible differences, for head waves, have been seen between the RANS method and the other two (Figure 9). Comparing the Pitch RAO functions between the three hydrodynamic models (Figures 8, 10, 13, 15 and 18) (Section 6), it turned out that the maximum values are obtained for head wave conditions and are very small for beam wave conditions. As the ship's speed and wave height increase, the hydrodynamic nonlinearities induce visible differences between the results, especially close to the peak values of Pitch RAO. Except for 0.3 rad/s, on head waves, the differences between the RANS and the other two methods are quite scattered for the analyzed wave's frequency domain (Figure 10). Comparing the Roll RAO functions between the BEM and 2D strip hydrodynamic results (Figures 11 and 16) (Section 6), it turned out that the maximum values are obtained for beam waves condition, being a narrow frequency band response amplitude operator. The differences are noticeable at a beam wave condition close to the RAO peak value, especially due to the different hydrodynamic damping formulation of the two methods. As an overall analysis, we can conclude that the RAO's values predicted by the linear 2D strip theory can be considered as average values compared to the BEM and RANS results, being suitable for practical seakeeping analyses of mono-hull slender body ships. Further studies will extend this parametric analysis to more numerical results based on the RANS method considering other ship types, being focused on the sensitivity of the hydrodynamic methods used for ship's motions prediction. Additionally, the next step consists of short-term seakeeping analysis in irregular waves, where, besides the BEM and RANS methods, also a nonlinear strip theory with time-domain solution is to be applied. Author Contributions: Conceptualization, F.P. and L.D.; methodology, F.P., L.D. and S.P.; software, F.P., L.D. and S.P.; validation, F.P. and L.D.; formal analysis, S.P.; investigation, F.P., L.D. and S.P.; resources, F.P., L.D. and S.P.; data curation, F.P.; writing—original draft preparation, F.P., L.D. and S.P.; writing—review and editing, S.P., F.P. and L.D.; visualization, S.P. and F.P.; supervision, L.D.; project administration, S.P.; funding acquisition, S.P. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Acknowledgments: The research study presented in this article was developed in the frame of Dunarea de Jos University of Galati, Naval Architecture Research Centre. Conflicts of Interest: The author declares no conflict of interest. #### Abbreviations #### References Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). MDPI St. Alban-Anlage 66 4052 Basel Switzerland Tel. +41 61 683 77 34 Fax +41 61 302 89 18 www.mdpi.com Journal of Marine Science and Engineering Editorial Office E-mail: [email protected] www.mdpi.com/journal/jmse MDPI St. Alban-Anlage 66 4052 Basel Switzerland Tel: +41 61 683 77 34 Fax: +41 61 302 89 18	doab	2025-04-07T04:13:04.634590	11-1-2022 14:43	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "ffefa398-de0d-4481-a8ce-0276e7d09a9c", "url": "https://mdpi.com/books/pdfview/book/4264", "author": "", "title": "Stability and Seakeeping of Marine Vessels", "publisher": "MDPI - Multidisciplinary Digital Publishing Institute", "isbn": "9783036509709", "section_idx": 15 }
fffbeb8d-bfd4-49af-82cd-f97f975045ea	# The Unicode Cookbook for Linguists Managing writing systems using orthography profiles Steven Moran Michael Cysouw Translation and Multilingual Natural Language Processing 10 ### Translation and Multilingual Natural Language Processing Editors: Oliver Czulo (Universität Leipzig), Silvia Hansen-Schirra (Johannes Gutenberg-Universität Mainz), Reinhard Rapp (Johannes Gutenberg-Universität Mainz) In this series: # The Unicode Cookbook for Linguists Managing writing systems using orthography profiles Steven Moran Michael Cysouw Steven Moran & Michael Cysouw. 2018. The Unicode Cookbook for Linguists: Managing writing systems using orthography profiles (Translation and Multilingual Natural Language Processing 10). Berlin: Language Science Press. This title can be downloaded at: http://langsci-press.org/catalog/book/176 © 2018, Steven Moran & Michael Cysouw Published under the Creative Commons Attribution 4.0 Licence (CC BY 4.0): http://creativecommons.org/licenses/by/4.0/ ISBN: 978-3-96110-090-3 (Digital) 978-3-96110-091-0 (Hardcover) ISSN: 2364-8899 DOI:10.5281/zenodo.773250 Source code available from www.github.com/langsci/176 Collaborative reading: paperhive.org/documents/remote?type=langsci&id=176 Cover and concept of design: Ulrike Harbort Typesetting: Michael Cysouw, Steven Moran Proofreading: Sandra Auderset, Aleksandrs Berdičevskis, Rosey Billington, Varun deCastro-Arrazola, Simon Cozens, Aniefon Daniel, Bev Erasmus, Amir Ghorbanpour, Linda Leembruggen, David Lukeš, Antonio Machicao y Priemer, Hugh Paterson III, Stephen Pepper, Katja Politt, Felix Rau, Lea Schäfer, Benedikt Singpiel, James Tauber, Luigi Talamo, Jeroen van de Weijer, Viola Wiegand, Alena Witzlack-Makarevich, and Esther Yap Fonts: Linux Libertine, Libertinus Math, Arimo, DejaVu Sans Mono Typesetting software: XƎLATEX Language Science Press Unter den Linden 6 10099 Berlin, Germany langsci-press.org Storage and cataloguing done by FU Berlin # Preface This text is meant as a practical guide for linguists and programmers who work with data in multilingual computational environments. We introduce the basic concepts needed to understand how writing systems and character encodings function, and how they work together. The intersection of the Unicode Standard and the International Phonetic Alphabet is often met with frustration by users. Nevertheless, the two standards have provided language researchers with the computational architecture needed to process, publish and analyze data from many different languages. We bring to light common, but not always transparent, pitfalls that researchers face when working with Unicode and IPA. In our research, we use quantitative methods to compare languages to uncover and clarify their phylogenetic relationships. However, the majority of lexical data available from the world's languages is in author- or document-specific orthographies. Having identified and overcome the pitfalls involved in making writing systems and character encodings syntactically and semantically interoperable (to the extent that they can be), we have created a suite of open-source Python and R software packages to work with languages using profiles that adequately describe their orthographic conventions. Using these tools in combination with orthography profiles allows users to tokenize and transliterate text from diverse sources, so that they can be meaningfully compared and analyzed. We welcome comments and corrections regarding this book, our source code, and the supplemental case studies that we provide online.<sup>1</sup> Please use the issue tracker, email us directly, or make suggestions on PaperHive.<sup>2</sup> Steven Moran Michael Cysouw <sup>1</sup>https://github.com/unicode-cookbook/ <sup>2</sup>https://paperhive.org/ # Acknowledgments We gratefully acknowledge Robert Forkel, Jeff Good, Jeremy Kahn, Dan McCloy, Sebastian Nordhoff, and Richard Wright, for insights and inspiration. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007- 2013)/ERC grant agreement n° 240816 (PI Michael Cysouw). # Contents ### Contents ### Contents # 1 Writing systems ### 1.1 Introduction Writing systems arise and develop in a complex mixture of cultural, technological and practical pressures. They tend to be highly conservative, in that people who have learned to read and write in a specific way – however impractical or tedious – are mostly unwilling to change their habits. Writers tend to resist spelling reforms. In all literate societies there exists a strong socio-political mainstream that tries to force unification of writing (for example by strongly enforcing "right" from "wrong" spelling in schools). However, there are also communities of users who take as many liberties in their writing as they can get away with. For example, the writing of tone diacritics in Yoruba is often proclaimed to be the right way to write, although many users of Yoruba orthography seem to be perfectly fine with leaving them out. As pointed out by the proponents of the official rules, there are some homographs when leaving out the tone diacritics (Olúmúyı̀w 2013: 44). However, writing systems (and the languages they represent) are normally full of homographs (and homophones), which is not a problem at all for speakers of the language. More importantly, writing is not just a purely functional tool, but just as importantly it is a mechanism to signal social affiliation. By showing that you know the rules of expressing yourself in writing, others will more easily accept you as a worthy participant in their group – whether it means following the official rules when writing a job application or conforming to the informal rules when writing text messages. The case of Yoruba writing is an exemplary case, as even after more than a century of efforts to standardize the writing systems, there is still a wide range of variation of writing in daily use (Olúmúyı̀w 2013). ### Formalizing orthographic structure The resulting cumbersome and often illogical structure of writing systems, and the enormous variability of existing writing systems for the world's languages, is a fact of life that scholars have to accept and they should try to adapt to as well as they can. Our goal in this book is a proposal for how to do exactly that: ### 1 Writing systems formalize knowledge about individual writing systems in a form that is easy to use for linguists in daily practice, and at the same time computer-readable for automated processing. When considering worldwide linguistic diversity, including the many lesserstudied and endangered languages, there exist numerous different orthographies using symbols from the same scripts. For example, there are hundreds of orthographies using Latin-based alphabetic scripts. All of these orthographies use the same symbols, but these symbols differ in meaning and usage throughout the various orthographies. To be able to computationally use and compare different orthographies, we need a way to specify all orthographic idiosyncrasies in a computer-readable format. We call such specifications orthography profiles. Ideally, these specifications have to be integrated into so-called Unicode Locales,<sup>1</sup> though we will argue that in practice this is often not the most useful solution for the kind of problems arising in the daily practice of many linguists. Consequently, a central goal of this book is to flesh out the linguistic-specific challenges regarding Unicode Locales and to work out suggestions to simplify their structure for usage in a linguistic context. Conversely, we also aim to improve linguists' understanding and appreciation for the accomplishments of the Unicode Consortium in the development of the Unicode Standard. The need to use computational methods to compare different orthographies arises most forcefully in the context of language comparison. Concretely, the proper processing of orthographies and transcription systems becomes critical for the development of quantitative methods for language comparison and historical reconstruction. In order to investigate worldwide linguistic variation and to model the historical and areal processes that underlie linguistic diversity, it is crucial that we are able to flexibly process numerous resources in different orthographies. In many cases even different resources on the same language use different orthographic conventions. Another orthographic challenge that we encounter regularly in our linguistic practice is electronic resources on a particular language that claim to follow a specific orthographic convention (often a resource-specific convention), but on closer inspection such resources are almost always not consistently encoded. Thus, a second goal of our orthography profiles is to allow for an easy specification of orthographic conventions, and use such profiles to check consistency and to report errors to be corrected. A central step in our proposed solution to this problem is the tailored grapheme separation of strings of symbols, a process we call grapheme tokenization. Basically, given some strings of symbols (e.g. morphemes, words, sentences) in <sup>1</sup>http://cldr.unicode.org/locale\_faq-html ### 1.1 Introduction a specific source, our first processing step is to specify how these strings should be separated into graphemes, considering the specific orthographic conventions used in a particular source document. Our experience is that such a graphemic tokenization can often be performed reasonably accurately without extensive indepth knowledge about the phonetic and phonological details of the language in question. For example, the specification that <ou> is a grapheme of English is a much easier task than to specify what exactly the phonetic values of this grapheme are in any specific occurrence in English words. Grapheme separation is a task that can be performed relatively reliably and with limited time and resources (compare, for example, the daunting task of creating a complete phonetic or phonological normalization). Although grapheme tokenization is only one part of the solution, it is an important and highly fruitful processing step. Given a grapheme tokenization, various subsequent tasks become easier, for instance (a) temporarily reducing the orthography in a processing pipeline, e.g. only distinguishing high versus low vowels; (b) normalizing orthographies across sources (often including temporary reduction of oppositions), e.g. specifying an (approximate) mapping to the International Phonetic Alphabet; (c) using co-occurrence statistics across different languages (or different sources in the same language) to estimate the probability of grapheme matches, e.g. with the goal to find regular sound changes between related languages or transliterations between different sources in the same language. ### Structure of this book Before we deal with these proposals we will first discuss the theoretical background on text encoding, on the Unicode Standard, and on the International Phonetic Alphabet. In the remainder of this chapter, we give an extended introduction to the notion of encoding (Section 1.2) and the principles of writing systems from a linguistic perspective (Section 1.3). In Chapter 2, we discuss the notions of encoding and writing systems from the perspective of the Unicode Consortium. We consider the Unicode Standard to be a breakthrough (and ongoing) development that fundamentally changed the way we look at writing systems, and we aim to provide here a slightly more in-depth survey of the many techniques that are available in the standard. A good appreciation for the solutions that the Unicode Consortium has created allows for a thorough understanding of the possible pitfalls that one might encounter when using the Unicode Standard in general (Chapter 3). Linguists are more often interested in using the Unicode Standard with the International Phonetic Alphabet (IPA). We first provide a history of the ### 1 Writing systems development of the IPA and early attempts to encode it electronically (Chapter 4) before we discuss the rather problematic marriage of the IPA with the Unicode Standard (Chapter 5). In the second part of the book (Chapters 6, 7 & 8) we describe our proposals of how to deal with the Unicode Standard in the daily practice of (comparative) linguistics. First, we provide some practical recommendations for using the Unicode Standard and IPA for ordinary working linguists and for computer programmers (Chapter 6). Second, we discuss the challenges of characterizing a writing system; to solve these problems, we propose the notions of orthography profiles, closely related to Unicode locale descriptions (Chapter 7). Lastly, we provide an introduction to two open source libraries that we have developed, in Python and R, for working with linguistic data and orthography profiles (Chapter 8). ### Conventions The following conventions are adhered to in this book. All phonemic and phonetic representations are given in the International Phonetic Alphabet (IPA), unless noted otherwise (The International Phonetic Association 2015). Standard conventions are used for distinguishing between graphemic < >, phonemic / / and phonetic [ ] representations. For character descriptions, we follow the notational conventions of the Unicode Standard (The Unicode Consortium 2018). Character names are represented in small capital letters (e.g. latin small letter schwa) and code points are expressed as U+n, where n is a four to six digit hexadecimal number, e.g. U+0256, which can be rendered as the glyph <ə>. ### 1.2 Encoding There are many in-depth histories of the origin and development of writing systems (e.g. Robinson 1995; Powell 2012), a story that we therefore will not repeat here. However, the history of turning writing into machine-readable code is not so often told, so we decided to offer a short survey of the major developments of such encoding here.<sup>2</sup> This history turns out to be intimately related to the history of telegraphic communication. <sup>2</sup>Because of the recent history as summarized in this section, we have used mostly rather ephemeral internet sources. When not referenced by traditional literature in the bibliography, we have used http://www.unicode.org/history/ and various Wikipedia pages for the information presented here. A useful survey of the historical development of the physical hardware of telegraphy and telecommunication is Huurdeman (2003). Most books that discuss the development of encoding of telegraphic communication focus of cryptography, e.g. Singh (1999), ### 1.2 Encoding ### Telegraphy Writing systems have existed for roughly 6000 years, allowing people to exchange messages through time and space. Additionally, to quickly bridge large geographic distances, telegraphic systems of communication (from Greek τῆλε γράφειν 'distant writing') have a long and widespread history since ancient times. The most common telegraphic systems worldwide are so-called whistled languages (Meyer 2015), but also drumming languages (Meyer et al. 2012) and signaling by smoke, fire, flags, or even changes in water levels through hydraulic pressure have been used as forms of telegraphy. Telegraphy was reinvigorated at the end of the eighteenth century through the introduction of so-called semaphoric systems by Claude Chapelle to convey messages over large distances. Originally, various specially designed contraptions were used to send messages. Today, descendants of these systems are still in limited use, for example utilizing flags or flashing lights. The innovation of those semaphoric systems was that all characters of the written language were replaced one-to-one by visual signals. Since then, all telegraphic systems have adopted this principle,<sup>3</sup> namely that any language to be transmitted first has to be turned into some orthographic system, which subsequently is encoded for transmission by the sender, and then turned back into orthographic representation at the receiver side. This of course implies that the usefulness of any such telegraphic encoding completely depends on the sometimes rather haphazard structure of orthographic systems. In the nineteenth century, electric telegraphy led to a further innovation in which written language characters were encoded by signals sent through a copper wire. Originally, bisignal codes were used, consisting of two different signals. For example, Carl Friedrich Gauss in 1833 used positive and negative current (Mania 2008: 282). More famous and influential, Samuel Morse in 1836 used long and short pulses. In those bisignal codes each character from the written language was encoded with a different number of signals (between one and five), so two different separators are needed: one between signals and one between characters. For example, in Morse-code there is a short pause between signals and a long pause between characters.<sup>4</sup> and forego the rather interesting story of open, i.e. non-cryptographic, encoding that is related here. <sup>3</sup>Sound- and video-based telecommunication take a different approach by ignoring the written version of language and they directly encode sound waves or light patterns. <sup>4</sup>Actually, Morse-code also includes an extra long pause between words. Interestingly, it took a long time to consider the written word boundary – using white-space – as a bona-fide character ### 1 Writing systems ### Binary encoding From those bisignal encodings, true binary codes developed with a fixed length of signals per character. In such systems only a single separator between signals is needed, because the separation between characters can be established by counting until a fixed number of signals has passed.<sup>5</sup> In the context of electric telegraphy, such a binary code system was first established by Émile Baudot in 1870, using a fixed combination of five signals for each written character.<sup>6</sup> There are 2 <sup>5</sup> = 32 possible combinations when using five binary signals; an encoding today designated as 5-bit. These codes are sufficient for all Latin letters, but of course they do not suffice for all written symbols, including punctuation and digits. As a solution, the Baudot code uses a so-called shift character, which signifies that from that point onwards – until shifted back – a different encoding is used, allowing for yet another set of 32 codes. In effect, this means that the Baudot code, and the International Telegraph Alphabet (ITA) derived from it, had an extra bit of information, so the encoding is actually 6-bit (with 2 <sup>6</sup> = 64 different possible characters). For decades, this encoding was the standard for all telegraphy and it is still in limited use today. To also allow for different uppercase and lowercase letters and for a large variety of control characters to be used in the newly developing technology of computers, the American Standards Association decided to propose a new 7-bit encoding in 1963 (with 2 <sup>7</sup> = 128 different possible characters), known as the American Standard Code for Information Interchange (ASCII), geared towards the encoding of English orthography. With the ascent of other orthographies in computer usage, the wish to encode further variations of Latin letters (including German <ß> and various letters with diacritics, e.g. <è>) led the Digital Equipment Corporation to introduce an 8-bit Multinational Character Set (MCS, with 2 <sup>8</sup> = 256 different possible characters), first used with the introduction of the VT220 Terminal in 1983. that should simply be encoded with its own code point. This happened only with the revision of the Baudot-code (see below) by Donald Murray in 1901, in which he introduced a specific white-space code. This principle has been followed ever since. <sup>5</sup>Of course, no explicit separator is needed at all when the timing of the signals is known, which is the principle used in all modern telecommunication systems. An important modern consideration is also how to know where to start counting when you did not catch the start of a message, something that is known in Unicode as self synchronization. <sup>6</sup>True binary codes have a longer history, going back at least to the Baconian cipher devised by Francis Bacon in 1605. However, the proposal by Baudot was the quintessential proposal leading to all modern systems. ### 1.3 Linguistic terminology Because 256 characters were clearly not enough for the unique representation of many different characters needed in the world's writing systems, the ISO/IEC 8859 standard in 1987 extended the MCS to include 16 different 8-bit code pages. For example, part 5 was used for Cyrillic characters, part 6 for Arabic, and part 7 for Greek. This system was almost immediately understood to be insufficient and impractical, so various initiatives to extend and reorganize the encoding started in the 1980s. This led, for example, to various proprietary encodings from Microsoft (e.g. Windows Latin 1) and Apple (e.g. Mac OS Roman), which one still sometimes encounters today. In the 1980s various people started to develop true international code sets. In the United States, a group of computer scientists formed the unicode consortium, proposing a 16-bit encoding in 1991 (with 2 <sup>16</sup> = 65, 536 different possible characters). At the same time in Europe, the international organization for standardization (ISO) was working on ISO 10646 to replace the ISO/IEC 8859 standard. Their first draft of the universal character set (UCS) in 1990 was 31 bit (with theoretically 2 <sup>31</sup> = 2, 147, 483, 648 possible characters, but because of some technical restrictions only 679,477,248 were allowed). Since 1991, the Unicode Consortium and the ISO jointly develop the unicode standard, or ISO/IEC 10646, leading to the current system including the original 16-bit Unicode proposal as the basic multilingual plane, and 16 additional planes of 16-bit for further extensions (with in total (1 + 16) 2 <sup>16</sup> = 1, 114, 112 possible characters). The most recent version of the Unicode Standard (currently at version number 11.0.0) was published in June 2018 and it defines 137,374 different characters (The Unicode Consortium 2018). In the next section we provide a very brief overview of the linguistic terminology concerning writing systems before turning to the slightly different computational terminology in the subsequent chapter on the Unicode Standard. ### 1.3 Linguistic terminology Linguistically speaking, a writing system is a symbolic system that uses visible or tactile signs to represent language in a systematic way. The term writing system has two mutually exclusive meanings. First, it may refer to the way a particular language is written. In this sense the term refers to the writing system of a particular language, as, for example, in the Serbian writing system uses two scripts: Latin and Cyrillic. Second, the term writing system may also refer to a type of symbolic system as, for example, in alphabetic writing system. In this lat- ### 1 Writing systems ter sense the term refers to how scripts have been classified according to the way that they encode language, as in, for example, the Latin and Cyrillic scripts are both alphabetic writing systems. To avoid confusion, this second notion of writing system would more aptly have been called script system. ### Writing systems Focusing on the first sense of writing system described above, we distinguish between two different kinds of writing systems used for a particular language, namely transcriptions and orthographies. First, transcription is a scientific procedure (and also the result of that procedure) for graphically representing the sounds of human speech at the phonetic level. It incorporates a set of unambiguous symbols to represent speech sounds, including conventions that specify how these symbols should be combined. A transcription system is a specific system of symbols and rules used for transcription of the sounds of a spoken language variety. In principle, a transcription system should be language-independent, in that it should be applicable to all spoken human languages. The International Phonetic Alphabet (IPA) is a commonly used transcription system that provides a medium for transcribing languages at the phonetic level. However, there is a long history of alternative kinds of transcription systems (see Kemp 2006) and today various alternatives are in widespread use (e.g. X-SAMPA and Cyrillic-based phonetic transcription systems). Many users of IPA do not follow the standard to the letter, and many dialects based on the IPA have emerged, e.g. the Africanist and Americanist transcription systems. Note that IPA symbols are also often used to represent language on a phonemic level. It is important to realize that in this usage the IPA symbols are not a transcription system, but rather an orthography (though with strong links to the pronunciation). Further, a transcription system does not need to be as highly detailed as the IPA. It can also be a system of broad sound classes. Although such an approximative transcription is not normally used in linguistics, it is widespread in technological approaches (Soundex and variants, e.g. Knuth 1973: 391–392; Postel 1969; Beider & Morse 2008), and it is sometimes fruitfully used in automatic approaches to historical linguistics (Dolgopolsky 1986; List 2012; Brown et al. 2013). Second, an orthography specifies the symbols, punctuations, and the rules in which a specific language is written in a standardized way. Orthographies are often based on a phonemic analysis, but they almost always include idiosyncrasies because of historical developments (like sound changes or loans) and because of the widely-followed principle of lexical integrity (i.e. the attempt to write the same lexical root in a consistent way, also when synchronic phonemic ### 1.3 Linguistic terminology rules change the pronunciation, as for example with final devoicing in many Germanic languages). Orthographies are language-specific (and often even resourcespecific), although individual symbols or rules might be shared between languages. A practical orthography is a strongly phoneme-based writing system designed for practical use by speakers. The mapping relation between phonemes and graphemes in practical orthographies is purposely shallow, i.e. there is mostly a systematic and faithful mapping from a phoneme to a grapheme. Practical orthographies are intended to jumpstart written materials development by correlating a writing system with the sound units of a language (Meinhof & Jones 1928). Symbols from the IPA are often used by linguists in the development of such practical orthographies for languages without writing systems, though this usage of IPA symbols should not be confused with transcription (as defined above). Further, a transliteration is a mapping between two different orthographies. It is the process of "recording the graphic symbols of one writing system in terms of the corresponding graphic symbols of a second writing system" (Kemp 2006: 396). In straightforward cases, such a transliteration is simply a matter of replacing one symbol with another. However, there are widespread complications, like one-to-many or many-to-many mappings, which are not always easy, or even possible, to solve without listing all cases individually (cf. Moran 2012: Ch. 2). ### Script systems Different kinds of writing systems are classified into script systems. A script is a collection of distinct symbols as employed by one or more orthographies. For example, both Serbian and Russian are written with subsets of the Cyrillic script. A single language, like Serbian or Japanese, can also be written using orthographies based on different scripts. Over the years linguists have classified script systems in a variety of ways, with the tripartite classification of logographic, syllabic, and alphabetic remaining the most popular, even though there are at least half a dozen different types of script systems that can be distinguished (Daniels 1990; 1996). Breaking it down further, a script consists of graphemes, which are writing system-specific minimally distinctive symbols (see below). Graphemes may consist of one or more characters. The term character is overladen. In the linguistic terminology of writing systems, a character is a general term for any self-contained element in a writing system. A second interpretation is used as a conventional term for a unit in the Chinese writing system (Daniels 1996). In technical terminology, a character refers to the electronic encoding of a component in a writing system that has semantic value (see Section 2.3). Thus in this ### 1 Writing systems work we must navigate between the general linguistic and technical terms for character and grapheme because of how these notions are defined and how they relate at the intersection between the International Phonetic Alphabet and the Unicode Standard (Chapter 5). Although in literate societies most people have a strong intuition about what the characters are in their particular orthography or orthographies, it turns out that the separation of an orthography into separate characters is far from trivial. The widespread intuitive notion of a character is strongly biased towards educational traditions, like the alphabet taught at schools, and technological possibilities, like the available type pieces in a printer's job case, the keys on a typewriter, or the symbols displayed in Microsoft Word's symbol browser. In practice, characters often consist of multiple building blocks, each of which could be considered a character in its own right. For example, although a Chinese character may be considered to be a single basic unanalyzable unit, at a more fine-grained level of analysis the internal structure of Chinese characters is often comprised of smaller semantic and phonetic units that should be considered characters (Sproat 2000). In alphabetic scripts, this problem is most forcefully exemplified by diacritics. A diacritic is a mark, or series of marks, that may be above, below, before, after, through, around, or between other characters (Gaultney 2002). Diacritics are sometimes used to distinguish homophonous words, but they are more often used to indicate a modified pronunciation (Daniels & Bright 1996: xli). The central question is whether, for example, <e>, <è>, <a> and <à> should be considered four characters, or different combinations of three characters, i.e. <a>, <e>, and <◌̀>. In general, multiple characters together can form another character, and it is not always possible to decide on principled grounds what should be the basic building blocks of an orthography. For that reason, it is better to analyze an orthography as a collection of graphemes. A grapheme is the basic, minimally distinctive symbol of a particular writing system. It was modeled after the term phoneme (an abstract representation of a distinct sound in a specific language) and as such it represents a contrastive graphical unit in a writing system (see Kohrt 1986 for a historical overview of the term grapheme). Most importantly, a single grapheme regularly consists of multiple characters, like <th>, <ou> and <gh> in English (note that each character in these graphemes is also a separate grapheme in English). Such complex graphemes are often used to represent single phonemes. So, a combination of characters is used to represent a single phoneme. Note that the opposite is also found in writing systems, in cases in which a single character represents a com- bination of two or more phonemes. For example, <x> in English orthography sometimes represents a combination of the phonemes /k/ and /s/, as in the word 'index' [ˈɪnˌdɛks]; other times it is pronounced as /z/, such as in the words 'Xerox' [ˈzɪrˌɑks]; and in 'example' [ɪɡˈzæmpəl] it is a combination of /g/ and /s/. As one can see, there can be non-trivial mappings between graphemes and phonemes in orthographies like English, e.g. 'give', 'gin', 'jingle', where the graphemes <g> and <j> and the phonemes /g/ and /dʒ/ have a complex mapping. Further, conditioned or free variants of a grapheme are called allographs. For example, the distinctive forms of Greek sigma are conditioned, with <σ> being used word-internally and <ς> being used at the end of a word. In sum, there are many-to-many relationships between phonemes and graphemes as they are expressed in the myriad of language- and resource-specific orthographies. ### Summary This exposition of the linguistic terminology involved in describing writing systems has been purposely brief. We have highlighted some of the linguistic notions that are pertinent to, yet sometimes confused with, the technical definitions developed for the computational processing of the world's writing systems, which we describe in the next Chapter. # 2 The Unicode approach ### 2.1 Background The conceptualization and terminology of writing systems was rejuvenated by the development of the Unicode Standard, with major input from Mark Davis, co-founder and long-term president of the Unicode Consortium. For many years, "exotic" writing systems and phonetic transcription systems on personal computers were constrained by the American Standard Code for Information Interchange (ASCII) character encoding scheme, based on the Latin script, which only allowed for a strongly limited number of different symbols to be encoded. This implied that users could either use and adopt the (extended) Latin alphabet or they could assign new symbols to the small number of code points in the ASCII encoding scheme to be rendered by a specifically designed font (Bird & Simons 2003). In this situation, it was necessary to specify the font together with each document to ensure the rightful display of its content. To alleviate this problem of assigning different symbols to the same code points, in the late 80s and early 90s the Unicode Consortium set itself the ambitious goal of developing a single universal character encoding to provide a unique number, a code point, for every character in the world's writing systems. Nowadays, the Unicode Standard is the default encoding of the technologies that support the World Wide Web and for all modern operating systems, software and programming languages. ### 2.2 The Unicode Standard The Unicode Standard represents a massive step forward because it aims to eradicate the distinction between universal (ASCII) versus language-particular (font) by adding as much language-specific information as possible into the universal standard. However, there are still language/resource-specific specifications necessary for the proper usage of Unicode, as will be discussed below. Within the Unicode structure many of these specifications can be captured by so-called Unicode Locales, so we are moving to a new distinction of universal (Unicode Standard) versus language-particular (Unicode Locale). The major gain is much ### 2 The Unicode approach larger compatibility on the universal level (because Unicode standardizes a much greater portion of writing system diversity), and much better possibilities for automated processing on the language-particular level (because Unicode Locales are machine-readable specifications). Each version of the Unicode Standard (The Unicode Consortium 2018, as of writing at version 11.0.0) consists of a set of specifications and guidelines that include (i) a core specification, (ii) code charts, (iii) standard annexes and (iv) a character database.<sup>1</sup> The core specification is a book aimed at human readers that describes the formal standard for encoding multilingual text. The code charts provide a human-readable online reference to the character contents of the Unicode Standard in the form of PDF files. The Unicode Standard Annexes (UAX) are a set of technical standards that describe the implementation of the Unicode Standard for software development, web standards, and programming languages. The Unicode Character Database (UCD) is a set of computer-readable text files that describe the character properties, including a set of rich character and writing system semantics, for each character in the Unicode Standard. In this section, we introduce the basic Unicode concepts, but we will leave out many details. Please consult the above-mentioned full documentation for a more detailed discussion. Further note that the Unicode Standard is exactly that, namely a standard. It normatively describes notions and rules to be followed. In the actual practice of applying this standard in a computational setting, a specific implementation is necessary. The most widely used implementation of the Unicode Standard is the International Components for Unicode (ICU), which offers C/C++ and Java libraries implementing the Unicode Standard.<sup>2</sup> ### 2.3 Character encoding system The Unicode Standard is a character encoding system whose goal is to support the interchange and processing of written characters and text in a computational <sup>1</sup>All documents of the Unicode Standard are available at: http://www.unicode.org/versions/ latest/. For a quick survey of the use of terminology inside the Unicode Standard, their glossary is particularly useful, available at: http://www.unicode.org/glossary/. For a general introduction to the principles of Unicode, Chapter 2 of the core specification, called general structure, is particularly insightful. Unlike many other documents in the Unicode Standard, this general introduction is relatively easy to read and illustrated with many interesting examples from various orthographic traditions from all over the world. <sup>2</sup>More information about the ICU is available here: http://icu-project.org. ### 2.3 Character encoding system setting.<sup>3</sup> Underlyingly, the character encoding is represented by a range of numerical values called a code space, which is used to encode a set of characters. A code point is a unique non-negative integer within a code space (i.e. within a certain numerical range). In the Unicode Standard character encoding system, an abstract character, for example the latin small letter p, is mapped to a particular code point, in this case the decimal value 112, normally represented in hexadecimal, which then looks in Unicode parlance as U+0070. That encoded abstract character is rendered on a computer screen (or printed page) as a glyph, e.g. <p>, depending on the font and the context in which that character appears. In Unicode Standard terminology, an (abstract) character is the basic encoding unit. The term character can be quite confusing due to its alternative definitions across different scientific disciplines and because in general the word character means many different things to different people. It is therefore often preferable to refer to Unicode characters simply as code points, because there is a one-to-one mapping between Unicode characters and their numeric representation. In the Unicode approach, a character refers to the abstract meaning and/or general shape, rather than a specific shape, though in code tables some form of visual representation is essential for the reader's understanding. Unicode defines characters as abstractions of orthographic symbols, and it does not define visualizations for these characters (although it does present examples). In contrast, a glyph is a concrete graphical representation of a character as it appears when rendered (or rasterized) and displayed on an electronic device or on printed paper. For example, <g g g g g g> are different glyphs of the same character, i.e. they may be rendered differently depending on the typography being used, but they all share the same code point. From the perspective of Unicode they are the same thing. In this approach, a font is then simply a collection of glyphs connected to code points. Allography is not specified in Unicode (barring a few exceptional cases, due to legacy encoding issues), but can be specified in a font as a contextual variant (aka presentation form). Each code point in the Unicode Standard is associated with a set of character properties as defined by the Unicode character property model.<sup>4</sup> Basically, those <sup>3</sup>An insightful reviewer notes that the term encoding is used for both sequences of code points and text encoded as bit patterns. Hence a Unicode-aware programmer might prefer to say that UTF-8, UTF-16, etc., are Unicode encoding systems. The issue is that the Unicode Standard introduces a layer of indirection between characters and bit patterns, i.e. the code point, which can be encoded differently by different encoding systems. <sup>4</sup>The character property model is described in http://www.unicode.org/reports/tr23/, but the actual properties are described in http://www.unicode.org/reports/tr44/. A simplified overview of the properties is available at: http://userguide.icu-project.org/strings/properties. The ac- ### 2 The Unicode approach properties are just a long list of values for each character. For example, code point U+0047 has the following properties (among many others): These properties contain the basic information of the Unicode Standard and they are necessary to define the correct behavior and conformance required for interoperability in and across different software implementations (as defined in the Unicode Standard Annexes). The character properties assigned to each code point are based on each character's behavior in real-world writing traditions. For example, the corresponding lowercase character to U+0047 is U+0067. <sup>5</sup> Another use of properties is to define the script of a character.<sup>6</sup> In practice, script is simply defined for each character as the explicit script property in the Unicode Character Database. One frequently referenced property is the block property, which is often used in software applications to impose some structure on the large number of Unicode characters. Each character in Unicode belongs to a specific block. These blocks are basically an organizational structure to alleviate the administrative burden of keeping Unicode up-to-date. Blocks consist of characters that in some way belong together, so that characters are easier to find. Some blocks are connected with a specific script, like the Hebrew block or the Gujarati block. However, blocks are predefined ranges of code points, and often there will come a point after which the range is completely filled. Any extra characters will have to be assigned somewhere else. There is, for example, a block Arabic, which contains most Arabic symbols. However, there is also a block Arabic Supplement, Arabic Presentation Forms-A and Arabic Presentation Forms-B. The situation with Latin symbols is even more extreme. In general, the names of blocks tual code tables listing all properties for all Unicode code points are available at: http://www. unicode.org/Public/UCD/latest/ucd/. <sup>5</sup>Note that the relation between uppercase and lowercase is in many situations much more complex than this, and Unicode has further specifications for those cases. <sup>6</sup>The Glossary of Unicode Terms defines the term script as a "collection of letters and other written signs used to represent textual information in one or more writing systems. For example, Russian is written with a subset of the Cyrillic script; Ukrainian is written with a different subset. The Japanese writing system uses several scripts." ### 2.4 Grapheme clusters should not be taken as a definitional statement. For example, many IPA symbols are not located in the aptly-named block IPA extensions, but in other blocks (see Section 5.2). ### 2.4 Grapheme clusters There are many cases in which a sequence of characters (i.e. a sequence of more than one code point) represents what a user perceives as an individual unit in a particular orthographic writing system. For this reason the Unicode Standard differentiates between abstract character and user-perceived character. Sequences of multiple code points that correspond to a single user-perceived characters are called grapheme clusters in Unicode parlance. Grapheme clusters come in two flavors: (default) grapheme clusters and tailored grapheme clusters. The (default) grapheme clusters are locale-independent graphemes, i.e. they always apply when a particular combination of characters occurs independent of the writing system in which they are used. These character combinations are defined in the Unicode Standard as functioning as one text element. <sup>7</sup> The simplest example of a grapheme cluster is a base character followed by a letter modifier character. For example, the sequence <n> + <◌̃> (i.e. latin small letter n at U+006E, followed by combining tilde at U+0303) combines visually into <ñ>, a user-perceived character in writing systems like that of Spanish. In effect, what the user perceives as a single character actually involves a multi-code-point sequence. Note that this specific sequence can also be represented with a single so-called precomposed code point, the latin small letter n with tilde at U+00F1, but this is not the case for all multi-code-point character sequences. A solution to the problem of multiple encodings for the same text element was developed early on in the Unicode Standard. It is called canonical eqivalence, e.g. for <ñ>, the sequence U+006E U+0303 should in all situations be treated identically to the precomposed U+00F1. By doing so, Unicode can also support special or precomposed characters in legacy character sets. To determine canonical equivalence, the Unicode Standard offers different kinds of normalization to either decompose precomposed characters (called NFD for normalization form canonical decomposition) or to combine sequences of code points into precomposed characters (called NFC for normalization form canonical compo- <sup>7</sup>The Glossary of Unicode Terms defines text element as: "A minimum unit of text in relation to a particular text process, in the context of a given writing system. In general, the mapping between text elements and code points is many-to-many." ### 2 The Unicode approach sition).<sup>8</sup> In current software development practice, NFC seems to be preferred in most situations and is widely proposed as the preferred canonical form. We discuss Unicode normalization in detail in Section 3.9. More difficult for text processing, because less standardized, is what the Unicode Standard terms tailored grapheme clusters. <sup>9</sup> Tailored grapheme clusters are locale-dependent graphemes, i.e. such combination of characters do not function as text elements in all situations. Examples include the sequence <c> + <h> for the Slovak digraph <ch> and the sequence <ky> in the Sisaala practical orthography, which is pronounced as IPA /tʃ/ (Moran 2006). These grapheme clusters are tailored in the sense that they must be specified on a language-bylanguage or writing-system-by-writing-system basis. They are also grapheme clusters in these orthographies for processes such as collation (i.e. sorting).<sup>10</sup> The Unicode Standard provides technical specifications for creating locale specific data in so-called Unicode Locales, i.e. specifications that define a set of language-specific elements (e.g. tailored grapheme clusters, collation order, capitalization equivalence), as well as other special information, like how to format numbers, dates, or currencies. Locale descriptions are saved in the Common Locale Data Repository (CLDR), <sup>11</sup> a repository of language-specific definitions of writing system properties, each of which describes specific usages of characters. Each locale can be encoded in a document using the Locale Data Markup Language (LDML). LDML is an XML format and vocabulary for the exchange of structured locale data. Unicode Locale Descriptions allow users to define language- or even resource-specific writing systems or orthographies.<sup>12</sup> However, Unicode Locales have various drawbacks for the daily practice of scientific linguistic research in a multilingual setting. <sup>8</sup>See the Unicode Standard Annex #15, Unicode Normalization Forms (http://unicode.org/ reports/tr15/), which provides a detailed description of normalization algorithms and illustrated examples. <sup>9</sup>http://unicode.org/reports/tr29/ <sup>10</sup>https://www.unicode.org/glossary/#collation <sup>11</sup>More information about the CLDR can be found here: http://cldr.unicode.org/. <sup>12</sup>The Glossary of Unicode Terms defines writing system only very loosely, as it is not a central concept in the Unicode Standard. A writing system is, "A set of rules for using one or more scripts to write a particular language. Examples include the American English writing system, the British English writing system, the French writing system, and the Japanese writing system." # 3 Unicode pitfalls ### 3.1 Wrong it ain't In this chapter we describe some of the most common pitfalls that we have encountered when using the Unicode Standard in our own work, or in discussion with other linguists. This section is not meant as a criticism of the decisions made by the Unicode Consortium; rather we aim to highlight where the technical aspects of the Unicode Standard diverge from many users' intuitions. What have sometimes been referred to as problems or inconsistencies in the Unicode Standard are mostly due to legacy compatibility issues, which can lead to unexpected behavior by linguists using the standard. However, there are also some cases in which the Unicode Standard has made decisions that theoretically could have been made differently, but for some reason or another (mostly very good reasons) were accepted as they are now. We call such behavior that executes without error but does something different than the user expected – often unknowingly – a pitfall. In this context, it is important to realize that the Unicode Standard was not developed to solve linguistic problems per se, but to offer a consistent computational environment for written language. In those cases in which the Unicode Standard behaves differently than expected, we think it is important not to dismiss Unicode as wrong or deficient, because our experience is that in almost all cases the behavior of the Unicode Standard has been particularly well thought through. The Unicode Consortium has a wide-ranging view of matters and often examines important practical use cases that are not normally considered from a linguistic point of view. Our general guideline for dealing with the Unicode Standard is to accept it as it is, and not to tilt at windmills. Alternatively, of course, it is possible to actively engage in the development of the standard itself, an effort that is highly appreciated by the Unicode Consortium. ### 3 Unicode pitfalls ### 3.2 Pitfall: Characters are not glyphs A central principle of Unicode is the distinction between character and glyph. A character is the abstract notion of a symbol in a writing system, while a glyph is the visual representation of such a symbol. In practice, there is a complex interaction between characters and glyphs. A single Unicode character may of course be rendered as a single glyph. However, a character may also be a piece of a glyph, or vice-versa. Actually, all possible relations between glyphs and characters are attested. First, a single character may have different contextually determined glyphs. For example, characters in writing systems like Hebrew and Arabic have different glyphs depending on where they appear in a word. Some letters in Hebrew change their form at the end of the word, and in Arabic, primary letters have four contextually-sensitive variants (isolated, word initial, medial and final). Second, a single character may be rendered as a sequence of multiple glyphs. For example, in Tamil one Unicode character may result in a combination of a consonant and vowel, which are rendered as two adjacent glyphs by fonts that support Tamil, e.g. tamil letter au at U+0B94 represents a single character <ஔ>, composed of two glyphs <ஓ> and <ன>. Perhaps confusingly, in the Unicode Standard there are also two individual characters, i.e. tamil letter oo at U+0B93 and U+0BA9 tamil letter nnna, each of which is a glyph. Another example is Sinhala sinhala vowel sign kombu deka at U+0DDB <ෛ◌>, which is visually two glyphs, each represented by sinhala vowel sign kombuva at U+0DD9 <ෙ◌>. Third, a single glyph may be a combination of multiple characters. For example, the ligature <fi>, a single glyph, is the result of two characters, <f> and <i>, that have undergone glyph substitution by font rendering (see also Section 3.5). Like contextually-determined glyphs, ligatures are (intended) artifacts of text processing instructions. Finally, a single glyph may be a part of a character, as exemplified by diacritics like the diaeresis <◌̈> in <ë>. Further, the rendering of a glyph is dependent on the font being used. For example, the Unicode character latin small letter g appears as <g> and <g> in the Linux Libertine and Courier fonts, respectively, because their typefaces are designed differently. Furthermore, the font face may change the visual appearance of a character, for example Times New Roman two-story <a> changes to a single-story glyph in italics <a>. This becomes a real problem for some phonetic typesetting (see Section 5.3). ### 3.3 Pitfall: Characters are not graphemes In sum, character-to-glyph mappings are complex technical issues that the Unicode Consortium has had to address in the development of the Unicode Standard. However, they can can be utterly confusing for the lay user because visual rendering does not (necessarily) indicate logical encoding. ### 3.3 Pitfall: Characters are not graphemes The Unicode Standard encodes characters. This becomes most clear with the notion of grapheme. From a linguistic point of view, graphemes are the basic building blocks of a writing system (see Section 1.3). It is extremely common for writing systems to use combinations of multiple symbols (or letters) as a single grapheme, such as <sch>, <th> or <ei>. There is no way to encode such complex graphemes using the Unicode Standard. The Unicode Standard deals with complex graphemes only inasmuch as they consist of base characters with diacritics (see Section 5.9 for a discussion of the notion of diacritic). The Unicode Standard calls such combinations grapheme clusters. Complex graphemes consisting of multiple base characters, like <sch>, are called tailored grapheme clusters (see Chapter 2). There are special Unicode characters that glue together characters into larger tailored grapheme clusters, specifically the zero width joiner at U+200D and the combining grapheme joiner at U+034F. However, these characters are confusingly named (cf. Section 3.7). Both code points actually do not join characters, but explicitly separate them. The zero-width joiner (ZWJ) can be used to solve special problems related to ordering (called collation in Unicode parlance). The combining grapheme joiner (CGJ) can be used to separate characters that are not supposed to form ligatures. To solve the issue of tailored grapheme clusters, Unicode offers some assistance in the form of Unicode Locales.<sup>1</sup> However, in the practice of linguistic research, this is not a real solution. To address this issue, we propose to use orthography profiles (see Chapter 7). Basically, both orthography profiles and Unicode Locales offer a way to specify tailored grapheme clusters. For example, for English one could specify that <sh> is such a cluster. Consequently, this sequence of characters is then always interpreted as a complex grapheme. For cases in which this is not the right decision, like in the English word mishap, the zero width joiner at U+200D has to be entered between <s> and <h>. <sup>1</sup>http://cldr.unicode.org/locale\_faq-html ### 3 Unicode pitfalls ### 3.4 Pitfall: Missing glyphs The Unicode Standard is often praised (and deservedly so) for solving many of the perennial problems with the interchange and display of the world's writing systems. Nevertheless, a common complaint from users is that some symbols do not display correctly, i.e. not at all or from a fall back font, e.g. a rectangle <>, question mark <?>, or the Unicode replacement character <�>. The user's computer does not have the fonts installed that map the desired glyphs to Unicode characters. Therefore the glyphs cannot be displayed. This is not the Unicode Standard's fault because it is a character encoding system and not a font. Computerinternally everything works as expected; any handling of Unicode code points works independently of how they are displayed on the screen. So although users might see alien faces on display, they should not fret because everything is still technically in order below the surface. There are two obstacles regarding missing glyphs. One is practical: designing glyphs includes many different considerations and it is a time-consuming process, especially when done well. Traditional expectations of what specific characters should look like need to be taken into account when designing glyphs. Those expectations are often not well documented, and it is mostly up to the knowledge and expertise of the font designer to try and conform to them. Furthermore, the number of characters supported by Unicode is vast. Therefore, most designers produce fonts that only include glyphs for certain parts of the Unicode Standard. The second obstacle is technical: the maximum number of glyphs that can be defined by the TrueType font standard and the OpenType specification (ISO/IEC 14496-22:2015) is 65,535. The current version of the Unicode Standard contains 137,374 characters. Thus, no single font can provide individual glyphs for all Unicode characters. A simple solution to missing glyphs is to install additional fonts providing additional glyphs. For broad coverage, there is the Noto font family, a project developed by Google, which covers over 100 scripts and nearly 64,000 characters.<sup>2</sup> The Unicode Consortium also provides, but does not endorse, an extensive list of fonts and font libraries online.<sup>3</sup> For the more exotic characters there is often not much choice. We have had success using Michael Everson's Everson Mono font, which has 9,756 different glyphs (not including Chinese)<sup>4</sup> and with the somewhat older Titus Cyberbit <sup>2</sup>https://www.google.com/get/noto/ <sup>3</sup>http://unicode.org/resources/fonts.html <sup>4</sup>http://www.evertype.com/emono/ ### 3.5 Pitfall: Faulty rendering Basic font by Jost Gippert and Carl-Martin Bunz. It includes 10,044 different glyphs (not including Chinese).<sup>5</sup> We also suggest installing at least one fall-back font, which provides glyphs that show the user some information about the underlying encoded character. Apple computers have such a font (which is invisible to the user), which is designed by Michael Everson and made available for other systems through the Unicode Consortium.<sup>6</sup> Further, the GNU Unifont is a clever way to produce bitmaps approximating the intended glyph of each available character.<sup>7</sup> Finally, SIL International provides a SIL Unicode BMP Fallback Font. This font does not show a real glyph, but instead shows the hexadecimal code inside a box for each character, so a user can at least see the Unicode code point of the character intended for display.<sup>8</sup> ### 3.5 Pitfall: Faulty rendering A similar complaint to missing glyphs, discussed previously, is that while a glyph might be displayed, it does not look right. There are two reasons for unexpected visual display, namely automatic font substitution and faulty rendering. Like missing glyphs, any such problems are independent from the Unicode Standard. The Unicode Standard only includes very general information about characters and leaves the specific visual display for others to decide on. Any faulty display is thus not to be blamed on the Unicode Consortium, but on a complex interplay of different mechanisms happening in a computer to turn Unicode code points into visual symbols. We will only sketch a few aspects of this complex interplay here. Most modern software applications (like Microsoft Word) offer some approach to automatic font substitution. This means that when a text is written in a specific font (e.g. Times New Roman) and an inserted Unicode character does not have a glyph within this font, then the software application will automatically search for another font to display the glyph. The result will be that this specific glyph will look slightly different from the others. This mechanism works differently depending on the software application; only limited user influence is usually expected and little feedback is given. This may be rather frustrating to font-aware users. <sup>5</sup>http://titus.fkidg1.uni-frankfurt.de/unicode/tituut.asp <sup>6</sup>http://www.unicode.org/policies/lastresortfont\_eula.html <sup>7</sup>http://unifoundry.com/unifont.html <sup>8</sup>http://scripts.sil.org/UnicodeBMPFallbackFont ### 3 Unicode pitfalls Another problem with visual display is related to so-called font rendering. Font rendering refers to the process of the actual positioning of Unicode characters on a page of written text. This positioning is actually a highly complex challenge and many things can go wrong in the process. Well-known rendering difficulties, like proportional glyph size or ligatures, are reasonably well understood by developers. Nevertheless, the positioning of multiple diacritics relative to a base character is still a widespread problem. Especially problematic is when more than one diacritic is supposed to be placed above (or below) another. Even within the Latin script vertical placement often leads to unexpected effects in many modern software applications. The rendering problems arising in Arabic and in many scripts of Southeast Asia (like Devanagari or Burmese) are even more complex. To understand why these problems arise it is important to realize that there are basically three different approaches to font rendering. The most widespread is Adobe's and Microsoft's OpenType system. This approach makes it relatively easy for font developers, but the font itself does not include all details about the precise placement of individual characters. For those details, additional script descriptions are necessary. All such systems can lead to unexpected behavior.<sup>9</sup> Alternative systems are Apple Advanced Typography (AAT) and the open-source Graphite system produced and maintained by the Non-Roman Script Initiative of SIL International (SIL).<sup>10</sup> In these systems, a larger burden is placed on the description inside the font. There is no complete solution to the problems arising from faulty font rendering. Switching to another software application that offers better handling is the only real alternative, but this is normally not an option for daily work. Font rendering is developing quickly in the software industry, so we can expect the situation to only get better. ### 3.6 Pitfall: Blocks The Unicode code space is subdivided into blocks of contiguous code points. For example, the block called Cyrillic runs from U+0400 till U+04FF. These blocks <sup>9</sup> For more details about OpenType, see http://www.adobe.com/products/type/opentype.html and http://www.microsoft.com/typography/otspec/. Additional systems for complex text layout are, among others, Microsoft's DirectWrite (https://msdn.microsoft.com/library/dd368038. aspx) and the open-source project HarfBuzz (http://www.freedesktop.org/wiki/Software/ HarfBuzz/). <sup>10</sup>More information about AAT can be found at: https://developer.apple.com/fonts/. Graphite is described in detail at: http://scripts.sil.org/default. ### 3.7 Pitfall: Names arose as an attempt at ordering the enormous number of characters in Unicode, but the idea of blocks very quickly ran into problems. First, the size of a block is fixed, so when a block is full, a new block will have to be instantiated somewhere else in the code space. For example, this led to the blocks Cyrillic Supplement, Cyrillic Extended-A (both of which are already full) and Cyrillic Extended-B. Second, when a specific character already exists, it is not duplicated in another block, although the name of the block might indicate that a specific symbol should be available there. In general, names of blocks are just an approximate indication of the kind of characters that will be in the block. The problem with blocks arises because finding the right character among the thousands of Unicode characters is not easy. Many software applications present blocks as a primary search mechanism, because the block names suggest where to look for a particular character. However, when a user searches for an IPA character in the block IPA Extensions, then many IPA characters will not be found there. For example, the velar nasal <ŋ> is not part of the block IPA Extensions because it was already included as latin small letter eng at U+014B in the block Latin Extensions-A. In general, finding a specific character in the Unicode Standard is often nontrivial. The names of the blocks can help, but they are not (and were never supposed to be) a foolproof structure. It is neither the goal nor the aim of the Unicode Consortium to provide a user interface to the Unicode Standard. If one often encounters the problem of needing to find a suitable character, there are various other useful services for end-users available.<sup>11</sup> ### 3.7 Pitfall: Names The names of characters in the Unicode Standard are sometimes misnomers and should not be misinterpreted as definitions. For example, the combining grapheme joiner at U+034F does not join characters into larger graphemes (see Section 3.3) and the latin letter retroflex click U+01C3 is actually not the IPA symbol for a retroflex click, but for an alveolar click (see Section 5.3). In a sense, these names can be seen as errors. However, it is probably better to realize that <sup>11</sup>The Unicode website offers a basic interface to the code charts at: http://www.unicode.org/ charts/index.html. As a more flexible interface, we particularly like PopChar from Ergonis Software, available for both Mac and Windows. There are also various free websites that offer search interfaces to the Unicode code tables, like http://unicode-search.net or http://unicodesearch.net. Another useful approach for searching for characters using shape matching (Belongie et al. 2002) is: http://shapecatcher.com. ### 3 Unicode pitfalls such names are just convenience labels that are not going to be changed. Just like the block names (Section 3.6), the character names are often helpful, but they are not supposed to be definitions. The actual intended meaning of a Unicode code point is a combination of the name, the block and the character properties (see Chapter 2). Further details about the underlying intentions with which a character should be used are only accessible by perusing the actual decisions of the Unicode Consortium. All proposals, discussions and decisions of the Unicode Consortium are publicly available. Unfortunately there is not (yet) any way to easily find everything that is ever proposed, discussed and decided in relation to a specific code point of interest, so many of the details are often somewhat hidden.<sup>12</sup> ### 3.8 Pitfall: Homoglyphs Homoglyphs are visually indistinguishable glyphs (or highly similar glyphs) that have different code points in the Unicode Standard and thus different character semantics. As a principle, the Unicode Standard does not specify how a character appears visually on the page or the screen. So in most cases, a different appearance is caused by the specific design of a font, or by user-settings like size or boldface. Taking an example already discussed in Section 2.3, the following symbols <g g g g g g> are different glyphs of the same character, i.e. they may be rendered differently depending on the typography being used, but they all share the same code point (viz. latin small letter g at U+0067). In contrast, the symbols <AАΑᎪᗅᴀꓮ> are all different code points, although they look highly similar – in some cases even sharing exactly the same glyph in some fonts. All these different A-like characters include the following code points in the Unicode Standard: <A> latin capital letter a, at U+0041 <А> cyrillic capital letter a, at U+0410 <Α> greek capital letter alpha, at U+0391 <Ꭺ> cherokee letter go, at U+13AA <ᗅ> canadian syllabics carrier gho, at U+15C5 <ᴀ> latin small letter capital a, at U+1D00 <sup>12</sup>All proposals and other documents that are the basis of Unicode decisions are available at: http: //www.unicode.org/L2/all-docs.html. The actual decisions that make up the Unicode Standard are documented in the minutes of the Unicode Technical Committee, available at: http://www. unicode.org/consortium/utc-minutes.html. 3.9 Pitfall: Canonical equivalence <ꓮ> lisu letter a, at U+A4EE <> carian letter a, at U+102A0 <> mathematical sans-serif capital a, U+1D5A0 <> mathematical monospace capital a, at U+1D670 The existence of such homoglyphs is partly due to legacy compatibility, but for the most part these characters are simply different characters that happen to look similar.<sup>13</sup> Yet, they are suppose to behave differently from the perspective of a font designer. For example, when designing a Cyrillic font, the <A> will have different aesthetics and different traditional expectations compared to a Latin <A>. Thus, the Unicode Standard has character properties associated with each code point which define certain expectations, e.g. characters belong to different blocks, they have different lower case variants (see Section 2.3). Homoglyphs are a widespread problem for consistent encoding. Although for most users it looks like the words <voces> and <νοсеѕ> are nearly identical, in fact they do not share any code points.<sup>14</sup> For computers these two words are completely different entities. Sometimes when users with Cyrillic or Greek keyboards have to type some Latin-based orthography, they mix similar looking Cyrillic or Greek characters into their text, because those characters are so much easier to type. Similarly, when users want to enter an unusual symbol, they normally search by visual impression in their favorite software application, and just pick something that looks reasonably alike to what they expect the glyph to look like. It is very easy to make errors during text entry and add characters that are not supposed to be included. Our proposals for orthography profiles (see Chapter 7) are a method for checking the consistency of any text. In situations in which interoperability is important, we consider it crucial to add such checks in any workflow. ### 3.9 Pitfall: Canonical equivalence For some characters, there is more than one possible encoding in the Unicode Standard. This means that for the computer there exists multiple different entities, which for the user, may be visually the same. This leads to, for example, <sup>13</sup>A particularly nice interface to look for homoglyphs is http://shapecatcher.com, based on the principle of recognizing shapes (Belongie et al. 2002). <sup>14</sup>The first words consists completely of Latin characters: U+0076, U+006F, U+0063, U+0065 and U+0073. The second is a mix of Cyrillic and Greek characters: U+03BD, U+03BF, U+0041, U+0435 and U+0455. ### 3 Unicode pitfalls problems with search. The computer searches for specific code points and by design does not return all visually similar characters. As a solution, the Unicode Standard includes a notion of canonical eqivalence. Different encodings are explicitly declared as equivalent in the Unicode Standard code tables. Further, to harmonize all encodings in a specific piece of text, the Unicode Standard proposes a mechanism of normalization. The process of normalization and the Unicode Normalization Forms are described in detail in the Unicode Standard Annex #15 online.<sup>15</sup> Here we provide a brief summary of that material as it pertains to canonical equivalence. Consider for example the characters and following Unicode code points: The character, represented here by glyph <Å>, is encoded in the Unicode Standard in the first two examples by a single-character sequence; each is assigned a different code point. In the third example, the glyph is encoded in a multiplecharacter sequence that is composed of two character code points. All three sequences are , i.e. they are strings that represent the same abstract character and because they are not distinguishable by the user, the Unicode Standard requires them to be treated the same in regards to their behavior and appearance. Nevertheless, they are encoded differently. For example, if one were to search an electronic text (with software that does not apply Unicode Standard normalization) for angstrom sign (U+212B), then the instances of latin capital letter a with ring above (U+00C5) would not be found. In other words, there are equivalent sequences of Unicode characters that should be normalized, i.e. transformed into a unique Unicode-sanctioned representation of a character sequence called a normalization form. Unicode provides a Unicode Normalization Algorithm, which puts combining marks into a specific logical order and it defines decomposition and composition transformation rules to convert each string into one of four normalization forms. We will discuss here the two most relevant normalization forms: NFC and NFD. The first of the three characters above is considered the Normalization Form C (NFC), where C stands for composition. When the process of NFC normalization is applied to the characters in 2 and 3, both are normalized into the precomposed character sequence in 1. Thus all three canonical character sequences <sup>15</sup>http://unicode.org/reports/tr15/ ### 3.9 Pitfall: Canonical equivalence are standardized into one composition form in NFC.The other frequently encountered Unicode normalization form is the Normalization Form D (NFD), where D stands for decomposition. When NFD is applied to the three examples above, all three, including importantly the single-character sequences in 1 and 2, are normalized into the decomposed multiple-sequence of characters in 3. Again, all three are then logically equivalent and therefore comparable and syntactically interoperable. As illustrated, some characters in the Unicode Standard have alternative representations (in fact, many do), but the Unicode Normalization Algorithm can be used to transform certain sequences of characters into canonical forms to test for equivalency. To determine equivalence, each character in the Unicode Standard is associated with a combining class, which is formally defined as a character property called canonical combining class which is specified in the Unicode Character Database. The combining class assigned to each code point is a numeric value between 0 and 254 and is used by the Unicode Canonical Ordering Algorithm to determine which sequences of characters are . Normalization forms, as very briefly described above, can be used to ensure character equivalence by ordering character sequences so that they can be faithfully compared. It is very important to note that any software application that is Unicode Standard compliant is free to change the character stream from one representation to another. This means that a software application may compose, decompose or reorder characters as its developers desire; as long as the resultant strings are to the original. This might lead to unexpected behavior for users. Various players, like the Unicode Consortium, the W3C, or the TEI recommend NFC in most user-directed situations, and some software applications that we tested indeed seem to automatically convert strings into NFC.<sup>16</sup> This means in practice that if a user, for example, enters <a> and <◌̀>, i.e. latin small letter a at U+0061 and combining grave accent at U+0300, this might be automatically converted into <à>, i.e. latin small letter a with grave at U+00E0. 17 <sup>16</sup>See the summary of various recommendation here: http://www.win.tue.nl/~aeb/linux/uc/nfc\_ vs\_nfd.html. <sup>17</sup>The behavior of software applications can be quite erratic in this respect. For example, Apple's TextEdit does not do any conversion on text entry. However, when you copy and paste some text inside the same document in rich text mode (i.e. RTF-format), it will be transformed into NFC on paste. Saving a document does not do any conversion to the glyphs on screen, but it will save the characters in NFC. ### 3.10 Pitfall: Absence of canonical equivalence Although in most cases canonical equivalence will take care of alternative encodings of the same character, there are some cases in which the Unicode Standard decided against equivalence. This leads to identical characters that are not equivalent, like <ø> latin small letter o with stroke at U+00F8 and <o̷> a combination of latin small letter o at U+006F with combining short solidus overlay at U+0037. The general rule followed is that extensions of Latin characters that are connected to the base character are not separated as combining diacritics. For example, characters like <ŋ ɲ ɳ> or <ɖ ɗ> are obviously derived from <n> and <d> respectively, but they are treated like new separate characters in the Unicode Standard. Likewise, characters like <ø> and <ƈ> are not separated into a base character <o> and <c> with an attached combining diacritic. Interestingly, and somewhat illogically, there are three elements which are directly attached to their base characters, but which are still treated as separable in the Unicode Standard. Such characters are decomposed (in NFD normalization) into a base character with a combining diacritic. However, it is these cases that should be considered the exceptions to the rule. These three elements are the following: There are further combinations that deserve special care because it is actually possible to produce identical characters in different ways without them being . In these situations, the general rule holds, namely that characters with attached extras are not decomposed. However, in the following cases the extras actually exist as combining diacritics, so there is also the possibility to construct a character by using a base character with those combining diacritics. 3.11 Pitfall: Encodings To harmonize the encoding in these cases it is not sufficient to use Unicode normalization. Additional checks are necessary, for example by using orthography profiles (see Chapter 7). ### 3.11 Pitfall: Encodings Before we discuss the pitfall of different file formats in Section 3.12, it is pertinent to point out that the common usage of the term encoding unfortunately does not distinguish between encoded sequences of code points and text encoded as bit patterns. Recall, a code point is simply a numerical representation of some defined entity; in other words, a code point is a character encoding-specific unique identifier or ID. In the Unicode Standard encoding, code points are numbers that serve as unique identifiers, each of which is associated with a set of character properties defined by the Unicode Consortium in the Unicode Character Database.<sup>18</sup> The number of each code point can be encoded in various formats, including as a decimal integer (e.g. 112), as an 8-bit binary sequence (01110000) or hexadecimal (0070). This example Unicode code point, U+0070, represents latin small letter p and its associated Unicode properties, such as it belongs to the category Letter, Lowercase [Ll], in the Basic Latin block, and that its title case and upper case is associated with code point U+0050. 19 The other meaning of encoding has to do with the fact that computers represent data and instructions in patterns of bits. A bit pattern is a combination of binary digits arranged in a sequence. And how these sequences are carved up into bit patterns is determined by how they are encoded. Thus the term encoding is used for both sequences of code points and text encoded as bit patterns. Hence <sup>18</sup>https://www.unicode.org/ucd/ <sup>19</sup>See also Chapter 2. ### 3 Unicode pitfalls a Unicode-aware programmer might prefer to say that UTF-8, UTF-16, etc., are Unicode encoding systems because they determine how sequences of bit patterns are determined, which are then mapped to characters.<sup>20</sup> The terminological issue here is that the Unicode Standard introduces a layer of indirection between characters and bit patterns, i.e. the code point, which can be encoded differently by different encoding systems. Note also that all computer character encodings include so-called control characters, which are non-printable sometimes action-inducing characters, such as the null character, bell code, backspace, escape, delete, and line feed. Control characters can interact with encoding schemes. For example, some programming languages make use of the null character to mark the end of a string. Line breaks are part of the text, and as such as covered by the Unicode Standard. But they can be problematic because line breaks differ from operating system to operating system in how they are encoded. These variants are discussed in Section 3.12. ### 3.12 Pitfall: File formats Unicode is a character encoding standard, but characters of course appear inside some kind of computer file. The most basic Unicode-based file format is pure line-based text, i.e. strings of Unicode-encoded characters separated by line breaks (note that these line breaks are what for most people intuitively corresponds to paragraph breaks). Unfortunately, even within this apparently basic setting there exists a multitude of variants. In general these different possibilities are well-understood in the software industry, and nowadays they normally do not lead to any problems for the end user. However, there are some situations in which a user is suddenly confronted with cryptic questions in the user interface involving abbreviations like LF, CR, BE, LE or BOM. Most prominently this occurs with exporting or importing data in several software applications from Microsoft. Basically, there are two different issues involved. First, the encoding of line breaks and, second, the encoding of the Unicode characters into code units and the related issue of endianness. <sup>20</sup>UTF stands for Unicode Transformation Format. It a method for translating numbers into binary data and vice versa. There are several different UTF encoding formats, e.g. UTF-8 is a variable-length encoding that uses 8-bit code units, is compatible with ASCII, and is common on the web. UTF-16 is also variable-length, uses 16-bit code units, and is used system-internally by Windows and Java. See further discussion under Code units in Section 3.12. For more indepth discussion, refer to the Unicode Frequently Asked Questions and additional sources therein: http://unicode.org/faq/utf\_bom.html. 3.12 Pitfall: File formats ### Line breaks The issue with line breaks originated with the instructions necessary to direct a printing head of a physical printer to a new line. This involves two movements, known as carriage return (CR, returning the printing head to the start of the line on the page) and line feed (LF, moving the printing head to the next line on the page). Physically, these are two different events, but conceptually together they form one action. In the history of computing, various encodings of line breaks have been used (e.g. CR+LF, LF+CR, only LF, or only CR). Currently, all Unix and Unix-derived systems use only LF as code for a line break, while software from Microsoft still uses a combination of CR+LF. Today, most software applications recognize both options, and are able to deal with either encoding of line breaks (until rather recently this was not the case, and using the wrong line breaks would lead to unexpected errors). Our impression is that there is a strong tendency in software development to standardize on the simpler "only LF" encoding for line breaks, and we suggest that everybody should use this encoding whenever possible. ### Code units The issue with code units stems from the question how to separate a stream of binary ones and zeros, i.e. bits, into chunks representing Unicode characters. A code unit is the sequence of bits used to encode a single character in an encoding. The Unicode Standard offers three different approaches, called UTF-32, UTF-16 and UTF-8, that are intended for different use cases.<sup>21</sup> The details of this issue are extensively explained in section 2.5 of the Unicode Core Specification (The Unicode Consortium 2018). Basically, UTF-32 encodes each character in 32 bits (32 binary units, i.e. 32 zeros or ones) and is the most disk-space-consuming variant of the three. However, it is the most efficient encoding processing-wise, because the computer simply has to separate each character after 32 bits. In contrast, UTF-16 uses only 16 bits per character, which is sufficient for the large majority of Unicode characters, but not for all of them. A special system of surrogates is defined within the Unicode Standard to deal with these additional characters. The effect is a more disk-space efficient encoding (approximately half <sup>21</sup>The letters UTF stand for Unicode Transformation Format, but the notion of "transformation" is a legacy notion that does not have meaning anymore. Nevertheless, the designation UTF (in capitals) has become an official standard designation, but should probably best be read as simply "Unicode Format". ### 3 Unicode pitfalls the size), while adding a limited computational overhead to manage the surrogates. Finally, UTF-8 is a more complex system that dynamically encodes each character with the minimally necessary number of bits, choosing either 8, 16 or 32 bits depending on the character. This represents again a strong reduction in space (particularly due to the high frequency of data using erstwhile ASCII characters, which need only 8 bits) at the expense of even more computation necessary to process such strings. However, because of the ever growing computational power of modern machines, the processing overhead is in most practical situations a non-issue, while saving on space is still useful, particularly for sending texts over the Internet. As a result, UTF-8 has become the dominant encoding on the World Wide Web. We suggest that everybody uses UTF-8 as their default encoding. A related problem is a general issue about how to store information in computer memory, which is known as endianness. The details of this issue go beyond the scope of this book. It suffices to realize that there is a difference between big-endian (BE) storage and little-endian (LE) storage. The Unicode Standard offers a possibility to explicitly indicate what kind of storage is used by starting a file with a so-called byte order mark (BOM). However, the Unicode Standard does not require the use of BOM, preferring other non-Unicode methods to signal to computers which kind of endianness is used. This issue only arises with UTF-32 and UTF-16 encodings. When using the preferred UTF-8, using a BOM is theoretically possible, but strongly dispreferred according to the Unicode Standard. We suggest that everyone tries to prevent the inclusion of BOM in their data. ### 3.13 Pitfall: Incomplete implementations Another pitfall that we encounter when using the Unicode Standard is its incomplete implementation in different standards and programming languages, e.g. SQL, XML, XLST, Python. For example, although the Unicode Standard mandates that the comparison of Unicode text be done using normalized text, this is not the case with the equality operator "==" in Python. Furthermore, it is not always transparent what the operating system or specific software applications do when text is being copied and pasted. For example, copy and pasting the character sequence U+0061 latin small letter a <a> and U+0301 combining acute accent <◌́>, visually <á>, into the text editor TextWrangler leaves the sequence decomposed as two characters. But when pasting the decomposed sequence into ### 3.14 Recommendations RStudio, and other software programs, the sequence becomes precomposed as U+00E1 latin small letter a with acute, i.e. <á>. ### 3.14 Recommendations Summarizing the pitfalls discussed in this chapter, we propose the following recommendations: I prefer it UTF-8 NFC LF no BOM # 4 The International Phonetic Alphabet In this chapter we present a brief history of the IPA (Section 4.1), which dates back to the late 19th century, not long after the creation of the first typewriter with a QWERTY keyboard. An understanding of the IPA and its premises and principles (Section 4.2) leads to a better appreciation of the challenges that the International Phonetic Association faced when digitally encoding the IPA's set of symbols and diacritics (Section 4.3). Occurring a little over a hundred years after the inception of the IPA, its encoding was a major challenge (Section 4.4); many linguists have encountered the pitfalls when the two are used together (Chapter 5). ### 4.1 Brief history Established in 1886, the international phonetic association (henceforth Association) has long maintained a standard alphabet, the international phonetic alphabet or IPA, which is a standard in linguistics to transcribe sounds of spoken languages. It was first published in 1888 as an international system of phonetic transcription for oral languages and for pedagogical purposes. It contained phonetic values for English, French and German. Diacritics for length and nasalization were already present in this first version, and the same symbols are still used today. Originally, the IPA was a list of symbols with pronunciation examples using words in different languages. In 1900 the symbols were first organized into a chart and were given phonetic feature labels, e.g. for manner of articulation among others plosives, nasales, fricatives, for place of articulation among others bronchiales, laryngales, labiales and for vowels e.g. fermées, mi-fermées, mi-ouvertes, ouvertes. Throughout the last century, the structure of the chart has changed with increases in phonetic knowledge. Thus, similar to notational systems in other scientific disciplines, the IPA reflects facts and theories of phonetic knowledge that have developed over time. It is natural then that the IPA is modified occasionally to accommodate scientific innovations and discoveries. In fact, updates are part ### 4 The International Phonetic Alphabet of the Association's mandate. These changes are captured in revisions to the IPA chart.<sup>1</sup> Over the years there have been several revisions, but mostly minor ones. Articulation labels – what are often called features even though the IPA deliberately avoids this term – have changed, e.g. terms like lips, throat or rolled are no longer used. Phonetic symbol values have changed, e.g. voiceless is no longer marked by <h>. Symbols have been dropped, e.g. the caret diacritic denoting 'long and narrow' is no longer used. And many symbols have been added to reflect contrastive sounds found in the world's very diverse phonological systems. The use of the IPA is guided by principles outlined in the Handbook of the International Phonetic Association (The International Phonetic Association 1999), henceforth simply called Handbook. Today, the IPA is designed to meet practical linguistic needs and is used to transcribe the phonetic or phonological structure of languages. It is also used increasingly as a foreign language learning tool, as a standard pronunciation guide and as a tool for creating practical orthographies of previously unwritten languages. The IPA suits many linguists' needs because: Several styles of transcription with the IPA are possible, as illustrated in the Handbook, and they are all valid.<sup>3</sup> Therefore, there are different but equivalent transcriptions, or as noted by Ladefoged (1990: 64), "perhaps now that the Association has been explicit in its eclectic approach, outsiders to the Association will no longer speak of the IPA transcription of a given phenomenon, as if there were only one approved style." Clearly not all phoneticians agree, nor are they likely <sup>1</sup> For a detailed history, we refer the reader to: https://en.wikipedia.org/wiki/History\_of\_the\_ International\_Phonetic\_Alphabet. <sup>2</sup>Although the chart uses traditional manner and place of articulation labels, the symbols can be used as a representation of any defined bundle of features, binary or otherwise, to define phonetic dimensions. <sup>3</sup> For an illustration of the differences, see the 29 languages and their transcriptions in the Illustrations of the IPA (The International Phonetic Association 1999: 41–154). ### 4.2 Premises and principles to ever completely agree, on all aspects of the IPA or on transcription approaches and practices in general. As noted above, there have been several revisions in the IPA's long history, but the current version (2005) is strikingly similar to the 1926 version, which shows the viability of the IPA as a common standard for linguistic transcription. ### 4.2 Premises and principles ### Premises Any IPA transcription is based on two premises: (i) that it is possible to describe the acoustic speech signal (sound waves) in terms of sequentially ordered discrete segments, and, (ii) that each segment can be characterized by an articulatory target. Once spoken language data are segmented, the IPA provides symbols to unambiguously represent phonetic details. However, since phonetic detail could potentially include anything, e.g. something like "deep voice", the IPA restricts phonetic detail to linguistically relevant aspects of speech. Phonological considerations thus inextricably play a roll in transcription. In other words, phonetic observations beyond quantitative acoustic analysis are always made in terms of some phonological framework. Today, the IPA chart reflects a linguistic theory grounded in principles of phonological contrast and in knowledge about the attested linguistic variation. This fact is stated explicitly in several places, including in the Report on the 1989 Kiel convention published in the Journal of the International Phonetic Association (Roach 1989: 67–68): The IPA is intended to be a set of symbols for representing all the possible sounds of the world's languages. The representation of these sounds uses a set of phonetic categories which describe how each sound is made. These categories define a number of natural classes of sounds that operate in phonological rules and historical sound changes. The symbols of the IPA are shorthand ways of indicating certain intersections of these categories. and in the Handbook (The International Phonetic Association 1999: 18): […] a symbol can be regarded as a shorthand equivalent to a phonetic description, and a way of representing the contrasting sounds that occur in a language. Thus [m] is equivalent to "voiced bilabial nasal", and is also a ### 4 The International Phonetic Alphabet way of representing one of the contrasting nasal sounds that occur in English and other languages. […] When a symbol is said to be suitable for the representation of sounds in two languages, it does not necessarily mean that the sounds in the two languages are identical. From its earliest days the Association aimed to provide "a separate sign for each distinctive sound; that is, for each sound which, being used instead of another, in the same language, can change the meaning of a word" (The International Phonetic Association 1999: 27). Distinctive sounds became later known as phonemes and the IPA has developed historically into a notational device with a strictly segmental phonemic view. A phoneme is an abstract theoretical notion derived from an acoustic signal as produced by speakers in the real world. Therefore the IPA contains a number of theoretical assumptions about speech and how to transcribe speech in written form. ### Principles Essentially, transcription has two parts: a text containing symbols and a set of conventions for interpreting those symbols (and their combinations). The symbols of the IPA distinguish between letter-like symbols and diacritics (symbol modifiers). The use of the letter-like symbols to represent a language's sounds is guided by the principle of contrast; where two words are distinguishable by phonemic contrast, those contrasts should be transcribed with different letter symbols (and not just diacritics). Allophonic distinction falls under the rubric of diacritically-distinguished symbols, e.g. the difference in English between an aspirated /p/ in [pʰæt] and an unreleased /p/ in [stop̚]. Yet, in some situations diacritics are used to mark phonemic contrasts. The Handbook recommends to limit the use of phonemic diacritics to the following situations: ### 4.2 Premises and principles The interpretation of the IPA symbols in specific usage is not trivial. Although the articulatory properties of the IPA symbols themselves are rather succinctly summarized by the normative description in the Handbook, it is common in practical applications that the transcribed symbols do not precisely represent the phonetic value of the sounds that they represent. So an IPA symbol <t> in one transcription is not always the same as an IPA <t> in another transcription (or even within a single transcription). The interpretation of any particular <t> is mostly a language-specific convention (or even resource-specific and possibly even context-specific), a fact which – unfortunately – is in most cases not made explicit by users of the IPA. There are different reasons for this difficulty to interpret IPA symbols, all officially sanctioned by the IPA. An important principle of the IPA is that different representations resulting from different underlying analyses are allowed. Because the IPA does not provide phonological analyses for specific languages, the IPA does not define a single correct transcription system. Rather, the IPA aims to provide a resource that allows users to express any analysis so that it is widely understood. Basically, the IPA allows for both a narrow phonetic transcription and a broad phonological transcription. A narrow phonetic transcription may freely use all symbols in the IPA chart with direct reference to their phonetic value, i.e. the transcriber can indicate with the symbols <ŋ͡m> that the phonetic value of the attested sound is a simultaneous labial and velar closure which is voiced and contains nasal airflow, independently of the phonemic status of this sound in the language in question. In contrast, the basic goal of a broad phonemic transcription is to distinguish all words in a language with a minimal number of transcription symbols (Abercrombie 1964: 19). A phonemic transcription includes the conventions of a particular language's phonological rules. These rules determine the realization of that language's phonemes. For example, in the transcription of German, Dutch, English and French a symbol <t> might be used for the voiceless plosive in the alveolar and dental areas. This symbol is sufficient for a succinct transcription of these languages because there is no further phonemic subdivisions in this domain in either of these languages. However, the language-specific realization of this consonant is closer to [tʰ], [t], [tʰ] and [t ̪ ], respectively. Similarly, the five ̪ vowels of Greek can be represented phonemically in IPA as /ieaou/, though phonetically they are closer to [iεaɔu]. The Japanese five-vowel system can also be transcribed in IPA as /ieaou/, while the phonetic targets in this case are closer to [ieaoɯ]. ### 4 The International Phonetic Alphabet Note also that there can be different systems of phonemic transcription for the same variety of a language, so two different resources on the "same" language might use different symbols that represent the same sound. The differences may result from the fact that more than one phonetic symbol may be appropriate for a phoneme, or the differences may be due to different phonemic analyses, e.g. Standard German's vowel system is arguably contrastive in length, tenseness or vowel quality. Finally, even within a single phonemic transcription a specific symbol can have different realizations because of allophonic variation which might not be explicitly transcribed. In sum, there are three different reasons why phonemically-based IPA transcription is difficult to interpret: Ideally, all such implicit conventions of a phonemic transcription would be explicitly codified. This could very well be performed by using an orthography profile (see Chapter 7), linking the selected phonemic transcription symbols to narrow phonetic transcriptions, possibly also including specifications of contextual interpretation. ### 4.3 IPA encodings In 1989, an IPA revision convention was held in Kiel, Germany. As in previous meetings, there were changes made to the repertoire of phonetic symbols in the IPA chart, which reflected what had been discovered, described and cataloged by linguists about the phonological systems in the world's languages in the interim. Personal computers were also becoming more commonplace, and linguists were using them to create databases. A cogent example is the UCLA Phonological Segment Inventory Database (UPSID; Maddieson 1984), which was expanded (Maddieson & Precoda 1990) and then encoded and distributed in a computer ### 4.3 IPA encodings program (Maddieson & Precoda 1992).<sup>4</sup> The programmers used only ASCII characters to maximize compatibility (e.g. <kpW> for [kpʷ]), but were faced with unavoidable arbitrary mappings between ASCII letters and punctuation, and the more than 900 segment types documented in their sample of world's languages' phonological systems. The developers devised a system of base characters with secondary diacritic marks (e.g. in the previous example <kp>, the base character, is modified with <W>). This encoding approach is also used in SAMPA and X-SAMPA (Section 4.3) and in the ASJP.<sup>5</sup> But before UPSID, SAMPA and ASJP, IPA was encoded with numbers. ### IPA Numbers Prior to the Kiel Convention for the modern revision of the IPA in 1989, Wells (1987) collected and published practical approaches to coded representations of the IPA, which dealt mainly with the assignment of characters on the keyboard to IPA symbols. The process of assigning standardized computer codes to phonetic symbols was given to the workgroup on computer coding (henceforth working group) at the Kiel Convention. This working group was given the following tasks (Esling 1990; Esling & Gaylord 1993): The identification of IPA symbols with unique identifiers was a first step in formalizing the IPA computationally because it would give each symbol an unambiguous numerical identifier called an ipa number. The numbering system was to be comprehensive enough to support future revisions of the IPA, including symbol specifications and diacritic placement. The application of diacritics was also to be made explicit. Although the Association had never officially approved a set of names for the IPA symbols, each IPA symbol received a unique ipa name. Many symbols already had an informal name (or two) used by linguists, but consensus on symbol names was growing due to the recent publication of the Phonetic Symbol Guide <sup>4</sup> It could be installed via floppy disk on an IBM PC, or compatible, running DOS with 1MB free disk space and 360K available RAM. <sup>5</sup>See the ASJP use case in the online supplementary materials to this book: https://github.com/ unicode-cookbook/recipes. ### 4 The International Phonetic Alphabet (Pullum & Ladusaw 1986). Thus most of the IPA symbol names were taken from that source (The International Phonetic Association 1999: 31). The working group decided insightfully that the computing-coding convention for the IPA should be independent of computer environments or formats, i.e. the ipa number was not meant to be encoded at the bit pattern level. The working group report's declaration includes the following explanatory remarks (Roach 1989: 82): The recommendation of a 7-bit ASCII or 8-bit extended-ASCII coding system would be short-sighted in view of development towards 16-bit and 32 bit processors. In fact, any specific recommendations would tie the Association to a stage of technological development which is bound to be outdated long before the next revision of the handbook. The coding convention was not meant to address the engineering aspects of the actual encoding in computers (cf. Anderson (1984)). However, it was meant to serve as a basis for a interchange standard for creating mapping tables from various computer encodings, fonts, phonetic-character-set software, etc., to common IPA numbers, and therefore symbols.<sup>6</sup> Furthermore, the assignment of computer codes to IPA symbols was meant to represent an unbiased formulation. The Association here played the role of an international advisory body and it stated that it should not recommend a particular existing system of encoding. In fact, during this time there were a number of coding systems used (see Section 1.2), but none of them had a dominant international position. The differences between systems were also either too great or too subtle to warrant an attempt at combining them (Roach 1989). The working group assigned each IPA symbol to a unique three-digit IPA number. Encoded in this number scheme implicitly is information about the status of each symbol (see below). The IPA numbers were listed with the IPA symbols and they were also illustrated in IPA chart form (see Esling & Gaylord (1993: 84) or The International Phonetic Association (1999: App. 2)). The numbers were assigned in linear order (e.g. [p] 101, [b] 102, [t] 103…) following the IPA revision of 1989 and its update in 1996. Although the numbering scheme still exists, in practice it is superseded by the Unicode codification of symbols. <sup>6</sup>Remember, at this time in the late 1980s there was no stable multilingual computing environment. But some solution was needed because scholars were increasingly using personal computers for their research and many were quickly adopting electronic mail or discussion boards like Usenet as a medium for international exchanges. Most of these systems ran on 8-bit hardware systems using a 7-bit ASCII character encoding. ### 4.3 IPA encodings The working group made the decision that no IPA symbol, past or present, could be ignored. The comprehensive inclusion of all IPA symbols was to anticipate the possibility that some symbols might be added, withdrawn, or reintroduced into current or future usage. For example, in the 1989 revision voiceless implosives < ƥ, ƭ, ƈ, ƙ, ʠ > were added; in the 1993 revision they were removed. Ligatures like < ʧ, ʤ > are included as formerly recognized IPA symbols; they are assigned to the 200 series of IPA numbers as members of the group of symbols formerly recognized by the IPA. To ensure backwards compatibility, legacy IPA symbols would retain an IPA number and an IPA name for reference purposes. As we discuss below, this decision is later reflected in the Unicode Standard as many legacy IPA symbols still reside in the IPA Extensions block. The IPA number is expressed as a three-digit number. The first digit indicates the symbol's category (Esling 1990; Esling & Gaylord 1993): After a symbol is categorized, it is assigned a number sequentially, e.g. [i] 301, [e] 302, [ɛ] 303. The system allows for the addition of new symbols within the various series by appending them, e.g. [ⱱ] 184. Former non-IPA symbols (or often-used but non-official IPA symbols) for consonants, vowels and diacritics are numbered from 299 backwards. For example, the voiceless and voiced postalveolar affricates and fricatives < č, ǰ, š, ž > are assigned the IPA numbers 299, 298, 297 and 296, respectively, because they are not sanctioned IPA symbols. The assignment of the IPA numbers to IPA symbols provided the basis for uniquely identifying the set of past and present IPA symbols as a type of computational representational standard of the IPA. Within each revision of the IPA, the coding defines a closed and clearly defined set of characters. The benefits of this standardization are clear in at least two ways: it is used in translation tables that reference ASCII representations of the IPA, and this early computational representation of the IPA became the basis for X-SAMPA and for the inclusion of the IPA into the Unicode Standard version 1.0. ### 4 The International Phonetic Alphabet ### SAMPA and X-SAMPA True to the working group's aim, the IPA numbers provided a mechanism for an interchange standard for creating mapping tables to various computer encodings. For example, the IPA coding system was used as a mapping system in the creation of SAMPA (Wells et al. 1992), an ASCII representation of the IPA symbols. For a long time, linguists, like all other computer users, were limited to ASCIIencoded 7-bit characters, which only includes Latin characters, numbers and some punctuation and symbols. Restricted to these standard character sets that lacked IPA support or other language-specific graphemes that they needed, linguists devised their own solutions.<sup>7</sup> For example, some chose to represent unavailable graphemes with substitutes, e.g. the combination of <ng> to represent <ŋ>. Tech-savvy linguists redefined selected characters from a character encoding by mapping custom-made fonts to specific code points.<sup>8</sup> However, one linguist's electronic text would not render properly on another linguist's computer without access to the same font. Furthermore, if two character encodings defined two character sets differently, then data could not be reliably and correctly displayed. This is a commonly encountered example of the non-interoperability of data and data formats. One solution was the ASCII-ification of the IPA, which simply involved defining keyboard-able sequences consisting of ASCII combinations as IPA symbols. For example, Wells (1987) provides an in-depth description of IPA codings from country-to-country. Later ASCII-IPAs include Kirshenbaum (created in 1992 in a Usenet group and named after its lead developer who was at Hewlett-Packard Laboratories) and Worldbet (published by Hieronymus (1993), who was at AT&T Laboratories). The most successful effort was SAMPA (Speech Assessment Methods Phonetic Alphabet), which was created between 1988–1991 in Europe to represent IPA symbols with ASCII character sequences (Wells 1987; Wells et al. 1992), using e.g. <p\> for [ɸ]. SAMPA was developed by a group of speech scientists from nine countries in Europe and it constituted the ASCII-IPA symbols needed for phonemic transcription of the principal European languages (Wells 1995). It is still widely used in language technology. Two problems with SAMPA are that (i) it is only a partial encoding of the IPA and (ii) it encodes different languages in separate data tables, instead of using <sup>7</sup>Early work addressing the need for a universal computing environment for writing systems and their computational complexity is discussed in Simons (1989). A more recent survey of practical recommendations for language resources, including notes on encoding, can be found in Bird & Simons (2003). <sup>8</sup> For example, SIL's popular font SIL IPA 1990. ### 4.4 The need for a single multilingual environment a universal alphabet, like IPA. SAMPA tables were developed as part of a European Commission-funded project to address technical problems like electronic mail exchange (what is now simply called email). SAMPA is essentially a hack to work around displaying IPA characters, but it provided speech technology and other fields a basis that has been widely adopted and often still used in code. So, SAMPA is a collection of tables to be compared, instead of a large universal table representing all languages. An extended version of SAMPA, called X-SAMPA, set out to include every symbol, including all diacritics, in the IPA chart (Wells 1995). X-SAMPA is considered more universally applicable because it consists of one table that encodes all characters in IPA. In line with the principles of the IPA, SAMPA and X-SAMPA include a repertoire of symbols. These symbols are intended to represent phonemes rather than all allophonic distinctions. Additionally, both ASCII-ifications of IPA – SAMPA and X-SAMPA – are (reportedly) uniquely parsable (Wells 1995). However, like the IPA, X-SAMPA has different notations for encoding the same phonetic phenomena (cf. Section 5.5). SAMPA and X-SAMPA have been widely used for speech technology and as an encoding system in computational linguistics. In fact, they are still used in popular software packages that require ASCII input, e.g. RuG/L04 and SplitsTree4.<sup>9</sup> ### 4.4 The need for a single multilingual environment In hindsight it is easy to lose sight of how impactful 30 years of technological development have been on linguistics, from theory development using quantitative means to pure data collection and dissemination. But at the end of the 1970s, virtually no ordinary working linguist was using a personal computer (Simons 1996). Personal computer usage, however, dramatically increased throughout the 1980s. By 1990, dozens of character sets were in common use. They varied in their architecture and in their character repertoires, which made things a mess. During the 1980s, it became increasingly clear that an adequate solution to the problem of multilingual computing environments was needed. Linguists were on the forefront of addressing this issue because they faced these challenges headon by wishing to publish and communicate electronic text with phonetic symbols which were not included in basic ASCII. One only needs to look at facsimiles of older electronic documents to see exotic symbols written in by hand after the preparation of typed version. <sup>9</sup>See http://www.let.rug.nl/kleiweg/L04/ and http://www.splitstree.org/, respectively. ### 4 The International Phonetic Alphabet A major benefit of the standardization of the IPA in a computational representation by the Kiel working group is that it provided the basis for a formal proposal to be submitted to various international standards organizations, several of which were trying to tackle (and in a sense win) the multilingual computing environment problem (cf. Section 1.2). Basically, everyone – from corporations to governments to language scientists – wanted a single unified multilingual character encoding set for all the world's writing systems, even if they did not understand or appreciate the challenges involved in creating and adopting a solution. Industry was starting to tackle the issues involved in developing a single multilingual computing environment on a variety of fronts, including the then new technology of bitmap fonts and the creation of Font Manager and Script Manager by Apple (Apple Computer 1985; 1986; 1988). As noted above, around this time linguists were developing work-arounds such as SAMPA, so that they could communicate IPA transcription and use ASCII-based software. Some linguists formalized the issues of multilingual text processing from a computational perspective (Anderson 1984; Becker 1984; Simons 1989). The study of writing systems was also being invigorated (Sampson 1985: 11–15) by the computational challenges in making computers work in a multilingual environment. The engineering problems and solutions had been spelled out years before, e.g. a two-byte encoding for multilingual text (Anderson 1984). Although languages vary to an astounding extent (cf. Evans & Levinson (2009)), writing systems are quite similar formally and the issue of formal representation of the world's orthographic systems had already been addressed (Simons 1989). After the Kiel Convention in 1989, the working group assisted the International Phonetic Association in representing the IPA to the international organization for standardization (ISO) and to the text encoding initiative (TEI) (Esling & Gaylord 1993). The working group's formalization of the IPA, i.e. a full listing of agreed-upon computer codings for phonetic symbols, was used in developing writing system descriptions, which were at the time being solicited for scripts to be included in the new multilingual international character encoding standards. The working group for ISO/IEC 10646 and Unicode were two such initiatives. In the historical context of the IPA being considered for inclusion in ISO/IEC 10646, it is important to realize that there were a variety of sources (i.e. not just from the Association) which submitted character proposals for phonetic alphabets. These proposals, including the one from the Association via the Kiel working group, were considered as a whole by the ISO working groups that were responsible for incorporating a phonetic script into the universal character set ### 4.4 The need for a single multilingual environment (UCS). The ISO working groups that were responsible for assigning a phonetic character set then made their own submissions as part of a review process by ISO for approval based on both informatics and phonetic criteria (Esling & Gaylord 1993: 86). Character set ISO/IEC 10646 was approved by ISO, including the phonetic characters submitted to them in May 1993. The set of IPA characters were assigned UCS codes in 16-bit representation (in hexadecimal) and were published as Tables 2 and 3 in Esling & Gaylord (1993), which include a graphical representation of the IPA symbol, its IPA name, phonetic description, IPA number, UCS code and AFII code.<sup>10</sup> When the character sets of ISO/IEC 10646 and the Unicode Standard later converged (see Chapter 2), the IPA proposal was included in the Unicode Standard Version 1.0 – largely as we know it today. With subsequent revisions to the IPA, one might have expected that the Unicode Consortium would update the Unicode Standard in a way that is in line with the development of linguistic insights. However, updates that go against the principle of maintaining backwards compatibility lose out, i.e. it is more important to deal with the pitfalls created along the way than it is to change the standard. Therefore, many of the pitfalls we encounter today when using Unicode IPA are historic relics that we have to come to grips with. It was a long journey, but the goal of achieving a single multilingual computing environment has largely been accomplished. As such, we should not dismiss the IPA numbers or pre-Unicode encoding attempts, such as SAMPA/X-SAMPA, as misguided. The parallels between the IPA numbers and Unicode Code points, for example, are striking because both the IPA and the Unicode Consortium came up with the solution of an additional layer of indirection (an abstraction layer) between symbols/characters and encoding on the bit pattern level. SAMPA/X-SAMPA is also still useful as an input method for IPA in ASCII and required by some software. Current users of the Unicode Standard must cope with the pitfalls that were dug along the way, as will be discussed in the next chapter. As the Association foresightfully remarked about Unicode: > "When this character set is in wide use, it will be the normal way to encode IPA symbols." (The International Phonetic Association 1999: 164). <sup>10</sup>The Association for Font Information Interchange (AFII) was an international database of glyphs created to promote the standardization of font data required to produce ISO/IEC 10646. # 5 IPA meets Unicode ### 5.1 The twain shall meet The International Phonetic Alphabet (IPA) is a common standard in linguistics to transcribe sounds of spoken language into discrete segments using a Latin-based alphabet. Although IPA is reasonably easily adhered to with pen and paper, it is not trivial to encode IPA characters electronically. In this chapter we discuss various pitfalls with the encoding of IPA in the Unicode Standard. We will specifically refer to the 2015 version of the IPA (The International Phonetic Association 2015) and the 11.0.0 version of Unicode (The Unicode Consortium 2018). As long as a transcription is only directed towards phonetically trained eyes, then all the details of the Unicode-encoding are unimportant. For a linguist reading an IPA transcription, many of the details that will be discussed in this chapter might seem like hair-splitting trivialities. However, if IPA transcriptions are intended to be used across resources (e.g. searching similar phenomena across different languages) then it becomes crucial that there are strict encoding guidelines. Our main goal in this chapter is to present the encoding issues and propose recommendations for a strict IPA encoding for situations in which cross-resource consistency is crucial. There are several pitfalls to be aware of when using the Unicode Standard to encode IPA. As we have said before, from a linguistic perspective it might sometimes look like the Unicode Consortium is making incomprehensible decisions, but it is important to realize that the consortium has tried and is continuing to try to be as consistent as possible across a wide range of use cases, and it does place linguistic traditions above other orthographic choices. Furthermore, when we look at the history of how the IPA met Unicode, we see that many of the decisions for IPA symbols in the Unicode Standard come directly from the International Phonetic Association itself. Therefore, many pitfalls that we will encounter have their grounding in the history of the principles of the IPA, as well as in the technological considerations involved in creating a single multilingual encoding. In general, we strongly suggest to linguists to not complain about any decisions in the Unicode Standard, but to try and understand the rationale of the ### 5 IPA meets Unicode International Phonetic Association and the Unicode Consortium (both of which are almost always well-conceived in our experience) and devise ways to work with any unexpected behavior. Many of the current problems derive from the fact that the IPA is clearly historically based on the Latin script, but different enough from most other Latin-based writing systems to warrant special attention. This ambivalent status of the IPA glyphs (partly Latin, partly special) is unfortunately also attested in the treatment of IPA in the Unicode Standard. In retrospect, it might have been better to consider the IPA (and other transcription systems) to be a special kind of script within the Unicode Standard, and treat the obvious similarity to Latin glyphs as a historical relic. All IPA glyphs would then have their own code points, instead of the current situation in which some IPA glyphs have special code points, while others are treated as being identical to the regular Latin characters. Yet, the current situation, however unfortunate, is unlikely to change, so as linguists we must learn to deal with the specific pitfalls of IPA within the Unicode Standard. ### 5.2 Pitfall: No complete IPA code block The ambivalent nature of IPA glyphs arises because, on the one hand, the IPA uses Latin-based glyphs like <a>, <b> or <p>. From this perspective, the IPA seems to be just another orthographic tradition using Latin characters, all of which do not get a special treatment within the Unicode Standard (just like e.g. the French, German, or Danish orthographic traditions do not have a special status). On the other hand, the IPA uses many special symbols (like turned <ɐ>, mirrored <ɘ> and/or extended <ɧ> Latin glyphs) not found in any other Latin-based writing system. For this reason a special block with code points, called IPA Extensions was already included in the first version of the Unicode Standard (Version 1.0 from 1991). As explained in Section 3.6, the Unicode Standard code space is subdivided into character blocks, which generally encode characters from a single script. However, as is illustrated by the IPA, characters that form a single writing system may be dispersed across several different character blocks. With its diverse collection of symbols from various scripts and diacritics, the IPA is spread across 12 blocks in the Unicode Standard:<sup>1</sup> <sup>1</sup>This number of blocks depends on whether only IPA-sanctioned symbols are counted or if the phonetic symbols commonly found in the literature are also included, see Moran (2012: Appendix C). The 159 characters from 12 code blocks shown here are the characters proposed for strict IPA encoding, as discussed in Section 5.13. ### 5.3 Pitfall: IPA homoglyphs in Unicode Another problem is the large number of homoglyphs, i.e. different characters that have highly similar glyphs (or even completely identical glyphs, depending on the font rendering). For example, a user of a Cyrillic computer keyboard should ideally not use the <а> cyrillic small letter a at code point U+0430 for IPA transcriptions, but instead use the <a> latin small letter a at code point U+0061, although visually they are mostly indistinguishable, and the Cyrillic char- ### 5 IPA meets Unicode acter is more easily typed on a Cyrillic keyboard. Some further problematic homoglyphs related to encoding IPA in the Unicode Standard are the following: Conversely, non-linguists are unlikely to distinguish any semantic difference between an open back unrounded vowel, which is encoded in IPA with a "singlestory" <ɑ> latin small letter alpha at U+0251, and the open front unrounded <sup>2</sup>Note that many word processors (like Microsoft Word) by default will replace straight quotes by curly quotes, depending on the whitespace around it. <sup>3</sup> In the Unicode Standard the <ǃ> at U+01C3 is labeled latin letter retroflex click, but in IPA that glyph is used for an alveolar or postalveolar click (not retroflex). This naming is probably best seen as an error in the Unicode Standard. For the real retroflex click, see Section 5.12. ### 5.3 Pitfall: IPA homoglyphs in Unicode vowel, which is encoded in IPA with a "double-story" <a> latin small letter a at U+0061, basically treating them as homoglyphs, although they are different phonetic symbols. But even among linguists this distinction leads to problems. For example, as pointed out by Mielke (2009), there is a problem stemming from the fact that about 75% of languages are reported to have a five-vowel system (Maddieson 1984). Historically, linguistic descriptions tend not to include precise audio recording and measurements of formants, so this may lead one to ask if the many <a> characters that are used in phonological description reflects a transcriptional bias. The common use of <a> in transcriptions could be in part due to the ease of typing the letter on an English keyboard (or for older descriptions, the typewriter). We found it to be exceedingly rare that a linguist uses <ɑ> for a low back unrounded vowel.<sup>4</sup> They simply use <a> as long as there is no opposition to <ɑ>. Making things even more problematic, there is an old typographic tradition that the double-story <a> uses a single-story <ɑ> in italics. This leads to the unfortunate effect that even in many well-designed fonts the italics of <a> and <ɑ> use the same glyph. For example, in Linux Libertine (the font of this book) the italics of these characters are highly similar, <a> and <ɑ>, while in Charis SIL they are identical: <a> and <ɑ>. If this distinction has to be kept upright in italics, the only solution we can currently offer is to use slanted glyphs (i.e. artificially italicized glyphs) instead of real italics (i.e. special italics glyphs designed by a typographer).<sup>5</sup> This approach was taken by the Language Science Press to <sup>4</sup>One example is Vidal (2001: 75), in which the author states: "The definition of Pilagá /a/ as [+back] results from its behavior in certain phonological contexts. For instance, uvular and pharyngeal consonants only occur around /a/ and /o/. Hence, the characterization of /a/ and /o/ as a natural class of (i.e. [+back] vowels), as opposed to /i/ and /e/." <sup>5</sup> For example, the widely used IPA font Doulos SIL (https://software.sil.org/doulos/) does not have real italics. This leads some word-processing software, like Microsoft Word, to produce slanted glyphs instead. That particular combination of font and software application will thus lead to the desired effect distinguishing <a> from <ɑ> in italics. However, note that when the text is transferred to another font (i.e. one that includes real italics) and/or to another software application (like Apple Pages, which does not perform slanting), then this visual appearance will be lost. In this case we are thus still in the pre-Unicode situation in which the choice of font and rendering software actually matters. The ideal solution from a linguistic point of view would be the introduction of a new IPA code point for a different kind of <a>, which explicitly specifies that it should still be rendered as a double-story character when italicized. After informal discussion with various Unicode players, our impression is that this highly restricted problem is not sufficiently urgent to introduce even more <a> homographs in Unicode (which already lead to much confusion, see Section 3.8). ### 5 IPA meets Unicode distinguish between the two different orthographic <a>'s in Chakali in Brindle (2017). 6 Lastly, before we move on from the pitfall of IPA homoglyphs in Unicode to the pitfall of homoglyphs in IPA, we are aware of one example that illustrates both pitfalls. Consider for example what one reviewer coined i dot-suppression. When combining, say the latin small letter i <i> at U+0069 with the combining acute accent <◌́> at U+0301, the result is the combination of these two characters into <í> or the associated precomposed form latin small letter i with acute <í> at U+00ED. Typographically, the accent mark replaces the dot. In IPA, the <í> denotes a high front unrounded vowel with high tone. However, the result of losing the dot makes this IPA symbol look very similar to the nearhigh near-front unrounded vowel <ɪ>, when it also has the high tone marker: <ɪ>. ́ To boot, when an accent mark is added to latin small letter i with stroke <ɨ> at U+0268, the dot is not suppressed but retained, i.e. <ɨ>. ́ 7 ### 5.4 Pitfall: Homoglyphs in IPA Reversely, there are a few cases in which the IPA distinguishes different phonetic concepts, but the visual characters used by the IPA look very much alike. Such cases are thus homoglyphs in the IPA itself, which of course need different encodings. <sup>6</sup>http://langsci-press.org/catalog/book/74 <sup>7</sup>According to the Unicode Standard, latin small letter i with stroke <ɨ> at U+0268 cannot be decomposed into, say, latin small letter i <i> at U+0069 and combining short stroke overlay <◌̵> at U+0335. We discuss the pitfall of missing decomposition forms in Section 5.8. 5.5 Pitfall: Multiple encoding options in IPA • There are two different dashed-l characters in IPA, namely the <ɫ> latin small letter l with middle tilde at U+026B and the <ɬ> latin small letter l with belt at U+026C. These of course look highly similar, although they are different sounds. As a solution, we will actually propose to not use the middle tilde at all (see Section 5.5). ### 5.5 Pitfall: Multiple encoding options in IPA It is not just the Unicode Standard that offers multiple options for encoding the IPA. Even the IPA specification itself offers some flexibility in how transcriptions have to be encoded. There are a few cases in which the IPA explicitly allows for different options of transcribing the same phonetic content. This is understandable from a transcriber's point of view, but it is not acceptable when the goal is interoperability between resources written in IPA. We consider it crucial to distinguish between valid IPA, for which it is sufficient that any phonetically-trained reader is able to understand the transcription, and strict IPA, which should be standardized on a single unique encoding for each sound, so search will work across resources. We are aware of the following non-unique encoding options in the IPA, which will be discussed in turn below: The first case in which the IPA allows for different encodings is the question of how to transcribe tone (cf. Maddieson (1990)). There is an old tradition to use diacritics on vowels to mark different tone levels (The International Phonetic Association 1949). Prior to the 1989 Kiel convention, IPA-approved tone symbols included diacritics above or below the vowel or syllable, e.g. high and low tones marked with macrons (<◌̄>, <◌̱>), and acute and grave accents for high rising tone <◌́>, low rising tone <◌̗>, high falling tone <◌̀> and low falling tone <◌̖>. These tone symbols, however, had failed to catch on (probably) due to aesthetic objections and matters of adequacy for transcription (Maddieson 1990: 29). After the 1989 Kiel convention, the accent tone symbols were updated to the tradition that we are familiar with today and which was already in wide use by Africanists and others, namely level tones <◌̋, ◌́, ◌̄, ◌̀, ◌̏> and contour tones ### 5 IPA meets Unicode <◌̌, ◌̂, ◌᷄, ◌᷅, ◌᷈>.<sup>8</sup> In addition, the IPA also adopted tone letters developed by Chao (1930), e.g. <˥˦˧˨˩>, which were in wide use by Asianists.<sup>9</sup> Tone letters in the IPA have five different levels, and sequences of these letters can be used to indicate contours. Well-designed fonts will even merge a sequence of tone letters into a contour. For example, compare the font Linux Libertine, which does not merge tone letters <˥˨˧˩>, with the font CharisSIL, which merges this sequence of four tone letters into a single contour <˥˨˧˩>. For strict IPA encoding we propose to standardize on tone letters. Second, we commonly encounter the use of <g> latin small letter g at U+0067, instead of the Unicode Standard IPA character for the voiced velar stop <ɡ> latin small letter script g at U+0261. One begins to question whether this issue is at all apparent to the working linguist, or if they simply use the U+0067 because it is easily keyboarded and thus saves time, whereas the latter must be cumbersomely inserted as a special symbol in most software. The International Phonetic Association has taken the stance that both the keyboard latin small letter g and the latin small letter script g are valid input characters for the voiced velar plosive (The International Phonetic Association 1999: 19).<sup>10</sup> Unfortunately, this decision further introduces ambiguity for linguists trying to adhere to a strict Unicode Standard IPA encoding. For strict IPA encoding we propose to standardize on the more idiosyncratic latin small letter script g at U+0261. Third, the IPA has special markers for velarization <◌ˠ> and pharyngealization <◌ˤ>. Confusingly, there is also a marker for "velarized or pharyngealized", using the <◌̴> combining tilde overlay at U+0334. The tilde overlay seems to be extremely rarely used. We suggest to try and avoid using the tilde overlay, though for reasons of backward compatibility we will allow it in valid-IPA. Finally, the IPA states that "diacritics may be placed above a symbol with a descender". For example, for marking of voiceless pronunciation of voiced segments the IPA uses the ring diacritic. Originally, the ring should be placed below the <sup>8</sup>To make things even more complicated, there are at least two different Unicode homoglyphs for the low and high level tones, namely <◌̀> combining grave tone mark at U+0340 vs. <◌̀> combining grave accent at U+0300 for low tone, and <◌́> combining acute tone mark at U+0341 vs.<◌́> combining acute accent at U+0301 for high tone. <sup>9</sup>Not sanctioned by the IPA, but nevertheless widely attested, is the use of superscript numbers for marking tones, also proposed by Chao (1930). One issue to note here is that superscript numbers can be either regular numbers that are formatted as superscript with a text processor, or they can be separate superscript characters, as defined in the Unicode Standard (see: https: //en.wikipedia.org/wiki/Superscripts\_and\_Subscripts). This divide means that searching text is dependent on how the author formatted or encoded the superscript numbers. <sup>10</sup>Note however that the current instructions for contributors to the Journal of the International Phonetic Association requires the use of opentail <ɡ> and not looptail <g>. 5.6 Pitfall: Tie bar base character, like in <m̥>, using the combining ring below at U+0325. However, in letters with long descenders the IPA also allows to put the ring above the base, like in <ŋ̊>, using the combining ring above at U+030A. Yet, proper font design does not have any problem with rendering the ring below the base character, like in <ŋ̥>, so for strict IPA encoding we propose to standardize on the ring below. As a principle, for strict IPA encoding only one option should be allowed for all diacritics. The variable encoding as allowed by the IPA becomes even more troublesome for the tilde and diaeresis diacritics. In these cases, the IPA itself attaches different semantics to the symbols above and below a base characters. The tilde above a character (like in <ã>, using the combining tilde at U+0303) is used for nasalization, while the tilde below a character (like in <a̰>, using the combining tilde below at U+0330) indicates creaky voice. Likewise, the diaeresis above (like in <ä>, using the combining diaeresis at U+0308) is used for centralization, while the diaeresis below a character (like in <a>, using the ̤ combining diaeresis below at U+0324) indicates breathy voice. These cases strengthen our plea to not allow diacritics to switch position for typographic convenience. ### 5.6 Pitfall: Tie bar In the major revision of the IPA in 1932, affricates were represented by two consonants <tʃ>, ligatures <ʧ>, or with the tie bar <t͡ʃ>. In the 1938 revision the tie bar's semantics were broadened to indicate simultaneous articulation, as for example in labial velars such as <k͡p>. Thus, the tie bar is a convenient diacritic for visually tokenizing input strings into chunks of phonetically salient groups, including affricates, doubly articulated consonants or diphthongs. The tie bar can be placed above or below the base characters, e.g. <t͡s> or <t͜s>. IPA allows both options. The choice between the two symbols is purely for legible rendering; there is no difference in semantics between the two symbols. However, rendering is such a problematic issue for tie bars in general that many linguists simply do not use them. Just looking at a few different fonts already indicates that actually no font designer really gets the placement right in combination with superscripts and subscripts. If really necessary, we propose to standardize on the tie bar above the base characters, using a combining double inverted breve at U+0361. 11 <sup>11</sup>Also note that the undertie at U+203F looks like the tie bar below and is easily confused with it. However, it is a different character and has a different function in IPA. The undertie is ### 5 IPA meets Unicode Times new Roman: t̥ʰ͡s t̥ʰ͜s CharisSIL: t̥ʰ͡s t̥ʰ͜s Monaco: t̥ʰ ͡s t̥ʰ͜s DoulosSIL: t ̥ʰ͡s t ̥ʰ͜s Linux Libertine: tʰ͡s t ̥ ʰ͜s̥ Tie bars are a special type of character in the sense that they do not belong to a segment, but bind two graphemes together. This actually turns out to be rather different from Unicode conceptions. The Unicode encoding of this character belong to the Combining Diacritical Marks, namely either combining double inverted breve at U+0361 or combining double breve below at U+035C. Such a combining mark is by definition tied to the character in front, but not the character following it. The Unicode treatment of this character thus only partly corresponds to the IPA conception, which ideally would have the tie bar linked both to the character in front and to the character following. Further, according to the spirit of the IPA, it would also be possible to combine more than two base characters into one tie bar, but this is not possible with Unicode (i.e. there is no possibility to draw a tie bar over three or four characters). It is possible to indicate such larger groups by repeating the tie bar, like for a triphthong <a͡ʊ͡ə> in the English word hour. If really necessary, we consider this possible, even though the rendering will never look good. Most importantly though, in comparison to normal Unicode processing, the tie bar actually takes a reversed approach to complex graphemes. Basically, the Unicode principle (see Section 3.3) is that fixed sequences in a writing system have to be specified as tailored grapheme clusters. Only in case the sequence is not a cluster, then this has to be explicitly indicated. IPA takes a different approach. In IPA by default different base letters are not connected into larger clusters; only when it is specified in the string itself (using the tie bar). ### 5.7 Pitfall: Ligatures and digraphs One important distinction to acknowledge is the difference between multigraphs and ligatures. Multigraphs are groups of characters (in the context of IPA e.g. <tʃ> or <ou>) while ligatures are single characters (e.g. <ʧ> latin small letter tesh used as a linking symbol to indicate the lack of a boundary, e.g. French petit ami [pətit‿ami] 'boyfriend'. 5.8 Pitfall: Missing decomposition digraph at U+02A7). Ligatures arose in the context of printing easier-to-read texts, and are included in the Unicode Standard for reasons of legacy encoding. However, their usage is discouraged by the Unicode core specification. Specifically related to IPA, various phonetic combinations of characters (typically affricates) are available as single code points in the Unicode Standard, but are designated digraphs. Such glyphs might be used by software to produce a pleasing display, but they should not be hard-coded into the text itself. In the context of IPA, characters like the following ligatures should thus not be used. Instead a combination of two characters is preferred: <ʣ> latin small letter dz digraph at U+02A3 (use <dz>) <ʤ> latin small letter dezh digraph at U+02A4 (use <dʒ>) <ʥ> latin small letter dz digraph with curl at U+02A5 (use <dʑ>) <ʦ> latin small letter ts digraph at U+02A6 (use <ts>) <ʧ> latin small letter tesh digraph at U+02A7 (use <tʃ>) <ʨ> latin small letter tc digraph with curl at U+02A8 (use <tɕ>) <ʩ> latin small letter feng digraph at U+02A9 (use <fŋ>) However, there are a few Unicode characters that are historically ligatures, but which are today considered as simple characters in the Unicode Standard and thus should be used when writing IPA, namely: <ɮ> latin small letter lezh at U+026E <œ> latin small ligature oe at U+0153 <ɶ> latin letter small capital oe at U+0276 <æ> latin small letter ae at U+00E6 ### 5.8 Pitfall: Missing decomposition Although many combinations of base character with diacritic are treated as with precomposed characters, there are a few combinations in IPA that allow for multiple, apparently identical, encodings that are not (see Section 3.9 on the principle of canonical equivalence). For that reason, the following elements should not be treated as diacritics when encoding IPA in Unicode: <◌̡> combining palatalized hook below at U+0321 <◌̢> combining retroflex hook below at U+0322 <◌̵> combining short stroke overlay at U+0335 <◌̷> combining short solidus overlay at U+0337 ### 5 IPA meets Unicode There turn out to be a lot of characters in the IPA that could be conceived as using any of these elements, like <ɲ>, <ɳ>, <ɨ> or <ø>. However, all such characters exist as well as precomposed combination in Unicode, and these precomposed characters should preferably be used. When combinations of a base character with diacritic are used instead, then these combinations are not to the precomposed combinations. This means that any search will not find both at the same time. A similar problem arises with the rhotic hook. There are two precomposed characters in Unicode with a rhotic hook, which are not with a combination of the vowel with a separately encoded hook: <ɚ> latin small letter schwa with hook at U+025A <ɝ> latin small letter reversed open e with hook at U+025D All other combinations of vowels with rhotic hooks will have to be made by using <◌˞> modifier letter rhotic hook at U+02DE, because there is no complete set of precomposed characters with rhotic hooks in Unicode. For that reason we propose to not use the two precomposed characters with hooks mentioned above, but always use the separate rhotic hook at U+02DE in IPA. A similar situation arises with <◌̴> combining tilde overlay at U+0334. The main reason some phoneticians like to use this in IPA is to mark the dark <l> in English codas, using the character <ɫ> latin small letter l with middle tilde at U+026B. This character is not canonically equivalent to the combination <l> + <◌̴>, so one of the two possible encodings has to be chosen. Because the tilde overlay is described as a general mechanism by the IPA, we propose to use the separated <◌̴> combining tilde overlay at U+0334. However, note that phonetically this seems to be (almost) superfluous (see Section 5.5) and the typical usage in the form of <ɫ> is (almost) a homoglyph with <ɬ> (see Section 5.4). For these reasons we also suggest to try and avoid the tilde overlay completely. Reversely, note that the <ç> latin small letter c with cedilla at U+00E7 is with <c> with <◌̧> combining cedilla at U+0327, so it will be separated into two characters by Unicode canonical decomposition, also if such a decomposition is not intended in the IPA. However, because of the nature of canonical equivalence (see Section 3.9), these two encodings are completely identical in any computational treatment, so this decomposition does not have any practical consequences. 5.9 Pitfall: Different notions of diacritics ### 5.9 Pitfall: Different notions of diacritics Another pitfall relates to the question, what is a diacritic? The problem is that the meaning of the term diacritic as used by the IPA is not the same as it is used in the Unicode Standard. Specifically, diacritics in the IPA-sense are either so-called combining diacritical marks or spacing modifier letters in the Unicode Standard. Crucially, Combining Diacritical Marks are by definition combined with the character before them (to form so-called default grapheme clusters, see Chapter 2). In contrast, Spacing Modifier Letters are by definition not combined into grapheme clusters with the preceding character, but simply treated as separate letters. In the context of the IPA, the following IPA-diacritics are actually Spacing Modifier Letters in the Unicode Standard: Length marks, namely: ``` <◌ː> modifier letter triangular colon at U+02D0 <◌ˑ> modifier letter half triangular colon at U+02D1 ``` Tone letters, including but not limited to: <˥> modifier letter extra-high tone bar at U+02E5 <˨> modifier letter low tone bar at U+02E8 Superscript letters, including but not limited to:<sup>12</sup> <◌ʰ> modifier letter small h at U+02B0 <◌ˤ> modifier letter small reversed glottal stop at U+02E4 <◌ⁿ> superscript latin small letter n at U+207F The rhotic hook:<sup>13</sup> <◌˞> modifier letter rhotic hook at U+02DE Although linguists might expect these characters to belong together with the character in front of them, at least for tone letters, stress symbols and <ʰ> modi- <sup>12</sup>The Unicode Standard defines the Phonetic Extensions block that defines symbols used in phonetic notation systems, including the Uralic Phonetic Alphabet, Americanist and Russianist phonetic notations, Oxford English and American dictionaries, etc. Among other symbols, the Phonetic Extensions block includes the superscript letters <m, ŋ, b>, which are not valid IPA characters, although we have seen them used in linguistic practice. <sup>13</sup>It is really unfortunate that the rhotic hook in Unicode is classified as a Spacing Modifier, and not as a Combining Diacritical Mark. Although the rhotic hook is placed to the right of its base character (and not above or below), it still is always connected to the character in front, even physically connected to it. We cannot find any reason for this treatment, and consider it an error in Unicode. We hope it will be possible to change this classification in the future. ### 5 IPA meets Unicode fier letter small h at U+02B0 the Unicode Consortium's decision to treat it as a separate character is also linguistically correct. If intended, then any default combination of Spacing Modifiers with the preceding character can be specified in orthography profiles (see Chapter 7). ### 5.10 Pitfall: No unique diacritic ordering Also related to diacritics is the question of ordering. To our knowledge, the International Phonetic Association does not specify an ordering for diacritics that combine with phonetic base symbols; this exercise is left to the reasoning of the transcriber. However, such marks have to be explicitly ordered if sequences of them are to be interoperable and compatible computationally. An example is a labialized aspirated alveolar plosive: <tʷʰ>. There is nothing holding linguists back from using <tʰʷ> instead (with exactly the same intended meaning). However, from a technical standpoint, these two sequences are different; if both sequences are used in a document, searching for <tʷʰ> will not find any instances of <tʰʷ>, and vice versa. Likewise, a creaky voiced syllabic dental nasal can be encoded in various orders, e.g. <n̪ ̰̩ >, <n̩ ̰̪ > or <n̩ ̪ ̰ >. 5.10 Pitfall: No unique diacritic ordering ### Canonical combining classes In accordance with the absence of any specification of ordering in the IPA, the Unicode Standard likewise does not propose any standardized orders. Both leave it to the user to be consistent; this approach naturally invites inconsistency across different authored resources. There is one (minor) aspect of ordering for which the Unicode Standard does present a canonical solution. Fortunately, this is uncontroversial from a linguistic perspective. Diacritics in the Unicode Standard (i.e. Combining Diacritical Marks, see Section 5.9) are classified in so-called canonical combining classes. In practice, the diacritics are distinguished by their position relative to the base character.<sup>14</sup> When applying a Unicode normalization (NFC or NFD, see Section 3.9), the diacritics in different positions are put in a specified order. This process therefore harmonizes the difference between different encodings in some situations, for example in the case of an extra-short creaky voice vowel <ḛ̆>. This grapheme cluster can be encoded either as <e>+<◌̆>+<◌̰> or as <e>+<◌̰>+<◌̆>. To prevent this twofold encoding, the Unicode Standard specifies the second ordering as canonical (namely, diacritics below are put before diacritics above). When encoding a string according to the Unicode Standard, it is possible to do this either using the NFC (composition) or NFD (decomposition) normalization (see Section 3.9). Decomposition implies that precomposed characters (like <á> latin small letter a with acute at U+00E1) will be split into its parts. This might sound preferable for a linguistic analysis, as the different diacritics are separated from the base characters. However, note that most attached elements like strokes (e.g. in the <ɨ>), retroflex hooks (e.g. in <ʐ>) or rhotic hooks (e.g. in <ɝ>) will not be decomposed. In general, Unicode decomposition does not behave like a feature decomposition as expected from a linguistic perspective. It is thus important to consider Unicode decomposition only as a technical procedure, and not assume that it is linguistically sensible. ### Proposal for diacritic ordering Facing the problem of specifying a consistent ordering of diacritics while developing a large database of phonological inventories from the world's languages, Moran (2012: 540) defined a set of diacritic ordering conventions. The conventions are influenced by the linguistic literature, though some ad-hoc decisions had to be taken given the vast variability of phonological segments described <sup>14</sup>For a detailed description, see: http://unicode.org/reports/tr44/#Canonical\_Combining\_Class\_ Values. ### 5 IPA meets Unicode by linguists. The most recent version of the conventions is published online by Moran & McCloy (2014). 15 According to Unicode Canonical Combining Classes, overlay diacritics like <◌̴> (Combining Class number 1) always come before diacritics below (Combining Class number 220), which in turn always come before diacritics above (Combining Class number 230), which in turn come before diacritics over multiple characters like the tie bar <◌͡◌> (Combining Class number 233). We follow this order, but add the other IPA diacritics (which are not diacritics in the Unicode sense) between diacritics below and the tie bar. Further, within all these classes of diacritics there is no canonical ordering specified by Unicode, so we propose an explicit ordering here. Starting with the diacritics below: if a character sequence contains more than one diacritic below the base character, then the place features are applied first (linguolabial, dental, apical, laminal, advanced, retracted), followed by the manner features (raised, lowered, advanced and retracted tongue root), then secondary articulations (more round, less round), laryngeal settings (creaky, breathy, voiced, devoiced), and finally the syllabic or non-syllabic marker. So, the order that is proposed is the following, where <\|> indicates or and <→> indicates precedes. Note that the groups of alternatives (as marked by <\|>) are supposed never to occur together with the same base character. In effect, this represents yet another restriction on possible diacritic sequences. Combining Diacritical Marks (below) ordering: Next, if a character sequence contains more than one diacritic above the base character, we propose the following order: Combining Diacritical Marks (above) ordering: <sup>15</sup>http://phoible.github.io/conventions/ 5.11 Pitfall: Revisions to the IPA ``` → extra short <◌̆> ``` ``` → no audible release <◌̚ > ``` Then, when a character sequence contains more than one character of the Spacing Modifier Letters, these will be placed after all combining diacritical marks in the following order: Spacing Modifier Letters ordering: ``` → rhotic hook <◌˞> ``` Finally, the tie bar follows at the very end of any such sequence: Tie bar: → tie bar <◌͡◌> ### 5.11 Pitfall: Revisions to the IPA With each revision of the IPA, many decisions need to be made by the Association as to which symbols should be added, removed or changed. For example, in the 1989 revision of the IPA at the Kiel Convention, changes to specific symbols (in previous charts) were debated and the Association's members made certain decisions. The prevailing mood at the convention was not to change specific symbols unless a strong case was made (Ladefoged 1990). For example, two such decisions included: ### 5 IPA meets Unicode These decisions have practical consequences for transcribers of IPA, particularly those who wish to follow current recommended practices of encoding electronic text in the Unicode Standard. For example, the Unicode Standard contains latin small letter turned t <ʇ> at U+0287, which is no longer part of the IPA. It still exists, however, in the Unicode IPA Extensions block, with the comment "dental click (sound of 'tsk tsk')". In such cases, the IPA transcriber must know the status of legacy symbols in the current version of the IPA and the correct characters in the Unicode Standard. The most controversial issue regarding symbols debated at the convention was the representation for voiceless implosives (Ladefoged 1990: 62). In accordance with the principles of the IPA, as outlined in Section 4, distinct symbols are favored for cases of phonological contrast. Further, convenience of display in the chart must also be taken into account when arguing for or against the inclusion or deletion of IPA symbols in the IPA chart. Finally, the inclusion or deletion of symbols should consider the current state of phonetic knowledge of the world's languages. Ladefoged (1990) argued against the inclusion of the symbols < ƥ, ƭ, ƈ, ƙ, ʠ > for voiceless implosives, noting (i) that they are not contrastive (e.g. in Mayan languages); (ii) that there is no instrumental evidence supporting voiceless implosives in Africa; and (iii) that the sounds are sufficiently rare so as not to need a whole new row of symbols in the chart. Ladefoged favored symbolizing the sounds using a voiceless diacritic ring below voiced implosives, e.g. <ɓ̥>. Nevertheless, in the 1989 IPA chart there is indeed a row for implosives containing voiceless and voiced pairs.<sup>16</sup> But in the next revision, in 1993 (with an update in 1996), the voiceless implosives were dropped. The implosives row from the IPA consonantal chart disappeared and voiced implosives were given a column in the non-pulmonic consonants table (which is still reflected in the latest revision to date, IPA 2005). The Journal of the International Phonetic Association follows its own published standard for the IPA at the time of publication, even when it may conflict with the Association's principle of using different symbols for contrastive sounds and diacritics for phonetic variation. For example, in the case of voiceless implosives, McLaughlin (2005)shows that Seereer-Siin (Niger-Congo, Atlantic; ISO 639-3 srr) has a phonologically contrastive set of voiced and voiceless implosive stops at the labial, coronal and palatal places of articulation. These symbols are transcribed in an Illustrations of the IPA article in the IPA journal as < ɓ̥, ɗ̥, ʄ̥>. <sup>16</sup>https://en.wikipedia.org/wiki/File:IPA\_as\_of\_1989.png 5.12 Additions to the IPA The point of this pitfall is to highlight that revisions to the IPA will continue into the future, albeit infrequently. Nevertheless, given the Unicode Standard's principle of maintaining backwards compatibility (at all costs), transcribers and consumers of IPA cannot rely solely on remarks in the Unicode Standard to reflect current standard IPA usage. There is the possibility that at a later revision of the IPA, symbols that are not currently encoded in the Unicode Standard will be added to the IPA – although we think this is unlikely. ### 5.12 Additions to the IPA In the course of collecting a large sample of phoneme systems across the world's languages, Moran et al. (2014) found that in order to preserve distinctions both within and across language descriptions, additions to the approved IPA glyph set were needed. Wherever possible these additions were drawn from the extIPA symbols for disordered speech (Duckworth et al. 1990).<sup>17</sup> This section describes these proposed additions to the IPA glyph set. The additions are not part of the official IPA recommendations, so they should be used with caution. • Retroflex click Retroflex clicks can be represented by <‼> double exclamation mark at U+203C. Note that the (post-)alveolar click <ǃ> at U+01C3 is confusingly referred to as latin letter retroflex click in the Unicode Standard, which is probably best considered an error. • Voiced retroflex implosive Although the IPA includes a series of voiced implosives (marked with a hook on top, see Section 5.8), there is no voiced retroflex implosive. Following the spirit of the IPA, we propose to use <ᶑ> latin small letter d with hook and tail at U+1D91 for this sound. • Fortis/lenis Languages described as having a fortis/plain/lenis distinction that corresponds poorly with the traditional voiced/voiceless-unaspirated/voicelessaspirated continuum can be marked using the voiceless glyph for the plain phoneme, and then <◌͈> combining double vertical line below at U+0348 to mark the fortis articulation, and/or <◌͉> combining left angle below at U+0349 for the lenis articulation. • Frictionalization The diacritic <◌͓> combining x below at U+0353 can be used to represent <sup>17</sup>https://www.internationalphoneticassociation.org/sites/default/files/extIPAChart2008.pdf ### 5 IPA meets Unicode three types of frictionalized sounds: First, click consonants where the release of the anterior closure involves an ingressive sucking sound similar to a fricative, for example <kǃʰ>; second, frictionalized vowels (sounds that ͓ are phonologically vocalic, but with sufficiently close closures to create buzzing); and third, fricative sounds at places of articulation that do not have dedicated fricative glyphs, for example sounds with voiceless velar lateral frication, like <ʟ̥>. ͓ • Derhoticization For derhoticization we propose to use <◌̮> combining breve below at U+032E. • Coronal non-sibilant Languages described as having a sibilant/non-sibilant distinction among coronal fricatives and affricates can be handled using the subscript <◌͇> combining eqals sign below at U+0347 to mark the non-sibilant phoneme. • Glottalization Glottalized sounds can be indicated using <◌ˀ> modifier letter glottal stop at U+02C0, unless it is clear that either ejective or creaky voicing are the intended sounds (in which cases the standard IPA diacritics should be used). Pre-glottalized sounds can be marked with <ˀ◌> to the left of the base glyph, for example <ˀt>. • Voiced pre-aspiration Voiced sounds having pre-aspiration can be marked with <ʱ◌> modifier letter small h with hook at U+02B1 to the left of the base glyph, for example <ʱd>. • Epilaryngeal phonation There are some rare articulations that make use of an epilaryngeal phonation mechanism (e.g. the "sphincteric vowels" of !Xóõ). To represent these vowels, we propose to use the modifier <◌ᴱ> modifier letter capital e at U+1D31 to denote such sphincteric phonation. ### 5.13 Unicode IPA Recommendations Summarizing the pitfalls as discussed in this chapter, we propose to define three different IPA encodings: strict-IPA, valid-IPA and widened-IPA. Informally speaking, valid-IPA represents the current state of the IPA (The International Phonetic Association 2015). Strict-IPA represents a more constrained version of IPA, while widened-IPA is a slightly extended version of IPA, allowing a few more symbols. 5.13 Unicode IPA Recommendations Strict-IPA encoding is supposed to be used when interoperability of phonetic resources is intended. It is a strongly constrained subset of IPA geared towards uniqueness of encoding. Ideally, for each transcription there should be exactly one possible strict-IPA encoding. For each phonetic feature there is only one possibility (see Section 5.5) and the IPA diacritics are forced into a canonical ordering (see Section 5.10). Valid-IPA does allow alternative symbols with the same phonetic meaning, as specified in the official IPA specifications. Also, valid-IPA does not enforce a specific ordering of diacritics, because the IPA does not propose any such ordering. This means that in valid-IPA the same phonetic intention can be encoded in multiple ways. This is sufficient for phonetically trained human eyes, but it is not sufficient for automatic interoperability. Finally, widened-IPA includes a few more symbols which seem to be useful for various special cases (see Section 5.12). At the end of this chapter we have added a few longish tables summarizing all 159 different Unicode code points that form the basis of strict-IPA encoding (107 letters, 36 diacritics and 16 remaining symbols). We also make these tables available online in CSV format.<sup>18</sup> Each of these tables shows a typical glyph, and then lists the Unicode Code point, Unicode Name and IPA description for each symbol. Further, there is a table with the additional options for valid-IPA and a table with the additional options for widened-IPA. • strict-IPA letters The 107 different IPA letters as allowed in strict-IPA encoding are listed in Table 5.1 starting on page 73. • strict-IPA diacritics The 36 different IPA diacritics and tone markers (both Unicode Modifier Letters and Combining Diacritical Marks) as allowed in strict-IPA encoding are listed in Table 5.2 starting on page 76. • strict-IPA remainders The 16 remaining IPA symbols (boundary, stress, tone letters and intonation markers) as allowed in strict-IPA encoding are listed in Table 5.3 on page 77. <sup>18</sup>https://github.com/unicode-cookbook/cookbook/tree/master/book/tables ### 5 IPA meets Unicode Table 5.1: Strict-IPA letters with Unicode encodings Table 5.1 Strict-IPA letters with Unicode encodings — continued Table 5.1 Strict-IPA letters with Unicode encodings — continued Table 5.1 Strict-IPA letters with Unicode encodings — continued Table 5.2: Strict-IPA diacritics with Unicode encodings Table 5.2 Strict-IPA diacritics with Unicode encodings — continued Table 5.3: Other Strict-IPA symbols with Unicode encodings ### 5 IPA meets Unicode Table 5.3 Other Strict-IPA symbols with Unicode encodings — continued Table 5.4: Additional characters for valid-IPA with Unicode encodings Table 5.4 Additional characters for valid-IPA with Unicode encodings — continued Table 5.5: Additions to widened-IPA with Unicode encodings # 6 Practical recommendations This chapter is meant to be a short guide for novice users who are not interested in the programmatic aspects presented in Chapters 7 & 8. Instead, we provide links to quickly find general information about the Unicode Standard and the International Phonetic Alphabet (IPA). We target ordinary working linguists who want to know how to easily insert special characters into their digital documents and applications. ### 6.1 Unicode We discussed the Unicode Consortium's approach to computationally encoding writing systems in Chapter 2. The common pitfalls that we have encountered when using the Unicode Standard are discussed in detail in Chapter 3. Together these chapters provide users with an in-depth background about the hurdles they may encounter when using the Unicode Standard for encoding their data or for developing multilingual applications. For general background information about Unicode and character encodings, see these resources: For practical purposes, users need a way to insert special characters (i.e. characters that are not easily entered via their keyboards) into documents and software applications. There are a few basic approaches for inserting special characters. One way is to use software-specific functionality, when it is available. For example, Microsoft Word has an insert-special-symbol-or-character function that allows users to scroll through a table of special characters across different scripts. Special characters can be then inserted into the document by clicking on them. Another way is to install a system-wide application for special character insertion. We have long been fans of the PopChar application from Ergonis Software, ### 6 Practical recommendations which is a small program that can insert most Unicode characters (note however that the full version requires a paid subscription).<sup>1</sup> There are also web-based Unicode character pickers available through the browser that allow for the creation and insertion of special characters, which can then be copied & pasted into documents or software applications. For example, try: Yet another option for special character insertion includes operating systemspecific shortcuts. For example on the Mac, holding down a key on the keyboard for a second, say <u>, triggers a pop up with the options <û, ü, ù, ú, ū> which can then be inserted by keying the associated number (1–5). This method is convenient for occasionally inserting type accented characters, but the full range of special characters is limited and this method is burdensome for rapidly inserting many different characters. For complete access to special characters, Mac provides a Keyboard Viewer application available in the Keyboard pane of the System Preferences. On Windows, accented characters can be inserted by using alt-key shortcuts, i.e. holding down the alt-key and keying in a sequence of numbers (which typically reflect the Unicode character's decimal representation). For example, latin small letter c with cedilla at U+00E7 with the decimal code 231 can be inserted by holding the alt-key and keying the sequence 0231. Again, this method is burdensome for rapidly inserting characters. For access to the full range of Unicode characters, the Character Map program comes preinstalled on all Microsoft operating systems. There are also many third-party applications that provide custom keyboard layouts. These programs typically override keys or keystrokes on the user's keyboard allowing them to quickly enter special characters (once the layout of the new keyboard is mastered). They can be language-specific or devoted specifically to IPA. Two popular programs are: <sup>1</sup>http://www.ergonis.com/products/popcharx/ 6.2 IPA ### 6.2 IPA In Chapter 4 we described in detail the history and principles of the International Phonetic Alphabet (IPA) and how it became encoded in the Unicode Standard. In Chapter 5 we describe the resulting pitfalls from their marriage. These two chapters provide a detailed overview of the challenges that users face when working with the two standards. For general information about the IPA, the standard text is the Handbook of the International Phonetic Association: A Guide to the Use of the International Phonetic Alphabet (The International Phonetic Association 1999). The handbook describes in detail the principles and premises of the IPA, which we have summarized in Section 4.2. The handbook also provides many examples of how to use the IPA. The Association also makes available information about itself online<sup>2</sup> and it provides the most current IPA charts.<sup>3</sup> Wikipedia also has a comprehensive article about the IPA.<sup>4</sup> There are several good Unicode IPA character pickers available through the browser, including: Various linguistics departments also provide information about IPA fonts, software, and inserting Unicode IPA characters. Two useful resources are: Regarding fonts that display Unicode IPA correctly, many linguists turn to the IPA Unicode fonts developed by SIL International. The complete SIL font list is available online.<sup>5</sup> There is also a page that describes IPA transcription using the SIL fonts and provides an informative discussion on deciding which font to use.<sup>6</sup> Traditionally, IPA fonts popular with linguists were created and maintained by SIL International, so it is often the case in our experience that we encounter <sup>2</sup>https://www.internationalphoneticassociation.org/ <sup>3</sup>https://www.internationalphoneticassociation.org/content/ipa-chart <sup>4</sup>https://en.wikipedia.org/wiki/International\_Phonetic\_Alphabet <sup>5</sup>http://scripts.sil.org/SILFontList <sup>6</sup>http://scripts.sil.org/ipahome ### 6 Practical recommendations linguistics data in legacy IPA fonts, i.e. pre-Unicode fonts such as SIL IPA93.<sup>7</sup> SIL International does a good job of describing how to convert from legacy IPA fonts to Unicode IPA. The most popular Unicode IPA fonts are Doulos SIL and Charis SIL: Lastly, here are some online resources that we find particularly useful for finding more information about individual Unicode characters and also for converting between encodings: ### 6.3 For programmers and potential programmers If you have made it this far, and you are eager to know more about the technical aspects of the Unicode Standard and how they relate to software programming, we recommend two light-hearted blog posts on the topic. The classic blog post about what programmers should know about the Unicode Standard is Joel Spolsky's The Absolute Minimum Every Software Developer Absolutely, Positively Must Know About Unicode and Character Sets (No Excuses!). <sup>8</sup> A more recent blogpost, with a bit more of the technical details, is by David C. Zentgraf and is titled, What Every Programmer Absolutely, Positively Needs To Know About Encodings And Character Sets To Work With Text. <sup>9</sup> This post is aimed at software developers and uses the PHP language for examples. For users of Python, see the standard documentation on how to use Unicode in your programming applications.<sup>10</sup> For R users we recommend the stringi library.<sup>11</sup> For LATEX users the TIPA package is useful for inserting IPA characters into your typeset documents. See these resources: <sup>7</sup>http://scripts.sil.org/FontFAQ\_IPA93 <sup>8</sup>https://www.joelonsoftware.com/2003/10/08/the-absolute-minimum-every-software- developer-absolutely-positively-must-know-about-unicode-and-character-sets-no-excuses/ <sup>9</sup>http://kunststube.net/encoding/ <sup>10</sup>https://docs.python.org/3/howto/unicode.html <sup>11</sup>https://cran.r-project.org/web/packages/stringi/index.html ### 6.3 For programmers and potential programmers But we find it much easier to use the Unicode-aware XƎTEX typesetting system.<sup>12</sup> Unicode characters can be directly inserted into your TEX documents and compiled into typeset PDF with XƎLATEX. Lastly, we leave you with some Unicode humor for making it this far: <sup>12</sup>http://xetex.sourceforge.net/ # 7 Orthography profiles ### 7.1 Characterizing writing systems The Unicode Standard offers a very detailed technical approach for characterizing writing systems computationally. As such, it is sometimes too complex for the day-to-day practice of many linguists, as exemplified by the need to understand the common pitfalls that we discussed in Chapters 3 & 5. Therefore, in this section we propose some simple guidelines for linguists working in multilingual environments. Our aims for adopting a Unicode-based solution are: (i) to improve the consistency of the encoding of sources, (ii) to transparently document knowledge about the writing system (including transliteration), and (iii) to do all of that in a way that is easy and quick to manage for many different sources with many different writing systems. The central concept in our proposal is the orthography profile, a simple delimited text file, that characterizes and documents a writing system. We also offer basic implementations in Python and R to assist with the production of such files, and to apply orthography profiles for consistency testing, grapheme tokenization and transliteration. Not only can orthography profiles be helpful in the daily practice of linguistics, they also succinctly document the orthographic details of a specific source, and, as such, might fruitfully be published alongside sources (e.g. in digital archives). Also, in high-level linguistic analyses in which the graphemic detail is of central importance (e.g. phonotactic or comparative-historical studies), orthography profiles can transparently document the decisions that have been taken in the interpretation of the orthography in the sources used. Given these goals, Unicode Locales (see Chapter 2) might seem like the ideal orthography profiles. However, there are various practical obstacles preventing the use of Unicode Locales in the daily linguistic practice, namely: (i) the XML structure<sup>1</sup> is too verbose to easily and quickly produce or correct manually, (ii) Unicode Locales are designed for a wide scope of information (like date formats or names of weekdays) most of which is not applicable for documenting writing <sup>1</sup>http://unicode.org/reports/tr35/ systems, and (iii) most crucially, even if someone made the effort to produce a technically correct Unicode Locale for a specific source at hand, then it is wellnigh impossible to deploy the description. This is because a locale description has to be submitted to and accepted by the Unicode Common Locale Data Repository. The repository is (rightly so) not interested in descriptions that only apply to a limited set of sources (e.g. descriptions for only a single dictionary). The major challenge, then, is developing an infrastructure to identify the elements that are individual graphemes in a source, specifically for the enormous variety of sources using some kind of alphabetic writing system. Authors of source documents (e.g. dictionaries, wordlists, corpora) use a variety of writing systems that range from their own idiosyncratic transcriptions to already well-established practical or longstanding orthographies. Although the IPA is one practical choice as a sound-based normalization for writing systems (which can act as an interlingual pivot to attain interoperability across writing systems), graphemes in each writing system must also be identified and standardized if interoperability across different sources is to be achieved. In most cases, this amounts to more than simply mapping a grapheme to an IPA segment because graphemes must first be identified in context (e.g. is the sequence one sound or two sounds or both?) and strings must be tokenized, which may include taking orthographic rules into account (e.g. a nasal sound may be transcribed as <n> when it appears between two vowels, but when it appears between a vowel and a consonant it becomes a nasalized vowel <Ṽ>). In our experience, data from each source must be individually tokenized into graphemes so that its orthographic structure can be identified and its contents can be extracted. To extract data for analysis, a source-by-source approach is required before an orthography profile can be created. For example, almost every available lexicon on the world's languages is idiosyncratic in its orthography and thus requires lexicon-specific approaches to identify graphemes in the writing system and to map graphemes to phonemes, if desired. Our key proposal for the characterization of a writing system is to use a grapheme tokenization as an inter-orthographic pivot. Basically, any source document is tokenized by graphemes, and only then a mapping to IPA (or any other orthographic transliteration) is performed. An orthography profile then is a description of the units and rules that are needed to adequately model a graphemic tokenization for a language variety as described in a particular source document. An orthography profile summarizes the Unicode (tailored) graphemes and orthographic rules used to write a language (the details of the structure and assumptions of such a profile will be presented in the next section). ### 7.2 Informal description As an example of graphemic tokenization, note the three different levels of technical and linguistic elements that interact in the hypothetical lexical form <tsʰṍ̰shi>: In (1), the string <tsʰṍ̰shi> has been tokenized into ten Unicode code points (using NFD normalization), delimited here by space. Unicode normalization is required because sequences of code points can differ in their visual and logical orders. For example, <õ̰> is ambiguous to whether it is the sequence of <o> + <◌̃> + <◌̰> or <o> + <◌̰> + <◌̃>. Although these two variants are visually homoglyphs, computationally they are different (see Sections 5.3 & 5.4). Unicode normalization should be applied to this string to reorder the code points into a canonical order, allowing the data to be treated for search and comparison. In (2), the Unicode code points have been logically normalized and visually organized into grapheme clusters, as specified by the Unicode Standard. The combining character sequence <õ̰> is normalized and visually grouped together. Note that the modifier letter small h at U+02B0 is not grouped with any other character. This is because it belongs to the Spacing Modifier Letters category. The Unicode Standard does not specify the direction that these characters modify a host character. For example, it can indicate either pre- or post-aspiration (whereas the nasalization or creaky diacritic is defined in the Unicode Standard to apply to a specified base character). Finally, to arrive at the graphemic tokenization in (3), tailored grapheme clusters are needed, possibly as specified in an orthography profile. For example, an orthography profile might specify that the sequence of characters <tsʰ> form a single grapheme. The orthography profile could also specify orthographic rules, e.g. when tokenizing graphemes in English, the sequences <sh> in the forms <mishap> and <mishmash> should be treated as distinct sequences depending on their contexts. ### 7.2 Informal description An orthography profile describes the Unicode code points, characters, graphemes and orthographic rules in a writing system. An orthography profile is a languagespecific (and often even resource-specific) description of the units and rules that ### 7 Orthography profiles are needed to adequately model a writing system. An important assumption is that we assume a resource is encoded in Unicode or has been converted to Unicode. Any data source that the Unicode Standard is unable to capture will also not be captured by an orthography profile. Informally, an orthography profile specifies the graphemes – in Unicode parlance tailored grapheme clusters – that are expected to occur in any data to be analyzed or checked for consistency. These graphemes are first identified throughout the whole data, a step which we call tokenization, and simply returned as such, possibly including error messages about any parts of the data that are not specified by the orthography profile. Once the graphemes are identified, they might also be changed into other graphemes – a step which we call transliteration. When a grapheme has different possible transliterations, then these differences should be separated by contextual specification, possibly down to listing individual exceptional cases. The crucial difference between our current proposal and traditional computational approaches to transliteration is the strict separation between tokenization and transliteration. Most computational approaches to transliteration are based on finite-state transducers (including the transliteration as described in the Unicode Locale Data Markup Language).<sup>2</sup> Finite-state transducers attempt to describe the mapping from input to output string directly as a set of rewrite rules. Although such systems are computationally well understood, we feel that they are not well-suited for day-to-day linguistic practice. First, by forcing a first step of grapheme tokenization, our system tries to keep close to the logic of the writing system. Second, by separating tokenization from transliteration there is no problem with 'feeding' and 'bleeding' of rules, common with transducers (cf. Section 8.4). Note that to deal with ambiguous parsing cases, it is still possible to use the Unicode approach of including the zero-width non-joiner character at U+200C into the text. The idea is to add this character into the text to identify cases in which a sequence of characters is not supposed to be a complex grapheme cluster – even though the sequence is in the orthography profile. In practice, we foresee a workflow in which orthography profiles are iteratively refined, while at the same time inconsistencies and errors in the data to be tokenized are corrected. In some more complex use cases there might even be a need for multiple different orthography profiles to be applied in sequence (see Sections 8.3 & 8.4 on various exemplary use cases). The result of any such workflow will normally be a cleaned dataset and an explicit description of the <sup>2</sup>http://www.unicode.org/reports/tr35/ 7.3 Formal specification orthographic structure in the form of an orthography profile. Subsequently, the orthography profiles can be easily distributed in scholarly channels alongside the cleaned data, for example in supplementary material added to journal papers or in electronic archives. ### 7.3 Formal specification ### File Format The formal specifications of an orthography profile (or simply profile for short) are the following: <sup>3</sup>See Section 3.12 in which we suggest to use NFC, no-BOM and LF line breaks because of the pitfalls they avoid. A keen reviewer notes, however, that specifying a convention for line endings and BOM is overly strict because most computing environments (now) transparently handle both alternatives. For example, using Python a file can be decoded using the encoding "utf-8 sig", which strips away the BOM (if present) and reads an input full in text mode, so that both line feed variants "LF" and "CRLF" will be stripped. <sup>4</sup>https://www.w3.org/TR/tabular-metadata/ <sup>5</sup>http://dublincore.org/ <sup>6</sup>http://w3c.github.io/csvw/metadata/#dfn-common-property ### 7 Orthography profiles also specify (v) a stable language identifier of the target language of the profile using BCP 47/ISO 639-3 or Glottocode as per the CLDF ontology.<sup>7</sup> Further, the metadata file should provide information about the orthography profile's structure and contents, including: (vi) its dialect description,<sup>8</sup> and (vii) proper column descriptions,<sup>9</sup> which describe how a column should be interpreted and processed (e.g. whether they should be processed as regular expressions; see below). Finally, in accordance with the Metadata Vocabulary for Tabular Data, the metadata's filename should consist of the orthography profile's filename appended with "-metadata.json".<sup>10</sup> The content of a profile consists of lines, each describing a grapheme of the orthography, using the following columns: <sup>7</sup>http://cldf.clld.org/v1.0/terms.rdf <sup>8</sup>http://w3c.github.io/csvw/metadata/#dfn-dialect-descriptions <sup>9</sup>http://w3c.github.io/csvw/metadata/#dfn-datatype-description <sup>10</sup>JSON-LD metadata is also the choice for datasets conforming to the Cross-Linguistic Data Formats standard, see: http://cldf.clld.org/. column to indicate a group of graphemes, which can then be used in the description of the graphemes or the context. The identifiers should of course be chosen so that they do not conflate with any symbols used in the orthography. Note that such classes only refer to the graphemes, not to the context. ### Processing For the automated processing of the profiles, the following technical standards will be expected: ### 7 Orthography profiles ternally, the contexts in the columns Left and Right are combined with the column Grapheme to form a complex regular expression like: (?<=Left)Grapheme(?=Right). B4. The regular expressions will be applied in the order as specified in the profile, from top to bottom. A software implementation can offer help in figuring out the optimal ordering of the regular expressions, but then it should be made explicit in the orthography profile because regular expressions are executed in order from top to bottom. The actual implementation of the profile on some text-string will function as follows: ### 7.3 Formal specification they choose to encode their profile. Several sources suggest to use NFC when possible for text encoding,<sup>11</sup> including SIL International with regard to data archiving.<sup>12</sup> In our experience, in some use cases it turns out to be practical to treat both text and profile as NFD. This typically happens when many different combinations of diacritics occur in the data. An NFD profile can then be used to first check which individual diacritics are used, before turning to the more cumbersome inspection of all combinations. We suggest that any software application using orthography profiles should offer both approaches (i.e. NFC or NFD) to the user. The approach used can be documented in the metadata as unicode normalization. ### Software applications Any software application offering to use orthography profile: - C1. the name of the column to be used for transliteration (if any). - C2. the symbol-string to be inserted between graphemes. Optionally, a warning might be given if the chosen string includes characters from the orthography itself. - C3. the symbol-string to be inserted for unmatched strings in the tokenized and transliterated output. - C4. the tokenization method, i.e. whether the tokenization should proceed as global or linear (see B6 above). - C5. unicode normalization, i.e. whether the text-string and profile should use NFC or NFD. - C6. to assist in the ordering of the graphemes. In our experience working with idiosyncratic transcriptions and orthographies from <sup>11</sup>http://www.win.tue.nl/~aeb/linux/uc/nfc\_vs\_nfd.html <sup>12</sup>http://scripts.sil.org/cms/scripts/page.php?item\_id=NFC\_vs\_NFD ### 7 Orthography profiles low-resource languages, it is helpful to identify multi-sequence graphemes before single graphemes, and to identify graphemes with context before graphemes without context. Further, frequently relevant rules might be applied after rarely relevant rules (though frequency is difficult to establish in practice, as it depends on the available data). Also, if this all fails to give any decisive ordering between rules, it seems useful to offer linguists the option to reverse the ordering from any manual specified ordering, because linguists tend to write the more general rule first, before turning to exceptions or special cases. - C9. the original text-strings to be processed in the specified Unicode normalization, i.e. in either NFC or NFD as specified by the user. - C10. the tokenized strings, with additionally any transliterated strings, if transliteration is requested. - C11. a survey of all errors encountered, ideally both (i) in which text-strings any errors occurred and (ii) which characters in the textstrings lead to errors. - C12. a reordered profile, when any automatic reordering is offered. <sup>13</sup>For example compare the different first-letter capitalization practices of the digraphs <Nj> and <sup>&</sup>lt;IJ> (single-character ligatures in the Unicode Standard) in the Latin-based scripts of Southern-Slavic languages and Dutch, respectively. # 8 Implementation ### 8.1 Overview To illustrate the practical applications of orthography profiles, we have implemented two versions of the specifications presented in Chapter 7: one in Python<sup>1</sup> and one in R.<sup>2</sup> In this chapter, we introduce these two software libraries and provide practical step-by-step guidelines for installing and using them. Various simple and sometimes somewhat abstract examples will be discussed to show the different options available, and to illustrate the intended usage of orthography profiles in general. Note that our two libraries have rather different implementation histories, thus they may not give the same results in all situations (as discussed in Chapter 7). However, we do provide extensive test suites for each implementation that follow standard practices to make sure that results are correct. Users should refer to these tests and to the documentation in each release for specifics about each implementation. Note that due to the different naming convention practices in Python and R, function names differ between the two libraries. Also, the performance with larger datasets may not be comparable between the Python and R implementations. In sum, our two libraries should be considered as proofs of concept and not as the final word on the practical application of the specifications discussed in the previous chapter. In our experience, the current versions are sufficiently fast and stable to be useful for academic practice (e.g. checking data consistency, or analyzing and transliterating small to medium sized data sets), but they should probably not be used for full-scale industry applications without adaptation. First, in Section 8.2 we explain how to install Python<sup>3</sup> and R.<sup>4</sup> Then in Sections 8.3 & 8.4, we discuss our Python and R software packages, respectively. In addition to the material presented here to get users started, we maintain several case <sup>1</sup>https://pypi.python.org/pypi/segments <sup>2</sup>https://github.com/cysouw/qlcData <sup>3</sup>https://www.python.org/ <sup>4</sup>https://www.r-project.org/ ### 8 Implementation studies online that illustrate how to use orthography profiles in action. For convenience, we make these recipes available as Jupyter Notebooks<sup>5</sup> in our GitHub repository.<sup>6</sup> In the final section in this chapter, we also briefly describe a few recipes that we do not go into detail in this book. ### 8.2 How to install Python and R When one encounters problems installing software, or bugs in programming code, search engines are your friend! Installation problems and incomprehensible error messages have typically been encountered and solved by other users. Try simply copying and pasting the output of an error message into a search engine; the solution is often already somewhere online. We are fans of Stack Exchange<sup>7</sup> – a network of question-and-answer websites – which are extremely helpful in solving issues regarding software installation, bugs in code, etc. Searching the web for "install r and python" returns numerous tutorials on how to set up your machine for scientific data analysis. Note that there is no single correct setup for a particular computer or operating system. Both Python and R are available for Windows, Mac, and Unix operating systems from the Python and R project websites. Another option is to use a so-called package manager, i.e. a software program that allows the user to manage software packages and their dependencies. On Mac, we use Homebrew,<sup>8</sup> a simple-to-install (via the Terminal App) free and open source package management system. Follow the instructions on the Homebrew website and then use Homebrew to install R and Python (as well as other software packages such as Git and Jupyter Notebooks). Alternatively for R, RStudio<sup>9</sup> provides a free and open source integrated development environment (IDE). This application can be downloaded and installed (for Mac, Windows and Unix) and it includes its own R installation and R libraries package manager. For developing in Python, we recommend the free community version of PyCharm,<sup>10</sup> an IDE which is available for Mac, Windows, and Unix. Once you have R or Python (or both) installed on your computer, you are ready to use the orthography profiles software libraries presented in the next two sections. As noted above, we make this material available online on GitHub,<sup>11</sup> a <sup>5</sup>http://jupyter.org/ <sup>6</sup>https://github.com/unicode-cookbook/ <sup>7</sup>https://stackexchange.com/ <sup>8</sup>https://brew.sh/ <sup>9</sup>https://www.rstudio.com/ <sup>10</sup>https://www.jetbrains.com/pycharm/ <sup>11</sup>https://github.com/ 8.3 Python package: segments web-based version control system for source code management. GitHub repositories can be cloned or downloaded,<sup>12</sup> so that you can work through the examples on your local machine. Use your favorite search engine to figure out how to install Git on your computer and learn more about using Git.<sup>13</sup> In our GitHub repository, we make the material presented below (and more use cases described briefly in Section 8.5) available as Jupyter Notebooks. Jupyter Notebooks provide an interface where you can run and develop source code using the browser as an interface. These notebooks are easily viewed in our GitHub repository of use cases.<sup>14</sup> ### 8.3 Python package: segments The Python package segments is available both as a command line interface (CLI) and as an application programming interface (API). ### Installation To install the Python package segments (Forkel & Moran 2018) from the Python Package Index (PyPI) run: ``` $ pip install segments ``` on the command line. This will give you access to both the CLI and programmatic functionality in Python scripts, when you import the segments library. You can also install the segments package from the GitHub repository,<sup>15</sup> in particular if you would like to contribute to the code base:<sup>16</sup> ``` $ git clone https://github.com/cldf/segments $ cd segments $ python setup.py develop ``` ### Application programming interface The segments API can be accessed by importing the package into Python. Here is an example of how to import the library, create a tokenizer object, tokenize a <sup>12</sup>https://help.github.com/articles/cloning-a-repository/ <sup>13</sup>https://git-scm.com/ <sup>14</sup>https://github.com/unicode-cookbook/recipes <sup>15</sup>https://github.com/cldf/segments <sup>16</sup>https://github.com/cldf/segments/blob/master/CONTRIBUTING.md ### 8 Implementation string, and create an orthography profile. Begin by importing the Tokenizer from the segments library. >>> from segments.tokenizer import Tokenizer Next, instantiate a tokenizer object, which takes optional arguments for an orthography profile and an orthography profile rules file. >>> t = Tokenizer() The default tokenization strategy is to segment some input text at the Unicode Extended Grapheme Cluster boundaries,<sup>17</sup> and to return, by default, a spacedelimited string of graphemes. White space between input string sequences is by default separated by a hash symbol <#>, which is a linguistic convention used to denote word boundaries. The default grapheme tokenization is useful when you encounter a text that you want to tokenize to identify potential orthographic or transcription elements. ``` >>> result = t('ĉháɾãct'ɛ↗ʐː\| k ̌ p') ͡ >>> print(result) >>> 'ĉ h á ɾ ã̌ c t ' ɛ ↗ ʐ ː \| # k͡p' >>> result = t('ĉháɾãct'ɛ↗ʐː\| k ̌ p', segment_separator='-') ͡ >>> print(result) >>> 'ĉ-h-á-ɾ-ã-c-t-'-ɛ-↗-ʐ-ː-\| # k ̌ ͡-p' >>> result = t('ĉháɾãct'ɛ↗ʐː\| k ̌ p', separator=' // ')) ͡ >>> print(result) >>> 'ĉ h á ɾ ã̌ c t ' ɛ ↗ ʐ ː \| // k͡p' ``` The optional ipa parameter forces grapheme segmentation for IPA strings.<sup>18</sup> Note here that Unicode Spacing Modifier Letters,<sup>19</sup> such as <ː> and <◌͡◌>, will be segmented together with base characters (although you might need orthography profiles and rules to correct these in your input source; see Section 5.9 for details). >>> result = t('ĉháɾãct'ɛ↗ʐː\| k ̌ p', ipa=True) ͡ >>> print(result) >>> 'ĉ h á ɾ ã̌ c t ' ɛ ↗ ʐː \| # kp'͡ <sup>17</sup>http://www.unicode.org/reports/tr18/tr18-19.html#Default\_Grapheme\_Clusters <sup>18</sup>https://en.wikipedia.org/wiki/International\_Phonetic\_Alphabet <sup>19</sup>https://en.wikipedia.org/wiki/Spacing\_Modifier\_Letters ### 8.3 Python package: segments You can also load an orthography profile and tokenize input strings with it. In the data directory,<sup>20</sup> we've placed an example orthography profile. Let's have a look at it using more on the command line. ``` $ more data/orthography profile.tsv Grapheme IPA XSAMPA COMMENT a a a aa aː a: b b b c c c ch tʃ tS on õ o~ n n n ih í i_H inh ĩ́ i~_H ``` An orthography profile is a delimited UTF-8 text file (here we use tab as a delimiter for reading ease). The first column must be labeled Grapheme, as discussed in Section 7.3. Each row in the Grapheme column specifies graphemes that may be found in the orthography of the input text. In this example, we provide additional columns IPA and XSAMPA, which are mappings from our graphemes to their IPA and X-SAMPA transliterations. The final column COMMENT is for comments; if you want to use a tab "quote that string"! Let's load the orthography profile with our tokenizer. ``` >>> from segments.tokenizer import Profile >>> t = Tokenizer('data/orthography profile.tsv') ``` Now let's segment the graphemes in some input strings with our orthography profile. The output is segmented given the definition of graphemes in our orthography profile, e.g. we specified the sequence of two <a a> should be a single unit <aa>, and so should the sequences <c h>, <o n> and <i h>. >>> t('aabchonn-ih') >>> 'aa b ch on n - ih' This example shows how we can tokenize input text into our orthographic specification. We can also segment graphemes and transliterate them into other forms, which is useful when you have sources with different orthographies, but you <sup>20</sup>https://github.com/unicode-cookbook/recipes/tree/master/Basics/data want to be able to compare them using a single representation like IPA or X-SAMPA. ``` >>> t('aabchonn-ih', column='IPA') >>> 'aː b tʃ õ n í' >>> t('aabchonn-ih', column='XSAMPA') >>> 'a: b tS o~ n i_H' ``` It is also useful to know which characters in your input string are not in your orthography profile. By default, missing characters are displayed with the Unicode replacement character at U+FFFD, which appears below as a white question mark within a black diamond. >>> t('aa b ch on n - ih x y z') >>> 'aa b ch on n - ih � � �' You can change the default by specifying a different replacement character when you load the orthography profile with the tokenizer. ``` >>> t = Tokenizer('data/orthography-profile.tsv', errors_replace=lambda c: '?') >>> t('aa b ch on n - ih x y z') >>> 'aa b ch on n - ih ? ? ?' >>> t = Tokenizer('data/orthography-profile.tsv', errors_replace=lambda c: '<{0}>'.format(c)) >>> t('aa b ch on n - ih x y z') >>> 'aa b ch on n - ih <x> <y> <z>' ``` Perhaps you want to create an initial orthography profile that also contains those graphemes <x>, <y>, and <z>? Note that the space character and its frequency are also captured in this initial profile. ``` >>> profile = Profile.from_text('aa b ch on n - ih x y z') >>> print(profile) Grapheme frequency mapping 9 a 2 a h 2 h n 2 n b 1 b ``` ### Command line interface From the command line, access segments and its various arguments. For help, run: ``` $ segments -h usage: segments [-h] [--verbosity VERBOSITY] [--encoding ENCODING] [--profile PROFILE] [--mapping MAPPING] command ... Main command line interface of the segments package. positional arguments: command tokenize \| profile args optional arguments: -h, --help show this help message and exit --verbosity VERBOSITY increase output verbosity --encoding ENCODING input encoding --profile PROFILE path to an orthography profile --mapping MAPPING column name in ortho profile to map graphemes ``` Use 'segments help <cmd>' to get help about individual commands. ### 8 Implementation We have created some test data<sup>21</sup> with the German word Schächtelchen, which is the diminutive form of Schachtel, meaning 'box', 'packet', or 'carton' in English. ``` $ more sources/german.txt ``` Schächtelchen We can create an initial orthography profile of the German text by passing it to the segments profile command. The initial profile tokenizes the text on Unicode grapheme clusters, lists the frequency of each grapheme, and provides an initial mapping column by default. ``` $ cat sources/german.txt \| segments profile Grapheme frequency mapping c 3 c h 3 h e 2 e S 1 S ä 1 ä t 1 t l 1 l n 1 n ``` Next, we know a bit about German orthography and which characters combine to form German graphemes. We can use the information from our initial orthography profile to hand-curate a more precise German orthography profile that takes into account capitalization (German orthography obligatorily capitalizes nouns) and grapheme clusters, such as <sch> and <ch>. We can use the initial orthography profile above as a starting point (note that, in large texts, the frequency column may signal errors in the input, such as typos, if a grapheme occurs with very low frequency). The initial orthography profile can be edited with a text editor or spreadsheet program. As per the orthography profile specifications (see Chapter 7), we can adjust rows in the Grapheme column and then add additional columns for transliterations or comments. ``` $ more data/german orthography profile.tsv Grapheme IPA XSAMPA COMMENT Sch ʃ S German nouns are capitalized ``` <sup>21</sup>https://github.com/unicode-cookbook/recipes/tree/master/Basics/sources 8.4 R library: qlcData Using the command line segments function and passing it our orthography profile, we can now segment our German text example into graphemes. ``` $ cat sources/german.txt \| segments --profile=data/german-orthography-profile.tsv tokenize ``` ``` 'Sch ä ch t e l ch e n' ``` By providing segments a column for transliteration, we can convert the text into IPA. ``` $ cat sources/german.txt \| segments --mapping=IPA --profile=data/german-orthography-profile.tsv tokenize ``` 'ʃ ɛː ç t e l ç e n' ### And we can transliterate to X-SAMPA. ``` $ cat sources/german.txt \| segments --mapping=XSAMPA --profile=data/german-orthography-profile.tsv tokenize ``` 'S E: C t e l C e n' More examples are available online.<sup>22</sup> ### 8.4 R library: qlcData ### Installation The R implementation is available in the package qlcData (Cysouw 2018), which is directly available from the central R repository CRAN (Comprehensive R Archive Network). The R software environment itself has to be downloaded from its website.<sup>23</sup> After starting the included R program, the qlcData package for dealing with orthography profiles can be simply installed as follows: <sup>22</sup>https://github.com/unicode-cookbook/recipes <sup>23</sup>https://www.r-project.org ### 8 Implementation ``` # download and install the qlcData software install.packages("qlcData") # load the software, so it can be used library(qlcData) ``` The version available through CRAN is the latest stable version. To obtain the most recent bug-fixes and experimental additions, please use the development version, which is available on GitHub.<sup>24</sup> This development version can be easily installed using the github-install helper software from the devtools package. ``` # download and install helper software install.packages("devtools") # install the qlcData package from GitHub devtools::install_github("cysouw/qlcData", build_vignettes = TRUE) # load the software, so it can be used library(qlcData) ``` Inside the qlcData package, there are two functions for orthography processing, write.profile and tokenize. The package includes help files with illustrative examples, and also a so-called vignette with explanations and examples. ``` # view help files help(write.profile) help(tokenize) # view vignette with explanation and examples vignette("orthography_processing") ``` Basically, the idea is to use write.profile to produce a basic orthography profile from some data and then tokenize to apply the (possibly edited) profile on some data, as exemplified in the next section. This can of course be performed though R, but additionally there are two more interfaces to the R code supplied in the qlcData package: (i) Bash executables and (ii) Shiny webapps. The Bash executables are little files providing an interface to the R code that can be used in a shell on a UNIX-like machine. The exact location of these executables is best found after installation of R the packages. The location can be found by the following command in R. ``` # show the path to the bash executables file.path(find.package("qlcData"), "exec") ``` These executables can be used in the resulting file path, or they can be linked and/or copied to any location as wanted. For example, a good way to use the executables in a terminal is to make softlinks (using ln) from the executables to a <sup>24</sup>http://github.com/cysouw/qlcData directory in your PATH, e.g. to /usr/local/bin/. The two executables are named tokenize and writeprofile, and the links can be made directly by using Rscript to get the paths to the executables within the terminal. ``` # get the paths to the R executables in bash pathT=`Rscript -e 'cat(file.path(find.package("qlcData"), "exec", "tokenize"))'` pathW=`Rscript -e 'cat(file.path(find.package("qlcData"), "exec", "writeprofile"))'` # make softlinks to the R executables in /usr/local/bin # you will have to enter your user's password! sudo ln -is $pathT $pathW /usr/local/bin ``` After inserting this softlink it should be possible to access the tokenize function from the shell. Try tokenize --help to test the functionality. To make the functionality even more accessible, we have prepared webapps with the Shiny framework for the R functions. The webapps are included inside the qlcData package and can be started with the helper function (in R): launch\_ shiny('tokenize'). ### Profiles and error reporting (test <- c("AABB", "AАBВ")) The first example of how to use these functions concerns finding errors in the encoding of texts. In the following example, it looks as if we have two identical strings, AABB. However, this is just a surface-impression delivered by the current font, which renders Latin and Cyrillic capitals identically. We can identify this problem when we produce an orthography profile from the strings. Using the R implementation of orthography profiles, we first assign the two strings to a variable test, and then produce an orthography profile with the function write.profile. As it turns out, some of the letters are Cyrillic. ``` ## [1] "AABB" "AАBВ" write.profile(test) ## Grapheme Frequency Codepoint UnicodeName ## 1 A 3 U+0041 LATIN CAPITAL LETTER A ## 2 B 3 U+0042 LATIN CAPITAL LETTER B ## 3 А 1 U+0410 CYRILLIC CAPITAL LETTER A ## 4 В 1 U+0412 CYRILLIC CAPITAL LETTER VE ``` ### 8 Implementation The function of error-message reporting can also nicely be illustrated with this example. Suppose we made an orthography profile with just the two Latin letters <A> and <B> as possible graphemes, then this profile would not be sufficient to tokenize the strings. There are graphemes in the data that are not in the profile, so the tokenization produces an error, which can be used to fix the encoding (or the profile). In the example below, we can see that the Cyrillic encoding is found in the second string of the test input. ``` test <- c("AABB", "AАBВ") tokenize(test, profile = c("A", "B")) ## Warning in tokenize(test, profile = c("A", "B")): ## There were unknown characters found in the input data. ## Check output$errors for a table with all problematic strings. ## $strings ## originals tokenized ## 1 AABB A A B B ## 2 AАBВ A ⁇ B ⁇ ## ## $profile ## Grapheme Frequency ## 1 B 3 ## 2 A 3 ## ## $errors ## originals errors ## 2 AАBВ A ⁇ B ⁇ ## ## $missing ## Grapheme Frequency Codepoint UnicodeName ## 1 А 1 U+0410 CYRILLIC CAPITAL LETTER A ## 2 В 1 U+0412 CYRILLIC CAPITAL LETTER VE ``` ### Different ways to write a profile The function write.profile can be used to prepare a skeleton for an orthography profile from some data.The preparation of an orthography profile from some data might sound like a trivial problem, but actually there are various different ways in which strings can be separated into graphemes by write.profile. Consider the following string of characters called example below. The default settings of write.profile separates the string into Unicode graphemes according to grapheme clusters (called user-perceived characters; see Chapter 2 for an explanation). 8.4 R library: qlcData The results are shown in Table 8.1. As it turns out, some of these graphemes are single code points, others are combinations of two code points (see Section 3.2). example <- "ÙÚÛÙÚÛ" profile\_1 <- write.profile(example) Table 8.1: Profile 1 (default settings, splitting grapheme clusters) By specifying the splitting separator as the empty string sep = "", it is possible to split the string into Unicode code points, thus separating the combining diacritics. The idea behind this option sep is that separating by a character allows for user-determined separation. The most extreme choice here is the empty string sep = "", which is interpreted as separation everywhere. The other extreme is the default setting sep = NULL, which means that the separation is not user-defined, but relegated to the Unicode grapheme definitions. The result is shown in Table 8.2. profile\_2 <- write.profile(example, sep = "") Table 8.2: Profile 2 (splitting by code points) Some characters look identical, although they are encoded differently. Unicode offers different ways of normalization (see Section 3.9), which can be invoked here as well using the option normalize. NFC normalization turns everything into the precomposed characters, while NFD normalization separates everything into base characters with combining diacritics. Splitting by code points (i.e. sep = "") shows the results of these two normalizations in Tables 8.3 & 8.4. ### 8 Implementation # after NFC normalization Unicode code points have changed profile\_3 <- write.profile(example, normalize = "NFC", sep = "") # NFD normalization gives another structure of the code points profile\_4 <- write.profile(example, normalize = "NFD", sep = "") Table 8.3: Profile 3 (splitting by NFC code points) Table 8.4: Profile 4 (splitting by NFD code points) It is important to realize that for Unicode grapheme definitions, NFC and NFD normalization are equivalent. This can be shown by normalizing the example in either NFD or NFC, as shown in Tables 8.5 & 8.6, by using the default separation in write.profile. To be precise, default separation means setting sep = NULL, but that has not be added explicitly below. ``` # note that NFC and NFD normalization are identical # for Unicode grapheme definitions profile_5 <- write.profile(example, normalize = "NFD") profile_6 <- write.profile(example, normalize = "NFC") ``` Table 8.5: Profile 5 (splitting by graphemes after NFD) 8.4 R library: qlcData Table 8.6: Profile 6 (splitting by graphemes after NFC) These different profiles can also be produced using the bash executable writeprofile (see above for how to install the Bash executable). This example is also included in the help file of the executable. ### Using an orthography profile skeleton A common workflow to use these functions is to first make a skeleton for an orthography profile and then edit this profile by hand. For example, Table 8.7 shows the profile skeleton after a few graphemes have been added to the file. Note that in this example, the profile is written to the desktop, and this file has to be edited manually. We simply add a few multigraphs to the column Grapheme and leave the other columns empty. These new graphemes are then included in the graphemic parsing. ``` # a few words to be graphemically parsed example <- c("mishmash", "mishap", "mischief", "scheme") # write a profile skeleton to a file write.profile(example, file = "~/Desktop/profile_skeleton.txt") # edit the profile, and then use the edited profile to tokenize tokenize(example, profile = "~/Desktop/profile_skeleton.txt")$strings ## originals tokenized ## 1 shampoo sh a m p oo ``` ## 2 mishap m i sh a p ## 3 mischief m i sch ie f ## 4 scheme sch e m e To leave out the Unicode information in the profile skeleton, use the option info = FALSE. It is also possible not to use a separate file at all, but process everything within R. In simple situations this is often useful (see below), but in general we prefer to handle everything through a separately saved orthography profile. This profile often contains highly useful information that is nicely coded and saved inside this one file, and can thus be easily distributed and shared. Doing the same as above completely within R might look as follows: ### 8 Implementation Table 8.7: Manually edited profile skeleton ``` # make a profile, just select the column 'Grapheme' profile <- write.profile(example)[, "Grapheme"] # extend the profile with multigraphs profile <- c("sh", "ch", "sch", "ie", "oo", profile) # use the profile to tokenize tokenize(example, profile)$strings ``` ## originals tokenized ## 1 shampoo sh a m p oo ## 2 mishap m i sh a p ## 3 mischief m i sch ie f ## 4 scheme sch e m e ### Rule ordering Everything is not yet correct with the graphemic parsing of the example discussed previously. The sequence <sh> in 'mishap' should not be a digraph, and conversely the sequence <sch> in 'mischief' should of course be separated into <s> and <ch>. One of the important issues to get the graphemic parsing right is the order in which graphemes are parsed. For example, currently the grapheme <sch> is parsed before the grapheme <ch>, leading to <m i sch ie f> instead of the intended <m i s ch ie f>. The reason that <sch> is parsed before <ch> is that by default longer graphemes are parsed before shorter ones. Our experience is that in most cases this is expected behavior. You can change the ordering by specifying the option ordering. Setting this option to NULL results in no preferential ordering, i.e. the graphemes are parsed in the order of the profile, from top to bottom. Now 'mischief' is parsed correctly, but 'scheme' is wrong. So this ordering is not the solution in this case. ``` # do not reorder the profile # just apply the graphemes from top to bottom tokenize( example , profile = "~/Desktop/profile_skeleton.txt" , ordering = NULL )$strings ## originals tokenized ## 1 shampoo sh a m p oo ## 2 mishap m i sh a p ## 3 mischief m i s ch ie f ## 4 scheme s ch e m e ``` There are various additional options for rule ordering implemented. Please check the help description in R, i.e. help(tokenize), for more details on the possible rule ordering specifications. In summary, there are four different ordering options, that can also be combined: • size This option orders the lines in the profile by the size of the grapheme, largest first. Size is measured by number of Unicode characters after normalization as specified in the option normalize. For example, <é> has a size of 1 with normalize = "NFC", but a size of 2 with normalize = "NFD". • context This option orders the lines by whether they have any context specified (see next section). Lines with context will then be used first. Note that this only works when the option regex = TRUE is also chosen (otherwise context specifications are not used). • reverse This option orders the lines from bottom to top. Reversing order can be useful because hand-written profiles tend to put general rules before specific rules, which mostly should be applied in reverse order. • freqency This option orders the lines by the frequency with which they match in the specified strings before tokenization, least frequent coming first. This frequency of course depends crucially on the available strings, so it will lead to different orderings when applied to different data. Also note that this frequency is (necessarily) measured before graphemes are identified, ### 8 Implementation so these ordering frequencies are not the same as the final frequencies shown in the output. Frequency of course also strongly differs on whether context is used for the matching through regex = TRUE. By specifying more than one ordering, these orderings are used to break ties, e.g. the default setting ordering = c("size", "context", "reverse") will first order by size, and for those with the same size, it will order by whether there is any context specified or not. For lines that are still tied (i.e. have the same size and both/neither have context) the order will be reversed compared to the order as attested in the profile, because most hand-written specifications of graphemes will first write the general rule, followed by more specific regularities. To get the right tokenization, these rules should in most cases be applied in reverse order. Note that different ordering of the rules does not result in feeding and bleeding effects found with finite-state rewrite rules.<sup>25</sup> The graphemic parsing advocated here is crucially different from rewrite rules in that there is nothing being rewritten: each line in an orthography profile specifies a grapheme to be captured in the string. All lines in the profile are processed in a specified order (as determined by the option ordering). At the processing of a specific line, all matching graphemes in the data are marked as captured, but not changed. Captured parts cannot be captured again, but they can still be used to match contexts of other lines in the profile. Only when all lines are processed the captured graphemes are separated (and possibly transliterated). In this way the result of the applied rules is rather easy to predict. To document a specific case of graphemic parsing, it is highly useful to save all results of the tokenization to file by using the option file.out, for example as follows: ``` # save the results to various files tokenize( example , profile = "~/Desktop/profile_skeleton.txt" , file.out = "~/Desktop/result" ) ``` This will lead to the following four files being written. Crucially, a new profile is produced with the re-ordered orthography profile. To reproduce the tokenization, this re-ordered profile can be used with the option ordering = NULL. <sup>25</sup>Bleeding is the effect that the application of a rule changes the string, so as to prevent a following rule from applying. Feeding is the opposite: a specific rule will only be applied because a previous rule changed the string already. The interaction of rules with such feeding and bleeding effects is extremely difficult to predict. 8.4 R library: qlcData ``` • result_strings.tsv: ``` A tab-separated file with the original and the tokenized/transliterated strings. • result\_profile.tsv: A tab-separated file with the graphemes with added frequencies of occurrence in the data. The lines in the file are re-ordered according to the order that resulted from the ordering specifications (see Section 8.4). • result\_errors.tsv: A tab-separated file with all original strings that contain unmatched parts. Unmatched parts are indicated with the character as specified with the option missing. By default the character double qestion mark <⁇> at U+2047 is used. When there are no errors, this file is absent. • result\_missing.tsv: A tab-separated file with the graphemes that are missing from the original orthography profile, as indicated in the errors. When there are no errors, then this file is absent. ### Contextually specified graphemes To refine a profile, it is also possible to add graphemes with contextual specifications. An orthography profile can have columns called Left and Right to specify the context in which the grapheme is to be separated.<sup>26</sup> For example, we are adding an extra line to the profile from above, resulting in the profile shown in Table 8.8. The extra line specifies that <s> is a grapheme when it occurs after <mi>. Such contextually-specified graphemes are based on regular expressions so you can also use regular expressions in the description of the context. For such contextually specified graphemes to be included in the graphemic parsing we have to specify the option regex = TRUE. This contextually specified grapheme should actually be handled first, so we could try ordering = NULL. However, we can also explicitly specify that rules with contextual information should be applied first by using ordering = "context". That gives the right results for this toy example, as shown in Table 8.8. ``` # add a contextual grapheme, and then use the edited # profile to tokenize tokenize( example , profile = "~/Desktop/profile_skeleton.txt" , regex = TRUE ``` <sup>26</sup>The column names Left, Right and Grapheme are currently hard-coded, so these exact column names should be used for these effects to take place. The position of the columns in the profile is unimportant. So the column Left can occur anywhere. ### 8 Implementation ``` , ordering = "context" )$strings ## originals tokenized ## 1 shampoo sh a m p oo ## 2 mishap m i s h a p ## 3 mischief m i s ch ie f ## 4 scheme s ch e m e ``` Table 8.8: Orthography profile with contextual specification for <s> Note that with the option regex = TRUE all content in the profile is treated as regular expressions, so the characters with special meaning in regular expressions should be either omitted or escaped (by putting a < \ > reverse solidus at U+005C before the character). Specifically, this concerns the following characters: <-> hyphen-minus at U+002D 8.4 R library: qlcData ``` <}> right curly bracket at U+007D <\|> vertical line at U+007C <> asterisk at U+002A <\> reverse solidus at U+005C <ˆ> circumflex accent at U+005E <+> plus sign at U+002B <$> dollar sign at U+0024 ``` ### Profile skeleton with columns for editing* When it is expected that context might be important for a profile, then the profile skeleton can be created with columns prepared for the contextual specifications. This is done by using the option editing = TRUE (cf. Table 8.9 for a toy profile of some Italian words). ``` example <- c('cane', 'cena', 'cine') write.profile(example , file = "~/Desktop/profile_skeleton.txt" , editing = TRUE , info = FALSE ) ``` Besides the columns Left, Grapheme, and Right as discussed in the previous sections, there are also columns Class and Replacement.The column Class can be used to specify classes of graphemes that can then be used in the contextual specification. The column Replacement is just a copy of the column Grapheme, providing a skeleton to specify transliteration. The name of the column Replacement is not fixed – there can actually be multiple columns with different kinds of transliterations in a single profile. To achieve contextually determined replacements it is possible to use a regular expression in the contextual column. For example, consider the edited toy ### 8 Implementation Table 8.10: Orthography profile with regex as context profile for Italian in Table 8.10 (where <c> becomes /k/ except before <i,e>, then it becomes /tʃ/). To use this profile, you have to add the option regex = TRUE. Also note that we have changed the name of the transliteration column, so we have to tell the tokenization process to use this column to transliterate. This is done by adding the option transliterate = "IPA". ``` # add a contextual grapheme, and then use the edited # profile to tokenize tokenize( example , profile = "~/Desktop/profile_skeleton.txt" , regex = TRUE , transliterate = "IPA" )$strings ## originals tokenized transliterated ## 1 cane c a n e k a n e ## 2 cena c e n a tʃ e n a ## 3 cine c i n e tʃ i n e ``` Another equivalent possibility is to use a column Class to specify a class of graphemes, and then use this class in the specification of context. This is useful to keep track of recurrent classes in larger profiles. You are free to use any classname you like, as long as it does not clash with the rest of the profile. The example shown in Table 8.11 should give the same result as obtained previously by using a regular expression. ``` # add a class, and then use the edited profile to tokenize tokenize( example , profile = "~/Desktop/profile_skeleton.txt" , regex = TRUE , transliterate = "IPA" )$strings ``` Table 8.11: Orthography profile with Class as context ### Formatting grapheme separation In all examples above we have used the default formatting for grapheme separation using space as a separator, which is obtained by the default setting sep = " ". It is possible to specify any other separator here, including the empty string, i.e. sep = "". This will not show the graphemic tokenization anymore (although it has of course been used in the background). ``` # Use the empty string as separator tokenize( example , profile = "~/Desktop/profile_skeleton.txt" , regex = TRUE , transliterate = "IPA" , sep = "" )$strings ## originals tokenized transliterated ## 1 cane cane kane ## 2 cena cena tʃena ## 3 cine cine tʃine ``` Normally, the separator specified should not occur in the data. If it does, unexpected things might happen, so consider removing the chosen separator from your strings first. However, there is also an option sep.replace to replace the separator with something else. When sep.replace is specified, this mark is inserted in the string at those places where the separator occurs. Typical usage in linguistics would be sep = " ", sep.replace = "#" adding spaces between graphemes and replacing spaces in the input string by hashes in the output string. ### 8 Implementation ``` # Replace separator in string to be tokenized tokenize( "test test test" , sep = " " , sep.replace = "#" )$strings$tokenized ## [1] "t e s t # t e s t # t e s t" ``` ### Remaining issues Given a set of graphemes, there are at least two different methods to tokenize strings. The first is called method = "global". This approach takes the first grapheme in the profile, then matches this grapheme globally at all places in the string, and then turns to process the next string in the profile. The other approach is called method = "linear". This approach walks through the string from left to right. At the first character it looks through all graphemes whether there is any match, and then walks further to the end of the match and starts again. This approach is more akin to finite-state rewrite rules (though note that it still works differently from such rewrite rules, as previously stated). The global method is used by default in the R implementation. In some special cases these two tokenization methods can lead to different results, but these special situations are very unlikely to happen in natural language. The example below shows that a string 'abc' can be parsed differently in case of a very special profile with a very special ordering of the graphemes. ``` # different parsing methods can lead to different results # the global method first catches 'bc' tokenize( "abc" , profile = c("bc","ab","a","c") , order = NULL , method = "global" )$strings ## originals tokenized ## 1 abc a bc # the linear method catches the first grapheme, which is 'ab' tokenize( "abc" , profile = c("bc","ab","a","c") , order = NULL , method = "linear" )$strings ``` 8.4 R library: qlcData ``` ## originals tokenized ## 1 abc ab c ``` Further, the current R implementation has a limitation when regular expressions are used. The problem is that overlapping matches are not captured when using regular expressions.<sup>27</sup> Everything works as expected without regular expressions, but there might be warnings/errors in case of regex = TRUE. However, just as in the previous issue, this problem should only very rarely (when at all) happen in natural language data. The problem can be exemplified by a sequence <bbbb> in which a grapheme <bb> should be matched. With the default regex = FALSE there are three possible matches, but with regex = TRUE only the first two <b>'s or the last two <b>'s are matched. The middle two <b>'s are not matched because they overlap with the other matches. In the example below this leads to an error, because the second <bb> is not matched. However, we have not been able to produce a real example in any natural language in which this limitation might lead to an error. ``` # Everything perfect without regular expressions tokenize( "abbb" , profile = c("ab","bb") , order = NULL , regex = FALSE )$strings ## originals tokenized ## 1 abbb ab bb # Matching with regular expressions does not catch overlap tokenize( "abbb" , profile = c("ab","bb") , order = NULL , regex = TRUE )$strings ## Warning in tokenize("abbb", profile = c("ab", "bb"), order = NULL, regex = TRUE): ## There were unknown characters found in the input data. ## Check output$errors for a table with all problematic strings. ## originals tokenized ## 1 abbb ab ⁇ ⁇ ``` <sup>27</sup>This restriction is an effect of the underlyingly used ICU implementation of the Unicode Standard as implemented in R through the package stringi. ### 8 Implementation ### 8.5 Recipes online We provide several use cases online – what we refer to as recipes – that illustrate the applications of orthography profiles using our implementations in Python and R.<sup>28</sup> Here we briefly describe these use cases and we encourage users to try them out using Git and Jupyter Notebooks. First, as we discussed above, we provide a basic tutorial on how to use the Python segments<sup>29</sup> and R qlcData<sup>30</sup> libraries. This recipe simply shows the basic functions of each library to get you started.<sup>31</sup> The two recipes using the Python segments package include a tutorial on how to segment graphemes in IPA text: • https://github.com/unicode-cookbook/recipes/tree/master/JIPA and an example of how to create an orthography profile to tokenize fieldwork data from a large comparative wordlist. • https://github.com/unicode-cookbook/recipes/tree/master/Dogon The JIPA recipes uses excerpts from The North Wind and the Sun passages from the Illustrations of the IPA published in the Journal of the International Phonetic Alphabet. Thus the recipe shows how a user might tokenize IPA proper. The Dogon recipe uses fieldwork data from the Dogon languages of Mali language documentation project.<sup>32</sup> This recipe illustrates how a user might tokenize fieldwork data from numerous linguists using different transcription practices by defining these practices with an orthography profile to make the output unified and comparable. The two recipes using the R qlcData library include a use case for tokenizing wordlist data from the Automated Similarity Judgment Program (ASJP):<sup>33</sup> • https://github.com/unicode-cookbook/recipes/tree/master/ASJP and for tokenizing a corpus of text in Dutch orthography: • https://github.com/unicode-cookbook/recipes/tree/master/Dutch <sup>28</sup>https://github.com/unicode-cookbook/recipes <sup>29</sup>https://pypi.python.org/pypi/segments <sup>30</sup>https://github.com/cysouw/qlcData <sup>31</sup>https://github.com/unicode-cookbook/recipes/tree/master/Basics <sup>32</sup>http://dogonlanguages.org/ <sup>33</sup>http://asjp.clld.org/ 8.5 Recipes online The ASJP use case shows how to download the full set of ASJP wordlists, to combine them into a single large CSV file, and to tokenize the ASJP orthography. The Dutch use case takes as input the 10K corpus for Dutch ("nld") from the Leipzig Corpora Collection,<sup>34</sup> which is then cleaned and tokenized with an orthography profile that captures the intricacies of Dutch orthography. <sup>34</sup>http://wortschatz.uni-leipzig.de/en/download/ # References Abercrombie, David. 1964. English phonetic texts. London: Faber & Faber LTD. ### References ### References # Name index Abercrombie, David, 41 Anderson, Lloyd B., 44, 48 Apple Computer, 48 Becker, Joseph D., 48 Beider, Alexander, 8 Belongie, Serge, 27 Bird, Steven, 13, 46 Bright, William, 10 Brindle, Jonathan, 56 Brown, Cecil H., 8 Chao, Yuen Ren, 58 Daniels, Peter T., 9, 10 Dolgopolsky, Aharon B., 8 Duckworth, Martin, 69 Esling, John H., 43–45, 48, 49 Evans, Nicholas, 48 Gaultney, J. Victor, 10 Gaylord, Harry, 43–45, 48, 49 Hieronymus, James L., 46 Huurdeman, Anton A., 4 Jones, Daniel, 9 Kemp, Alan, 8, 9 Knuth, Donald E., 8 Kohrt, Manfred, 10 Ladefoged, Peter, 38, 67, 68 Ladusaw, William A., 44 Levinson, Stephen C., 48 List, Johann-Mattis, 8 Maddieson, Ian, 42, 43, 55, 57 Mania, Hubert, 5 McCloy, Daniel, 66 McLaughlin, Fiona, 68 Meinhof, Carl, 9 Meyer, Julien, 5 Mielke, Jeff, 55 Moran, Steven, 9, 18, 52, 65, 66, 69 Morse, Stephen P., 8 Olúmúyı̀w, Tèmıtọ́ ́pẹ́, 1 Postel, Hans J., 8 Powell, Barry B., 4 Precoda, Kristin, 42, 43 Pullum, Geoffrey K., 44 Roach, P. J., 39, 44 Robinson, Andrew, 4 Sampson, Geoffrey, 48 Simons, Gary F., 13, 46–48 Singh, Simon, 4 Sproat, Richard, 10 The International Phonetic Association, 4, 38–40, 44, 49, 51, 57, 58, 70, 83 The Unicode Consortium, 4, 7, 14, 33, 51 Name index Vidal, Alejandra, 55 Wells, John C., 43, 46, 47 # Did you like this book? This book was brought to you for free Please help us in providing free access to linguistic research worldwide. Visit http://www.langsci-press.org/donate to provide financial support or register as a community proofreader or typesetter at http://www.langsci-press.org/register. # The Unicode Cookbook for Linguists This text is a practical guide for linguists, and programmers, who work with data in multilingual computational environments. We introduce the basic concepts needed to understand how writing systems and character encodings function, and how they work together at the intersection between the Unicode Standard and the International Phonetic Alphabet. Although these standards are often met with frustration by users, they nevertheless provide language researchers and programmers with a consistent computational architecture needed to process, publish and analyze lexical data from the world's languages. Thus we bring to light common, but not always transparent, pitfalls which researchers face when working with Unicode and IPA. Having identified and overcome these pitfalls involved in making writing systems and character encodings syntactically and semantically interoperable (to the extent that they can be), we created a suite of open-source Python and R tools to work with languages using orthography profiles that describe author- or document-specific orthographic conventions. In this cookbook we describe a formal specification of orthography profiles and provide recipes using open source tools to show how users can segment text, analyze it, identify errors, and to transform it into different written forms for comparative linguistics research.	doab	2025-04-07T04:13:04.642283		{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/4.0/", "book_id": "fffbeb8d-bfd4-49af-82cd-f97f975045ea", "url": "https://library.oapen.org/bitstream/20.500.12657/28277/1/1001685.pdf\|\|https://library.oapen.org/bitstream/20.500.12657/28277/1/1001685.pdf\|\|https://library.oapen.org/bitstream/20.500.12657/28277/1/1001685.pdf", "author": "Moran, Steven\|\|Cysouw, Michael", "title": "The Unicode cookbook for linguists", "publisher": "Language Science Press", "isbn": "", "section_idx": 0 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.0	Edited by Vishwanath Venketaraman Some of the topics covered in this book are: HIV infection, HIV transmission, Clinical symptoms of AIDS, AIDS and opportunistic infection, Prevention and treatment of HV, Treatment of HIV infection and immune reconstitution ISBN 978-953-307-671-3 Global View of HIV Infection Photo by xrender / iStock	doab	2025-04-07T04:13:04.667809	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 0 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.1	Global View of HIV Infection Edited by Vishwanath Venketaraman GLOBAL VIEW OF Edited by Vishwanath Venketaraman HIV INFECTION INTECHOPEN.COM	doab	2025-04-07T04:13:04.667903	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 1 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.2	GLOBAL VIEW OF HIV INFECTION INTECHOPEN.COM Edited by Vishwanath Venketaraman http://dx.doi.org/10.5772/848 Edited by Vishwanath Venketaraman #### Contributors Obed Nanjul Goselle, Ranjitha Krishna, Saiprasad Zemse, Scott Derossi, Bruno Pedroso, Gustavo Luis Gutierrez, Edison Duarte, Luiz Alberto Pilatti, Claudia Tania Picinin, Lilian Maria Mederos Cuervo, Adrian Muwonge, Patience Ashemeire, Clovice Kankya, James Oloya, Eystein Skjerve, Biffa Demelash, Marcus Vinicius De Souza, Marcelle Bispo, Raoni Schroeder Gonçalves, Carlos Roland Kaiser, Claver Pedzisai Bhunu, Steady Mushayabasa, Adamu Ahmed, Haruna Muktar #### © The Editor(s) and the Author(s) 2011 The moral rights of the and the author(s) have been asserted. All rights to the book as a whole are reserved by INTECH. The book as a whole (compilation) cannot be reproduced, distributed or used for commercial or non-commercial purposes without INTECH's written permission. Enquiries concerning the use of the book should be directed to INTECH rights and permissions department ([email protected]). Violations are liable to prosecution under the governing Copyright Law. Individual chapters of this publication are distributed under the terms of the Creative Commons Attribution 3.0 Unported License which permits commercial use, distribution and reproduction of the individual chapters, provided the original author(s) and source publication are appropriately acknowledged. If so indicated, certain images may not be included under the Creative Commons license. In such cases users will need to obtain permission from the license holder to reproduce the material. More details and guidelines concerning content reuse and adaptation can be foundat http://www.intechopen.com/copyright-policy.html. #### Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. First published in Croatia, 2011 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia Legal deposit, Croatia: National and University Library in Zagreb Additional hard and PDF copies can be obtained from [email protected] Global View of HIV Infection Edited by Vishwanath Venketaraman p. cm. ISBN 978-953-307-671-3 eBook (PDF) ISBN 978-953-51-6532-3	doab	2025-04-07T04:13:04.667941	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 2 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.3	We are IntechOpen, the world's leading publisher of Open Access books Built by scientists, for scientists 4,100+ Open access books available 116,000+ International authors and editors 120M+ Downloads Our authors are among the Top 1% most cited scientists 12.2% Contributors from top 500 universities Selection of our books indexed in the Book Citation Index in Web of Science™ Core Collection (BKCI)	doab	2025-04-07T04:13:04.668227	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 3 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.4	Interested in publishing with us? Contact [email protected] Numbers displayed above are based on latest data collected. For more information visit www.intechopen.com	doab	2025-04-07T04:13:04.668284	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 4 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.5	Meet the editor Upon completion of his doctorate in microbiology and immunology at the Tuberculosis Research Center in Chennai, India, Dr. Venketaraman was awarded a UNESCO fellowship to conduct post-doctoral research on tuberculosis at the University of Ferrara, Italy. Dr. Venketaraman continued his post-doctoral research at the University of Michigan Medical School and at the UMDNJ-New Jersey Medical School. Mycobacterial research has always fascinated Dr. Venketaraman, especially in characterization of the host immune defense mechanisms that are crucial for the control of Mycobacterium tuberculosis. Dr. Venketaraman has published more than 22 papers in peer-reviewed journals, and is currently an Assistant Professor at the College of Osteopathic Medicine of Pacific, Western University of Health Sciences, CA. His laboratory is actively trying to elucidate the role of glutathione in enhancing the host immune cell functions to control of Mycobacterium tuberculosis, a novel and previously undescribed phenomenon. More than eight publications were generated from this body of work. Most notably, the study on glutathione enhancing the functions of natural killer cells to control Mycobacterium tuberculosis infection, which was published in 2008 issue of "Journal of Interferon and cytokine research" and later cited in "Natural Immunology" as well as appeared on the cover page of the recent issue of "Journal of Interferon and Cytokine research" (March 2010). Dr. Venketaraman's long term goal is to discover immunomodulatory agents that can be given an adjunct to chemotherapy for controlling Mycobacterium tuberculosis infections in both non-HIV and HIV-infected individuals. Contents Preface IX Chapter 2 Non-Tuberculous James Oloya Part 2 HIV Transmission 41 Goselle Obed Nanjul Part 1 HIV and Altered Immune Responses 1 Lilian María Mederos Cuervo Chapter 1 Infection for Mycobacterium tuberculosis and Adrian Muwonge, Ashemeire Patience, Chapter 3 Human Immunodeficiency Virus Transmission 43 C.P. Bhunu and S. Mushayabasa Chapter 5 Individuals with HIV/AIDS: Clinical A. Ahmed and H.M. Muktar Chapter 7 Thiourea Derivatives: A Promising Chapter 4 HIV/AIDS Transmission Dynamics in Male Prisons 67 Part 3 Prevention and Treatment of AIDS-Related Diseases 77 Ranjitha Krishna, Saiprasad Zemse and Scott Derossi Chapter 6 Epidemiology and Treatment of Kaposi's Sarcoma in Class Against HIV/TB Co-Infection 127 Manifestations in the Oral Cavity in the Post-HAART Era 79 HIV-1 Infected Individuals in a Poor Resource Setting 103 Marcus Vinicius Nora de Souza, Marcelle de Lima Ferreira Bispo, Raoni Schroeder Borges Gonçalves and Carlos Roland Kaiser Nontuberculous Mycobacteria in the HIV/AIDS Patients 3 Mycobacteria in Uganda: A Problem or Not? 21 Clovice Kankya, Demelash Biffa, Eystein Skjerve and	doab	2025-04-07T04:13:04.668315	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 5 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.6	Contents #### Preface XI #### Part 2 HIV Transmission 41 - Part 3 Prevention and Treatment of AIDS-Related Diseases 77 X Contents Chapter 8 Quality of Life Assessment in People Living with HIV/AIDS: Clarifying the WHOQOL-HIV and WHOQOL-HIV-Bref Instruments 163 Bruno Pedroso, Gustavo Luis Gutierrez, Edison Duarte, Luiz Alberto Pilatti and Claudia Tania Picinin	doab	2025-04-07T04:13:04.668502	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 6 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.7	Preface Both HIV-1 and HIV-2 cause AIDS, but HIV-1 is found worldwide, whereas HIV-2 is found primarily in West Africa. It is estimated that approximately 40 million people worldwide are infected with HIV, and two-thirds of them live in the sub-Saharan Africa. Three regions, Africa, Asia, and Latin America, have the highest rates of new infections, and AIDS is the fourth leading cause of death worldwide. Since 1981, more than 980,000 cases of AIDS have been reported in the US alone, and according to CDC, more than 1,000,000 Americans may be infected with HIV. HIV preferentially infects and kills CD4+ T lymphocytes, and by killing or damaging CD4+ T cells of the body's immune system, HIV progressively destroys the body's ability to fight infections. People diagnosed with AIDS often suffer from lifethreatening diseases caused by opportunistic infections. HIV also infects other cells, such as macrophages, monocytes and dendritic cells. This book provides a detailed overview on the HIV transmission, how HIV infection alters the host immune responses, and on the prevention and treatment of AIDS related diseases. > Vishwanath Venketaraman Ph.D., Assistant Professor Microbiology/Immunology, Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences United States Part 1 HIV and Altered Immune Responses	doab	2025-04-07T04:13:04.668541	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 7 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.8	Part 1 HIV and Altered Immune Responses 1 Cuba Infection for Mycobacterium tuberculosis and National Reference Laboratory TB/Mycobacteria Collaborate Center PAHO / WHO Tuberculosis (TB) is a disease also know as consumption, wasting disease, and the white plague, it has affected humans for centuries. Until the mid-1800s, people thought that tuberculosis, or TB, was hereditary. They did not realize that it could be spread from person to person through the air. Also, until the 1940s and 1950s there was no cure for TB. For In 1865 a French surgeon, Jean-Antoine Villemin, proved that TB was contagious, and in 1882 a german scientist named Robert Koch discovered the bacteria causes TB, denominated as Mycobacterium tuberculosis. Yet half a century passed before drugs were discovered that could cure TB, until then, many people with TB were sent to sanatoriums, special rest homes where they followed a prescribed routine every day. A breakthrough came in 1943, an american scientist, Selman Waksman discovered a drug that could kill TB bacteria. Between 1943 and 1952, two more drugs were found, after these discoveries, many people with TB were cured and the death rate for TB in the United States dropped dramatically, and fewer Overall, one-third of the world's population is currently infected with the TB bacillus. 5-10 % of people who are infected with TB bacilli become sick or infectious at some time TB program activities, reinforced by successful chemotherapy, resulted in a pronounced reduction of infection and death rates. The disease became greatly controlled but it never quite disappeared. Then, in around 1985, cases of TB began to rise again in industrialized countries. Several inter-related forces drove this resurgence, including increase in prison populations, homelessness, injection drug use, crowded housing and increased immigration from countries where TB continued to be endemic. Above all, the decline in TB control activities and the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic were two major factors fuelling each other in the re-emergence of TB. People with HIV and TB infection are much more likely to develop TB. The HIV/AIDS epidemic has produced a devastating effect on TB control worldwide. While one out of ten many people, a diagnosis of TB was a slow death sentence 1-4. Someone in the world is newly infected with TB bacilli every second. 1. Introduction and fewer people got TB 5. A global health emergency 6, 7: during their life. Nontuberculous Mycobacteria in the HIV/AIDS Patients Lilian María Mederos Cuervo Tropical Medicine Institute Pedro Kourí (IPK)	doab	2025-04-07T04:13:04.668651	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 8 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.9	Infection for Mycobacterium tuberculosis and Nontuberculous Mycobacteria in the HIV/AIDS Patients Lilian María Mederos Cuervo National Reference Laboratory TB/Mycobacteria Collaborate Center PAHO / WHO Tropical Medicine Institute Pedro Kourí (IPK) Cuba ## 1. Introduction Tuberculosis (TB) is a disease also know as consumption, wasting disease, and the white plague, it has affected humans for centuries. Until the mid-1800s, people thought that tuberculosis, or TB, was hereditary. They did not realize that it could be spread from person to person through the air. Also, until the 1940s and 1950s there was no cure for TB. For many people, a diagnosis of TB was a slow death sentence 1-4. In 1865 a French surgeon, Jean-Antoine Villemin, proved that TB was contagious, and in 1882 a german scientist named Robert Koch discovered the bacteria causes TB, denominated as Mycobacterium tuberculosis. Yet half a century passed before drugs were discovered that could cure TB, until then, many people with TB were sent to sanatoriums, special rest homes where they followed a prescribed routine every day. A breakthrough came in 1943, an american scientist, Selman Waksman discovered a drug that could kill TB bacteria. Between 1943 and 1952, two more drugs were found, after these discoveries, many people with TB were cured and the death rate for TB in the United States dropped dramatically, and fewer and fewer people got TB 5. A global health emergency 6, 7: TB program activities, reinforced by successful chemotherapy, resulted in a pronounced reduction of infection and death rates. The disease became greatly controlled but it never quite disappeared. Then, in around 1985, cases of TB began to rise again in industrialized countries. Several inter-related forces drove this resurgence, including increase in prison populations, homelessness, injection drug use, crowded housing and increased immigration from countries where TB continued to be endemic. Above all, the decline in TB control activities and the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic were two major factors fuelling each other in the re-emergence of TB. People with HIV and TB infection are much more likely to develop TB. The HIV/AIDS epidemic has produced a devastating effect on TB control worldwide. While one out of ten Infection for Mycobacterium tuberculosis and will develop at some point 5-7. by pulmonary TB 3, 8, 16-23. 4. Epidemiology of TB Nontuberculous Mycobacteria in the HIV/AIDS Patients 5 when the macrophages die. These bacilli can spread through the lymphatic channels to regional lymph nodes and then through the bloodstream to more distant tissues and organs, including areas in which TB disease is most likely to develop: the apices of the lung, the kidneys, the brain, and bone. Extracellular bacilli attract macrophages form the bloodstream. The immune response kills most of the bacilli, leading to the formation of a granuloma. At this point the person has TB infection, which can be detected by using the tuberculin skin test. It may take 2-10 weeks for the infected person to develop a positive reaction to the tuberculin skin test. Immune responses soon develop to kill the bacilli. Within 2-10 weeks after infection, the immune system is usually able to halt the In persons infected with Mycobacterium tuberculosis but that don't have TB disease cannot spread the infection to other people. TB infection in persons who does not have TB disease is not considered a case of TB and referred to as ¨latent TB infection¨. In some persons, TB bacilli overcome the defenses or the immune system and begin to multiply, resulting in the progression from TB infection to TB disease. This process may occur soon after or many years after infection. Some study demonstrated that approximately 5% of person who have been infected with Mycobacterium tuberculosis will develop TB disease in the first year or two after infection and another 5% will develop disease some time later in life. Recent infection (with the past 2 years) with Mycobacterium tuberculosis is therefore an important risk factor for progression to TB disease and in approximately 10% of persons with normal immune system who are infected with Mycobacterium tuberculosis , TB disease Some medical conditions increase the risk that TB infection will progress to disease. Some studies suggest that the risk is mayor in inmmunosuppressed patients, for example persons with Diabetes mellitus, prolonged therapy with corticosteroids, immunosuppressive therapy, certain types of cancer, severe kidney disease, injection of illicit drugs, and TB disease most commomly affects the lung, 73% of TB cases are exclusively pulmonary, and however, TB is a systemic disease and may also commonly occur in the following ways;as pleural effusion in the central nervous, lymphatic, or genitourinary systems, as disseminated disease (military TB). Also the infection for Mycobacterium tuberculosis can occur in the other body sites; in the breast, skin, or peritoneum 16,20-23. Extrapulmonary TB is more common in immunosuppressed persons and in young children; meningoencephalitis TB, lymphatic TB and military disease are particularly common in immunosuppressed persons, in some case the extrapulmonary TB is often accompanied TB infection is one of the most common infections in the world. It is estimated that 30-60% of adults in developing countries have TB infection. Annually about 8-10 million people develop TB disease and 2-3 million people die of the disease. TB disease is the leading cause of death due to infectious disease around the world 24, 25. When the health department learns about a new case of TB, it should take steps to ensure that the person receives appropriate treatment. Is very important that the health authorities should also start a contact investigation, this means interviewing a person who has TB disease to determinate multiplication of the tubercle bacilli, preventing further spread 4, 17-19. infection with Human Immunodeficient Virus (HIV) 2,3,12. immunocompetent people infected with M. tuberculosis will fall sick in their lifetimes, among those with HIV infection, one in ten per year will develop active TB. In developing countries, the impact of HIV infection on the TB situation, especially in the 20-35 age groups, is overwhelming. While wealthy industrialized countries with good public health care systems can be expected to keep TB under control, in much of the developing world a catastrophe awaits. In poorly developed countries, TB remains a significant threat to public health, as incidences remain high, even after the introduction of vaccination and drug treatment. The registered number of new cases of TB worldwide roughly correlates with economic conditions: highest incidences are seen in the countries of Africa, Asia, and Latin America with the lowest gross national products. Supervised treatment, including sometimes direct observation of therapy (DOT), was proposed as a means of helping patients to take their drugs regularly and complete treatment, thus achieving cure and preventing the development of drug resistance 5-7.	doab	2025-04-07T04:13:04.668839	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 9 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.10	2. Transmission and pathogenesis TB is spread from person through the air. When a person with pulmonary or laryngeal TB coughs, sneezes, speaks, or sings, droplet nuclei containing Mycobacterium tuberculosis are expelled into the air. Depending on the environment, these tiny particles (1-5 microns in diameter) can remain suspended in the air for several hours. If another person inhales air containing droplet nuclei, transmission may occur. The probability that TB will be transmitted depends on these factors 4, 5: The best way to stop transmission is to isolate patients with infectious TB immediately and start effective TB therapy. Infectiousness declines rapidly after adequate therapy is started, as long as the patient adheres to the prescribed regimen. Persons at the highest risk of becoming infected with Mycobacterium tuberculosis are close contacts, the persons who had prolonged, frequent, or intense contact with a person with infectious TB. Close contacts may be family members, roommates, friends, coworkers, or others. Data collected by CDC since 1987 show that infection rates have been relatively stable, ranging form 21-23% for the contacts of infectious TB patients 6-9. Some people with infection develop TB disease. This disease develops when the immune system cannot keep the tubercle bacilli under control and the bacilli begin to multiply rapidly. The risk that TB disease will develop is higher for some people than for others 3, 10-12. Among contacts of persons with drug-resistant TB, infection rates seem to be similar. However, because they may have a poor response to treatment persons with drug-resistant disease are often infectious for longer periods and therefore have the potential to infect more contacts 10-13. Extra pulmonary TB is rarely contagious; however, transmission from extrapulmonary sites has been reported during aerosol-producing procedures, such as autopsies and tissue irrigation 14-16. #### 3. Pathogenesis The tubercle bacilli that alveoli are ingested by alveolar macrophages, the majority of these bacilli are destroyed or inhibited. A small number multiply intracellulary and are released immunocompetent people infected with M. tuberculosis will fall sick in their lifetimes, among those with HIV infection, one in ten per year will develop active TB. In developing countries, the impact of HIV infection on the TB situation, especially in the 20-35 age groups, is overwhelming. While wealthy industrialized countries with good public health care systems can be expected to keep TB under control, in much of the developing world a catastrophe awaits. In poorly developed countries, TB remains a significant threat to public health, as incidences remain high, even after the introduction of vaccination and drug treatment. The registered number of new cases of TB worldwide roughly correlates with economic conditions: highest incidences are seen in the countries of Africa, Asia, and Latin America with the lowest gross national products. Supervised treatment, including sometimes direct observation of therapy (DOT), was proposed as a means of helping patients to take their drugs regularly and complete treatment, thus achieving cure and TB is spread from person through the air. When a person with pulmonary or laryngeal TB coughs, sneezes, speaks, or sings, droplet nuclei containing Mycobacterium tuberculosis are expelled into the air. Depending on the environment, these tiny particles (1-5 microns in diameter) can remain suspended in the air for several hours. If another person inhales air containing droplet nuclei, transmission may occur. The probability that TB will be The infectiousness of the person with TB (the number of organisms expelled into the air). The best way to stop transmission is to isolate patients with infectious TB immediately and start effective TB therapy. Infectiousness declines rapidly after adequate therapy is started, as long as the patient adheres to the prescribed regimen. Persons at the highest risk of becoming infected with Mycobacterium tuberculosis are close contacts, the persons who had prolonged, frequent, or intense contact with a person with infectious TB. Close contacts may be family members, roommates, friends, coworkers, or others. Data collected by CDC since 1987 show that infection rates have been relatively stable, ranging form 21-23% for the contacts of infectious TB patients 6-9. Some people with infection develop TB disease. This disease develops when the immune system cannot keep the tubercle bacilli under control and the bacilli begin to multiply rapidly. The risk that TB disease will develop is higher for some people than for others 3, 10-12. Among contacts of persons with drug-resistant TB, infection rates seem to be similar. However, because they may have a poor response to treatment persons with drug-resistant disease are often infectious for longer periods and Extra pulmonary TB is rarely contagious; however, transmission from extrapulmonary sites has been reported during aerosol-producing procedures, such as autopsies and tissue The tubercle bacilli that alveoli are ingested by alveolar macrophages, the majority of these bacilli are destroyed or inhibited. A small number multiply intracellulary and are released preventing the development of drug resistance 5-7. 2. Transmission and pathogenesis transmitted depends on these factors 4, 5: The environment in which exposure occurred. therefore have the potential to infect more contacts 10-13. irrigation 14-16. 3. Pathogenesis The duration of exposure and the virulence of the organism. when the macrophages die. These bacilli can spread through the lymphatic channels to regional lymph nodes and then through the bloodstream to more distant tissues and organs, including areas in which TB disease is most likely to develop: the apices of the lung, the kidneys, the brain, and bone. Extracellular bacilli attract macrophages form the bloodstream. The immune response kills most of the bacilli, leading to the formation of a granuloma. At this point the person has TB infection, which can be detected by using the tuberculin skin test. It may take 2-10 weeks for the infected person to develop a positive reaction to the tuberculin skin test. Immune responses soon develop to kill the bacilli. Within 2-10 weeks after infection, the immune system is usually able to halt the multiplication of the tubercle bacilli, preventing further spread 4, 17-19. In persons infected with Mycobacterium tuberculosis but that don't have TB disease cannot spread the infection to other people. TB infection in persons who does not have TB disease is not considered a case of TB and referred to as ¨latent TB infection¨. In some persons, TB bacilli overcome the defenses or the immune system and begin to multiply, resulting in the progression from TB infection to TB disease. This process may occur soon after or many years after infection. Some study demonstrated that approximately 5% of person who have been infected with Mycobacterium tuberculosis will develop TB disease in the first year or two after infection and another 5% will develop disease some time later in life. Recent infection (with the past 2 years) with Mycobacterium tuberculosis is therefore an important risk factor for progression to TB disease and in approximately 10% of persons with normal immune system who are infected with Mycobacterium tuberculosis , TB disease will develop at some point 5-7. Some medical conditions increase the risk that TB infection will progress to disease. Some studies suggest that the risk is mayor in inmmunosuppressed patients, for example persons with Diabetes mellitus, prolonged therapy with corticosteroids, immunosuppressive therapy, certain types of cancer, severe kidney disease, injection of illicit drugs, and infection with Human Immunodeficient Virus (HIV) 2,3,12. TB disease most commomly affects the lung, 73% of TB cases are exclusively pulmonary, and however, TB is a systemic disease and may also commonly occur in the following ways;as pleural effusion in the central nervous, lymphatic, or genitourinary systems, as disseminated disease (military TB). Also the infection for Mycobacterium tuberculosis can occur in the other body sites; in the breast, skin, or peritoneum 16,20-23. Extrapulmonary TB is more common in immunosuppressed persons and in young children; meningoencephalitis TB, lymphatic TB and military disease are particularly common in immunosuppressed persons, in some case the extrapulmonary TB is often accompanied by pulmonary TB 3, 8, 16-23.	doab	2025-04-07T04:13:04.669180	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 10 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.11	4. Epidemiology of TB TB infection is one of the most common infections in the world. It is estimated that 30-60% of adults in developing countries have TB infection. Annually about 8-10 million people develop TB disease and 2-3 million people die of the disease. TB disease is the leading cause of death due to infectious disease around the world 24, 25. When the health department learns about a new case of TB, it should take steps to ensure that the person receives appropriate treatment. Is very important that the health authorities should also start a contact investigation, this means interviewing a person who has TB disease to determinate Infection for Mycobacterium tuberculosis and 5. Diagnosis of tuberculosis well as in countries with increasing prevalence of HIV/AIDS 32-34 . diagnostic for TB disease. Tuberculin skin testing useful for 29: To examine person who has symptoms of TB. 5.1 Chest radiography The chest radiography is for: superior segments of lower lobe. Nontuberculous Mycobacteria in the HIV/AIDS Patients 7 tuberculosis strain that is resistant to at least rifampicin and isoniazid among the first-line antitubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three second-line drugs, namely amikacin, kanamycin and/or capreomycin. Current studies have described XDR-TB strains from all continents. Worldwide prevalence of XDR-TB is estimated in 6.6% in all the studied countries among MDR-TB strains. The emergence of XDR-TB strains is a reflection of poor tuberculosis management, and controlling its emergence constitutes an urgent global health reality and a challenge to tuberculosis control activities in all parts of the world, especially in developing countries and those lacking resources and as The systemic symptom of Tuberculosis include fever, chills, night sweats, appetite loss, weigh loss, and easy fatigability, the symptoms of pulmonary TB are productive and prolonged cough (>14-21 week) , chest pain and in some case the patient present hemoptysis. It is important to ask persons suspected of having tuberculosis about their history of TB exposure, infection, or disease. The clinicians may also contact the local health department for information about whether a patient has received tuberculosis treatment in the past, if the drug regimen was inadequate or if the patient may did not adhere to therapy, this disease may recur and may be drug resistant. Also is important to consider demographic factors; country of origin, age, ethnic or racial group and occupation, this factors may increase the patient's risk for exposure to TB or drug-resistant TB disease. Clinicians should determinate whether the patient has medical conditions, especially HIV infection, because this infection increases the risk for TB disease. All patients who do not know their current HIV status should be referred for HIV counseling and testing 26, 27. The tuberculin skin test and the chest radiography, are two probes that help in the To examine a person who is not ill but may be infected with Mycobacterium tuberculosis, such as a person who has been exposed to someone who has TB. This test is the only way to diagnose tuberculosis infection before it has progressed to tuberculosis disease. To determine how many people in group are infected with Mycobacterium tuberculosis. A negative reaction to the tuberculin skin test does not exclude the diagnosis of TB, especially for patients with severe TB illness or infection with HIV. Some persons may not react to the tuberculin skin test if they are tested too soon after being exposed to the infection. Generally it takes 2-10 week after infection for a person to develop an immune response to tuberculin. In children younger than 6 months of age may not react to the To detect abnormalities often seen in apical or posterior segments of upper lobe or To detect atypical images in immunosuppressed persons an in HIV-positive persons. In HIV-infected persons, pulmonary TB may appear in the chets radiograph. For example; TB disease may cause infiltrates without cavities in any lung zone, or it may cause tuberculin skin test because their immune systems are not yet fully developed 32. who may have been exposed to TB, this person are screened for TB infection and disease 8, 26- 28. In order to the decrease in the number of TB cases reported annually is very important to comply three factors 29: In the control of TB disease is also important to know the Groups at High Risk for TB 29, 30: People at Higher Risk for Exposure or Infection: People at Higher Risk for TB disease: Infection with HIV makes people susceptible to rapidly progressive tuberculosis; over 10 millions peoples are infected with both HIV and Mycobacterium tuberculosis <sup>8</sup>. TB in Children: The occurrence of TB infection and disease in children provide important information about the spread of TB in homes and communities. When a child has TB infection or disease is important to learn if 29-31 : #### 4.1 Drug-resistant tuberculosis Drug-resistant TB is transmitted in the same way as drug-susceptible TB. The earlier outbreaks of multidrugs-resistant (MDR) TB support the findings that drug-resistant TB is no less infectious than drug-susceptible TB, although prolonged periods of infectiousness that often occur in the patients with drug-resistant TB may facililate transmission. Drug resistance was divided in two types; primary resistance and secondary or acquired resistance. Primary resistance develops in persons who are initially infected, with resistant organisms. Second resistance, or acquired resistance develops during TB therapy, either because the patient was treated with an inadequate regimen or because the patient did not take the prescribed regimen appropriately 27, 29, 32. The MDR-TB are resistant to rifampicin and isoniazid drugs. Recently drug-resistant tuberculosis (XDR-TB) is defined as tuberculosis caused by a Mycobacterium tuberculosis strain that is resistant to at least rifampicin and isoniazid among the first-line antitubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three second-line drugs, namely amikacin, kanamycin and/or capreomycin. Current studies have described XDR-TB strains from all continents. Worldwide prevalence of XDR-TB is estimated in 6.6% in all the studied countries among MDR-TB strains. The emergence of XDR-TB strains is a reflection of poor tuberculosis management, and controlling its emergence constitutes an urgent global health reality and a challenge to tuberculosis control activities in all parts of the world, especially in developing countries and those lacking resources and as well as in countries with increasing prevalence of HIV/AIDS 32-34 .	doab	2025-04-07T04:13:04.669410	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 11 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.12	5. Diagnosis of tuberculosis 6 Global View of HIV Infection who may have been exposed to TB, this person are screened for TB infection and disease 8, 26- In order to the decrease in the number of TB cases reported annually is very important to To improve prevention and TB control programs in state and local health department. To Increase attention to ensuring that patients complete drug therapy through directly In the control of TB disease is also important to know the Groups at High Risk for TB 29, 30: Low-income groups with poor access to health care, including homeless people. People who live or work in residential facilities (Example: nursing correctional Infection with HIV makes people susceptible to rapidly progressive tuberculosis; over 10 The occurrence of TB infection and disease in children provide important information about the spread of TB in homes and communities. When a child has TB infection or disease is Other adults and children in the household or community have probably been exposed Drug-resistant TB is transmitted in the same way as drug-susceptible TB. The earlier outbreaks of multidrugs-resistant (MDR) TB support the findings that drug-resistant TB is no less infectious than drug-susceptible TB, although prolonged periods of infectiousness that often occur in the patients with drug-resistant TB may facililate transmission. Drug resistance was divided in two types; primary resistance and secondary or acquired resistance. Primary resistance develops in persons who are initially infected, with resistant organisms. Second resistance, or acquired resistance develops during TB therapy, either because the patient was treated with an inadequate regimen or because the patient did not take the prescribed regimen appropriately 27, 29, 32. The MDR-TB are resistant to rifampicin and isoniazid drugs. Recently drug-resistant tuberculosis (XDR-TB) is defined as tuberculosis caused by a Mycobacterium To increase federal resources for TB control and other public health efforts. 28. comply three factors 29: Elderly people. facilities). TB in Children: important to learn if 29-31 : Recent TB transmition. 4.1 Drug-resistant tuberculosis observed therapy (DOT). People who inject illicit drugs. People at Higher Risk for TB disease: People who inject illicit drugs. People with HIV infection. People at Higher Risk for Exposure or Infection: Close contacts of people with infectious TB disease. People born in areas of the world where TB is common. Other people who may be exposed to TB on the job. People recently infected with Mycobacterium tuberculosis. People with chest x-ray suggestive of previous TB disease. People in other groups as identified by local public health officials. People with other medical conditions that can increase the risk for TB. millions peoples are infected with both HIV and Mycobacterium tuberculosis <sup>8</sup>. to TB; if they are infected, they may develop TB disease in the future. The systemic symptom of Tuberculosis include fever, chills, night sweats, appetite loss, weigh loss, and easy fatigability, the symptoms of pulmonary TB are productive and prolonged cough (>14-21 week) , chest pain and in some case the patient present hemoptysis. It is important to ask persons suspected of having tuberculosis about their history of TB exposure, infection, or disease. The clinicians may also contact the local health department for information about whether a patient has received tuberculosis treatment in the past, if the drug regimen was inadequate or if the patient may did not adhere to therapy, this disease may recur and may be drug resistant. Also is important to consider demographic factors; country of origin, age, ethnic or racial group and occupation, this factors may increase the patient's risk for exposure to TB or drug-resistant TB disease. Clinicians should determinate whether the patient has medical conditions, especially HIV infection, because this infection increases the risk for TB disease. All patients who do not know their current HIV status should be referred for HIV counseling and testing 26, 27. The tuberculin skin test and the chest radiography, are two probes that help in the diagnostic for TB disease. Tuberculin skin testing useful for 29: A negative reaction to the tuberculin skin test does not exclude the diagnosis of TB, especially for patients with severe TB illness or infection with HIV. Some persons may not react to the tuberculin skin test if they are tested too soon after being exposed to the infection. Generally it takes 2-10 week after infection for a person to develop an immune response to tuberculin. In children younger than 6 months of age may not react to the tuberculin skin test because their immune systems are not yet fully developed 32. #### 5.1 Chest radiography The chest radiography is for: In HIV-infected persons, pulmonary TB may appear in the chets radiograph. For example; TB disease may cause infiltrates without cavities in any lung zone, or it may cause Infection for Mycobacterium tuberculosis and were more better 44-46. solutions 47-51. they often are diluted by the large fluid volume 16-19, 37-39. Nontuberculous Mycobacteria in the HIV/AIDS Patients 9 receive a variety of extrapulmonary specimens: aseptically collected body fluids, surgically excised tissue, aspirated or draining pus, and urine. Others ascetically collected specimens are the body fluids as spinal, pleural, pericardial, synovial, ascetic, blood, pus, and bone marrow are aseptically collected by the physician using aspiration techniques or surgical procedure. Acid-fast bacilli may be difficult to isolate from some of these specimens because The identification of TB can be done by traditional culture materials include egg-based solid media, such as Löwenstein-Jensen medium, and synthetic solid media as Middlebrook 7H10 and 7H11 agars. The identification depends on the visualization of mycobacterial colonies and is limited by the slow growth rate of these organisms. A major advance in laboratory diagnosis of TB has been the development of systems based on detecting growth in liquid media with the use of radiometric methods as Bactec System. In this, the medium contains palmitic acid labeled with carbon-14. The metabolism of this fatty acid by growing mycobacteria liberates radioactive carbon dioxide, periodic sampling of the gasses in the Species identification was accomplished with biochemical test that often involved additional diagnostic delays. Others techniques, currently being evaluated in a number of clinical settings include identification based on chromatography techniques for the studies of some specific lipids present in the wall of Mycobacterium 42, 43. Also genetic probes are now availed for the identification of Mycobacterium tuberculosis and several other common mycobacterial species. These probes recognize species-specific sequences of ribosomal RNA. Theoretically, genetic probe as polymerase chain reaction (PCR), may permit diagnosis directly form patients specimens, eliminating the need for culture of organism. In practice, the utility of PCR has been limited by problems with the sensitivity and particularly, the specificity of results. In some laboratories, the sensitivity and specificity have been reported to exceed 85%. However, in several laboratories, false-positive rates ranged from 3% to 20%, and in one, 77% of positive results were false. In the last time the Genotype Mycobacteria Direct Assay (GTMD), a novel commercial assay based on nucleic acid sequence-based amplification technology, was evaluated for detection of Mycobacterium tuberculosis complex and some atypical mycobacterial species from clinical samples, and your sensitivity, specificity, positive predictive, and negative predictive were evaluated and these results Environmental opportunistic mycobacteria are those that are recovered form natural and human influenced environments and can infect and cause disease in humans, animals, and birds. Other names for these mycobacteria are nontuberculous, however, they cause tuberculous lesions, also other name is atypical mycobacterial, it distinguish from ¨typical¨ Mycobacterium tuberculosis, and them nontuberculous mycobacteria (NTM). The environmental opportunistic mycobacteria are normal inhabitants of natural waters, drinking water, and soils. They can be isolated from biofilms, aerosol, and dusts. The distribution of NTM and the incidence of disease caused by them is perhaps are not fully understood in most parts of the world. NTM are widely distributed in nature and have been isolated from natural water, rap water, tap water, and water used in showers and surgical culture-containing flask permits rapid detection of mycobacterial growth 40-41. 6. Nontuberculous mycobacteria in the environment mediastinal or hiliar lymphadenophaty with or without accompanying infiltrates and/or cavities. In HIV-positive persons, almost any abnormality on a chest radiographic may indicate TB. In fact, the radiograph of an HIV-positive person with TB disease may even appear entirely normal. Abnormalities on chest radiographs may be suggestive of, but are never diagnostic of TB. However, chest radiographic may be used to rule out the possibility of pulmonary TB in a person who has a positive reaction to the tuberculin skin test and no symptoms of disease 29, 31, 32, 34. Summarizing the possibility of TB should be considered in persons who have these symptoms, person suspected of having this disease should be referred for a medical evaluation, which should include a medical history, a physical examination, a Mantoux tuberculin skin test or tuberculosis purified protein derivate (PPD) skin test, a chest radiograph. Also, it is very important any appropriate bacteriologic or histological examinations in this patients, principally in all inmmunosuppressed patients, of course including the HIV patients 29. Person with symptoms of TB pulmonary disease should have at least three sputum specimens examined by smear and culture. The bets way would be to get serial specimens collected early in the morning on 3 consecutive days. A health care worked should be prepared and directly supervise at least during the first time sputum collection. This personal should give properly instructed in how to produce a good specimen, the patients should be informed that sputum is the material brought up form the lungs and that mucus from the nose or throat and saliva are not good specimens 35, 36. Recommends for Specimen Collection: #### 5.2 Laboratory examination Detection of acid-fast bacilli (AFB) in stained smears examined microscopically may provide the first bacteriologic of TB. The traditional method for to detect AFB is the Zielh-Neelsen coloration, it is a method more economic. There are other methods that increased sensitivity as fluorescent methods. Smear examination is an easy and quick procedure, because the results should be available within 24 hours of specimen collection. However, smear examination permits only the presumptive diagnosis of TB because many TB patients have negative AFB smears. The sensitivity of smear examination may be reduced if the directed inflammatory response and relative absence of cavitary lesions results in fewer organisms expectorated in sputum. There has been concern that the utility of sputum acid-fast smears may be reduced in HIV-infected populations 36, 37. #### 5.3 Extrapulmonary TB disease This disease is not taking in account as causative agent of an extrapulmonary disease because the chest radiography is normal or tuberculin skin test is negative, or both. Mycobacteria may infect almost any organ in the body, the laboratory should expect to mediastinal or hiliar lymphadenophaty with or without accompanying infiltrates and/or cavities. In HIV-positive persons, almost any abnormality on a chest radiographic may indicate TB. In fact, the radiograph of an HIV-positive person with TB disease may even appear entirely normal. Abnormalities on chest radiographs may be suggestive of, but are never diagnostic of TB. However, chest radiographic may be used to rule out the possibility of pulmonary TB in a person who has a positive reaction to the tuberculin skin Summarizing the possibility of TB should be considered in persons who have these symptoms, person suspected of having this disease should be referred for a medical evaluation, which should include a medical history, a physical examination, a Mantoux tuberculin skin test or tuberculosis purified protein derivate (PPD) skin test, a chest radiograph. Also, it is very important any appropriate bacteriologic or histological examinations in this patients, principally in all inmmunosuppressed patients, of course Person with symptoms of TB pulmonary disease should have at least three sputum specimens examined by smear and culture. The bets way would be to get serial specimens collected early in the morning on 3 consecutive days. A health care worked should be prepared and directly supervise at least during the first time sputum collection. This personal should give properly instructed in how to produce a good specimen, the patients should be informed that sputum is the material brought up form the lungs and that mucus In persons unable to cough up sputum, induce sputum, bronchoscopy or gastric To use clean, sterile, one-use, plastic, disposable containers that have been washed with Detection of acid-fast bacilli (AFB) in stained smears examined microscopically may provide the first bacteriologic of TB. The traditional method for to detect AFB is the Zielh-Neelsen coloration, it is a method more economic. There are other methods that increased sensitivity as fluorescent methods. Smear examination is an easy and quick procedure, because the results should be available within 24 hours of specimen collection. However, smear examination permits only the presumptive diagnosis of TB because many TB patients have negative AFB smears. The sensitivity of smear examination may be reduced if the directed inflammatory response and relative absence of cavitary lesions results in fewer organisms expectorated in sputum. There has been concern that the utility of sputum acid-fast smears This disease is not taking in account as causative agent of an extrapulmonary disease because the chest radiography is normal or tuberculin skin test is negative, or both. Mycobacteria may infect almost any organ in the body, the laboratory should expect to from the nose or throat and saliva are not good specimens 35, 36. Get 3 sputum specimens for smear examination and culture. To transport specimens to the laboratory as soon as possible. Before chemotherapy and drug therapy is started. dichromate sulfuric acid and sterilized. may be reduced in HIV-infected populations 36, 37. test and no symptoms of disease 29, 31, 32, 34. including the HIV patients 29. aspiration. 5.2 Laboratory examination 5.3 Extrapulmonary TB disease Recommends for Specimen Collection: receive a variety of extrapulmonary specimens: aseptically collected body fluids, surgically excised tissue, aspirated or draining pus, and urine. Others ascetically collected specimens are the body fluids as spinal, pleural, pericardial, synovial, ascetic, blood, pus, and bone marrow are aseptically collected by the physician using aspiration techniques or surgical procedure. Acid-fast bacilli may be difficult to isolate from some of these specimens because they often are diluted by the large fluid volume 16-19, 37-39. The identification of TB can be done by traditional culture materials include egg-based solid media, such as Löwenstein-Jensen medium, and synthetic solid media as Middlebrook 7H10 and 7H11 agars. The identification depends on the visualization of mycobacterial colonies and is limited by the slow growth rate of these organisms. A major advance in laboratory diagnosis of TB has been the development of systems based on detecting growth in liquid media with the use of radiometric methods as Bactec System. In this, the medium contains palmitic acid labeled with carbon-14. The metabolism of this fatty acid by growing mycobacteria liberates radioactive carbon dioxide, periodic sampling of the gasses in the culture-containing flask permits rapid detection of mycobacterial growth 40-41. Species identification was accomplished with biochemical test that often involved additional diagnostic delays. Others techniques, currently being evaluated in a number of clinical settings include identification based on chromatography techniques for the studies of some specific lipids present in the wall of Mycobacterium 42, 43. Also genetic probes are now availed for the identification of Mycobacterium tuberculosis and several other common mycobacterial species. These probes recognize species-specific sequences of ribosomal RNA. Theoretically, genetic probe as polymerase chain reaction (PCR), may permit diagnosis directly form patients specimens, eliminating the need for culture of organism. In practice, the utility of PCR has been limited by problems with the sensitivity and particularly, the specificity of results. In some laboratories, the sensitivity and specificity have been reported to exceed 85%. However, in several laboratories, false-positive rates ranged from 3% to 20%, and in one, 77% of positive results were false. In the last time the Genotype Mycobacteria Direct Assay (GTMD), a novel commercial assay based on nucleic acid sequence-based amplification technology, was evaluated for detection of Mycobacterium tuberculosis complex and some atypical mycobacterial species from clinical samples, and your sensitivity, specificity, positive predictive, and negative predictive were evaluated and these results were more better 44-46. ## 6. Nontuberculous mycobacteria in the environment Environmental opportunistic mycobacteria are those that are recovered form natural and human influenced environments and can infect and cause disease in humans, animals, and birds. Other names for these mycobacteria are nontuberculous, however, they cause tuberculous lesions, also other name is atypical mycobacterial, it distinguish from ¨typical¨ Mycobacterium tuberculosis, and them nontuberculous mycobacteria (NTM). The environmental opportunistic mycobacteria are normal inhabitants of natural waters, drinking water, and soils. They can be isolated from biofilms, aerosol, and dusts. The distribution of NTM and the incidence of disease caused by them is perhaps are not fully understood in most parts of the world. NTM are widely distributed in nature and have been isolated from natural water, rap water, tap water, and water used in showers and surgical solutions 47-51. Infection for Mycobacterium tuberculosis and 7.1 Clinical manifestations mycobacteria is quite broad 8, 51. 7.2 Pulmonary infections 7.3 Cutaneous infection Nontuberculous Mycobacteria in the HIV/AIDS Patients 11 age. Many investigations have observed decreasing rates of TB concomitant with the increases in NTM. Finally, an interaction between the host and pathogen could involve a Environmental opportunist or nontuberculous mycobacteria (NMT) include both slowly and rapidly growing. The range of infections caused by environmental opportunist Mycobacterium avium-intracellulare complex (MAC) strains have been a major cause of pulmonary and other infections, principally in the HIV patients. MAC infections were commonly seen in chronic obstructive airway disease and in the in the geriatric patients too. Mycobacterium kansasii and Mycobacterium scrofulaceum have been considered an important cause of pulmonary infections. Mycobacterium xenopi, an unusual specie has been encountered as a pathogen in patients with other underlying lung diseases. Others species of slow grown as Mycobacterium simiae (Mycobacterium ´habana´), Mycobacterium szulgai, Mycobacterium malmoense and Mycobacterium fortuitum of rapid grown are other pathogens Mycobacterium szulgai, Mycobacterium marinum, Mycobacterium ulcerans and Mycobacterium vaccae have been reported to be a cause of skin infectious. Mycobacterium marinum, specie has been recognized as a causative organism of swimming pool granuloma or fish tank granuloma. It causes papular lesions in the extremities and may be confused with sporotricosis. Mycobacterium ulcerans is established cause of buruli ulcer, Mycobacterium Mycobacterium fortuitum causes pyogenic lesions in the soft tissue, joints, bursae and injection abscesses, while Mycobacterium chelonae abscessus is a well known cause of wound infections, a new related species Mycobacterum immunogenum has been recently been recognized as a cause of sepsis. Mycobacterium marinum also causes infections of bones, joints, tendon sheaths especially in AIDS patients. Mycobacterium smegmatis, and more recently Mycobacterium wolinskyi and Mycobacterium thermoresistible have been reported to cause wound infection and also bacteraemia. Mycobacterium terrae complex (Mycobacterium terrae, Mycobacterium nonchromogenicum and Mycobacterium triviale) may be associated with mycobacterial disease. Also occasionally Mycobacterium nonchromogenicum and Mycobacterium chelonae have been identified as causes of acupuncture induced infections. Mycobacterium septicum a new rapidly growing species has been reported to be associated Infection of the submaxillar, cervical, inguinal or preauricular lymph nodes is the most common presentation of NTM lymphadenitis. The involved lymph nodes are generally unilateral (95%) and not tender 54-57. The nodes may enlarge rapidly, and even rupture, with major increase in pathogen exposure or potential inoculum size 63-67. reported to be associated with pulmonary infections 51, 65-68. vaccae has also been reported to be a cause of skin infections 51-56. 7.4 Wound infection bone, joints and bursae and sepsis with catheter related bacteremia 49, 51, 57,58. 7.5 Lymphadenitis It is common observation that environmental mycobacteria cause disease in individuals who offer some opportunity due to altered local or systemic immunity. Chronic obstructive pulmonary diseases, emphysema, pneumoconiosis, bronchiectasis, cystic fibrosis, thoracic scoliosis, aspiration due to esophageal disease, previous gastrectomy and chronic alcoholism are some of conditions which have been linked to disease due to NTM. While the reasons may be less clear in conditions like adenitis in children, such factors may be quite obvious in other conditions like bronchiectasis, surgical procedures, injections, break in skin surface due to wounds and generalized immune deficiency states like AIDS, use of immunosuppressive agents as used in transplant patients, etc 50, 51. #### 6.1 Pathogenesis The mechanisms of pathogenesis of NTM are not very clear and have not been adequately investigated. Very low CD4 counts and defective cytokine response have been linked to severe infections in AIDS patients 50. Nontuberculous mycobacteria have been reported to cause localized or disseminated disease depending on local predisposition and/or degree of immune deficit. In non-HIV patients, different NTM may cause localized pulmonary disease, adenitis, soft tissue infections, infections of joints and bones, bursae, skin ulcers and generalized disease in individuals like leukemia, transplant patients, etc. In AIDS patients the manifestations may range from localized to disseminated disease. Clinical features will include local organ specific signs and symptoms to persistent high grade fever, night sweats, anemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhea, myalgia and occasional painful adenopathy 52-57. #### 7. Epidemiology of human infection with nontuberculous mycobacteria The frequency of NTM pulmonary disease has been reported to be increasing on several continents. Changing patient populations, most notably from infection with HIV, have greatly increased the numbers of people at risk 57-60. Studies addressing the epidemiology of NTM infection may be broadly divided into three types: cutaneous delayed-type hypersensitivity to NTM antigens has been used to study large samples of people in many countries. These studies have the strength of providing information regarding simple infection in large groups of people but suffer from the lack of information regarding the prevalence of disease. Another drawback of this study type reflects the relatively poor specificity of the skin test, as well as overlap in reactivity among various Mycobacterial species. The second useful type of epidemiologic study of NMT infection includes investigations reviewing consecutive isolates from a mycobacterial laboratory. In the presence of adequate laboratory protocols to avoid contamination with environmental organisms, these studies provide unequivocal evidence of infection but have the obvious shortcoming of a lack of clinical data, preventing the assessment regarding the presence or absence of disease. The final and most useful study type combines information from the mycobacterial laboratory and the clinician's assessment 55-62. A true increase in rates of infection and disease could be related to the host, the pathogen, or some interaction between the two. Host changes leading to increased numbers of susceptibility could play an important role, with increased numbers of patients with inadequate defenses from diseases such as HIV infection, malignancy, or simply advanced age. Many investigations have observed decreasing rates of TB concomitant with the increases in NTM. Finally, an interaction between the host and pathogen could involve a major increase in pathogen exposure or potential inoculum size 63-67. #### 7.1 Clinical manifestations 10 Global View of HIV Infection It is common observation that environmental mycobacteria cause disease in individuals who offer some opportunity due to altered local or systemic immunity. Chronic obstructive pulmonary diseases, emphysema, pneumoconiosis, bronchiectasis, cystic fibrosis, thoracic scoliosis, aspiration due to esophageal disease, previous gastrectomy and chronic alcoholism are some of conditions which have been linked to disease due to NTM. While the reasons may be less clear in conditions like adenitis in children, such factors may be quite obvious in other conditions like bronchiectasis, surgical procedures, injections, break in skin surface due to wounds and generalized immune deficiency states like AIDS, use of The mechanisms of pathogenesis of NTM are not very clear and have not been adequately investigated. Very low CD4 counts and defective cytokine response have been linked to Nontuberculous mycobacteria have been reported to cause localized or disseminated disease depending on local predisposition and/or degree of immune deficit. In non-HIV patients, different NTM may cause localized pulmonary disease, adenitis, soft tissue infections, infections of joints and bones, bursae, skin ulcers and generalized disease in individuals like leukemia, transplant patients, etc. In AIDS patients the manifestations may range from localized to disseminated disease. Clinical features will include local organ specific signs and symptoms to persistent high grade fever, night sweats, anemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhea, myalgia and 7. Epidemiology of human infection with nontuberculous mycobacteria mycobacterial laboratory and the clinician's assessment 55-62. The frequency of NTM pulmonary disease has been reported to be increasing on several continents. Changing patient populations, most notably from infection with HIV, have greatly increased the numbers of people at risk 57-60. Studies addressing the epidemiology of NTM infection may be broadly divided into three types: cutaneous delayed-type hypersensitivity to NTM antigens has been used to study large samples of people in many countries. These studies have the strength of providing information regarding simple infection in large groups of people but suffer from the lack of information regarding the prevalence of disease. Another drawback of this study type reflects the relatively poor specificity of the skin test, as well as overlap in reactivity among various Mycobacterial species. The second useful type of epidemiologic study of NMT infection includes investigations reviewing consecutive isolates from a mycobacterial laboratory. In the presence of adequate laboratory protocols to avoid contamination with environmental organisms, these studies provide unequivocal evidence of infection but have the obvious shortcoming of a lack of clinical data, preventing the assessment regarding the presence or absence of disease. The final and most useful study type combines information from the A true increase in rates of infection and disease could be related to the host, the pathogen, or some interaction between the two. Host changes leading to increased numbers of susceptibility could play an important role, with increased numbers of patients with inadequate defenses from diseases such as HIV infection, malignancy, or simply advanced immunosuppressive agents as used in transplant patients, etc 50, 51. 6.1 Pathogenesis severe infections in AIDS patients 50. occasional painful adenopathy 52-57. Environmental opportunist or nontuberculous mycobacteria (NMT) include both slowly and rapidly growing. The range of infections caused by environmental opportunist mycobacteria is quite broad 8, 51. #### 7.2 Pulmonary infections Mycobacterium avium-intracellulare complex (MAC) strains have been a major cause of pulmonary and other infections, principally in the HIV patients. MAC infections were commonly seen in chronic obstructive airway disease and in the in the geriatric patients too. Mycobacterium kansasii and Mycobacterium scrofulaceum have been considered an important cause of pulmonary infections. Mycobacterium xenopi, an unusual specie has been encountered as a pathogen in patients with other underlying lung diseases. Others species of slow grown as Mycobacterium simiae (Mycobacterium ´habana´), Mycobacterium szulgai, Mycobacterium malmoense and Mycobacterium fortuitum of rapid grown are other pathogens reported to be associated with pulmonary infections 51, 65-68. #### 7.3 Cutaneous infection Mycobacterium szulgai, Mycobacterium marinum, Mycobacterium ulcerans and Mycobacterium vaccae have been reported to be a cause of skin infectious. Mycobacterium marinum, specie has been recognized as a causative organism of swimming pool granuloma or fish tank granuloma. It causes papular lesions in the extremities and may be confused with sporotricosis. Mycobacterium ulcerans is established cause of buruli ulcer, Mycobacterium vaccae has also been reported to be a cause of skin infections 51-56. #### 7.4 Wound infection bone, joints and bursae and sepsis Mycobacterium fortuitum causes pyogenic lesions in the soft tissue, joints, bursae and injection abscesses, while Mycobacterium chelonae abscessus is a well known cause of wound infections, a new related species Mycobacterum immunogenum has been recently been recognized as a cause of sepsis. Mycobacterium marinum also causes infections of bones, joints, tendon sheaths especially in AIDS patients. Mycobacterium smegmatis, and more recently Mycobacterium wolinskyi and Mycobacterium thermoresistible have been reported to cause wound infection and also bacteraemia. Mycobacterium terrae complex (Mycobacterium terrae, Mycobacterium nonchromogenicum and Mycobacterium triviale) may be associated with mycobacterial disease. Also occasionally Mycobacterium nonchromogenicum and Mycobacterium chelonae have been identified as causes of acupuncture induced infections. Mycobacterium septicum a new rapidly growing species has been reported to be associated with catheter related bacteremia 49, 51, 57,58. #### 7.5 Lymphadenitis Infection of the submaxillar, cervical, inguinal or preauricular lymph nodes is the most common presentation of NTM lymphadenitis. The involved lymph nodes are generally unilateral (95%) and not tender 54-57. The nodes may enlarge rapidly, and even rupture, with Infection for Mycobacterium tuberculosis and 40, 43,44,48, 83, 84 in the HIV/AIDS patients infected with HIV 53,85,86. effusions 24,30,67,69,89. Nontuberculous Mycobacteria in the HIV/AIDS Patients 13 qualitative and quantitative, grown on MaConkey agar, sodium chloride tolerance, etc, are adequate to identify majority of clinically relevant mycobacteria. This strategy is very necessary and important for the diagnostic of NTM, however, some time consuming and is not conclusive for many isolates with variable characters. For this reason others alternative diagnostic techniques are recommended, for example, the analysis of the mycolic acids of mycobacteria by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), and more recently the identification and characterization of NTM by molecular methods, based on new knowledge about the gene sequences of mycobacteria many gene probes for the identification of isolates as well as amplification of specific gene fragments from the lesions and mycobacterial culture isolates have been developed; gene probes, polymerase chain reaction (PCR) techniques, DNA fingerprinting techniques, etc, 35- 9. Mycobacterium tuberculosis and nontuberculous mycobacteria diseases After years of worldwide decline of tuberculosis (TB), this disease has returned as a big problem in the Public Health. The resurgence of TB in the past decades is closely linked to acquired immunodeficiency syndrome (AIDS) pandemic. The high susceptibility of patients infected with the human immunodeficiency virus (HIV) to TB and others mycobacterial infections is unique, creating a lot of diagnostic and therapeutic challenges for clinicians 12,32,24. Pulmonary tuberculosis is the most common manifestation of tuberculosis in adults HIV/TB co-infection occurs in various stages of HIV infection, with the clinical pattern correlating with the patient's immune status. In the early stages of HIV infection, when immunity is only partially compromised, the features are more typical of tuberculosis, commonly with upper lobe cavitations, and the disease resembles that seen in the pre-HIV era. HIV-infected patients present with atypical pulmonary disease due to immune deficiency advances, resembling primary tuberculosis or extra pulmonary and disseminated The clinical symptoms are severally similar in HIV-infected and HIV-negative patients. However, cough is reported less frequently by HIV-infected patients, probably because there is less cavitations, inflammation and endobronchial irritation as a result of a reduction in cell-mediated immunity. Similarly, haemoptysis, which results from caseous necrosis of In general, the traits that characterize HIV-TB co-infection include the potential for rapid progression from primary infection to disseminated disease, atypical radiographic features of pulmonary disease, increased frequency of extrapulmonary disease and involvement of unusual sites of infection. All of these atypical features seem to occur more commonly with more advance stages of immunosuppression and the paradigm that emerges is one of typical TB early in the course of HIV infection and atypical manifestation with advanced HIV disease, in this case the atypical features included lower lobe alveolar opacities, multifocal alveolar opacities, interstitial infiltrates, mediastinal adenopathy and pleural disease, commonly with hilar adenopathy and lower lobe infection 87. the bronchial arteries, is less common in HIV-infected patients 87.88. 9.1 Clinical symptoms in pulmonary tuberculosis formation of sinus tracts that result in prolonged local drainage. Other nodal groups outside of the head and neck may be involved occasionally. Distinguishing tuberculous from nontuberculous lymphadenitis is key because the former requires drug therapy and public health tracking, whereas the latter does not. A definitive diagnosis of NTM lymphadenitis is made by recovery of the causative organism form lymph node cultures. A simple diagnostic biopsy or incision and drainage of the involved lymph nodes should be avoided, since most of these procedures will be followed by fistulae formation with chronic drainage. However, even with excised nodes with compatible histopathology, only about 50% will yield positive cultures, because in some case these smear-positive, culture-negative cases may be due to fastidious species such as Mycobacterium haemophilum or Mycobacterium genavence. Approximately 80% of culture-proven cases of NTM lymphadenitis are due to MAC. It´s predominance is due to a change approximately from 20-30 years ago, when most geographic areas reported Mycobacterium scrofulaceum as the most common etiologic agent, only about 10% of the culture-proved mycobacterial cervical lymphadenitis in children is due to Mycobacterium avium complex and Mycobacterium scrofulaceum. Also Mycobacterium haemophilum, Mycobacterium malmoense, Mycobacterium fortuitum and others have been isolated from cases of lymphadenitis including HIV patients. In contrast, in adults more than 90% of the culture-proven mycobacterial lymphadenitis is due to Mycobacterium tuberculosis 8, 67, 70-76. #### 7.6 Disseminated disease in immunocompromized individuals Disseminated disease due to NTM in AIDS patients usually occurs only in those with very advanced immunosuppressant, because these patients frequently have other complications, the diagnosis of mycobacterial infection may be confused or delayed. The diagnosis is exceedingly rare in person with >100 CD4 cells, and it should usually be suspected only in persons with <50 CD4 cells 53. MAC have been found to be more commonly isolated from HIV-positive and HIV-negative patients, in their the portal of entry mainly through the gut 31 67,69. Persistent high grade fever, night sweats, anemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhoea, myalgia and occasional painfuladenopathy are common signs and symptoms associated with MAC disease in AIDS cases. Others pulmonary and extrapulmonary mycobacterial infections in AIDS patients are for Mycobacterium kansasii , Mycobacterium scrofulaceum, Mycobacterium xenopi, Mycobacterium simiae, Mycobacterium fortuitum-Mycobacterium chelonei complex, Mycobacterium malmoense, Mycobacterium szulgai, and more recently Mycobacterium genavense, Mycobacterium haemophilum and Mycobacterium celatum 74-82. #### 8. Identification of nontuberculous mycobacteria Traditional identification of NTM, as well as Mycobacterium tuberculosis, has relied upon statistical probabilities of presenting a characteristic reaction pattern in battery biochemical test. The niacin test was the most useful for separating NTM and Mycobacterium tuberculosis because the former is usually negative, whereas isolates of Mycobacterium tuberculosis are positive. Runyon devised the first good scheme for grouping NTM based on growth rates and colony pigmentation. For the diagnostic of NTM is very important to know the growth rates and colony pigmentation, and biochemical test such as, niacin production, nitrate reduction, tween-80 hydrolysis, arylsulphatase, urease, tellurite reduction, catalase formation of sinus tracts that result in prolonged local drainage. Other nodal groups outside of the head and neck may be involved occasionally. Distinguishing tuberculous from nontuberculous lymphadenitis is key because the former requires drug therapy and public health tracking, whereas the latter does not. A definitive diagnosis of NTM lymphadenitis is made by recovery of the causative organism form lymph node cultures. A simple diagnostic biopsy or incision and drainage of the involved lymph nodes should be avoided, since most of these procedures will be followed by fistulae formation with chronic drainage. However, even with excised nodes with compatible histopathology, only about 50% will yield positive cultures, because in some case these smear-positive, culture-negative cases may be due to fastidious species such as Mycobacterium haemophilum or Mycobacterium genavence. Approximately 80% of culture-proven cases of NTM lymphadenitis are due to MAC. It´s predominance is due to a change approximately from 20-30 years ago, when most geographic areas reported Mycobacterium scrofulaceum as the most common etiologic agent, only about 10% of the culture-proved mycobacterial cervical lymphadenitis in children is due to Mycobacterium avium complex and Mycobacterium scrofulaceum. Also Mycobacterium haemophilum, Mycobacterium malmoense, Mycobacterium fortuitum and others have been isolated from cases of lymphadenitis including HIV patients. In contrast, in adults more than 90% of the culture-proven mycobacterial lymphadenitis is due to Mycobacterium Disseminated disease due to NTM in AIDS patients usually occurs only in those with very advanced immunosuppressant, because these patients frequently have other complications, the diagnosis of mycobacterial infection may be confused or delayed. The diagnosis is exceedingly rare in person with >100 CD4 cells, and it should usually be suspected only in persons with <50 CD4 cells 53. MAC have been found to be more commonly isolated from HIV-positive and HIV-negative patients, in their the portal of entry mainly through the gut 31 67,69. Persistent high grade fever, night sweats, anemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhoea, myalgia and occasional painfuladenopathy are common signs and symptoms associated with MAC disease in AIDS cases. Others pulmonary and extrapulmonary mycobacterial infections in AIDS patients are for Mycobacterium kansasii , Mycobacterium scrofulaceum, Mycobacterium xenopi, Mycobacterium simiae, Mycobacterium fortuitum-Mycobacterium chelonei complex, Mycobacterium malmoense, Mycobacterium szulgai, and more recently Mycobacterium genavense, Mycobacterium Traditional identification of NTM, as well as Mycobacterium tuberculosis, has relied upon statistical probabilities of presenting a characteristic reaction pattern in battery biochemical test. The niacin test was the most useful for separating NTM and Mycobacterium tuberculosis because the former is usually negative, whereas isolates of Mycobacterium tuberculosis are positive. Runyon devised the first good scheme for grouping NTM based on growth rates and colony pigmentation. For the diagnostic of NTM is very important to know the growth rates and colony pigmentation, and biochemical test such as, niacin production, nitrate reduction, tween-80 hydrolysis, arylsulphatase, urease, tellurite reduction, catalase 7.6 Disseminated disease in immunocompromized individuals haemophilum and Mycobacterium celatum 74-82. 8. Identification of nontuberculous mycobacteria tuberculosis 8, 67, 70-76. qualitative and quantitative, grown on MaConkey agar, sodium chloride tolerance, etc, are adequate to identify majority of clinically relevant mycobacteria. This strategy is very necessary and important for the diagnostic of NTM, however, some time consuming and is not conclusive for many isolates with variable characters. For this reason others alternative diagnostic techniques are recommended, for example, the analysis of the mycolic acids of mycobacteria by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), and more recently the identification and characterization of NTM by molecular methods, based on new knowledge about the gene sequences of mycobacteria many gene probes for the identification of isolates as well as amplification of specific gene fragments from the lesions and mycobacterial culture isolates have been developed; gene probes, polymerase chain reaction (PCR) techniques, DNA fingerprinting techniques, etc, 35- 40, 43,44,48, 83, 84 #### 9. Mycobacterium tuberculosis and nontuberculous mycobacteria diseases in the HIV/AIDS patients After years of worldwide decline of tuberculosis (TB), this disease has returned as a big problem in the Public Health. The resurgence of TB in the past decades is closely linked to acquired immunodeficiency syndrome (AIDS) pandemic. The high susceptibility of patients infected with the human immunodeficiency virus (HIV) to TB and others mycobacterial infections is unique, creating a lot of diagnostic and therapeutic challenges for clinicians 12,32,24. Pulmonary tuberculosis is the most common manifestation of tuberculosis in adults infected with HIV 53,85,86. HIV/TB co-infection occurs in various stages of HIV infection, with the clinical pattern correlating with the patient's immune status. In the early stages of HIV infection, when immunity is only partially compromised, the features are more typical of tuberculosis, commonly with upper lobe cavitations, and the disease resembles that seen in the pre-HIV era. HIV-infected patients present with atypical pulmonary disease due to immune deficiency advances, resembling primary tuberculosis or extra pulmonary and disseminated disease, commonly with hilar adenopathy and lower lobe infection 87. #### 9.1 Clinical symptoms in pulmonary tuberculosis The clinical symptoms are severally similar in HIV-infected and HIV-negative patients. However, cough is reported less frequently by HIV-infected patients, probably because there is less cavitations, inflammation and endobronchial irritation as a result of a reduction in cell-mediated immunity. Similarly, haemoptysis, which results from caseous necrosis of the bronchial arteries, is less common in HIV-infected patients 87.88. In general, the traits that characterize HIV-TB co-infection include the potential for rapid progression from primary infection to disseminated disease, atypical radiographic features of pulmonary disease, increased frequency of extrapulmonary disease and involvement of unusual sites of infection. All of these atypical features seem to occur more commonly with more advance stages of immunosuppression and the paradigm that emerges is one of typical TB early in the course of HIV infection and atypical manifestation with advanced HIV disease, in this case the atypical features included lower lobe alveolar opacities, multifocal alveolar opacities, interstitial infiltrates, mediastinal adenopathy and pleural effusions 24,30,67,69,89. Infection for Mycobacterium tuberculosis and 3B) and Mycobacterium fortuitum (Figure 3C) Care Med1994;149:1359-1374. 10. References Nontuberculous Mycobacteria in the HIV/AIDS Patients 15 Fig. 2. Biopsy of liver pedicle lymph nodes for Mycobacterium tuberculosis in AIDS patients. A B C Fig. 3. AIDS patients with skin lesions from Mycobacterium avium complex (Figure 3A, Figure A B C [1] Center for Disease Control and Prevention. A strategic plan for the elimination of tuberculosis from the United States. MMWR 1989;38 (Suppl No. S-3). [2] American Thoracic Society and Center for Disease Control and Prevention. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Fig. 4. Lymphadenitis cervical from Mycobacterium tuberculosis (Figure 4A), inguinal-testes lesions from Mycobacterium avium complex in lymphatic system (Figure 4B, Figure 4C). #### 9.2 Clinical symptoms in extrapulmonary tuberculosis The main manifestation of extrapulmonary tuberculosis in AIDS patients are lymphadenopathy, pleural effusion, meningitis, pericardial effusion and miliary tuberculosis. This diagnostic is often difficult because the patients with HIV are prone to all of the usual bacterial and viral infection that affect a non-HIV infected patients, so, the presentation of extrapulmonary tuberculosis in HIV-infected patients is generally no different 8, 69. #### 9.3 Nontuberculous mycobacterial infection in HIV/AIDS patients The clinical relevant of NMT infection in HIV/AIDS patients are very frequent, this infection can be pulmonary and extrapulmonary and their symptoms are the same that Mycobacterium tuberculosis 51-54, 69. Recently, the nontuberculous mycobacterial are also denominated as environmental opportunist mycobacterial. Normally, they live as environmental saprophytes and they cause opportunist disease in human. Many cases of NTM are associated with some form of immune deficiency in special HIV/AIDS patients. In this group of patients is frequently to find this mycobacterial species as etiological agent for this reason is very important their microbiology diagnostic which is different to Mycobacterium tuberculosis 90, 91. Disseminate Mycobacterium avium complex (MAC) diseases was one of the first opportunist infections recognized in the syndrome of AIDS since 20 years ago. The interest of the diagnostic of disseminated MAC and others species of nontuberculous mycobacteria infection have been increased as a result of the HIV pandemic. The prevention and treatment in nontuberculous mycobacteria are life long because cure of them were not achievable in AIDS patients with profound immune suppression. The precise immune defect predisposing HIV/AIDS patients to disseminated diseases is unknown 92 . The main manifestation of pulmonary and extrapulmonary infections for Mycobacterium tuberculosis and nontuberculous mycobacterial are the same affecting lung, pleura, skin, lymphatic system and producing dissemination infection (Figure 1, Figure 2), (Figure 3A-3B-3C, Figure 4A-4B) 8, 63,69. For this reason is very important the highly active antiretroviral therapy (HAART) for treatment of AIDS patients that has been associated with a market reduction in the incidence of most opportunistic infection 82,89,92. So, is very important that the mycobacteriology laboratory should give a definitive diagnostic, because in immunosuppressed patients is important to find resistant alcohol acid bacillus in order to detect the co-infection with Mycobacterium tuberculosis which is the most frequently agent found. Nevertheless, others species of mycobacteria may be causing infection and should be search for. Fig. 1. Messenteric lymph nodes for Mycobacterium tuberculosis in AIDS patients. The main manifestation of extrapulmonary tuberculosis in AIDS patients are lymphadenopathy, pleural effusion, meningitis, pericardial effusion and miliary tuberculosis. This diagnostic is often difficult because the patients with HIV are prone to all of the usual bacterial and viral infection that affect a non-HIV infected patients, so, the presentation of extrapulmonary tuberculosis in HIV-infected patients is generally no The clinical relevant of NMT infection in HIV/AIDS patients are very frequent, this infection can be pulmonary and extrapulmonary and their symptoms are the same that Mycobacterium tuberculosis 51-54, 69. Recently, the nontuberculous mycobacterial are also denominated as environmental opportunist mycobacterial. Normally, they live as environmental saprophytes and they cause opportunist disease in human. Many cases of NTM are associated with some form of immune deficiency in special HIV/AIDS patients. In this group of patients is frequently to find this mycobacterial species as etiological agent for this reason is very important their microbiology diagnostic which is different to Disseminate Mycobacterium avium complex (MAC) diseases was one of the first opportunist infections recognized in the syndrome of AIDS since 20 years ago. The interest of the diagnostic of disseminated MAC and others species of nontuberculous mycobacteria infection have been increased as a result of the HIV pandemic. The prevention and treatment in nontuberculous mycobacteria are life long because cure of them were not achievable in AIDS patients with profound immune suppression. The precise immune The main manifestation of pulmonary and extrapulmonary infections for Mycobacterium tuberculosis and nontuberculous mycobacterial are the same affecting lung, pleura, skin, lymphatic system and producing dissemination infection (Figure 1, Figure 2), (Figure 3A-3B-3C, Figure 4A-4B) 8, 63,69. For this reason is very important the highly active antiretroviral therapy (HAART) for treatment of AIDS patients that has been associated with a market So, is very important that the mycobacteriology laboratory should give a definitive diagnostic, because in immunosuppressed patients is important to find resistant alcohol acid bacillus in order to detect the co-infection with Mycobacterium tuberculosis which is the most frequently agent found. Nevertheless, others species of mycobacteria may be causing defect predisposing HIV/AIDS patients to disseminated diseases is unknown 92 . Fig. 1. Messenteric lymph nodes for Mycobacterium tuberculosis in AIDS patients. reduction in the incidence of most opportunistic infection 82,89,92. 9.2 Clinical symptoms in extrapulmonary tuberculosis 9.3 Nontuberculous mycobacterial infection in HIV/AIDS patients different 8, 69. Mycobacterium tuberculosis 90, 91. infection and should be search for. Fig. 2. Biopsy of liver pedicle lymph nodes for Mycobacterium tuberculosis in AIDS patients. Fig. 3. AIDS patients with skin lesions from Mycobacterium avium complex (Figure 3A, Figure 3B) and Mycobacterium fortuitum (Figure 3C) Fig. 4. Lymphadenitis cervical from Mycobacterium tuberculosis (Figure 4A), inguinal-testes lesions from Mycobacterium avium complex in lymphatic system (Figure 4B, Figure 4C). #### 10. References Infection for Mycobacterium tuberculosis and CDC 1995:3-23. MMWR 1997;46:695-70. Planning, Financing, 2005. Academy of Pediatrics;1997:541-563. tuberculosis. Chest 1996;109:420-23. Dis 1995;21:291-9. Nontuberculous Mycobacteria in the HIV/AIDS Patients 17 [22] Kaplan JB, Masur H, Holmes KK. Guidelines for preventing opportunistic infections and the Infectious Diseases Society of America MMWR 2002;51(RR-8):1-52. [23] Mederos LM, Banderas JF, Valdés L, Capó V, Fleites G, Martínez MR, Montoro EH. [24] Rieder HL, Cauthen GM, Comstock GW, Snider DE. Epidemiology of tuberculosis in [25] Center for Disease Control and Prevention, National Center for HIV, STD, and TB [26] Center for Disease Control and Prevention. Tuberculosis morbility- United States, 1996. [27] World Health Organization, Geneva. Toman´s Tuberculosis. Case detection, treatment, and monitoring: questions and answers. Ed. Frieden T, Second Edition, 2004. [28] Department of Health and Human Services, Center for Disease Control and [29] World Health Organization. WHO Report. Global Tuberculosis Control. Surveillance, [30] American Academic of Pediatrics. Tuberculosis. In: Peter G, ed. 1997 Red Book: Report [31] Center for Disease Control and Prevention. Prevention and treatment of tuberculosis [34] Cohen R, Muzaffar S, Capellan J, Azar H, Chinikamwala M. The validity of classic [35] Kent PT, Kubica GP. Public Health Mycobacteriology. A Guide for the Level III [36] Tenover FC, Crawford JT, Huebner RE, Geiter LJ, Horsburgh LR, Good RC. The resource of tuberculosis: Is your laboratory ready?. J Clin Microbiol 1993:31:767-770. [37] Crawford JT. New Technologies in the diagnosis. Semin Respir Infect 1994;9:62-70. [38] Shinnick TN, Good RC. Diagnostic mycobacteriology laboratory practices. Clin Infect [39] Organización Panamericana de la Salud. Manual para el diagnostic bacteriológico de la therapy and revised recommendations. MMWR 1998;47(No. RR-20). [32] Jain A, Mondal R. Extensively drug-resistant tuberculosis: current challenges and threats. FEMS Immunol Med Microbiol 2008;53:145-150. Centers for Disease Control, Atlanta, Georgia, 1985: 21-27. Tuberculosis. Normas y Guía Técnicas. Parte II, Cultivo, 2008. [33] Jassal M, Bishai WR. Extensively drug-resistant tuberculosis. www.thelancet.com/infection Vol 9, January 2009. inmunodeficiencia humana (sida). AVFT 2010;29:35-38. the Unites States. Epidemiol Rev 1989;11:79-98. Tuberculosis. CDC, Fourth Edition, 2000: 15-21. among HIV infected persons. 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Comparison of mycobacterial lymphadenitis [17] Artesntein AW, Kim JH, Williams WJ, Chungg RC. Isolated peripheral tuberculous [18] Rojas A, La Cruz H, Salinas P, Rangel D, Hernández M. Adenitis tuberculosa inguinal. [19] Al Soub H, Al Alousi FS, Al-Khal AL. Tuberculoma of the cavernous sinus. Sand J Infect [20] Donald PR. Schoeman JF. Tuberculous Meningitis. Tehe New England Journal of Medicine [21] Karande S, Gupta V, Kulkarni M. Tuberculous Meningitis and HIV. Indian Journal of drugs users with cutaneous anergy. JAMA 1992;268:504-509. the United States. Am Rev Respir Dis 1990;141:347-51. controls. Clin Infect Dis 1992;15:601-5. Reporte de um caso. MedULA, 2006;15:37-9. [6] Daniel TM. The history of tuberculosis. Respir Med 2006; 100: 1862-70. Mycobacteria. Annu Rev Microbiol 2003;57:641-671. Infect Control Hosp Epidemiol 1995;16:160-165. of Tuberculosis. CDC 1995:8-19. 50-89. 366-372. Tubercle 1987;68:147-150. Med 1989;320:545-550. 20:876-82. 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Nontuberculous Mycobacteria in the HIV/AIDS Patients 19 [57] American Thoracic Society. Diagnosis and treatment of disease cause by nontuberculous mycobacteria. Am J Respir Crit Care Med 1997;156:S1-19. [58] Moore JE, Kruijshaar ME, Ormerod LP, Drobniewski F, Abubakar I. Increasing reports [59] O´Brien RJ, Geiter LJ, Snider Jr. DE. The epidemiology of nontuberculous [60] Tsukamura, M, Kita N, Shimoide H, Arakawa H, Kuze A. Studies on the epidemiology of nontuberculous mycobacteriosis in Japan. Am Rev Respir Dis 1988;137:1280-1284. [61] Frappier-Davignon L, Fortin R, Desy M. Sensitivity to ¨atypical¨ mycobacteria in high [63] de Armas Y, Capó V, González I, Mederos LM, Díaz R, de Waard JH, Rodríguez A, [64] Marras TK, Daley CL. Epidemiology of human pulmonary infection with [65] Chakrabarti A, Sharma M, Dubey ML. Isolation rates of different mycobacterial species [66] Levy-Frebaulth V, Pangon B, Bure A, Katima C, Marche C, David HL. Mycobacterium [67] Wagner D, Young LS. Nontuberculous mycobacterial infections: a clinical review. [68] Gupta AK, Nayar M, Chandra M. Critical appraisal cytology of fine needle aspiration [69] Ioachim HL, Medeiros LJ. Lymph Node Pathology. 2009;Chapter 21- Section III:130- [70] Mederos LM, González D, Pérez D, Paneque A, Montoro EH. Linfadenitis causada por [71] Mederos LM, González D, Montoro EH. Linfadenitis ulcerativa por Mycobacterium fortuitum en un paciente con sida. Enferm Infecc Microbiol Clin 2005;23:573-77. [72] Mederos LM, Rodríguez ME, Mantecón B, Sardiñas M, Montoro EH. Adenitis [73] Nightingale SD, Byrd LT, Southern PM, Jockusch JD, Cal SX, Wynne BA. Incidence of [74] Horsburgh CR. Mycobacterium avium complex in deficiency syndrome infection in the cytology in tuberculosis lymphadenitis. Acta Cytol 1992;36:391-94. nontuberculous mycobacteria. Clin Chest Med 2002;23:553-567. from Chandinarh (north India). Indian J Res 1990;111-4. 2006. BMC Public Health 2010;10:612, Article URL: http://www.biomedcentral.com/1471-2458/10/612. [62] Sackett DL. Bias in analytic research. J Chronic Dis 1979;32:51-63. Rev Respir Dis 1987;135:1007-1014. of non-tuberculous mycobacteria in England, Wales and Norther Ireland, 1995- mycobacterial diseases in the United States. Results from a national survey. Am school children in two community health departments. Canadian J of Public Health García Y, Cabanas R. Concomitant Mycobacterium avium infection and Hodgkin´s disease in lymph node from an HIV-negative child. Pathol Oncol Res 2011;17:139-140. simiae, Mycobacterium avium-intrecellulare mixed infection in AIDS. J Clin Microbiol 135, and Chapter 23-Section III:137-143, Fourth Edition, Lippincott William & Mycobacterium malmoense en paciente infectado con el virus de inmunodeficiencia submaxilar en niño causada por Mycobacterium fortuitum . Folia Dermatológica Mycobacterium avium-intracellularecomplex in humans immunodeficiency virus- [40] Ruiz P, Zerolo FJ, Casal M. Comparison of susceptibility of Mycobacterium tuberculisis [41] Valero-Guillén PL, Martín-Luengo F, Larsson L, Jiménez J, Juhlin I, Portaels F. Fatty and mycolic acids of Mycobactarium malmoense . L Clin Microbiol 1988;26:153-154. [42] Leite CQF, Souza CWO, Leite SRA. Identification of Mycobacteria by thin layer [43] Mederos LM, Frantz JL, Perovani MA, Sardiñas M, Montoro EH. Identificación de [44] Forbes SA, Hicks KE. Direct detection of Mycobacterium tuberculosis in respiratory [45] Noordhoek GT, Kolk AH, Bjune G et al. Sensitivity and specificity of PCR for detection [46] Franco-Alvarez F, Ruiz P, Gutierrez J, Casal M. Evaluation of the GenoType [47] Wolinsky E. Nontuberculous mycobacteria and associated disease. Am Rev Respir Dis [48] Wallace RJ Jr, O´Brein R, Glassroth J, Raleigh J, Dutta A. Diagnosis and treatment of [49] DeVita VT, Hellman S, Rosenberg SA. AIDS Etiology, Diagnosis, Treatment and [50] Murphy SM, Brook G, Birchall MA. HIV Infection and AIDS. Churchill Livinsgstone-ELSEVIER, Second Edition, Chapter: Tuberculosis 2000: 23-24, 63,71,119-120. [51] Katoch VM. Infections due to non-tuberculous mycobacteria (NTM). Indian J Med Res [52] García-Río I, Fernádez-Peñas P, Fernández-Herrera J, Gracía-Díez A. Infección cutánea [53] Guía Práctica Clínica de Dermatología Tropical. Colegio Ibero Latinoamericano de [54] Saggese D, compadretti GC, Burnelli R. Nontuberculous mycobacterial adenitis in children: Diagnostic and therapeutic management. Am J Otolaryngol 2003; 24:79-84. [55] Panesar J, Higgins K, Daya H, Forte V, Allen U. Nontuberculous mycobacterial cervical adenitis: a ten-year retrospective review. Laryngoscope 2003; 113:149-54. [56] Barr KL, Lowe L, Su LD. Mycobacterium marinum infection simulating interstitial granuloma annulare: a report of two case. Am J Dermatopathol 2003;25:148-151. Four years of experience. Mem Inst Oswaldo Cruz 1998;93:801-805. Microbiol 2000;38:4663-4664. Microbiología 2007;27:50-53. Clin Microbiol 1994;32:277. 1993;31:1688. 2006;44:3025-3027. 1979;119:107-159. 2004;120:290-304. 2002;8:125-127. Capítulo ¨Micobacteriosis Atípica¨: 11-14. 953. using the ESP Culture System II with that using the BACTEC Method. J Clin chromatographic analysis of mycolic acid and conventional biochemical method: Micobacterias no tuberculosas en pacientes VIH/SIDA por métodos convencionales y de fracciones de ácidos micólicos. Rev Soc Venezolana de specimens in clinical laboratory by polymerase chain reaction. J Clin Microbiol of Mycobacterium tuberculosis: a blind comparison study among seven laboratories. J Mycobacteria Direct Assay for detection Mycobacterium tuberculosis complex and Four Atypical Mycobacterial Species in clinical samples. J of Clin Microbiol disease caused by nontuberculous mycobacteria. Am Rev Respir Dis 1990;142:940- Prevention. Fourth Edition, Chapter: Tuberculosis and Human Inmmunodeficiency Virus Infection 1997: 245-257, Lippincott-Raven Publishers, Philadelphia, New York. por Mycobacterium chelonae. Revisión de seis casos. Clin Microbiol & Infection Dermatología (CILAD), Madrid, J´Editor Prof. Vilata JJ, Editora ¨adalia¨ , 2009; 2 1Norway 2,4Uganda 3USA 5Ethiopia A Problem or Not? Medicine, Makerere University Non-Tuberculous Mycobacteria in Uganda: 1Department of Food Safety and Infection Biology, Norwegian School of Veterinary Science 2Department of Veterinary Public Health and Preventive Medicine, Faculty of Veterinary 3Department of Epidemiology and Biostatistics/ Population Health, college of Public health, HIV/AIDS scourge has been and still is a devastating disease since its advent in the late 70's, claiming up to 25 million lives globally (WHO, 2010). The United Nations program on AIDS (UNAIDS) estimated that 39.5 million people were living with HIV/AIDS by the end of 2006, 63% of these were in Sub Saharan Africa. Furthermore, 4.3 million people were reported to be newly infected with HIV while 2.9 million had lost their lives to AIDS in 2006 alone (UNAIDS, 2010). It is also reported that young people of age 15 and above account for 40% of new infections (CWYF, 2007). Epidemiological models predict a growing trend of the disease most notably the alarming incidence of new infections in sub-Saharan Africa, In many regards, Uganda is considered a global role model in awareness, prevention and control of HIV/AIDS (Aidsmap, 2006; Kaiser family foundation, 2005). The first cases of AIDS in Uganda were identified in Rakai district off the shores of Lake Victoria in 1982 (Serwadda et al 1985; MOH, 2006). AIDS was clinically characterized by wasting, this is why it is popularly known as 'slim disease' (Serwadda et al., 1985). Just as before, this disease is still characterized by opportunistic infections, notable are Mycobacterium avium complex infections which are usually the causes of fatality in victims (Serwadda et al., 1985; MOH, 2006). In the late 1980's a famous Ugandan Musician Philly Bongole Lutaaya paved the way 1. Introduction 1.1 HIV/AIDS Western Europe and Asia (UNAIDS, 2010). 1.2 HIV/AIDS in Uganda: Past and current situation Adrian Muwonge1, Ashemeire Patience4, Clovice Kankya2, Demelash Biffa5, Eystein Skjerve1 and James Oloya3 132 Coverdell centre, University of Georgia Athens, 4Faculty of Community Psychology, Makerere University, 5Schools of Veterinary Medicine, Hawassa University,	doab	2025-04-07T04:13:04.669871	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 12 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.13	Non-Tuberculous Mycobacteria in Uganda: A Problem or Not? Adrian Muwonge1, Ashemeire Patience4, Clovice Kankya2, Demelash Biffa5, Eystein Skjerve1 and James Oloya3 1Department of Food Safety and Infection Biology, Norwegian School of Veterinary Science 2Department of Veterinary Public Health and Preventive Medicine, Faculty of Veterinary Medicine, Makerere University 3Department of Epidemiology and Biostatistics/ Population Health, college of Public health, 132 Coverdell centre, University of Georgia Athens, 4Faculty of Community Psychology, Makerere University, 5Schools of Veterinary Medicine, Hawassa University, 1Norway 2,4Uganda 3USA 5Ethiopia	doab	2025-04-07T04:13:04.672936	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 13 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.14	1. Introduction #### 1.1 HIV/AIDS 20 Global View of HIV Infection [75] Maloney JM, Gregg CM, Stephens DS, Manian FA, Rimland D. Infections caused by [76] Corti M, Palmero D. Mycobacterium avium complex infection in HIV/AIDS patients. [77] Mederos LM, Pomier O, Trujillo A, Fonseca C, Montoro EH. Micobacteriosis sistémica por Mycobacterium avium en paciente con SIDA. AVFT 2009;28:61-63. [78] Lawn SD, Checkley A, Wansbrough MH. Acute bilateral parotiditis caused by [79] Botteger EC, Teske A, Kirschner P, Bost S, Chang HR, Beer V. Disseminated Mycobacterium genavense infection in patients with AIDS. Lancet 1992;340:76-80. [80] Dever LL, Martin JWm Seaworth B, Jorgense JH. Varied presentation and responses to [81] Jones D, Havlir DV. Nontuberculous mycobacteria in the HIV infected patient. Clin in [82] Olalla J, Pombo M, Aguado JM, Rodríguez E, Palenque E, Costa JR, Riopérez. [83] Casal MM, Casal M. Las micobacterias atípicas como patógenos emergentes. Enf [84] Zumla A, Grange J. Infection and disease caused by environmental mycobacteria. Curr [85] Lanjewar DN, Duggal RP. Pulmonary pathology in patients with AIDS: an autopsy [86] Escombe AR, Moore DA, Gilman RH, Pan W, Navincova M, Ticona E, Martínez C, [87] Nunes EA, De Capitani EM, Coelho E, Panunto AC, Joaquim AO, Ramos Mde C. [88] Buchacz K, Baker RK, Palella FJ, Chmiel JS, Lichtenstein KA, Novak RM, Wood KC, [89] Browth-Elliot BA, Griffith DE, Wallace RJ. Diagnosis of nontuberculous mycobacterial [90] Catanzaro A. Diagnosis, differentiating colonization, infection, and disease. Clin Chest [91] Horsburgh CJJr, Selik RM. Th epidemiology of disseminated nontuberculous [92] Dos Santos RP, Scheid K, Goldani LZ. Disseminated nontuberculous mycobacterial Caviedes L, Sheen P, Gonzalez A, Noakes CJ, Friedland JS, Evans CA. The Infectiousness of Tuberculosis Patients Coinfected with HIV. PLoS Med 2008;5: 188. Mycobacterium tuberculosis and nontuberculous mycobacterial isolates among patients with recent HIV infection in Mozambique. J Bras Pneumol 2008;34:822-828. Brooks JT. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort mycobacterial infectio in the Acquired Immunodeficiency Syndrome (AIDS). Am disease in patients with acquired immune deficiency syndrome in the south of Mycobacterium scrofulaceum: immune reconstruction disease in a patient with AIDS. treatment of infections caused by Mycobacterium haemophilum in patients with Mycobacterium fortuitum complex endocarditis-case report and literature review. Mycobacterium szulgai in human. Rev Infect Dis 1987;9:1120-1126. Expert Rev Anti Infect Ther 2008;6:351-563. Sex Trasm Infect 2005;5:361-73. Chest Med 2002;23: 312-24. Emerg 2000;2:220-230. AIDS. Clin Infect Dis 1992;32:1195-2000. Clin Microbiol & Infect 2002;8:197-201. study from Mumbai. HIV Med 2001; 2:266-271. Opin Pulm Med 2002;8:166-172. study. AIDS 2010; 10:1549-1459. Rev Respir Dis 1989;99:1-132. Brazil. Trop Doct 2010;40:211-213. Med 2002;23:599-601. infections. Clin Lab Med 2002;22:911-915. HIV/AIDS scourge has been and still is a devastating disease since its advent in the late 70's, claiming up to 25 million lives globally (WHO, 2010). The United Nations program on AIDS (UNAIDS) estimated that 39.5 million people were living with HIV/AIDS by the end of 2006, 63% of these were in Sub Saharan Africa. Furthermore, 4.3 million people were reported to be newly infected with HIV while 2.9 million had lost their lives to AIDS in 2006 alone (UNAIDS, 2010). It is also reported that young people of age 15 and above account for 40% of new infections (CWYF, 2007). Epidemiological models predict a growing trend of the disease most notably the alarming incidence of new infections in sub-Saharan Africa, Western Europe and Asia (UNAIDS, 2010). #### 1.2 HIV/AIDS in Uganda: Past and current situation In many regards, Uganda is considered a global role model in awareness, prevention and control of HIV/AIDS (Aidsmap, 2006; Kaiser family foundation, 2005). The first cases of AIDS in Uganda were identified in Rakai district off the shores of Lake Victoria in 1982 (Serwadda et al 1985; MOH, 2006). AIDS was clinically characterized by wasting, this is why it is popularly known as 'slim disease' (Serwadda et al., 1985). Just as before, this disease is still characterized by opportunistic infections, notable are Mycobacterium avium complex infections which are usually the causes of fatality in victims (Serwadda et al., 1985; MOH, 2006). In the late 1980's a famous Ugandan Musician Philly Bongole Lutaaya paved the way Non-Tuberculous Mycobacteria in Uganda: A Problem or Not? 23 Tuberculosis (TB) caused by M. tuberculosis complex group remains a major public health problem in Uganda. It is documented to be endemic in poor peri- urban and urban areas mainly due to; 1) congested living conditions (Banerjee, 1999; Tupasi, 2000; Asimwe et al., 2009), 2) high prevalence of HIV, malnutrition and use of immunesupressive therapy in use today (Cosivi, 1998; Asimwe, 2009). Uganda is ranked 16th among the countries with the highest burden of TB in Sub-Saharan Africa, with an estimated incidence rate of 559 cases per 100,000 per year (WHO, 2007). There are other pathogenic mycobacteria other than M.tuberculosis and M.bovis that have been documented in Uganda, and these include M. ulcerans and M. leprae (Giuseppe et al, 1997). M. ulcerans, the cause of Buruli Ulcer is a skin infection clinically characterized by a nodular skin lesion that busts open into a non healing ulcer (Giuseppe et al, 1997). In the 60's and 70's Buruli ulcer was reported in the Busoga District on the east side of the Victoria Nile, north of Lake Victoria (Barker, 1971). Although cases were known in the other parts of the country, it was unknown in the district before 1965. In this study Barker postulated that the outbreaks were related to the unprecedented flooding of the lakes of Uganda from 1962 to 1964 as a result of heavy rainfall (Barker, 1971). Leprosy in comparison to TB is an old disease documented in the Bible as affecting people even before Christ. It is caused by M. leprae, which damages the skin and the peripheral nervous system resulting in skin lesions and deformities, most often affecting the cooler places on the body for example, eyes, nose, earlobes, hands, feet, and testicles (Giuseppe et al, 1997). In Uganda, it was first documented in the South Eastern part in 1978 by a Christian based hospital (Kawuma, 1999). Currently, the prevalence of leprosy is 2.8 cases per 100,000 population, with a case detection rate of 2.5 per 100,000 (WHO, 2002&2004). In 2004, new cases were reported in Iganga, Hoima, Kabarole, Kyenjonjo, Rukungiri and Lira district. The latter had has as high as 86 new cases reported (Nation TB and Leprosy, 2004). Recent incidence reports on leprosy in Uganda showed a slight increase in the years 2004/05, but case detection rate continues to decline. It is At the beginning of the AIDS pandemic, Non-Tuberculous Mycobacteria (NTM) were reported as emerging pathogens responsible for opportunistic infections, found in almost half of HIV/AIDS infected patients, usually associated with CD4 cell counts B/100/ml and a survival of less than one year (Masur,1993). The species documented to cause opportunistic human infections are : Mycobacterium avium, M. intracellulare, M. kansasii, M. paratuberculosis, M. scrofulaceum, M. simiae, M. habana, M. interjectum, M. xenopi, M. heckeshornense, M. szulgai, M. fortuitum, M. immunogenum, M.chelonae, M. marinum, M. genavense, M. haemophilum, M. celatum, M. conspicuum, M. malmoense, M. ulcerans, M. smegmatis, M. wolinskyi, M. goodii, M. thermoresistible, M. neoaurum, M. vaccae, M.palustre, M. elephantis, M. bohemicam and M. septicum (Katoch, 2004). It has previously been estimated that up to one-quarter of all patients with AIDS will acquire this infection during their lifetime (Horsburgh, 1991). It is difficult to accurately describe the situation in Sub Saharan Africa since most of the data on which these inferences are made comes from northern Europe or North America (Horsburgh, 1989). Notably, these regions have experienced a gradual decline in the prevalence of TB and increase in mycobacterial infection caused by NTM's in the past several years (Claudio et al., 2008). It is still unclear if this trend is real or is the result of technologic developments in diagnostics (Claudio et al., 2008). Worse so, little has been done in developing countries especially in the sub Saharan Africa to capture this 2. Mycobacterial infections in Uganda therefore too early to envisage a Uganda free of leprosy. for the awareness campaign by publically disclosing his sero-positive status at a time when the epidemic prevalence was up to 29% in peri-urban and urban areas of Uganda (Open Vision Club, 2004; Hooper, 1990; Hogle, 2002). This campaign later evolved into the first ever control programme designed to educate the general population on measures of avoidance coined in the abbreviation ABC; 1) Abstinence, 2) being faithful to your partner and 3) the use of condoms (Hooper, 1990; Hogle, 2002). The success of this open campaign was characterized by a drastic fall in the incidence and prevalence of HIV/AIDS among young adults as well as pregnant women (Stoneburner, 2004; STI/AIDS, 2002). This prevalence has been kept at a record low in part due to this awareness, global funds and subsidies on anti-retroviral therapy in addition to a steady development in palliative treatment and counseling offered by nongovernmental organizations like 'The AIDS support organization' (TASO) (Hogle, 2002;UAC,2004;Ashemeire,2010). Unfortunately this effort together with the evolving life style trends today have bred an army of complacent and risk taking youth (Chinaview, 2008), therefore the resilience of this control strategy is yet to be fully tested. Early age at first sex is reported to be among the key risk factors for HIV infection. In this regard, records from the ministries of health and Gender Labour and Social Development estimates age at first sex being 16.7 and 18.8 for girls & boys respectively in 2005 (MGLSD,2004; MOH,2006). Furthermore, by age 17, half of young women are sexually active and 62.7% have already begun child bearing by the age of 19 (MOH, 2006). This explains the current prevalence estimated at 7% (UNAIDS, 2010) with the highest records of 17% and 18% in HIV/AIDS hot-spot districts of Mubende and Nakasongola, respectively (Anonymous, 2004 and Anonymous, 2008). Fig. 1. Median HIV prevalence among pregnant women in Uganda (Hogle, 2002) Likewise the Ministry of Health's indices in Uganda also indicate that to date this disease has affected approximately 7.4 % of the total national population and that 3.2% of the deaths that have occurred since its advent globally have been in Uganda ( MOH,2006; UNAIDS, 2010). The socio-economic effects of AIDS on communities have recently been documented in a study conducted among public service officers with AIDS. It showed a significant increase in direct and indirect costs on HIV/AIDS related illness in addition to claiming the lives of family breadwinners. This has given rise to orphans who are left at the mercy of nongovernmental support groups (MOH report, 2010). #### 2. Mycobacterial infections in Uganda 22 Global View of HIV Infection for the awareness campaign by publically disclosing his sero-positive status at a time when the epidemic prevalence was up to 29% in peri-urban and urban areas of Uganda (Open This campaign later evolved into the first ever control programme designed to educate the general population on measures of avoidance coined in the abbreviation ABC; 1) Abstinence, 2) being faithful to your partner and 3) the use of condoms (Hooper, 1990; Hogle, 2002). The success of this open campaign was characterized by a drastic fall in the incidence and prevalence of HIV/AIDS among young adults as well as pregnant women (Stoneburner, 2004; STI/AIDS, 2002). This prevalence has been kept at a record low in part due to this awareness, global funds and subsidies on anti-retroviral therapy in addition to a steady development in palliative treatment and counseling offered by nongovernmental organizations like 'The AIDS support organization' (TASO) (Hogle, 2002;UAC,2004;Ashemeire,2010). Unfortunately this effort together with the evolving life style trends today have bred an army of complacent and risk taking youth (Chinaview, 2008), therefore the resilience of this control strategy is yet to be fully tested. Early age at first sex is reported to be among the key risk factors for HIV infection. In this regard, records from the ministries of health and Gender Labour and Social Development estimates age at first sex being 16.7 and 18.8 for girls & boys respectively in 2005 (MGLSD,2004; MOH,2006). Furthermore, by age 17, half of young women are sexually active and 62.7% have already begun child bearing by the age of 19 (MOH, 2006). This explains the current prevalence estimated at 7% (UNAIDS, 2010) with the highest records of 17% and 18% in HIV/AIDS hot-spot districts of Mubende and Nakasongola, respectively (Anonymous, 2004 and Anonymous, 2008). Fig. 1. Median HIV prevalence among pregnant women in Uganda (Hogle, 2002) nongovernmental support groups (MOH report, 2010). Likewise the Ministry of Health's indices in Uganda also indicate that to date this disease has affected approximately 7.4 % of the total national population and that 3.2% of the deaths that have occurred since its advent globally have been in Uganda ( MOH,2006; UNAIDS, 2010). The socio-economic effects of AIDS on communities have recently been documented in a study conducted among public service officers with AIDS. It showed a significant increase in direct and indirect costs on HIV/AIDS related illness in addition to claiming the lives of family breadwinners. This has given rise to orphans who are left at the mercy of Vision Club, 2004; Hooper, 1990; Hogle, 2002). Tuberculosis (TB) caused by M. tuberculosis complex group remains a major public health problem in Uganda. It is documented to be endemic in poor peri- urban and urban areas mainly due to; 1) congested living conditions (Banerjee, 1999; Tupasi, 2000; Asimwe et al., 2009), 2) high prevalence of HIV, malnutrition and use of immunesupressive therapy in use today (Cosivi, 1998; Asimwe, 2009). Uganda is ranked 16th among the countries with the highest burden of TB in Sub-Saharan Africa, with an estimated incidence rate of 559 cases per 100,000 per year (WHO, 2007). There are other pathogenic mycobacteria other than M.tuberculosis and M.bovis that have been documented in Uganda, and these include M. ulcerans and M. leprae (Giuseppe et al, 1997). M. ulcerans, the cause of Buruli Ulcer is a skin infection clinically characterized by a nodular skin lesion that busts open into a non healing ulcer (Giuseppe et al, 1997). In the 60's and 70's Buruli ulcer was reported in the Busoga District on the east side of the Victoria Nile, north of Lake Victoria (Barker, 1971). Although cases were known in the other parts of the country, it was unknown in the district before 1965. In this study Barker postulated that the outbreaks were related to the unprecedented flooding of the lakes of Uganda from 1962 to 1964 as a result of heavy rainfall (Barker, 1971). Leprosy in comparison to TB is an old disease documented in the Bible as affecting people even before Christ. It is caused by M. leprae, which damages the skin and the peripheral nervous system resulting in skin lesions and deformities, most often affecting the cooler places on the body for example, eyes, nose, earlobes, hands, feet, and testicles (Giuseppe et al, 1997). In Uganda, it was first documented in the South Eastern part in 1978 by a Christian based hospital (Kawuma, 1999). Currently, the prevalence of leprosy is 2.8 cases per 100,000 population, with a case detection rate of 2.5 per 100,000 (WHO, 2002&2004). In 2004, new cases were reported in Iganga, Hoima, Kabarole, Kyenjonjo, Rukungiri and Lira district. The latter had has as high as 86 new cases reported (Nation TB and Leprosy, 2004). Recent incidence reports on leprosy in Uganda showed a slight increase in the years 2004/05, but case detection rate continues to decline. It is therefore too early to envisage a Uganda free of leprosy. At the beginning of the AIDS pandemic, Non-Tuberculous Mycobacteria (NTM) were reported as emerging pathogens responsible for opportunistic infections, found in almost half of HIV/AIDS infected patients, usually associated with CD4 cell counts B/100/ml and a survival of less than one year (Masur,1993). The species documented to cause opportunistic human infections are : Mycobacterium avium, M. intracellulare, M. kansasii, M. paratuberculosis, M. scrofulaceum, M. simiae, M. habana, M. interjectum, M. xenopi, M. heckeshornense, M. szulgai, M. fortuitum, M. immunogenum, M.chelonae, M. marinum, M. genavense, M. haemophilum, M. celatum, M. conspicuum, M. malmoense, M. ulcerans, M. smegmatis, M. wolinskyi, M. goodii, M. thermoresistible, M. neoaurum, M. vaccae, M.palustre, M. elephantis, M. bohemicam and M. septicum (Katoch, 2004). It has previously been estimated that up to one-quarter of all patients with AIDS will acquire this infection during their lifetime (Horsburgh, 1991). It is difficult to accurately describe the situation in Sub Saharan Africa since most of the data on which these inferences are made comes from northern Europe or North America (Horsburgh, 1989). Notably, these regions have experienced a gradual decline in the prevalence of TB and increase in mycobacterial infection caused by NTM's in the past several years (Claudio et al., 2008). It is still unclear if this trend is real or is the result of technologic developments in diagnostics (Claudio et al., 2008). Worse so, little has been done in developing countries especially in the sub Saharan Africa to capture this Non-Tuberculous Mycobacteria in Uganda: A Problem or Not? 25 source Geographical location Reported by Muwonge et al.,2011 under review, Kankya et al 2011;Oloya et al 2007; Eaton et al 1995; Stanford et al Muwonge et al.,2011 under review, Kankya et al 2011; stanford et al.,2011 under review;Oloya et al Muwonge et al.,2011 under review, Kankya et al 2011;Oloya et al al.,2011 under review, Kankya et al 2011;Oloya et al Kankya et al 2011; Stanford et al 1976 Kankya et al 2011; Muwonge et al.,2011 under review; Ssali, 1998 Muwonge et al.,2011 under review Muwonge et al.,2011 under review al.,2011 under review, Kankya et 1976 al 1976 2007a&b 2007 2007 al 2011 Kampala, Karamoja, Mubende ,Kyoga,Toro and Nakasongola,Kyoga, Toro Mubende, Nakasongola and Mubende, Kampala, Kyoga Karamoja and Mubende Muwonge et Mubende and Nakasongola Muwonge et Nakasongola Mubende, Karamoja and Toro Household water Mubende, Nakasongola and Kampala and Kampala Species Host Environmental Household & valley dam water, swine shelter, cattle kraal Household & stream water Household & valley dam water, swine shelter, cattle kraal valley dam water, swine shelter, cattle kraal stream water M. parafortuitum Swine Household water Mubende and Nakasongola Muwonge et M. chubuense Household water Mubende and Nakasongola Kankya et al 2011; M. vanbaalenii Household water Mubende and Nakasongola Kankya et al 2011; M. engbaekii cattle kraal Mubende and Nakasongola Kankya et al 2011; M. kubicae Household water Mubende and Nakasongola Kankya et al 2011; M. hiberniae cattle kraal Mubende and Nakasongola Kankya et al 2011 M. terrae Swine Household water Mubende and Nakasongola Kankya et al 2011; M. senuense Swine valley dam water Mubende and Nakasongola Kankya et al 2011; Household, swine, cattle human Swine and human human, cattle M. fortuitum Swine Household & human M. avium Human, M. gordonae Swine and M. intracellure Swine, M. avium subsp hominisuis M. nonchromgenicum M. simiae Swine, trend (Narang, 2008). Studies in 1990's in Kenya, Uganda, Tanzania, and the Ivory Coast (Gilks et al., 1995; Okello et al., 1990; Archibald et al., 1998; Lucas et al., 1993) concluded that disseminated NTM infections were relatively uncommon in Africa. On the contrary, recent studies in Zambia and South Africa using better diagnostic tools have actually reported a high prevalence of NTM infections in HIV/AIDS patients. These dismissed the previous notion and warned that the problem was bigger than previously documented (Clive, 2001; Buijtels, 2009). #### 3. Non tuberculous mycobacteria in the environment The distribution of NTM and the incidence of NTM diseases is still an enigma in most parts of the world however; consistent reports show that NTM are widely distributed in nature. Therefore, the environment is regarded to the biggest reservoir and source of NTMs for animal and human hosts (Falkinham, 1996; Falkinham, 2009; Van ingen 2009). This is in resonance with earlier studies done in Ugandan environments, in which Stanford et al., in 1972 reported that areas around Kampala and Kyoga had 67%, 34% and 98%, 56% of NTM isolation from mud and grass respectively. Of the districts from which mud samples were taken, the isolation rate and the greatest variety of mycobacteria species recovered was from east Bunyoro (present day Kibaale District), southern Lango ( present day Oyam, Apac and Dokolo districts) and northern Busoga (present day Kamuli district). Species isolated included M. chelonae, M. fortuitum, M. avium and others which were more prevalent in areas with surface water pH values between 5.5 and 5.7 (Barker et al., 1972). Subsequent studies showed that Mycobacterium avium complex (MAC) was the most prevalent in urban environments, these accounted for 43% of the recovered NTM from water and soil environments in Kampala, Uganda (Eaton et al., 1995).These were mostly recovered from water and soil with pH ranges (6.0, 6.0-6.9, and > 7.0) respectively. Meanwhile, the most recent studies in pastoral environments have shown that MAC accounted for 29% of NTM recovered in Mubende and Nakasongola (Kankya et al 2011). M. gordonae, M. nonchromogenicum M. engbaekii, M. hiberniae, M. kubicae, M. simiae, M. arupense, M. terrae, M. parafortuitum were some of the other NTM isolated from pastoral ecosystems of Uganda (Table 1). Water is considered to be the primary source of NTM infections in humans while domestic and wild animals may be reservoirs (Biet et al., 2005). In the highly mobile pastoral systems of Uganda, humans, livestock domestic and wildlife share open natural water sources. The sharing of these stagnant open water sources provides yet another NTM infection challenge at the human- environmentdomestic/ wildlife interface (HELI) (Kankya et al 2010). Subsequent studies on these natural water sources and follow up of this water that was being used in households revealed a high prevalence of Mycobacterium species including those known to be pathogenic (Kankya et al., 2011). Host-environment interaction is a key element in colonization and maintenance of Mycobacterium in a niche (Falkinham 1996; Biet al , 2005). This is held true by the vast amounts of mycobacteria that were recently isolated from animal environments (Krizova et al., 2010; Ofukwu et al., 2010). Kankya et al 2011a also recovered a wide variety of NTMs from swine and cattle environments, which included M. fortuitum peregrinum complex, M. avium complex, M. parafortuitum, M. hiberniae and M. engbaekii (table 1). trend (Narang, 2008). Studies in 1990's in Kenya, Uganda, Tanzania, and the Ivory Coast (Gilks et al., 1995; Okello et al., 1990; Archibald et al., 1998; Lucas et al., 1993) concluded that disseminated NTM infections were relatively uncommon in Africa. On the contrary, recent studies in Zambia and South Africa using better diagnostic tools have actually reported a high prevalence of NTM infections in HIV/AIDS patients. These dismissed the previous notion and warned that the problem was bigger than previously documented (Clive, 2001; The distribution of NTM and the incidence of NTM diseases is still an enigma in most parts of the world however; consistent reports show that NTM are widely distributed in nature. Therefore, the environment is regarded to the biggest reservoir and source of NTMs for animal and human hosts (Falkinham, 1996; Falkinham, 2009; Van ingen 2009). This is in resonance with earlier studies done in Ugandan environments, in which Stanford et al., in 1972 reported that areas around Kampala and Kyoga had 67%, 34% and 98%, 56% of NTM isolation from mud and grass respectively. Of the districts from which mud samples were taken, the isolation rate and the greatest variety of mycobacteria species recovered was from east Bunyoro (present day Kibaale District), southern Lango ( present day Oyam, Apac and Dokolo districts) and northern Busoga (present day Kamuli district). Species isolated included M. chelonae, M. fortuitum, M. avium and others which were more prevalent in areas with surface water pH values between 5.5 and 5.7 (Barker et al., 1972). Subsequent studies showed that Mycobacterium avium complex (MAC) was the most prevalent in urban environments, these accounted for 43% of the recovered NTM from water and soil environments in Kampala, Uganda (Eaton et al., 1995).These were mostly recovered from water and soil with pH ranges (6.0, 6.0-6.9, and > 7.0) respectively. Meanwhile, the most recent studies in pastoral environments have shown that MAC accounted for 29% of NTM recovered in Mubende and Nakasongola (Kankya et al 2011). M. gordonae, M. nonchromogenicum M. engbaekii, M. hiberniae, M. kubicae, M. simiae, M. arupense, M. terrae, M. parafortuitum were some of the other NTM isolated from pastoral ecosystems of Uganda (Table 1). Water is considered to be the primary source of NTM infections in humans while domestic and wild animals may be reservoirs (Biet et al., 2005). In the highly mobile pastoral systems of Uganda, humans, livestock domestic and wildlife share open natural water sources. The sharing of these stagnant open water sources provides yet another NTM infection challenge at the human- environmentdomestic/ wildlife interface (HELI) (Kankya et al 2010). Subsequent studies on these natural water sources and follow up of this water that was being used in households revealed a high prevalence of Mycobacterium species including those known to be pathogenic (Kankya et al., 2011). Host-environment interaction is a key element in colonization and maintenance of Mycobacterium in a niche (Falkinham 1996; Biet al , 2005). This is held true by the vast amounts of mycobacteria that were recently isolated from animal environments (Krizova et al., 2010; Ofukwu et al., 2010). Kankya et al 2011a also recovered a wide variety of NTMs from swine and cattle environments, which included M. fortuitum peregrinum complex, M. avium complex, M. parafortuitum, M. hiberniae and M. 3. Non tuberculous mycobacteria in the environment Buijtels, 2009). engbaekii (table 1). Non-Tuberculous Mycobacteria in Uganda: A Problem or Not? 27 The subject of NTM in humans and animals in the sub-Saharan Africa has received increasing attention in the recent past. Major concerns in the NTM transmission especially in immuno-compromised individuals has been associated with high levels of interactions Avian tuberculosis is caused by M. avium, it is mostly known to occur in temperate zones and has been widely documented in North and South America and Australia (Barnes et al., 2003). In the United states Avian tuberculosis has been reported to be responsible the condemnation of 1870 per 100,000 birds slaughtered however the figures here were anticipated to be higher than this given that only visual inspection was used (Barnes et al., 2003). The incidence is reported to be low in South Africa while in Kenya it has only been documented in lesser flamingoes (Barnes et al., 2003). Uganda has 37 million chickens and about half a million turkey's. Unfortunately there has not been any studies done to document the prevalence of fowl tuberculosis despite the constant reports of clinical signs typical of this disease in poultry in the east and central region Bovine tuberculosis just like its human cousin M. tuberculosis has been given top priority in Uganda, simply because it is a well-documented zoonosis. Worldwide, the proportion of human cases caused by Mycobacterium bovis is estimated to be 3.1% of all forms of TB (Cosivi, 1998). In the most recent studies on the prevalence of bovine TB in pastoral areas of Uganda, tuberculin reactors were reported to be 6% of cattle in Mbarara district, an important dairy cattle area in the south west (Bernard et al., 2005), and a prevalence of 2·8% in nomadic cattle of Karamoja in the north east of the country (Oloya et al., 2006). Cattle herds in Uganda are concentrated along the cattle corridor that stretches from the south west to the north east through the central parts of the country. In another study done by Oloya (2007) in the same area gave the initial indication that Non tuberculous mycobacteria could be a public health force to reckon. This study found that NTMs were an integral part of bacteria isolated from disseminated tuberculous lesions and surprisingly these were almost equal in proportions (48.6:51.4) to M.bovis (Oloya et al 2007). Similarly a study done by Asimwe et al., 2009 on slaughtered cattle in Kampala revealed a similar pattern of isolation with M.bovis and NTMs accounting for 64.7% and 35.3% of the mycobacterium These finding further reaffirm the key role played by NTM in the tuberculosis pathogenesis. In two separate studies by Oloya et al., 2006 and Inangolet et al., 2007, shared water sources were identified as the responsible factor for a high prevalence of high avian reactors to the The highest response to avian purified protein derivative (PPD) was observed in cattle 7-9 years old (figure 1) which was attributed to non specific immune response to environmental mycobacteria of the Mycobacterium avium complex prevalent in the natural water sources animals drink from. Therefore it is no longer disputable that NTMs are prevalent in cattle in Uganda but rather the effort should be on the role if any played by cattle in disseminating 4. Non tuberculous mycobacteria in animals 4.1 Poultry 4.2 Cattle occurring at the human-environment-livestock-wildlife interface. of Uganda (rural poultry farmers' personal communication). isolated from various tuberculous lymph node lesions respectively. purified protein derivative ( PPD) skin test. them to human populations. Table 1. Non-tuberculous mycobacteria isolated from Human, Animals and environments in Uganda #### 4. Non tuberculous mycobacteria in animals The subject of NTM in humans and animals in the sub-Saharan Africa has received increasing attention in the recent past. Major concerns in the NTM transmission especially in immuno-compromised individuals has been associated with high levels of interactions occurring at the human-environment-livestock-wildlife interface. #### 4.1 Poultry 26 Global View of HIV Infection M. arupense Household water Mubende and Nakasongola Kankya et al 2011 M. asiaticum Swine Mubende Muwonge et M. parascrofulaceum Swine Mubende Muwonge et M. bejali Swine Mubende and Nakasongola Muwonge et M. smegmitis Swine Mubende Muwonge et M. salmonphilum Swine Mubende Muwonge et M. rhodesia Swine Mubende Muwonge et M. septicum Swine Mubende Muwonge et M. chelonae Swine Mubende Kampala,Kyoga Muwonge et M. marinum swine Mubende Muwonge et M. komamatonse Swine Mubende Muwonge et Valley dam water Mubende, Karamoja and Kampala Table 1. Non-tuberculous mycobacteria isolated from Human, Animals and environments in Mubende,Kampala,Kyoga and Toro and Kyoga Mubende, Toro, Kampala source Geographical location Reported by al.,2011 under review al.,2011 under review al.,2011 under review Muwonge et al.,2011 under review; Stanford, Muwonge et al.,2011 under review; Stanford, al.,2011 under review al.,2011 under review al.,2011 under review al.,2011 under review al.,2011 under review;Stanford, al.,2011 under review al.,2011 under review Muwonge et al.,2011 under review; Oloya et al.,2007; Assimwe et al 2009 1976 1976 1976 Species Host Environmental Human Human M. neoaurum Swine, M.duvalii Swine, Unidentified NTM Cattle, Uganda human, swine Avian tuberculosis is caused by M. avium, it is mostly known to occur in temperate zones and has been widely documented in North and South America and Australia (Barnes et al., 2003). In the United states Avian tuberculosis has been reported to be responsible the condemnation of 1870 per 100,000 birds slaughtered however the figures here were anticipated to be higher than this given that only visual inspection was used (Barnes et al., 2003). The incidence is reported to be low in South Africa while in Kenya it has only been documented in lesser flamingoes (Barnes et al., 2003). Uganda has 37 million chickens and about half a million turkey's. Unfortunately there has not been any studies done to document the prevalence of fowl tuberculosis despite the constant reports of clinical signs typical of this disease in poultry in the east and central region of Uganda (rural poultry farmers' personal communication). #### 4.2 Cattle Bovine tuberculosis just like its human cousin M. tuberculosis has been given top priority in Uganda, simply because it is a well-documented zoonosis. Worldwide, the proportion of human cases caused by Mycobacterium bovis is estimated to be 3.1% of all forms of TB (Cosivi, 1998). In the most recent studies on the prevalence of bovine TB in pastoral areas of Uganda, tuberculin reactors were reported to be 6% of cattle in Mbarara district, an important dairy cattle area in the south west (Bernard et al., 2005), and a prevalence of 2·8% in nomadic cattle of Karamoja in the north east of the country (Oloya et al., 2006). Cattle herds in Uganda are concentrated along the cattle corridor that stretches from the south west to the north east through the central parts of the country. In another study done by Oloya (2007) in the same area gave the initial indication that Non tuberculous mycobacteria could be a public health force to reckon. This study found that NTMs were an integral part of bacteria isolated from disseminated tuberculous lesions and surprisingly these were almost equal in proportions (48.6:51.4) to M.bovis (Oloya et al 2007). Similarly a study done by Asimwe et al., 2009 on slaughtered cattle in Kampala revealed a similar pattern of isolation with M.bovis and NTMs accounting for 64.7% and 35.3% of the mycobacterium isolated from various tuberculous lymph node lesions respectively. These finding further reaffirm the key role played by NTM in the tuberculosis pathogenesis. In two separate studies by Oloya et al., 2006 and Inangolet et al., 2007, shared water sources were identified as the responsible factor for a high prevalence of high avian reactors to the purified protein derivative ( PPD) skin test. The highest response to avian purified protein derivative (PPD) was observed in cattle 7-9 years old (figure 1) which was attributed to non specific immune response to environmental mycobacteria of the Mycobacterium avium complex prevalent in the natural water sources animals drink from. Therefore it is no longer disputable that NTMs are prevalent in cattle in Uganda but rather the effort should be on the role if any played by cattle in disseminating them to human populations. Non-Tuberculous Mycobacteria in Uganda: A Problem or Not? 29 Swine tuberculosis is a chronic infectious disease characterized by inflammatory reactions in various body parts but mostly in the digestive system. Calcification prone tubercles, inflamed lymph nodes and sarcoid-like granulomas are the most common features of this disease (Cvetnic, 2007; Coetzer, 2004; Ofukwu, 2010). The disease in swine is caused by M. bohemicum, M. intracellulare, M. avium, M. hemophilum, M. malmose, M. szulgai, M. kansasii, M. scrofuleceum, M. tuberculosis, M.simiae, M. palustre, M. gordonae, M. terrae, M. xenopi and M. heckershornense and other potentially pathogenic mycobacteria (PPM) (Jakko van Ingen, The only study in Uganda done on swine mycobacterial infection showed 9.3% and 3.1% prevalence based on necropsy examination and culture isolation, respectively (Muwonge et al 2010). A seasonal variation in prevalence of lesions typical of mycobacterial infections was also found in which lesions tended to increase after the rain season (figure 3).In a follow up molecular study on slaughter pigs in Mubende (Muwonge et al., 2011), Mycobacterium avium was the most prevalent mycobacterium specie accounting for 18% of the isolates from lymph nodes. Other species isolated included; M. senuense, M. terrae, M. asiaticum, M. parascrofulaceum, M. bejali and M. neoaurum, M. simie, M. duvalii, M. smegmitis and M. parafortuitum,M.salmonphilum, M. rhodesia, M. septicum, M. chelonae, M. marinum,M. parafinicum, M. komamatonse and M. gordona (Table 1).In general these findings are reflective of the NTMs load (infection/colonization) in swine reared in semi and free range systems, since the majority of the pigs in Uganda are reared in this Fig. 3. Temperal occurrence of pathological lesions in slaughtered pigs in Mubende district 4.3 Swine system (Muwonge et al., 2010) 2010, Cvetnic, 2007). Fig. 2. Variation of skin reactions to comparative intradermal tuberculin test with age adapted from Oloya et al.,2006 #### 4.3 Swine 28 Global View of HIV Infection Fig. 2. Variation of skin reactions to comparative intradermal tuberculin test with age adapted from Oloya et al.,2006 Swine tuberculosis is a chronic infectious disease characterized by inflammatory reactions in various body parts but mostly in the digestive system. Calcification prone tubercles, inflamed lymph nodes and sarcoid-like granulomas are the most common features of this disease (Cvetnic, 2007; Coetzer, 2004; Ofukwu, 2010). The disease in swine is caused by M. bohemicum, M. intracellulare, M. avium, M. hemophilum, M. malmose, M. szulgai, M. kansasii, M. scrofuleceum, M. tuberculosis, M.simiae, M. palustre, M. gordonae, M. terrae, M. xenopi and M. heckershornense and other potentially pathogenic mycobacteria (PPM) (Jakko van Ingen, 2010, Cvetnic, 2007). The only study in Uganda done on swine mycobacterial infection showed 9.3% and 3.1% prevalence based on necropsy examination and culture isolation, respectively (Muwonge et al 2010). A seasonal variation in prevalence of lesions typical of mycobacterial infections was also found in which lesions tended to increase after the rain season (figure 3).In a follow up molecular study on slaughter pigs in Mubende (Muwonge et al., 2011), Mycobacterium avium was the most prevalent mycobacterium specie accounting for 18% of the isolates from lymph nodes. Other species isolated included; M. senuense, M. terrae, M. asiaticum, M. parascrofulaceum, M. bejali and M. neoaurum, M. simie, M. duvalii, M. smegmitis and M. parafortuitum,M.salmonphilum, M. rhodesia, M. septicum, M. chelonae, M. marinum,M. parafinicum, M. komamatonse and M. gordona (Table 1).In general these findings are reflective of the NTMs load (infection/colonization) in swine reared in semi and free range systems, since the majority of the pigs in Uganda are reared in this system Fig. 3. Temperal occurrence of pathological lesions in slaughtered pigs in Mubende district (Muwonge et al., 2010) Non-Tuberculous Mycobacteria in Uganda: A Problem or Not? 31 better treatment. Given the ubiquitous presence of NTMs in the environment and animal hosts, establishing the true causal relationship is highly dependent on representative sampling and stringent laboratory practices as contamination can easily occur. Another important problem is the overlapping of clinical manifestation of the disease caused by M.tuberculosis which makes the specific diagnosis of NTM disease practically impossible in poor health care settings. In Uganda, definitive NTM diagnosis in clinical setting is rarely done therefore, at the time of treatment commencement the only diagnosis available is presence/absence of acid fast rod like bacteria. This diagnosis is arrived at with the use of Ziehl-Neelsen (ZN) staining (Nation leprosy and tuberculosis programme). Literature on ZN staining indicates that the specificity is compromised by bacteria like Rodococcus that have the same acid fast characteristics thus giving some false positives (Coetzer, 2004). Definitive diagnosis on the other hand requires that a physician knows exactly which type of Mycobacterium is causing the clinical signs. This can be achieved using fast clinical diagnostic methods like; gene probes, Ino-lipa and Mycobacterium growth indicator (MGIT). Fig. 4 & 5. Show the insertion sequences 1311 and 1245 of M. avium sub sp hominissuis isolated from humans with cervical lymphadenitis and cattle with disseminated tuberculosis respectively adapted from Oloya et al.,2007 a&b. #### 5. Non-tuberculous mycobacteria in human The absence of documented human to human transmission in the last 30 years has led to the conclusion that the environment is the source of NTM for human (Falkinham, 2009). In comparison to developed countries, NTM infections in humans are not well documented in Uganda. The few earlier studies did not show that disseminated Mycobacterium avium complex (MAC) infections was a problem in terminally sick AIDS patients unlike in the western world (Okello, 1990; Valadas, 2004; Chih-Cheng Lai, 2006). Subsequent studies further seem to support the absence of M. avium in HIV-infected Ugandans (Eaton et al., 1995). On the other hand Ugandan immigrants with AIDS in London had previously been diagnosed with symptomatic mycobacterium avium complex (MAC) infections (Nigel, 1993). These patients at the time of diagnosis had a CD4 count of 10X106/L and some had been receiving treatment for extra pulmonary tuberculosis (Nigel, 1993). This disparity in prevalence at the time was explained by the speculation that temperate areas were preferential niches for NTMs and the superiority in diagnostics. It is now known that it was the latter, Nambuya et al., (1988) documented the prevalence of tuberculous lymphadenitis (which today is known to be caused by MTCs and NTM) but surprisingly they were unable to culture specimen to prove the cause. In 1998 Ssali et al reported for the first time presence of disseminated MAC and Mycobacterium simiae infections in HIV/AIDS patients in Mulago hospital in Uganda. This study showed that mycobacteriamia among febrile HIV-infected Ugandan adults accounted for 13% (Ssali et al., 1998). M. avium is also known to be one of the leading causes of infant lymphadenitis worldwide (Coetzer, 2004; Johansen, 2007; Van Ingen et al., 2009). This is in agreement with a study done in Uganda on the cause of cervical lymphadenitis. In that study the prevalence was highest among infants below 7 years of age and M. avium was the most frequently isolated NTM in this group (Oloya et al 2007). It is a common observation that NTM cause disease in individuals whose immunity has been compromised (Wolinsky, 1979; Wallace et al.,1990; von Reyn et al 1994; Falkinham et al 2009). Pneumoconiosis, cystic fibrosis, bronchiestasis , smoking and chronic alcoholism are some of the predisposing factors to NTM infections. The current technological advancements in diagnostics seem to indicate a possible further identification of more NTM zoonoses. In Netherland, Komjin et al., (1999) showed a close genetic relatedness between M. avium subsp. hominissuis isolated from swine and humans. Since then many scholars have continued to document more evidence re affirming the role pigs play in the transmission of mycobacterial infections to immunecompromised and immunecompetent indivuals. In 2007, Oloya et al isolated M. avium subsp.hominissuis from tuberculous lesions in cattle and T.B patients with cervical lymphadenitis in pastoral areas of Karamoja in Uganda. The molecular findings showed a very high genetic relatedness between animal and human isolates (figure 4 and 5). Although the true source of human infection is still a matter of dispute, these findings tend to point us to zoonotic scenario, with shared environment, in this case water, playing an important role. The true picture of human non tuberculous infections in Uganda is yet to be unveiled, but studies done elsewhere in Africa have indicated that this problem is bigger than previously documented (Buitjel, 2009). #### 5.1 Diagnostics and therapeutics The greatest mistake in disease treatment arises when a physician is not well armed with facts about the cause of visible clinical signs, in other words a good diagnosis precedes a The absence of documented human to human transmission in the last 30 years has led to the conclusion that the environment is the source of NTM for human (Falkinham, 2009). In comparison to developed countries, NTM infections in humans are not well documented in Uganda. The few earlier studies did not show that disseminated Mycobacterium avium complex (MAC) infections was a problem in terminally sick AIDS patients unlike in the western world (Okello, 1990; Valadas, 2004; Chih-Cheng Lai, 2006). Subsequent studies further seem to support the absence of M. avium in HIV-infected Ugandans (Eaton et al., 1995). On the other hand Ugandan immigrants with AIDS in London had previously been diagnosed with symptomatic mycobacterium avium complex (MAC) infections (Nigel, 1993). These patients at the time of diagnosis had a CD4 count of 10X106/L and some had been receiving treatment for extra pulmonary tuberculosis (Nigel, 1993). This disparity in prevalence at the time was explained by the speculation that temperate areas were preferential niches for NTMs and the superiority in diagnostics. It is now known that it was the latter, Nambuya et al., (1988) documented the prevalence of tuberculous lymphadenitis (which today is known to be caused by MTCs and NTM) but surprisingly they were unable to culture specimen to prove the cause. In 1998 Ssali et al reported for the first time presence of disseminated MAC and Mycobacterium simiae infections in HIV/AIDS patients in Mulago hospital in Uganda. This study showed that mycobacteriamia among febrile HIV-infected Ugandan adults accounted for 13% (Ssali et al., 1998). M. avium is also known to be one of the leading causes of infant lymphadenitis worldwide (Coetzer, 2004; Johansen, 2007; Van Ingen et al., 2009). This is in agreement with a study done in Uganda on the cause of cervical lymphadenitis. In that study the prevalence was highest among infants below 7 years of age and M. avium was the most frequently isolated NTM in this group (Oloya et al 2007). It is a common observation that NTM cause disease in individuals whose immunity has been compromised (Wolinsky, 1979; Wallace et al.,1990; von Reyn et al 1994; Falkinham et al 2009). Pneumoconiosis, cystic fibrosis, bronchiestasis , smoking and chronic alcoholism are some of the predisposing factors to NTM infections. The current technological advancements in diagnostics seem to indicate a possible further identification of more NTM zoonoses. In Netherland, Komjin et al., (1999) showed a close genetic relatedness between M. avium subsp. hominissuis isolated from swine and humans. Since then many scholars have continued to document more evidence re affirming the role pigs play in the transmission of mycobacterial infections to immunecompromised and immunecompetent indivuals. In 2007, Oloya et al isolated M. avium subsp.hominissuis from tuberculous lesions in cattle and T.B patients with cervical lymphadenitis in pastoral areas of Karamoja in Uganda. The molecular findings showed a very high genetic relatedness between animal and human isolates (figure 4 and 5). Although the true source of human infection is still a matter of dispute, these findings tend to point us to zoonotic scenario, with shared environment, in this case water, playing an important role. The true picture of human non tuberculous infections in Uganda is yet to be unveiled, but studies done elsewhere in Africa have indicated that this problem is bigger than previously documented (Buitjel, 2009). The greatest mistake in disease treatment arises when a physician is not well armed with facts about the cause of visible clinical signs, in other words a good diagnosis precedes a 5.1 Diagnostics and therapeutics 5. Non-tuberculous mycobacteria in human better treatment. Given the ubiquitous presence of NTMs in the environment and animal hosts, establishing the true causal relationship is highly dependent on representative sampling and stringent laboratory practices as contamination can easily occur. Another important problem is the overlapping of clinical manifestation of the disease caused by M.tuberculosis which makes the specific diagnosis of NTM disease practically impossible in poor health care settings. In Uganda, definitive NTM diagnosis in clinical setting is rarely done therefore, at the time of treatment commencement the only diagnosis available is presence/absence of acid fast rod like bacteria. This diagnosis is arrived at with the use of Ziehl-Neelsen (ZN) staining (Nation leprosy and tuberculosis programme). Literature on ZN staining indicates that the specificity is compromised by bacteria like Rodococcus that have the same acid fast characteristics thus giving some false positives (Coetzer, 2004). Definitive diagnosis on the other hand requires that a physician knows exactly which type of Mycobacterium is causing the clinical signs. This can be achieved using fast clinical diagnostic methods like; gene probes, Ino-lipa and Mycobacterium growth indicator (MGIT). Fig. 4 & 5. Show the insertion sequences 1311 and 1245 of M. avium sub sp hominissuis isolated from humans with cervical lymphadenitis and cattle with disseminated tuberculosis respectively adapted from Oloya et al.,2007 a&b. Non-Tuberculous Mycobacteria in Uganda: A Problem or Not? 33 et al 2011 in press). Similarly in neighbouring sub county of Madudu residents said "our grandparents and great grandparents used to drink un boiled water and milk and their cause of death was not as a result of drinking un boiled water and milk. We grew up drinking all these consumables raw, and that we have made it a cultural norm not to boil milk and water before consumption" . Rural Africa is always punctuated with witchcraft, some communities have the belief that NTM infections can be caused by witchcraft (voodoo) and thus can be treated (Kankya et al 2011). Therefore families that have witches are believed to have the power to cause such diseases, and that this power can be inherited. Stigmatisation is probably one of the most important reason why these infections are under reported, rural communities are reported to say "Some of us are sick and infected with mycobacterial infections such as tuberculosis, but we fear to disclose since these infections are associated with HIV/AIDS…'' (Kankya et al 2011). The affected individual would quickly be associated with HIV/AIDS. For the same reason, therefore affected individuals tend to shy away from seeking health services from the qualified health professionals. This aspect greatly impacts the health seeking behaviour (HSB) among the pastoral communities (Ashemeire, The relative importance of mycobacterial diseases has been undergoing an evolution during the past few years, and further changes and modifications are expected to occur in the near future. The other concern especially in Africa has been the fact that non tuberculous mycobacteria diminishes the efficacy of the BCG (Brandt, 2002), the only available vaccine against tuberculosis. In a study done in Denmark it was shown in a mouse model that prior exposure to the Kalonga-Malawi environmental mycobacteria isolates resulted in reduction of efficacy or complete blockage of BCG activity (Brandt, 2002). This has however not yet been given its due attention in Uganda and therefore is anticipated to be a future challenge Non tuberculous mycobacterial infections have not been fully documented in Uganda because; 1) they are given less priority compared to TB regardless of the documented synergistic role they play in tuberculosis lesion development. 2) The dismissive attitude of communities, medical and veterinary fields as to their importance helps maintain their low priority status. With the wind of technological advancement in diagnostics and treatment blowing towards Africa, the increasing number of immune compromised individuals due to AIDS, it is anticipated that more infections due to NTM are likely to be discovered. Therefore the threat of NTM infections in Uganda is as real as the pandemic that precedes 1. NTMs are a force to reckon in the world today and therefore should be given priority 2. The Ministry of Health and the available health marketing groups should put more emphasis on the campaigns geared towards a stigma free environment with regards to HIV/AIDS so as to improve the health reporting behavior among Ugandans by government, public, medical and veterinary fields. 2010). 6. Conclusion 7. Recommendations them. 5.3 Challenges and futures trends in the control of Tuberculosis especially in infants. Most of these methods are available in Uganda however; they are mainly used for research and not routine clinical diagnostics. This is largely due to the fact that majority of people in Uganda cannot afford these extra costs to arrive at a definitive diagnosis. Fortunately, quickcheaper, specific and sensitive diagnostic tools have been developed for example the ESAT-6 polymerase chain reaction primers which has been tailor-made to definitively diagnose M. avium, Serotyping methods using serotype specific sera for Mycobacterium interacellulare scrofulaceum (MAIS complex) and M. avium usually associated with AIDS patients can also be used in small and medium scale laboratories for definitive diagnosis (Kiehn et al., 1985; Singh et al., 2007; Wisselink et al 2010). NTM are generally resistant to the standard therapy Isoniazid, Rifampicin and Clarithromycin (Bum-Joon et al 2004). The reported resistance of M. tuberculosis (Asimwe et al., 2010) can be a contributing factor for the resistance in NTM due to constant exposure to these antibiotics as a result of lack of definitive diagnosis. There is optimism because of the consistent reported developments in medication which may improve on the treatment of NTMs for example dalfopristin, quinupristin and methoxy moieties of floroquinolones that are reported to have better effects (Lu et al., 2001; Braback, 2002; Singhai et al., 2010; Griffith et al., 2010). Their affectivity is however yet to be tested by the self prescriptive behavior common among Ugandans #### 5.2 Attitudes surrounding NTM Uganda is blessed with a wide range of ethnic groups some with unique attitudes and perceptions with regard to prevention and control of infections (Nyanzi et al., 2005). Beliefs, myths, values, norms, taboos language, ritual and art are some of the cultural aspects that influence health of a given society. These cultural aspects describe the interaction between people, land and activities; they are also reported to influence the spread, control and prevention of diseases (Ntseane, 2004; Kyagaba, 2004). Tuberculosis, leprosy and Buruli ulcer are well documented simply because of the priority given to them by the Uganda health sector; this has negatively influenced the attitudes and perception of people towards the rest of NTMs that are regarded to be of less public health importance. #### 5.2.1 Socio-cultural attitudes in pastoral areas In Uganda, studies done in rural areas have shown that there are many beliefs, attitudes and practices associated with NTM and other mycobacterial infections even when it is largely known that farming communities lack awareness with regards to mycobacterial infection, their epidemiology, and prevention and control strategies. Apart from mycobacterial infections due to zoonotic tuberculosis and classic tuberculosis; infections due to NTM have rarely been reported. Farming communities in Nakasongola and Mubende districts of Uganda lay their emphasis on the sharing of drinking water from open water sources with both domestic and wild animals as one of the major transmission route of NTM infection to humans and animals at the human-environment- livestock /wildlife interface (Kankya et al., 2010). Furthermore, attitude based studies have shown complacency in pastoral communities which is reflected in reports from service providers highlighted by statements like ''we teach community members that drinking un-boiled water is dangerous but they are stubborn as they continue to drink un-boiled water….many times they tell us that they have not died yet they have been drinking un-boiled water for decades" commented; clinical officer Kiyuni Government Health Centre III, Mubende district Uganda (Kankya et al 2011 in press). Similarly in neighbouring sub county of Madudu residents said "our grandparents and great grandparents used to drink un boiled water and milk and their cause of death was not as a result of drinking un boiled water and milk. We grew up drinking all these consumables raw, and that we have made it a cultural norm not to boil milk and water before consumption" . Rural Africa is always punctuated with witchcraft, some communities have the belief that NTM infections can be caused by witchcraft (voodoo) and thus can be treated (Kankya et al 2011). Therefore families that have witches are believed to have the power to cause such diseases, and that this power can be inherited. Stigmatisation is probably one of the most important reason why these infections are under reported, rural communities are reported to say "Some of us are sick and infected with mycobacterial infections such as tuberculosis, but we fear to disclose since these infections are associated with HIV/AIDS…'' (Kankya et al 2011). The affected individual would quickly be associated with HIV/AIDS. For the same reason, therefore affected individuals tend to shy away from seeking health services from the qualified health professionals. This aspect greatly impacts the health seeking behaviour (HSB) among the pastoral communities (Ashemeire, 2010). #### 5.3 Challenges and futures trends The relative importance of mycobacterial diseases has been undergoing an evolution during the past few years, and further changes and modifications are expected to occur in the near future. The other concern especially in Africa has been the fact that non tuberculous mycobacteria diminishes the efficacy of the BCG (Brandt, 2002), the only available vaccine against tuberculosis. In a study done in Denmark it was shown in a mouse model that prior exposure to the Kalonga-Malawi environmental mycobacteria isolates resulted in reduction of efficacy or complete blockage of BCG activity (Brandt, 2002). This has however not yet been given its due attention in Uganda and therefore is anticipated to be a future challenge in the control of Tuberculosis especially in infants. #### 6. Conclusion 32 Global View of HIV Infection Most of these methods are available in Uganda however; they are mainly used for research and not routine clinical diagnostics. This is largely due to the fact that majority of people in Uganda cannot afford these extra costs to arrive at a definitive diagnosis. Fortunately, quickcheaper, specific and sensitive diagnostic tools have been developed for example the ESAT-6 polymerase chain reaction primers which has been tailor-made to definitively diagnose M. avium, Serotyping methods using serotype specific sera for Mycobacterium interacellulare scrofulaceum (MAIS complex) and M. avium usually associated with AIDS patients can also be used in small and medium scale laboratories for definitive diagnosis (Kiehn et al., 1985; Singh et al., 2007; Wisselink et al 2010). NTM are generally resistant to the standard therapy Isoniazid, Rifampicin and Clarithromycin (Bum-Joon et al 2004). The reported resistance of M. tuberculosis (Asimwe et al., 2010) can be a contributing factor for the resistance in NTM due to constant exposure to these antibiotics as a result of lack of definitive diagnosis. There is optimism because of the consistent reported developments in medication which may improve on the treatment of NTMs for example dalfopristin, quinupristin and methoxy moieties of floroquinolones that are reported to have better effects (Lu et al., 2001; Braback, 2002; Singhai et al., 2010; Griffith et al., 2010). Their affectivity is however yet to be tested by Uganda is blessed with a wide range of ethnic groups some with unique attitudes and perceptions with regard to prevention and control of infections (Nyanzi et al., 2005). Beliefs, myths, values, norms, taboos language, ritual and art are some of the cultural aspects that influence health of a given society. These cultural aspects describe the interaction between people, land and activities; they are also reported to influence the spread, control and prevention of diseases (Ntseane, 2004; Kyagaba, 2004). Tuberculosis, leprosy and Buruli ulcer are well documented simply because of the priority given to them by the Uganda health sector; this has negatively influenced the attitudes and perception of people towards the rest of NTMs that are regarded to be of less public In Uganda, studies done in rural areas have shown that there are many beliefs, attitudes and practices associated with NTM and other mycobacterial infections even when it is largely known that farming communities lack awareness with regards to mycobacterial infection, their epidemiology, and prevention and control strategies. Apart from mycobacterial infections due to zoonotic tuberculosis and classic tuberculosis; infections due to NTM have rarely been reported. Farming communities in Nakasongola and Mubende districts of Uganda lay their emphasis on the sharing of drinking water from open water sources with both domestic and wild animals as one of the major transmission route of NTM infection to humans and animals at the human-environment- livestock /wildlife interface (Kankya et al., 2010). Furthermore, attitude based studies have shown complacency in pastoral communities which is reflected in reports from service providers highlighted by statements like ''we teach community members that drinking un-boiled water is dangerous but they are stubborn as they continue to drink un-boiled water….many times they tell us that they have not died yet they have been drinking un-boiled water for decades" commented; clinical officer Kiyuni Government Health Centre III, Mubende district Uganda (Kankya the self prescriptive behavior common among Ugandans 5.2.1 Socio-cultural attitudes in pastoral areas 5.2 Attitudes surrounding NTM health importance. Non tuberculous mycobacterial infections have not been fully documented in Uganda because; 1) they are given less priority compared to TB regardless of the documented synergistic role they play in tuberculosis lesion development. 2) The dismissive attitude of communities, medical and veterinary fields as to their importance helps maintain their low priority status. With the wind of technological advancement in diagnostics and treatment blowing towards Africa, the increasing number of immune compromised individuals due to AIDS, it is anticipated that more infections due to NTM are likely to be discovered. Therefore the threat of NTM infections in Uganda is as real as the pandemic that precedes them. #### 7. Recommendations Non-Tuberculous Mycobacteria in Uganda: A Problem or Not? 35 Biet F, Boschiroli ML, Thorel MF, Guilloteau LA.(2005). Zoonotic aspects of Mycobacterium Braback M, Riesbeck K, Forsgren A.(2002).Susceptibilities of Mycobacterium marinum to Brandt L, Cunha JF, Weinreich A, Chilima B, Hirsch P, Appelberg R , Andersen P.( 2002). Buijtels CAMP, Marrianne AB, Graaf SDC, Parkinson S, Verbrugh AH, Petit LCP, Sooligen Bum-Joon K, Keun-Hwa L, Yeo-Jun Y, Eun-Mi P,Young-Gil P, Gil-Han B, Chang-Yong C, Byarugaba F, Marcel CEE, Godreuil S, Grimaud P(2009).Pulmonary Tuberculosis and Chinaview. (2008). 'Complacency, extramarital affairs pushing up Ugandan HIV infection Claudio P, Scarparo C.(2008). Review: Pulmonary infections associated with non- Clive AP, Alan SK, Mark H.(2001). Prevalence and Clinical Manifestations of Disseminated Commonwealth youth forum (cwyf).(2007). Health,HIV/AIDS and development: A case for Coetzer JAW, Tustin RC. (2004). Infectious Diseases of livestock, (3rd edition) Oxford University http://www.aidsuganda.org/HIV%20PDf/comnwealth.pdf tuberculosis, Journal of Infection and Immunity, vol. 70, pp (672–678) %20in%20african%20poultry&f=false> Research, vol.36, pp(411-436) Diseases, vol.15, pp (242–248) 06/02/content\_8302718.htm Press, New York, pp (1973-1987) vol.8, pp (323–334) (2068–2071) 2011, retrieved from: www.cdc.gov/eid pp (1114-1116) 118) uYkuL2z5jiW6kENfI8aqs&hl=en&ei=e4lrTZ3BGI2WswaR0tTdDA&sa=X&oi=book \_result&ct=result&resnum=1&ved=0CB4Q6AEwAA#v=onepage&q=m%20avium bovis and Mycobacterium avium-intracellulare complex (MAC), Journal of Veterinary gatifloxacin, gemifloxacin, levofloxacin, linezolid, moxifloxacin, telithromycin and quinupristin - dalfopristin (synercid) compared to its susceptibilities to reference macrolides and quinolones, Journal of Antimicrobial Agents and Chemotherapy, vol.46, Failure of the Mycobacterium bovis BCG vaccine: Some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to VD. (2009). Nontuberculous mycobacteria, Zambia, Journal of EmergingInfectious Yoon-Hoh K.(2004). Simultaneous identification of rifampin-resistant Mycobacterium tuberculosis and nontuberculous mycobacteria by polymerase chain reaction-single strand conformation polymorphism and sequence analysis of the RNA polymerase gene (rpoB), Journal of Microbiological Methods vol.58 pp (111 – Mycobacterium bovis, Uganda, Emerging Infectious Diseases ,vol 15 accessed march rate', Acessed: march 2011 http://news.xinhuanet.com/english/2008- tuberculous mycobacteria in immunocompetent patients, Lancet Infectious Disease, Mycobacterium avium Complex Infection in South Africans with Acquired Immunodeficiency Syndrome, Journal of Clinical Infectious Diseases, vol.33, pp Uganda, accessed December 2010, retrieved from: #### 8. References http://www.nemaug.org/district\_reports/mubende\_2004\_report.pdf <http://books.google.com/books?id=oBloqeMWktMC&pg=PA838&lpg=PA838& dq=m+avium+in+african+poultry&source=bl&ots=6DkwHUlYbw&sig=RQqwQY 2a. The government should invest in disseminating free clean water sources like bore holes and piped spring water in rural areas to replace the valley dams which are reported to 2b. The government should improve the current waters sources for livestock and sensitize pastoral communities on the need to maintain them at reasonably high standards in a 3. The government should invest in research and innovation so that Ugandans develop tailor made diagnostic and therapeutic for Uganda and the great lakes region. Aidsmap (2006). Is Uganda's HIV prevention success story 'unravelling' , Accessed march Anonymous.(2008). District State of Environment Report for Nakasongola District, pp(67) Anonymous. (2004). District State of Environment, Mubende District, pp21 accessed Ashemeire P. 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Factors associated with pastoral community knowledge and occurrence of mycobacterial infections in Human-Animal Interface areas of Nakasongola and Mubende districts, Uganda, BMC Public Health, vol.10, pp 471. http://www.measuredhs.com/pubs/pdf/AIS2/AIS2.pdf Ministry of Health, Uganda(MOH) (2005). Final Draft - Health Sector Strategic Plan II 2005/06 – 2009/10, October 2005, accessed march 2011, retrieved from: http://www.who.int/rpc/evipnet/Health%20Sector%20Strategic%20Plan%20II%2 02009-2010.pdf Non-Tuberculous Mycobacteria in Uganda: A Problem or Not? 39 Open vision youth club. (2004). My AIDS HERO,Accessed march 2011, retrieved from Oloya J , Kazwala R, Lund A, Opuda-Asibo J,Biffa D, Skjerve E, Johansen TB, Djønne B,.( regions of Uganda, BMC Microbiology, vol. 7 95, doi: 10.1186/1471-2180-7-95 Oloya J, Muma JB, Opuda-Asibo J, Djønne B, Kazwala R, Skjerve E.( 2007b). Risk factors for Serwadda D, Mugerwa RD, Sewankambo NK, Lwegaba A, Carswell JW, Kirya GB, Bayley Singh S, Gopinath K, Saba Shahbad MK, Singh B, Sharma P. (2007). Non tuberculous Singhal A, Gates C, Malhotra N, Irwin DA, Chansolme DH, Kohli V. (2010). Successful Stanford JL, Paul RC.(1976). A preliminary study of the effects of contact with Ssali FN, Kamya MR, Wabwire-Mangen F, Kasasa S, Joloba M, Williams D, Mugerwa RD, STD/AIDS Control Programme. (2002) Trends in HIV prevalence and sexual behavior, Tupasi TE, Radhakrishna S, Quelapio MI, Villa ML, Pascual ML, RiveraAB, Sarmiento A, Co UNAIDS (2010) 'UNAIDS report on the global AIDS epidemic, Accessed march 2011, retrieved from: http://www.unaids.org/globalreport/Global\_report.htm http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102253576.html The Body. (2005).Uganda's Decline in HIV/AIDS Prevalence Attributed to Increased tuberculins amongst Ugandan adults, Journal of hygiene, vol.76, pp (205) Stoneburner RL, Low-Beer D. (2004). Population-level HIV declines and behavioral risk 2007a). Characterisation of mycobacteria isolated from slaughter cattle in pastoral herd-level bovinetuberculosis seropositivity in transhumant cattle in Uganda, AC, Downing RG, Tedder RS, Clayden SA. (1985) 'Slim Disease: A New Disease in Uganda and its Association with HTLV-III Infection' Lancet vol. 2, No.8460, pp(849- mycobacterial infections in Indian AIDS patients detected by a novel set of ESAT-6 polymerase chain reaction primers, Japanese journal of infectious diseases, vol.60, pp management of primary nontuberculous mycobacterial infection of hepatic allograft following orthotopic liver transplantation for hepatitis C, Journal of environmental mycobacteria on the patterns of sensitivity to a range of new Ellner JJ, Johnson JL A.(1998). Prospective study of community-acquired bloodstream infections among febrile adults admitted to Mulago Hospital in Kampala, Uganda, Journal of Acquired Immune Deficiency Syndrom and Human Condom Use, Early Death From AIDS, Study Says Accessed march 2011,retrieved VM, Sarol JN, Beltran G, Legaspi JD, MangubatNV, Reyes AC, Solon M, Solon FS, Burton L, Mantala MJ.(2000). Tuberculosis in the urban poor settlements in the Philippines International Journal of Tuberculosis and Lung Disease, vol.4, No.1,pp(4- http://myhero.com/go/hero.asp?hero=PHILLY 852) (14-18) Journal of Preventive Veterinary Medicine, vol. 80, pp(318-329) Transplant and Infectious Disease, Vol.13, No.1, pp (47–51) avoidance in Uganda, Science, vol. 30 No.304, pp (714-718) from: http://www.thebody.com/content/art9249.html Retrovirology. Vol.19, No.5,pp(484-489) Accessed:March, 2011 11). Ministry of Gender Labour and Social Development. (2004). 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Kampala:Ministry of Gender Labour and Social Development, accessed march 2011, retieved from: http://www.aidsuganda.org/HIV%20PDf/comnwealth.pdf http://docs.google.com/viewer?a=v&q=cache:hdhWT8EccQIJ:www.kumihospital .org/reports/ZTLS%2520East%252005.doc+National+Tuberculosis+and+Leprosy+ Program,+Uganda.+(2005).+Status+Report+for+Leprosy+2004,&hl=en&pid=bl&src id=ADGEESgSuVljuLsCvaBic8bhpNBMX1NAgne886KXMrRL-BNSr- DV4FhX8nZq7-UnOjSxqcW5X1T4-UyZSYTeH-9ssQVwO5VM8m04ew89- E0ZobL13a4sL6Q606NFPppO5I2hHCZCXSsx&sig=AHIEtbSidkcnpZRCdO9em1yf PGESc7z11g http://docs.google.com/viewer?a=v&q=cache:hdhWT8EccQIJ:www.kumihospital .org/reports/ZTLS%2520East%252005.doc+Nkolo+A+,Kalyesubula+KS.(2006)+TO UR+OF+THE+DISTRICTS+IN+THE+EASTERN+ZONE+OF+UGANDA+12th+to+ 23rd+DECEMBER+2005:+ACTIVITY+REPORT+NATIONAL+TUBERCULOSIS+A NDF+LEPROSY+PROGRAM&hl=en&pid=bl&srcid=ADGEESgSuVljuLsCvaBic8bh pNBMX1NAgne886KXMrRL-BNSr-DV4FhX8nZq7-UnOjSxqcW5X1T4-UyZSYTeH-9ssQVwO5VM8m04ew89E0ZobL13a4sL6Q606NFPppO5I2hHCZCXSsx&sig=AHIE tbQnCC5xETzpnbfIYaM14cI5oYcHAA Ministry of Gender Labour and Social Development. (2004). National Strategic Programme Muwonge A, Kankya C, Godfroid J, Djonne B, Opuda-Asibo J, Biffa D, Skjerve Muwonge A, Kankya C, Johansen TB, Djonne B, Godfroid J, Biffa D, Vigdis E, Skjerve National Tuberculosis and Leprosy Program, Uganda. (2005). Status Report for Leprosy Mubende district, Uganda, BMC Veterinary research (Under review) id=ADGEESgSuVljuLsCvaBic8bhpNBMX1NAgne886KXMrRL-BNSr-DV4FhX8nZq7-UnOjSxqcW5X1T4-UyZSYTeH-9ssQVwO5VM8m04ew89- http://www.aidsuganda.org/HIV%20PDf/comnwealth.pdf march 2011, retieved from: PGESc7z11g Retrieved from: (43-46) vol. 162, pp(208–210) and Production, vol.42, pp(905-913) 2004, Accessed march 2011, retrieved from: Journal of Clinical Pathology, vol. 41, pp (93-96) Tuberculosis, vol.55, pp (175-178) tbQnCC5xETzpnbfIYaM14cI5oYcHAA Plan of Interventions for Orphans and Other Vulnerable Children Fiscal Year 2005/6-2009/10. Kampala:Ministry of Gender Labour and Social Development, accessed E.(2010).Prevalence and associated risk factors of mycobacterial infections in slaughter pigs from Mubende district in Uganda, Journal of Tropical Animal Health E.(2011). Non-tuberculous mycobacteria isolated from slaughtered pigs in http://docs.google.com/viewer?a=v&q=cache:hdhWT8EccQIJ:www.kumihospital .org/reports/ZTLS%2520East%252005.doc+National+Tuberculosis+and+Leprosy+ Program,+Uganda.+(2005).+Status+Report+for+Leprosy+2004,&hl=en&pid=bl&src E0ZobL13a4sL6Q606NFPppO5I2hHCZCXSsx&sig=AHIEtbSidkcnpZRCdO9em1yf lymphadenitis associated with human immunodeficiency virus (HIV) in Uganda, 23rd December 2005: Activity report National tuberculosis and leprosy program http://docs.google.com/viewer?a=v&q=cache:hdhWT8EccQIJ:www.kumihospital .org/reports/ZTLS%2520East%252005.doc+Nkolo+A+,Kalyesubula+KS.(2006)+TO UR+OF+THE+DISTRICTS+IN+THE+EASTERN+ZONE+OF+UGANDA+12th+to+ 23rd+DECEMBER+2005:+ACTIVITY+REPORT+NATIONAL+TUBERCULOSIS+A NDF+LEPROSY+PROGRAM&hl=en&pid=bl&srcid=ADGEESgSuVljuLsCvaBic8bh pNBMX1NAgne886KXMrRL-BNSr-DV4FhX8nZq7-UnOjSxqcW5X1T4-UyZSYTeH-9ssQVwO5VM8m04ew89E0ZobL13a4sL6Q606NFPppO5I2hHCZCXSsx&sig=AHIE Nambuya A, Sewankambo N, Mugerwa J, Goodgame R, Lucas S.(1988). Tuberculous Narang P.(2008).Prevalence of non-tuberculous mycobacteria in India, Indian Journal of Nkolo A ,Kalyesubula KS.(2006) Tour of the districts in the eastern zone of Uganda 12th to Ofukwo RA, lortyom BK, Akwuobu CA.(2010). Mycobacterium Avium and Mycobacterium Okello D, Sewankambo N, Goodgame R.(1990). Absence of bacteremia with Mycobacterium intracellulare Infections in Slaughtered Pigs in Makurdi, North-Central Nigeria: An Emerging Zoonosis, International Journal of Animal and Veterinary Advance, vol.2,pp avium-intracellulare in Ugandan patients with AIDS, Journal of Infection and Disease, http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102253576.html Part 2 HIV Transmission http://www.who.int/tdrold/diseases/leprosy/direction.htm World Health Organization (WHO). WHO Report (2007), global tuberculosis control, Uganda.WHO/HTM/TB/2007.376 Accessed 2008 march 2011, retrieved from: http://www.who.int/tb/publications/global\_report/2007/pdf/uga.pdf	doab	2025-04-07T04:13:04.672983	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 14 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.15	Part 2 HIV Transmission 40 Global View of HIV Infection Uganda AIDS commission (UAC). (2004-a). The Revised National Strategic Framework for Van Ingen J, Boeree MJ, Dekhuijzen PN, Soolingen VD.(2009). Environmental sources of Wisselink HJ, van Solt-Smits CB, Oorburg D, van Soolingen D, Overduin P, Maneschijn- Wolinsky E. (1979). Non-tuberculous mycobacteria and associated disease, American Review Wolinsky E. (1995). Mycobacterial lymphadenitis in children: a prospective study of 105 WHO/UNAIDS/UNICEF (2010) 'Towards universal access: Scaling up priority HIV/AIDS World Health Organization (WHO). WHO Report (2007), global tuberculosis control, http://www.who.int/tb/publications/global\_report/2007/pdf/uga.pdf http://www.who.int/hiv/pub/2010progressreport/en/index.html WHO, Tropical Disease Research Website. Strategic direction for research in Leprosy, February 2002, 2004, accessed January 2011, retrieved from: http://www.who.int/tdrold/diseases/leprosy/direction.htm http://www.aidsuganda.org/HIV%20PDf/comnwealth.pdf clinical Microbiology and Infection, vol.15, pp(888-893) journal of Respiratory Diseases, vol.119, pp (107-59) Microbiology, vol.142, pp(401–40) vol.20, pp(954–963) HIV/AIDS Activities in Uganda 2000/1 - 2005/6, A Guide for all HIV/AIDS Stakeholders, Uganda AIDS Commission, Kampala, Accessed march 2011 rapid growing nontuberculous mycobacteria causing disease in humans, Journal of Bonsing J, Stockhofe-Zurwieden N,Buys-Bergen H,Engel B Urlings BAP, Thole JER. (2010). Serodiagnosis of Mycobacterium avium infections in pigs, Veterinary nontuberculous cases with long-term follow-up, Journal of Clinical Infectious Disease, interventions in the health sector, Accessed march 2011, retrieved from: Uganda.WHO/HTM/TB/2007.376 Accessed 2008 march 2011, retrieved from: 3 1UK 2Nigeria Goselle Obed Nanjul1, 2 1School of Biological Sciences, Bangor University Human Immunodeficiency Virus Transmission 2Applied Entomology and Parasitology Unit, Department of Zoology, University of Jos, Human Immunodeficiency Virus (HIV) is the causative organism of AIDS which has become one of the greatest public health challenges faced by mankind. AIDS was first identified in 1981 in Los Angeles, USA. Two types of HIV exist presently- HIV-1 and HIV-2 (Alizon et al., 2010; Adoga et al., 2010). HIV-1 was first isolated in the early 1980s (Barre-Sinoussi et al., 1983) and linked as causative agent of AIDS (Gallo et al., 1984). HIV-2 which is similar to HIV-1 was later identified in the developing world (Clavel, 1987, Clavel et al., 1986), but found to be less virulent and can differ in its response to antiretroviral agents. HIV-1 is classified into three groups [M, N and O] based on the genetic diversity. Group M (major) has 10 subtypes (A-J), and Group O (outlier) represents a number of highly divergent strains (Carr et al., 1998; Jassens et al., 1997 Chen et al., 2010). Francois Simon and his group reported a group N of HIV-1. Despite the phenotypic classification of HIV-1 into subtypes, the number of sequenced isolates remains limited (Sharp et al., 1994). Both strains are spread in the same way and have the same AIDS causing consequences. While HIV-1 has been reported to have a shorter incubation period of 7-10years, HIV-2 is considerably HIV infection is usually followed by a chronic progressive destruction of the immune and neurologic system (Price, 1996), which if not managed leads to the possible invasion and establishment of multiple opportunistic infections.( Lindo et al., 1998; Pozio et al., 1997) and malignancy (Schulz et al., 1996). Although on average, an infected individual spends several years without manifesting the disease, AIDS has always been certain. The time from infection to AIDS varies widely between individuals, from a few months to as many as 20 years with existing evidences accepting that 50% of individuals progress to AIDS in 7-10years and this has been accepted as the incubation period of the virus (Del Amo et al., 1998; WHO, 1994). The concentration of virus in a body fluid and the extent of exposure to body fluids determine to a great extent the transmission of a virus. Jaffe and McMahon-Pratt (1983) first indicated in their Epidemiological studies conducted in 1981 and 1982 that the major channel of transmission of AIDS were intimate sexual contact and contaminated blood. Gottlieb et al (1981); Masur et al (1981); Siegal et al (1981); Callazos et al (2010); van longer and often less severe (Barre-Sinoussi, 1996; WHO, 1989). 2. Portals of HIV transmission 1. Introduction	doab	2025-04-07T04:13:04.677070	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 15 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.16	Human Immunodeficiency Virus Transmission ### Goselle Obed Nanjul1, 2 1School of Biological Sciences, Bangor University 2Applied Entomology and Parasitology Unit, Department of Zoology, University of Jos, 1UK 2Nigeria #### 1. Introduction Human Immunodeficiency Virus (HIV) is the causative organism of AIDS which has become one of the greatest public health challenges faced by mankind. AIDS was first identified in 1981 in Los Angeles, USA. Two types of HIV exist presently- HIV-1 and HIV-2 (Alizon et al., 2010; Adoga et al., 2010). HIV-1 was first isolated in the early 1980s (Barre-Sinoussi et al., 1983) and linked as causative agent of AIDS (Gallo et al., 1984). HIV-2 which is similar to HIV-1 was later identified in the developing world (Clavel, 1987, Clavel et al., 1986), but found to be less virulent and can differ in its response to antiretroviral agents. HIV-1 is classified into three groups [M, N and O] based on the genetic diversity. Group M (major) has 10 subtypes (A-J), and Group O (outlier) represents a number of highly divergent strains (Carr et al., 1998; Jassens et al., 1997 Chen et al., 2010). Francois Simon and his group reported a group N of HIV-1. Despite the phenotypic classification of HIV-1 into subtypes, the number of sequenced isolates remains limited (Sharp et al., 1994). Both strains are spread in the same way and have the same AIDS causing consequences. While HIV-1 has been reported to have a shorter incubation period of 7-10years, HIV-2 is considerably longer and often less severe (Barre-Sinoussi, 1996; WHO, 1989). HIV infection is usually followed by a chronic progressive destruction of the immune and neurologic system (Price, 1996), which if not managed leads to the possible invasion and establishment of multiple opportunistic infections.( Lindo et al., 1998; Pozio et al., 1997) and malignancy (Schulz et al., 1996). Although on average, an infected individual spends several years without manifesting the disease, AIDS has always been certain. The time from infection to AIDS varies widely between individuals, from a few months to as many as 20 years with existing evidences accepting that 50% of individuals progress to AIDS in 7-10years and this has been accepted as the incubation period of the virus (Del Amo et al., 1998; WHO, 1994). #### 2. Portals of HIV transmission The concentration of virus in a body fluid and the extent of exposure to body fluids determine to a great extent the transmission of a virus. Jaffe and McMahon-Pratt (1983) first indicated in their Epidemiological studies conducted in 1981 and 1982 that the major channel of transmission of AIDS were intimate sexual contact and contaminated blood. Gottlieb et al (1981); Masur et al (1981); Siegal et al (1981); Callazos et al (2010); van Human Immunodeficiency Virus Transmission 45 For conveniences, we will share the mode of infections into: Sexual and Non-sexual. Fig. 2. Routes of Transmission of Human Immuno-deficiency Virus. [HIV] Fig. 3. Levels of HIV load in semen [Courtesy:…] Low HIV plasma load, but high semen load Testis Griensven and de Lin van Wijngaarden (2010) all described the syndrome in homosexual and bisexual men and, intravenous drug users, while Harris et al (1983); Padian et al (1991); Cameron et al (1989); Quinn et al (2000) and Decker et al (2010) recognised their mode of transmission through heterosexual activity. Evidences later showed that transmission recipients and haemophiliacs could contract the illness from blood or blood products (CDC, 1982; Peterson, 1992; CDC, 2010) and newborn infants get infected from their mothers' (Ammann et al., 1983; Scarlatti, 1996; Brookmeyer, 1991; Landesman, et al., 1996; Goedert et al., 1989; Mackelprang et al., 2010). Brookmeyer (1991); Stoneburner et al (1990) all agreed that the three principal means of transmission – blood, sexual contact and mother-to-child have not changed which could be attributed to a greater degree to the relative amount of the virus in various body fluids. Fig. 1. Diagrammatic representation of HIV-1 and HIV-2 showing their dependent and independence on CD4+ [Courtesy-] HIV is present in semen (including pre-seminal fluid), vaginal/cervical secretions and blood, breast milk expressed through feeding; organ donations; sharing infected objects (needles, tattoos and piercing) which are the main vehicles through which the virus is transmitted (Kim et al., 2010; Yu et al., 2010; Suligoi et al., 2010; Pruss et al., 2010 and Baggaley et al., 2010). The virus may also be present in saliva, tears, urine, cerebrospinal fluid and infected discharges, but these are not vehicles of which HIV is spread. Epidemiological survey do not support transmission through water or food, sharing eating utensils, coughing or sneezing, vomiting, toilets, swimming pools, insect bites, shaking of hands or other casual contacts, hence there is no public health reason for discrimination and or restrictions. A study of French hospital patients by Grabar et al (2009) found that approximately 0.5% of HIV-1 infected individuals retain high levels of CD4+ T-cells and a low or clinically undetectable viral load without anti-retroviral treatment. These individuals are classified as HIV controllers or long-term non-progressors. Griensven and de Lin van Wijngaarden (2010) all described the syndrome in homosexual and bisexual men and, intravenous drug users, while Harris et al (1983); Padian et al (1991); Cameron et al (1989); Quinn et al (2000) and Decker et al (2010) recognised their mode of transmission through heterosexual activity. Evidences later showed that transmission recipients and haemophiliacs could contract the illness from blood or blood products (CDC, 1982; Peterson, 1992; CDC, 2010) and newborn infants get infected from their mothers' (Ammann et al., 1983; Scarlatti, 1996; Brookmeyer, 1991; Landesman, et al., 1996; Goedert et al., 1989; Mackelprang et al., 2010). Brookmeyer (1991); Stoneburner et al (1990) all agreed that the three principal means of transmission – blood, sexual contact and mother-to-child have not changed which could be attributed to a greater degree to the relative amount of Fig. 1. Diagrammatic representation of HIV-1 and HIV-2 showing their dependent and HIV is present in semen (including pre-seminal fluid), vaginal/cervical secretions and blood, breast milk expressed through feeding; organ donations; sharing infected objects (needles, tattoos and piercing) which are the main vehicles through which the virus is transmitted (Kim et al., 2010; Yu et al., 2010; Suligoi et al., 2010; Pruss et al., 2010 and Baggaley et al., 2010). The virus may also be present in saliva, tears, urine, cerebrospinal fluid and infected discharges, but these are not vehicles of which HIV is spread. Epidemiological survey do not support transmission through water or food, sharing eating utensils, coughing or sneezing, vomiting, toilets, swimming pools, insect bites, shaking of hands or other casual contacts, hence there is A study of French hospital patients by Grabar et al (2009) found that approximately 0.5% of HIV-1 infected individuals retain high levels of CD4+ T-cells and a low or clinically undetectable viral load without anti-retroviral treatment. These individuals are classified as the virus in various body fluids. independence on CD4+ [Courtesy-] no public health reason for discrimination and or restrictions. HIV controllers or long-term non-progressors. For conveniences, we will share the mode of infections into: Sexual and Non-sexual. Fig. 2. Routes of Transmission of Human Immuno-deficiency Virus. [HIV] Low HIV plasma load, but high semen load Fig. 3. Levels of HIV load in semen [Courtesy:…] Human Immunodeficiency Virus Transmission 47 Transcriptase Inhibitor (NNRTIs) and Fusion Inhibitor Enfuvirtide have no activity against HIV-2 and in the light of the current albeit limited data, zidovudine mono-therapy should not be used. These factors make it crucial that proper selection of and adherence to the first antiretroviral combination regimen is in place in order to achieve a successful treatment response. Though of recent, a combination of Combivir and nevarapine is given to mothers to prevent transmission of HIV to children. The Emergency Lower Segment Caesarian Section (ELSCS) could be planned at 38 weeks of gestation with regards to the mode of delivery if the viral load is undetectable or the mother is either symptomatic or has low CD4 cell count. HIV is present in breast milk and postnatal transmission via breastfeeding is an important component of MTCT in Sub-Saharan Africa (Kreiss, 1997). World-wide, an estimated one in three of vertical transmission may be due to breastfeeding with above 12months of age carrying higher risk (Bulterys et al., 1995). Kuhn and Stein (1997) demonstrated that under certain conditions prevailing in specific settings in developing countries, breast feeding for six months would be preferable to breast feeding beyond this age. Breastfeeding has been reported to account for 5-15% of infants becoming infected with HIV-1 after delivery (ECS 1991; Ryder et al., 1989; Mok et al., 1989). Although the placental entry of some infections is a critical aspect of these infections, the role of placental cells and the mechanism by which pathogens pass from the maternal to the foetal circulation varies. The placenta provides a barrier that prevents transmission of some viruses, but allows others to reach the foetal circulation. Mother to foetus placental transmission of some viruses occurs through transcytosis across placental cells. The placenta may also act as a reservoir in which virus replicates before reaching the foetus. Placental transmission of HIV-1 is a complex incompletely understood process which requires advanced studies (Al-husaini, 2009). The antiretroviral therapy, zidovudine (ZDV) is metabolized into its active form in the placenta (Qian et al., 1994). ZDV inhibits HIV replication within placental cells. To reach the foetal circulation, HIV-1 should cross the trophoblastic placental barrier (cytotrophoblasts and syncitiotrophoblasts). Blood borne maternal pathogens that arrive at the uteroplacental circulation and intervillous space may reach the foetus through the villous capillaries. HIV-1 has been detected on both the maternal and the foetal parts of the placenta. HIV-1 experiences replication in the placenta. The virus may cross the trophoblastic barrier by endocytosis, or by an injured villous surface. However, superficial breaks in syncytiotrophoblast cells do not radically affect the vertical transmission of viruses (Burton et al., 1996). The reverse transcriptase enzyme of HIV-1 is important in the life cycle of the virus by converting the single-stranded RNA genome into double-stranded DNA that integrates into the host chromosome. There is a lower degree of viral heterogeneity in transmitting mothers compared with nontransmitting mothers (Sundaravaradan et al., 2005). of vertical transmission (Al-husaini, 2009). years earlier)[UNAIDS, 2010]. Human chorionic gonadotropin (hCG) has been shown in vitro to inhibit reverse transcriptase and to block viral transmission between virus-carrying lymphocytes and placental trophoblasts (Bourinbaiar and Lee-Huang, 1995). However, role of hCG in protecting the foetus from vertical transmission HIV-1 needs to be studied. In summary, the restricted heterogeneity of HIV-1 in the infected mothers is more likely associated with lack As access to services for preventing the mother-to-child transmission of HIV has increased, the total number of children being born with HIV has also decreased. An estimated 370 000 [230 000–510 000] children were newly infected with HIV in 2009 (a drop of 24% from five	doab	2025-04-07T04:13:04.677491	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 16 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.17	3. Vertical or Mother To Child Tranmission (MTCT) The major source of paediatric infection of Human immunodeficiency virus one (HIV-1) is from mother to child. Since the first reported case of HIV-1 transmission in children in 1983, the global pandemic has had a serious impact on the health and survival of children. Transmission rates have been reported to be about 14% in industrialised countries and about 35-45% in developing countries especially in Africa (Bryson, 1996; Reinhardt et al., 1995). It was estimated that MTCT accounts for over 1.5million HIV infection in children (Burton, 1996) with the WHO projecting between 5-10million child infections through MTCT during the next decade. HIV-2 though is related to HIV-1 is less readily transmitted from mother to child, this could be attributed to their differences which influences pathogenecity, natural history and therapy so that their susceptibility to antiretroviral therapy (ART) follows different mutation pathways to develop drug resistance (Mamata and Merchant, 2010). According to Wollinsky et al (1992) as quoted by Pasquier et al (1998), the transmission of HIV-1 from mother to child occur utero, intrapartum, or postnatally by breastfeeding and a fourth dimension as reported by Pasquier et al (1998) which involves the transmission of multiple maternal variants to the infant and a rapid, fatal outcome in the child and the development of an HIV-based clinical disease in children seems to be correlated with the timing of the vertical transmission. Infection in about two-thirds of children are thought to have occurred at the terminal end of pregnancy or at delivery with the disease progressing slowly; while in one-thirds, it is thought to progress rapidly to AIDS with increased indices of viral replication (De Rossi et al., 1998), these children appear to have been infected during pregnancy. Infected children with slow progression to AIDS have a higher viral diversity than children who progress rapidly as evidenced in molecular variability studies (Halapi et al., 1996; Strunnikora et al., 1995) as reported in Adults (Delwart et al., 1997; Pasquier et al., 1998). Although progress has been made in recent years in the curbing of MTCT, the mechanisms and timing of transmission remains uncertain and the relative contributions of each of the three modes of transmission is still not well defined. Bryson et al (1992) proposed that in most non-breastfeeding population; the lack of detection of virus in the child at birth might indicate that contamination took place at or shortly before delivery while detection of virus at birth indicates utero contamination. Evidences for both early and late utero transmission have been documented (Peckham and Gibb, 1995; Kuhn and Stein, 1995). Most prior estimates and hypothesis seem to agree that transmission usually occur during the intrapartum HIV exposure just as premature infants. Perinatal or Antepartum HIV transmission has been documented as a route of infection estimated to occur in 13-30% of infants delivered to HIV-1 infected mothers (Andiman et al., 1990). High proviral DNA/ or RNA concentration of virus is a risk factor for the transmission of HIV-1 from an untreated mother to infant. The reduction in such transmission after zidovudine is only partly explained by the reduction in plasma levels of viral RNA. To prevent HIV-1 transmission initiating maternal treatment with zidovudine is recommended regardless of the plasma level of HIV-1 RNA or the CD4+ Count (Sperling et al., 1996). Because of the different mutation pathways to develop drug resistance, pregnant women with detectable HIV-2 should be ideally managed using a Highly Active antiretroviral therapy (HAART) regimen to which the virus is sensitive. Non-nucleoside Reverse The major source of paediatric infection of Human immunodeficiency virus one (HIV-1) is from mother to child. Since the first reported case of HIV-1 transmission in children in 1983, the global pandemic has had a serious impact on the health and survival of children. Transmission rates have been reported to be about 14% in industrialised countries and about 35-45% in developing countries especially in Africa (Bryson, 1996; Reinhardt et al., It was estimated that MTCT accounts for over 1.5million HIV infection in children (Burton, 1996) with the WHO projecting between 5-10million child infections through MTCT during the next decade. HIV-2 though is related to HIV-1 is less readily transmitted from mother to child, this could be attributed to their differences which influences pathogenecity, natural history and therapy so that their susceptibility to antiretroviral therapy (ART) follows different mutation pathways to develop drug resistance (Mamata and Merchant, 2010). According to Wollinsky et al (1992) as quoted by Pasquier et al (1998), the transmission of HIV-1 from mother to child occur utero, intrapartum, or postnatally by breastfeeding and a fourth dimension as reported by Pasquier et al (1998) which involves the transmission of multiple maternal variants to the infant and a rapid, fatal outcome in the child and the development of an HIV-based clinical disease in children seems to be correlated with the Infection in about two-thirds of children are thought to have occurred at the terminal end of pregnancy or at delivery with the disease progressing slowly; while in one-thirds, it is thought to progress rapidly to AIDS with increased indices of viral replication (De Rossi et Infected children with slow progression to AIDS have a higher viral diversity than children who progress rapidly as evidenced in molecular variability studies (Halapi et al., 1996; Strunnikora et al., 1995) as reported in Adults (Delwart et al., 1997; Pasquier et al., 1998). Although progress has been made in recent years in the curbing of MTCT, the mechanisms and timing of transmission remains uncertain and the relative contributions of each of the three modes of transmission is still not well defined. Bryson et al (1992) proposed that in most non-breastfeeding population; the lack of detection of virus in the child at birth might indicate that contamination took place at or shortly before delivery while detection of virus at birth indicates utero contamination. Evidences for both early and late utero transmission have been documented (Peckham and Gibb, 1995; Kuhn and Stein, 1995). Most prior estimates and hypothesis seem to agree that transmission usually occur during the Perinatal or Antepartum HIV transmission has been documented as a route of infection estimated to occur in 13-30% of infants delivered to HIV-1 infected mothers (Andiman et al., High proviral DNA/ or RNA concentration of virus is a risk factor for the transmission of HIV-1 from an untreated mother to infant. The reduction in such transmission after zidovudine is only partly explained by the reduction in plasma levels of viral RNA. To prevent HIV-1 transmission initiating maternal treatment with zidovudine is recommended regardless of the plasma level of HIV-1 RNA or the CD4+ Count (Sperling et al., 1996). Because of the different mutation pathways to develop drug resistance, pregnant women with detectable HIV-2 should be ideally managed using a Highly Active antiretroviral therapy (HAART) regimen to which the virus is sensitive. Non-nucleoside Reverse al., 1998), these children appear to have been infected during pregnancy. intrapartum HIV exposure just as premature infants. 3. Vertical or Mother To Child Tranmission (MTCT) 1995). 1990). timing of the vertical transmission. Transcriptase Inhibitor (NNRTIs) and Fusion Inhibitor Enfuvirtide have no activity against HIV-2 and in the light of the current albeit limited data, zidovudine mono-therapy should not be used. These factors make it crucial that proper selection of and adherence to the first antiretroviral combination regimen is in place in order to achieve a successful treatment response. Though of recent, a combination of Combivir and nevarapine is given to mothers to prevent transmission of HIV to children. The Emergency Lower Segment Caesarian Section (ELSCS) could be planned at 38 weeks of gestation with regards to the mode of delivery if the viral load is undetectable or the mother is either symptomatic or has low CD4 cell count. HIV is present in breast milk and postnatal transmission via breastfeeding is an important component of MTCT in Sub-Saharan Africa (Kreiss, 1997). World-wide, an estimated one in three of vertical transmission may be due to breastfeeding with above 12months of age carrying higher risk (Bulterys et al., 1995). Kuhn and Stein (1997) demonstrated that under certain conditions prevailing in specific settings in developing countries, breast feeding for six months would be preferable to breast feeding beyond this age. Breastfeeding has been reported to account for 5-15% of infants becoming infected with HIV-1 after delivery (ECS 1991; Ryder et al., 1989; Mok et al., 1989). Although the placental entry of some infections is a critical aspect of these infections, the role of placental cells and the mechanism by which pathogens pass from the maternal to the foetal circulation varies. The placenta provides a barrier that prevents transmission of some viruses, but allows others to reach the foetal circulation. Mother to foetus placental transmission of some viruses occurs through transcytosis across placental cells. The placenta may also act as a reservoir in which virus replicates before reaching the foetus. Placental transmission of HIV-1 is a complex incompletely understood process which requires advanced studies (Al-husaini, 2009). The antiretroviral therapy, zidovudine (ZDV) is metabolized into its active form in the placenta (Qian et al., 1994). ZDV inhibits HIV replication within placental cells. To reach the foetal circulation, HIV-1 should cross the trophoblastic placental barrier (cytotrophoblasts and syncitiotrophoblasts). Blood borne maternal pathogens that arrive at the uteroplacental circulation and intervillous space may reach the foetus through the villous capillaries. HIV-1 has been detected on both the maternal and the foetal parts of the placenta. HIV-1 experiences replication in the placenta. The virus may cross the trophoblastic barrier by endocytosis, or by an injured villous surface. However, superficial breaks in syncytiotrophoblast cells do not radically affect the vertical transmission of viruses (Burton et al., 1996). The reverse transcriptase enzyme of HIV-1 is important in the life cycle of the virus by converting the single-stranded RNA genome into double-stranded DNA that integrates into the host chromosome. There is a lower degree of viral heterogeneity in transmitting mothers compared with nontransmitting mothers (Sundaravaradan et al., 2005). Human chorionic gonadotropin (hCG) has been shown in vitro to inhibit reverse transcriptase and to block viral transmission between virus-carrying lymphocytes and placental trophoblasts (Bourinbaiar and Lee-Huang, 1995). However, role of hCG in protecting the foetus from vertical transmission HIV-1 needs to be studied. In summary, the restricted heterogeneity of HIV-1 in the infected mothers is more likely associated with lack of vertical transmission (Al-husaini, 2009). As access to services for preventing the mother-to-child transmission of HIV has increased, the total number of children being born with HIV has also decreased. An estimated 370 000 [230 000–510 000] children were newly infected with HIV in 2009 (a drop of 24% from five years earlier)[UNAIDS, 2010]. Human Immunodeficiency Virus Transmission 49 as well which are thought to occur when the infant ingests the mothers blood through a Other known correlates include high maternal plasma viremia, advanced clinical HIV disease, degraded maternal immunocompetence or prolonged rupture of the amniotic membranes before delivery. Others include vaginal delivery process and prematurity of low High frequency of sexual activity and ''hard'' drug injection during pregnancy had previously been identified, along with unprotected sexual intercourse during pregnancy as certain behavioural risk factors for mother-to-child-transmission (Bulterys et al., 1997; Bulterys and Goedert, 1996). Firstly, unprotected intercourse might increase the concentration of strain diversity of HIV-1, particularly in the birth canal where ejaculated virus could be partially sequestered. Secondly, frequent intercourse might increase inflammation of the cervix or vagina either micro abrasion or if unprotected, by STDs. Third, frequent intercourse might increase the risk of chorioamnionitis or otherwise alter the integrity of the placenta (Bulterys and Goedert, 1996). Matheson et al (1997) found that continued drug users had significantly higher mother-to-child-transmission rates in maternal drug use during pregnancy. However, this was confounded by other variables such as premature delivery, prolonged membrane rupture, zidovudine non-use and In the USA, cigarettes' smoking during pregnancy has been identified as independent risk factor for mother-to-child-transmission. The effect was greatest among women with critical evidence of more advanced HIV disease (Turner et al., 1996). Intensive nurse care management in supporting zidovudine use in women with HIV infection and their infants is a proven effective method in decreasing mother-to-child-transmission (Havens et al., 1997). MTCT of HIV is influenced by multiple factors. Known correlates include high maternal plasma viremia, advanced clinical HIV disease, degraded maternal immunocompetence or prolonged rupture of the amniotic membranes before delivery. Others include vaginal delivery process and prematurity of low birth weight of the neonate (Bryson 1996; John and Results from zidovudine therapy to bridge MTCT have improved understanding of the pathophysiology of MTCT. First, the reduction in plasma viremia and MTCT (from 25.5% to 8.3%) by treating the mother and neonates suggests that relatively small changes in maternal viral load might have substantial effects on MTCT (Bulterys and Godert 1996; CDC, 1994). Secondly, cleaning of birth canal with chlorhexidine had no overall effect yet apparently did reduce MTCT for one subgroups of high-risk deliveries; those after 4hrs of membrane Maternal immunologic and virologic factors such as quantitative HIV-1 RNA (though insufficient) are strongly correlated with Mother-to-child-transmission. When stratified by the stage of HIV disease, the only group with significant association between viral load and mother-to-child-transmission were AIDS-free women with high CD4+ Counts. The interactions of virus burden and maternal immune status has also demonstrated that CD4+, CD8+ cell subsets are percentages of CD8+ cell subsets (e.g. activation markers CD8/CD38 and CD8/DR) were all associated with vertical transmission. Women in the highest CD4+ cell percentage quartile or the lowest CD8+ cell percentage quartile had only less than or equal to 4 percent of mother-to-child-transmission (Njoku, 2004). birth weight of the neonate (Bryson, 1996; John and Kreiss, 1996; Lambert, 1996). cracked and bleeding nipples. unprotected sexual intercourse. Kreiss, 1996; Lambert, 1996). rupture (Scarlatti, 1996). #### 4. Risk factors for vertical transmission of HIV Documented evidence primarily based on PCR and virus culture studies or co-culture studies but short of serology which revealed maternal antibodies present in infants at birth showed that transmission of HIV from mother to child appears to occur in 11-60% of children delivered by HIV-positive mothers but reasons for the wide variations in virus transmission and sources of virus in newborn which could have provided approach to prevention are not known (Ades et. al., 1991; Courgnaud et. al., 1991; Lindgren et. al., 1991; Newell et. al., 1992; Scarlatti et. al., 1991; Tovo and Martino, 1988; Oxtoby, 1990; Rogers et. al., 1991). Maternal, viral, obstetric, foetal, infant factors all affect transmission making it essentially multifactorial. Frequency of sexual activity, 'hard' drug ingestion during pregnancy, unprotected sexual intercourse, cigarette smoking during pregnancy, lack of adherence to drugs, HIV disease, degraded maternal immunocompetence or prolonged rupture of the amniotic membranes before delivery (Havens et al., 1997; Turner et al., 1996; Bryson, 1996; John and Kreiss, 1996; Lambert, 1996; Glenn and Dietrich, 1993). The maternal factors involve transmission through the placenta to the unborn child, at the time of labour and delivery, or through breast-feeding. (CDC HIV/AIDS surveillance, October, 1989), seroconversion during pregnancy, advanced stage of the disease with high viral load and low immunity, concomitant malnutrition, micronutrient deficiencies, sexually transmitted diseases, no or suboptimal therapy; in the intranatal period, risk factors for increased transmission are mode of delivery, prolonged contact with maternal blood or cervicovaginal secretions, prolonged rupture of membranes, chorioamnionitis, invasive procedures like episiotomy, foetal scalp electrode, instrumental delivery; thin skin, susceptible mucous membranes, immature immune functions and low levels of maternal antibodies make prematurity a risk factor for increased transmission. In the postnatal period, risk factors are breast feeding, feeding with cracked nipples/mastitis, mixed feeding, new seroconversion of the mother, high viral load, low CD4 cell count; In the absence of any intervention, rates of MTCT of HIV-1 can vary from 15 to 30% in developed countries and increase to 30 to 45% in developing countries, the difference mainly attributable to infant feeding practices that comprise almost universally of breastfeeds for prolonged duration (De Cock et al., 2000 as quoted by Mamata and Merchant, 2001). The foetus and mother circulatory systems though different, there still exists tiny mixing of blood that could serve as portal for the flow of infected maternal white blood cells or the AIDS virus in the maternal serum to be transmitted to the foetus with a confirmation found in the foetal tissues affirming such spread (CDC HIV/AIDS surveillance, October 1989; Glenn and Dietrich, 1993). Bruising, abrasions and local swelling could occur to the baby and mother during labour owing to a great deal of trauma which produces visible and microscopic openings that could allow the virus to penetrate blood stream of infant. Another means of infection could be experienced or seen when the mother's perineum tears or if she receives an episiotomy which might lead to a large amounts of blood ingested by the baby or might get into the baby's mouth, eyes, rectum or vagina. Glenn et al (1993) reported that breastfeeding is another means of risks exposure and it has been confirmed in the spread of hepatitis B from mother to infant and hepatitis B and AIDS Documented evidence primarily based on PCR and virus culture studies or co-culture studies but short of serology which revealed maternal antibodies present in infants at birth showed that transmission of HIV from mother to child appears to occur in 11-60% of children delivered by HIV-positive mothers but reasons for the wide variations in virus transmission and sources of virus in newborn which could have provided approach to prevention are not known (Ades et. al., 1991; Courgnaud et. al., 1991; Lindgren et. al., 1991; Newell et. al., 1992; Scarlatti et. al., 1991; Tovo and Martino, 1988; Oxtoby, 1990; Rogers et. Maternal, viral, obstetric, foetal, infant factors all affect transmission making it essentially multifactorial. Frequency of sexual activity, 'hard' drug ingestion during pregnancy, unprotected sexual intercourse, cigarette smoking during pregnancy, lack of adherence to drugs, HIV disease, degraded maternal immunocompetence or prolonged rupture of the amniotic membranes before delivery (Havens et al., 1997; Turner et al., 1996; Bryson, 1996; The maternal factors involve transmission through the placenta to the unborn child, at the time of labour and delivery, or through breast-feeding. (CDC HIV/AIDS surveillance, October, 1989), seroconversion during pregnancy, advanced stage of the disease with high viral load and low immunity, concomitant malnutrition, micronutrient deficiencies, sexually transmitted diseases, no or suboptimal therapy; in the intranatal period, risk factors for increased transmission are mode of delivery, prolonged contact with maternal blood or cervicovaginal secretions, prolonged rupture of membranes, chorioamnionitis, invasive procedures like episiotomy, foetal scalp electrode, instrumental delivery; thin skin, susceptible mucous membranes, immature immune functions and low levels of maternal antibodies make prematurity a risk factor for increased transmission. In the postnatal period, risk factors are breast feeding, feeding with cracked nipples/mastitis, mixed feeding, new seroconversion of the mother, high viral load, low CD4 cell count; In the absence of any intervention, rates of MTCT of HIV-1 can vary from 15 to 30% in developed countries and increase to 30 to 45% in developing countries, the difference mainly attributable to infant feeding practices that comprise almost universally of breastfeeds for prolonged duration (De Cock et al., 2000 as quoted by Mamata and The foetus and mother circulatory systems though different, there still exists tiny mixing of blood that could serve as portal for the flow of infected maternal white blood cells or the AIDS virus in the maternal serum to be transmitted to the foetus with a confirmation found in the foetal tissues affirming such spread (CDC HIV/AIDS surveillance, October 1989; Bruising, abrasions and local swelling could occur to the baby and mother during labour owing to a great deal of trauma which produces visible and microscopic openings that could allow the virus to penetrate blood stream of infant. Another means of infection could be experienced or seen when the mother's perineum tears or if she receives an episiotomy which might lead to a large amounts of blood ingested by the baby or might get into the Glenn et al (1993) reported that breastfeeding is another means of risks exposure and it has been confirmed in the spread of hepatitis B from mother to infant and hepatitis B and AIDS 4. Risk factors for vertical transmission of HIV John and Kreiss, 1996; Lambert, 1996; Glenn and Dietrich, 1993). al., 1991). Merchant, 2001). Glenn and Dietrich, 1993). baby's mouth, eyes, rectum or vagina. as well which are thought to occur when the infant ingests the mothers blood through a cracked and bleeding nipples. Other known correlates include high maternal plasma viremia, advanced clinical HIV disease, degraded maternal immunocompetence or prolonged rupture of the amniotic membranes before delivery. Others include vaginal delivery process and prematurity of low birth weight of the neonate (Bryson, 1996; John and Kreiss, 1996; Lambert, 1996). High frequency of sexual activity and ''hard'' drug injection during pregnancy had previously been identified, along with unprotected sexual intercourse during pregnancy as certain behavioural risk factors for mother-to-child-transmission (Bulterys et al., 1997; Bulterys and Goedert, 1996). Firstly, unprotected intercourse might increase the concentration of strain diversity of HIV-1, particularly in the birth canal where ejaculated virus could be partially sequestered. Secondly, frequent intercourse might increase inflammation of the cervix or vagina either micro abrasion or if unprotected, by STDs. Third, frequent intercourse might increase the risk of chorioamnionitis or otherwise alter the integrity of the placenta (Bulterys and Goedert, 1996). Matheson et al (1997) found that continued drug users had significantly higher mother-to-child-transmission rates in maternal drug use during pregnancy. However, this was confounded by other variables such as premature delivery, prolonged membrane rupture, zidovudine non-use and unprotected sexual intercourse. In the USA, cigarettes' smoking during pregnancy has been identified as independent risk factor for mother-to-child-transmission. The effect was greatest among women with critical evidence of more advanced HIV disease (Turner et al., 1996). Intensive nurse care management in supporting zidovudine use in women with HIV infection and their infants is a proven effective method in decreasing mother-to-child-transmission (Havens et al., 1997). MTCT of HIV is influenced by multiple factors. Known correlates include high maternal plasma viremia, advanced clinical HIV disease, degraded maternal immunocompetence or prolonged rupture of the amniotic membranes before delivery. Others include vaginal delivery process and prematurity of low birth weight of the neonate (Bryson 1996; John and Kreiss, 1996; Lambert, 1996). Results from zidovudine therapy to bridge MTCT have improved understanding of the pathophysiology of MTCT. First, the reduction in plasma viremia and MTCT (from 25.5% to 8.3%) by treating the mother and neonates suggests that relatively small changes in maternal viral load might have substantial effects on MTCT (Bulterys and Godert 1996; CDC, 1994). Secondly, cleaning of birth canal with chlorhexidine had no overall effect yet apparently did reduce MTCT for one subgroups of high-risk deliveries; those after 4hrs of membrane rupture (Scarlatti, 1996). Maternal immunologic and virologic factors such as quantitative HIV-1 RNA (though insufficient) are strongly correlated with Mother-to-child-transmission. When stratified by the stage of HIV disease, the only group with significant association between viral load and mother-to-child-transmission were AIDS-free women with high CD4+ Counts. The interactions of virus burden and maternal immune status has also demonstrated that CD4+, CD8+ cell subsets are percentages of CD8+ cell subsets (e.g. activation markers CD8/CD38 and CD8/DR) were all associated with vertical transmission. Women in the highest CD4+ cell percentage quartile or the lowest CD8+ cell percentage quartile had only less than or equal to 4 percent of mother-to-child-transmission (Njoku, 2004). Human Immunodeficiency Virus Transmission 51 semen viral load (Gupta et al., 1997; Tachet et al., 1999; Kalichman et al., 2008; Butler et al., 2008), stage of HIV infection (Mastro et al., 1994; Fauci et al., 1996; Wawer et al., 2005), comorbid sexually transmitted diseases (Royce et al., 1997), vaginal or anal canal, co-occurring Sexual forms of transmission are seen as a major portal of entry of HIV as 10-30% of seminal/vaginal fluids have transmissible virus (Royce et al., 1997; Henin et al., 1993). In semen viral load, the males HIV-1 infected cells forms about 104 of the 106 leucocytes per ejaculation (Winkelstein et al., 1987), which confirms AIDS first association with sexual route, with the high prevalence in homosexual men. The virus subsequently became synonymous with heterosexual activity and is now attributed to the AIDS pandemic (UNAIDS 1986; Nkowane 1991; Stoneburner et al., 1990). Bouvier et al (1997) believes that The chances of transmission also depends on the type of sexually transmitted infections (STI), as co-infection with genital ulcers have been reported to increase the chances of transmission by increasing the susceptibility to HIV infection which also depends on HIV subtypes efficient (Gray et al., 2001; Mahiane et al., 2009; Limpakarnianarat et al., 1993; Male circumcision have been documented to decrease the chances of HIV transmission (Mahiane et al., 2009; Lavreys et al., 1999; Gray et al., 2000; Reynolds et al., 2004; Gray et al., 2007; Donoval et al., 2006), but this also depends on the country (Ben et al., 2008; Sullivan et The high level of heterosexual spread of HIV in Sub-Saharan Africa and developing countries where genital ulcers from existing venereal diseases (e.g. Chanchroid Chlamydia, Syphilis or Herpes virus infections) are aligned with increased HIV seroprevalence (UNAIDS, 1998, Hook et al., 1992; Plummer et al., 1991) could be tight to abrasions at the site of entry in the vagina or anal canal. Heise et al (1991) however reported that HIV could directly infect the bowel mucosa and perhaps cervical epithelium without the need for ulcerations which gave clue to the relatively low risk of the mucosal lining of the foreskin, urethral canal and oral genital contact (through minimal) to be implicated (Winkelstein et Men having Sex with Men (MSM) have been reported as one of the first way of transmission of HIV. Various authors have showed evidence that the involvement of MSM could be traced to psychosocial behaviour (PB). These PB are said to be depression, violent victimisation, substance abuse, alcohol, psychiatric disorders, psychological distress, lower perceived social support (Berlan et al., 2010; King et al., 2008; Meyer , 2003; Cochran et al., 2003; Cochran and Mays, 2000; Gilman et al., 2001., Marshal et al., 2008; Mimiaga et al., 2009a; b; Safren and Heimberg, 1999; Stall et al., 2001; Chesney et al., 2003; The EXPLORE Study Team, 2004; Herbst et al., 2005). Although some studies have shown how substance use and high risk of HIV transmission are correlated (Stall et al., 2001; Hirshfield et al., 2004), most recent studies are now focussing on how 'syndemic'- a situation where these diverse psychosocial issues could interact to enhance HIV risky behaviour among MSM (Mustanski et al., 2007; 2010; Stall et al., 2008; Centers for Disease Control and Prevention, 2010). However, varieties of cognitive behavioural interventions have been studied and validated for the treatment of mood and anxiety disorders (Barlow, 2008) behavioural activation therapy and HIV risk reduction counselling in MSM who abuse crystal vaginal pH neutralization by semen is a co-factor of HIV transmission. psychosocial risk factors (Safren et al., 2010). al., 2009; Ruan et al., 2009; Wawer et al., 2009). methamphetamine (Mimiaga et al., 2010). Wang, 2009; Xu, 2009). al., 1987).	doab	2025-04-07T04:13:04.677983	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 17 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.18	5. Parental, saliva and other body fluids Prior to Groopman and Greenspan (1996) report of oral manifestation of AIDS which increases the potentials of HIV transmission through several lesions which form exists for virus into the saliva, it was assumed that about 10% of both free virus and infected cells report in saliva were not very important in the spread of HIV (Groopman et al., 1984). Dean et al (1988) and Mundy et al (1987) reported none or low level of pathogens in urine, sweat, breast milk, branchoalvolar lavage fluid, amniotic fluid, synovial fluid, faeces and tears which were not thought to be important source in virus transmission (Fujikawa et al., 1985), but this assumption has also changed with the report of Groopman and Greenspan (1996); Amory et al. (1992); Scarlatti (1996); van da Perre et al. (1991). Though not a natural source of HIV transmission, cerebrospinal fluid (CSF) in neurologic patients have been shown to contain large amount of virus when compared to other body fluids (Hollander and Levy, 1987; Ho et al., 1989).	doab	2025-04-07T04:13:04.679537	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 18 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.19	6. Organs, blood, tissue donors and occupational health workers Prior to 1985 (PPHS/MMWR, 1985; MMWR, 1985), when screening of blood, organ and tissue donors for HIV-1 antibody became available, several reports have documented the transmission of HIV-1 by transplantation of kidney (MMWR, 1987; Kumar et al., 1987; Erice et al., 1991; Schwartz et al., 1987; Prompt et al., 1985; L'age-Stehr et al., 1985; Neumayer et al., 1987; Quarto et al., 1989; Carbone et al., 1988), liver (MMWR, 1987; Kumar et al., 1987; Erice et al., 1991; Schwartz et al., 1987; Prompt et al., 1985; L'age-Stehr et al., 1985; Neumayer et al., 1987; Quarto et al., 1989; Carbone et al., 1988; Samuel et al., 1988), heart (Erice et al., 1991; Dummer et al., 1989), pancreas (Erice et al., 1991), bone (MMWR, 1988a) and possibly skin(Clarke, 1987) and In most cases involving donors whose serum had not been tested for HIV-1 antibody (MMWR, 1987; Kumar et al., 1987; Erice et al., 1991; Schwartz et al., 1987; Prompt et al., 1985; L'age-Stehr et al., 1985; Neumayer et al., 1987; Quarto et al., 1989; Carbone et al., 1988; Samuel et al., 1988; Dummer et al., 1989; MMWR, 1988a; Clarke, 1987). As proposed by Simonds et al (1992), approaches to prevention could include: the screening of prospective donors and laboratory markers for HIV1 infection (MMWR, 1985); the inactivation of HIV-1 in allograft through processing techniques (Hilfenhaus et al., 1990; Kitchen et al., 1989; Wells et al., 1986) and the quarantining of tissues from living donors until repeated antibody testing more definitely excludes the possibility of subsequent seroconversion in the donor (MMWR, 1988a ; MMWR, 1988b). The U.S. Centers for Disease Control and Prevention (2002) reported that in the health care industry there have been 57 confirmed cases and an additional 139 possible cases of health care workers in the U.S. who have become HIV positive from exposure to HIV in the work place. The Canadian HIV/AIDS Legal Network (2001) has also reported two of such cases in the laboratory workers and one health-care provider in Canada. #### 7. Horizontal (heterosexual) transmission These could be through unprotected and protected sexual process. Ma et al (2010) reported that the probability of unprotected heterosexual transmission may vary with population and be influenced by many factors, these could include: the type of sex (Mastro et al., 1994: De Vincenzi, 1994; Varghese et al., 2002); bleeding during intercourse (Royce et al., 1997), Prior to Groopman and Greenspan (1996) report of oral manifestation of AIDS which increases the potentials of HIV transmission through several lesions which form exists for virus into the saliva, it was assumed that about 10% of both free virus and infected cells report in saliva were not very important in the spread of HIV (Groopman et al., 1984). Dean et al (1988) and Mundy et al (1987) reported none or low level of pathogens in urine, sweat, breast milk, branchoalvolar lavage fluid, amniotic fluid, synovial fluid, faeces and tears which were not thought to be important source in virus transmission (Fujikawa et al., 1985), but this assumption has also changed with the report of Groopman and Greenspan (1996); Amory et al. (1992); Scarlatti (1996); van da Perre et al. (1991). Though not a natural source of HIV transmission, cerebrospinal fluid (CSF) in neurologic patients have been shown to contain large amount of virus when compared to other body fluids (Hollander and 6. Organs, blood, tissue donors and occupational health workers seroconversion in the donor (MMWR, 1988a ; MMWR, 1988b). in the laboratory workers and one health-care provider in Canada. 7. Horizontal (heterosexual) transmission Prior to 1985 (PPHS/MMWR, 1985; MMWR, 1985), when screening of blood, organ and tissue donors for HIV-1 antibody became available, several reports have documented the transmission of HIV-1 by transplantation of kidney (MMWR, 1987; Kumar et al., 1987; Erice et al., 1991; Schwartz et al., 1987; Prompt et al., 1985; L'age-Stehr et al., 1985; Neumayer et al., 1987; Quarto et al., 1989; Carbone et al., 1988), liver (MMWR, 1987; Kumar et al., 1987; Erice et al., 1991; Schwartz et al., 1987; Prompt et al., 1985; L'age-Stehr et al., 1985; Neumayer et al., 1987; Quarto et al., 1989; Carbone et al., 1988; Samuel et al., 1988), heart (Erice et al., 1991; Dummer et al., 1989), pancreas (Erice et al., 1991), bone (MMWR, 1988a) and possibly skin(Clarke, 1987) and In most cases involving donors whose serum had not been tested for HIV-1 antibody (MMWR, 1987; Kumar et al., 1987; Erice et al., 1991; Schwartz et al., 1987; Prompt et al., 1985; L'age-Stehr et al., 1985; Neumayer et al., 1987; Quarto et al., 1989; Carbone et al., 1988; Samuel et al., 1988; Dummer et al., 1989; MMWR, 1988a; Clarke, 1987). As proposed by Simonds et al (1992), approaches to prevention could include: the screening of prospective donors and laboratory markers for HIV1 infection (MMWR, 1985); the inactivation of HIV-1 in allograft through processing techniques (Hilfenhaus et al., 1990; Kitchen et al., 1989; Wells et al., 1986) and the quarantining of tissues from living donors until repeated antibody testing more definitely excludes the possibility of subsequent The U.S. Centers for Disease Control and Prevention (2002) reported that in the health care industry there have been 57 confirmed cases and an additional 139 possible cases of health care workers in the U.S. who have become HIV positive from exposure to HIV in the work place. The Canadian HIV/AIDS Legal Network (2001) has also reported two of such cases These could be through unprotected and protected sexual process. Ma et al (2010) reported that the probability of unprotected heterosexual transmission may vary with population and be influenced by many factors, these could include: the type of sex (Mastro et al., 1994: De Vincenzi, 1994; Varghese et al., 2002); bleeding during intercourse (Royce et al., 1997), 5. Parental, saliva and other body fluids Levy, 1987; Ho et al., 1989). semen viral load (Gupta et al., 1997; Tachet et al., 1999; Kalichman et al., 2008; Butler et al., 2008), stage of HIV infection (Mastro et al., 1994; Fauci et al., 1996; Wawer et al., 2005), comorbid sexually transmitted diseases (Royce et al., 1997), vaginal or anal canal, co-occurring psychosocial risk factors (Safren et al., 2010). Sexual forms of transmission are seen as a major portal of entry of HIV as 10-30% of seminal/vaginal fluids have transmissible virus (Royce et al., 1997; Henin et al., 1993). In semen viral load, the males HIV-1 infected cells forms about 104 of the 106 leucocytes per ejaculation (Winkelstein et al., 1987), which confirms AIDS first association with sexual route, with the high prevalence in homosexual men. The virus subsequently became synonymous with heterosexual activity and is now attributed to the AIDS pandemic (UNAIDS 1986; Nkowane 1991; Stoneburner et al., 1990). Bouvier et al (1997) believes that vaginal pH neutralization by semen is a co-factor of HIV transmission. The chances of transmission also depends on the type of sexually transmitted infections (STI), as co-infection with genital ulcers have been reported to increase the chances of transmission by increasing the susceptibility to HIV infection which also depends on HIV subtypes efficient (Gray et al., 2001; Mahiane et al., 2009; Limpakarnianarat et al., 1993; Wang, 2009; Xu, 2009). Male circumcision have been documented to decrease the chances of HIV transmission (Mahiane et al., 2009; Lavreys et al., 1999; Gray et al., 2000; Reynolds et al., 2004; Gray et al., 2007; Donoval et al., 2006), but this also depends on the country (Ben et al., 2008; Sullivan et al., 2009; Ruan et al., 2009; Wawer et al., 2009). The high level of heterosexual spread of HIV in Sub-Saharan Africa and developing countries where genital ulcers from existing venereal diseases (e.g. Chanchroid Chlamydia, Syphilis or Herpes virus infections) are aligned with increased HIV seroprevalence (UNAIDS, 1998, Hook et al., 1992; Plummer et al., 1991) could be tight to abrasions at the site of entry in the vagina or anal canal. Heise et al (1991) however reported that HIV could directly infect the bowel mucosa and perhaps cervical epithelium without the need for ulcerations which gave clue to the relatively low risk of the mucosal lining of the foreskin, urethral canal and oral genital contact (through minimal) to be implicated (Winkelstein et al., 1987). Men having Sex with Men (MSM) have been reported as one of the first way of transmission of HIV. Various authors have showed evidence that the involvement of MSM could be traced to psychosocial behaviour (PB). These PB are said to be depression, violent victimisation, substance abuse, alcohol, psychiatric disorders, psychological distress, lower perceived social support (Berlan et al., 2010; King et al., 2008; Meyer , 2003; Cochran et al., 2003; Cochran and Mays, 2000; Gilman et al., 2001., Marshal et al., 2008; Mimiaga et al., 2009a; b; Safren and Heimberg, 1999; Stall et al., 2001; Chesney et al., 2003; The EXPLORE Study Team, 2004; Herbst et al., 2005). Although some studies have shown how substance use and high risk of HIV transmission are correlated (Stall et al., 2001; Hirshfield et al., 2004), most recent studies are now focussing on how 'syndemic'- a situation where these diverse psychosocial issues could interact to enhance HIV risky behaviour among MSM (Mustanski et al., 2007; 2010; Stall et al., 2008; Centers for Disease Control and Prevention, 2010). However, varieties of cognitive behavioural interventions have been studied and validated for the treatment of mood and anxiety disorders (Barlow, 2008) behavioural activation therapy and HIV risk reduction counselling in MSM who abuse crystal methamphetamine (Mimiaga et al., 2010). Human Immunodeficiency Virus Transmission 53 Alizon, S., von Wyl, V., Stadler, T., Kouyos, D.R., Yerly, S., Hirschel, B., Boni, J., Shah, C., Amory, J., Martin, N., Levy, J.A and Wara, W.W. (1992). The large molecular weight Baggaley, R.F., White, R.G. and Boily, M. (2010). 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Phylogenetic approach reveals that virus genotype largely determines H.A. (1983). Acquired Immunodeficiency in an infant: possible transmission by glycoprotein (MGI) a component of human saliva inhibits HIV-1 infectivity. Clinical intercourse: systematic review, meta-analysis and implifications for HIV C., Axler-Blin, C., Vezinet-Brun, F., Rouzioux, W., Rozenbaum, W. and Montagnier, L. (1983). Isolation of a T-lymphotrophic retrovirus from a patient at risk for AIDS. (2008). Promoting male circumcision in China for preventing HIV infection and improving reproductive health. National Journal of Andrology 14(4), 291-297. (In orientation and bullying among adolescents in the Growing up Today Study. Mauris, A., Robert, C. (1997). Seasonality and malaria in a West African village: does high parasite density predict fever incidence? American Journal of Epidemiology, utero versus intrapartum transmission of HIV-1. New England Journal of Medicine, Addressing co-occurring psychosocial behaviour is a means to increase the effective size of current HIV prevention intervention and allow for more effective uptake by MSM, since they have been reported to be more than 44 times more likely to be newly diagnosed with HIV than other men (Purcell et al., 2010) and the focus on ameliorating disparities in HIV infection is essential for enhancing the health of MSM at the population level (Sanfren et al., 2010). The Centers for Diseases Control and Prevention (CDC, 2007) reported the prevalence rate among heterosexual African American (AA) women and men with data indicating that more heterosexual AA women having a 74% HIV/AIDS prevalence as compared to the 27% in their male counterpart. Myths and misperceptions of HIV/AIDS such as HIV being a genocide, suspicion of government information, belief that it is possible to identify risky partners by odour and appearance, belief that partners reported histories are accurate, misperceptions about the meaning of safe sex and the believe that specific classes of people (not one self) are at risk of HIV that resulted from sexual risk contributes to the risky behaviours of HIV transmission (Essien et al.,2002; Catania et al.,1994; Smith et al., 2000; Coleman et al., 2010; Coleman and Ball, 2007; Coleman, 2007). The increase in the number of sexual partners also increases HIV transmission (Stranford, 1999; Coleman, 2007; Catania et al., 1994; Smith et al., 2000; Coleman et al., 2010; Coleman and Ball, 2007) with most under the influence of alcohol or drugs. Unprotected oral and vaginal sex have been reported as a risk factor in the transmission of HIV especially where it is carried out in high risk settings, having sex more often under the influence of alcohol and/or drugs (Milam et al., 2006; Catania et al., 1994; Smith et al., 2000). Even under protection for example the use of condoms, many cases has been reported where the barrier has failed especially where risky behaviours are undertaken. A case in study which made the People Living With HIV/AIDS (PLWHA) in Nigeria to sue the Federal Government of Nigeria to Court for promotion of condoms (Ogundele, 2010). Though Tenofovir gel has been advocated for women to prevent HIV transmission (Karim et al., 2010). The nature of HIV transmission from anecdotal records has not changed neither is a new means of transmission of the virus recorded. In view of this development, it is the earnest desire of this write up to bring to fore genealogical reports of the transmission of HIV and to also continue to write on the various modes of transmission as a way of curtailing the spread of the dreaded virus. ## 8. References Andiman, W.A. et al. (1990). American Journal of Diseases of Children, 144:75. Al-husaini, A.M. (2009). Role of placenta in the vertical transmission of HIV. Journal of Perinatology, 29:321-326. Addressing co-occurring psychosocial behaviour is a means to increase the effective size of current HIV prevention intervention and allow for more effective uptake by MSM, since they have been reported to be more than 44 times more likely to be newly diagnosed with HIV than other men (Purcell et al., 2010) and the focus on ameliorating disparities in HIV infection is essential for enhancing the health of MSM at the population level (Sanfren et al., The Centers for Diseases Control and Prevention (CDC, 2007) reported the prevalence rate among heterosexual African American (AA) women and men with data indicating that more heterosexual AA women having a 74% HIV/AIDS prevalence as compared to the 27% Myths and misperceptions of HIV/AIDS such as HIV being a genocide, suspicion of government information, belief that it is possible to identify risky partners by odour and appearance, belief that partners reported histories are accurate, misperceptions about the meaning of safe sex and the believe that specific classes of people (not one self) are at risk of HIV that resulted from sexual risk contributes to the risky behaviours of HIV transmission (Essien et al.,2002; Catania et al.,1994; Smith et al., 2000; Coleman et al., 2010; Coleman and The increase in the number of sexual partners also increases HIV transmission (Stranford, 1999; Coleman, 2007; Catania et al., 1994; Smith et al., 2000; Coleman et al., 2010; Coleman Unprotected oral and vaginal sex have been reported as a risk factor in the transmission of HIV especially where it is carried out in high risk settings, having sex more often under the influence of alcohol and/or drugs (Milam et al., 2006; Catania et al., 1994; Smith et al., 2000). 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Lancet, 2004; 364:41–50. recommendations. MMWR, 1988; 37:597-9. factors of paediatric HIV infection. Lancet, ii: 1043-1045. semen: identification of a 2008:251. 106. 7558. 178-85. 240. 831. 337. D., Coates, T.J., Catania, J.A. (2001). Alcohol use, drug use, and alcohol related problems among men who have sex with men: The Urban Men's Health Study. theory of syndemic production among urban gay men. In: Wolitski RJ, Stall R, Valdiserri RO, eds. Unequal Opportunity: Health Disparities Affecting Gay and Bisexual Men in the United States. New York, NY: Oxford University Press; AIDS and HIV-1 infection among homosexuals in New York City. AIDS, 4: 99- Convergent evolution within the V3 loop domain of human immunodeficiency virus type 1 in association with disease progression. Journal of Virology, 69:7548– HIV infection in blood donations in Europe and Italy. Blood Transfusion, 8(3): Chinese men. JAIDS Journal of Acquired Immune Deficiency Syndromes 50(2), 238- and limited heterogeneity of HIV-1 reverse transcriptase gene following vertical 0 4 Zimbabwe C.P. Bhunu\and S. Mushayabasa National University of Science and Technology, Bulawayo* HIV/AIDS Transmission Dynamics in Male Prisons The imprisonment of large numbers of drug addicts has the potential to create environments within which social networks that enhances the transmission of infectious diseases form (7–11; 14). About 668,000 men and women are incarcerated in sub-Saharan Africa with South Africa having the highest prison population with 157,402 people behind bars in the region and 335 prisoners per 100,000 of the national population; it has the ninth largest prison population in the world (21). International data show that HIV prevalence among prisoners is between six to fifty times higher than that of the general adult population. For example, in the USA the ratio is 6:1, in France it is 10:1; in Switzerland 27:1 and in Mauritius 50:1 (17). On a global scale, the prison population is growing rapidly, with high incarceration rates leading to overcrowding, which largely stems from national law and criminal justice policies. In most countries, overcrowding and poor physical conditions prevail (20). This phenomenon poses significant health concerns with regard to control of infectious diseases-and HIV prevention and care most of all (21). Prisons are high risk settings for HIV transmission. However, HIV prevention, treatment are not adequately developed and implemented to respond to HIV in prisons (13). There is evidence to show that health programmes for the particular needs of imprisoned drug users are not enough in USA and Canada (15; 22). In Russia, a study of intravenous drug users demonstrated the critical role of prisons in the transmission of HIV through high levels of needle (syringes) sharing among the imprisoned (23). \Visiting Fellow, Clare Hall College, University of Cambridge Prison populations are predominantly male and most prisons are male-only institutions, including the prison staff. In such a gender exclusive environment, male-to-male sexual activity (prisoner-to-prisoner and guard-to-prisoner) is frequent (18). While much of the sex among men in prisons is consensual, rape and sexual abuse are often used to exercise dominance in the culture of violence that is typical of prison life (19). Inmate rape, including male rape, is considered one of the most ignored crimes. Sexual and physical abuse in custody remains a tremendous human rights problem (1). Intravenous drug use, tattooing and the following aspects of man-to-man sexual activity in prison make it a high risk for HIV transmission: anal intercourse, rape and the presence of sexually transmitted infections (STIs). Related problems in prisons across Southern Africa include overcrowding, shortages, corruption, and the presence of juveniles alongside adult prisoners. The potential for the spread of HIV is also increased by a lack of information and education, and a lack of proper medical care. STIs, if left untreated, can greatly increase a person's vulnerability to HIV 1. Introduction* Department of Applied Mathematics, Modelling Biomedical Systems Research Group	doab	2025-04-07T04:13:04.679645	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 19 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.20	HIV/AIDS Transmission Dynamics in Male Prisons #### C.P. Bhunu\and S. Mushayabasa Department of Applied Mathematics, Modelling Biomedical Systems Research Group National University of Science and Technology, Bulawayo Zimbabwe* #### 1. Introduction 66 Global View of HIV Infection Xu, J. (2009). Prospective cohort study to the incidence of HIV/STIs among FSWs in Yu, M. and Vajdy, M. (2010). Mucosal HIV transmission and vaccination strategies through and Prevention. 10(8): 1181-1195. Kaiyuan City. PhD [dissertation].Beijing, China: China Center for Disease Control oral compared with vaginal and rectal routes. Expert Opinion on Biological Therapy, The imprisonment of large numbers of drug addicts has the potential to create environments within which social networks that enhances the transmission of infectious diseases form (7–11; 14). About 668,000 men and women are incarcerated in sub-Saharan Africa with South Africa having the highest prison population with 157,402 people behind bars in the region and 335 prisoners per 100,000 of the national population; it has the ninth largest prison population in the world (21). International data show that HIV prevalence among prisoners is between six to fifty times higher than that of the general adult population. For example, in the USA the ratio is 6:1, in France it is 10:1; in Switzerland 27:1 and in Mauritius 50:1 (17). On a global scale, the prison population is growing rapidly, with high incarceration rates leading to overcrowding, which largely stems from national law and criminal justice policies. In most countries, overcrowding and poor physical conditions prevail (20). This phenomenon poses significant health concerns with regard to control of infectious diseases-and HIV prevention and care most of all (21). Prisons are high risk settings for HIV transmission. However, HIV prevention, treatment are not adequately developed and implemented to respond to HIV in prisons (13). There is evidence to show that health programmes for the particular needs of imprisoned drug users are not enough in USA and Canada (15; 22). In Russia, a study of intravenous drug users demonstrated the critical role of prisons in the transmission of HIV through high levels of needle (syringes) sharing among the imprisoned (23). Prison populations are predominantly male and most prisons are male-only institutions, including the prison staff. In such a gender exclusive environment, male-to-male sexual activity (prisoner-to-prisoner and guard-to-prisoner) is frequent (18). While much of the sex among men in prisons is consensual, rape and sexual abuse are often used to exercise dominance in the culture of violence that is typical of prison life (19). Inmate rape, including male rape, is considered one of the most ignored crimes. Sexual and physical abuse in custody remains a tremendous human rights problem (1). Intravenous drug use, tattooing and the following aspects of man-to-man sexual activity in prison make it a high risk for HIV transmission: anal intercourse, rape and the presence of sexually transmitted infections (STIs). Related problems in prisons across Southern Africa include overcrowding, shortages, corruption, and the presence of juveniles alongside adult prisoners. The potential for the spread of HIV is also increased by a lack of information and education, and a lack of proper medical care. STIs, if left untreated, can greatly increase a person's vulnerability to HIV <sup>\</sup>Visiting Fellow, Clare Hall College, University of Cambridge with βi, i* = (n, d) is probabbility on individual being infected with HIV by an individual from the n- or d-class per sexual contact; cj, j = (n, d) are the number of sexual partners an individual acquires per year (partner acquistion rates); βd<sup>2</sup> is the probability an intravenous drug user getting HIV infection through sharing non-sterile needles during drug injections HIV/AIDS Transmission Dynamics in Male Prisons 69 It is assumed people are recruited into prison at rate Λ through committing various crimes and the following proportions π1, π2, π<sup>3</sup> and π<sup>4</sup> recruited enter the classes Sn(t), Sd(t), In(t) and Id(t), respectively. We further assume that AIDS cases are too sick to commit a crime, so there are no recruitment of prisoners already in the AIDS stage of disease. Furthermore, it is assumed that intravenous drug using prisoners showing AIDS symptoms are nolonger able to exert peer pressure strong enough to make one become a drug user. Individuals in Sn(t) and In(t) acquire drug misusing habits at rate λd(t) due to peer pressure > <sup>λ</sup>dd <sup>=</sup> <sup>β</sup>d<sup>1</sup> cd<sup>1</sup> (Sd <sup>+</sup> Id) Nd where βd<sup>1</sup> is the probability of becoming an intravenous drug user (IDU) following contact with an IDU and cd<sup>1</sup> are the number of contacts necessary for one to become an IDU (partner acquistion rate). Individuals in Sn(t) class acquire HIV infection at a rate λnh (t) to move into In(t). Individuals in Sd(t) class acquire HIV infection at a rate λdh (t) to move Id(t) class. Individuals infected with HIV-only not yet displaying symptoms (In(t), Id(t)) progress to the AIDS stage ((An(t), Ad(t)) at a rate γ. Individuals in Ad(t) leave the intravenous drug using habits at a rate α to get into An(t) class. Individuals in all classes experience natural death at a rate μ and those in AIDS stage of the disease experience an additional disease induced death at a rate ν. Individuals in all classes leave the prison at rate ω upon completion of their sentences. Individuals in the AIDS stage of the disease (final terminal stages) are further released from prison due to sickness at rate φ. The model flow diagram is shown in Figure 1. Based on these assumptions the following system of differential equations describe the model. <sup>n</sup>(t) = π1Λ − (λ<sup>d</sup> + λnh )Sn − (μ + ω)Sn, <sup>n</sup>(t) = γIn + αAd − (μ + ω + φ + ν)An, <sup>d</sup>(t) = π2Λ + λdSn − λdhSd − (μ + ω)Sd, <sup>d</sup>(t) = π4Λ + λdhSd + λ<sup>d</sup> In − (μ + ω + γ)Id, In this section, we study the basic results of solutions of model system (5), which are essential <sup>d</sup>(t) = γId − (μ + α + ω + φ + ν)An. <sup>n</sup>(t) = π3Λ + λnhSn − λ<sup>d</sup> In − (μ + ω + γ)In, , (4) (5) and cd<sup>2</sup> are the number drug sharing partners an individual acquires. and move into Sd(t) and Id(t, respectively with S� I � A� S� I � A� 2.1 Model basic properties in the proofs of stability results. through sexual contact, UNAIDS noted (26). Men get tattooed in prison (12). In the absence of proper precautions and access to safe equipment tattooing can be a high-risk activity for the transmission of HIV (24; 25). The literature and development of mathematical epidemiology is well documented (2; 3; 6). This paper seeks to use mathematical models to gain insights on transimission of HIV among male prisoners while in prison in the context of homosexuality and intravenous drug use. The rest of this paper is organized as follows. In the next section, the model and its basic properties are presented. In Section 3, we determine stability analysis of the equilibria states. Numerical simualtions are presented in Section 4 and finally the last section concludes the paper. #### 2. Model description The model sub-divides the total male prisoner population into the following sub-populations of susceptible intravenous drug users Sd(t), susceptible non-drug users Sn(t), intravenous drug using HIV-only infected people not yet showing AIDS symptoms In(t), non-drug using HIV-only infected people not yet showing AIDS symptoms Id(t), intravenous drug using AIDS cases Ad(t) and non-drug using AIDS cases Ad(t). There is sexual interaction between intravenous drug users and non-drug users making HIV transmission across different these two distinct distinct groups possible. The population is patterns is heterogeneous mixing with regard to sexual behaviour. The total population is given by; $$N(t) = N\_d(t) + N\_n(t),\ N\_d(t) = S\_d(t) + I\_d(t) + A\_d(t),\ N\_n(t) = S\_n(t) + I\_n(t) + A\_n(t),\tag{1}$$ with Nn(t) and Nd(t) being the total number of non-drug using and intravenous drug using male prisoners (intravenous drug users-IDU), respectively. The group j members make cj, j = (d, n) sexual contacts per unit time, and that a fraction of the contacts made by a member of group j is with a member of group i is pji , i = (d, n). Then pnn + pnd = pdd + pdn = 1. The total number of sexual contacts per unit time by members of group 'n' (non-drug users) with members of group 'd' (intravenous drug users) is cn pnd Nn and because this must be equal to the number of contacts made by members of group 'd' with members of group 'n', we have a balance relation $$\frac{p\_{\text{n}\_d}c\_{\text{n}}}{N\_d} = \frac{p\_{d\_{\text{n}}}c\_d}{N\_{\text{n}}}.\tag{2}$$ In this case the sexual contact rates (partner acquistion rates) cd and cn are saturating terms for the total population and the mixing proportions may change with time. It is worth mentioning here that intravenous drug users are more likely to have more sexual partners than the general population. Therefore, cd = Bcn, B ≥ 1. We assume that male prisoners in AIDS stage of the disease are nolonger sexually active as they are nolonger capable of attracting sexual mates among prisoners. Also drug using AIDS patients nolonger share their needles with others as other prisoners do not like sharing needles with someone whose AIDS symptoms are visible. The forces of HIV infection for intravenous drug users and non-drug users in the male prison are: $$\begin{aligned} \lambda\_{d\_h} &= \frac{p\_{d\_d} c\_d \beta\_d I\_d}{N\_d} + \frac{p\_{d\_n} c\_d \beta\_n I\_n}{N\_n} + \frac{c\_{d\_2} \beta\_{d\_2} I\_d}{N\_d}, \\\\ \text{and } \lambda\_{n\_h} &= \frac{p\_{n\_n} c\_n \beta\_{n} I\_n}{N\_n} + \frac{p\_{n\_d} c\_n \beta\_d I\_d}{N\_d}, \text{ respectively} \end{aligned} \tag{3}$$ 2 Will-be-set-by-IN-TECH through sexual contact, UNAIDS noted (26). Men get tattooed in prison (12). In the absence of proper precautions and access to safe equipment tattooing can be a high-risk activity for the The literature and development of mathematical epidemiology is well documented (2; 3; 6). This paper seeks to use mathematical models to gain insights on transimission of HIV among male prisoners while in prison in the context of homosexuality and intravenous drug use. The rest of this paper is organized as follows. In the next section, the model and its basic properties are presented. In Section 3, we determine stability analysis of the equilibria states. Numerical simualtions are presented in Section 4 and finally the last section concludes the paper. The model sub-divides the total male prisoner population into the following sub-populations of susceptible intravenous drug users Sd(t), susceptible non-drug users Sn(t), intravenous drug using HIV-only infected people not yet showing AIDS symptoms In(t), non-drug using HIV-only infected people not yet showing AIDS symptoms Id(t), intravenous drug using AIDS cases Ad(t) and non-drug using AIDS cases Ad(t). There is sexual interaction between intravenous drug users and non-drug users making HIV transmission across different these two distinct distinct groups possible. The population is patterns is heterogeneous mixing with N(t) = Nd(t) + Nn(t), Nd(t) = Sd(t) + Id(t) + Ad(t), Nn(t) = Sn(t) + In(t) + An(t), (1) , i = (d, n). Then pnn + pnd = pdd + pdn = 1. The . (2) (3) with Nn(t) and Nd(t) being the total number of non-drug using and intravenous drug using male prisoners (intravenous drug users-IDU), respectively. The group j members make cj, j = (d, n) sexual contacts per unit time, and that a fraction of the contacts made by a member of total number of sexual contacts per unit time by members of group 'n' (non-drug users) with members of group 'd' (intravenous drug users) is cn pnd Nn and because this must be equal to the number of contacts made by members of group 'd' with members of group 'n', we have a In this case the sexual contact rates (partner acquistion rates) cd and cn are saturating terms for the total population and the mixing proportions may change with time. It is worth mentioning here that intravenous drug users are more likely to have more sexual partners than the general population. Therefore, cd = Bcn, B ≥ 1. We assume that male prisoners in AIDS stage of the disease are nolonger sexually active as they are nolonger capable of attracting sexual mates among prisoners. Also drug using AIDS patients nolonger share their needles with others as other prisoners do not like sharing needles with someone whose AIDS symptoms are visible. The forces of HIV infection for intravenous drug users and non-drug users in the male prison > <sup>+</sup> pdn cdβ<sup>n</sup> In Nn + <sup>+</sup> pnd cnβ<sup>d</sup> Id Nd cd<sup>2</sup> βd<sup>2</sup> Id Nd , , respectively <sup>=</sup> pdn cd Nn pnd cn Nd regard to sexual behaviour. The total population is given by; <sup>λ</sup>dh <sup>=</sup> pdd cdβ<sup>d</sup> Id Nd and <sup>λ</sup>nh <sup>=</sup> pnn cnβ<sup>n</sup> In Nn group j is with a member of group i is pji transmission of HIV (24; 25). 2. Model description balance relation are: with βi, i = (n, d) is probabbility on individual being infected with HIV by an individual from the n- or d-class per sexual contact; cj, j = (n, d) are the number of sexual partners an individual acquires per year (partner acquistion rates); βd<sup>2</sup> is the probability an intravenous drug user getting HIV infection through sharing non-sterile needles during drug injections and cd<sup>2</sup> are the number drug sharing partners an individual acquires. It is assumed people are recruited into prison at rate Λ through committing various crimes and the following proportions π1, π2, π<sup>3</sup> and π<sup>4</sup> recruited enter the classes Sn(t), Sd(t), In(t) and Id(t), respectively. We further assume that AIDS cases are too sick to commit a crime, so there are no recruitment of prisoners already in the AIDS stage of disease. Furthermore, it is assumed that intravenous drug using prisoners showing AIDS symptoms are nolonger able to exert peer pressure strong enough to make one become a drug user. Individuals in Sn(t) and In(t) acquire drug misusing habits at rate λd(t) due to peer pressure and move into Sd(t) and Id(t, respectively with $$ \lambda\_{d\_d} = \frac{\beta\_{d\_1} c\_{d\_1} (S\_d + I\_d)}{N\_d}, \tag{4} $$ where βd<sup>1</sup> is the probability of becoming an intravenous drug user (IDU) following contact with an IDU and cd<sup>1</sup> are the number of contacts necessary for one to become an IDU (partner acquistion rate). Individuals in Sn(t) class acquire HIV infection at a rate λnh (t) to move into In(t). Individuals in Sd(t) class acquire HIV infection at a rate λdh (t) to move Id(t) class. Individuals infected with HIV-only not yet displaying symptoms (In(t), Id(t)) progress to the AIDS stage ((An(t), Ad(t)) at a rate γ. Individuals in Ad(t) leave the intravenous drug using habits at a rate α to get into An(t) class. Individuals in all classes experience natural death at a rate μ and those in AIDS stage of the disease experience an additional disease induced death at a rate ν. Individuals in all classes leave the prison at rate ω upon completion of their sentences. Individuals in the AIDS stage of the disease (final terminal stages) are further released from prison due to sickness at rate φ. The model flow diagram is shown in Figure 1. Based on these assumptions the following system of differential equations describe the model. $$\begin{aligned} S'\_{\eta}(t) &= \pi\_1 \Lambda - (\lambda\_d + \lambda\_{\eta\_k}) S\_{\eta} - (\mu + \omega) S\_{\eta \nu} \\\\ I'\_{\eta}(t) &= \pi\_3 \Lambda + \lambda\_{\eta\_k} S\_{\eta} - \lambda\_d I\_{\eta} - (\mu + \omega + \gamma) I\_{\nu \nu} \\\\ A'\_{\eta}(t) &= \gamma I\_{\mathfrak{n}} + \alpha A\_d - (\mu + \omega + \phi + \nu) A\_{\mathfrak{n} \nu} \\\\ S'\_d(t) &= \pi\_2 \Lambda + \lambda\_d S\_{\mathfrak{n}} - \lambda\_{d\_h} S\_d - (\mu + \omega) S\_{d \nu} \\\\ I'\_d(t) &= \pi\_4 \Lambda + \lambda\_{d\_h} S\_d + \lambda\_d I\_{\mathfrak{n}} - (\mu + \omega + \gamma) I\_{d \nu} \\\\ A'\_d(t) &= \gamma I\_d - (\mu + \alpha + \omega + \phi + \nu) A\_{\mathfrak{n}} \end{aligned} \tag{5}$$ #### 2.1 Model basic properties In this section, we study the basic results of solutions of model system (5), which are essential in the proofs of stability results. 3. Disease-free equilibrium and stability analysis <sup>E</sup><sup>0</sup> <sup>=</sup> S0 <sup>n</sup>, I 0 <sup>n</sup>, <sup>A</sup><sup>0</sup> <sup>n</sup>, <sup>S</sup><sup>0</sup> d, I 0 <sup>d</sup> , <sup>A</sup><sup>0</sup> d = + Watmough (27). given by system (5) is given as <sup>R</sup>SD <sup>=</sup> cd<sup>2</sup> <sup>β</sup>d2+cd pdd <sup>β</sup><sup>d</sup> cd<sup>2</sup> <sup>β</sup>d2+cd pdd <sup>β</sup><sup>d</sup> RSD < 1 and unstable otherwise. driving HIV/AIDS in male prisons. Increase in intravenous drug users Analysis of the effective reproduction number, RSD The reproduction number is differentiated into categories: Case 1: No intravenous drug users in the community <sup>2</sup>a<sup>3</sup> + cn <sup>2</sup>a<sup>3</sup> + cn The disease free equilibrium of model system (5), <sup>E</sup><sup>0</sup> is given by π1Λ <sup>π</sup><sup>1</sup> pnd <sup>a</sup>1cd<sup>1</sup> <sup>β</sup>d<sup>1</sup> <sup>β</sup><sup>d</sup> <sup>π</sup><sup>1</sup> pnd <sup>a</sup>1cd<sup>1</sup> <sup>β</sup>d<sup>1</sup> <sup>β</sup><sup>d</sup> μ + ω + βd<sup>1</sup> cd<sup>1</sup> <sup>2</sup>a<sup>3</sup> <sup>a</sup><sup>4</sup> <sup>a</sup><sup>6</sup> <sup>+</sup> pnn <sup>β</sup><sup>n</sup> <sup>2</sup>a<sup>3</sup> <sup>a</sup><sup>4</sup> <sup>a</sup><sup>6</sup> <sup>+</sup> pnn <sup>β</sup><sup>n</sup> with a<sup>1</sup> = μ + ω, a<sup>2</sup> = μ + ω + φ + ν, a<sup>3</sup> = μ + ω + γ, a<sup>4</sup> = μ + ω + γ + cd<sup>1</sup> βd<sup>1</sup> , Following van den Driessche and Watmough (27), the effective reproduction number of model HIV/AIDS Transmission Dynamics in Male Prisons 71 2a<sup>4</sup> <sup>2</sup> 2a<sup>4</sup> a<sup>5</sup> = μ + ω + φ + ν, a<sup>6</sup> = π2(μ + ω) + cd<sup>1</sup> βd<sup>1</sup> throughout the manuscript. The reproduction number RSD is defined as the number of secondary HIV infections produced by one HIV infected individual during his/ her entire infectious period in a mixed population of non-drug users and intravenous drug male prisoners. Theorem 2 follows from van den Driessche and Theorem 2. The disease free equilibrium <sup>E</sup><sup>0</sup> of model system (5) is locally asymptotically stable if In this case β<sup>d</sup> = βdc cdc = βdcd = pnd = pdn = 0, pnn = 1 so that RSD becomes R0<sup>S</sup> which is <sup>R</sup>0<sup>S</sup> <sup>=</sup> <sup>β</sup>ncn a3 which is the number of secondary HIV infections produced by one HIV infected individual through homosexual tendencies in a male prison. It is important to note R0<sup>S</sup> is a decreasing function of ω, suggesting that increasing the number of prisoners leaving the prison reduces the concentration of HIV cases in prison. Theoretically this is feasible, in reality this begs more questions than answers as sentences communicated cannot be reversed because of HIV. Perhaps, it may be necessary to consider the use of open prison systems where prisoners with less serious crimes can serve their sentences while staying at their homes. This has a further advantage of reducing the high levels of raping of man by man in prisons and the homosexual tendencies which male prisoners resort to in enclosed prisons which is one of the major forces > <sup>R</sup>0<sup>D</sup> <sup>=</sup> <sup>β</sup>dcd <sup>+</sup> <sup>β</sup>d<sup>1</sup> cd<sup>1</sup> a3 In this case (ppp , βd<sup>1</sup> cd<sup>1</sup> ) → (1, ∞) so that RSD becomes R0<sup>D</sup> which is given by , 0, 0, Λ(π2(μ + ω) + βd<sup>1</sup> cd<sup>1</sup> ) (μ + ω)(μ + ω + βd<sup>1</sup> cd<sup>1</sup> ) <sup>−</sup> cn <sup>β</sup>n(cd<sup>2</sup> pnn <sup>β</sup>d2+cdβ<sup>d</sup> (pnn pdd−pnd pdn )) a<sup>3</sup> a<sup>4</sup> , (9) . (10) , 0, 0 . (7) (8) Fig. 1. Structure of the model. Lemma 1. The equations preserve positivity of solutions. Proof. The vector field given by the right hand side of (5) points inward on the boundary of R<sup>6</sup> <sup>+</sup> \ {0}. For example, if Sn = 0 then S� <sup>n</sup> = π1Λ ≥ 0. All the other components are similar. Lemma 2. Each non-negative solution is bounded in L1-norm by max {N(0), <sup>Λ</sup>/μ}. Proof. The norm L<sup>1</sup> norm of each non-negative solution is N and it satisfies the inequality N� ≤ Λ − μN. Solutions to the equation M� = Λ − μM are monotone increasing and bounded by Λ/μ if M(0) < Λ/μ. They are monotone decreasing and bounded above if M(0) ≥ Λ/μ. Since N� ≤ M� the claim follows. Corollary 1. The region $$\Phi = \left\{ (\mathbb{S}\_{\mathbb{II}} \, \_{\mathbb{II}} A\_{\mathbb{II}} \, \_{\mathbb{II}} \mathbb{S}\_{d \prime} I\_d \, A\_d) \in \mathbb{R}\_+^6 : N \le \frac{\Lambda}{\mu} \right\}.\tag{6}$$ is invariant and attracting for system (5). Theorem 1. For every non-zero, non-negative initial value, solutions of model system (5) exist for all times Proof. Local existence of solutions follow from standard arguments since the right hand side of (5) is locally Lipschitz. Global existence follows from the a-priori bounds. 4 Will-be-set-by-IN-TECH Proof. The vector field given by the right hand side of (5) points inward on the boundary of Proof. The norm L<sup>1</sup> norm of each non-negative solution is N and it satisfies the inequality N� ≤ Λ − μN. Solutions to the equation M� = Λ − μM are monotone increasing and bounded by Λ/μ if M(0) < Λ/μ. They are monotone decreasing and bounded above if M(0) ≥ Λ/μ. (Sn, In, An, Sd, Id, Ad) <sup>∈</sup> <sup>R</sup><sup>6</sup> Theorem 1. For every non-zero, non-negative initial value, solutions of model system (5) exist for all Proof. Local existence of solutions follow from standard arguments since the right hand side of (5) is locally Lipschitz. Global existence follows from the a-priori bounds. Lemma 2. Each non-negative solution is bounded in L1-norm by max {N(0), <sup>Λ</sup>/μ}. <sup>n</sup> = π1Λ ≥ 0. All the other components are similar. <sup>+</sup> : N ≤ Λ μ . (6) Fig. 1. Structure of the model. R<sup>6</sup> times Lemma 1. The equations preserve positivity of solutions. Φ = <sup>+</sup> \ {0}. For example, if Sn = 0 then S� Since N� ≤ M� the claim follows. is invariant and attracting for system (5). Corollary 1. The region #### 3. Disease-free equilibrium and stability analysis The disease free equilibrium of model system (5), <sup>E</sup><sup>0</sup> is given by $$\mathcal{L}^{0} = \left( S\_{\nu\nu}^{0} I\_{\nu\nu}^{0} A\_{\nu\nu}^{0} S\_{d\prime}^{0} I\_{d\prime}^{0} A\_{d}^{0} \right) = \left( \frac{\pi\_{1} \Lambda}{\mu + \omega + \beta\_{d1} \mathfrak{c}\_{d\_{1}}}, 0, 0, \frac{\Lambda (\pi\_{2}(\mu + \omega) + \beta\_{d\_{1}} \mathfrak{c}\_{d\_{1}})}{(\mu + \omega)(\mu + \omega + \beta\_{d\_{1}} \mathfrak{c}\_{d\_{1}})}, 0, 0 \right) . \tag{7}$$ Following van den Driessche and Watmough (27), the effective reproduction number of model system (5) is given as $$\begin{split} \mathcal{R}\_{SD} &= \frac{c\_{\sharp f}\delta\_{\sharp} + c\_{\sharp}\mu\_{\sharp}\delta\_{\sharp}}{2a\_{3}} + c\_{\mathrm{n}} \left( \frac{\pi\_{1}p\_{u\sharp}a\_{1}c\_{\sharp d\_{1}}\mathfrak{f}\_{d\_{1}}\mathfrak{f}\_{d}}{2a\_{3}a\_{4}a\_{6}} + \frac{p\_{u\sharp}\mathfrak{f}\_{u}}{2a\_{4}} \right) \\ &+ \sqrt{\left( \frac{c\_{\sharp}\mathfrak{f}\_{2}\mathfrak{f}\_{d\_{2}} + c\_{\sharp}p\_{d\_{4}}\mathfrak{f}\_{d}}{2a\_{3}} + c\_{\mathrm{n}} \left( \frac{\pi\_{1}p\_{u\sharp}a\_{1}c\_{\sharp d\_{1}}\mathfrak{f}\_{d\_{1}}\mathfrak{f}\_{d}}{2a\_{3}a\_{4}a\_{6}} + \frac{p\_{u\sharp}\mathfrak{f}\_{u}}{2a\_{4}} \right) \right)^{2} - \frac{c\_{\sharp}\mathfrak{f}\_{\sharp}\left(c\_{\sharp}\mathfrak{f}\_{d}p\_{u\sharp}\mathfrak{f}\_{d} + c\_{\sharp}\mathfrak{f}\_{d}(p\_{u\sharp}p\_{d\_{4}} - p\_{u\sharp}p\_{d\_{4}})\right)}{a\_{3}a\_{4}}} \end{split} \tag{8}$$ with a<sup>1</sup> = μ + ω, a<sup>2</sup> = μ + ω + φ + ν, a<sup>3</sup> = μ + ω + γ, a<sup>4</sup> = μ + ω + γ + cd<sup>1</sup> βd<sup>1</sup> , a<sup>5</sup> = μ + ω + φ + ν, a<sup>6</sup> = π2(μ + ω) + cd<sup>1</sup> βd<sup>1</sup> throughout the manuscript. The reproduction number RSD is defined as the number of secondary HIV infections produced by one HIV infected individual during his/ her entire infectious period in a mixed population of non-drug users and intravenous drug male prisoners. Theorem 2 follows from van den Driessche and Watmough (27). Theorem 2. The disease free equilibrium <sup>E</sup><sup>0</sup> of model system (5) is locally asymptotically stable if RSD < 1 and unstable otherwise.	doab	2025-04-07T04:13:04.683875	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 20 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.21	Analysis of the effective reproduction number, RSD The reproduction number is differentiated into categories: #### Case 1: No intravenous drug users in the community In this case β<sup>d</sup> = βdc cdc = βdcd = pnd = pdn = 0, pnn = 1 so that RSD becomes R0<sup>S</sup> which is given by $$\mathcal{R}\_{0\_{\rm S}} = \frac{\beta\_{\rm n} c\_{\rm n}}{a\_{\rm 3}},$$ which is the number of secondary HIV infections produced by one HIV infected individual through homosexual tendencies in a male prison. It is important to note R0<sup>S</sup> is a decreasing function of ω, suggesting that increasing the number of prisoners leaving the prison reduces the concentration of HIV cases in prison. Theoretically this is feasible, in reality this begs more questions than answers as sentences communicated cannot be reversed because of HIV. Perhaps, it may be necessary to consider the use of open prison systems where prisoners with less serious crimes can serve their sentences while staying at their homes. This has a further advantage of reducing the high levels of raping of man by man in prisons and the homosexual tendencies which male prisoners resort to in enclosed prisons which is one of the major forces driving HIV/AIDS in male prisons. #### Increase in intravenous drug users In this case (ppp , βd<sup>1</sup> cd<sup>1</sup> ) → (1, ∞) so that RSD becomes R0<sup>D</sup> which is given by $$\mathcal{R}\_{\mathbf{0}\_{\mathrm{D}}} = \frac{\beta\_d \mathbf{c}\_d + \beta\_{d\_1} \mathbf{c}\_{d\_1}}{a\_{\mathbf{3}}}.\tag{10}$$ (a) (b) <sup>0</sup> <sup>5</sup> <sup>10</sup> <sup>15</sup> <sup>20</sup> <sup>0</sup> Time (years) <sup>0</sup> <sup>5</sup> <sup>10</sup> <sup>15</sup> <sup>20</sup> <sup>0</sup> Time (years) 50 An(t) 100 150 In(t) 200 250 300 are in Table 1. (a) (a) are in Table 1. Fig. 2. Effects of varying the HIV infected-only initial conditions when RSD > 1. Parameter values used HIV/AIDS Transmission Dynamics in Male Prisons 73 (b) (b) Fig. 3. Simulations showing the effects of varying the rate at which non-drug using prisoners become intravenous drug users on the population on drug using HIV-infected prisoners. Parameter values used <sup>0</sup> <sup>5</sup> <sup>10</sup> <sup>15</sup> <sup>20</sup> <sup>0</sup> Time (years) <sup>0</sup> <sup>5</sup> <sup>10</sup> <sup>15</sup> <sup>20</sup> <sup>0</sup> Time (years) Ad(t) Id(t) R0<sup>D</sup> just like is R0<sup>S</sup> is a decreasing function of ω, meaning that use of open prison systems will be beneficial in the control of HIV among male prisoners. It is important to note that levels of sexual contact are higher among intravenous drug users than non-drug users, with it increased risk of contracting HIV, so cnβ<sup>n</sup> < cdβ<sup>d</sup> and this translates R0<sup>S</sup> < R0<sup>D</sup> . This suggest that intravenous drug use enhances HIV transmission in male prisons. Drug using prisoners are at an increased risk of HIV infection than their non-drug using counterparts. May be introducing drug substitution treatment together with introducing needle free exchange programmes will reduce the epidemic in prisons. A reduction in needle in sharing among prisoners result in HIV/AIDS prevalence as the sharing of unsterile needles in a major source of HIV transmission among male prisoners. #### 4. Numerical simulations In this section, we carry out detailed numerical simulations using MatLab programming language to assess the effects of HIV transmission among male prisoners in the absence any interventional strategy which is more common in developing countries in Africa for different initial conditions. The parameter values that we use for numerical simulations are in Table 1. In Table 1, NPA denotes National Prison Administration (Zimbabwe). For influence of Table 1. Model parameters and their interpretations. peer pressure forces influencing one to become an IDU, we used values adapted from Bhunu et al. (4) which are peer pressure forces necessary for one to start smoking, for the sake of illustration. For influence of peer pressure forces influencing one to become an IDU, we used values adapted from Bhunu et al. (2010) (4) which are peer pressure forces necessary for one to start smoking. Figure 2 is a graphical representation showing the effect of varying initial conditions when RSD > 1. In Figures 2(a) and 2(b) show the effects of varying the HIV-infected not yet showing sysmptoms on HIV-infected only and AIDS, respectively. Both graphs show a higher number of HIV-only and AIDS among intravenous drug using male prisoners than non-drug users. This tends to show intravenous drug using male prisoners are at increased risk of HIV infection due to sharing of unsterile needles and increased rates of homosexual sex habits. 6 Will-be-set-by-IN-TECH R0<sup>D</sup> just like is R0<sup>S</sup> is a decreasing function of ω, meaning that use of open prison systems will be beneficial in the control of HIV among male prisoners. It is important to note that levels of sexual contact are higher among intravenous drug users than non-drug users, with it increased risk of contracting HIV, so cnβ<sup>n</sup> < cdβ<sup>d</sup> and this translates R0<sup>S</sup> < R0<sup>D</sup> . This suggest that intravenous drug use enhances HIV transmission in male prisons. Drug using prisoners are at an increased risk of HIV infection than their non-drug using counterparts. May be introducing drug substitution treatment together with introducing needle free exchange programmes will reduce the epidemic in prisons. A reduction in needle in sharing among prisoners result in HIV/AIDS prevalence as the sharing of unsterile needles in a major source In this section, we carry out detailed numerical simulations using MatLab programming language to assess the effects of HIV transmission among male prisoners in the absence any interventional strategy which is more common in developing countries in Africa for different initial conditions. The parameter values that we use for numerical simulations are in Table 1. In Table 1, NPA denotes National Prison Administration (Zimbabwe). For influence of Parameter Symbol Value Source Recruitment rate <sup>Λ</sup> 0.00163yr−<sup>1</sup> <sup>∗</sup> 3000000 NPA Natural mortality rate μ 0.02yr−<sup>1</sup> (5) Natural rate of progression to AIDS γ 0.1yr−<sup>1</sup> (5) Rate of leaving prison due to AIDS related sickness φ 0.25 Assumed AIDS related death rate ν 0.4yr−<sup>1</sup> (5) per drug injection cd<sup>2</sup> <sup>β</sup>d<sup>2</sup> 0.562yr−<sup>1</sup> (16) Probability of HIV transmission per sexual contact βn, β<sup>d</sup> 0.125 (0.01-0.95)yr−<sup>1</sup> (5) Sexual acquistion rate cn, cd 3yr−<sup>1</sup> (5) drug misuser per contact with a misuser cd<sup>1</sup> <sup>β</sup>d<sup>1</sup> 0.4yr−<sup>1</sup> (4) Rate of quitting drug misuse of sickness α 0.3yr−<sup>1</sup> (4) Rate of release from prison ω 0.25yr−<sup>1</sup> Assumed Proportion recruited into Sn, Sd, In, Id classes π1, π2, π3, π<sup>4</sup> 0.375,0.375,0.125,0.125 Assumed peer pressure forces influencing one to become an IDU, we used values adapted from Bhunu et al. (4) which are peer pressure forces necessary for one to start smoking, for the sake of illustration. For influence of peer pressure forces influencing one to become an IDU, we used values adapted from Bhunu et al. (2010) (4) which are peer pressure forces necessary for one Figure 2 is a graphical representation showing the effect of varying initial conditions when RSD > 1. In Figures 2(a) and 2(b) show the effects of varying the HIV-infected not yet showing sysmptoms on HIV-infected only and AIDS, respectively. Both graphs show a higher number of HIV-only and AIDS among intravenous drug using male prisoners than non-drug users. This tends to show intravenous drug using male prisoners are at increased risk of HIV infection due to sharing of unsterile needles and increased rates of homosexual sex habits. of HIV transmission among male prisoners. 4. Numerical simulations Product of effective contact rate for HIV infection and probability of HIV transmission Product of effective contact rate for becoming a drug user and probability of becoming a to start smoking. Table 1. Model parameters and their interpretations. Fig. 2. Effects of varying the HIV infected-only initial conditions when RSD > 1. Parameter values used are in Table 1. Fig. 3. Simulations showing the effects of varying the rate at which non-drug using prisoners become intravenous drug users on the population on drug using HIV-infected prisoners. Parameter values used are in Table 1. [4] Bhunu CP, Mushayabasa S, Tchuenche JM. A theoretical assessment of the effects of smoking on the transmission dynamics of tuberculosis. Bulletin of Mathematical Biology DOI 10.1007/s11538-010-9568-6, 2010(a). Available at HIV/AIDS Transmission Dynamics in Male Prisons 75 [5] Bhunu CP, Garira W, Mukandavire Z. Modelling HIV/AIDS and tuberculosis [6] Brauer F, C. Castillo-Chavez. Mathematical Models in Population Biology and [7] Buavirat A, Page-Shafer K, van Griensven GJP, Mandel JS, Evans J, Chuaratanaphong J, Chiamwongpat S, Sacks R, Moss A. Risk of prevalent HIV infection associated with incarceration among injecting drug users in Bangkok, Thailand: case-control study. BMJ [8] Centers for Disease Control and Prevention (CDC). HIV transmission among male inmates in a state prison system-Georgia, 1992-2005. MMWR Morb Mortal Wkly Rep [9] Centers for Disease Control and Prevention (CDC). National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. Prevention and control of tuberculosis in correctional and detention facilities: recommendations from CDC, endorsed by the Advisory Council for the Elimination of Tuberculosis, the National Commission on Correctional Health Care, and the American Correctional Association. MMWR Recomm Rep 55(RR-9): 1–44, [10] Centers for Disease Control and Prevention. Tuberculosis outbreaks in prison housing units for HIV-infected inmatesUCalifornia, 1995–1996. ˚ MMWR Morb Mortal Wkly Rep [11] Crofts N, Stewart T, Hearne P, Ping XY, Breschkin AM, Locarnini SA. Spread of bloodborne viruses among Australian prison entrants. BMJ 310(6975): 285–288, 1995. [13] Dolan J, Kite B, Aceijas C, Stimson GV. HIV in prison in low income and middle-income [14] Dolan KA, Wodak A. HIV transmission in a prison system in an Australian state. Med J [15] Flanigan TP, Rich JD, Spaulding A. HIV care among incarcerated persons: a missed [16] Green D, Al-Fwzan W. An improved optimistic three-stage model for the spread of HIV amongst injecting intravenous drug users. J Discrete Contin Dyn Sys (Supplement 2009): [18] Human Rights Watch. World Report; Special Programs and CampaignsUPrisons, 2002. ˚ [20] International Centre for Prison Studies. The World Female Imprisonment List. KingŠs [21] International Centre for Prison Studies. The World Prison Population List. KingŠs [22] Martin RE, Gold F, Murphy W, Remple V, Berkowitz J, Money D. Drug use and risk of bloodborne infections: a survey of female prisoners in British Columbia. Can J Public [12] Doll D. Tattooing in prison and HIV infection. The Lancet 2(9): 66-67, 1988. countries. Lancet Infectious Diseases 7: 32-43, 2007. [17] Human Rights Watch. HIV/AIDS in prisons, 2006. [19] Human Rights Watch. No Escape: Male Rape in USA Prisons, 1991. (http://www.springerlink.com/content/4n410216p3555249/fulltext.pdf) coinfection. Bulletin of Mathematical Biology 71: 1745-1780, 2009. Epidemiology, Springer, 2000. 326(7384): 308, 2003. 55(15): 421–426, 2006. 48(4):79–82, 1999. Aust 171(1):14–17, 1999. College, London, UK, 2006. College, London, UK, 2007. Health 96(2):97–101, 2005. 286-299, 2009. opportunity. AIDS 13(17): 2475, 1999. 2006. Figure 3 shows the effects of intravenous drug use on HIV/AIDS transmission dynamics among male prisoners is illustrated by varying the rate a male prisoner becoming an intravenous drug user while in prison. It shows an increase in the number of HIV/AIDS cases among drug users cases with increase in drug use while the opposite will be happening among non-drug users. This suggest that effective control of HIV among male prisoners to some extent on the control of intravenous drug use. #### 5. Discussion A mathematical model have been presented in attempt to understand the transmission dynamics of HIV/AIDS among male prisoners. Male prisoners are infected with HIV while in prison through intravenous drug use using unsterile needles (syringes) and homosexual tendencies. Intravenous drug use in male prisons act in two way: (i) sharing of unsterile needles/ syringes enhance the transmission of HIV; (ii) flashing blood that drawing is blood from someone who would have injected himself with a drug and inject it into one self which on its own exposes the injector to the HIV infection. Also intravenous drug using prisoners are more likely to engage in homosexual relations with other male prisoners and with it increased risky of HIV transmission. Analysis of the reproduction number have shown that (i) a reduction in drug use results in a decrease of HIV/ AIDS prevalence among male prisoners, (ii) release of prisoners may also act in reducing the concentration HIV/AIDS cases in prisons. The later fact is not feasible, but perhaps implementing opening prison systems where prisoners of less serious crimes are allowed to save their crimes while staying with their families enables male prisoners to cope up with stressful prison conditions. Open prison systems will reduce the influence of peer pressure among prisoners as they will have moral and pyschological support from the family which does not exist in enclosed prison systems. Numerical simulations carried also support the analytic results that increase in drug use and tattooing increases HIV/ AIDS prevalence among male prisoners. The result of this study have a public health implication considering high rates of syringe lending and borrowing in prisons. This might explain why there are more HIV cases in prisons than the general population in the case of the USA (8) and this might be the case world wide. HIV infected men in prison pose a risk to their communities upon release from prison, especially in Africa where partners in marriage rarely discuss safe sex so in the absence open prison systems, it may be best to have mandatory HIV/ AIDS screening and specific educational programmes for prisoners. This will reduce the prevalence of high-risk behaviours and lower HIV transmission in male prisons, thus reducing post-release public health threat. Given the high levels of HIV in prisons about three and half times higher among prisoners than the general population, it may be best to consider the introduction of needle/ syringe free exchange programme and drug substitution treatment as a way of keeping in check HIV transmission in men prisons. Additionally provision of condoms might also help given the high levels of homosexuality in male prisons. #### 6. References 8 Will-be-set-by-IN-TECH Figure 3 shows the effects of intravenous drug use on HIV/AIDS transmission dynamics among male prisoners is illustrated by varying the rate a male prisoner becoming an intravenous drug user while in prison. It shows an increase in the number of HIV/AIDS cases among drug users cases with increase in drug use while the opposite will be happening among non-drug users. This suggest that effective control of HIV among male prisoners to A mathematical model have been presented in attempt to understand the transmission dynamics of HIV/AIDS among male prisoners. Male prisoners are infected with HIV while in prison through intravenous drug use using unsterile needles (syringes) and homosexual tendencies. Intravenous drug use in male prisons act in two way: (i) sharing of unsterile needles/ syringes enhance the transmission of HIV; (ii) flashing blood that drawing is blood from someone who would have injected himself with a drug and inject it into one self which on its own exposes the injector to the HIV infection. Also intravenous drug using prisoners are more likely to engage in homosexual relations with other male prisoners and with it increased risky of HIV transmission. Analysis of the reproduction number have shown that (i) a reduction in drug use results in a decrease of HIV/ AIDS prevalence among male prisoners, (ii) release of prisoners may also act in reducing the concentration HIV/AIDS cases in prisons. The later fact is not feasible, but perhaps implementing opening prison systems where prisoners of less serious crimes are allowed to save their crimes while staying with their families enables male prisoners to cope up with stressful prison conditions. Open prison systems will reduce the influence of peer pressure among prisoners as they will have moral and pyschological support from the family which does not exist in enclosed prison systems. Numerical simulations carried also support the analytic results that increase in drug use and tattooing increases HIV/ AIDS prevalence among male prisoners. The result of this study have a public health implication considering high rates of syringe lending and borrowing in prisons. This might explain why there are more HIV cases in prisons than the general population in the case of the USA (8) and this might be the case world wide. HIV infected men in prison pose a risk to their communities upon release from prison, especially in Africa where partners in marriage rarely discuss safe sex so in the absence open prison systems, it may be best to have mandatory HIV/ AIDS screening and specific educational programmes for prisoners. This will reduce the prevalence of high-risk behaviours and lower HIV transmission in male prisons, thus reducing post-release public health threat. Given the high levels of HIV in prisons about three and half times higher among prisoners than the general population, it may be best to consider the introduction of needle/ syringe free exchange programme and drug substitution treatment as a way of keeping in check HIV transmission in men prisons. Additionally provision of condoms might also help given the [1] Amnesty International. Abuse of Women in Custody: Sexual Misconduct and Shackling [2] Anderson, May RM. Infectious Diseases of Humans, Dynamics and Control, Oxford [3] Bailey N, The Mathematical Theory of Infectious Diseases, Charles Griffin, 1975. some extent on the control of intravenous drug use. high levels of homosexuality in male prisons. of Pregnant Women, 2001. University Press, 1991. 6. References 5. Discussion Part 3 Prevention and Treatment of AIDS-Related Diseases	doab	2025-04-07T04:13:04.685015	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 21 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.22	Part 3 Prevention and Treatment of AIDS-Related Diseases 10 Will-be-set-by-IN-TECH 76 Global View of HIV Infection [23] Sarang A, Rhodes T, Platt L, Kirzhanova, V, Shelkovnikova O, Volnov V, Blagovo D, Rylkov A. Drug injecting and syringe use in the HIV risk environment of Russian [25] United Nations Office On Drugs and Crime (UNODC). HIV/AIDS prevention and care for female injecting drug users. http://www.unodc.org/pdf/HIV-AIDS\_femaleIDUs [27] van den Driessche P, Watmough J. Reproduction numbers and sub-threshold endemic equilibria for the compartmental models of disease transmission. Math Biosci 180: 29-48, penitentiary institutions: qualitative study. Addiction 101(12): 1787-1796, 2006. [24] United Nations Office On Drugs and Crime (UNODC). Women and HIV in prison settings. http://www.unodc.org/documents/hiv-aids/Women and HIV in prison [26] UNAIDS. AIDS Epidemic Update. Geneva, UNAIDS, 2006. settings.pdf, 2008. \_Aug06.pdf, 2006. 2002. 5 Individuals with HIV/AIDS: Clinical Ranjitha Krishna, Saiprasad Zemse and Scott Derossi Georgia Health Sciences University, College of Dental Medicine Oral lesions are very common in individuals with HIV (human immunodeficiency virus) infection and AIDS (acquired immune deficiency syndrome). They are reported to occur in 50% of people infected with HIV and in about 80% of people diagnosed with AIDS (Palmer, et al., 1996). Introduction of HAART (highly active anti-retroviral therapy) in 1996 has reduced the mortality and morbidity in people affected with HIV and AIDS as well as improved their quality of life. It has also resulted in a decrease, to a certain extent, in the Since HIV infection was first diagnosed in 1981, a variety of oral lesions has been associated with infected individuals, and they can be good indicators of the disease in otherwise healthy people. Oral lesions can also help determine the progression of the disease. In developed countries, CD4 lymphocyte counts and HIV viral load are the two main laboratory markers that are used to determine disease progression. However, in certain developing countries, people do not always have access to these tests, and severity of the Table 1 highlights the importance of diagnosing and treating oral lesions in individuals with 5. Used in staging and classification of HIV diseases as determinants of opportunistic The EC-Clearinghouse on oral problems related to HIV infection and WHO Collaborating Centre on Oral manifestations of the immunodeficiency virus proposed the classification of oral manifestations of HIV infection in September of 1992 based on their strength of 1. Can help diagnose the presence of HIV infection in otherwise healthy individuals 1. Introduction incidence and prevalence of oral lesions. HIV (Coogan, et al., 2005) 2. Develop early in an infection 4. Entry and end-points in vaccine trials infection and anti-HIV therapy oral lesions can serve as good indicators of disease progression. 3. Help determine the progression of HIV infection to AIDS Table 1. Importance of oral manifestations of HIV disease 1.1 Classification of oral lesions associated with HIV Manifestations in the Oral Cavity in the Post-HAART Era United States of America	doab	2025-04-07T04:13:04.685997	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 22 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.23	Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era Ranjitha Krishna, Saiprasad Zemse and Scott Derossi Georgia Health Sciences University, College of Dental Medicine United States of America	doab	2025-04-07T04:13:04.686332	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 23 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.24	1. Introduction Oral lesions are very common in individuals with HIV (human immunodeficiency virus) infection and AIDS (acquired immune deficiency syndrome). They are reported to occur in 50% of people infected with HIV and in about 80% of people diagnosed with AIDS (Palmer, et al., 1996). Introduction of HAART (highly active anti-retroviral therapy) in 1996 has reduced the mortality and morbidity in people affected with HIV and AIDS as well as improved their quality of life. It has also resulted in a decrease, to a certain extent, in the incidence and prevalence of oral lesions. Since HIV infection was first diagnosed in 1981, a variety of oral lesions has been associated with infected individuals, and they can be good indicators of the disease in otherwise healthy people. Oral lesions can also help determine the progression of the disease. In developed countries, CD4 lymphocyte counts and HIV viral load are the two main laboratory markers that are used to determine disease progression. However, in certain developing countries, people do not always have access to these tests, and severity of the oral lesions can serve as good indicators of disease progression. Table 1 highlights the importance of diagnosing and treating oral lesions in individuals with HIV (Coogan, et al., 2005) Table 1. Importance of oral manifestations of HIV disease #### 1.1 Classification of oral lesions associated with HIV The EC-Clearinghouse on oral problems related to HIV infection and WHO Collaborating Centre on Oral manifestations of the immunodeficiency virus proposed the classification of oral manifestations of HIV infection in September of 1992 based on their strength of Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 81 high in developing countries (Tukutuku, et al., 1990). Since the discovery of HIV in 1981, candidiasis has been shown to be associated with HIV-infected individuals (Gottlieb, et al., 1981). Previous reports show that oral candidiasis occurs in 54-93% of individuals with AIDS (Schmidt-Westhausen, et al., 1991). In recent reports, due to the introduction of antiretroviral therapy only 20% of individuals infected with HIV showed oral candidiasis Oral candidiasis is primarily caused by a dimorphic ubiquitous Candida albicans. The cell wall of Candida is primarily made up of three polysaccharides, mannan, glucan and chitin. Candida attaches to oral tissues and dentures with the help of adhesins such as Als1p, Als5p, Int1p and Hwp1p (Chaffin, et al., 1998, Hostetter, 1994). These glycoproteins bind to the extracellular matrix of mammalian cells such as fibrinogen, laminin and collagen (Chaffin, et al., 1998). Candidal adhesion to endothelial surfaces is achieved by the cell surface polysaccharide mannan, which binds to complement receptor 3 (CR3), an integrin found on human cells (Calderone and Braun, 1991). There is increased association of integrin analogs (iC3B and CR3d receptor) and fibronectin receptor with most of the virulent forms of Candida (Ollert, et al., 1990). Thus, CR3-like proteins promote adherence of Candida albicans There are three clinical forms of candidiasis: pseudo-membranous (thrush), erythematous (atrophic) and perioral angular chelitis. Proliferation of pseudomembranous fungi forms a gray-white structure composed of inflammatory substrate and matted organisms resting on an erythematous base. These lesions are most commonly evident on the tongue, buccal mucosa, hard and soft palate and pharyngeal tissues. The erythematous form shows mucosal hyperemia and inflammation with a reddened erythematous patches (Calderone and Fonzi, 2001). The mucous membrane appears dry, red and glazed. Affected individuals show burning sensitivity and pain sensation of dry mouth, odynophagia, dysgeusia and smell of yeast infection. Angular chelitis shows commissural involvement as erythematous/hyperkeratotic with fissuring and sensitivity. Individuals receiving HAART show low occurrence of these clinical features. Before the emergence of HAART, the incidence of oral candidiasis was An early study for treatment of Candida infections was carried out by Williams in 1977, where nystatin was compared to no treatment in 56 patients (Williams, et al., 1977). Since then ketoconazole, fluconazole, clotrimazole, itraconazole, neomycin sulphate, colistin, trimethoprin and sulphamethoxazole have been tried in combination and at different concentrations for treatment of oral candidiasis (Hann, et al., 1982, Owens, et al., 1984, Palmblad, et al., 1992, Philpott-Howard, et al., 1993, Rozenberg-Arska, et al., 1991, Vogler, et al., 1987). Most recently ketoconazole and clotrimazole were found most effective in treatment of oral candidiasis (Worthington, et al., 2002). Initial local treatments are first line of therapy (Bensadoun, et al., 2008). Mucosal contact for 2 minutes is recommended either by rinsing, gargling or swallowing. (Davies, et al., 2006). 2.2 Pathogenesis to host cells. 2.4 Treatment 2.3 Clinical features relatively high in persons with AIDS. association with the presence of HIV infection: ("Classification and Diagnostic Criteria for Oral Lesions in HIV Infection. EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus," 1993). More recently in 2002, an international workshop was convened to discuss the classification of oral lesions associated with HIV/AIDS almost 2 decades after the virus was first identified (Patton, et al., 2002) and it was agreed that the original EC-Clearinghouse classification could still be used in current times. Table 2 summarizes the classification of oral lesions associated with HIV. Table 2. Classification of oral lesions associated with HIV In this chapter, we will discuss only those lesions that are commonly seen in persons infected with HIV. #### 2. Candidiasis #### 2.1 Background Candidiasis is a common opportunistic infection caused by an overgrowth of the Candida microorganisms already present in the oral cavity. Incidence of oral candidiasis has been high in developing countries (Tukutuku, et al., 1990). Since the discovery of HIV in 1981, candidiasis has been shown to be associated with HIV-infected individuals (Gottlieb, et al., 1981). Previous reports show that oral candidiasis occurs in 54-93% of individuals with AIDS (Schmidt-Westhausen, et al., 1991). In recent reports, due to the introduction of antiretroviral therapy only 20% of individuals infected with HIV showed oral candidiasis (Davies, et al., 2006). ### 2.2 Pathogenesis 80 Global View of HIV Infection association with the presence of HIV infection: ("Classification and Diagnostic Criteria for Oral Lesions in HIV Infection. EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus," 1993). More recently in 2002, an international workshop was convened to discuss the classification of oral lesions associated with HIV/AIDS almost 2 decades after the virus was first identified (Patton, et al., 2002) and it was agreed that the original EC-Clearinghouse classification could still be used in current times. Table 2 summarizes the classification of > Group 2: Lesions less commonly associated with Bacterial infections: Mycobacterium avium- hyperpigmentation Necrotizing (ulcerative) Salivary gland disease Dry mouth due to decreased salivary flow Unilateral/bilateral swelling of salivary glands Thrombocytopenia purpura Non-specific ulcerations Viral infections: Herpes simplex virus Human papillomavirus Condyloma acuminatum Focal epithelial hyperplasia Verruca vulgaris Varicella-zoster virus In this chapter, we will discuss only those lesions that are commonly seen in persons Candidiasis is a common opportunistic infection caused by an overgrowth of the Candida microorganisms already present in the oral cavity. Incidence of oral candidiasis has been Table 2. Classification of oral lesions associated with HIV Mycobacterium tuberculosis Group 3: Lesions seen in Bacterial infections: Actinomyces israelii Escherichia coli Klebsiella pneumonia Cat-scratch disease Drug reactions (ulcerative, erythema multiforme, lichenoid, toxic epidermolysis) Epitheliod (bacillary) Fungal infection other than Neurological disturbances: Trigeminal neuralgia Cryptococcus neoformans Geotrichum candidum Histoplasma capsulatum Mucoraceae (mucomycosis HIV infection angiomatosis candidiasis zygomycosis) Aspergilus flavus Facial palsy HIV infection intracellularae Melanogic stomatitis oral lesions associated with HIV. Group 1: Lesions strongly associated with HIV Non-Hodgkin's lymphoma Periodontal disease (linear gingival erythema, necrotizing ulcerative gingivitis, necrotizing ulcerative periodontitis) infected with HIV. 2. Candidiasis 2.1 Background infection Candidiasis Hairy leukoplakia Kaposi's sarcoma Oral candidiasis is primarily caused by a dimorphic ubiquitous Candida albicans. The cell wall of Candida is primarily made up of three polysaccharides, mannan, glucan and chitin. Candida attaches to oral tissues and dentures with the help of adhesins such as Als1p, Als5p, Int1p and Hwp1p (Chaffin, et al., 1998, Hostetter, 1994). These glycoproteins bind to the extracellular matrix of mammalian cells such as fibrinogen, laminin and collagen (Chaffin, et al., 1998). Candidal adhesion to endothelial surfaces is achieved by the cell surface polysaccharide mannan, which binds to complement receptor 3 (CR3), an integrin found on human cells (Calderone and Braun, 1991). There is increased association of integrin analogs (iC3B and CR3d receptor) and fibronectin receptor with most of the virulent forms of Candida (Ollert, et al., 1990). Thus, CR3-like proteins promote adherence of Candida albicans to host cells. ## 2.3 Clinical features There are three clinical forms of candidiasis: pseudo-membranous (thrush), erythematous (atrophic) and perioral angular chelitis. Proliferation of pseudomembranous fungi forms a gray-white structure composed of inflammatory substrate and matted organisms resting on an erythematous base. These lesions are most commonly evident on the tongue, buccal mucosa, hard and soft palate and pharyngeal tissues. The erythematous form shows mucosal hyperemia and inflammation with a reddened erythematous patches (Calderone and Fonzi, 2001). The mucous membrane appears dry, red and glazed. Affected individuals show burning sensitivity and pain sensation of dry mouth, odynophagia, dysgeusia and smell of yeast infection. Angular chelitis shows commissural involvement as erythematous/hyperkeratotic with fissuring and sensitivity. Individuals receiving HAART show low occurrence of these clinical features. Before the emergence of HAART, the incidence of oral candidiasis was relatively high in persons with AIDS. #### 2.4 Treatment An early study for treatment of Candida infections was carried out by Williams in 1977, where nystatin was compared to no treatment in 56 patients (Williams, et al., 1977). Since then ketoconazole, fluconazole, clotrimazole, itraconazole, neomycin sulphate, colistin, trimethoprin and sulphamethoxazole have been tried in combination and at different concentrations for treatment of oral candidiasis (Hann, et al., 1982, Owens, et al., 1984, Palmblad, et al., 1992, Philpott-Howard, et al., 1993, Rozenberg-Arska, et al., 1991, Vogler, et al., 1987). Most recently ketoconazole and clotrimazole were found most effective in treatment of oral candidiasis (Worthington, et al., 2002). Initial local treatments are first line of therapy (Bensadoun, et al., 2008). Mucosal contact for 2 minutes is recommended either by rinsing, gargling or swallowing. Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 83 Fig. 3. Pseudo-membranous Candidiasis Fig. 4. Atrophic/Erythematous Candidiasis Systemic treatments are considered in high-risk patients only when local therapy fails (Charlier, et al., 2006). When topical and systemic therapy fails, intravenously administered amphotericin B and echinocandins are considered in high-risk patients. Intermittent use of antifungal agents has been advocated to prevent development of resistant fungal infections (Samaranayake, et al., 2002). Recently, gel formulation of fluconazole has proven to be a better alternative treatment form than tablet formulation (Nairy, et al.). Fig. 1. Cell wall of Candida albicans Fig. 2. Hypertrophic Candidiasis Fig. 3. Pseudo-membranous Candidiasis Systemic treatments are considered in high-risk patients only when local therapy fails (Charlier, et al., 2006). When topical and systemic therapy fails, intravenously administered amphotericin B and echinocandins are considered in high-risk patients. Intermittent use of antifungal agents has been advocated to prevent development of resistant fungal infections (Samaranayake, et al., 2002). Recently, gel formulation of fluconazole has proven to be a better alternative treatment form than tablet formulation (Nairy, et al.). Fig. 1. Cell wall of Candida albicans Fig. 2. Hypertrophic Candidiasis Fig. 4. Atrophic/Erythematous Candidiasis Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 85 anti-retroviral drugs. However, if OHL is seen in an HIV-infected person, it may indicate failure of current therapy. Differential diagnosis of this condition includes oral candidiasis, lichen planus, other forms of leukoplakia, HPV (human papilloma virus) associated OHL is a relatively benign condition with low morbidity and does not require any specific treatment. Most of the time, these lesions resolve spontaneously. However, several treatment options are available for those who feel uncomfortable or have cosmetic concerns due to the lesion. Since the lesion is caused by multiplication of the Epstein-Barr virus topical and systemic anti-viral agents work effectively in resolving the lesion. High doses of Acyclovir (800 mg 5 times a day) (Resnick, et al., 1988), Valacyclovir (1000 mg 3 times a day), and Famciclovir (500 mg 3 times a day) have all been shown to resolve the lesions in 1-2 weeks (Schofer, et al., 1987). However, once the effect of the anti-viral agent wears off, the Topical application of Podophyllin resin in 25% solution has produced resolution of the lesion in 1-2 weeks (Gowdey, et al., 1995). Topical therapy with retinoic acid has also been shown to cause resolve the lesions due to inhibition of Epstein-Barr virus replication. Ablative and cryotherapy have also had success in treatment of the lesions. Although the above treatment options are effective in resolving the lesion, OHL can recur several weeks after treatment since none of these agents eliminate the latent state intraepithelial neoplasia, and oral squamous cell carcinoma. Fig. 6. Oral Hairy Leukoplakia lesions can recur several weeks later. 3.4 Treatment of infection. Fig. 5. Angular Chelitis	doab	2025-04-07T04:13:04.686363	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 24 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.25	3. Hairy leukoplakia ## 3.1 Background OHL (Oral hairy leukoplakia) is caused by Epstein-Barr virus and was first described in 1984. 50% of individuals with HIV present with this condition and it is a very good indicator of immunosuppression. The lesion usually presents itself when the CD4 cell counts fall below 0.3\109/L (Bravo, et al., 2006). According to the CDC (Centers for Disease Control and Prevention), this condition has a clear prognostic value in predicting the future development of AIDS ("1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS among Adolescents and Adults," 1992). #### 3.2 Pathogenesis* The pathogenesis of OHL is due to the replication of Epstein-Barr virus and increased virulence in conjunction with a decrease in local and systemic host immunity. #### 3.3 Clinical features OHL present themselves as white, corrugated lesions on the lateral surface of the tongue and are not painful. There has been a decrease in the incidence of OHL due to the potent anti-retroviral drugs. However, if OHL is seen in an HIV-infected person, it may indicate failure of current therapy. Differential diagnosis of this condition includes oral candidiasis, lichen planus, other forms of leukoplakia, HPV (human papilloma virus) associated intraepithelial neoplasia, and oral squamous cell carcinoma. Fig. 6. Oral Hairy Leukoplakia #### 3.4 Treatment 84 Global View of HIV Infection OHL (Oral hairy leukoplakia) is caused by Epstein-Barr virus and was first described in 1984. 50% of individuals with HIV present with this condition and it is a very good indicator of immunosuppression. The lesion usually presents itself when the CD4 cell counts fall below 0.3\109/L (Bravo, et al., 2006). According to the CDC (Centers for Disease Control and Prevention), this condition has a clear prognostic value in predicting the future development of AIDS ("1993 Revised Classification System for HIV Infection and Expanded The pathogenesis of OHL is due to the replication of Epstein-Barr virus and increased OHL present themselves as white, corrugated lesions on the lateral surface of the tongue and are not painful. There has been a decrease in the incidence of OHL due to the potent Surveillance Case Definition for AIDS among Adolescents and Adults," 1992). virulence in conjunction with a decrease in local and systemic host immunity. Fig. 5. Angular Chelitis 3. Hairy leukoplakia* 3.1 Background 3.2 Pathogenesis 3.3 Clinical features OHL is a relatively benign condition with low morbidity and does not require any specific treatment. Most of the time, these lesions resolve spontaneously. However, several treatment options are available for those who feel uncomfortable or have cosmetic concerns due to the lesion. Since the lesion is caused by multiplication of the Epstein-Barr virus topical and systemic anti-viral agents work effectively in resolving the lesion. High doses of Acyclovir (800 mg 5 times a day) (Resnick, et al., 1988), Valacyclovir (1000 mg 3 times a day), and Famciclovir (500 mg 3 times a day) have all been shown to resolve the lesions in 1-2 weeks (Schofer, et al., 1987). However, once the effect of the anti-viral agent wears off, the lesions can recur several weeks later. Topical application of Podophyllin resin in 25% solution has produced resolution of the lesion in 1-2 weeks (Gowdey, et al., 1995). Topical therapy with retinoic acid has also been shown to cause resolve the lesions due to inhibition of Epstein-Barr virus replication. Ablative and cryotherapy have also had success in treatment of the lesions. Although the above treatment options are effective in resolving the lesion, OHL can recur several weeks after treatment since none of these agents eliminate the latent state of infection. Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 87 indicated for lesions on the face, hands and upper extremities, obstructive lymphadenopathy, periorbital edema, lesions on soles of the feet, anorectal or genital lesions, oral lesions and ulcerating cutaneous lesions. Radiotherapy shows merits in symptomatic disease where systemic treatment is not necessary and expensive chemotherapy can be avoided (Swift, 1996). If an active opportunistic infection is observed, chemotherapeutic agents should be considered. Systemic chemotherapeutic treatment is indicated in extensive KS of oral cavity, widespread skin involvement, pedal or scrotal edema, symptomatic visceral involvement and flare induced by immune reconstitution inflammatory syndrome (Osoba, et al., 2001). Individuals may suffer from neutropenia and thrombocytopenia and hence controlled therapy should be the choice of treatment. Only nodular and symptomatic lesions of oropharynx should be treated with radiation. Recombinant and non-recombinant alpha interferons can be used for treatment HPV is the leading cause of orpharyngeal carcinomas (D'Souza, et al., Rosenquist, 2005). HPV16 is a common cause for the majority of oropharyngeal carcinomas (Kreimer, et al., 2005) . HPV-positive individuals are most frequently Caucasian and belong to high socioeconomic status (Gillison, et al., 2008). HIV-infected individuals have two to four-fold increase in risk for developing HPV-related oral cancers (Gilbert, et al.). HPV has also been considered as one of the etiologic factors for OHL (oral hairy leukoplakia) (Fejerskov, et al., 1977), as shown by identification of HPV antigens and HPV DNA (Loning, et al., 1985). HPV-induced OL shows prevalence ranged from 17% to 68.6% (Shroyer, et al., 1993, of epidemic KS (De Wit, et al., 1988). Fig. 7. Kaposi's Sarcoma Sugiyama, et al., 2003). 5.1 Background 5. Human Papilloma Virus (HPV) infections	doab	2025-04-07T04:13:04.686975	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 25 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.26	4. Kaposi's sarcoma #### 4.1 Background KS (Kaposi's sarcoma) is an angioproliferative tumor described by the Hungarian pathologist Moritz Kaposi in 1872. It is caused by KSHV (Kaposi's sarcoma-associated herpes virus) or γ2-herpes virus. KSHV belongs to the genus Rhadinovirus and has a DNA sequence similar to other rhadinoviruses (Albrecht, et al., 1992). With the introduction of HAART in 1996, the incidence of AIDS-related cancers such as KS and NHL (non - Hodgkin's lymphoma) has decreased (Shiels, et al., 2008). During the 1980s and early 1990s, US population rates of KS increased 30 fold (Eltom, et al., 2002). There were no KS cases during 1975-1979, before the advent of AIDS. In an HIV cancer match study, 81% of KS cases matched to HIV registries during 1980-2007 (Shiels, et al., 2011). AIDS occurred in a higher proportion of patients with Kaposi's sarcoma in age groups of 0-29 and 30-59 years (Shiels, et al., 2011). #### 4.2 Pathogenesis KS lesions show varying cell diversity. Lesions are flat, comprising of inflammatory cells (T, B cells and monocytes). Neovascularization develops prior to development of these lesions and contain spindle-shaped cells. This dermal stage progresses to the plaque stage, in which the lesions are more indurated, edematous, and red or violet in color. The lesion eventually reaches the nodular stage and is characterized by visible masses with dominant spindle cells and inflammatory cells. These spindle cells express lymphatic-specific markers (e.g., Podoplanin and lymphatic vessel hyaluronan receptor LYVE-1) as well as participate in the signaling process during lymphangiogenesis (Skobe, et al., 1999, Weninger, et al., 1999). #### 4.3 Clinical features There are four types of KS: classic type, endemic African KS, KS in organ transplant recipients, and HIV-infection/AIDS associated KS (Trattner, et al., 1993). KS is the most common neoplasm (20-50%) found in HIV-infected individuals (mostly homosexual and bisexual men) (Scully, et al., 1991).Oral lesions are evident in 40% of KS (Greenspan and Greenspan, 1990).Red or purplish macules, papules or nodules appear most frequently on the hard palate (Greenspan and Greenspan, 1990). Unless infected or ulcerated, these lesions do not blanch on pressure (Greenspan and Greenspan, 1990). Laryngeal involvement is also evident in individuals with KS (Pantanowitz and Dezube, 2006). Primary symptoms are hoarseness, throat discomfort, urge to cough, aphonia, dysphagia, stridor, and complete airway obstruction. #### 4.4 Treatment The extent and bulk of the disease determines the therapeutic alternative that needs to be considered. Individuals with fewer than five cutaneous lesions are kept on watch until rapid proliferation, widespread dissemination or KS-related symptoms become more apparent. Treatment with HAART or other anti-retroviral therapies are beneficial and have shown histologic regression of existing lesions (Eng and Cockerell, 2004). HAART therapy causes inhibition of HIV replication, diminishes the HIV-1 transactivating protein Tat, ameliorates the immune response against KSHV, and shows direct anti-angiogenic activity (Cattelan, et al., 1999, Pati, et al., 2002, Sgadari, et al., 2002). Radiotherapy is indicated for lesions on the face, hands and upper extremities, obstructive lymphadenopathy, periorbital edema, lesions on soles of the feet, anorectal or genital lesions, oral lesions and ulcerating cutaneous lesions. Radiotherapy shows merits in symptomatic disease where systemic treatment is not necessary and expensive chemotherapy can be avoided (Swift, 1996). If an active opportunistic infection is observed, chemotherapeutic agents should be considered. Systemic chemotherapeutic treatment is indicated in extensive KS of oral cavity, widespread skin involvement, pedal or scrotal edema, symptomatic visceral involvement and flare induced by immune reconstitution inflammatory syndrome (Osoba, et al., 2001). Individuals may suffer from neutropenia and thrombocytopenia and hence controlled therapy should be the choice of treatment. Only nodular and symptomatic lesions of oropharynx should be treated with radiation. Recombinant and non-recombinant alpha interferons can be used for treatment of epidemic KS (De Wit, et al., 1988). Fig. 7. Kaposi's Sarcoma ## 5. Human Papilloma Virus (HPV) infections #### 5.1 Background 86 Global View of HIV Infection KS (Kaposi's sarcoma) is an angioproliferative tumor described by the Hungarian pathologist Moritz Kaposi in 1872. It is caused by KSHV (Kaposi's sarcoma-associated herpes virus) or γ2-herpes virus. KSHV belongs to the genus Rhadinovirus and has a DNA sequence similar to other rhadinoviruses (Albrecht, et al., 1992). With the introduction of HAART in 1996, the incidence of AIDS-related cancers such as KS and NHL (non - Hodgkin's lymphoma) has decreased (Shiels, et al., 2008). During the 1980s and early 1990s, US population rates of KS increased 30 fold (Eltom, et al., 2002). There were no KS cases during 1975-1979, before the advent of AIDS. In an HIV cancer match study, 81% of KS cases matched to HIV registries during 1980-2007 (Shiels, et al., 2011). AIDS occurred in a higher proportion of patients with Kaposi's sarcoma in age groups of 0-29 and 30-59 years (Shiels, KS lesions show varying cell diversity. Lesions are flat, comprising of inflammatory cells (T, B cells and monocytes). Neovascularization develops prior to development of these lesions and contain spindle-shaped cells. This dermal stage progresses to the plaque stage, in which the lesions are more indurated, edematous, and red or violet in color. The lesion eventually reaches the nodular stage and is characterized by visible masses with dominant spindle cells and inflammatory cells. These spindle cells express lymphatic-specific markers (e.g., Podoplanin and lymphatic vessel hyaluronan receptor LYVE-1) as well as participate in the signaling process during lymphangiogenesis (Skobe, et al., 1999, Weninger, et al., 1999). There are four types of KS: classic type, endemic African KS, KS in organ transplant recipients, and HIV-infection/AIDS associated KS (Trattner, et al., 1993). KS is the most common neoplasm (20-50%) found in HIV-infected individuals (mostly homosexual and bisexual men) (Scully, et al., 1991).Oral lesions are evident in 40% of KS (Greenspan and Greenspan, 1990).Red or purplish macules, papules or nodules appear most frequently on the hard palate (Greenspan and Greenspan, 1990). Unless infected or ulcerated, these lesions do not blanch on pressure (Greenspan and Greenspan, 1990). Laryngeal involvement is also evident in individuals with KS (Pantanowitz and Dezube, 2006). Primary symptoms are hoarseness, throat discomfort, urge to cough, aphonia, dysphagia, stridor, and complete The extent and bulk of the disease determines the therapeutic alternative that needs to be considered. Individuals with fewer than five cutaneous lesions are kept on watch until rapid proliferation, widespread dissemination or KS-related symptoms become more apparent. Treatment with HAART or other anti-retroviral therapies are beneficial and have shown histologic regression of existing lesions (Eng and Cockerell, 2004). HAART therapy causes inhibition of HIV replication, diminishes the HIV-1 transactivating protein Tat, ameliorates the immune response against KSHV, and shows direct anti-angiogenic activity (Cattelan, et al., 1999, Pati, et al., 2002, Sgadari, et al., 2002). Radiotherapy is 4. Kaposi's sarcoma 4.1 Background et al., 2011). 4.2 Pathogenesis 4.3 Clinical features airway obstruction. 4.4 Treatment HPV is the leading cause of orpharyngeal carcinomas (D'Souza, et al., Rosenquist, 2005). HPV16 is a common cause for the majority of oropharyngeal carcinomas (Kreimer, et al., 2005) . HPV-positive individuals are most frequently Caucasian and belong to high socioeconomic status (Gillison, et al., 2008). HIV-infected individuals have two to four-fold increase in risk for developing HPV-related oral cancers (Gilbert, et al.). HPV has also been considered as one of the etiologic factors for OHL (oral hairy leukoplakia) (Fejerskov, et al., 1977), as shown by identification of HPV antigens and HPV DNA (Loning, et al., 1985). HPV-induced OL shows prevalence ranged from 17% to 68.6% (Shroyer, et al., 1993, Sugiyama, et al., 2003). Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 89 Treatment of HPV infection can be achieved either by use of targeted therapy against the virus or immune-stimulating therapy. Most dysplastic tissue can be treated by ablative and excisional therapy. Use of radiochemotherapy in the form of radiation ± cisplatin or cetuximal has shown beneficial results in treatment of oropharyngeal carcinoma. The overall survival rate was 60 % in HPV-positive individuals and 73 % in HPV-negative individuals This lesion is also known as 'red-band gingivitis' or 'HIV-associated gingivitis'. LGE is commonly seen in immune-compromised individuals and is considered to be a potential precursor for necrotizing ulcerative gingivitis (NUG)/ necrotizing ulcerative periodontitis (NUP). According to the recent classification of periodontal diseases (Armitage, 1999), LGE There is an increased number of bacteria and Candida species in the gingival sulcus associated with LGE. The bacteria seen include those commonly observed in periodontal disease such as Bacteriodes gingivalis, Bacteriodes intermedius, Actinomyces viscosus, The lesions present themselves as 2-3 mm wide red band around the marginal gingival of Typically, no treatment is needed for this condition. Although LGE is listed under 'Lesions of fungal origin', it is not typically treated with anti-fungal medications. Mechanical removal of plaque and calculus helps reduce inflammation and excessive bleeding. Chlorhexidine gluconate (0.12%) mouth rinses can be used twice daily. If the lesion persists, NUG is a painful condition of the gingiva characterized by ulcerations, bleeding, and foul breath. It is also called Vincent's infection, Vincent's angina, or trench mouth. When the infection spreads to the alveolar bone, it is called NUP. Prevalence of NUP in HIV-infected individuals has been reported by various researchers. Its prevalence with HIV was reported in 1994 as 6% (Glick, et al., 1994). Over a period of a decade, the incidence of HIV in NUP patients increased to 69.6% (Shangase, et al., 2004). Recent reports suggest 43% of patients with NUP were HIV-seropositive (Phiri, et al.). Studies have shown that HIV-infected individuals with NUP are 20.8% more likely to have a CD4+ count lower than 200 (Glick, et systemic antibiotics (metronidazole) may be prescribed to reduce the bacterial load. 6.2 Necrotizing Ulcerative Gingivitis and Periodontitis (NUG and NUP) 5.4 Treatment (Lill, et al.). 6.1.1 Background 6.1.2 Pathogenesis 6.1.3 Clinical features 6.1.4 Treatmen 6.2.1 Background al., 1994). 6. Periodontal lesions associated with HIV is classified under 'Gingival diseases of fungal origin.' Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. the teeth. These lesions are not typically painful, but bleed readily. 6.1 Linear Gingival Erythema (LGE) #### 5.2 Pathogenesis HPV is mainly infectious through expression of oncogenes such as E6/E7 (Al-Bakkal, et al., 1999), which cause phosphorylation of CHK2, leading to caspase activation (Al-Bakkal, et al., 1999, Moody and Laimins, 2009, Tominaga, et al., 1999). The intrinsic apoptotic pathway of caspase activation plays an important role in HPV replication (Moody, et al., 2007). HPV proteins flourish and regulate amplification primarily by caspase activation, leading to immortalization of the suprabasal layer of epithelium, specifically the keratinocytes (Sakai, et al., 1996). ### 5.3 Clinical features HPV induced oral and pharyngeal cancers are most evident in younger females (<40 years). OSCC (oral squamous cell carcinoma) normally occur on the buccal mucosa (2-10%), lip (4- 40%), alveolar ridge (2-18%) retromolar trigonous (2-6%), hard palate (3-6%), floor of mouth (25%), ventral two third of tongue (50%), alveolar ridge (2-18%), floor of mouth (25%) and oropharynx (25%). Squamous cell carcinoma of the oropharynx most commonly originates in the tonsils and tongue base (the two most common sites), pharyngeal walls, and soft palate. Fig. 8. Human Papilloma Virus Lesions ### 5.4 Treatment 88 Global View of HIV Infection HPV is mainly infectious through expression of oncogenes such as E6/E7 (Al-Bakkal, et al., 1999), which cause phosphorylation of CHK2, leading to caspase activation (Al-Bakkal, et al., 1999, Moody and Laimins, 2009, Tominaga, et al., 1999). The intrinsic apoptotic pathway of caspase activation plays an important role in HPV replication (Moody, et al., 2007). HPV proteins flourish and regulate amplification primarily by caspase activation, leading to immortalization of the suprabasal layer of epithelium, specifically the keratinocytes (Sakai, HPV induced oral and pharyngeal cancers are most evident in younger females (<40 years). OSCC (oral squamous cell carcinoma) normally occur on the buccal mucosa (2-10%), lip (4- 40%), alveolar ridge (2-18%) retromolar trigonous (2-6%), hard palate (3-6%), floor of mouth (25%), ventral two third of tongue (50%), alveolar ridge (2-18%), floor of mouth (25%) and oropharynx (25%). Squamous cell carcinoma of the oropharynx most commonly originates in the tonsils and tongue base (the two most common sites), pharyngeal walls, and soft 5.2 Pathogenesis et al., 1996). palate. 5.3 Clinical features Fig. 8. Human Papilloma Virus Lesions Treatment of HPV infection can be achieved either by use of targeted therapy against the virus or immune-stimulating therapy. Most dysplastic tissue can be treated by ablative and excisional therapy. Use of radiochemotherapy in the form of radiation ± cisplatin or cetuximal has shown beneficial results in treatment of oropharyngeal carcinoma. The overall survival rate was 60 % in HPV-positive individuals and 73 % in HPV-negative individuals (Lill, et al.).	doab	2025-04-07T04:13:04.687238	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 26 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.28	6.1 Linear Gingival Erythema (LGE) 6.1.1 Background This lesion is also known as 'red-band gingivitis' or 'HIV-associated gingivitis'. LGE is commonly seen in immune-compromised individuals and is considered to be a potential precursor for necrotizing ulcerative gingivitis (NUG)/ necrotizing ulcerative periodontitis (NUP). According to the recent classification of periodontal diseases (Armitage, 1999), LGE is classified under 'Gingival diseases of fungal origin.' #### 6.1.2 Pathogenesis There is an increased number of bacteria and Candida species in the gingival sulcus associated with LGE. The bacteria seen include those commonly observed in periodontal disease such as Bacteriodes gingivalis, Bacteriodes intermedius, Actinomyces viscosus, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. #### 6.1.3 Clinical features The lesions present themselves as 2-3 mm wide red band around the marginal gingival of the teeth. These lesions are not typically painful, but bleed readily. #### 6.1.4 Treatmen Typically, no treatment is needed for this condition. Although LGE is listed under 'Lesions of fungal origin', it is not typically treated with anti-fungal medications. Mechanical removal of plaque and calculus helps reduce inflammation and excessive bleeding. Chlorhexidine gluconate (0.12%) mouth rinses can be used twice daily. If the lesion persists, systemic antibiotics (metronidazole) may be prescribed to reduce the bacterial load. #### 6.2 Necrotizing Ulcerative Gingivitis and Periodontitis (NUG and NUP) 6.2.1 Background NUG is a painful condition of the gingiva characterized by ulcerations, bleeding, and foul breath. It is also called Vincent's infection, Vincent's angina, or trench mouth. When the infection spreads to the alveolar bone, it is called NUP. Prevalence of NUP in HIV-infected individuals has been reported by various researchers. Its prevalence with HIV was reported in 1994 as 6% (Glick, et al., 1994). Over a period of a decade, the incidence of HIV in NUP patients increased to 69.6% (Shangase, et al., 2004). Recent reports suggest 43% of patients with NUP were HIV-seropositive (Phiri, et al.). Studies have shown that HIV-infected individuals with NUP are 20.8% more likely to have a CD4+ count lower than 200 (Glick, et al., 1994). Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 91 The clinical characteristics of NUG includes ulcerated and necrotic papillary and marginal gingival covered by a yellowish-white or grayish slough or "pseudomembrane", blunting and cratering of papillae, spontaneous bleeding or bleeding on probing, pain and fetid breath (Barnes, et al., 1973, Falkler, et al., 1987, Horning and Cohen, 1995). It may be accompanied by fever, lymphadenopathy, and malaise. Progression of gingivitis to NUP is The first treatment for NUG was devised by Dr. S. Schluger in 1949 (Schluger, 1949).Bacterial pathogens were controlled or eliminated by mechanical debridement or use of antibiotics in earlier days (Johnson and Engel, 1986). Aureomycin and penicillin were the first antibiotics considered for treatment of NUG in 1950 (Goldman and Bloom, 1950, Montis, 1950). Mechanical treatment consists of scaling and root planing. In addition to mechanical debridement, antibiotic and antimicrobial therapies are essential for management of NUP. Oxidizing mouthwash such as 3% hydrogen peroxide has also shown There are three subtypes of on-Hodgkin's lymphoma (NHL): diffuse large B cell lymphoma (DLBCL), Burkitt's lymphoma (BL) and central nervous system lymphoma (CNSL)(Engels, commonly associated with clinical attachment loss and alveolar bone destruction. 6.2.3 Clinical features Fig. 10. Necrotizing Ulcerative Periodontitis 7. Non-Hodgkin lymphoma to have beneficial effects in management of NUG and NUP. 6.2.4 Treatment 7.1 Background Fig. 9. Linear Gingival Erythema #### 6.2.2 Pathogenesis NUP is commonly a progression of NUG that demonstrates bone loss and clinical attachment levels (MacCarthy and Claffey, 1991). Both are primarily caused by bacterial infection with microflora consisting of Treponema and Selenomonas species, Prevotella intermedia, Fusobacterium nucleatum and Porphyromonas gingivalis (Falkler, et al., 1987, Loesche, et al., 1982). Malnutrition, smoking, stress, trauma and preexisting gingivitis are other etiologic factors (Peruzzo, et al., 2007, Taiwo, 1993). Most persons with NUG have alterations in the immune system making them more prone to microbial infections (Cogen, et al., 1983). This immunosuppression is also evident in infection by HIV (Goedert, et al., 1984). Treponema denticola (T. denticola) is the principal oral helical-shaped anaerobic spirochete that plays an essential role in immunosuppression. The disease process is mediated through adherence to mucosal surfaces, specific cleavage of cell surface receptors, inhibition of host defense mechanisms, penetration in epithelial cells, and induction of gingival inflammation and bone resorption. Proteases such as chymotrypsin, phospholipase C, oligopeptidase and cystalysin play an important role in pathogenicity (Chi, et al., 2003, Ellen and Galimanas, 2005, Fenno and McBride, 1998) and is induced by a range of proinflammatory cytokines such as IL-1α, IL-1β, tumor necrosis factor-α, IL-6 and IL-8 (Gemmell and Seymour, 1998, Nixon, et al., 2000). These cytokines affect connective tissue destruction and alveolar bone desorption (Gemmell and Seymour, 1998). Phosphorylation of intracellular receptors such as Fos-c, MKK1, MAP kinase and nuclear factor κB molecules by T. denticola affect these changes (Tanabe, et al., 2008). ### 6.2.3 Clinical features 90 Global View of HIV Infection NUP is commonly a progression of NUG that demonstrates bone loss and clinical attachment levels (MacCarthy and Claffey, 1991). Both are primarily caused by bacterial infection with microflora consisting of Treponema and Selenomonas species, Prevotella intermedia, Fusobacterium nucleatum and Porphyromonas gingivalis (Falkler, et al., 1987, Loesche, et al., 1982). Malnutrition, smoking, stress, trauma and preexisting gingivitis are other etiologic factors (Peruzzo, et al., 2007, Taiwo, 1993). Most persons with NUG have alterations in the immune system making them more prone to microbial infections (Cogen, et al., 1983). This immunosuppression is also evident in infection by HIV (Goedert, et al., 1984). Treponema denticola (T. denticola) is the principal oral helical-shaped anaerobic spirochete that plays an essential role in immunosuppression. The disease process is mediated through adherence to mucosal surfaces, specific cleavage of cell surface receptors, inhibition of host defense mechanisms, penetration in epithelial cells, and induction of gingival inflammation and bone resorption. Proteases such as chymotrypsin, phospholipase C, oligopeptidase and cystalysin play an important role in pathogenicity (Chi, et al., 2003, Ellen and Galimanas, 2005, Fenno and McBride, 1998) and is induced by a range of proinflammatory cytokines such as IL-1α, IL-1β, tumor necrosis factor-α, IL-6 and IL-8 (Gemmell and Seymour, 1998, Nixon, et al., 2000). These cytokines affect connective tissue destruction and alveolar bone desorption (Gemmell and Seymour, 1998). Phosphorylation of intracellular receptors such as Fos-c, MKK1, MAP kinase and nuclear factor κB molecules by Fig. 9. Linear Gingival Erythema T. denticola affect these changes (Tanabe, et al., 2008). 6.2.2 Pathogenesis The clinical characteristics of NUG includes ulcerated and necrotic papillary and marginal gingival covered by a yellowish-white or grayish slough or "pseudomembrane", blunting and cratering of papillae, spontaneous bleeding or bleeding on probing, pain and fetid breath (Barnes, et al., 1973, Falkler, et al., 1987, Horning and Cohen, 1995). It may be accompanied by fever, lymphadenopathy, and malaise. Progression of gingivitis to NUP is commonly associated with clinical attachment loss and alveolar bone destruction. Fig. 10. Necrotizing Ulcerative Periodontitis #### 6.2.4 Treatment The first treatment for NUG was devised by Dr. S. Schluger in 1949 (Schluger, 1949).Bacterial pathogens were controlled or eliminated by mechanical debridement or use of antibiotics in earlier days (Johnson and Engel, 1986). Aureomycin and penicillin were the first antibiotics considered for treatment of NUG in 1950 (Goldman and Bloom, 1950, Montis, 1950). Mechanical treatment consists of scaling and root planing. In addition to mechanical debridement, antibiotic and antimicrobial therapies are essential for management of NUP. Oxidizing mouthwash such as 3% hydrogen peroxide has also shown to have beneficial effects in management of NUG and NUP. ## 7. Non-Hodgkin lymphoma #### 7.1 Background There are three subtypes of on-Hodgkin's lymphoma (NHL): diffuse large B cell lymphoma (DLBCL), Burkitt's lymphoma (BL) and central nervous system lymphoma (CNSL)(Engels, Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 93 Involvement of two or more lymph node regions on the same side of the diaphragm (II) alone or with localized involvement of an Involvement of lymph node regions on both sides of the diaphragm (III) alone or with localized involvement of an extralymphatic organ or site (IIIE) or spleen (IIIS) or both (IIISE) extralymphatic organs with or without associated lymph node Diffuse or disseminated involvement of one or more Stage I Involvement of a single lymph node region (I) or a single extralymphatic organ or site (IE) extralymphatic organ or site (IIE) Table 3. Ann Arbor Classification of Non-Hodgkin's Lymphomas (Rupniewska, 1979) Oral NHL lesions are often in disseminated disease states. The most common oral sites of involvement are the palate, tonsil, buccal mucosa, floor of the mouth, and the retromolar region. These lesions are non-tender, diffuse swellings usually involving the gingiva, buccal vestibule and posterior hard palate. Gnathic lesions arise from soft tissue invading the bony skeleton. One third of patients show fever, weight loss, adenopathy, night sweats, or hepatosplenomegaly. Oral lesions are fluctuant swellings showing ulceration, pain, tooth mobility and paresthesia when peripheral nerves are involved (Vega, et al., 2005). Salivary gland lymphomas account for approximately 3% of all salivary gland tumors (Barnes, et al., 1998). About 80% of the cases are reported in parotid gland, 16% in submandibular, 2% in sublingual and 2% in minor salivary glands. Affected bony areas show a "punched out" pattern that is due to multiple areas of destruction with ill defined radiolucent lesion. Involvement of the maxillary sinus will cause opacification with eroded cortical walls and associated sinus mass (Fukuda, et al., 1987). The Ann Arbor staging system, originally A prognostic index has been developed by the International NHL prognostic factors project based on data from 2,031 patients with aggressive lymphomas treated with regimens containing doxorubicin ("A Predictive Model for Aggressive Non-Hodgkin's Lymphoma," 1993). Analysis of 1274 patients younger than 60 years showed three clinical features independently associated with survival: serum LDL (lactate dehydrogenase) levels, tumor stage, and their performance status ("A Predictive Model for Aggressive Non-Hodgkin's Lymphoma," 1993). Past studies showed the importance of gallium-67 uptake in lymphomas as a useful prognostic indicator (Janicek, et al., 1997). The importance of prognostic index is that good-risk patients can be identified for standard therapy and poor-risk patients can be identified for new research protocols to improve the rate of therapy. With conventional therapy only 25% of patients who were gallium-positive midway through therapy had durable responses , while 70% of those who were gallium-negative remained free of disease (Janicek, et al., 1997). In patients with stage I or II disease, regional therapy leads to longterm control, with relapse rate of 44%-47% at 10 years and survival rates of 75% for patients younger than 60 years (Vaughan Hudson, et al., 1994). Stage III and IV patients can be treated by alkylating agents, combination chemotherapy regimens with 2-4 drugs, and high involvement designed for Hodgkin's disease, is used for NHL as evident above. Stage II Stage III Stage IV 7.3 Clinical features 7.4 Treatment et al., 2006). An increase in occurrence of DLBCL (10.2%), BL (27.8%) and CNSL (48.3%) was seen in individuals with AIDS during 1990-1995 (Shiels, et al., 2011). The 5-year survival rate improved from 1960 to the mid 1970s, but not much after that in the USA (Shiels, et al., 2011). NHL relates to congenital and acquired immunodeficiency diseases (Filipovich, et al., 1992). The relative risk of NHL in individuals with AIDS is about 150-250 in Western countries and over 1000 in children (Goedert, 2000). ### 7.2 Pathogenesis The head and neck regions are the most common sites for NHL, showing in 30-40% of cases (Economopoulos, et al., 1996). The neoplastic cells express CD20, CD79, BCL-2 and BCL-6, most of which are B-cell antigens (Hoefnagel, et al., 2003). The hallmark of B-cell malignancies is chromosomal translocation involving the immunoglobulin heavy chain (IGH) gene at band 14q32.33 with specific oncogene loci, referred to as the 14q32 translocation. Among these specific 14q32 translocations, de novo acute leukemia/lymphoma with c-MYC and/or BCL6 abnormalities in addition to t(14;18) was characterized by an extremely aggressive clinical course with nodal and/or extranodal involvement, and massive bone marrow infiltration(Kramer, et al., 1991). Incidence of IGH translocation on Bcell NHL has been reported in previous studies (Kramer, et al., 1998). Thus multiple involvement of the IGH gene in chromosomal rearrangements is associated with the pathogenesis and the progression of NHL. Fig. 11. Histology of NUP lesion- Infiltration of Spirochetes into the Connective Tissue Table 3. Ann Arbor Classification of Non-Hodgkin's Lymphomas (Rupniewska, 1979) #### 7.3 Clinical features 92 Global View of HIV Infection et al., 2006). An increase in occurrence of DLBCL (10.2%), BL (27.8%) and CNSL (48.3%) was seen in individuals with AIDS during 1990-1995 (Shiels, et al., 2011). The 5-year survival rate improved from 1960 to the mid 1970s, but not much after that in the USA (Shiels, et al., 2011). NHL relates to congenital and acquired immunodeficiency diseases (Filipovich, et al., 1992). The relative risk of NHL in individuals with AIDS is about 150-250 in Western The head and neck regions are the most common sites for NHL, showing in 30-40% of cases (Economopoulos, et al., 1996). The neoplastic cells express CD20, CD79, BCL-2 and BCL-6, most of which are B-cell antigens (Hoefnagel, et al., 2003). The hallmark of B-cell malignancies is chromosomal translocation involving the immunoglobulin heavy chain (IGH) gene at band 14q32.33 with specific oncogene loci, referred to as the 14q32 translocation. Among these specific 14q32 translocations, de novo acute leukemia/lymphoma with c-MYC and/or BCL6 abnormalities in addition to t(14;18) was characterized by an extremely aggressive clinical course with nodal and/or extranodal involvement, and massive bone marrow infiltration(Kramer, et al., 1991). Incidence of IGH translocation on Bcell NHL has been reported in previous studies (Kramer, et al., 1998). Thus multiple involvement of the IGH gene in chromosomal rearrangements is associated with the Fig. 11. Histology of NUP lesion- Infiltration of Spirochetes into the Connective Tissue countries and over 1000 in children (Goedert, 2000). pathogenesis and the progression of NHL. 7.2 Pathogenesis Oral NHL lesions are often in disseminated disease states. The most common oral sites of involvement are the palate, tonsil, buccal mucosa, floor of the mouth, and the retromolar region. These lesions are non-tender, diffuse swellings usually involving the gingiva, buccal vestibule and posterior hard palate. Gnathic lesions arise from soft tissue invading the bony skeleton. One third of patients show fever, weight loss, adenopathy, night sweats, or hepatosplenomegaly. Oral lesions are fluctuant swellings showing ulceration, pain, tooth mobility and paresthesia when peripheral nerves are involved (Vega, et al., 2005). Salivary gland lymphomas account for approximately 3% of all salivary gland tumors (Barnes, et al., 1998). About 80% of the cases are reported in parotid gland, 16% in submandibular, 2% in sublingual and 2% in minor salivary glands. Affected bony areas show a "punched out" pattern that is due to multiple areas of destruction with ill defined radiolucent lesion. Involvement of the maxillary sinus will cause opacification with eroded cortical walls and associated sinus mass (Fukuda, et al., 1987). The Ann Arbor staging system, originally designed for Hodgkin's disease, is used for NHL as evident above. #### 7.4 Treatment A prognostic index has been developed by the International NHL prognostic factors project based on data from 2,031 patients with aggressive lymphomas treated with regimens containing doxorubicin ("A Predictive Model for Aggressive Non-Hodgkin's Lymphoma," 1993). Analysis of 1274 patients younger than 60 years showed three clinical features independently associated with survival: serum LDL (lactate dehydrogenase) levels, tumor stage, and their performance status ("A Predictive Model for Aggressive Non-Hodgkin's Lymphoma," 1993). Past studies showed the importance of gallium-67 uptake in lymphomas as a useful prognostic indicator (Janicek, et al., 1997). The importance of prognostic index is that good-risk patients can be identified for standard therapy and poor-risk patients can be identified for new research protocols to improve the rate of therapy. With conventional therapy only 25% of patients who were gallium-positive midway through therapy had durable responses , while 70% of those who were gallium-negative remained free of disease (Janicek, et al., 1997). In patients with stage I or II disease, regional therapy leads to longterm control, with relapse rate of 44%-47% at 10 years and survival rates of 75% for patients younger than 60 years (Vaughan Hudson, et al., 1994). Stage III and IV patients can be treated by alkylating agents, combination chemotherapy regimens with 2-4 drugs, and high Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 95 Calderone, R. A., and P. C. Braun. "Adherence and Receptor Relationships of Candida Calderone, Richard A., and William A. Fonzi. "Virulence Factors of Candida Albicans." Cattelan, A. M., M. L. Calabro, S. M. L. Aversa, M. Zanchetta, F. Meneghetti, A. De Chaffin, W. Lajean, Jose Luis Lopez-Ribot, Manuel Casanova, Daniel Gozalbo, and Jose P. Function, and Expression." Microbiol. Mol. Biol. Rev. 62, no. 1 (1998): 130-80. Charlier, C., E. Hart, A. Lefort, P. Ribaud, F. Dromer, D. W. Denning, and O. Lortholary. "Classification and Diagnostic Criteria for Oral Lesions in Hiv Infection. Ec-Clearinghouse Cogen, R. B., A. W. Stevens, Jr., S. Cohen-Cole, K. Kirk, and A. Freeman. "Leukocyte Coogan, M. M., J. Greenspan, and S. J. Challacombe. "Oral Lesions in Infection with Human Immunodeficiency Virus." Bull World Health Organ 83, no. 9 (2005): 700-6. D'Souza, Gypsyamber, Hao H. Zhang, Warren D. D'Souza, Robert R. Meyer, and Maura L. Davies, Andrew N., Susan R. Brailsford, and David Beighton. "Oral Candidosis in Patients De Wit, Ronald, CharlesA B. Boucher, KeesH N. Veenhof, JanK M. E. Schattenkerk, PietJ M. Economopoulos, Theofanis, Niki Asprou, Nicholas Stathakis, Efstathios Papageorgiou, John Ellen, Richard P., and Vaia B. Galimanas. "Spirochetes at the Forefront of Periodontal with Advanced Cancer." 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Conclusions Thorough examination of the oral cavity should be part of the physical examination for everybody, but especially in HIV-positive individuals and those who are at a high risk for acquiring HIV infection. Oral lesions can not only compromise the quality of life and increase morbidity in patients with HIV/AIDS, but can also serve as indicators for the presence of the disease and disease progression. It is also very important for health care providers and medical practitioners from different specialties to collaborate in providing the overall care for these immune-compromised patients. #### 9. References dose therapy with bone marrow transplant reinfusion(Freedman, et al., 1996, Govindan, et Thorough examination of the oral cavity should be part of the physical examination for everybody, but especially in HIV-positive individuals and those who are at a high risk for acquiring HIV infection. 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Oral Pathol 71, no. 2 (1991): 158-66. 8, no. 3 (2002): 225-32. 485-90. 6. 6 Epidemiology and Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals in a 1Departments of Surgery, HIV Control Programme Ahmadu Bello University 2Haematology and Blood Transfusion, HIV Control Programme Ahmadu Bello University Kaposi's sarcoma was first described in 1872 by Moritz Kaposi, a Vienna-based Hungarian dermatologist, as a rare multifocal angioproliferative tumour involving blood and lymphatic vessels in elderly men of Jewish origin (Kaposi, 1872). Before the AIDS epidemic three clinico-epidemiological forms with similar histological features have been described. The classic Kaposi's sarcoma (KS) originally described by Kaposi is primarily a skin disease with a chronic indolent course that can sometimes regress spontaneously (Kaposi, 1872). Most of the cases occurred in elderly men of Mediterranean and Jewish origin. The African-endemic KS is seen in the indigenous population of sub-Saharan Africa (Franceschi & Geddes, 1995). It is also seen more commonly among male patients, but differs from the classic form in that it may affect a younger population and is more likely to spread to visceral organs and lymphatics. In addition, it has a variable clinical presentation ranging from a benign disease with few skin lesions to a widely disseminated disease associated with high morbidity and mortality (Franceschi & Geddes, 1995; Taylor et al 1971). Kaposi's sarcoma seen in patients as a result of immunosuppression complicating organ transplantation may have chronic or progressive course and spontaneous remission after discontinuation of immunosuppressive The first description of AIDS-associated Kaposi's sarcoma (AAKS) was in 1981, when Friedman-Kien et al (1981) reported some previously healthy young homosexual men with Kaposi's sarcoma involving lymph nodes, viscera, and mucosa as well as skin. This was associated with life-threatening opportunistic infections and a profound defect in cellmediated immunity. This aggressive and frequently fatal form of Kaposi's sarcoma is the most common cancer in patients with HIV infection (Schwartz, 2004). Before the discovery and widespread use of highly active antiretroviral therapy (HAART) KS was over 20,000 times more common in AIDS patients than the general population (Engels et al 2006). However, several studies showed that HAART reduced the incidence of KS in high income countries (.Franceschi et al, 2008; Pipkin et al, 2011; Simard et al, 2011). The cumulative incidence of Kaposi sarcoma declined from 14.3% during 1980 to 1989, to 6.7% during 1990 therapy is observed in the majority of patients (Penn, 1979). 1. Introduction Poor Resource Setting Ahmed A.1 and Muktar H.M.2 Teaching Hospital Zaria Teaching Hospital Zaria Nigeria	doab	2025-04-07T04:13:04.687922	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 28 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.29	Epidemiology and Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals in a Poor Resource Setting Ahmed A.1 and Muktar H.M.2 1Departments of Surgery, HIV Control Programme Ahmadu Bello University Teaching Hospital Zaria 2Haematology and Blood Transfusion, HIV Control Programme Ahmadu Bello University Teaching Hospital Zaria Nigeria #### 1. Introduction 102 Global View of HIV Infection Williams, C., J. M. Whitehouse, T. A. Lister, and P. F. Wrigley. "Oral Anticandidal Worthington, H. V., J. E. Clarkson, and O. B. Eden. "Interventions for Preventing Oral Pediatr Oncol 3, no. 3 (1977): 275-80. Rev, no. 3 (2002): CD003807. Prophylaxis in Patients Undergoing Chemotherapy for Acut- Leukemia." Med Candidiasis for Patients with Cancer Receiving Treatment." Cochrane Database Syst Kaposi's sarcoma was first described in 1872 by Moritz Kaposi, a Vienna-based Hungarian dermatologist, as a rare multifocal angioproliferative tumour involving blood and lymphatic vessels in elderly men of Jewish origin (Kaposi, 1872). Before the AIDS epidemic three clinico-epidemiological forms with similar histological features have been described. The classic Kaposi's sarcoma (KS) originally described by Kaposi is primarily a skin disease with a chronic indolent course that can sometimes regress spontaneously (Kaposi, 1872). Most of the cases occurred in elderly men of Mediterranean and Jewish origin. The African-endemic KS is seen in the indigenous population of sub-Saharan Africa (Franceschi & Geddes, 1995). It is also seen more commonly among male patients, but differs from the classic form in that it may affect a younger population and is more likely to spread to visceral organs and lymphatics. In addition, it has a variable clinical presentation ranging from a benign disease with few skin lesions to a widely disseminated disease associated with high morbidity and mortality (Franceschi & Geddes, 1995; Taylor et al 1971). Kaposi's sarcoma seen in patients as a result of immunosuppression complicating organ transplantation may have chronic or progressive course and spontaneous remission after discontinuation of immunosuppressive therapy is observed in the majority of patients (Penn, 1979). The first description of AIDS-associated Kaposi's sarcoma (AAKS) was in 1981, when Friedman-Kien et al (1981) reported some previously healthy young homosexual men with Kaposi's sarcoma involving lymph nodes, viscera, and mucosa as well as skin. This was associated with life-threatening opportunistic infections and a profound defect in cellmediated immunity. This aggressive and frequently fatal form of Kaposi's sarcoma is the most common cancer in patients with HIV infection (Schwartz, 2004). Before the discovery and widespread use of highly active antiretroviral therapy (HAART) KS was over 20,000 times more common in AIDS patients than the general population (Engels et al 2006). However, several studies showed that HAART reduced the incidence of KS in high income countries (.Franceschi et al, 2008; Pipkin et al, 2011; Simard et al, 2011). The cumulative incidence of Kaposi sarcoma declined from 14.3% during 1980 to 1989, to 6.7% during 1990 Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 105 For a long time, the aetiology and pathogenesis of KS remained unclear. The discovery in 1994 of KS-associated herpes virus (KSHV), also known as human herpes virus-8 (HHV-8), in cells isolated from an AAKS lesion was followed by molecular and epidemiological data confirming an aetiological link between this virus and all clinical forms of KS (Chang et al, 1994; Hengge et al, 2002). Though infection with HHV-8 is not sufficient for tumour development, the virus has developed various mechanisms to manipulate host cell signal transduction, and thereby lead to the activation of numerous pro-growth and anti-apoptotic pathways. HIV-1 transactivation (Tat) protein is a short-term growth factor for KS (Guadalupe et al, 2011; Hassman et al, 2011). Tat protein through the mediation of IFN-γ, b-FGF and other cytokines has the capacity to induce endothelial cell proliferation and facilitate invasion of extracellular matrix (Hassman et al, 2011). In addition, it enhances HHV-8 infectivity for endothelial cells and increases its viral load by reactivating it from latent state (Guadalupe et al, 2011). On the other hand, HHV-8 activates nuclear receptors NF-kappa and NF-AT and this level of activation is synergistically increased by HIV-1 Tat protein (Guadalupe et al, 2011). Thus, infection with HHV-8 is associated with KS the risk for which correlates with HHV-8 viral load. However, for a given HHV-8 titre, the risk is greater in HIV-seropositive, as compared to HIV-seronegative individuals (Casper, 2011). Exceptions have been found in some parts of West Africa, South America and Australia where although the incidence of HHV-8 infection is high only few cases of KS are found (Ablashi et al 1999; Rezza et al, 2001). This indicates that other factors are important in the In Nigeria, the incidence of HIV/AIDS was estimated at 4.1 million and is on the downward trend (National Action Committee on AIDS (NACA) 2010). KS has become the most common malignant skin tumour with the disease appearing in areas where it did not exit in the past (Asuquo & Ebughe, 2009; Iregbu & Elegba, 2006). A report from Calabar South Eastern Nigeria showed that KS is the most common malignant skin tumour accounting for 38.0% cases (Asuquo & Ebughe, 2009). Reports from Abuja and Benin both in Nigeria showed KS in 0.8% of newly diagnosed HIV infected patients compared to a prevalence of 0.5% a decade earlier (Akinsete et al, 1998; Iregbu & Elegba, 2006; Onunu et al, 2007). Most of our patients present with extensive and advanced disease that usually required a combination of HAART and chemotherapy. This together with limited therapeutic facilities resulted in poor outcome of treatment (Ahmed et al, 2001; Asuquo & Ebughe, 2009). With improved AIDS awareness and access to HAART more patients are likely to present earlier. Our institution is one of the Federal Government HIV/AIDS designated treatment centre and we see patients from various parts of Nigeria. There is little information on the treatment and outcome of KS in HIV-1infected patients who have been treated with HAART in Africa. The objective of this study was to review the clinical features, treatment and outcome of AIDS –associated Kaposi's sarcoma patients in our institution particularly in the context of increasing use of highly active antiretroviral therapy. We shall also highlight the This prospective study was carried out at Ahmadu Bello University Teaching Hospital Zaria, the premier referral and teaching hospital in Northern Nigeria. Patients with concurrent diagnosis of HIV infection and Kaposi's sarcoma seen between January 2007 and difficulties in the evaluation and treatment of these patients. 1.1 Aetiology and pathogenesis pathogenesis of KS. 2. Patients and method to 1995, and to 1.8% during 1996 to 2006 (Simard et al, 2011). In a Swiss HIV cohort study, the overall KS incidence was 33.3 per 1000 person year (py) in 1984–1986 and did not change significantly in the subsequent periods until 1996–1998, when it fell to 5.1 (95% CI, 3.9–6.5) . The incidence further decreased to 1.4 per 1000 py in 1999–2001 and remained constant thereafter (Franceschi et al, 2008). In another recent pan-European multi-centre study, there was a decrease in the incidence rate of KS from 24.7 cases (95% CI 17.2–32.2) per 1000 py in 1994 to 4.7 (95% CI 2.7–6.7) per 1000 py in 1997 and 1.7 (95% CI 0.7–3.4) per 1000 in recent years among HIV-infected individuals (Pipkin et al, 2011). In a report from Sao Paulo Brazil, a low income country, 17% of a cohort of patients on HAART was seropositive for human herpesvirus-8 of which only 2% developed AAKS in 5 years compared to 20% prevalence of AAKS detected in the same region before the HAART era (Yoshioka et al, 2004). In contrast, the incidence of KS has been steadily increasing in parallel with the AIDS epidemic in sub-Saharan Africa (Bassett et al, 1995; Parkin et al, 2008; Sasco et al, 2010). In 2002, of 66,200 estimated KS cases worldwide, 58,800 ware estimated to be in Africa (Parkin et al, 2008). Of these, about 39,500 cases in males and 17,100 cases in females occurred in sub-Saharan Africa compared to 102 males and 17 females in Northern Africa (Parkin et al, 2008). In areas such as Malawi, Uganda and Zimbabwe where Kaposi's sarcoma was common before the AIDS epidemic, the incidence of this cancer has increased by about 20-times and it is now the most common cancer in males and second most common cancer in females (Sasco et al, 2010). In Zimbabwe, the age-adjusted incidence of KS per 100,000 population was 2.3 in men and 0.3 in women before the AIDS epidemic, compared to 48 and 18, respectively, during the AIDS epidemic (Bassett et al, 1995). Recent studies conducted in South Africa and Rwanda found a clear association between HIV infection and KS with odd ratio ranging from 21.9 (95% CI 12.5–38.6) to 47.1 (95% CI 31.9–69.8) (Newton et al, 1995; Stein et al, 2008). Similarly, Newton et al (2001)in a study carried out in Kampala, Uganda found a higher risk of KS among HIV- infected compared to HIV-negative children with an odd ratio of 94.9 (95% CI 28.5–315.3). Although the course of AAKS is variable most patients would eventually develop progressive and disseminated disease requiring active therapy. The choice of treatment is determined by the stage of KS, its rate of progression, the degree of immune competence and HIV associated diseases. Several therapeutic options are available for AAKS but the optimal therapy is still unclear. Highly active antiretroviral therapy including protease inhibitors may be the first treatment step for indolent slowly progressive disease (Martellotta et al, 2009). Following treatment with HAART, there may be complete remission in patients with good immunological response and limited disease (Martellotta et al, 2009). However, recent studies indicate that there is no significant regression when patients with advanced, symptomatic AAKS are treated with HAART without simultaneous chemotherapy (Krown, 2004; Martin-Carbonero 2004). A wide variety of chemotherapeutic agents, individually and in combination, have been evaluated for the treatment of AAKS. In high income countries, combination of vincristine, doxorubicin and bleomycin (VAB) that was considered the standard chemotherapy regimen for AAKS has been supplanted by liposomal anthracylines due to their higher efficacy and reduced toxicity (Ashish et al 2007; Cooley, 2007). In addition, the angiogenic nature of KS makes it particularly suitable for therapies based on targeted agents such as metalloproteinase inhibitors, angiogenesis inhibitors and tyrosine kinase inhibitors (Koon et al, 2011; Sullivan et al, 2009). In low income countries, the choice of therapeutic agents is limited to the combination of VAB or even more toxic drugs such as therlidomide because liposomal anthracyclines are not available or affordable (Makombe et al, 2009). #### 1.1 Aetiology and pathogenesis 104 Global View of HIV Infection to 1995, and to 1.8% during 1996 to 2006 (Simard et al, 2011). In a Swiss HIV cohort study, the overall KS incidence was 33.3 per 1000 person year (py) in 1984–1986 and did not change significantly in the subsequent periods until 1996–1998, when it fell to 5.1 (95% CI, 3.9–6.5) . The incidence further decreased to 1.4 per 1000 py in 1999–2001 and remained constant thereafter (Franceschi et al, 2008). In another recent pan-European multi-centre study, there was a decrease in the incidence rate of KS from 24.7 cases (95% CI 17.2–32.2) per 1000 py in 1994 to 4.7 (95% CI 2.7–6.7) per 1000 py in 1997 and 1.7 (95% CI 0.7–3.4) per 1000 in recent years among HIV-infected individuals (Pipkin et al, 2011). In a report from Sao Paulo Brazil, a low income country, 17% of a cohort of patients on HAART was seropositive for human herpesvirus-8 of which only 2% developed AAKS in 5 years compared to 20% prevalence of AAKS detected in the same region before the HAART era (Yoshioka et al, 2004). In contrast, the incidence of KS has been steadily increasing in parallel with the AIDS epidemic in sub-Saharan Africa (Bassett et al, 1995; Parkin et al, 2008; Sasco et al, 2010). In 2002, of 66,200 estimated KS cases worldwide, 58,800 ware estimated to be in Africa (Parkin et al, 2008). Of these, about 39,500 cases in males and 17,100 cases in females occurred in sub-Saharan Africa compared to 102 males and 17 females in Northern Africa (Parkin et al, 2008). In areas such as Malawi, Uganda and Zimbabwe where Kaposi's sarcoma was common before the AIDS epidemic, the incidence of this cancer has increased by about 20-times and it is now the most common cancer in males and second most common cancer in females (Sasco et al, 2010). In Zimbabwe, the age-adjusted incidence of KS per 100,000 population was 2.3 in men and 0.3 in women before the AIDS epidemic, compared to 48 and 18, respectively, during the AIDS epidemic (Bassett et al, 1995). Recent studies conducted in South Africa and Rwanda found a clear association between HIV infection and KS with odd ratio ranging from 21.9 (95% CI 12.5–38.6) to 47.1 (95% CI 31.9–69.8) (Newton et al, 1995; Stein et al, 2008). Similarly, Newton et al (2001)in a study carried out in Kampala, Uganda found a higher risk of KS among HIV- infected compared to HIV-negative children with an odd ratio of 94.9 Although the course of AAKS is variable most patients would eventually develop progressive and disseminated disease requiring active therapy. The choice of treatment is determined by the stage of KS, its rate of progression, the degree of immune competence and HIV associated diseases. Several therapeutic options are available for AAKS but the optimal therapy is still unclear. Highly active antiretroviral therapy including protease inhibitors may be the first treatment step for indolent slowly progressive disease (Martellotta et al, 2009). Following treatment with HAART, there may be complete remission in patients with good immunological response and limited disease (Martellotta et al, 2009). However, recent studies indicate that there is no significant regression when patients with advanced, symptomatic AAKS are treated with HAART without simultaneous chemotherapy (Krown, 2004; Martin-Carbonero 2004). A wide variety of chemotherapeutic agents, individually and in combination, have been evaluated for the treatment of AAKS. In high income countries, combination of vincristine, doxorubicin and bleomycin (VAB) that was considered the standard chemotherapy regimen for AAKS has been supplanted by liposomal anthracylines due to their higher efficacy and reduced toxicity (Ashish et al 2007; Cooley, 2007). In addition, the angiogenic nature of KS makes it particularly suitable for therapies based on targeted agents such as metalloproteinase inhibitors, angiogenesis inhibitors and tyrosine kinase inhibitors (Koon et al, 2011; Sullivan et al, 2009). In low income countries, the choice of therapeutic agents is limited to the combination of VAB or even more toxic drugs such as therlidomide because liposomal anthracyclines are not available or affordable (Makombe et al, 2009). (95% CI 28.5–315.3). For a long time, the aetiology and pathogenesis of KS remained unclear. The discovery in 1994 of KS-associated herpes virus (KSHV), also known as human herpes virus-8 (HHV-8), in cells isolated from an AAKS lesion was followed by molecular and epidemiological data confirming an aetiological link between this virus and all clinical forms of KS (Chang et al, 1994; Hengge et al, 2002). Though infection with HHV-8 is not sufficient for tumour development, the virus has developed various mechanisms to manipulate host cell signal transduction, and thereby lead to the activation of numerous pro-growth and anti-apoptotic pathways. HIV-1 transactivation (Tat) protein is a short-term growth factor for KS (Guadalupe et al, 2011; Hassman et al, 2011). Tat protein through the mediation of IFN-γ, b-FGF and other cytokines has the capacity to induce endothelial cell proliferation and facilitate invasion of extracellular matrix (Hassman et al, 2011). In addition, it enhances HHV-8 infectivity for endothelial cells and increases its viral load by reactivating it from latent state (Guadalupe et al, 2011). On the other hand, HHV-8 activates nuclear receptors NF-kappa and NF-AT and this level of activation is synergistically increased by HIV-1 Tat protein (Guadalupe et al, 2011). Thus, infection with HHV-8 is associated with KS the risk for which correlates with HHV-8 viral load. However, for a given HHV-8 titre, the risk is greater in HIV-seropositive, as compared to HIV-seronegative individuals (Casper, 2011). Exceptions have been found in some parts of West Africa, South America and Australia where although the incidence of HHV-8 infection is high only few cases of KS are found (Ablashi et al 1999; Rezza et al, 2001). This indicates that other factors are important in the pathogenesis of KS. In Nigeria, the incidence of HIV/AIDS was estimated at 4.1 million and is on the downward trend (National Action Committee on AIDS (NACA) 2010). KS has become the most common malignant skin tumour with the disease appearing in areas where it did not exit in the past (Asuquo & Ebughe, 2009; Iregbu & Elegba, 2006). A report from Calabar South Eastern Nigeria showed that KS is the most common malignant skin tumour accounting for 38.0% cases (Asuquo & Ebughe, 2009). Reports from Abuja and Benin both in Nigeria showed KS in 0.8% of newly diagnosed HIV infected patients compared to a prevalence of 0.5% a decade earlier (Akinsete et al, 1998; Iregbu & Elegba, 2006; Onunu et al, 2007). Most of our patients present with extensive and advanced disease that usually required a combination of HAART and chemotherapy. This together with limited therapeutic facilities resulted in poor outcome of treatment (Ahmed et al, 2001; Asuquo & Ebughe, 2009). With improved AIDS awareness and access to HAART more patients are likely to present earlier. Our institution is one of the Federal Government HIV/AIDS designated treatment centre and we see patients from various parts of Nigeria. There is little information on the treatment and outcome of KS in HIV-1infected patients who have been treated with HAART in Africa. The objective of this study was to review the clinical features, treatment and outcome of AIDS –associated Kaposi's sarcoma patients in our institution particularly in the context of increasing use of highly active antiretroviral therapy. We shall also highlight the difficulties in the evaluation and treatment of these patients. #### 2. Patients and method This prospective study was carried out at Ahmadu Bello University Teaching Hospital Zaria, the premier referral and teaching hospital in Northern Nigeria. Patients with concurrent diagnosis of HIV infection and Kaposi's sarcoma seen between January 2007 and Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 107 and eosin. Special stains were employed in selected cases. Serum urea and electrolytes, liver function test and complete blood count with differential and platelet count were done at the time of diagnosis of AAKS and before administration of chemotherapy. Chest radiographs, ECG, abdominal ultrasound, faecal occult blood and gastrointestinal endoscopic Our protocol for the treatment of AAKS has been presented previously (Ahmed et al, 2001). Following evaluation, patients were resuscitated and started on HAART which we defined as therapy consisting of at least three antiretroviral drugs in accordance with national guidelines (NACA, 2007). Our protocol recommends that patients with AAKS are started on HAART irrespective of CD4 count. Stable patients that have KPS of ≥40 and adequate bone marrow, renal and hepatic functions were then commenced on specific anti-KS chemotherapy. This consisted of six courses of three weekly cycles of vincristine 1.5mg/m2, doxorubicin 10mg/m2 and bleomycin 15mg/m2 by bolus intravenously. Treatments were delayed for up to two weeks for recovery from grade ≥3 neutropenia, thrombocytopenia or severe diarrhoea. Patients with relapse were treated with same course. Radiotherapy and surgical excision of localised lesions were performed in appropriate cases. Treatment complications and outcome were monitored. Patients were followed-up at four to eight We analysed data using SPSS statistical software (version 17.0, SPSS, Chicago IL). Data were reported as proportions, mean ± standard deviation (SD) or median (range). Categorical variables and proportions were compared by Fisher's exact test while continuous variables were compared by Wilcoxon two-sample test. In patients that responded to treatment, the duration of response was summarised using Kaplan Meier method. Fisher's exact test was used to test for agreement between the occurrence of clinical benefit and the presence of clinical response. Survival was calculated from the day of KS diagnosis until death or the date of last follow-up. Overall survival duration curves and duration of tumour response were plotted according to Kaplan-Meier method. Logistic regression modeling performed to identify independent determinants of survival and tumour response was done using the following clinicopathologic variables: age, sex, presence of comorbid condition, presence of systemic symptoms, KPS, stage of tumour, viral load and CD4 count at presentation. Risk factors were first analysed univariately, and the statistically significant variables were used to construct a multivariate model. Interactions were also analysed to confirm independence. During the period of study 7,155 patients with HIV infection were seen of which 98 (1.4%) had associated Kaposi's sarcoma. The number of patients with AAKS increased steadily from 2007 to 2010 (table 1). Their ages ranged from 18 to 54 years (Figure 1), mean of 33.6 ± 3.8 SD. Nine (9.2%) patients were less than 21 years old while 44 (44.9%) were in the third decade. There were 56 males and 42 females, male to female ration of 1.3:1. The male to female ratio decreased from 1.5:1 in 2007 to 1:1 in 2010. Females were younger than males (mean age of 27years vs. males 34; p< 0.04). Comorbid conditions were seen in 43 (43.9%) examination were performed in appropriate cases. weekly intervals until death or lost to follow-up. We considered p ≤ 0.05 to be statistically significant. 2.2 Statistical analysis 3. Results 3.1 Patient's characteristics December 2010 were included. Only patients 18 years or more were included. Consent was obtained from each patient after counselling and at the time of taking blood sample, tissue specimen or taking photographs of accessible lesions. Permission for the study was also obtained from the hospital ethical committee. #### 2.1 Patient's evaluation and treatment Patients were assessed at the time of diagnosis of AAKS and at four to eight weekly intervals during follow-up. At each visit, weight, vital signs and Kaposi's sarcoma symptoms were recorded, and a physical examination was performed. During evaluation efforts were made to discover the probable mode of HIV transmission to the patient. The dimension, number, appearance and sites of involvement of KS lesions were recorded. Lesions causing disfigurement were photographed. Tumour size was defined as the sum of the greatest diameters of each measurable tumour. The Karnofsky score status of the patients was also recorded. The tumour was staged according to AIDS Clinical Trials Group (ACTG) classification using the tumour (T), immune system (I) and systemic illness (S) (Krown et al, 1997). Tumour was defined as T0 if disease was confined to the skin and lymph nodes or oral involvement was confined to the hard palate, or T1 if there was pulmonary or gastrointestinal involvement, tumour associated oedema or ulceration, or extensive oral involvement. Cutaneous KS lesions confined to one anatomical area were classified as local while lesions involving two or more sites as disseminated. Morphologically the lesions were classified as macular, nodular and ulcerative. Tumour response was assessed by comparing lesion characteristics to the baseline tumour evaluations. Treatment responses were assessed according to ACTG criteria. A complete response (CR) was defined as the absence of any detectable residual disease, including tumour-associated oedema, persisting for at least four weeks. Partial response (PR) was defined as ≥50% decrease in the number or size of previously existing evaluable lesions lasting for at least four weeks without the appearance of new lesions or tumour-associated oedema. Stable disease (SD) was defined as any response that did not meet the criteria for progression or PR. Overall response rate was defined as both complete and partial response rates. Progressive disease (PD) was defined as ≥25% increase in the size of previously existing lesions or the appearance of new ones or the development of new or increasing tumour-associated oedema or effusion. Relapse was defined as the development of progressive disease in the presence of a documented CR, or PR. Screening test for HIV antibodies were performed by parallel testing using Enzyme-linked immunoabsorvent assay (ELISA) with Immunocomb II, HIV-1 and HIV-2 (M/S Orgenics, Israel) and Stat Pak (Trinity Biotech, Wicklow, Ireland). Positive test results from the two different kits were taken as confirmatory evidence of HIV antibodies. The CD4 cell counts were performed using the Dynabeads method (Dynal Biotech LLC, Milwaukee, WI, USA). Patients that presented from 2008 to 2010 were screened with Stat Pak (Trinity Biotech, Wicklow, Ireland) and Bundi HIV-1 and HIV-2 (Bundi International Diagnostics, Abia, Nigeria) and confirmed with Western blot method. Their CD4 count was performed with Partec flow cytometre (Partec GmbH, Munster, Germany). Plasma HIV-1 RNA levels were measured with Roche-Ampiclor HIV-1 monitor test, (version 1.5 (Roche-Ampiclor-Roche Diagnostics, Branchburg, USA). Viral load less than 400 copies/mL was considered undetectable. Diagnosis of Kaposi's sarcoma was based on histological examination of tissue specimens fixed in 10% formalin embedded in paraffin wax and stained with haematoxylin and eosin. Special stains were employed in selected cases. Serum urea and electrolytes, liver function test and complete blood count with differential and platelet count were done at the time of diagnosis of AAKS and before administration of chemotherapy. Chest radiographs, ECG, abdominal ultrasound, faecal occult blood and gastrointestinal endoscopic examination were performed in appropriate cases. Our protocol for the treatment of AAKS has been presented previously (Ahmed et al, 2001). Following evaluation, patients were resuscitated and started on HAART which we defined as therapy consisting of at least three antiretroviral drugs in accordance with national guidelines (NACA, 2007). Our protocol recommends that patients with AAKS are started on HAART irrespective of CD4 count. Stable patients that have KPS of ≥40 and adequate bone marrow, renal and hepatic functions were then commenced on specific anti-KS chemotherapy. This consisted of six courses of three weekly cycles of vincristine 1.5mg/m2, doxorubicin 10mg/m2 and bleomycin 15mg/m2 by bolus intravenously. Treatments were delayed for up to two weeks for recovery from grade ≥3 neutropenia, thrombocytopenia or severe diarrhoea. Patients with relapse were treated with same course. Radiotherapy and surgical excision of localised lesions were performed in appropriate cases. Treatment complications and outcome were monitored. Patients were followed-up at four to eight weekly intervals until death or lost to follow-up. #### 2.2 Statistical analysis 106 Global View of HIV Infection December 2010 were included. Only patients 18 years or more were included. Consent was obtained from each patient after counselling and at the time of taking blood sample, tissue specimen or taking photographs of accessible lesions. Permission for the study was also Patients were assessed at the time of diagnosis of AAKS and at four to eight weekly intervals during follow-up. At each visit, weight, vital signs and Kaposi's sarcoma symptoms were recorded, and a physical examination was performed. During evaluation efforts were made to discover the probable mode of HIV transmission to the patient. The dimension, number, appearance and sites of involvement of KS lesions were recorded. Lesions causing disfigurement were photographed. Tumour size was defined as the sum of the greatest diameters of each measurable tumour. The Karnofsky score status of the patients was also recorded. The tumour was staged according to AIDS Clinical Trials Group (ACTG) classification using the tumour (T), immune system (I) and systemic illness (S) (Krown et al, 1997). Tumour was defined as T0 if disease was confined to the skin and lymph nodes or oral involvement was confined to the hard palate, or T1 if there was pulmonary or gastrointestinal involvement, tumour associated oedema or ulceration, or extensive oral involvement. Cutaneous KS lesions confined to one anatomical area were classified as local while lesions involving two or more sites as disseminated. Morphologically the lesions were classified as macular, nodular and ulcerative. Tumour response was assessed by comparing lesion characteristics to the baseline tumour evaluations. Treatment responses were assessed according to ACTG criteria. A complete response (CR) was defined as the absence of any detectable residual disease, including tumour-associated oedema, persisting for at least four weeks. Partial response (PR) was defined as ≥50% decrease in the number or size of previously existing evaluable lesions lasting for at least four weeks without the appearance of new lesions or tumour-associated oedema. Stable disease (SD) was defined as any response that did not meet the criteria for progression or PR. Overall response rate was defined as both complete and partial response rates. Progressive disease (PD) was defined as ≥25% increase in the size of previously existing lesions or the appearance of new ones or the development of new or increasing tumour-associated oedema or effusion. Relapse was defined as the development of obtained from the hospital ethical committee. progressive disease in the presence of a documented CR, or PR. Screening test for HIV antibodies were performed by parallel testing using Enzyme-linked immunoabsorvent assay (ELISA) with Immunocomb II, HIV-1 and HIV-2 (M/S Orgenics, Israel) and Stat Pak (Trinity Biotech, Wicklow, Ireland). Positive test results from the two different kits were taken as confirmatory evidence of HIV antibodies. The CD4 cell counts were performed using the Dynabeads method (Dynal Biotech LLC, Milwaukee, WI, USA). Patients that presented from 2008 to 2010 were screened with Stat Pak (Trinity Biotech, Wicklow, Ireland) and Bundi HIV-1 and HIV-2 (Bundi International Diagnostics, Abia, Nigeria) and confirmed with Western blot method. Their CD4 count was performed with Partec flow cytometre (Partec GmbH, Munster, Germany). Plasma HIV-1 RNA levels were measured with Roche-Ampiclor HIV-1 monitor test, (version 1.5 (Roche-Ampiclor-Roche Diagnostics, Branchburg, USA). Viral load less than 400 copies/mL was considered undetectable. Diagnosis of Kaposi's sarcoma was based on histological examination of tissue specimens fixed in 10% formalin embedded in paraffin wax and stained with haematoxylin 2.1 Patient's evaluation and treatment We analysed data using SPSS statistical software (version 17.0, SPSS, Chicago IL). Data were reported as proportions, mean ± standard deviation (SD) or median (range). Categorical variables and proportions were compared by Fisher's exact test while continuous variables were compared by Wilcoxon two-sample test. In patients that responded to treatment, the duration of response was summarised using Kaplan Meier method. Fisher's exact test was used to test for agreement between the occurrence of clinical benefit and the presence of clinical response. Survival was calculated from the day of KS diagnosis until death or the date of last follow-up. Overall survival duration curves and duration of tumour response were plotted according to Kaplan-Meier method. Logistic regression modeling performed to identify independent determinants of survival and tumour response was done using the following clinicopathologic variables: age, sex, presence of comorbid condition, presence of systemic symptoms, KPS, stage of tumour, viral load and CD4 count at presentation. Risk factors were first analysed univariately, and the statistically significant variables were used to construct a multivariate model. Interactions were also analysed to confirm independence. We considered p ≤ 0.05 to be statistically significant. #### 3. Results #### 3.1 Patient's characteristics During the period of study 7,155 patients with HIV infection were seen of which 98 (1.4%) had associated Kaposi's sarcoma. The number of patients with AAKS increased steadily from 2007 to 2010 (table 1). Their ages ranged from 18 to 54 years (Figure 1), mean of 33.6 ± 3.8 SD. Nine (9.2%) patients were less than 21 years old while 44 (44.9%) were in the third decade. There were 56 males and 42 females, male to female ration of 1.3:1. The male to female ratio decreased from 1.5:1 in 2007 to 1:1 in 2010. Females were younger than males (mean age of 27years vs. males 34; p< 0.04). Comorbid conditions were seen in 43 (43.9%) Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 109 Fig. 1. Age and sex distribution of patients with AIDS-associated Kaposi's sarcoma Fig. 2. Nodular Kaposi's sarcoma with swelling of the lower limb patients including 20 (20.4%) pulmonary tuberculosis, 17 (17.3%) oral candidiasis, 15(15.3%) hypertension and 2 diabetes mellitus. Duration of symptoms of AAKS ranged from 1 to 13 months, mean 5.7 ±1.2SD. Symptoms were present in 91 (92.9%) patients and included pain (62.2%), swelling of the limbs (figure 2) (52.6%) and cosmetic disability (31.6%). Seven (7.1%) patients had no symptoms of Kaposi's sarcoma and the diagnosis was made during routine clinical evaluation (figure 3) at antiretroviral therapy (ART) clinic. Kaposi's sarcoma was the AIDS defining disease in 64 (65.3%) patients while in the remaining 34 (34.7%) it was diagnosed between 1 and 15 months after the initial diagnosis of AIDS. Sixteen patients had used HAART for 1- 13 months at the time of diagnosis of AAKS. The KPS ranged from 20% to 100%, median of 60%. All the patients were heterosexual although 11 were men having sex with men (MSM). Patients on anti-retroviral therapy at the time of diagnosis had a mean CD4 count of 267± 65SD cell/mm3. Overall, the mean CD4 count at presentation was 165 cells/mm3 (range: 26 – 875; 95% CI: 97 - 425). The mean HIV-1 viral load (VL) assessed in 71 patients was 48,593 copies/mL (range: 200- 989,571; 95% CI: 28,593- 76,225). #### 3.2 Tumour characteristics The anatomic distribution of AAKS lesions is shown in table 2. All patients had multiple lesions the lower limbs being most frequently involved (45.9%). In 20 (20.4%) patients, tumour was limited to extremities, with fungating and exophytic growth invading and destroying the subcutaneous and surrounding tissues including the underlying bones (Figure 4). Unusual sites including 7 conjunctiva, 9 penile and 12 vulva were also involved. Perineal involvement was more common in females. Visceral lesions included 3 rectal, 5 intestinal and 2 gastric tumours. Tumour size ranged from 2.0 to 58.0cm, mean 29± 15.7SD. The histological type was mixed cellularity in 63 (64.3%) patients and anaplastic in 9 (9.2%). KS stage at presentation was T1, I1, S1 in 47 (48.0%); T1, I1, S0 in 22 (22.4%); T0, I0, S1, in 8 (8.2%) and T0, I0, S0 in 21 (21.4%). Overall, 77 (78.6%) patients had poor prognosis stage comprising 38 (90.5%) females and 39 (69.6%) males (OR= 3.5, 95% CI 1.7–5.6, P < 0.01). Women also had more disseminated cutaneous AAKS lesions involving an increased number of lesions at multiple anatomical sites, compared to more localised lesions in males (OR =3.4, 95% CI = 1.7–5.5, P = 0.001). Despite the differences in age and disease severity between males and females, no gender-specific differences were observed in CD4 counts or plasma HIV-1 viral load. However, when males and females were analysed separately, there were significant correlations between the severity of KS and the degree of immune suppression as measured by CD4 count (χ2 test, P= 0.001) and between poor disease prognosis and immune suppression (P= 0.001) Table 1. Prevalence of HIV infection and AIDS-associated Kaposi's sarcoma patients including 20 (20.4%) pulmonary tuberculosis, 17 (17.3%) oral candidiasis, 15(15.3%) hypertension and 2 diabetes mellitus. Duration of symptoms of AAKS ranged from 1 to 13 months, mean 5.7 ±1.2SD. Symptoms were present in 91 (92.9%) patients and included pain (62.2%), swelling of the limbs (figure 2) (52.6%) and cosmetic disability (31.6%). Seven (7.1%) patients had no symptoms of Kaposi's sarcoma and the diagnosis was made during routine clinical evaluation (figure 3) at antiretroviral therapy (ART) clinic. Kaposi's sarcoma was the AIDS defining disease in 64 (65.3%) patients while in the remaining 34 (34.7%) it was diagnosed between 1 and 15 months after the initial diagnosis of AIDS. Sixteen patients had used HAART for 1- 13 months at the time of diagnosis of AAKS. The KPS ranged from 20% to 100%, median of 60%. All the patients were heterosexual although 11 were men having sex with men (MSM). Patients on anti-retroviral therapy at the time of diagnosis had a mean CD4 count of 267± 65SD cell/mm3. Overall, the mean CD4 count at presentation was 165 cells/mm3 (range: 26 – 875; 95% CI: 97 - 425). The mean HIV-1 viral load (VL) assessed in 71 The anatomic distribution of AAKS lesions is shown in table 2. All patients had multiple lesions the lower limbs being most frequently involved (45.9%). In 20 (20.4%) patients, tumour was limited to extremities, with fungating and exophytic growth invading and destroying the subcutaneous and surrounding tissues including the underlying bones (Figure 4). Unusual sites including 7 conjunctiva, 9 penile and 12 vulva were also involved. Perineal involvement was more common in females. Visceral lesions included 3 rectal, 5 intestinal and 2 gastric tumours. Tumour size ranged from 2.0 to 58.0cm, mean 29± 15.7SD. The histological type was mixed cellularity in 63 (64.3%) patients and anaplastic in 9 (9.2%). KS stage at presentation was T1, I1, S1 in 47 (48.0%); T1, I1, S0 in 22 (22.4%); T0, I0, S1, in 8 (8.2%) and T0, I0, S0 in 21 (21.4%). Overall, 77 (78.6%) patients had poor prognosis stage comprising 38 (90.5%) females and 39 (69.6%) males (OR= 3.5, 95% CI 1.7–5.6, P < 0.01). Women also had more disseminated cutaneous AAKS lesions involving an increased number of lesions at multiple anatomical sites, compared to more localised lesions in males (OR =3.4, 95% CI = 1.7–5.5, P = 0.001). Despite the differences in age and disease severity between males and females, no gender-specific differences were observed in CD4 counts or plasma HIV-1 viral load. However, when males and females were analysed separately, there were significant correlations between the severity of KS and the degree of immune suppression as measured by CD4 count (χ2 test, P= 0.001) and between poor disease HIV infected patients AIDS associated Kaposi's sarcoma patients patients Male: Female No % No. % of HIV 2007 1667 23.3 20 1.2 1.5:1 2008 1755 24.5 23 1.3 1.3:1 2009 1837 25.7 25 1.4 1.2:1 2010 1896 26.5 30 1.6 1:1 Total 7155 100 98 1.4 1.3:1 Table 1. Prevalence of HIV infection and AIDS-associated Kaposi's sarcoma patients was 48,593 copies/mL (range: 200- 989,571; 95% CI: 28,593- 76,225). 3.2 Tumour characteristics prognosis and immune suppression (P= 0.001) Year Fig. 1. Age and sex distribution of patients with AIDS-associated Kaposi's sarcoma Fig. 2. Nodular Kaposi's sarcoma with swelling of the lower limb Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 111 Fig. 4. Fungating Kaposi's sarcoma lesions of upper and lower limbs Fig. 3. Asymptomatic Kaposi's sarcoma lesion discovered during routine clinical evaluation Table 2. Anatomical distribution of AIDS-associated Kaposi's sarcoma lesions Fig. 3. Asymptomatic Kaposi's sarcoma lesion discovered during routine clinical evaluation Site No. % Lower limb 45 45.9 Trunk 37 37.8 Lymph node 33 33.7 Perineum 19 19.4 Oropharynx 15 15.3 Upper limb 13 13.3 Visceral 9 9.2 Other 6 6.1 Table 2. Anatomical distribution of AIDS-associated Kaposi's sarcoma lesions Fig. 4. Fungating Kaposi's sarcoma lesions of upper and lower limbs Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 113 Fifty four (80.6%) patients treated with HAART and VAB had tumour response compared to 8 (42.1%) of those treated with HAART alone (p< 0.005). Patients treated with both HAART and VAB were more likely to have tumour response or stable disease (OR 2.7; CI: 1.8- 3.6) compared to those that had HAART alone (table 4). There was a positive correlation between symptoms control and tumour response (Pearson correlation coefficient, r = 0.35 and r = 0.28; p < 0.05 by two tailed Fisher exact test). While haematotoxicity was the most frequent toxicity in both treatment groups, neutropenia grades three and four was higher in patients treated with both HAART and VAB (22.4%) compared to HAART alone (10.5%)(P < 0.001). Digestive toxicity was frequently observed in both groups, with a higher rate of diarrhea in the HAART and VAB group. Five patients had peripheral neuropathy while two others had asymptomatic cardiomyopathy. These toxicities delayed chemotherapy by 1-2 alone (n=19) Symptom control 0.003 control, months (range) 5 (1- 13) 12 (5- 54) 0.001 Overall tumour response 8 (42.1) 54 (80.6) 0.005 response, months (range) 5 (1-17) 11 (2- 54) 0.001 (range) 3 (2.5-15) 9 (5-26) 0.001 At diagnosis of KS 60 (30-90) 60 (30-90) No. (%) 7 (36.8) 38 (56.7) 0.015 3 months after diagnosis of KS 60 (20-90) 60 (40-90) 0.017 No. (%) 6 (31.5) 7 (10.4) 0.005 HAART= highly active antiretroviral therapy; VAB= combination of Vincristine, Doxorubicin and Table 4. Response of patients to treatment with HAART alone or HAART and VAB. Complete response 2 (10.5) 31 (46.3) 0.001 Partial response 6 (31.6) 23 (34.3) 0.075 No. (%) 10 (52.6) 59 (88.1) HAART +VAB (n=67) P -value weeks in 15 patients. Median duration of symptoms Median duration of tumour Median time to relapse, months Treatment related complications KS= Kaposi's sarcoma; KPS= Kernofsky performance score Median KPS (range) Mortality at 6 months Bleomycin Patient's response HAART SD= standard deviation; ACTG = AIDS clinical trials group; KS= Kaposi's sarcoma HAART= highly active antiretroviral therapy; VAB= combination of Vincristine, Doxorubicin and Bleomycin Table 3. Characteristics of patients that were treated with HAART alone or HAART and VAB #### 3.3 Treatment and outcome Overall, 67 (68.4%) patients were treated with both HAART and VAB of which 53 had completed six cycles. Of the 14 patients that did not complete anti-KS therapy, eight died in the course of treatment after two to five courses, treatment was stopped in two because of severe side effects and four were lost to follow-up (LTF). The median time to start chemotherapy after diagnosis of AAKS was three months (range 1 to 5months). Because of financial constraints, 19 (19.4%) patients had only antiretroviral therapy. The patients that had both HAART and VAB and those that had HAART alone had similar ACTG clinical stage, KPS and CD4 counts (table3). The remaining 12(12.2%) patients had only supportive care because of poor KPS (7) and refusal of consent (5). Two patients had limb amputation, five had excision of localised ulcerated lesions while 17(17.4%) had radiotherapy. Overall, 69 (70.4%) patients had improvement of AAKS symptoms that lasted a median duration of ten months (range 3 months to 4 years). The cumulative tumour response is shown in figure 5. Standard error of mean Age (years) 19 32.5 (4.7) 4.21 67 31.8 (7.5) 2.94 0.29 copies/mL) 10 503 (128.8) 17.50 41 512 (125.0) 15.9 0.15 (cell/uL) 19 162 (56.4) 2.37 67 168 (55.8) 1.45 0.07 Sex 0.75 diagnosis of KS 0.18 7 (36.8%) 24 (35.8%) HAART= highly active antiretroviral therapy; VAB= combination of Vincristine, Doxorubicin and Overall, 67 (68.4%) patients were treated with both HAART and VAB of which 53 had completed six cycles. Of the 14 patients that did not complete anti-KS therapy, eight died in the course of treatment after two to five courses, treatment was stopped in two because of severe side effects and four were lost to follow-up (LTF). The median time to start chemotherapy after diagnosis of AAKS was three months (range 1 to 5months). Because of financial constraints, 19 (19.4%) patients had only antiretroviral therapy. The patients that had both HAART and VAB and those that had HAART alone had similar ACTG clinical stage, KPS and CD4 counts (table3). The remaining 12(12.2%) patients had only supportive care because of poor KPS (7) and refusal of consent (5). Two patients had limb amputation, five had excision of localised ulcerated lesions while 17(17.4%) had radiotherapy. Overall, 69 (70.4%) patients had improvement of AAKS symptoms that lasted a median duration of ten months (range 3 months to 4 years). The cumulative tumour response is shown in figure 5. Table 3. Characteristics of patients that were treated with HAART alone or HAART and Male 12 42 Female 7 25 prognosis 4 (21.1%) 16 (23.9%) prognosis 15 (78.9%) 51 (76.1%) of AIDS 12 (63.2%) 43 (64.2%) SD= standard deviation; ACTG = AIDS clinical trials group; KS= Kaposi's sarcoma HAART alone HAART +VAB n Mean (SD) value 19 3.5 (1.7) 0.84 67 3.9 (1.3) 1.25 0.14 n Mean (SD) P - Standard error of mean Characteristics at presentation Duration of symptom (months) Viral load (x103 CD4 count ACTG Stage Good Poor After diagnosis of AIDS Bleomycin VAB At diagnosis 3.3 Treatment and outcome Time of Fifty four (80.6%) patients treated with HAART and VAB had tumour response compared to 8 (42.1%) of those treated with HAART alone (p< 0.005). Patients treated with both HAART and VAB were more likely to have tumour response or stable disease (OR 2.7; CI: 1.8- 3.6) compared to those that had HAART alone (table 4). There was a positive correlation between symptoms control and tumour response (Pearson correlation coefficient, r = 0.35 and r = 0.28; p < 0.05 by two tailed Fisher exact test). While haematotoxicity was the most frequent toxicity in both treatment groups, neutropenia grades three and four was higher in patients treated with both HAART and VAB (22.4%) compared to HAART alone (10.5%)(P < 0.001). Digestive toxicity was frequently observed in both groups, with a higher rate of diarrhea in the HAART and VAB group. Five patients had peripheral neuropathy while two others had asymptomatic cardiomyopathy. These toxicities delayed chemotherapy by 1-2 weeks in 15 patients. KS= Kaposi's sarcoma; KPS= Kernofsky performance score HAART= highly active antiretroviral therapy; VAB= combination of Vincristine, Doxorubicin and Bleomycin Table 4. Response of patients to treatment with HAART alone or HAART and VAB. Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 115 Overall, median survival was 14 months from the time of diagnosis of AAKS. The median survival was 12 months for patients treated with HAART compared to 18 months for those treated with both HAART and VAB (figure 6). Overall 56 (57.1%) patients had significant improvement in quality of life. Seven (7.1%) patients died during their first admission in the hospital while additional 7 were lost to follow-up. At one year 34 (34.7%) patients had died, comprising of 12 (100%) patients that had only supportive treatment, 9(47.4.0%) of those treated with HAART and 13 (19.4%) treated with HAART and VAB (figure 6). Univariate analysis showed that females, poor ACTG stage, CD4 count <200 cells/mm3, viral load > 21,000 copies/mL, and not using antiretroviral therapy were significantly associated with poorer survival (table 5). When these factors were subjected to multiple regression analysis, poor ACTG stage (p=0.015), viral load > 21,000 copies/mL (p=0.001), not using antiretroviral (p=0.005) and not using anticancer chemotherapy (p=0.003) were the significant independent factors associated with poorer survival. Patient's follow-up ranged from one month to four years. Fifty two (53.1%) patients were followed-up for one year. Death Female 42 20 47.6 1.4 1.2 – 2.9 0.049 41-60 13 5 38.5 1.3 1.1 –2.7 0.175 disease 64 27 42.2 1.7 1.5 – 4.9 0.075 Poor prognosis 77 35 45.5 4.8 3.7 – 12.4 0.005 ≤200 58 25 43.1 2.4 1.6 – 3.9 0.016 ≥ 21,000 40 19 47.5 2.9 2.7 – 6.5 0.003 No 12 12 100.0 5.5 3.9 – 14.6 0.001 No 31 22 71.0 3.2 2.1 – 5.7 0.001 HAART= highly active antiretroviral therapy; VAB= combination of Vincristine, Doxorubicin and Bleomycin Table 5. Univariate analysis of factors related to mortality in patients with AIDS-associated OR= odd ratio; CI = confidence interval; ACTG = AIDS clinical trials group; KS= Kaposi's sarcoma 21-40 76 32 42.1 1.5 1.4 – 3.5 OR 95% CI P - No % value Variable Number Sex Age (years) ACTG stage Time of diagnosis of KS CD4 count (cells/mm3) Viral load (copies/mL) Use of HAART Kaposi's sarcoma Use of VAB As AIDS defining of patients Male 56 21 37.5 1 1-20 9 4 44.4 1 After diagnosis of AIDS 34 13 38.2 1 Good prognosis 21 5 23.8 1 >200 40 15 37.5 1 0-20,000 11 2 18.2 1 Yes 86 28 32.5 1 Yes 67 18 26.8 1 Fig. 5. Cumulative tumour response following treatment of AIDS-associated Kaposi's sarcoma Fig. 5. Cumulative tumour response following treatment of AIDS-associated Kaposi's sarcoma Overall, median survival was 14 months from the time of diagnosis of AAKS. The median survival was 12 months for patients treated with HAART compared to 18 months for those treated with both HAART and VAB (figure 6). Overall 56 (57.1%) patients had significant improvement in quality of life. Seven (7.1%) patients died during their first admission in the hospital while additional 7 were lost to follow-up. At one year 34 (34.7%) patients had died, comprising of 12 (100%) patients that had only supportive treatment, 9(47.4.0%) of those treated with HAART and 13 (19.4%) treated with HAART and VAB (figure 6). Univariate analysis showed that females, poor ACTG stage, CD4 count <200 cells/mm3, viral load > 21,000 copies/mL, and not using antiretroviral therapy were significantly associated with poorer survival (table 5). When these factors were subjected to multiple regression analysis, poor ACTG stage (p=0.015), viral load > 21,000 copies/mL (p=0.001), not using antiretroviral (p=0.005) and not using anticancer chemotherapy (p=0.003) were the significant independent factors associated with poorer survival. Patient's follow-up ranged from one month to four years. Fifty two (53.1%) patients were followed-up for one year. OR= odd ratio; CI = confidence interval; ACTG = AIDS clinical trials group; KS= Kaposi's sarcoma HAART= highly active antiretroviral therapy; VAB= combination of Vincristine, Doxorubicin and Bleomycin Table 5. Univariate analysis of factors related to mortality in patients with AIDS-associated Kaposi's sarcoma Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 117 other centres in Nigeria (Agaba et al, 2009; Iregbu & Elegba, 2006; Chu et al 2010). The high incidence of HHV-8 infection and limited access to HAART and other preventive measures Prior to the HIV epidemic KS was a disease of middle-aged men (Penn, 1979; Taylor et al, 1971). The mean age of 33.6 years in the present study is similar to that reported in other studies in our sub-region (Chu et al, 2010; Phipps et al, 2010). The lower age of these patients is probably due to the high risk behaviour and incidence of HIV infection is highest in the age group 20-40 years in sub-Saharan Africa. In addition, our female patients were younger than males. The finding that AAKS occurs at an earlier age in women when compared with men has been reported previously (Mosam et al, 2008; Phipps et al, 2010). In the present study, the proportion of KS patients was highest among women in their mid-20s who heterosexually acquired HIV-1 infection. This indicates that females acquire HIV-1 infection at an earlier age than males. Alternatively, immunosuppression from HIV infection and KS pathogenesis might progress more rapidly in females compared to males. Previous studies have shown that the age-specific distribution pattern for female KS was essentially similar to that previously reported for HIV-1 infection (Jombo et al, 2006). Therefore, the risk of developing AAKS is closely related to the epidemiology of HIV-1 infection in females. Variable Category OR 95% CI P-value Use of HAART No vs. Yes 2.8 2.3- 6.9 0.005 Use of VAB No vs. Yes 1.9 1.5- 3.8 0.003 HAART= highly active antiretroviral therapy; VAB= combination of Vincristine, Doxorubicin and In Western countries all forms of KS are more common among men than women (Simard et al, 2011; Martellotta et al 2009). This is similar to the findings in Africa before the advent of HIV infection (Sasco et al, 2010; Taylor et al, 1971). Among HIV-infected individuals other than MSM, reported incidence rates of KS are still higher in men in other studies (Kagu et al, 2006; Sissolak & Mayaud, 2005). In a recent study from Brazil 94.4% of 107 AAKS patients were men, giving a male to female ratio of 18:1 (Yoshioka et al, 2004). The observations that a tumorigenic KS cell line could not be established in pregnant immunodeficient mice and that human chorionic gonadotropin (hCG) inhibited KS growth in-vitro suggested a possible biologic basis for the lower KS incidence among women (Lunardi-Iskandar et al, 1995; Table 6. Multiple regression analysis of factors related to mortality in patients with AIDS- Poor vs. Good prognosis OR= odd ratio; CI = confidence interval; ACTG = AIDS clinical trials group; Male 1.8 1.5- 2.9 0.075 > 200 1.6 1.3- 3.8 0.075 < 21,000 3.1 2.6- 9.5 0.001 5.3 2.2- 17.3 0.015 Sex Female vs. CD4 count (cells/mm3) ≤ 200 vs. Viral load (copies/mL) ≥ 21,000 vs. ACTG stage Bleomycin associated Kaposi's sarcoma explain in part the reason for increasing incidence of AAKS in sub-Saharan Africa. Fig. 6. Cumulative survival following treatment of patients with AIDS-associated Kaposi's sarcoma #### 4. Discussion To our knowledge, this is the largest study to date on the treatment and outcome of patients with AIDS-associated Kaposi's sarcoma from Nigeria. The present study identified KS in 1.4% of HIV-1 infected patients. The patients are young with female patients being relatively younger than males. The male to female ratio decreased from 1.5:1 in 2007 to 1:1 four years later. Majority of the patients (78.6%) presented with high tumour burden that was categorised as poor prognosis disease, while 20 (20.4%) had pulmonary tuberculosis. Simultaneous treatment with HAART and combination chemotherapy was carried out on 67(68.4%) patients. This treatment was associated with significant morbidity but was the only chance for control of symptoms and prolonged survival. In high income countries the incidence of AAKS has decreased significantly from mid 1990s (Franceschi et al, 2008; Pipkin et al, 2011). This reduced AAKS incidence is due to wide spread use of HAART which has the effect of immune reconstitution and direct inhibitory effects on angiogenesis. In addition, there are safer sex practices and other preventive and therapeutic measures against HIV infection. Recently, Phatak et al (2010) from India identified no case of KS among 46 AIDS-associated cancers reviewed over 5 years. In another report from Thailand, the incidence was 0.026 per 100,000 despite high incidence of HIV infection because HHV-8 infection is low at 4.0% (Sriplung & Parkin, 2004). In the present study, there was progressive increase in prevalence of AAKS over the study period (table 1). In a previous report from our institution, 15 AAKS patients were seen from 1991 to 1995 compared to 98 patients seen from 2007 to 2010 in the present study (Ahmed et al, 2001). Overall, the prevalence of AAKS in this study was 1.4% which is lower than 1.6% reported from Jos, Nigeria and 3.4% from South Africa, but higher than 0.8% reported from Fig. 6. Cumulative survival following treatment of patients with AIDS-associated Kaposi's To our knowledge, this is the largest study to date on the treatment and outcome of patients with AIDS-associated Kaposi's sarcoma from Nigeria. The present study identified KS in 1.4% of HIV-1 infected patients. The patients are young with female patients being relatively younger than males. The male to female ratio decreased from 1.5:1 in 2007 to 1:1 four years later. Majority of the patients (78.6%) presented with high tumour burden that was categorised as poor prognosis disease, while 20 (20.4%) had pulmonary tuberculosis. Simultaneous treatment with HAART and combination chemotherapy was carried out on 67(68.4%) patients. This treatment was associated with significant morbidity but was the In high income countries the incidence of AAKS has decreased significantly from mid 1990s (Franceschi et al, 2008; Pipkin et al, 2011). This reduced AAKS incidence is due to wide spread use of HAART which has the effect of immune reconstitution and direct inhibitory effects on angiogenesis. In addition, there are safer sex practices and other preventive and therapeutic measures against HIV infection. Recently, Phatak et al (2010) from India identified no case of KS among 46 AIDS-associated cancers reviewed over 5 years. In another report from Thailand, the incidence was 0.026 per 100,000 despite high incidence of HIV infection because HHV-8 infection is low at 4.0% (Sriplung & Parkin, 2004). In the present study, there was progressive increase in prevalence of AAKS over the study period (table 1). In a previous report from our institution, 15 AAKS patients were seen from 1991 to 1995 compared to 98 patients seen from 2007 to 2010 in the present study (Ahmed et al, 2001). Overall, the prevalence of AAKS in this study was 1.4% which is lower than 1.6% reported from Jos, Nigeria and 3.4% from South Africa, but higher than 0.8% reported from only chance for control of symptoms and prolonged survival. sarcoma 4. Discussion other centres in Nigeria (Agaba et al, 2009; Iregbu & Elegba, 2006; Chu et al 2010). The high incidence of HHV-8 infection and limited access to HAART and other preventive measures explain in part the reason for increasing incidence of AAKS in sub-Saharan Africa. Prior to the HIV epidemic KS was a disease of middle-aged men (Penn, 1979; Taylor et al, 1971). The mean age of 33.6 years in the present study is similar to that reported in other studies in our sub-region (Chu et al, 2010; Phipps et al, 2010). The lower age of these patients is probably due to the high risk behaviour and incidence of HIV infection is highest in the age group 20-40 years in sub-Saharan Africa. In addition, our female patients were younger than males. The finding that AAKS occurs at an earlier age in women when compared with men has been reported previously (Mosam et al, 2008; Phipps et al, 2010). In the present study, the proportion of KS patients was highest among women in their mid-20s who heterosexually acquired HIV-1 infection. This indicates that females acquire HIV-1 infection at an earlier age than males. Alternatively, immunosuppression from HIV infection and KS pathogenesis might progress more rapidly in females compared to males. Previous studies have shown that the age-specific distribution pattern for female KS was essentially similar to that previously reported for HIV-1 infection (Jombo et al, 2006). Therefore, the risk of developing AAKS is closely related to the epidemiology of HIV-1 infection in females. OR= odd ratio; CI = confidence interval; ACTG = AIDS clinical trials group; HAART= highly active antiretroviral therapy; VAB= combination of Vincristine, Doxorubicin and Bleomycin Table 6. Multiple regression analysis of factors related to mortality in patients with AIDSassociated Kaposi's sarcoma In Western countries all forms of KS are more common among men than women (Simard et al, 2011; Martellotta et al 2009). This is similar to the findings in Africa before the advent of HIV infection (Sasco et al, 2010; Taylor et al, 1971). Among HIV-infected individuals other than MSM, reported incidence rates of KS are still higher in men in other studies (Kagu et al, 2006; Sissolak & Mayaud, 2005). In a recent study from Brazil 94.4% of 107 AAKS patients were men, giving a male to female ratio of 18:1 (Yoshioka et al, 2004). The observations that a tumorigenic KS cell line could not be established in pregnant immunodeficient mice and that human chorionic gonadotropin (hCG) inhibited KS growth in-vitro suggested a possible biologic basis for the lower KS incidence among women (Lunardi-Iskandar et al, 1995; Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 119 reason for the increased severity of AAKS in women is not related to virological or immunological differences since both men and women in our study had similar mean VL and mean CD4 counts. This is in agreement with studies from Zimbabwe and South Africa (Meditz et al, 2007; Mosam et al, 2008). Of special interest is a small cohort of 14 patients who were on HAART for 6-13 months at the time of diagnosis of KS. These patients had a median CD4 count of 375 cells/mm3 and undetectable HIV viral load. They required systemic therapy to control their KS but were more likely to have complete resolution of their tumours and demonstrated a trend towards better survival than patients having KS with lesser CD4 counts and detectable HIV viral loads. In the past, AAKS has been reported in African patients with CD4 counts of >350 cells /mm3 indicating that severe immunosuppression is not necessary for development of KS (Morgan et al, 2000). Similarly, recent reports from high income countries have identified a group of patients that developed AAKS despite effective and sustained HIV suppression and good immune system function (Crum-Cianflone et al, 2010; Mani et al, 2009; Maurer et al, 2007). This raises questions about the integrity of the immune system and its ability to control certain viruses in patients with long-standing HIV infection. It has been suggested that with the ageing of HIV infected patients those who are co-infected with HHV-8 may develop KS despite good control of HIV infection (Crum-Cianflone et al, 2010). The impacts of AAKS on quality of life are varied. In our patients, extensive oedema of the lower limbs was associated with stiffness and pain that may interfere with walking while ulcerated tumours were infected and foul smelling. Lesions of the face and genitalia also have social and emotional consequences, including isolation because of obvious disfiguring lesions, and depression The disability and suffering associated with AAKS means that treatment to reduce symptoms and improve quality of life should be carried out promptly and efficiently. HAART is an essential treatment for all AAKS patients (Krown, 2004; Tirelli & Bernardi, 2001). In patients with low tumour burden and slowly progressing disease, histological regression of existing KS lesions has been shown in response to HAART (Martellotta et al, 2009). However, HAART alone can not effectively control all cases of KS and there may be initial tumour progression as part of the immunoreconstitution syndrome (Bower et al, 2005). In addition, it is not possible to state with certainty what proportion of patients with AAKS will benefit from HAART alone, or what are the precise characteristics that can be use to identify such patients. In our patients as in others, HAART is an effective postchemotherapy maintenance treatment in patients with advanced and extensive disease that has been reduced significantly as a result of conventional chemotherapy (Cooley et al, 2007; Martin-Carbonero, 2004). The effects of HAART on Kaposi's sarcoma are multifactorial and include inhibition of HIV replication, diminished production of HIV-1 transactivating protein Tat, reconstitution of immune response against HHV-8 and possibly direct antiangiogenic activity by inclusion of protease inhibitors (Tirelli & Bernardi, 2001). In the present study, decision to initiate systemic chemotherapy was based on the extent of Kaposi's sarcoma in addition to other considerations such as patient KPS, end organ Our patients were treated with a combination of vincristine, doxorubicin and bleomycin, similar to reports from other low income countries (Chu et al, 2010; Dedicoat et al, 2003). In high income countries liposomal anthracyclines and taxanes are being used for treatment of AAKS due to higher efficacy and reduced toxicity (Ashish et al, 2007; Cooley et al, 2007). In and anxiety from the constant visible reminder of illness. function, degree of immunosuppression, and other HIV comorbidities. Rabkin et al, 1995). However, therapeutic trials with hCG have been inconclusive while studies in women with HIV infection revealed that pregnancy afforded no protection from KS development or dissemination (Rabkin et al, 1995). In our patients, the male to female ratio was 1.3:1 which decreased progressively from 1.5:1 in 2007 to 1:1 four years later. This is similar to 1.4:1 recently reported from South Africa (Chu et al, 2010). A report from Jos Nigeria revealed a reversal of the gender ratio from a male to female ratio of 10:1 about four decades ago to 1:1.4 (Agaba et al, 2009). The reason for the near equivalent distribution of AAKS cases among men and women in recent studies may be a reflection of the high proportion of HIV infected females with >60% of person living with the virus in Africa being women. Additionally, women are more frequently subjected to HIV testing as routine counselling and testing has been applied to perinatal settings, and this may lead to higher number of AAKS cases being identified among women. Finally, unlike in Western countries where MSM constitute a high proportion of AAKS cases, the heterosexual mode of HIV transmission in our patients mean that HHV-8 would be equally distributed among men and women. Therefore, the trend in increasing proportion of female patients with AAKS may continue until when females predominate. Patients in this study presented with extensive and disseminated disease with 78.6% having poor prognosis stage, a much higher proportion than reported from resource rich countries (Ashish et al, 2007; Krown 2004). Other reports from poor resource countries revealed that poor prognosis disease constitute 60-82% of cases (Agaba et al, 2009; Bassett et al, 1995; Phipps et al 2010). Cutaneous lesions were present in 64.7% of patients in this series followed in order of frequency by lymphadenopathy and visceral lesions. Moderate enlargement of peripheral lymph nodes is not uncommon in HIV infected patients. A biopsy of such nodes would often reveal a focus of KS, a finding that appears to have little clinical consequence (Krown 2004). However, 11 of our patients had massive generalised lympadenopathy in the absence of evidence of KS elsewhere. In sub-Saharan Africa lymphadenopathy is comparatively common and has various causes including tuberculosis, lymphoma, KS and HIV infection. There is a significant overlap in the clinical presentation of these diseases although each requires distinctly different treatment. Histology provides a reliable and cost effective definitive diagnosis since each disease can be distinctively diagnosed under the microscope. However, it has been suggested that co-existing lesions can be missed even in biopsy material if special stains for demonstration of microorganisms are not performed (Pantanowitz et al 2010). Involvement of the gastrointestinal tract (GIT) was seen in only nine of our patients. However, most patients with GIT KS are asymptomatic, and because the lesions are submucosal they are not visualized on contrast-enhanced radiographs (Kibria et al 2010). Previous studies showed that asymptomatic GIT lesions have little clinical consequences hence, endoscopy should be carried out only on symptomatic patients (Kibria et al, 2010; Sissolak & Mayaud, 2005). In our patients, KS involved multiple anatomical regions. The lower limbs were most frequently affected with an associated lymphoedema which may be extensive and disproportionate to the extent of cutaneous disease. This lymphoedema may result from tumour involvement of dermal lymphatics or from the production by KS cells of growth factors that increase vascular permeability (Feller et al, 2008). Additionally, HHV-8-induced exuberant proliferation of endothelial cells may lead to the occlusion of lymphatic vascular lumens leading to lymphoedema (Feller et al, 2008). In this as in other reports, at the time of diagnosis women had more widespread and advanced AAKS compared to men (Chu et al 2010; Meditz et al, 2007). It is probable that the Rabkin et al, 1995). However, therapeutic trials with hCG have been inconclusive while studies in women with HIV infection revealed that pregnancy afforded no protection from KS development or dissemination (Rabkin et al, 1995). In our patients, the male to female ratio was 1.3:1 which decreased progressively from 1.5:1 in 2007 to 1:1 four years later. This is similar to 1.4:1 recently reported from South Africa (Chu et al, 2010). A report from Jos Nigeria revealed a reversal of the gender ratio from a male to female ratio of 10:1 about four decades ago to 1:1.4 (Agaba et al, 2009). The reason for the near equivalent distribution of AAKS cases among men and women in recent studies may be a reflection of the high proportion of HIV infected females with >60% of person living with the virus in Africa being women. Additionally, women are more frequently subjected to HIV testing as routine counselling and testing has been applied to perinatal settings, and this may lead to higher number of AAKS cases being identified among women. Finally, unlike in Western countries where MSM constitute a high proportion of AAKS cases, the heterosexual mode of HIV transmission in our patients mean that HHV-8 would be equally distributed among men and women. Therefore, the trend in increasing proportion of female patients with AAKS Patients in this study presented with extensive and disseminated disease with 78.6% having poor prognosis stage, a much higher proportion than reported from resource rich countries (Ashish et al, 2007; Krown 2004). Other reports from poor resource countries revealed that poor prognosis disease constitute 60-82% of cases (Agaba et al, 2009; Bassett et al, 1995; Phipps et al 2010). Cutaneous lesions were present in 64.7% of patients in this series followed in order of frequency by lymphadenopathy and visceral lesions. Moderate enlargement of peripheral lymph nodes is not uncommon in HIV infected patients. A biopsy of such nodes would often reveal a focus of KS, a finding that appears to have little clinical consequence (Krown 2004). However, 11 of our patients had massive generalised lympadenopathy in the absence of evidence of KS elsewhere. In sub-Saharan Africa lymphadenopathy is comparatively common and has various causes including tuberculosis, lymphoma, KS and HIV infection. There is a significant overlap in the clinical presentation of these diseases although each requires distinctly different treatment. Histology provides a reliable and cost effective definitive diagnosis since each disease can be distinctively diagnosed under the microscope. However, it has been suggested that co-existing lesions can be missed even in biopsy material if special stains for demonstration of microorganisms are not performed (Pantanowitz et al 2010). Involvement of the gastrointestinal tract (GIT) was seen in only nine of our patients. However, most patients with GIT KS are asymptomatic, and because the lesions are submucosal they are not visualized on contrast-enhanced radiographs (Kibria et al 2010). Previous studies showed that asymptomatic GIT lesions have little clinical consequences hence, endoscopy should be carried out only on symptomatic patients (Kibria et al, 2010; Sissolak & Mayaud, 2005). In our patients, KS involved multiple anatomical regions. The lower limbs were most frequently affected with an associated lymphoedema which may be extensive and disproportionate to the extent of cutaneous disease. This lymphoedema may result from tumour involvement of dermal lymphatics or from the production by KS cells of growth factors that increase vascular permeability (Feller et al, 2008). Additionally, HHV-8-induced exuberant proliferation of endothelial cells may lead to the occlusion of lymphatic vascular lumens leading to In this as in other reports, at the time of diagnosis women had more widespread and advanced AAKS compared to men (Chu et al 2010; Meditz et al, 2007). It is probable that the may continue until when females predominate. lymphoedema (Feller et al, 2008). reason for the increased severity of AAKS in women is not related to virological or immunological differences since both men and women in our study had similar mean VL and mean CD4 counts. This is in agreement with studies from Zimbabwe and South Africa (Meditz et al, 2007; Mosam et al, 2008). Of special interest is a small cohort of 14 patients who were on HAART for 6-13 months at the time of diagnosis of KS. These patients had a median CD4 count of 375 cells/mm3 and undetectable HIV viral load. They required systemic therapy to control their KS but were more likely to have complete resolution of their tumours and demonstrated a trend towards better survival than patients having KS with lesser CD4 counts and detectable HIV viral loads. In the past, AAKS has been reported in African patients with CD4 counts of >350 cells /mm3 indicating that severe immunosuppression is not necessary for development of KS (Morgan et al, 2000). Similarly, recent reports from high income countries have identified a group of patients that developed AAKS despite effective and sustained HIV suppression and good immune system function (Crum-Cianflone et al, 2010; Mani et al, 2009; Maurer et al, 2007). This raises questions about the integrity of the immune system and its ability to control certain viruses in patients with long-standing HIV infection. It has been suggested that with the ageing of HIV infected patients those who are co-infected with HHV-8 may develop KS despite good control of HIV infection (Crum-Cianflone et al, 2010). The impacts of AAKS on quality of life are varied. In our patients, extensive oedema of the lower limbs was associated with stiffness and pain that may interfere with walking while ulcerated tumours were infected and foul smelling. Lesions of the face and genitalia also have social and emotional consequences, including isolation because of obvious disfiguring lesions, and depression and anxiety from the constant visible reminder of illness. The disability and suffering associated with AAKS means that treatment to reduce symptoms and improve quality of life should be carried out promptly and efficiently. HAART is an essential treatment for all AAKS patients (Krown, 2004; Tirelli & Bernardi, 2001). In patients with low tumour burden and slowly progressing disease, histological regression of existing KS lesions has been shown in response to HAART (Martellotta et al, 2009). However, HAART alone can not effectively control all cases of KS and there may be initial tumour progression as part of the immunoreconstitution syndrome (Bower et al, 2005). In addition, it is not possible to state with certainty what proportion of patients with AAKS will benefit from HAART alone, or what are the precise characteristics that can be use to identify such patients. In our patients as in others, HAART is an effective postchemotherapy maintenance treatment in patients with advanced and extensive disease that has been reduced significantly as a result of conventional chemotherapy (Cooley et al, 2007; Martin-Carbonero, 2004). The effects of HAART on Kaposi's sarcoma are multifactorial and include inhibition of HIV replication, diminished production of HIV-1 transactivating protein Tat, reconstitution of immune response against HHV-8 and possibly direct antiangiogenic activity by inclusion of protease inhibitors (Tirelli & Bernardi, 2001). In the present study, decision to initiate systemic chemotherapy was based on the extent of Kaposi's sarcoma in addition to other considerations such as patient KPS, end organ function, degree of immunosuppression, and other HIV comorbidities. Our patients were treated with a combination of vincristine, doxorubicin and bleomycin, similar to reports from other low income countries (Chu et al, 2010; Dedicoat et al, 2003). In high income countries liposomal anthracyclines and taxanes are being used for treatment of AAKS due to higher efficacy and reduced toxicity (Ashish et al, 2007; Cooley et al, 2007). In Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 121 significant bone marrow suppression which is at its nadir on day 14 after administration. This bone marrow suppression recovers slowly over 7-10 days but in an HIV infected individual the magnitude and duration of the bone marrow suppression may be longer, hence the need to wait for three weeks to allow the bone marrow to recover before the next cycle of chemotherapy is given. The selection of therapy for KS must take into account the potential benefit and adverse effects of treatment, interactions with other medications, and When dealing with localised bulky or cosmetically disturbing lesions, radiotherapy is the most effective local therapy. In this as in other reports, irradiated lesions regress with treatment, but regrowth, after 6 months is common (Bih et al, 2007; Nguyen et al, 2008). In addition to providing effective palliation, radiotherapy is associated with minimal side effects. Although surgery is effective in excision of localised isolated lesions, heroic surgery is unjustified. Our study has several limitations. Among the patients that died, other risk factors for mortality such as tuberculosis were not independently considered hence the actual death due to KS were not isolated. In addition, some of our patients were lost to follow-up and a previous study indicates that about 40% of these patients were actually dead (Brinkhof et al, 2009). Similarly, because many patients lost to follow-up were treated with VAB, the beneficial effects of chemotherapy may be underestimated. Finally, follow-up of patients was difficult and inconsistent hence, it was not possible to monitor the timing of In conclusion KS is not uncommon in patients with HIV-1 infection. The patients present with extensive and advanced disease that requires systemic treatment. All AAKS patients should receive HAART. In low income countries like ours, chemotherapy consisting of a combination of vincristine, doxorubicin and bleomycin should be given simultaneously with HAART to patients that can physiologically withstand such therapy. The usual number of cycles for effective therapy is six cycles. However, chemotherapy may continue for 1-2 cycles beyond complete remission to maximise the chance of attacking all microscopic KS cells. Following successful treatment chemotherapy can be restarted for recurrent tumour. If KS continues to grow in the presence of effective HAART regimen, chemotherapy with VAB should be stopped and alternative treatment modalities should be instituted if possible, or else palliative KS management should be started. Palliative care for KS may include adequate pain relief, reduction of the size of tumours with radiotherapy and reduction of the offensive smell of ulcerated lesions with appropriate dressing argent. Prevention and treatment of other opportunistic infections is necessary as uncontrolled infections may stimulate KS progression probably due to production of angiogenic cytokines. Using this approach we achieved quick and prolonged tumour response in addition to improved quality of life as evidenced by symptoms control and improved cosmetic appearance and KPS. High satisfaction and reduced toxicities as well as availability, affordability and ease of administration of the drugs led to good patient's compliance. This approach is recommended for treating AAKS patients in a poor resource setting. It is necessary to identify KS patients early in the disease when treatment is likely to provide significant benefits in terms of reducing the bulk of disease and improving long-term survival. However, early access to highly active antiretroviral therapy constitutes the best hope for the control of this stigmatizing and lethal disease in sub-Saharan Africa. With improvement potential impact on underlying immunosuppression. treatment outcome accurately. 5. Conclusion a meta- analysis comparing pegylated doxorubicin (PLD) and VAB among 499 patients, Dedicoat et al (2003) found a better response among the PLD group although there was no survival advantage by either group. However, liposomal anthracyclines are unlikely to be available or affordable in low income countries where the majority of AAKS patients live. In a recent analysis from Brazil, PLD was found to be associated with improved efficacy and less toxicity but in terms of cost effectiveness, the VAB regimen is the most rational treatment option for AAKS patients in poor resource settings (Vanni et al, 2006). Our results showed that six cycles of this regimen could produce a significant and quick response in symptomatic patients with advanced AAKS. Overall response rate of 80.6% in our patients compares favourably to 50% to 88% reported in other studies (Dedicoat et al, 2003; Makombe et al, 2008; Phipps et al, 2010). Differences in response rates are largely attributable to differences in the patient populations evaluated, the lack of strictly defined response criteria and variations in the dosing schedules used. Of the 67 patients that had chemotherapy in this study, 52% had complete resolution of their disease within 36 months of diagnosis. This is similar to observed resolution rates of 44%-60% reported using similar regimen (Bihl et al, 2007; Nasti et al, 2000; Nguyen et al, 2008). However, we found the median time to complete resolution to be 9 months which is considerably longer than 5 months previously reported (Bihl et al, 2007). This is provably because chemotherapy was not immediately started in many of our patients due to financial constraints. In the present study, both HAART and VAB were independently associated with complete resolution of tumour suggesting that even in the HAART era, chemotherapy plays a significant role in the treatment of advanced AAKS patients. In addition, HIV viral load was significantly associated with resolution of KS. This finding is consistent with other reports of AAKS improvement or resolution associated with significant decrease or undetectable HIV viral load (Nguyen et al, 2008). Indeed, it seems that controlling HIV viral load is essential for clinical improvement, disease resolution of KS, and perhaps decreased risk of relapse. In this as in other studies there was no association between CD4 T-cell count and KS response, suggesting that suppression of HIV replication plays a more vital role in the resolution of KS than immune reconstitution (Mosam et al, 2008; Iregbu & Elegba, 2006). In our patients, there was positive correlation between tumour response and clinical response, and the response was maintained for a significant period of time after discontinuation of chemotherapy. Clinical response was associated with improved quality of life as evidenced by control of fungating and foul smelling ulcers and improvement of pain, cosmetic appearance and KPS. In the present study, median survival was 18 months following chemotherapy compared to 12 months following HAART alone. Both VAB and HAART are independently associated with improved survival, similar to the Multicenter AIDS Cohort Study which demonstrated an 81% reduced risk of death for KS patients treated with HAART (Tam et al, 2002). Whilst CD4 count <200 cells/mm3 was associated with mortality on univariate analysis, it was not on multivariate analysis. This may be due to the effects of advanced KS disease (T1 and S1 stages) whose effects were stronger than CD4 count. The toxicities observed following chemotherapy in our patients are similar to those reported in other studies using same regimen and are well tolerated (Dedicoat et al, 2003; Guadalupe et al, 2011). In the absence of haemopoetic growth factors, cytotoxic chemotherapy was used cautiously in our patients to minimise the risk of bone marrow suppression that may lead to infectious complications. Bacterial infections which resulted from severe neutropenia secondary to chemotherapy were observed in three of our patients. Doxorubicin causes significant bone marrow suppression which is at its nadir on day 14 after administration. This bone marrow suppression recovers slowly over 7-10 days but in an HIV infected individual the magnitude and duration of the bone marrow suppression may be longer, hence the need to wait for three weeks to allow the bone marrow to recover before the next cycle of chemotherapy is given. The selection of therapy for KS must take into account the potential benefit and adverse effects of treatment, interactions with other medications, and potential impact on underlying immunosuppression. When dealing with localised bulky or cosmetically disturbing lesions, radiotherapy is the most effective local therapy. In this as in other reports, irradiated lesions regress with treatment, but regrowth, after 6 months is common (Bih et al, 2007; Nguyen et al, 2008). In addition to providing effective palliation, radiotherapy is associated with minimal side effects. Although surgery is effective in excision of localised isolated lesions, heroic surgery is unjustified. Our study has several limitations. Among the patients that died, other risk factors for mortality such as tuberculosis were not independently considered hence the actual death due to KS were not isolated. In addition, some of our patients were lost to follow-up and a previous study indicates that about 40% of these patients were actually dead (Brinkhof et al, 2009). Similarly, because many patients lost to follow-up were treated with VAB, the beneficial effects of chemotherapy may be underestimated. Finally, follow-up of patients was difficult and inconsistent hence, it was not possible to monitor the timing of treatment outcome accurately. ## 5. Conclusion 120 Global View of HIV Infection a meta- analysis comparing pegylated doxorubicin (PLD) and VAB among 499 patients, Dedicoat et al (2003) found a better response among the PLD group although there was no survival advantage by either group. However, liposomal anthracyclines are unlikely to be available or affordable in low income countries where the majority of AAKS patients live. In a recent analysis from Brazil, PLD was found to be associated with improved efficacy and less toxicity but in terms of cost effectiveness, the VAB regimen is the most rational treatment option for AAKS patients in poor resource settings (Vanni et al, 2006). Our results showed that six cycles of this regimen could produce a significant and quick response in symptomatic patients with advanced AAKS. Overall response rate of 80.6% in our patients compares favourably to 50% to 88% reported in other studies (Dedicoat et al, 2003; Makombe et al, 2008; Phipps et al, 2010). Differences in response rates are largely attributable to differences in the patient populations evaluated, the lack of strictly defined response criteria and variations in the dosing schedules used. Of the 67 patients that had chemotherapy in this study, 52% had complete resolution of their disease within 36 months of diagnosis. This is similar to observed resolution rates of 44%-60% reported using similar regimen (Bihl et al, 2007; Nasti et al, 2000; Nguyen et al, 2008). However, we found the median time to complete resolution to be 9 months which is considerably longer than 5 months previously reported (Bihl et al, 2007). This is provably because chemotherapy was not immediately started in many of our patients due to financial constraints. In the present study, both HAART and VAB were independently associated with complete resolution of tumour suggesting that even in the HAART era, chemotherapy plays a significant role in the treatment of advanced AAKS patients. In addition, HIV viral load was significantly associated with resolution of KS. This finding is consistent with other reports of AAKS improvement or resolution associated with significant decrease or undetectable HIV viral load (Nguyen et al, 2008). Indeed, it seems that controlling HIV viral load is essential for clinical improvement, disease resolution of KS, and perhaps decreased risk of relapse. In this as in other studies there was no association between CD4 T-cell count and KS response, suggesting that suppression of HIV replication plays a more vital role in the resolution of KS than immune reconstitution (Mosam et al, 2008; Iregbu & Elegba, 2006). In our patients, there was positive correlation between tumour response and clinical response, and the response was maintained for a significant period of time after discontinuation of chemotherapy. Clinical response was associated with improved quality of life as evidenced by control of fungating and foul smelling ulcers and improvement of pain, cosmetic appearance and KPS. In the present study, median survival was 18 months following chemotherapy compared to 12 months following HAART alone. Both VAB and HAART are independently associated with improved survival, similar to the Multicenter AIDS Cohort Study which demonstrated an 81% reduced risk of death for KS patients treated with HAART (Tam et al, 2002). Whilst CD4 count <200 cells/mm3 was associated with mortality on univariate analysis, it was not on multivariate analysis. This may be due to the effects of advanced KS disease (T1 and S1 stages) whose effects were stronger than CD4 count. The toxicities observed following chemotherapy in our patients are similar to those reported in other studies using same regimen and are well tolerated (Dedicoat et al, 2003; Guadalupe et al, 2011). In the absence of haemopoetic growth factors, cytotoxic chemotherapy was used cautiously in our patients to minimise the risk of bone marrow suppression that may lead to infectious complications. Bacterial infections which resulted from severe neutropenia secondary to chemotherapy were observed in three of our patients. Doxorubicin causes In conclusion KS is not uncommon in patients with HIV-1 infection. The patients present with extensive and advanced disease that requires systemic treatment. All AAKS patients should receive HAART. In low income countries like ours, chemotherapy consisting of a combination of vincristine, doxorubicin and bleomycin should be given simultaneously with HAART to patients that can physiologically withstand such therapy. The usual number of cycles for effective therapy is six cycles. However, chemotherapy may continue for 1-2 cycles beyond complete remission to maximise the chance of attacking all microscopic KS cells. Following successful treatment chemotherapy can be restarted for recurrent tumour. If KS continues to grow in the presence of effective HAART regimen, chemotherapy with VAB should be stopped and alternative treatment modalities should be instituted if possible, or else palliative KS management should be started. Palliative care for KS may include adequate pain relief, reduction of the size of tumours with radiotherapy and reduction of the offensive smell of ulcerated lesions with appropriate dressing argent. Prevention and treatment of other opportunistic infections is necessary as uncontrolled infections may stimulate KS progression probably due to production of angiogenic cytokines. Using this approach we achieved quick and prolonged tumour response in addition to improved quality of life as evidenced by symptoms control and improved cosmetic appearance and KPS. High satisfaction and reduced toxicities as well as availability, affordability and ease of administration of the drugs led to good patient's compliance. This approach is recommended for treating AAKS patients in a poor resource setting. It is necessary to identify KS patients early in the disease when treatment is likely to provide significant benefits in terms of reducing the bulk of disease and improving long-term survival. However, early access to highly active antiretroviral therapy constitutes the best hope for the control of this stigmatizing and lethal disease in sub-Saharan Africa. With improvement Treatment of Kaposi's Sarcoma in HIV-1 Infected Individuals 123 Cooley T, Henry D, Tonda M, Sun S, O'Connell M, Rackoff W. (2007) A Randomized, Crum-Cianflone NF, Hullsiek KH, Ganesan A, Weintrob A, Okulicz JF, Agan BK. (2010) Is Dedicoat M, Vaithilingum M, Newton RR. (2003) Treatment of Kaposi's sarcoma in HIV-1 Engels EA, Pfeiffer RM, Goedert JJ, et al. (2006) Trends in cancer risk among people with Feller L, Masipa JN, Wood NH, Raubenheimer EJ, Lemmer J. (2008) The prognostic Franceschi S, Dal Maso L, Rickenbach M. et al (2008) Kaposi sarcoma incidence in the Swiss Franceschi S, Geddes M. (1995). Epidemiology of classic Kaposi's sarcoma, with special Friedman-Kien A, Laubenstein L, Marmor M et al. (1981) Kaposi's sarcoma and Guadalupe M, Pollock BH, Westbrook S, et al. 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Part 1: epidemiology, environmental predispositions, clinical manifestations, and therapy. Lancet Infect patients seen in a designated HIV treatment and care centre in Abuja, Nigeria. J Int community of plateau state: Effcetive control measures still a nightmare. Nig J Med. associated Kaposi's sarcoma in Northeastern Nigeria. Singapore Med J 47: 1069- in the access to antiretroviral therapy in sub-Saharan Africa, it is necessary to designed studies that investigate the effects of cheaper and more widely available chemotherapeutic argents for the treatment of AIDS-associated Kaposi's sarcoma among patients on highly active antiretroviral therapy. #### 6. Acknowledgement We sincerely appreciate the cooperation of the patients and their relations that were included in this study. We are also very grateful to all physicians and other personnel that participated in the management of these patients. #### 7. 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AIDS-related symptomatic Kaposi's sarcoma. J Clin Oncol 22: 399–402. pregnancy hormone. Nature 375:64-68. conditions in Malawi. Trop Doct 38: 5–7 Trials Group Oncology Committee. J Clin Oncol 15:3085-3092. 56: 64-68 638. 1557. 1378–1379. Cancer 92: 622–627. topical halofuginone in AIDS-related Kaposi sarcoma. J Acquir Immune Defic Syndr. Implications for the design of therapeutic trials in patients with advanced, validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical neoplastic Kaposi's sarcoma cell line in immunodeficient mice blocked by a human Kaposi's sarcoma who start antiretroviral therapy under routine programme Kaposi's sarcoma in patients with undetectable HIV viral loads and CD4 counts Kaposi's sarcoma: state of the art and therapeutic strategies. Curr HIV Res. 7: 634- highly active antiretroviral therapy versus highly active antiretroviral therapy Differences in AIDS-Associated Kaposi Sarcoma in Harare, Zimbabwe. J Acquir HIV-1-associated Kaposi's sarcoma among women and men in South Africa. Int J AIDS-related Kaposi's sarcoma: results of a phase II study. J Clin Oncol. 18:1550- Department of Public Health Federal Ministry of Health Abuja, Nigeria in virus infection and cancer in adults and children residing in Kampala, Uganda. Int J 7 Brazil Thiourea Derivatives: A Promising Class Marcus Vinicius Nora de Souza1,2, Marcelle de Lima Ferreira Bispo1,2, Raoni Schroeder Borges Gonçalves1,2 and Carlos Roland Kaiser2 Nowadays, the Human Immunodeficiency Virus (HIV), which is the causative agent of Acquired Immune Deficiency Syndrome (AIDS), represents a serious public health problem. According to the World Health Organization (WHO), in 2009 there were 33.3 million people living with HIV worldwide, and more particularly in sub-Saharan Africa, where the overwhelming majority (67%) of cases appear. Furthermore, 2.6 million people have been recently infected with the virus in 2009, when HIV/AIDS was estimated to have caused 1.8 million deaths (United Nations Program on HIV/AIDS [UNAIDS], 2010). Due to the impairment of their immune system, HIV bearers are more susceptible to opportunistic infections, such as Tuberculosis (TB), which is a leading cause of HIV-related deaths worldwide. The risk for TB is 20-37-fold greater among HIV-infected individuals, depending on the status of the HIV epidemic. According to WHO, one-third of people living with HIV are infected with TB, and there was an estimate of 1.4 million new TB cases per year among said population. Moreover, one in four TB deaths occurs in HIV-positive patients, while TB was responsible for 23% of AIDS-related deaths (WHO, 2010a). 2. Challenges in the management of HIV infection-related TB above factors will be emphasized in the next section. 2.1 Diagnosis of TB in HIV-infected individuals This situation becomes especially alarming in view of the number of challenges in the control and management of TB in HIV-infected individuals, such as the difficulties to conclude a TB diagnosis, as well as the complexity involved in the treatment of HIV infection-related TB. Due to their great relevance to the subject matter of this work, the Within the context of lung diseases, there are some aspects that may constitute a bar to the diagnosis of TB (Box 1): HIV-infected patients are minimally symptomatic or asymptomatic, as they present few or less specific classic symptoms of TB (productive cough, chest pain, fever, night sweats, weight loss, hemoptysis); patients with low CD4+ T lymphocyte counts 1. Introduction Against HIV/TB Co-Infection Fármacos – Farmanguinhos Universidade Federal de Rio de Janeiro, 1Fundação Oswaldo Cruz (Fiocruz)- Instituto de Tecnologia em 2Programa de Pós-Graduação em Química, Instituto de Química,	doab	2025-04-07T04:13:04.690974	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 29 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.30	Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection Marcus Vinicius Nora de Souza1,2, Marcelle de Lima Ferreira Bispo1,2, Raoni Schroeder Borges Gonçalves1,2 and Carlos Roland Kaiser2 1Fundação Oswaldo Cruz (Fiocruz)- Instituto de Tecnologia em Fármacos – Farmanguinhos 2Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal de Rio de Janeiro, Brazil ## 1. Introduction 126 Global View of HIV Infection The National AIDS and STD Control Programme, Department of Public Health Federal Tirelli U, Bernardi D. (2001). Impact of HAART on the clinical management of AIDS-related Vanni T, Fonseca BAL, Polanczyk CA. (2006). Cost-Effectiveness Analysis Comparing Yoshioka MC, Alchorne MDA, Porro AM, Tomimori-Yamashita J. (2004). Epidemiology of Committee on AIDS Sentinel report. 2010. cancers. Euro J Cancer 37: 1320–1324 Brazil. HIV Clin Trials 7:194–202 Paolo, Brazil. Int J Dermatol 43:643–647 Ministry of Health Abuja, Nigeria in Collaboration with The National Action Chemotherapy Regimens in the Treatment of AIDS-Related Kaposi's Sarcoma in Kaposi's sarcoma in patients with acquired immunodeficiency syndrome in Sao Nowadays, the Human Immunodeficiency Virus (HIV), which is the causative agent of Acquired Immune Deficiency Syndrome (AIDS), represents a serious public health problem. According to the World Health Organization (WHO), in 2009 there were 33.3 million people living with HIV worldwide, and more particularly in sub-Saharan Africa, where the overwhelming majority (67%) of cases appear. Furthermore, 2.6 million people have been recently infected with the virus in 2009, when HIV/AIDS was estimated to have caused 1.8 million deaths (United Nations Program on HIV/AIDS [UNAIDS], 2010). Due to the impairment of their immune system, HIV bearers are more susceptible to opportunistic infections, such as Tuberculosis (TB), which is a leading cause of HIV-related deaths worldwide. The risk for TB is 20-37-fold greater among HIV-infected individuals, depending on the status of the HIV epidemic. According to WHO, one-third of people living with HIV are infected with TB, and there was an estimate of 1.4 million new TB cases per year among said population. Moreover, one in four TB deaths occurs in HIV-positive patients, while TB was responsible for 23% of AIDS-related deaths (WHO, 2010a). This situation becomes especially alarming in view of the number of challenges in the control and management of TB in HIV-infected individuals, such as the difficulties to conclude a TB diagnosis, as well as the complexity involved in the treatment of HIV infection-related TB. Due to their great relevance to the subject matter of this work, the above factors will be emphasized in the next section. #### 2. Challenges in the management of HIV infection-related TB #### 2.1 Diagnosis of TB in HIV-infected individuals Within the context of lung diseases, there are some aspects that may constitute a bar to the diagnosis of TB (Box 1): HIV-infected patients are minimally symptomatic or asymptomatic, as they present few or less specific classic symptoms of TB (productive cough, chest pain, fever, night sweats, weight loss, hemoptysis); patients with low CD4+ T lymphocyte counts Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 129 Providing another relevant instruction on TB treatment in HIV-infected patients, WHO also recommends a daily TB therapy within, at least, the intensive phase (WHO, 2010b). Such orientation is based on a recent study, which showed that the incidence of relapse and failure among HIV-positive TB patients who were treated with intermittent TB therapy throughout treatment was 2–3 times higher, in comparison with patients who received a daily intensive therapy (Kahn et al., 2010). Moreover, another study indicated that, among HIV-positive patients, the risk of acquired resistance to rifampicin is higher when failing a In relation to HIV treatment (Box 2), WHO recommends that the first-line ART regime should comprise a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI), as said drugs are effective, available at low costs in the market, and present generic and fixed-dose combinations (FDCs). Therefore, protease inhibitors (PIs) should be kept for second-line regimes (WHO, ART regime containing EFV is preferred, since interactions with anti-TB drugs EFV should not be administrated to women during the first trimester In cases of EFV intolerance, of HIV resistant to EFV, or contraindications to an EFV-based regime: [AZT + 3TC + NVP] or TDF + [3TC or FTC] + NVP or the triple AZT= zidovudine, TDF= tenofovir, 3TC= lamivudine, FTC= emtricitabine, EFV= efavirenz , NVP= If available, a rifabutin-based TB treatment should be preferable. A critical issue among HIV-infected individuals diagnosed with TB is to determine the precise moment to initiate ART. Although ART improves the survival of HIV-positive patients, including those with TB, the optimal deadline from the onset of TB to start such a treatment is a matter that still requires further clarification. According to WHO, the TB treatment should be initiated in all HIV bearers showing active TB disease, regardless of their CD4+ lymphocyte count. TB treatment should be started first, and, then, followed by ART as soon as possible, and preferably within the first weeks from the beginning of the TB treatment (WHO, 2010b). However, the concomitant treatment of both diseases results in In spite of a number of clinical trials intended to determine the optimal timing for ART administration in bearers of HIV infection-related TB, the question still requires further studies (Piggot & Karakousis, 2011). Among the above referred works, Abdool Karim and collaborators have been performing the Starting Antiviral Therapy at Three Points in TB (SAPIT), which is an open-label, randomized and controlled trial conducted in Durban, several disadvantages, whose examples are listed and discussed at the Table 2. three times weekly short-course intermittent regime (Kahn et al., 2010). Box 2. Combined regime for both HIV and TB treatment. pregnancy, due to its teratogenic effects . Hepatitis among healthy adults is recurrent. [AZT or TDF] and [3TC or FTC] plus [EFV or NVP]; NRTI regime [AZT + 3TC + ABC] or [AZT + 3TC + TDF] ART regime containing a boosted protease inhibitor (PIs) First-line regime: 2NRTIs + 1NNRTI are minimal; 2010b). nevirapine. 2.3 Optimal timing to start the ART treatment have atypical chest radiograph findings, with lower prevalence of cavitary disease, while the findings could be normal in up to 22% of HIV-infected individuals; the main method used worldwide for TB detection, namely the microscopic examination of Ziehl-Neelsenstained sputum smears, has low sensitivity among HIV-infected individuals, as they develop acid-faster smear negative diseases with higher frequency than HIV-uninfected people (Sterling et al., 2010). Furthermore, HIV-infected individuals present more often the subclinical form of TB, said factor leading to a delay in the diagnosis and treatment. Another difficulty for the TB diagnosis in HIV-infected individuals is the increased risk (10-20% in HIV-uninfected individuals, compared to 40-80% in HIV-infected persons) to develop extrapulmonary TB, whose most prevalent forms are pleural effusion, lymphadenopathy, pericardial disease, miliary disease, meningitis and disseminated TB (Chaisson et al., 1987). #### Box 1. Usual difficulties involved in the diagnosis of TB in HIV-infected individuals #### 2.2 TB treatment in HIV bearers In addition to diagnostic difficulties, the treatment of HIV infection-related TB also presents several challenges, such as duration and frequency, determining the precise moment to start antiretroviral therapy (ART), management of drug interactions, as well as several side effects from therapy. As regards the duration of TB therapy, WHO recommends a 6-month rifampicin-based treatment (2HRZE/4HR, Table 1), applying to both HIV-infected and uninfected individuals. Nevertheless, Perriens and collaborators showed that, after providing a 12 month therapy with 2HRZE/4HR, the recurrence rate at the 18th month shall be lower than those observed at the standard regime (Perriens et al., 1995). Furthermore, another study performed by Fitzgerald et al indicated that the administration of isoniazid for 1 year upon termination of the therapy under standard regime reduces the recurrence of TB only among HIV-infected patients (Fitzgerald et al., 2000). It is worthy to mention that, in both studies, patients had no access to antiretroviral therapy, which contributes to extend the beneficial effects from TB treatment, without presenting the risks that are inherent to the combination of TB-HIV drugs. a For the continuation phase, the optimal dosing frequency may be also daily; should the administration of such a dosage be impossible, three times per week is a suitable alternative. H = isoniazid, R= rifampicin, Z = pyrazinamide, E= ethambutol Table 1. TB treatment for HIV bearers, as recommended by WHO. have atypical chest radiograph findings, with lower prevalence of cavitary disease, while the findings could be normal in up to 22% of HIV-infected individuals; the main method used worldwide for TB detection, namely the microscopic examination of Ziehl-Neelsenstained sputum smears, has low sensitivity among HIV-infected individuals, as they develop acid-faster smear negative diseases with higher frequency than HIV-uninfected Furthermore, HIV-infected individuals present more often the subclinical form of TB, said factor leading to a delay in the diagnosis and treatment. Another difficulty for the TB diagnosis in HIV-infected individuals is the increased risk (10-20% in HIV-uninfected individuals, compared to 40-80% in HIV-infected persons) to develop extrapulmonary TB, whose most prevalent forms are pleural effusion, lymphadenopathy, pericardial disease, Box 1. Usual difficulties involved in the diagnosis of TB in HIV-infected individuals In addition to diagnostic difficulties, the treatment of HIV infection-related TB also presents several challenges, such as duration and frequency, determining the precise moment to start antiretroviral therapy (ART), management of drug interactions, as well as As regards the duration of TB therapy, WHO recommends a 6-month rifampicin-based treatment (2HRZE/4HR, Table 1), applying to both HIV-infected and uninfected individuals. Nevertheless, Perriens and collaborators showed that, after providing a 12 month therapy with 2HRZE/4HR, the recurrence rate at the 18th month shall be lower than those observed at the standard regime (Perriens et al., 1995). Furthermore, another study performed by Fitzgerald et al indicated that the administration of isoniazid for 1 year upon termination of the therapy under standard regime reduces the recurrence of TB only among HIV-infected patients (Fitzgerald et al., 2000). It is worthy to mention that, in both studies, patients had no access to antiretroviral therapy, which contributes to extend the beneficial effects from TB treatment, without presenting the risks that are inherent to the Phase Duration (months) Dosing Frequency Drugs Intensive 2 Daily HRZE Continuous 4 Daily or three times per weeka HR a For the continuation phase, the optimal dosing frequency may be also daily; should the administration of such a dosage be impossible, three times per week is a suitable alternative. Table 1. TB treatment for HIV bearers, as recommended by WHO. H = isoniazid, R= rifampicin, Z = pyrazinamide, E= ethambutol miliary disease, meningitis and disseminated TB (Chaisson et al., 1987). Minimally symptomatic or asymptomatic patients; Acute prevalence of acid--fast smear negative disease ; Increased risk of development of extrapulmonary TB. Atypical chest radiograph findings; High frequency of subclinical TB form; people (Sterling et al., 2010). 2.2 TB treatment in HIV bearers several side effects from therapy. combination of TB-HIV drugs. Providing another relevant instruction on TB treatment in HIV-infected patients, WHO also recommends a daily TB therapy within, at least, the intensive phase (WHO, 2010b). Such orientation is based on a recent study, which showed that the incidence of relapse and failure among HIV-positive TB patients who were treated with intermittent TB therapy throughout treatment was 2–3 times higher, in comparison with patients who received a daily intensive therapy (Kahn et al., 2010). Moreover, another study indicated that, among HIV-positive patients, the risk of acquired resistance to rifampicin is higher when failing a three times weekly short-course intermittent regime (Kahn et al., 2010). In relation to HIV treatment (Box 2), WHO recommends that the first-line ART regime should comprise a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI), as said drugs are effective, available at low costs in the market, and present generic and fixed-dose combinations (FDCs). Therefore, protease inhibitors (PIs) should be kept for second-line regimes (WHO, 2010b). #### Box 2. Combined regime for both HIV and TB treatment. - [AZT or TDF] and [3TC or FTC] plus [EFV or NVP]; - ART regime containing EFV is preferred, since interactions with anti-TB drugs are minimal; - EFV should not be administrated to women during the first trimester pregnancy, due to its teratogenic effects . - If available, a rifabutin-based TB treatment should be preferable. - Hepatitis among healthy adults is recurrent. AZT= zidovudine, TDF= tenofovir, 3TC= lamivudine, FTC= emtricitabine, EFV= efavirenz , NVP= nevirapine. #### 2.3 Optimal timing to start the ART treatment A critical issue among HIV-infected individuals diagnosed with TB is to determine the precise moment to initiate ART. Although ART improves the survival of HIV-positive patients, including those with TB, the optimal deadline from the onset of TB to start such a treatment is a matter that still requires further clarification. According to WHO, the TB treatment should be initiated in all HIV bearers showing active TB disease, regardless of their CD4+ lymphocyte count. TB treatment should be started first, and, then, followed by ART as soon as possible, and preferably within the first weeks from the beginning of the TB treatment (WHO, 2010b). However, the concomitant treatment of both diseases results in several disadvantages, whose examples are listed and discussed at the Table 2. In spite of a number of clinical trials intended to determine the optimal timing for ART administration in bearers of HIV infection-related TB, the question still requires further studies (Piggot & Karakousis, 2011). Among the above referred works, Abdool Karim and collaborators have been performing the Starting Antiviral Therapy at Three Points in TB (SAPIT), which is an open-label, randomized and controlled trial conducted in Durban, Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 131 The Table 3 below summarizes the most relevant interactions between rifamycins and Effects on pharmacokinetics parameters and comments Rifampicin Rifabutin Rifabutin AUC↓ by 38% (daily or intermittent) significantly changed Rifabutin AUC ↑ by 250% Rifabutin AUC ↑ by 34% Rifabutin AUC ↑ by 207% Rifabutin AUC ↑ by 303% day or 3x/week AUC is not affected adjustment. No interaction. No dose adjustment. DLV AUC↓ 95% Rifabutin AUC↑100% be avoided. 3x/week 3x/week 3x/week day or 3x/week Increase Rifabutin dose to 450-600mg Simultaneous use of such drugs should Rifabutin dose ↓ to 150mg/day or 300mg Rifabutin dose ↓ to 150mg every other Rifabutin dose ↓ to 150mg/day or 300mg Rifabutin dose ↓ to 150mg/day or 300mg Rifabutin dose ↓ to 150mg every other Change Maraviroc dose to 300mg twice daily and rifabutin to 300mg daily Rifabutin trough ↓ by 20% Raltegravir Change Rifabutin dose to 300mg daily and Raltegravir to 400mg twice daily NVP and Rifabutin AUC are not antiretroviral agents (Centers for Disease Control and Prevention [CDC], 2007). Antiretroviral agent EFV EFV AUC↓ by 22% NVP NVP AUC↓ 37-58% and Cmin<sup>↓</sup> of ritonavir Fos-Amprenavir Simultaneous use of such drugs should be avoided. DLV AUC↓ 95% should be avoided. Ritonavir AUC\↓ by 35% Atazanavir AUC↓ by >95% Simultaneous use of such drugs* should be avoided. should be avoided. should be avoided. should be avoided. hepatitis. hepatitis. twice-daily Raltegravir Raltegravir concentratios ↓ by 40- 61% Enfuvritide No interaction. No dose Indinavir AUC↓ by 89% Nelfinavir AUC↓ by 82% Simultaneous use of such drugs Saquinavir AUC↓ by 84% Simultaneous use of such drugs Caution. The use of this combination could cause Caution. The use of this combination could cause Maraviroc Cmin↓ by 78% Increase Maraviroc to 600mg \AUC= area under the plasma concentration time curve; estimated bioavailability. Table 3. Management of interactions among anti-TB and anti-HIV drugs. 68% with 200mg 2x/day dose Simultaneous use of such drugs* Monitor for antiretroviral activity Simultaneous use of such drugs NNRTIs DLV PIs Ritonavir Atazanavir Indinavir Nelfinavir Saquinavir Saquinavir + Ritonavir Lopinavir + Ritonavir Maraviroc Integrase Inhibitors Fusion Inhibitors CCR5 receptor antagonists South Africa, with 642 HIV-positive patients with a CD4 count <500/mm3 and with smearpositive TB (Abdool et al., 2010). The preliminary findings of SAPIT showed a decreased mortality rate among individuals who had started ART during anti-TB regime, in comparison with those who initiated ART only upon completion of the anti-TB therapy. Table 2. Disadvantages from the concomitant treatment of TB and HIV. Following these conclusions, another study performed by Blanc and collaborators provided strong evidences for an early start of ART administration (Blanc et al., 2010). The Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA) was an open label, prospective, randomized controlled trial, registering HIV-positive patients with a CD4 count <200/mm3 and smear-positive TB living in Cambodia. This study demonstrated that the group treated with ART within 2 weeks from the beginning of the TB therapy showed a relevant decline of 34% at the mortality rate, when compared with patients who received ART only 8 weeks after the initiation of TB treatment. In both studies, an increased incidence of IRIS was observed in patients who were early treated with ART. Nevertheless, the data shown by the SPIT trial, namely a lack of mortality or changes in antiretroviral regime attributable to IRIS, also corroborate the early ART initiation in HIV infection-related TB patients. #### 2.4 Management of drug-drug interactions between antiretroviral and anti-TB agents The most delicate kind of interactions involves the concomitant use of rifamycins (among which the most usual are rifampicin and rifabutin), NNRTIs and PIs, given that these last two classes of antiretroviral drugs are essentially metabolized through cytochrome P450 (CYP) 3A4 enzymes, whose expression is induced by rifamycins. Consequently, the plasma concentration and exposure of NNRTIs and PIs are significantly reduced, when they are concomitantly administrated with rifamycins (Burman et al., 2001). Furthermore, rifampicin improves the activity of the efflux multidrug transporter P-glicoprotein, which promotes the elimination of PIs (Kim et al., 1998; Schuetz et al., 1996). Due to the reduction of NNRTIs and PIs at the plasma concentration, as a result from the simultaneous administration of rifamycins, the HIV treatment can fail, thus giving rise to the emergence of drug resistance. South Africa, with 642 HIV-positive patients with a CD4 count <500/mm3 and with smearpositive TB (Abdool et al., 2010). The preliminary findings of SAPIT showed a decreased mortality rate among individuals who had started ART during anti-TB regime, in comparison with those who initiated ART only upon completion of the anti-TB therapy. High pill burden More than 10 pills daily; discourage treatment adherence. prior to ART, whenever it is possible. Following these conclusions, another study performed by Blanc and collaborators provided strong evidences for an early start of ART administration (Blanc et al., 2010). The Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA) was an open label, prospective, randomized controlled trial, registering HIV-positive patients with a CD4 count <200/mm3 and smear-positive TB living in Cambodia. This study demonstrated that the group treated with ART within 2 weeks from the beginning of the TB therapy showed a relevant decline of 34% at the mortality rate, when compared with patients who received ART only 8 weeks after the initiation of TB treatment. In both studies, an increased incidence of IRIS was observed in patients who were early treated with ART. Nevertheless, the data shown by the SPIT trial, namely a lack of mortality or changes in antiretroviral regime attributable to IRIS, Hepatotoxicity promoted by H, R and Z and also by PI and NNRTI; increased risk of hepatitis C virus infection (Velasco et al., 2009). Gastrointestinal upset and rash are common in both therapies Peripheral neuropathy promoted by H, didanosine and stavudine Although ART triggers the regeneration of immune cells, the immune system unexpectedly produces an overwhelming inflammatory response that unmasks or worsens the coinfection symptoms (TB is the most common among them); The risk of IRIS is the main ground to initiate TB treatment Its frequent symptoms comprise fever, swollen lymphonodes, skin lesions and rashes, changes in breathing, pneumonia, hepatitis, abscesses and eye inflammation. They often appear within 2–6 weeks from the beginning of HIV therapy (Antonelli et al., 2010). Disadvantage Comments Table 2. Disadvantages from the concomitant treatment of TB and HIV. also corroborate the early ART initiation in HIV infection-related TB patients. 2.4 Management of drug-drug interactions between antiretroviral and anti-TB agents The most delicate kind of interactions involves the concomitant use of rifamycins (among which the most usual are rifampicin and rifabutin), NNRTIs and PIs, given that these last two classes of antiretroviral drugs are essentially metabolized through cytochrome P450 (CYP) 3A4 enzymes, whose expression is induced by rifamycins. Consequently, the plasma concentration and exposure of NNRTIs and PIs are significantly reduced, when they are concomitantly administrated with rifamycins (Burman et al., 2001). Furthermore, rifampicin improves the activity of the efflux multidrug transporter P-glicoprotein, which promotes the elimination of PIs (Kim et al., 1998; Schuetz et al., 1996). Due to the reduction of NNRTIs and PIs at the plasma concentration, as a result from the simultaneous administration of rifamycins, the HIV treatment can fail, thus giving rise to the emergence of drug resistance. Overlapping of adverse effects Immune reconstitution inflammatory syndrome (IRIS) Drug-drug interactions See Table 3 The Table 3 below summarizes the most relevant interactions between rifamycins and antiretroviral agents (Centers for Disease Control and Prevention [CDC], 2007). \AUC= area under the plasma concentration time curve; estimated bioavailability. Table 3. Management of interactions among anti-TB and anti-HIV drugs. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 133 TIBO and HEPT [1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine] derivatives, yet discovered independently from each other, can be reputed a landmark in the history of the antiretroviral therapy. These compounds were the first congeners from a new category of anti-HIV drugs, currently known as NNRTIs (De Clercq, 2004). At the beginning of the 1990s, the only drug that had been approved for AIDS treatment was AZT, so that patients had to live at imminent risk to develop resistant mutant virus. Therefore, it becomes quite clear that the identification of a different class of antiretroviral drugs brought The development of TIBO derivatives started from a screening program from the library of Janssen Research Foundation, working with 600 compounds that were selected due to their failure in producing effects on the standard pharmacological assays, and to their low toxicity in rodents as well (De Clercq, 2004). Upon evaluation of the biological activity of these compounds against HIV-1/HTLVIIIB in MT-4 cells, researchers identified the tetrahydro-benzodiazepine derivative R14458* (Fig. 2), which presented a moderate anti-HIV-1 activity (IC50= 62µM) (Pauwels et al., 1990). Using this substance as a lead compound, they started a program aiming at the improvement of its anti-HIV properties. Thereafter, several analogues were synthesized, thus allowing the performance of an extensive 3.1 Thiourea derivatives showing a potential activity against HIV structure-activity relationship (SAR) study of this class of compounds. N R14458 IC50 = 62 mM Fig. 2. Structure of TIBO derivatives R4458 and R78305. <sup>6</sup> <sup>7</sup> <sup>8</sup> <sup>9</sup> O N 4 5 CH2 Considering that the compound R14458 is a racemic mixture, the authors initially investigated the role of stereochemistry in the biological activity of this substance. Although the two optical isomers were synthesized and tested against HIV-1, only the enantiomer R78305 (Fig. 2) with S configuration was found to be active, showing that this configuration is required for the anti-HIV-1 properties of TIBOs (Pauwels et al., 1990). The subsequent studies aimed at the evaluation of systematic alterations in the structure of the lead compound, and its scaffold was independently modified in four different portions: the substituent bonded to the 6-positon nitrogen of the diazepine ring (Kukla et al., 1991a), the 5-ring urea portion (Kukla et., 1991b), the 7-membered ring portion (Breslin et al., 1995) and the substituent of the aromatic ring (Ho et al., 1995). The results obtained in these studies are CH3 R78305 IC50 = 70 mM <sup>6</sup> <sup>7</sup> <sup>8</sup> <sup>9</sup> N O N 4 5 CH2 CH3 HN 10 1 2 3 HN 10 3.1.1.1 SAR of TIBO derivatives described in the next sections. 1 2 3 3.1.1 TIBO derivatives new perspectives in the treatment of AIDS. #### 3. Thiourea derivatives: A promising class against HIV/TB co-infection Due to such a number of complications that may possibly arise in the course of treatment of HIV-related TB, as described above, the development of new drugs against HIV and TB should be mandatory. Said medications should produce relevant effects, such as the improvement of patient well-being by means of the reduction of pill burden, as well as by the careful management of the overlapping toxicity resulting from the treatment of TB and HIV infections. Therefore, an alternative could be the development of drugs that might be able to simultaneously act in the treatment of both diseases. In this context, thiourea derivatives appear as a promising class of compounds. For instance, the tetrahydroimidazobenzodiazepinthiones (TIBO) derivative 9-Cl-TIBO and the phenylethylthiazolylthiourea (PETT) derivatives LY73497 and trovirdine (TRV) play a significant role in the inhibition of HIV reverse transcriptase (Fig. 1). On the other hand, the compound isoxyl (ISO, thiocarlide), another thiourea derivative, is known by its strong anti-TB activity (Fig. 1). By the way, although used as part of the TB clinical treatment since the 1960's, it may be pointed out that the relevance of ISO emerged from recent researches, and particularly from studies in the field of new treatments against MDR-TB. Therefore, the main purpose of this chapter is to highlight the importance of thioureas for the TB-HIV drug discovery, and to proceed with a review of data from recent literature, by focusing the most relevant contributions to the development of new prototypes containing this promising scaffold. Fig. 1. Active thioureas against HIV (9-Cl TIBO, LY73497 and trovirdine) or M. tuberculosis (ISO). Due to such a number of complications that may possibly arise in the course of treatment of HIV-related TB, as described above, the development of new drugs against HIV and TB should be mandatory. Said medications should produce relevant effects, such as the improvement of patient well-being by means of the reduction of pill burden, as well as by the careful management of the overlapping toxicity resulting from the treatment of TB and HIV infections. Therefore, an alternative could be the development of drugs that might be able to simultaneously act in the treatment of both diseases. In this context, thiourea derivatives appear as a promising class of compounds. For instance, the tetrahydroimidazobenzodiazepinthiones (TIBO) derivative 9-Cl-TIBO and the phenylethylthiazolylthiourea (PETT) derivatives LY73497 and trovirdine (TRV) play a significant role in the inhibition of HIV reverse transcriptase (Fig. 1). On the other hand, the compound isoxyl (ISO, thiocarlide), another thiourea derivative, is known by its strong anti-TB activity (Fig. 1). By the way, although used as part of the TB clinical treatment since the 1960's, it may be pointed out that the relevance of ISO emerged from recent researches, and particularly from studies in the field of new treatments against MDR-TB. Therefore, the main purpose of this chapter is to highlight the importance of thioureas for the TB-HIV drug discovery, and to proceed with a review of data from recent literature, by focusing the most relevant contributions to the development of new prototypes containing this 3. Thiourea derivatives: A promising class against HIV/TB co-infection N H N H S LY73497 N H N S Cl S O O > Isoxyl MIC= 2.5g/mL Fig. 1. Active thioureas against HIV (9-Cl TIBO, LY73497 and trovirdine) or M. tuberculosis N H N N CH3 H3C N S HN 9-Cl TIBO (R82913) ED50= 0.21M ED50= 1.33<sup>M</sup> Trovirdine (TRV) N H CH3 S N H ED50= 0.016M N Br promising scaffold. (ISO). #### 3.1 Thiourea derivatives showing a potential activity against HIV 3.1.1 TIBO derivatives TIBO and HEPT [1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine] derivatives, yet discovered independently from each other, can be reputed a landmark in the history of the antiretroviral therapy. These compounds were the first congeners from a new category of anti-HIV drugs, currently known as NNRTIs (De Clercq, 2004). At the beginning of the 1990s, the only drug that had been approved for AIDS treatment was AZT, so that patients had to live at imminent risk to develop resistant mutant virus. Therefore, it becomes quite clear that the identification of a different class of antiretroviral drugs brought new perspectives in the treatment of AIDS. The development of TIBO derivatives started from a screening program from the library of Janssen Research Foundation, working with 600 compounds that were selected due to their failure in producing effects on the standard pharmacological assays, and to their low toxicity in rodents as well (De Clercq, 2004). Upon evaluation of the biological activity of these compounds against HIV-1/HTLVIIIB in MT-4 cells, researchers identified the tetrahydro-benzodiazepine derivative R14458 (Fig. 2), which presented a moderate anti-HIV-1 activity (IC50= 62µM) (Pauwels et al., 1990). Using this substance as a lead compound, they started a program aiming at the improvement of its anti-HIV properties. Thereafter, several analogues were synthesized, thus allowing the performance of an extensive structure-activity relationship (SAR) study of this class of compounds. Fig. 2. Structure of TIBO derivatives R4458 and R78305. #### 3.1.1.1 SAR of TIBO derivatives Considering that the compound R14458 is a racemic mixture, the authors initially investigated the role of stereochemistry in the biological activity of this substance. Although the two optical isomers were synthesized and tested against HIV-1, only the enantiomer R78305 (Fig. 2) with S configuration was found to be active, showing that this configuration is required for the anti-HIV-1 properties of TIBOs (Pauwels et al., 1990). The subsequent studies aimed at the evaluation of systematic alterations in the structure of the lead compound, and its scaffold was independently modified in four different portions: the substituent bonded to the 6-positon nitrogen of the diazepine ring (Kukla et al., 1991a), the 5-ring urea portion (Kukla et., 1991b), the 7-membered ring portion (Breslin et al., 1995) and the substituent of the aromatic ring (Ho et al., 1995). The results obtained in these studies are described in the next sections. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 135 synthetic problems, where scientists had to use a cyclopropylmethyl, also able to lead to high levels of activity). The best results were found for 8-substituted analogues, which, in comparison to the lead compound, showed much higher potency, so that halogens reached the highest level of activities in the substituent group. Iodine was the only exception to the above conclusions, probably due to its larger volume. Compounds containing a methoxy or an acetylene group bounded at 8-positon displayed similar activities, when compared to the parent unsubstituted compound. Although the substitution of 8-methoxy group by 8-thiomethyl may have led to an improvement in the biological activity, the replacement of methoxy by the ethoxy group, which is larger, resulted in a decrease in anti-HIV activity. Amino, aminoacetyl, dimethylamino and nitro analogues remained inactive. Furthermore, the substitutions at 9-positon led to the formation of compounds, whose activities are similar to those of the parent unsubstituted compound, while 10-substituted compounds were found to be less active. The replacement of the aromatic ring by a heteroaromatic ring was also evaluated, but the derivatives were inactive Extensive SAR studies with TIBO derivatives allowed the identification of substances with similar or better activities than other known antiretroviral drugs, such as AZT, dideoxycytidine (ddC) and Dideoxyinosine (ddI). Among these substances, thiourea 9-Cl TIBO (R82913) (Fig. 1) was selected for a phase I clinical trial. This study evaluated 22 patients, within the age group between 27-59 years old, who showed HIV infection in an advanced stage (Pialoux et al., 1991). The drug was administrated by daily intravenous injection through a peripheral or a central venous catheter. R82913 had to be injected in a dose of 120-200mg, in order to reach the concentration observed in vitro (20-40ng/mL), which is required for the protection against HIV cytopathic effects. The measured half-life was of 3 days, and the pharmacokinetic profile of the substance was neither influenced by an increase of the dose, nor by its long-term administration. In spite of its side effects, which usually comprised phlebitis, drowsiness and fatigue, a general absence of toxicity Phenethylthiazolylthiourea (PETT) analogues integrate the powerful class of NNRTIs, first described by researchers from Lilly laboratories in the second half of the 1990's (Ahgren et al., 1995). These compounds were discovered in an attempt to indentify the minimal structural elements that might be necessary for the development of the thiourea derivative 9-Cl TIBO biological activity (Fig. 1). The researchers disconnected some bonds from the rigid tricyclic nucleus of this substance, thus producing simpler structures. The potential pharmacophores produced after the systematically disconnections were used to search similar structures in the organic compound database of Lilly Research Laboratories. The study disclosed approximately 250 substances, whose activity against HIV was duly evaluated. The N-(2-phenethyl)-N'-(2-thiazolyl)thiourea, LY73497 (Fig. 3), was identified as the lead compound, and used in subsequent SAR studies (Bell et al., SAR studies were performed by dividing LY73497 into four portions and proceeding with an aleatory variation of each of them (Fig. 3) (Bell et al., 1995). Initially, the authors (Ho et al., 1995). 3.1.1.1.5 Clinical trial with 9-Cl-TIBO (R82913) could be attributed to R82913. 3.1.2.1 Discovery of PETT series and preliminary SAR studies 3.1.2 PETT derivatives 1995). #### 3.1.1.1.1 Modifications in the substituent bonded to the 6-position nitrogen of the diazepine ring Initially, it was verified that the presence of bulky groups attached to this position was mandatory to trigger anti-HIV-1 activity, since compounds containing hydrogen, ethyl or a linear propargyl substituent were inactive. The strongest activities were observed whenever an unsaturated allyl group was attached to the 6-positon nitrogen, such as in the lead compound, and it was verified that the substitution at the 2-position of this group led to more active compounds. The improvement degree of said activity varied in accordance with the following sequence: ethyl > methyl = vinyl = bromo > H. On the other hand, all compounds containing 2-propyl, phenyl, benzyl or fused cyclohexenyl were inactive. Substitutions at the 3-positon of the allyl group were also verified, and the dimethyl substituted compound showed the highest degree of activity found in these series. Introduction of bulky groups at this position usually led to completely inactive compounds. In view of the above results, an optimum size to the substituent for both 2- and 3-positions is required, since the substance loses its activity, as the length of the side chain increases or decreases. Moreover, the groups attached to the nitrogen which led to inactive compounds were the following: acetylene, alkyl groups containing heteroatom, and methylene attached to functional groups such as, nitrile, ketone, ester, alcohol, ether or a heteroaromatic pyrrole or imidazole (Kukla et al., 1991a). #### 3.1.1.1.2 Modification in the 5-ring urea portion This portion of the tricyclic TIBO structures underwent several modifications, among which we can mention the replacement of carbonyl carbon by: nitrogen, sulfur dioxide or deletion of the carbonyl oxygen yielding, that are, respectively, a triazine, a sulfonamide and an imidazole. However, in the most part of trials, these modifications gave rise to inactive compounds. The most promising result was found by the replacement of the urea group by a thiourea, yielding a compound around one hundred times more active than the original prototype. The ring expansion, by insertion of a methylene or another carbonyl, led to a loss of anti-HIV-1 activity, and it was also verified that methylation of 1-positon nitrogen also gave rise to an inactive compound, probably in view of the need of NH to form hydrogen bonding (Kukla et., 1991b). #### 3.1.1.1.3 Modifications at the 7-membered ring portion The demethylation of carbon in 5-position or introduction of bulky groups at this position yielded inactive or less active compounds, thus demonstrating that the size of the methyl group is optimum for the biological activity. The C-4 position showed a greater tolerance for larger groups, and the analogues presented a good anti-HIV-1 activity. The 7-position also underwent replacements, whereby high levels of activity were once more achieved. However, among the modifications performed at the 7-membered ring, none of them led to the discovery of compounds showing a better HIV inhibitory activity than the simplest 5 mono-methyl-substituted analogue (Breslin et al., 1995). #### 3.1.1.1.4 Evaluation of substituent effect on the aromatic ring In order to evaluate the substituent effect on the aromatic ring, researchers used both urea and thiourea derivatives, and maintained the optimal conditions described by previous works, such as the attachment of a methyl group to the 5-position, and bonding of a dimethylallyl group to nitrogen at the 6-positon ( except in case of compounds presenting This portion of the tricyclic TIBO structures underwent several modifications, among which we can mention the replacement of carbonyl carbon by: nitrogen, sulfur dioxide or deletion of the carbonyl oxygen yielding, that are, respectively, a triazine, a sulfonamide and an imidazole. However, in the most part of trials, these modifications gave rise to inactive compounds. The most promising result was found by the replacement of the urea group by a thiourea, yielding a compound around one hundred times more active than the original prototype. The ring expansion, by insertion of a methylene or another carbonyl, led to a loss of anti-HIV-1 activity, and it was also verified that methylation of 1-positon nitrogen also gave rise to an inactive compound, probably in view of the need of NH to form hydrogen The demethylation of carbon in 5-position or introduction of bulky groups at this position yielded inactive or less active compounds, thus demonstrating that the size of the methyl group is optimum for the biological activity. The C-4 position showed a greater tolerance for larger groups, and the analogues presented a good anti-HIV-1 activity. The 7-position also underwent replacements, whereby high levels of activity were once more achieved. However, among the modifications performed at the 7-membered ring, none of them led to the discovery of compounds showing a better HIV inhibitory activity than the simplest 5- In order to evaluate the substituent effect on the aromatic ring, researchers used both urea and thiourea derivatives, and maintained the optimal conditions described by previous works, such as the attachment of a methyl group to the 5-position, and bonding of a dimethylallyl group to nitrogen at the 6-positon ( except in case of compounds presenting 3.1.1.1.1 Modifications in the substituent bonded to the 6-position nitrogen of the diazepine ring Initially, it was verified that the presence of bulky groups attached to this position was mandatory to trigger anti-HIV-1 activity, since compounds containing hydrogen, ethyl or a linear propargyl substituent were inactive. The strongest activities were observed whenever an unsaturated allyl group was attached to the 6-positon nitrogen, such as in the lead compound, and it was verified that the substitution at the 2-position of this group led to more active compounds. The improvement degree of said activity varied in accordance with the following sequence: ethyl > methyl = vinyl = bromo > H. On the other hand, all compounds containing 2-propyl, phenyl, benzyl or fused cyclohexenyl were inactive. Substitutions at the 3-positon of the allyl group were also verified, and the dimethyl substituted compound showed the highest degree of activity found in these series. Introduction of bulky groups at this position usually led to completely inactive compounds. In view of the above results, an optimum size to the substituent for both 2- and 3-positions is required, since the substance loses its activity, as the length of the side chain increases or decreases. Moreover, the groups attached to the nitrogen which led to inactive compounds were the following: acetylene, alkyl groups containing heteroatom, and methylene attached to functional groups such as, nitrile, ketone, ester, alcohol, ether or a heteroaromatic pyrrole or imidazole (Kukla et al., 1991a). bonding (Kukla et., 1991b). 3.1.1.1.2 Modification in the 5-ring urea portion 3.1.1.1.3 Modifications at the 7-membered ring portion mono-methyl-substituted analogue (Breslin et al., 1995). 3.1.1.1.4 Evaluation of substituent effect on the aromatic ring synthetic problems, where scientists had to use a cyclopropylmethyl, also able to lead to high levels of activity). The best results were found for 8-substituted analogues, which, in comparison to the lead compound, showed much higher potency, so that halogens reached the highest level of activities in the substituent group. Iodine was the only exception to the above conclusions, probably due to its larger volume. Compounds containing a methoxy or an acetylene group bounded at 8-positon displayed similar activities, when compared to the parent unsubstituted compound. Although the substitution of 8-methoxy group by 8-thiomethyl may have led to an improvement in the biological activity, the replacement of methoxy by the ethoxy group, which is larger, resulted in a decrease in anti-HIV activity. Amino, aminoacetyl, dimethylamino and nitro analogues remained inactive. Furthermore, the substitutions at 9-positon led to the formation of compounds, whose activities are similar to those of the parent unsubstituted compound, while 10-substituted compounds were found to be less active. The replacement of the aromatic ring by a heteroaromatic ring was also evaluated, but the derivatives were inactive (Ho et al., 1995). #### 3.1.1.1.5 Clinical trial with 9-Cl-TIBO (R82913) Extensive SAR studies with TIBO derivatives allowed the identification of substances with similar or better activities than other known antiretroviral drugs, such as AZT, dideoxycytidine (ddC) and Dideoxyinosine (ddI). Among these substances, thiourea 9-Cl TIBO (R82913) (Fig. 1) was selected for a phase I clinical trial. This study evaluated 22 patients, within the age group between 27-59 years old, who showed HIV infection in an advanced stage (Pialoux et al., 1991). The drug was administrated by daily intravenous injection through a peripheral or a central venous catheter. R82913 had to be injected in a dose of 120-200mg, in order to reach the concentration observed in vitro (20-40ng/mL), which is required for the protection against HIV cytopathic effects. The measured half-life was of 3 days, and the pharmacokinetic profile of the substance was neither influenced by an increase of the dose, nor by its long-term administration. In spite of its side effects, which usually comprised phlebitis, drowsiness and fatigue, a general absence of toxicity could be attributed to R82913. #### 3.1.2 PETT derivatives #### 3.1.2.1 Discovery of PETT series and preliminary SAR studies Phenethylthiazolylthiourea (PETT) analogues integrate the powerful class of NNRTIs, first described by researchers from Lilly laboratories in the second half of the 1990's (Ahgren et al., 1995). These compounds were discovered in an attempt to indentify the minimal structural elements that might be necessary for the development of the thiourea derivative 9-Cl TIBO biological activity (Fig. 1). The researchers disconnected some bonds from the rigid tricyclic nucleus of this substance, thus producing simpler structures. The potential pharmacophores produced after the systematically disconnections were used to search similar structures in the organic compound database of Lilly Research Laboratories. The study disclosed approximately 250 substances, whose activity against HIV was duly evaluated. The N-(2-phenethyl)-N'-(2-thiazolyl)thiourea, LY73497 (Fig. 3), was identified as the lead compound, and used in subsequent SAR studies (Bell et al., 1995). SAR studies were performed by dividing LY73497 into four portions and proceeding with an aleatory variation of each of them (Fig. 3) (Bell et al., 1995). Initially, the authors Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 137 TRV displayed a comparable or a better ED50 than other known antiretroviral drugs, such as 9-Cl TIBO, L697661, NVP, AZT, ddI and ddC, being capable of inhibiting the replication of HIV-1 in MT-4 cell culture, as well as the replication of various clinical HIV-1 isolates in MT-2 cells and PBL human cells. However, this substance showed no action against HIV-2. When it was tested against resistant isolates containing mutations in Ile-100, Cys-181, and Ile-100–H-188 reverse transcriptase (RT), the trials disclosed a cross resistance between trovirdine and other non-nucleoside compounds. Nevertheless, within the group of said non-nucleoside derivatives, trovirdine was found to present the highest level of activity In the enzymatic assay with wild-type and mutant RT enzymes, TRV was also more active After TRV oral administration in rats (20mg/kg), a peak concentration in plasma of 3.5µg/mL was observed at 0.5h. The overall half-life was of 1 h, and the area under the concentrationtime curve was 6.9µg/h/mL. The peak concentration in brain was 2.9µg/g, and the area under the concentration-time curve was 5.9µg/h/mL. This result shows that TRV crosses the bloodbrain barrier, which is a desirable property of anti-retroviral agents, due to the risk of HIV- Despite the promising outcomes related to the use of TRV as NNRTI, the clinical trials focused on this compound were suspended. Anyway, this substance is still considered a standard lead compound for the development of new PETT analogues, as it encouraged the course of an extensive serie of SAR studies based on modern approaches, such as crystallographic techniques and molecular modeling. These works will be discussed in the This study was initiated when Vig and collaborators (Vig et al., 1998) proposed to synthesize series of novel PETT derivatives based on the structure of the non-nucleoside inhibitor (NNI) binding pocket of HIV-1 reverse transcriptase (RT). This composite binding pocket was built by superimposing nine individual crystal structures of RT-NNI complexes (Sudbeck et al., 1998). After having conducted docking studies with TRV, they verified the existence of multiple sites, which can be used for incorporation of larger functional groups, mainly surrounding the pyridyl ring, the ethyl linker and near the 5-bromo position. Hence, they proposed that a better use of these spaces by strategically designed functional groups could lead to a high-affinity binding and to the discovery of more potent anti-HIV agents. In view of the above, they decided to study the effects of introduction of several substituents in different positions of the These results disclosed by a preliminary SAR study attest to the potency of PETT derivatives phenyl ring substitutions on various positions (Fig. 4). After analyzing the composite NNI binding pocket, the authors identified three promising PETT derivatives with ortho-F (HI-240), ortho-Cl (HI-253) and metha-F (HI-241) substituents on the phenyl ring, which showed potent anti-HIV activity (IC50 [p24] values of < 1nM), selectivity indexes (SI) of > 100,000, and were recognized to be more active than AZT or TRV. Among them, HI-240 has been chosen as the lead compound, as it presented the highest level of activity against wide-type HIV RT. This finding could be grounded on the examination of a composite binding pocket model, showing that Wing 2 region is predominantly hydrophobic, except at the area nearby ortho positions on both sides of the phenyl ring, which would be compatible with polar groups, such as, for instance, halogen atoms. than the non-nucleosides 9-Cl TIBO, L697661 and nevirapine, showing a lower IC50. associated encephalopathy in contaminated patients (Ahgren et al., 1995). phenyl ring, such as methoxy group, fluorine atom or chlorine atom (Table 4). 3.1.2.2 Rational design of new PETT analogues against these mutants. next section. modified the quadrant 1 of phenyl ring, introducing different substituents, or replacing it by other aromatic heterocycles. They observed that meta and ortho substitutions generally triggers better activities, when compared with the para one. As regards the electronic nature of ortho substituents, both small electron-donating and small electronwithdrawing groups presented good activities, and, among said elements, the preferred groups are the following: fluoro, chloro, azido and methoxy. A combination of alkoxy and halogen substitution resulted in compounds with improved activity. Although the introduction of an ethoxy group in meta position may have led to a good activity, the use of bulky alkoxy groups, such as propoxy and isopropoxy, seems to have been responsible for a reduction in the activities. Among the substances containing a heterocycle in replacement of the phenyl ring, the best activity was observed for the 2-pyridyl compound. Changes at the nitrogen atom for the 3- and 4-position induced a decrease in the activity. Fig. 3. SAR studies with PETTs derivatives. The modifications in quadrant 2 were characterized by changes in the length of the alkyl linker. The main conclusion was the identification of an ethyl linker as optimal to the activities. It was also noted that the introduction of a methyl group in the benzylic position of ethylene linker enhanced the activity, while a methyl group in the phenethyl position led to its reduction. The variations in quadrant 3 demonstrated the crucial role played by thiourea moiety at the anti-HIV activity of these compounds. In fact, the replacement of thiourea by urea resulted in an inactive compound and other isosters, such as cyanoguanidine derivatives, which appeared to be less potent. The methyl substitution at the nitrogen adjacent to the thiazole ring leads to a less active compound, while methyl substitution on the nitrogen adjacent to the phenethyl side chain provided compound with no activity at all. This result is attributed to presence of an internal hydrogen bond between the hydrogen bonded to nitrogen adjacent to the phenethyl side chain and the nitrogen of the thiazole nucleus in LY73497. As regards quadrant 4, it was observed that a heterocycle in this position is determinant to reach a good activity. In general, substituted thiazoles were highly active, excepting the 4 carboxythiazolyl compound, whose lack of activity indicated that the allosteric site of the enzyme does not accept a polar group. When thiazole nucleus was replaced by another heterocyle, the 2-pyridyl analog showed the highest level of activity. During a second phase of SAR studies, the authors combined the optimal substituents in quadrants 1-4, and observed that these parameters are additive, able to give rise to compounds with optimal activity. Among them, the compound LY300046, currently known as trovirdine (TRV; Fig. 1), was selected for further pharmacological examinations, since the hydrochloride salt of this compound showed acceptable blood levels, when orally administrated in rats (Ahgren et al., 1995). modified the quadrant 1 of phenyl ring, introducing different substituents, or replacing it by other aromatic heterocycles. They observed that meta and ortho substitutions generally triggers better activities, when compared with the para one. As regards the electronic nature of ortho substituents, both small electron-donating and small electronwithdrawing groups presented good activities, and, among said elements, the preferred groups are the following: fluoro, chloro, azido and methoxy. A combination of alkoxy and halogen substitution resulted in compounds with improved activity. Although the introduction of an ethoxy group in meta position may have led to a good activity, the use of bulky alkoxy groups, such as propoxy and isopropoxy, seems to have been responsible for a reduction in the activities. Among the substances containing a heterocycle in replacement of the phenyl ring, the best activity was observed for the 2-pyridyl compound. Changes at the nitrogen atom for the 3- and 4-position induced a decrease in > N H N <sup>S</sup> <sup>S</sup> N H LY73497 The modifications in quadrant 2 were characterized by changes in the length of the alkyl linker. The main conclusion was the identification of an ethyl linker as optimal to the activities. It was also noted that the introduction of a methyl group in the benzylic position of ethylene linker enhanced the activity, while a methyl group in the phenethyl position The variations in quadrant 3 demonstrated the crucial role played by thiourea moiety at the anti-HIV activity of these compounds. In fact, the replacement of thiourea by urea resulted in an inactive compound and other isosters, such as cyanoguanidine derivatives, which appeared to be less potent. The methyl substitution at the nitrogen adjacent to the thiazole ring leads to a less active compound, while methyl substitution on the nitrogen adjacent to the phenethyl side chain provided compound with no activity at all. This result is attributed to presence of an internal hydrogen bond between the hydrogen bonded to nitrogen adjacent to the phenethyl side chain and the nitrogen of the thiazole nucleus in As regards quadrant 4, it was observed that a heterocycle in this position is determinant to reach a good activity. In general, substituted thiazoles were highly active, excepting the 4 carboxythiazolyl compound, whose lack of activity indicated that the allosteric site of the enzyme does not accept a polar group. When thiazole nucleus was replaced by another During a second phase of SAR studies, the authors combined the optimal substituents in quadrants 1-4, and observed that these parameters are additive, able to give rise to compounds with optimal activity. Among them, the compound LY300046, currently known as trovirdine (TRV; Fig. 1), was selected for further pharmacological examinations, since the hydrochloride salt of this compound showed acceptable blood levels, when orally heterocyle, the 2-pyridyl analog showed the highest level of activity. 1 2 3 4 the activity. led to its reduction. LY73497. Fig. 3. SAR studies with PETTs derivatives. administrated in rats (Ahgren et al., 1995). TRV displayed a comparable or a better ED50 than other known antiretroviral drugs, such as 9-Cl TIBO, L697661, NVP, AZT, ddI and ddC, being capable of inhibiting the replication of HIV-1 in MT-4 cell culture, as well as the replication of various clinical HIV-1 isolates in MT-2 cells and PBL human cells. However, this substance showed no action against HIV-2. When it was tested against resistant isolates containing mutations in Ile-100, Cys-181, and Ile-100–H-188 reverse transcriptase (RT), the trials disclosed a cross resistance between trovirdine and other non-nucleoside compounds. Nevertheless, within the group of said non-nucleoside derivatives, trovirdine was found to present the highest level of activity against these mutants. In the enzymatic assay with wild-type and mutant RT enzymes, TRV was also more active than the non-nucleosides 9-Cl TIBO, L697661 and nevirapine, showing a lower IC50. After TRV oral administration in rats (20mg/kg), a peak concentration in plasma of 3.5µg/mL was observed at 0.5h. The overall half-life was of 1 h, and the area under the concentrationtime curve was 6.9µg/h/mL. The peak concentration in brain was 2.9µg/g, and the area under the concentration-time curve was 5.9µg/h/mL. This result shows that TRV crosses the bloodbrain barrier, which is a desirable property of anti-retroviral agents, due to the risk of HIVassociated encephalopathy in contaminated patients (Ahgren et al., 1995). Despite the promising outcomes related to the use of TRV as NNRTI, the clinical trials focused on this compound were suspended. Anyway, this substance is still considered a standard lead compound for the development of new PETT analogues, as it encouraged the course of an extensive serie of SAR studies based on modern approaches, such as crystallographic techniques and molecular modeling. These works will be discussed in the next section. #### 3.1.2.2 Rational design of new PETT analogues This study was initiated when Vig and collaborators (Vig et al., 1998) proposed to synthesize series of novel PETT derivatives based on the structure of the non-nucleoside inhibitor (NNI) binding pocket of HIV-1 reverse transcriptase (RT). This composite binding pocket was built by superimposing nine individual crystal structures of RT-NNI complexes (Sudbeck et al., 1998). After having conducted docking studies with TRV, they verified the existence of multiple sites, which can be used for incorporation of larger functional groups, mainly surrounding the pyridyl ring, the ethyl linker and near the 5-bromo position. Hence, they proposed that a better use of these spaces by strategically designed functional groups could lead to a high-affinity binding and to the discovery of more potent anti-HIV agents. In view of the above, they decided to study the effects of introduction of several substituents in different positions of the phenyl ring, such as methoxy group, fluorine atom or chlorine atom (Table 4). These results disclosed by a preliminary SAR study attest to the potency of PETT derivatives phenyl ring substitutions on various positions (Fig. 4). After analyzing the composite NNI binding pocket, the authors identified three promising PETT derivatives with ortho-F (HI-240), ortho-Cl (HI-253) and metha-F (HI-241) substituents on the phenyl ring, which showed potent anti-HIV activity (IC50 [p24] values of < 1nM), selectivity indexes (SI) of > 100,000, and were recognized to be more active than AZT or TRV. Among them, HI-240 has been chosen as the lead compound, as it presented the highest level of activity against wide-type HIV RT. This finding could be grounded on the examination of a composite binding pocket model, showing that Wing 2 region is predominantly hydrophobic, except at the area nearby ortho positions on both sides of the phenyl ring, which would be compatible with polar groups, such as, for instance, halogen atoms. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 139 The authors postulated that the lead compound HI-240 would be effective against HIV RT mutants (Mao et al., 1999). This hypothesis was confirmed, since HI-240 is three times more potent than TRV against the multiple-drug-resistant of HIV RT, thus emphasizing the relevance of a polar ring substituent, which could provide more favorable interactions with During this SAR study, Mao and collaborators (Mao et al., 1999) rationally designed a novel PETT analogue (HI-236), by using the computer model of NNI binding pocket. This derivative was designed through the optimization of van der Waals contact with the binding pocket, mainly at Wing 2 region, that presents unrecognized spacious regions surrounding the phenyl ring. This strategy would improve the potency against wild-type RT, and also against Wing 2 mutants of RT. In view of the above, the authors proposed the synthesis of HI-236, whose 2,5-dimethoxy-substituted phenyl ring allows favorable contacts with Wing 2 region, and also decreases the unoccupied volume surrounding phenyl ring of HI-240 by 25 Å3. Therefore, HI-236 showed a potent anti-HIV activity (IC50 < 0.001µM), which is lower than IC50 values for AZT (0.004 µM). This substance was not Furthermore, HI-236 was found to be highly effective against multidrug-resistant HIV-1 strain RT-MDR, whose multiple mutations involve several RT residues (Table 5). These results are consistent with the prediction according to which HI-236 would be more active than HI-240. Compounds IC50 p24 IC50 RT-MDRa IC50 A17b IC50 A17 variantb HI-236 <0.001 0.005 0.1 11 HI-240 <0.001 0.005 0.2 41 DLV 0.009 0.4 50 >100 NVP 0.034 5 >100 >100 TRV 0.007 0.02 N.D. N.D. b Genotypic NNRTI-resistant HIV-strains (A17 and A17 variant) carrying clinically relevant mutations In another work, Mao and collaborators (Mao et al, 1998) proposed the synthesis of new PETT analogues through replacement of the planar pyridyl ring of TVR by a non-planar ring, such as a piperidinyl (HI-172) or piperazinyl ring (HI-258). This modification was based on the presence of unrecognized spacious regions surrounding the pyridyl ring of TRV (molecular volume (MV)= 160Å3), which could be better filled than the spacious Wing 2 region of the butterfly-shaped NNI binding pocket. In comparison with the MV of TRV, HI-172 and HI-258 presented larger MVs (calculated in 276 and 272Å3 respectively), being Furthermore, these heterocyclic rings are conformationally more flexible than the pyridyl ring, such a factor being likely to contribute to fit an uncompromising binding pocket in a more efficient way. Table 6 shows that both compounds were more potent than TRV, and that they inhibited HIV replication at nanomolar concentrations, without showing cytotoxicity. These findings indicate that, when compared to TRV analogues, double substitutions at axial or equatorial positions on these heterocyclic rings could lead to PETT derivatives with a broader Table 5. Inhibitory activity of HI-236 and HI-240 on p24 production in peripheral blood mononuclear cells infected with HIV strains HIVIIIB, RT-MDR, A17 and A17 variant. AZT 0.004 0.15 0.006 0.004 a V106A mutation thus predicted to better fit into the potentially usable space of the binding site. range of curvatures, and that they would also better fit to Wing 2 region. binding site residues (Table 5). Y181C and K103N + Y181C, respectively. cytotoxic, and its calculated selectivity index was > 105. a Purified recombinant HIV RT assay. b IC50 p24 values represent the inhibition of HIV-1 replication in relation to the virus control, as measured by p24 EIA. c SI (selectivity index) = IC50[MTA]/ IC50[p24]. IC50[MTA] values were >100µM. Table 4. IC50 and SI values for series of PETT derivatives. Fig. 4. Preliminary SAR of PETT derivatives. The authors postulated that the lead compound HI-240 would be effective against HIV RT mutants (Mao et al., 1999). This hypothesis was confirmed, since HI-240 is three times more potent than TRV against the multiple-drug-resistant of HIV RT, thus emphasizing the relevance of a polar ring substituent, which could provide more favorable interactions with binding site residues (Table 5). During this SAR study, Mao and collaborators (Mao et al., 1999) rationally designed a novel PETT analogue (HI-236), by using the computer model of NNI binding pocket. This derivative was designed through the optimization of van der Waals contact with the binding pocket, mainly at Wing 2 region, that presents unrecognized spacious regions surrounding the phenyl ring. This strategy would improve the potency against wild-type RT, and also against Wing 2 mutants of RT. In view of the above, the authors proposed the synthesis of HI-236, whose 2,5-dimethoxy-substituted phenyl ring allows favorable contacts with Wing 2 region, and also decreases the unoccupied volume surrounding phenyl ring of HI-240 by 25 Å3. Therefore, HI-236 showed a potent anti-HIV activity (IC50 < 0.001µM), which is lower than IC50 values for AZT (0.004 µM). This substance was not cytotoxic, and its calculated selectivity index was > 105. Furthermore, HI-236 was found to be highly effective against multidrug-resistant HIV-1 strain RT-MDR, whose multiple mutations involve several RT residues (Table 5). These results are consistent with the prediction according to which HI-236 would be more active than HI-240. 138 Global View of HIV Infection Compound X IC50 rRT (µM)a IC50 p24 (µM)b SIc HI-237 o-OMe 1.0 0.01 >1 x 104 HI-240 o-F 0.6 <0.001 >1 x 105 HI-253 o-Cl 0.7 <0.001 >1 x 105 HI-239 m-OMe 0.4 0.003 >3 x 104 HI-241 m-F 0.7 <0.001 >1 x 105 HI-254 m-Cl 3.1 N.D. N.D. 1 p-OMe 0.9 0.015 >6 x 103 HI-242 p-F 6.4 N.D. N.D. HI-255 p-Cl 2.5 N.D. N.D. TRV ---- 0.8 0.007 >1 x 104 AZT ---- >100 0.004 7 x 103 b IC50 p24 values represent the inhibition of HIV-1 replication in relation to the virus control, as R1 Favorable substitutions Unfavorable substitutions R2 F, OMe Cl F, Cl, OMe Hydrophobic groups F, Cl R3 X N Br c SI (selectivity index) = IC50[MTA]/ IC50[p24]. IC50[MTA] values were >100µM. Table 4. IC50 and SI values for series of PETT derivatives. N HN N S H Br Fig. 4. Preliminary SAR of PETT derivatives. a Purified recombinant HIV RT assay. measured by p24 EIA. HN N H S b Genotypic NNRTI-resistant HIV-strains (A17 and A17 variant) carrying clinically relevant mutations Y181C and K103N + Y181C, respectively. Table 5. Inhibitory activity of HI-236 and HI-240 on p24 production in peripheral blood mononuclear cells infected with HIV strains HIVIIIB, RT-MDR, A17 and A17 variant. In another work, Mao and collaborators (Mao et al, 1998) proposed the synthesis of new PETT analogues through replacement of the planar pyridyl ring of TVR by a non-planar ring, such as a piperidinyl (HI-172) or piperazinyl ring (HI-258). This modification was based on the presence of unrecognized spacious regions surrounding the pyridyl ring of TRV (molecular volume (MV)= 160Å3), which could be better filled than the spacious Wing 2 region of the butterfly-shaped NNI binding pocket. In comparison with the MV of TRV, HI-172 and HI-258 presented larger MVs (calculated in 276 and 272Å3 respectively), being thus predicted to better fit into the potentially usable space of the binding site. Furthermore, these heterocyclic rings are conformationally more flexible than the pyridyl ring, such a factor being likely to contribute to fit an uncompromising binding pocket in a more efficient way. Table 6 shows that both compounds were more potent than TRV, and that they inhibited HIV replication at nanomolar concentrations, without showing cytotoxicity. These findings indicate that, when compared to TRV analogues, double substitutions at axial or equatorial positions on these heterocyclic rings could lead to PETT derivatives with a broader range of curvatures, and that they would also better fit to Wing 2 region. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 141 Uckun and collaborators (Uckun et al., 1999b) carried on performing their PETT derivatives SAR study, and decided to promote new replacements of the pyridyl ring of TRV with eight different heterocyclic substituents, including heterocyclic amines, heteroaromatic rings furan and thiophene, as well as aromatic acetal piperonyl. After evaluation of HIV-RT inhibitory activity, the authors concluded that these proposed modifications were critical for the biological activity of said series of compounds, as only the thiophene-substituted Ring pyrrolidine >100 >100 derivative HI-443 inhibited recombinant RT in vitro in more than 90% (Table 8). N Compound Ring IC50 rRT (µM) IC90 rRT (µM) HI-443 Thiophene 0.8 15.0 HI-230 Pyrrolidine 4.9 >100 HI-436 Imidazole >100 >100 HI-442 Indole 0.9 >100 HI-276 Morpholine >100 >100 HI-257 Piperonyl\* 0.7 >100 HI-503 Furan\* 1.2 >100 TRV Pyridine 0.6 12.0 Table 8. RT inhibitory activity of PETT derivatives, expressed as IC50 and IC90 values. After proceeding with docking studies, it was observed that the thiophene group of HI-443 occupies the same Wing 2 region of the NNI binding pocket of RT as TRV, although with a smaller molecular volume. Moreover, the geometry of hydrogen bond between 2´-NH atom and the amide carbonyl or TR residue 101 deviates from the optimum geometry that authors had observed in relation to TRV and other PETT derivatives, such as HI-172 (Table 6). Said remarks could justify the lower inhibitory activity of HI-443 against HTLVIIIB RT, in comparison with TRV (Table 9). Surprisingly, when HI-443 was assayed against NNIresistant and MDR-HIV strains, it showed excellent results (Table 9). This finding is in perfect accordance with the docking analysis, as this latter revealed that thiophene group is located very close to the Y181 residue. Therefore, in the Y181C mutant strains, the sulfur atom from its thiophene group may be more compatible with the sulfur-containing cysteine Br HI-206 1-methyl- \* Methylene linker group, instead of an ethyl linker. 181 residue than the pyridyl group of TRV. HN NH S \* MTA= Methyl tetrazolium assay Table 6. IC50 and SI values for series of PETT derivatives. Following their continuous program aiming at the development of new potent PETTs, Uckun and collaborators (Uckun et al., 1999a) decided to replace the pyridyl ring of TRV by an aciclyc cyclohexenyl, adamantly or cis-myrtanyl ring. Such a proposal of modifications was due to the fact that these chosen groups would fit well with Wing 2 region of the NNI binding pocket. Given the existence of a region compatible with polar atoms at Wing 1, the authors also suggested the replacement of bromine atom by chlorine or trifluoromethyl group (Table 7). After a biological evaluation, they observed that the replacement of the pyridyl ring of TRV by the adamantly (HI-504) or cis-myrtanyl (HI-444) rings resulted in a complete loss of RT inhibitory function. In another important finding, bromine (HI-346) / chlorine (HI-445) atoms were found to reach the best biological result, thanks to their capacity of making more hydrophobic contacts at the binding pocket, when compared to trifluoromethyl group (HI-347). Moreover, the lead compounds HI-346 and HI-445 showed a significant activity against the multidrug resistant (MDR) strain, without presenting cytotoxicity, when administrated at effective concentrations (Table 7). \* methylene group, instead of ethyl linker a N.D.= not determined, because IC50 rRT (µM) > 100 Table 7. CC50 and IC50 values for series of PETT derivatives. Following their continuous program aiming at the development of new potent PETTs, Uckun and collaborators (Uckun et al., 1999a) decided to replace the pyridyl ring of TRV by an aciclyc cyclohexenyl, adamantly or cis-myrtanyl ring. Such a proposal of modifications was due to the fact that these chosen groups would fit well with Wing 2 region of the NNI binding pocket. Given the existence of a region compatible with polar atoms at Wing 1, the authors also suggested the replacement of bromine atom by chlorine or trifluoromethyl group (Table 7). After a biological evaluation, they observed that the replacement of the pyridyl ring of TRV by the adamantly (HI-504) or cis-myrtanyl (HI-444) rings resulted in a complete loss of RT inhibitory function. In another important finding, bromine (HI-346) / chlorine (HI-445) atoms were found to reach the best biological result, thanks to their capacity of making more hydrophobic contacts at the binding pocket, when compared to trifluoromethyl group (HI-347). Moreover, the lead compounds HI-346 and HI-445 showed a significant activity against the multidrug resistant (MDR) strain, without presenting cytotoxicity, when administrated at effective concentrations (Table 7). CC50 MTA (µM) HI-346 Cyclo-hexenyl Br >100 0.003 0.020 N.D. 18.7 HI-445 Cyclo-hexenyl Br >100 0.003 0.001 0.068 30 HI-347 Cyclo-hexenyl Cl >100 0.079 0.038 0.300 >100 HI-504 Adamantyl\* CF3 N.D.a N.D.a N.D.a N.D.a N.D.a HI-444 Myrtanyl\* Br N.D.a N.D.a N.D.a N.D.a N.D.a TRV Pyridyl Br >100 0.007 0.020 0.500 >100 AZT ----- ---- >100 0.004 0.2 0.006 0.004 IC50 (µM) MDR A17 A17 variant p24 RT- *Compound IC50 p24 IC50 [MTA]\ SI HI-172 <0.001 >100 >1 x 105 HI-258 0.002 >100 >5 x 104 TRV 0.007 >100 >1 x 104 AZT** 0.006 50 8 x 103 \* MTA= Methyl tetrazolium assay Compound Ring X \* methylene group, instead of ethyl linker a N.D.= not determined, because IC50 rRT (µM) > 100 Table 7. CC50 and IC50 values for series of PETT derivatives. Table 6. IC50 and SI values for series of PETT derivatives. Uckun and collaborators (Uckun et al., 1999b) carried on performing their PETT derivatives SAR study, and decided to promote new replacements of the pyridyl ring of TRV with eight different heterocyclic substituents, including heterocyclic amines, heteroaromatic rings furan and thiophene, as well as aromatic acetal piperonyl. After evaluation of HIV-RT inhibitory activity, the authors concluded that these proposed modifications were critical for the biological activity of said series of compounds, as only the thiophene-substituted derivative HI-443 inhibited recombinant RT in vitro in more than 90% (Table 8). Br \* Methylene linker group, instead of an ethyl linker. Table 8. RT inhibitory activity of PETT derivatives, expressed as IC50 and IC90 values. After proceeding with docking studies, it was observed that the thiophene group of HI-443 occupies the same Wing 2 region of the NNI binding pocket of RT as TRV, although with a smaller molecular volume. Moreover, the geometry of hydrogen bond between 2´-NH atom and the amide carbonyl or TR residue 101 deviates from the optimum geometry that authors had observed in relation to TRV and other PETT derivatives, such as HI-172 (Table 6). Said remarks could justify the lower inhibitory activity of HI-443 against HTLVIIIB RT, in comparison with TRV (Table 9). Surprisingly, when HI-443 was assayed against NNIresistant and MDR-HIV strains, it showed excellent results (Table 9). This finding is in perfect accordance with the docking analysis, as this latter revealed that thiophene group is located very close to the Y181 residue. Therefore, in the Y181C mutant strains, the sulfur atom from its thiophene group may be more compatible with the sulfur-containing cysteine 181 residue than the pyridyl group of TRV. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 143 Among 13 compounds, six lead ones were detected (2, 4 and 6-9). They were 9-34 times more active than the standard NNRTI nevirapine and delavirdine. The compounds 2-9 and 14 were also tested against NNRTI-resistant strains A17 with Y181C mutation and A17 variant with a Y181C plus K103N mutations in RT. The most promising compounds were 6, 7, 9 and 14, as they were effective against both NNRTI-resistant HIV-1 isolates and showed much greater potency against both wild-type and NNRTI-resistant HIV-1 than nevirapine and delavirdine. Among these compounds, the most promising was the 7, due to its Subsequently, Venkatachalam and collaborators (Venkatachalam et al., 2000) proposed to study the influence of stereochemistry of Halopyridyl and Thiazolidyl thiourea compounds on their potency as NNRTI. For this purpose, they synthesized and measured anti-HIV activity of R and S stereoisomers of two cyclohexyl methyl haloperidyl thiourea compounds (HI-509 and HI-510), of two α-methyl benzylhalopyridyl thiourea compounds (HI-511 and HI-512) and of one cyclohexyl ethyl thiazolyl thiourea compound (HI-513) (Table 11). S CH3 X=Cl. HI-512 HI-509(R) 1.2 0.001 0.2 0.4 10.0 HI-509(S) >100 >1 N.D. N.D. N.D. HI-510(R) 1.4 0.025 0.06 0.07 8.2 HI-510(S) >100 >1 N.D. N.D. N.D. HI-511(R) 1.6 0.01 0.005 0.01 2.7 HI-511(S) >100 >1 N.D. N.D. N.D. HI-512(R) 1.2 0.010 0.010 0.2 10.2 HI-512(S) >100 >1 N.D. N.D. N.D. HI-513(R) 13.0 0.001 5.6 0.9 5.8 HI-513 (S) >100 >1 N.D. N.D. N.D. HI-542 (S) >100 >1 N.D. N.D. N.D. HI-543 (R) >100 >1 N.D. N.D. N.D. TRV 0.8 0.007 0.02 0.5 >100 Table 11. Effects of stereochemistry on anti-HIV activity of thiourea compounds. IC50 (µM) rRT HTLVIIIB RT-MDR A17 A17 HN NH N S X=Br; HI-511 HI-513 S CH3 variant minimal cytotoxic effects on PBMC, as well as to its selectivity index > 100,000. N HN NH X N Compound HN NH S CH3 X=Br; HI-509 X=Cl. HI-510 X=H; HI-542 (S) HI-543 (R) X Table 9. Anti-HIV activity of PETT derivatives. In their next work, Venkatachalam and collaborators (Venkatachalam et al., 2001) designed, synthesized and evaluated 13 aromatic/heterocyclic thiazolyl thiourea compounds, since thiazolyl group was expected to favorably bind to Wing 1 region of the binding pocket of HIV-1 RT (Table 10). Table 10. Anti-HIV activity of thiazolyl thiourea derivatives. HI-443 >100 0.030 0.004 0.048 3.3 HI-172 >100 <0.001 >100 >100 >100 HI-240 >100 <0.001 0.005 0.200 41 TRV >100 0.007 0.020 0.500 >100 AZT >100 0.004 0.2 0.006 0.004 In their next work, Venkatachalam and collaborators (Venkatachalam et al., 2001) designed, synthesized and evaluated 13 aromatic/heterocyclic thiazolyl thiourea compounds, since thiazolyl group was expected to favorably bind to Wing 1 region of the S Ring n <sup>S</sup> 2-14 N H 2 Et 2-Thiophene <0.001 >100 N.D. 71 71,000 4 Et 1-phenoxy <0.001 4.4 >100 >100 >100,000 Me 1-Adamantyl <0.001 0.6 1.3 40 40,000 Pr 2-Furan <0.001 2.0 0.6 >100 >100,000 Et 1-Imidazole <0.001 >100 >100 35 35,000 Et 3-indole <0.001 2.2 3.7 28 28,000 Et 1-pyperidine >100 N.D. N.D. N.D. N.D. 12 Et 2-pyridine 1 N.D. N.D. 100 100 14 2-Bu Phenyl 0.009 2.1 1.5 10 1111 NVP ---- ---- 0.034 >100 >100 N.D. N.D. DLV ---- ---- 0.009 50 >100 N.D. N.D. N N H IC50 (µM) p24 RT-MDR A17 A17 variant IC50 (µM) CC50 (µM) SI HTLVIIIB A17 A17 variant hexenyl 0.007 0.9 >100 4 571 phenyl 0.07 3.9 >100 >100 1459 phenyl >100 N.D. N.D. N.D. N.D. pyrrolidinone 9 N.D. N.D. 18 2 Compound CC50 MTA (µM) Table 9. Anti-HIV activity of PETT derivatives. binding pocket of HIV-1 RT (Table 10). Compound n Ring 3 Et 2-Cyclo- 5 Et 4-methyl- 11 Et 4-hydroxy- Table 10. Anti-HIV activity of thiazolyl thiourea derivatives. <sup>13</sup>Pr 1- Among 13 compounds, six lead ones were detected (2, 4 and 6-9). They were 9-34 times more active than the standard NNRTI nevirapine and delavirdine. The compounds 2-9 and 14 were also tested against NNRTI-resistant strains A17 with Y181C mutation and A17 variant with a Y181C plus K103N mutations in RT. The most promising compounds were 6, 7, 9 and 14, as they were effective against both NNRTI-resistant HIV-1 isolates and showed much greater potency against both wild-type and NNRTI-resistant HIV-1 than nevirapine and delavirdine. Among these compounds, the most promising was the 7, due to its minimal cytotoxic effects on PBMC, as well as to its selectivity index > 100,000. Subsequently, Venkatachalam and collaborators (Venkatachalam et al., 2000) proposed to study the influence of stereochemistry of Halopyridyl and Thiazolidyl thiourea compounds on their potency as NNRTI. For this purpose, they synthesized and measured anti-HIV activity of R and S stereoisomers of two cyclohexyl methyl haloperidyl thiourea compounds (HI-509 and HI-510), of two α-methyl benzylhalopyridyl thiourea compounds (HI-511 and HI-512) and of one cyclohexyl ethyl thiazolyl thiourea compound (HI-513) (Table 11). Table 11. Effects of stereochemistry on anti-HIV activity of thiourea compounds. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 145 R Among all synthesized compounds, the derivative 15 (Table 12), namely the R isomer 5 chloropyridyl (β-MPT Series), was 380-fold more active than nevirapine, 2-fold more active than trovirdine and 190-fold more potent against A17 than delavirdine. The compound 15 was also >200-fold more potent against A17V than nevirapine, trovirdine or delavirdine. In view of these results, the authors postulated that β-MPT compounds may be useful candidates to further development as anti-HIV agents, especially due to their remarkable > H <sup>N</sup> <sup>H</sup> N 15 CH3 S 15 0.1 <0.001 0.02 0.3 0.5 TRV 0.8 0.007 0.02 0.5 >100 Besides the modifications on the pyridyl ring, Sahlberg and collaborators (Sahlberg et al., 1998) decided to investigate the replacement of thiourea by urea moiety in PETT derivatives. Furthermore, they have prepared compounds with an ethyl linker (Series I) and other N IC50 (µM) rRT HTLVIIIB RT-MDR A17 A17 Cl N X R Poor activity Exhibited anti-HIV activity, but not better than 5-pyridyl derivatives variant Halogen or Methyl substitutions are preferred at 5-position N S R N S H <sup>N</sup> <sup>H</sup> N n n= 0 or 1 n=1 is preferred, because the two carbonlinker is adjustable and more forgiving into NNI binding pocket Fig. 6. Complementary SAR study of chiral thiourea compounds. activity against mutant strains of HIV-1. Table 12. Anti-HIV activity of thiourea derivative 15. conformationally restricted cyclopropyl analogues (Series II, Table 13). Compound CH3 R-stereoisomers are preferred. All S-stereoisomers are inactive S The results showed that R stereoisomers of all five compounds inhibited the recombinant RT in vitro with IC50 values that were 100-fold lower. Each one of these five compounds was also active against NNI-resistant HIV-1 strains. Among them, HI-511(R) (see Table 11) presented a potent antiviral activity against NNI-resistant and multidrug resistant strains of HIV-1. Molecular modeling studies indicated that the R steroisomer [HI-509(R)] would fit the target NNI binding pocket on HIV-RT much better than its enantiomer [HI-509(S)]. Due to the presence of unfavorable steric interactions with the NNI binding pocket residues near the Y181 side chain, HI-509(S) adopts an energetically unfavorable eclipsed conformation, which reflects in its higher IC50 value. These assumptions could also apply in favor of HI-510(R). As a relevant data concerning this study, it is worthy to mention that the methyl group on chiral carbon of HI-509(R) and HI-510(R) probably promotes the strong binding to the NNI binding pocket via van der Waals with residue V179. The substitution of the pyridyl ring of HI-509(R) and HI-510(R) by a thiazolyl ring (compound HI-513(R)) resulted in 10-fold higher IC50 values in cell free RT inhibition assays, as the unsubstituted thiazole could be better accommodated by the binding site than the unsubstituted pyridine (in combination with the bulky cyclohexylethyl group) as a whole molecule. Nevertheless, halogen substitution on pyridine adds a considerable number of favorable interactions at Wing 1 region, which improves the final interaction score for the substituted pyridine thiourea compounds. While studying the effect of stereochemistry on anti-HIV activity of chiral thiourea compounds, Venkatachalam and collaborators (Venkatachalam et al., 2004) synthesized two new series of PETT compounds: β-methyl phenylethyl thiourea (β-MPT), and α-methyl benzyl thioureas (α-MBT) (Fig. 5). Fig. 5. β-MPT and α-MBT series. These derivatives were evaluated against HIV-1 strain HTLVIIIB , and also against NNRTIresistant strains. Upon analysis of these results, the authors expressed critical positions regarding SAR of this class of compounds (Fig. 6). The results showed that R stereoisomers of all five compounds inhibited the recombinant RT in vitro with IC50 values that were 100-fold lower. Each one of these five compounds was also active against NNI-resistant HIV-1 strains. Among them, HI-511(R) (see Table 11) presented a potent antiviral activity against NNI-resistant and multidrug resistant strains of Molecular modeling studies indicated that the R steroisomer [HI-509(R)] would fit the target NNI binding pocket on HIV-RT much better than its enantiomer [HI-509(S)]. Due to the presence of unfavorable steric interactions with the NNI binding pocket residues near the Y181 side chain, HI-509(S) adopts an energetically unfavorable eclipsed conformation, which reflects in its higher IC50 value. These assumptions could also apply in favor of HI-510(R). As a relevant data concerning this study, it is worthy to mention that the methyl group on chiral carbon of HI-509(R) and HI-510(R) probably promotes the strong binding The substitution of the pyridyl ring of HI-509(R) and HI-510(R) by a thiazolyl ring (compound HI-513(R)) resulted in 10-fold higher IC50 values in cell free RT inhibition assays, as the unsubstituted thiazole could be better accommodated by the binding site than the unsubstituted pyridine (in combination with the bulky cyclohexylethyl group) as a whole molecule. Nevertheless, halogen substitution on pyridine adds a considerable number of favorable interactions at Wing 1 region, which improves the final interaction While studying the effect of stereochemistry on anti-HIV activity of chiral thiourea compounds, Venkatachalam and collaborators (Venkatachalam et al., 2004) synthesized two new series of PETT compounds: β-methyl phenylethyl thiourea (β-MPT), and α-methyl > X= 5-Cl, 5-Br, 5-Me, 6-Me 4,6-Me, N X= 5-Cl, 5-Br, 5-Me, 6-Me R=4-Me, 5-Me, 6-Me S N S R R= 4-Me R R= 4-Me, 4-methylene-carbo to the NNI binding pocket via van der Waals with residue V179. score for the substituted pyridine thiourea compounds. R1 <sup>=</sup> <sup>N</sup> N S X N X R These derivatives were evaluated against HIV-1 strain HTLVIIIB , and also against NNRTIresistant strains. Upon analysis of these results, the authors expressed critical positions N S benzyl thioureas (α-MBT) (Fig. 5). H <sup>N</sup> <sup>H</sup> N MBT Series N H CH3 MPT Series CH3 S S Fig. 5. β-MPT and α-MBT series. N H R1 <sup>R</sup><sup>2</sup> <sup>R</sup><sup>2</sup> regarding SAR of this class of compounds (Fig. 6). = HIV-1. Fig. 6. Complementary SAR study of chiral thiourea compounds. Among all synthesized compounds, the derivative 15 (Table 12), namely the R isomer 5 chloropyridyl (β-MPT Series), was 380-fold more active than nevirapine, 2-fold more active than trovirdine and 190-fold more potent against A17 than delavirdine. The compound 15 was also >200-fold more potent against A17V than nevirapine, trovirdine or delavirdine. In view of these results, the authors postulated that β-MPT compounds may be useful candidates to further development as anti-HIV agents, especially due to their remarkable activity against mutant strains of HIV-1. Table 12. Anti-HIV activity of thiourea derivative 15. Besides the modifications on the pyridyl ring, Sahlberg and collaborators (Sahlberg et al., 1998) decided to investigate the replacement of thiourea by urea moiety in PETT derivatives. Furthermore, they have prepared compounds with an ethyl linker (Series I) and other conformationally restricted cyclopropyl analogues (Series II, Table 13). Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 147 Following this study, Högberg and collaborators (Högberg et al., 2000) have proposed several bioisosteric substitutions of both thiourea and urea moieties of PETT compounds by sulfamide, cyanoguanidine and guanidine groups (Series III, Fig.8). Furthermore, they have promoted the replacement of the phenetyl group by benzophenethyl group, in an attempt to evaluate the influence of said modifications on the antiviral activities of this class X Fig. 8. Structures of two series of PETT analogues, obtained through bioisosteric modifications. The biological results showed that thiourea and urea moieties play an essential role in the optimal activity of PETT compounds, as all the proposed bioisosteric replacements lead to a reduction (compounds with guanidine group) or to the complete loss of activity (sulfamide and cianoguanidine derivatives). Moreover, the benzoylethyl derivatives were reasonably potent inhibitors of wild-type HIV-1 RT and HIV-1 virus in cell culture. However, these derivatives were less active than the phenethyl compounds (see compound 39, Table 14). > N <sup>H</sup> <sup>N</sup> Compound Ar Y X IC50 HIV-1 RT a HIV-1 RT assay which used (poly)rC.(oligo)dG as the templae/primer. b Anti-HIV activity assay, using MT4 cells (human T cell line) infected with HIV-1IIIB N H phenyl S Br <0.027 0.036 2-F- phenyl S Br 0.004 0.009 2-Cl- phenyl S Br 0.010 0.100 2-OMe- phenyl S Br 0.003 0.076 2-F- phenyl O Br 0.054 0.201 3-OMe- phenyl S Br 0.080 0.911 4-F- phenyl S Br 0.047 0.300 2,5-F- phenyl S Br <0.025 0.067 2,6-F- phenyl S Br 0.006 0.028 2,6-F- phenyl S Cl 0.003 0.050 2,6-F- phenyl\* S Br 0.001 0.010 Y O Series IV Series III Series IV N <sup>H</sup> <sup>N</sup> N H X= Br or Cl Y= S or O R= F, Cl, OMe Ar (µM)a ED50 (µM)b Y O R R of compounds (Series IV, Fig.8). X N Y = OMe or Cl or H \Phenylethyl, instead of benzoylethyl linker. Table 14. IC50 and ED50 values for Series IV. Y= Thiourea, Urea, Sulfamide, cyanoguanidine, guanidine n= Ethyl or cis-cyclopropyl linker n X R5 R1 R2 X= Cl or Br R1 R2 = OEt or H R5 = F or H Table 13. Inhibition of HIV-1 by urea-PETT compounds. Cyclopropyl compounds use to be more potent than the ethyl linked ones, especially on mutants (Table 13). The authors hypothesized that, in comparison with the most restricted cyclopropyl analogues, the most flexible ethyl derivatives might present inconvenient in adopting conformations that fit in the mutant enzymes. When compared with thiourea analogues, urea derivatives are less active (Fig. 7), although these compounds might have better toxicological and pharmacokinetic properties. In addition, it was verified later that, in cell culture and in the presence of added human serum, urea-PETT compounds keep their antiviral activity in standards that are much higher than those shown by the respective thiourea compounds. Fig. 7. Anti-HIV activities of thiourea and urea derivatives. R4 <sup>R</sup> Series I* Series II <sup>3</sup> 16-21 22-28 H F F Cl 0.03 0.85 >32 32 NMe2 F F Br 0.5 N.D. >25 >25 OMe F OMe Cl 0.011 0.09 3 17 OEt F OMe Cl 0.13 N.D. >27 14 COMe F OMe Cl 0.2 N.D. >27 >27 OEt Cl F Br 0.07 N.D. 8 15 H F F Cl 0.006 0.01 N.D. N.D. OEt Cl F Cl 0.016 0.06 N.D. 0.1 OEt Cl F CN 0.01 0.02 0.53 0.27 OEt F F Cl 0.008 0.03 0.27 0.75 OMe F OMe Cl 0.012 0.1 2.7 1.6 OEt F Cl Cl 0.008 N.D. 0.1 0.1 OEt F Br Br 0.025 0.8 N.D. N.D. TRV ---- ---- ---- ---- 0.02 5 >5 0.8 a The cell culture assay used MT4 cells infected with HIV-1IIIB. b The assay contains 15% human AB serum. Cyclopropyl compounds use to be more potent than the ethyl linked ones, especially on mutants (Table 13). The authors hypothesized that, in comparison with the most restricted cyclopropyl analogues, the most flexible ethyl derivatives might present inconvenient in When compared with thiourea analogues, urea derivatives are less active (Fig. 7), although these compounds might have better toxicological and pharmacokinetic properties. In addition, it was verified later that, in cell culture and in the presence of added human serum, urea-PETT compounds keep their antiviral activity in standards that are much F OMe N H Y= S : IC50= 1.3 nM Y= O: IC50= 50 nM TRV: IC50= 15nM N H N H O R2 wt wtb T181C L100I R1 N R1 R2 R3 Compound R1 R2 R3 R4 ED50 (µM)a N H O N H Table 13. Inhibition of HIV-1 by urea-PETT compounds. adopting conformations that fit in the mutant enzymes. Br higher than those shown by the respective thiourea compounds. Fig. 7. Anti-HIV activities of thiourea and urea derivatives. N <sup>H</sup> <sup>N</sup> Y N R4 Following this study, Högberg and collaborators (Högberg et al., 2000) have proposed several bioisosteric substitutions of both thiourea and urea moieties of PETT compounds by sulfamide, cyanoguanidine and guanidine groups (Series III, Fig.8). Furthermore, they have promoted the replacement of the phenetyl group by benzophenethyl group, in an attempt to evaluate the influence of said modifications on the antiviral activities of this class of compounds (Series IV, Fig.8). The biological results showed that thiourea and urea moieties play an essential role in the optimal activity of PETT compounds, as all the proposed bioisosteric replacements lead to a reduction (compounds with guanidine group) or to the complete loss of activity (sulfamide and cianoguanidine derivatives). Moreover, the benzoylethyl derivatives were reasonably potent inhibitors of wild-type HIV-1 RT and HIV-1 virus in cell culture. However, these derivatives were less active than the phenethyl compounds (see compound 39, Table 14). Series IV a HIV-1 RT assay which used (poly)rC.(oligo)dG as the templae/primer. b Anti-HIV activity assay, using MT4 cells (human T cell line) infected with HIV-1IIIB \Phenylethyl, instead of benzoylethyl linker. Table 14. IC50 and ED50 values for Series IV. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 149 Among all these substances, they identified several dual-function of thiourea compounds, such as the phenyl ring-containing derivatives HI-240* (2-fluoro), HI-253 (2-chloro) and HI-255 (4-chloro) and the cyclohexenyl ring-containing derivatives HI-346 and HI-445, which were identified as potential lead compounds for the development of clinically useful dualfunction anti-HIV spermicides (Table 15). In this study, the authors also demonstrated that, at a spermicidal concentration, the dual-function thiourea derivatives were selectively spermicidal, without cytotoxic effects against human vaginal, ectocervical and endocervical Compound IC50 (µM) EC50 (µM) HI-240 <0.001 0.60 147 ± 18 HI-253 <0.001 0.70 70 ± 8 HI-255 0.001 2.50 160 ± 16 HI-346 0.003 0.6 42 ± 9 HI-445 0.003 0.5 57 ± 5 HI-142 (TRV) 0.007 0.8 >500 Table 15. Effect of PETT derivatives on p24 antigen production in HIV-infected PBMC, as Considering that the most promising dual-function microbicides PETTs were HI-346 and HI-445, which are cyclohexenyl ring-containing derivatives, D´Cruz and collaborators decided to investigate other cyclohexenyl thiourea (CHET) compounds, in order to examine the way how heterocyclic rings and their functionalization affect the anti-HIV and SIA potency of these substances (D´Cruz et al., 2002a). Furthermore, some urea compounds were also evaluated, in an attempt to determine the role of thiourea moiety in the biological In view of the data obtained, the authors concluded that, among the thiazolyl-ring containing CHET compounds, only the 4-methyl-substituted derivative (42) showed a significant anti-HIV activity. As a matter of fact, compounds containing benzothiazole-ring generally present poor anti-HIV activities. Among the compounds containing N-pyridyl nucleus, the functionalization at 5-position with bromine, chlorine and methyl groups led to a potent anti-HIV activity of CHET compounds. The thiourea moiety was essential to trigger said anti-HIV activity, as its replacement by urea group either abolished (44) or Among 15 derivative compounds that were evaluated for spermicidal potential, 12 showed an improvement of spermicidal function, when analyzed at micromolar concentrations. The authors observed that compounds with methyl group at 4- or 6-postion were non-spermicidal, even at concentrations >500µM. The pyridyl-ring containing CHET compounds with bromine or chlorine attached to 5-position showed an excellent SIA activity, in addition to their remarkable anti-HIV activity. Interestingly, the urea compounds, although having retained SIA, presented a poor anti-HIV activity, . Another curious data arises from the comparison between the values of T1/2 relating to thiourea and urea compounds, showing that urea analogues immobilized sperm 38-fold faster than well as enzymatic activity of HIV-1 RT and human sperm mobility. p24 rRT SIA epithelial cells . activity of these series (Table 16). reduced (45) the biological activity. thiourea derivatives. #### 3.1.2.3 PETT derivatives as anti-HIV microbicides D´Cruz and collaborators started to develop a vaginal microbicidal contraceptive, which was potentially able to prevent HIV transmission. Thus, they decided to evaluate two potent anti-HIV PETT derivatives (HI-240 and HI-236, Table 5), that had been previously identified by Venkatachalam and collaborators (Vig et al, 1998; Mao et al., 1998), in an attempt to verify a possible dual-function, namely its anti-HIV and spermicidal activity. After proceeding with the analysis of the results, they observed that only the derivative HI-240 showed a spermicidal activity, although the underlying mechanism involved in such a function remains unknown. Moreover, HI-240 inhibited the sperm motility, in a concentration-and time-dependent way (D´Cruz & Venkatachalam et al., 1999). Subsequently, the authors investigated the cytotoxic characteristics and selectivity of this compound, and, then, compared their results to nonoxynol-9 (N-9), which is the most widely used vaginal spermicide. This substance immobilizes sperm, as a result from a detergent-type action on the sperm plasma membrane. Due to its membrane-disruptive properties, a continued use of N-9 has been shown to be likely to damage the cervicovaginal epithelium, causing an acute tissue inflammatory response, and thus enhancing the probability of HIV infection by heterosexual transmission. When compared with N-9, HI-240 was selectively spermicidal, without detergent-type toxicity against membrane of the female genital tract, which may present significant clinical advantages. Another important feature of HI-240 may still be pointed out, namely the possibility for spermicidal NNI to remain stable as protonated species, even within the acidic environment of the vagina, due to the presence of pyridine ring, containing a basic nitrogen atom. Furthermore, the vaginal concentrations of this substance required for dual-action anti-HIV and spermicidal activity are well below the systemic concentrations achieved by the oral dosages that are generally prescribed for NNIs. In view of these promising results, D´Cruz and collaborators (D´Cruz et al., 2000) decided to evaluate other 31 PETT derivatives for anti-HIV and sperm inhibitory activity (SIA) (Fig.9). Fig. 9. Structures of thiourea derivatives, evaluated as spermicidal microbicides. D´Cruz and collaborators started to develop a vaginal microbicidal contraceptive, which was potentially able to prevent HIV transmission. Thus, they decided to evaluate two potent anti-HIV PETT derivatives (HI-240 and HI-236, Table 5), that had been previously identified by Venkatachalam and collaborators (Vig et al, 1998; Mao et al., 1998), in an attempt to verify a possible dual-function, namely its anti-HIV and spermicidal activity. After proceeding with the analysis of the results, they observed that only the derivative HI-240 showed a spermicidal activity, although the underlying mechanism involved in such a function remains unknown. Moreover, HI-240 inhibited the sperm motility, in a Subsequently, the authors investigated the cytotoxic characteristics and selectivity of this compound, and, then, compared their results to nonoxynol-9 (N-9), which is the most widely used vaginal spermicide. This substance immobilizes sperm, as a result from a detergent-type action on the sperm plasma membrane. Due to its membrane-disruptive properties, a continued use of N-9 has been shown to be likely to damage the cervicovaginal epithelium, causing an acute tissue inflammatory response, and thus enhancing the probability of HIV infection by heterosexual transmission. When compared with N-9, HI-240 was selectively spermicidal, without detergent-type toxicity against membrane of the female genital tract, which may present significant clinical advantages. Another important feature of HI-240 may still be pointed out, namely the possibility for spermicidal NNI to remain stable as protonated species, even within the acidic environment of the vagina, due to the presence of pyridine ring, containing a basic nitrogen atom. Furthermore, the vaginal concentrations of this substance required for dual-action anti-HIV and spermicidal activity are well below the systemic concentrations achieved by the oral dosages that are generally prescribed for NNIs. In view of these promising results, D´Cruz and collaborators (D´Cruz et al., 2000) decided to evaluate other 31 PETT derivatives for anti-HIV and sperm inhibitory activity (SIA) (Fig.9). concentration-and time-dependent way (D´Cruz & Venkatachalam et al., 1999). R2 = Br = CF3 N <sup>H</sup> <sup>N</sup> H HI-244: Ring =Cis-Myrtanyl\; R2 HI-541: Ring =Cyclohexenyl; R<sup>2</sup> HI-346: Ring =Cyclohexenyl; R<sup>2</sup> HI-445:* Ring =Cyclohexenyl; R2 HI-347: Ring =Cyclohexenyl; R<sup>2</sup> \Methylene linker Fig. 9. Structures of thiourea derivatives, evaluated as spermicidal microbicides. S N <sup>H</sup> <sup>N</sup> H Ring S HI-142 (TRV):* Ring =Pyridyl; R<sup>2</sup> HI-172: Ring =Piperidinyl; R2 HI-258: Ring =Piperazinyl; R2 HI-230: Ring =Pyrrolidinyl; R<sup>2</sup> HI-344: Ring =Piperidinyl; R<sup>2</sup> HI-443: Ring =Thiophene; R2 HI-207: Ring =Pyridyl; R2 HI-309: Ring =Pyridyl; R2 R2 = Br = Br = H = Cl = CF3 R2 = Br = Br = Br = Br = CF3 = Br = H =CF3 =4 OH; R<sup>2</sup> =2 Cl; R<sup>2</sup> = Br =3 Cl; R<sup>2</sup> = Br =4 Cl; R<sup>2</sup> = Br =2,5 OMe; R<sup>2</sup> =H; R<sup>2</sup> = Br =H; R<sup>2</sup> = CF3 =2 F; R<sup>2</sup> = CF3 =3 F; R<sup>2</sup> = CF3 Ring 3.1.2.3 PETT derivatives as anti-HIV microbicides N <sup>H</sup> <sup>N</sup> H = Br = Br = Br = Br =3,4 OMe; R<sup>2</sup> =2,5 OMe; R<sup>2</sup> =2 OMe; R<sup>2</sup> =3 OMe; R<sup>2</sup> =2 F; R<sup>2</sup> = Br =3 F; R<sup>2</sup> = Br =4 F; R<sup>2</sup> = Br =4 Br; R2 = Br =4 Me; R<sup>2</sup> = Br R1 HI-232: R<sup>1</sup> HI-236: R<sup>1</sup> HI-237: R<sup>1</sup> HI-239: R<sup>1</sup> HI-240: R<sup>1</sup> HI-241: R<sup>1</sup> HI-242: R<sup>1</sup> HI-243: R<sup>1</sup> HI-244: R<sup>1</sup> S HI-256: R<sup>1</sup> HI-253: R<sup>1</sup> HI-254: R<sup>1</sup> HI-255: R<sup>1</sup> HI-275: R<sup>1</sup> HI-308: R<sup>1</sup> HI-310: R<sup>1</sup> HI-311:R1 HI-345:R1 Among all these substances, they identified several dual-function of thiourea compounds, such as the phenyl ring-containing derivatives HI-240 (2-fluoro), HI-253 (2-chloro) and HI-255 (4-chloro) and the cyclohexenyl ring-containing derivatives HI-346 and HI-445, which were identified as potential lead compounds for the development of clinically useful dualfunction anti-HIV spermicides (Table 15). In this study, the authors also demonstrated that, at a spermicidal concentration, the dual-function thiourea derivatives were selectively spermicidal, without cytotoxic effects against human vaginal, ectocervical and endocervical epithelial cells . Table 15. Effect of PETT derivatives on p24 antigen production in HIV-infected PBMC, as well as enzymatic activity of HIV-1 RT and human sperm mobility. Considering that the most promising dual-function microbicides PETTs were HI-346 and HI-445, which are cyclohexenyl ring-containing derivatives, D´Cruz and collaborators decided to investigate other cyclohexenyl thiourea (CHET) compounds, in order to examine the way how heterocyclic rings and their functionalization affect the anti-HIV and SIA potency of these substances (D´Cruz et al., 2002a). Furthermore, some urea compounds were also evaluated, in an attempt to determine the role of thiourea moiety in the biological activity of these series (Table 16). In view of the data obtained, the authors concluded that, among the thiazolyl-ring containing CHET compounds, only the 4-methyl-substituted derivative (42) showed a significant anti-HIV activity. As a matter of fact, compounds containing benzothiazole-ring generally present poor anti-HIV activities. Among the compounds containing N-pyridyl nucleus, the functionalization at 5-position with bromine, chlorine and methyl groups led to a potent anti-HIV activity of CHET compounds. The thiourea moiety was essential to trigger said anti-HIV activity, as its replacement by urea group either abolished (44) or reduced (45) the biological activity. Among 15 derivative compounds that were evaluated for spermicidal potential, 12 showed an improvement of spermicidal function, when analyzed at micromolar concentrations. The authors observed that compounds with methyl group at 4- or 6-postion were non-spermicidal, even at concentrations >500µM. The pyridyl-ring containing CHET compounds with bromine or chlorine attached to 5-position showed an excellent SIA activity, in addition to their remarkable anti-HIV activity. Interestingly, the urea compounds, although having retained SIA, presented a poor anti-HIV activity, . Another curious data arises from the comparison between the values of T1/2 relating to thiourea and urea compounds, showing that urea analogues immobilized sperm 38-fold faster than thiourea derivatives. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 151 Furthermore, the lead compounds HI-346 and HI-445 were evaluated in their activity against NNI-resistant strains (RT-MDR, A17 variant), and were found to be more effective than TRV, delavirdine and nevirapine. These findings established the dual-function compounds HI-346 and HI-445 as potent NNI of drug-sensitive, as well as multidrug- Due to the fact that the compound HI-346 is a broad-spectrum anti-HIV agent with SIA, and also to the characteristic of its urea analogue 44 as an extremely rapid spermicidal, the authors decided to evaluate the in vivo fertilizing ability of sperm exposed to the lead dualfunction CHET compound HI-346, either alone or in combination with its structural analogue (compound 44), in the rabbit model. They observed that the conception was completely As to the cytotoxic profile, CHET-NNIs showed high selectivity indexes against these genital tract epithelial cells in vitro. Moreover, in rabbits, the lead thiourea/urea compounds are not harmful to vaginal mucosa, in spite of their potent spermicidal properties, when These results indicated that the extremely rapid SIA of the urea analogue, as well as the broad-spectrum anti-HIV activity of spermicidal CHET-NNIs, together with their lack of mucosal toxicity and the remarkable ability to reduce in vivo fertility, appear as features that are particularly attractive to encourage the clinical development of a dual-function The next step performed by D´Cruz and collaborators was the investigation on subchronic intravaginal toxicity of HI-346 in mice. Thus, HI-346 was formulated via lipophilic gelmicroemulsion for intravaginal use as a potential dual-function microbicide. In order to evaluate the potential toxicity of short-term intravaginal exposure to HI-346, groups of 15 female B6C3F1 and CD-1 mice underwent an intravaginal exposure to a gel-microemulsion containing 0, 0.5, 1.0, or 2.0% HI-346, 5 days per week, for 13 consecutive weeks. Subsequently, the authors concluded that repetitive intravaginal administration of HI-346 to yield effective spermicidal and antiviral concentrations is not expected to lead to local, In another study, D´Cruz and collaborators decided to evaluate the PETT derivative HI-236 as microbicide, as, in accordance with a previous work, this compound had already presented a broad-spectrum of anti-HIV activity (Mao et al., 1999). In view of the above the authors demonstrated that HI-236 showed a high-selectivity index against both human vaginal and cervical epithelial cells, without affecting the human sperm functions. Furthermore, HI-236 was able to prevent the HIV systemic infection via vaginal route. Therefore, HI-236 presented a clinical utility as non-spermicidal microbicide to curb the transmission of HIV via semen: (a) in sexually active women, to allow pregnancy, while protecting both mother and her fetus or infant from HIV-1 and (b) as a prophylactic antiviral agent for HIV-1 serodiscordant couples, or for use before assisted reproductive technology The thiocarbanilide Isoxyl (ISO, thiocarlide, 4,4'-diisoamythio-carbanilide) (Fig.1) was synthesized in 1953 by Buu-Hoi an Xuong. In this work, the authors described the antimicobacterial activity of several thioureas, among which some are more active than ISO; however, this substance was chosen for subsequent assays, due to its better absorption, inhibited after insemination with semen treated with compound 44, or HI-346 plus 44. resistant strains of HIV-1. added either to human or to rabbit semen. spermicidal microbicide (D´Cruz et al., 2002a). systemic, or reproductive toxicity (D´Cruz et al., 2002b). 3.2 Thiourea derivatives with potential activity against TB procedures (D´Cruz & Uckun, 2005). 3.2.1 Isoxyl \* Time required for 50% sperm mobility loss. Table 16. Anti-HIV and sperm immobilization activity of a serie of PETT derivatives. N <sup>H</sup> <sup>N</sup> H \* Time required for 50% sperm mobility loss. Table 16. Anti-HIV and sperm immobilization activity of a serie of PETT derivatives. X R Furthermore, the lead compounds HI-346 and HI-445 were evaluated in their activity against NNI-resistant strains (RT-MDR, A17 variant), and were found to be more effective than TRV, delavirdine and nevirapine. These findings established the dual-function compounds HI-346 and HI-445 as potent NNI of drug-sensitive, as well as multidrugresistant strains of HIV-1. Due to the fact that the compound HI-346 is a broad-spectrum anti-HIV agent with SIA, and also to the characteristic of its urea analogue 44 as an extremely rapid spermicidal, the authors decided to evaluate the in vivo fertilizing ability of sperm exposed to the lead dualfunction CHET compound HI-346, either alone or in combination with its structural analogue (compound 44), in the rabbit model. They observed that the conception was completely inhibited after insemination with semen treated with compound 44, or HI-346 plus 44. As to the cytotoxic profile, CHET-NNIs showed high selectivity indexes against these genital tract epithelial cells in vitro. Moreover, in rabbits, the lead thiourea/urea compounds are not harmful to vaginal mucosa, in spite of their potent spermicidal properties, when added either to human or to rabbit semen. These results indicated that the extremely rapid SIA of the urea analogue, as well as the broad-spectrum anti-HIV activity of spermicidal CHET-NNIs, together with their lack of mucosal toxicity and the remarkable ability to reduce in vivo fertility, appear as features that are particularly attractive to encourage the clinical development of a dual-function spermicidal microbicide (D´Cruz et al., 2002a). The next step performed by D´Cruz and collaborators was the investigation on subchronic intravaginal toxicity of HI-346 in mice. Thus, HI-346 was formulated via lipophilic gelmicroemulsion for intravaginal use as a potential dual-function microbicide. In order to evaluate the potential toxicity of short-term intravaginal exposure to HI-346, groups of 15 female B6C3F1 and CD-1 mice underwent an intravaginal exposure to a gel-microemulsion containing 0, 0.5, 1.0, or 2.0% HI-346, 5 days per week, for 13 consecutive weeks. Subsequently, the authors concluded that repetitive intravaginal administration of HI-346 to yield effective spermicidal and antiviral concentrations is not expected to lead to local, systemic, or reproductive toxicity (D´Cruz et al., 2002b). In another study, D´Cruz and collaborators decided to evaluate the PETT derivative HI-236 as microbicide, as, in accordance with a previous work, this compound had already presented a broad-spectrum of anti-HIV activity (Mao et al., 1999). In view of the above the authors demonstrated that HI-236 showed a high-selectivity index against both human vaginal and cervical epithelial cells, without affecting the human sperm functions. Furthermore, HI-236 was able to prevent the HIV systemic infection via vaginal route. Therefore, HI-236 presented a clinical utility as non-spermicidal microbicide to curb the transmission of HIV via semen: (a) in sexually active women, to allow pregnancy, while protecting both mother and her fetus or infant from HIV-1 and (b) as a prophylactic antiviral agent for HIV-1 serodiscordant couples, or for use before assisted reproductive technology procedures (D´Cruz & Uckun, 2005). #### 3.2 Thiourea derivatives with potential activity against TB 3.2.1 Isoxyl The thiocarbanilide Isoxyl (ISO, thiocarlide, 4,4'-diisoamythio-carbanilide) (Fig.1) was synthesized in 1953 by Buu-Hoi an Xuong. In this work, the authors described the antimicobacterial activity of several thioureas, among which some are more active than ISO; however, this substance was chosen for subsequent assays, due to its better absorption, Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 153 Strain Designation Drug Resistance MIC (µg/mL) CSU 15 I 5.0 CSU 21 I, R, E, S, Rfb 5.0 CSU 22 I, R, E, S, Kan, Cap, AMK 10.0 CSU 31 I, R, E 10.0 CSU 32 I, R, E, Cyc, ETH, Z 10.0 CSU 37 ----------------------------------------------------- 5.0 CSU 39 I, R, S, Kan, AMK, ETH 10.0 CSU 44 I, R, E, S, Kan, Z 10.0 W 670 I, R, E, S, Kan 5.0 W 3432 I, R, E, S, Kan, AMK, ETH, Cip 5.0 BB ----------------------------------------------------- 1.0 LL I, R, S, Kan, AMK, Z 1.0 kanamycin (Kan), cycloserine (Cyc), rifabutin (Rfb), ethionamide (ETH), amikacin (AMK), capreomycin Table 18. Minimal inhibitory concentration of ISO against susceptible and MDR-TB strains. Similarly to what happens with Isoniazid, a substance used in the first line treatment of TB, and with ethionamide, a second line drug, ISO strongly inhibits the synthesis of mycolic acids. However, ISO can also inhibit shorter chain fatty acid synthesis, thus producing an effect that had never been observed in other drugs showing antimycobacterial properties (Phetsuksiri et ISO interferes in the fatty acid metabolism, through inhibition of the ∆9 desaturase DesA3. This mechanism leads to the inhibition of the of oleic acid synthesis, which is the most abundant unsaturated fatty acid in Mycobacterium spp. and a constituent of mycobacterial membrane phospholipids. Due to the vital functions of oleic acid, the inhibition of its synthesis leads to cell death. Another membrane phospholipid constituent which is indirectly affected during this pathway is the tuberculostearic acid, given that this substance ISO inhibitory mechanism in mycolic acids synthesis has not been described. Nevertheless, it was already demonstrated that there is no relationship between oleic acid and mycolic Another relevant aspect involved in the ISO mechanism of action concerns the fact that its activation by the flavin-containing monooxygenase EthA is mandatory to trigger an activity against M. tuberculosis (Korduláková, 2007). Based on the LC/MS analyses of the compounds formed after ISO treatment with the partially purified recombinant EthA (compounds 53, 55 and 57, Fig. 10), the following activation pathway was proposed: Initially, oxidation reactions with sulfur atom lead to the formation of intermediary 54, which undergoes an elimination reaction, yielding the formimidamide 55. Further reactions lead to the formation of carbodiimide 56, which can be hydrolyzed, yielding the urea derivative 57 (Fig. 10). The data obtained from previous studies with ETH and thiacetazone could suggest that ISO would be a prodrug, activated by oxidations reactions catalyzed by EthA, and that carbodiimide 56 would appear as its active form. However, the real function of this process and its role in the inhibition of oleic acid and/or mycolic acids synthesis are not well understood. Besides, it is worthy to consider that EthA could only serve to retain is synthesized through direct methylation of oleic acid by S-adenosylmethionine. acids synthesis inhibition (Phetsuksiri et al., 2003). ISO or its metabolites inside the bacterial cell. (Cap). al., 2003). 3.2.2 Mechanism of action and also to its good tolerance even at the highest therapeutic doses (König, 1970). Pharmacological data demonstrated that, upon this drug ingestion, the human serum presented fluctuating levels of ISO, that exceeded its minimum inhibitory concentration (Tousek, 1970). Besides, given its remarkable characteristics, this substance has been used at the clinical treatment of TB since the 1960's. ISO was employed both: in monotherapy and in combined therapy, such as: ISO-isoniazid (I), ISO-streptomycin (S), ISO-I-S and ISOpara-aminosalicylic acid (PAS). These studies reached good results (some of which are shown at Table 17), especially in patients with pulmonary TB resistant to isoniazid, streptomycin and PAS, as well as in patients with hyper allergic reactions against others drugs or hepatitis as a result from I (Tousek, 1970; Urbancik, 1970). However, when compared with other combinatory regimes, such as I-PAS and S-PAS, the results achieved with ISO appeared to be quite mediocre, thus culminating with the introduction of more powerful antituberculosis drugs, such as ethambutol, and with the consequent discontinuation of ISO administration. Nevertheless, in view of the worldwide dissemination of MDR-TB and XDR-TB (World Health Organization, 2010a), a reevaluation of drugs which were formerly deemed to be effective against TB is a promising strategy for the development of new treatments, so that, in this context, ISO may be considered as a strong candidate. apercentage of patients who had presented negative cultures. Table 17. Examples of results achieved in clinical trials with ISO (Tousek, 1970) In a recent report, Phetsuksiri and collaborators (Phetsuksiri et al., 1999) evaluated the minimal inhibitory concentration (MIC) of ISO against various clinical isolates of susceptible and MDR-TB strains (Table 18). The growing of all tested strains was inhibited at low concentrations, with a MIC ranging between 1-10µg/mL, which are smaller than the maximum serum levels observed in humans for ISO (10-13.2µg/mL) (König, 1970). The authors also verified the effect of ISO on viable M. tuberculosis in vitro bone marrow macrophage assay, where this substance showed an ability to inhibit bacterial growth inside the macrophage, as well as a bactericidal activity, by reducing the initial inoculum of virulent M. tuberculosis. Another interesting result from this assay disclosed that ISO showed no acute level of toxicity for mouse macrophages. Together with the early studies performed with ISO in the 1960s, the recent results corroborate the capacity of this substance to be used as an anti-TB drug, particularly in the development of new regimes to MDR and XDR-TB treatment. Such a characteristic is a direct result from ISO mechanism of action, which considerably differs from those presented by other known anti-TB drugs. kanamycin (Kan), cycloserine (Cyc), rifabutin (Rfb), ethionamide (ETH), amikacin (AMK), capreomycin (Cap). Table 18. Minimal inhibitory concentration of ISO against susceptible and MDR-TB strains. #### 3.2.2 Mechanism of action 152 Global View of HIV Infection and also to its good tolerance even at the highest therapeutic doses (König, 1970). Pharmacological data demonstrated that, upon this drug ingestion, the human serum presented fluctuating levels of ISO, that exceeded its minimum inhibitory concentration (Tousek, 1970). Besides, given its remarkable characteristics, this substance has been used at the clinical treatment of TB since the 1960's. ISO was employed both: in monotherapy and in combined therapy, such as: ISO-isoniazid (I), ISO-streptomycin (S), ISO-I-S and ISOpara-aminosalicylic acid (PAS). These studies reached good results (some of which are shown at Table 17), especially in patients with pulmonary TB resistant to isoniazid, streptomycin and PAS, as well as in patients with hyper allergic reactions against others drugs or hepatitis as a result from I (Tousek, 1970; Urbancik, 1970). However, when compared with other combinatory regimes, such as I-PAS and S-PAS, the results achieved with ISO appeared to be quite mediocre, thus culminating with the introduction of more powerful antituberculosis drugs, such as ethambutol, and with the consequent discontinuation of ISO administration. Nevertheless, in view of the worldwide dissemination of MDR-TB and XDR-TB (World Health Organization, 2010a), a reevaluation of drugs which were formerly deemed to be effective against TB is a promising strategy for the development of new treatments, so that, in this context, ISO may be Combination Months of therapy Negative on culture (%)a ISO (6 g) 1.5 – 4.5 47 In a recent report, Phetsuksiri and collaborators (Phetsuksiri et al., 1999) evaluated the minimal inhibitory concentration (MIC) of ISO against various clinical isolates of susceptible and MDR-TB strains (Table 18). The growing of all tested strains was inhibited at low concentrations, with a MIC ranging between 1-10µg/mL, which are smaller than the maximum serum levels observed in humans for ISO (10-13.2µg/mL) (König, 1970). The authors also verified the effect of ISO on viable M. tuberculosis in vitro bone marrow macrophage assay, where this substance showed an ability to inhibit bacterial growth inside the macrophage, as well as a bactericidal activity, by reducing the initial inoculum of virulent M. tuberculosis. Another interesting result from this assay disclosed that ISO Together with the early studies performed with ISO in the 1960s, the recent results corroborate the capacity of this substance to be used as an anti-TB drug, particularly in the development of new regimes to MDR and XDR-TB treatment. Such a characteristic is a direct result from ISO mechanism of action, which considerably differs from those ISO – I (6 g/600 mg) 4 89 ISO – I (6 g/10 mg/Kg) 6 75 ISO – I (6 g/5 mg/Kg) 6 63 ISO – S – I (4 g/1 g/200 mg) 6 83 ISO – PAS (6 g/12 g) 6 50 Table 17. Examples of results achieved in clinical trials with ISO (Tousek, 1970) considered as a strong candidate. apercentage of patients who had presented negative cultures. showed no acute level of toxicity for mouse macrophages. presented by other known anti-TB drugs. Similarly to what happens with Isoniazid, a substance used in the first line treatment of TB, and with ethionamide, a second line drug, ISO strongly inhibits the synthesis of mycolic acids. However, ISO can also inhibit shorter chain fatty acid synthesis, thus producing an effect that had never been observed in other drugs showing antimycobacterial properties (Phetsuksiri et al., 2003). ISO interferes in the fatty acid metabolism, through inhibition of the ∆9 desaturase DesA3. This mechanism leads to the inhibition of the of oleic acid synthesis, which is the most abundant unsaturated fatty acid in Mycobacterium spp. and a constituent of mycobacterial membrane phospholipids. Due to the vital functions of oleic acid, the inhibition of its synthesis leads to cell death. Another membrane phospholipid constituent which is indirectly affected during this pathway is the tuberculostearic acid, given that this substance is synthesized through direct methylation of oleic acid by S-adenosylmethionine. ISO inhibitory mechanism in mycolic acids synthesis has not been described. Nevertheless, it was already demonstrated that there is no relationship between oleic acid and mycolic acids synthesis inhibition (Phetsuksiri et al., 2003). Another relevant aspect involved in the ISO mechanism of action concerns the fact that its activation by the flavin-containing monooxygenase EthA is mandatory to trigger an activity against M. tuberculosis (Korduláková, 2007). Based on the LC/MS analyses of the compounds formed after ISO treatment with the partially purified recombinant EthA (compounds 53, 55 and 57, Fig. 10), the following activation pathway was proposed: Initially, oxidation reactions with sulfur atom lead to the formation of intermediary 54, which undergoes an elimination reaction, yielding the formimidamide 55. Further reactions lead to the formation of carbodiimide 56, which can be hydrolyzed, yielding the urea derivative 57 (Fig. 10). The data obtained from previous studies with ETH and thiacetazone could suggest that ISO would be a prodrug, activated by oxidations reactions catalyzed by EthA, and that carbodiimide 56 would appear as its active form. However, the real function of this process and its role in the inhibition of oleic acid and/or mycolic acids synthesis are not well understood. Besides, it is worthy to consider that EthA could only serve to retain ISO or its metabolites inside the bacterial cell. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 155 \* MIC99 is defined as the lowest concentration of compound that reduced 99% of the number of M. tuberculosis colonies on the plates, in comparison with those at the control plate free of compound. Table 19. ISO analogues prepared by Phetsuksiri and collaborators, as well as their respective MIC values. Fig. 10. Proposed pathway for ISO activation by EthA. #### 3.2.3 ISO analogues In spite of the interesting results shown by the prior clinical trials with ISO , this substance was found to present some pharmacokinetic disadvantages, which limited its clinical use as an antimycobacterial agent (Wang & Hickey, 2010). In view of the above, and in an attempt to overcome this kind of inconvenient, several ISO derivatives have been synthesized throughout the last years, as may be illustrated by the following examples. Phetsuksiri and collaborators described the antimycobacterial evaluation of series of ISO analogues (Phetsuksiri et al., 1999). These compounds were prepared through random substitutions in the side chains attached to the thiourea nucleus, which it is required for animycobacterial activity (Phetsuksiri et al., 2003; Korduláková, 2007). This strategy led to the formation of a pool of new ISO derivatives, which present variations both in the symmetric and asymmetric side chains with alkyl, alkoxy or sulfur fuctional groups substituted in para and para´ positions (Table 19). Said results show that the most part of derivatives presented a similar or a better activity (MIC <0.1 to 2.5µg/mL), when compared to ISO (MIC= 2.0µg/mL). Among some relevant aspects concerning SAR, it may be noted that the replacement of oxygen (58-60) by sulfur (62-64) in the side chain provides a considerable improvement in the antimycobacterial activity. Moreover, the introduction of a long alkyl chain plus an ester group leads to the formation of inactive compounds (67,68). Bulky groups, such as t-butyl, attached to para and para´ position of phenyl ring, also gave rise to an inactive derivative (65). These results suggest that chemical modifications on thiourea nucleus basis could lead to the constitution of an inhibitor, that would be even more powerful against M. tuberculosis. In another study, Bhowruth and collaborators (Bhowruth et al., 2006) synthesized and evaluated series of symmetrical and unsymmetrical ISO analogues against M. tuberculosis (Table 20). Several compounds disclosed by this study present similar or better activities than ISO (MIC <0.1 to 1.56µg/mL). It is worthy to mention that the introduction of an aliphatic C4 chain to either or both R1 and R2-positions increased the potency of the inhibitor (76-79, 81). Among them, the derivatives 78 and 79 were the most active, with a significant 10-fold increase in potency against M. tuberculosis, when compared to ISO. S N EthA EthA N C N 56 In spite of the interesting results shown by the prior clinical trials with ISO , this substance was found to present some pharmacokinetic disadvantages, which limited its clinical use as an antimycobacterial agent (Wang & Hickey, 2010). In view of the above, and in an attempt to overcome this kind of inconvenient, several ISO derivatives have been synthesized throughout the last years, as may be illustrated by the following examples. Phetsuksiri and collaborators described the antimycobacterial evaluation of series of ISO analogues (Phetsuksiri et al., 1999). These compounds were prepared through random substitutions in the side chains attached to the thiourea nucleus, which it is required for animycobacterial activity (Phetsuksiri et al., 2003; Korduláková, 2007). This strategy led to the formation of a pool of new ISO derivatives, which present variations both in the symmetric and asymmetric side chains with alkyl, alkoxy or sulfur fuctional groups Said results show that the most part of derivatives presented a similar or a better activity (MIC <0.1 to 2.5µg/mL), when compared to ISO (MIC= 2.0µg/mL). Among some relevant aspects concerning SAR, it may be noted that the replacement of oxygen (58-60) by sulfur (62-64) in the side chain provides a considerable improvement in the antimycobacterial activity. Moreover, the introduction of a long alkyl chain plus an ester group leads to the formation of inactive compounds (67,68). Bulky groups, such as t-butyl, attached to para and para´ position of phenyl ring, also gave rise to an inactive derivative (65). These results suggest that chemical modifications on thiourea nucleus basis could lead to the constitution In another study, Bhowruth and collaborators (Bhowruth et al., 2006) synthesized and evaluated series of symmetrical and unsymmetrical ISO analogues against M. tuberculosis (Table 20). Several compounds disclosed by this study present similar or better activities than ISO (MIC <0.1 to 1.56µg/mL). It is worthy to mention that the introduction of an aliphatic C4 chain to either or both R1 and R2-positions increased the potency of the inhibitor (76-79, 81). Among them, the derivatives 78 and 79 were the most active, with a significant of an inhibitor, that would be even more powerful against M. tuberculosis. 10-fold increase in potency against M. tuberculosis, when compared to ISO. R N H > N H N S N R R 55 R O OH R R OH R N H ISO 53 54 R H2O Fig. 10. Proposed pathway for ISO activation by EthA. substituted in para and para´ positions (Table 19). N H > N H 3.2.3 ISO analogues O N H 57 R R S N H R R \* MIC99 is defined as the lowest concentration of compound that reduced 99% of the number of M. tuberculosis colonies on the plates, in comparison with those at the control plate free of compound. Table 19. ISO analogues prepared by Phetsuksiri and collaborators, as well as their respective MIC values. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 157 S O O > N H > N H N H Improvement of hydrophilicity Carbohydrate Fig. 11. ISO derivatives containing carbohydrates moieties. molecule, being also responsible for adding specificity to it. Carbohydrate O 90 MIC=1.56-3.12g/mL OH OH HO Carbohydrate N <sup>H</sup> <sup>N</sup> H HO Fig. 12. Other ISO derivatives containing carbohydrates moieties. S O 91 MIC=3.12-6.25g/mL OH OH O 88 MIC= 50-100g/mL NHAc HO HO OH Carbohydrate S H3C HO N H O HO OH 89 MIC=8g/mL O <sup>O</sup> HO OH 92 MIC=6.25-12.5g/mL OH This promising result encouraged Liav and collaborators (Liav et al., 2008b) to synthesize and evaluate the D-aldopentofuranosyl derivatives (90-93, Fig.12). Arabino analogue (90) was re-tested, and found to be more potent than ISO, while the ribo analogue (91) presented a MIC value in the same range of ISO. The D-xylo analogue (92) was rather less active, and the D-lyxo product (93) only acted at a concentration of 50µg/mL. These results could suggest that the products are very sensitive to stereochemical configuration, thus indicating that the carbohydrate group does not only add the required hydrophilicity to the O O OH O OH OH 93 MIC=50g/mL HO 90 MIC=2.5g/mL OH HO Table 20. Structures and antimycobacterial activity of ISO derivatives. Liav and collaborators investigated the effect of replacement of one of the isoamyloxyphenyl ISO moieties by a carbohydrate (Liav et al., 2008a). Said modification aimed at the production of ISO analogues with better hydrophilic properties, which could be useful to mitigate the inconvenient represented by the poor bioavailability of this drug (Fig.11). Among these compounds, only the arabinfuranosyl derivative 90 has a MIC value of 2.5µg/mL, which is almost more potent than ISO. Table 20. Structures and antimycobacterial activity of ISO derivatives. 2.5µg/mL, which is almost more potent than ISO. Liav and collaborators investigated the effect of replacement of one of the isoamyloxyphenyl ISO moieties by a carbohydrate (Liav et al., 2008a). Said modification aimed at the production of ISO analogues with better hydrophilic properties, which could be useful to mitigate the inconvenient represented by the poor bioavailability of this drug (Fig.11). Among these compounds, only the arabinfuranosyl derivative 90 has a MIC value of Fig. 11. ISO derivatives containing carbohydrates moieties. This promising result encouraged Liav and collaborators (Liav et al., 2008b) to synthesize and evaluate the D-aldopentofuranosyl derivatives (90-93, Fig.12). Arabino analogue (90) was re-tested, and found to be more potent than ISO, while the ribo analogue (91) presented a MIC value in the same range of ISO. The D-xylo analogue (92) was rather less active, and the D-lyxo product (93) only acted at a concentration of 50µg/mL. These results could suggest that the products are very sensitive to stereochemical configuration, thus indicating that the carbohydrate group does not only add the required hydrophilicity to the molecule, being also responsible for adding specificity to it. Fig. 12. Other ISO derivatives containing carbohydrates moieties. Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection 159 Buu-Hoi, N.P., Xuong, N.D. 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In parallel, as refers to TB drug discovery, ISO was found to present promising activities against resistant strains, especially due to its unique mechanism of action. In view of said data, the development of substances containing thiourea moiety and showing a potential activity against both diseases could be considered an important research field, which should be particularly orientated towards the improvement of therapeutic options for HIV-TB co-infected patients. ## 5. References Thiourea is a very important functional group for anti-HIV and anti-TB drug discovery, and, as seen above, literature has already described the promising biological activities of several derivatives. In the context of AIDS drug discovery, this scaffold is found in two remarkably important classes of compounds, namely among PETT and TIBO derivatives. The PETT compound TRV has been exploited as an excellent lead compound, whose several derivatives have been described. 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Bioorganic & Medicinal Chemistry Letters, vol.18, No.8, pp. 2649–2651, ISSN 0960- piperidinylethyl)]-N´-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]- N´-[2-(5-bromopyridyl)]-thiourea a potent non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters, vol.8, No.16, pp. dimethoxyphenylethyl)]-N´-[2-(5-bromopyridyl)]-thiourea (HI-236) as a potent non-nucleoside inhibitor of drug-resistant human immunodeficiency virus. Bioorganic & Medicinal Chemistry Letters, vol.9, No.11, pp. 1593-1598, ISSN 0960- replication in vitro by a Novel Series of TIBO Derivatives. Nature, vol. 343, pp.470- infected patients in Zaire: a controlled trial of treatment for either 6 or 12 months. The New England Journal of Medicine, vol.332, No.12, (March 1995), pp.779–784, ISSN isoxyl and new derivatives through the inhibition of mycolic acid synthesis. Antimicrobial Agents and Chemotherapy, vol.43, No.5, (May 1999), p. 1042–1051, ISSN Thiourea Drug Isoxyl on Mycobacterium tuberculosis. The Journal of Biological 8 Brazil Quality of Life Assessment in People Living with HIV/AIDS: Clarifying the WHOQOL-HIV Assessing the quality of life (QoL) of people living with HIV/AIDS has become increasing. From 1995 to 2003, more than 300 papers on the subject were published. This fact encourages researchers to question the existence of suitable assessment instruments. Virtually all existing instruments until 2003 had been developed in the USA (Skevington & O'Connell, 2003). To apply these instruments in countries in which English is not the vernacular language, the instruments were subjected to literal translations, without the worry of a cultural adaptation. In this wise, came the proposal to develop an instrument from sundry centers, The fact that there is no consensus on the QoL concept is a major problem in developing instruments to assess the QoL, while it is not possible to state clearly what elements these From this premise, the starting point to build the instrument for QoL assessment of the World Health Organization (WHO) was to conceptualize QoL. In the concept adopted, QoL is understood as "individuals' perceptions of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, In face of this concept, WHO embarked on building the World Health Organization Quality of Life (WHOQOL) instruments, which assess QoL globally, e.g. WHOQOL-100 and WHOQOL-bref, and due to specific aspects, e.g. WHOQOL-HIV, WHOQOL-OLD, and WHOQOL-SRPB. One of these instruments, the WHOQOL-HIV, used to assess the QoL of Starting from the fact that 95% of people infected with HIV did not live in the USA but in developing countries of Asia, Latin America, and sub-Saharan Africa, WHO has developed a tool to assess the QoL directed to such audience. The instrument was designed based on the premise that a multidisciplinary approach, involving centers in several countries, would The WHOQOL-HIV is a complementary module for WHOQOL-100 instrument, and was also translated into other languages and validated in sundry studies, among which are a part of Starace et al. (2002), Zimpel & Fleck (2007), Saddki et al. (2009), Canavarro et al. allow for greater dissemination of the developed instrument (O'Connell, 2003). located in different countries (Skevington & O'Connell, 2003). standards and concerns" (The WHOQOL Group, 1998a, p. 25). instruments are assessing (Fleck, 2008). HIV carriers, is the object of this study. (2011) and Mweemba et al. (2011). 1. Introduction and WHOQOL-HIV-Bref Instruments Bruno Pedroso, Gustavo Luis Gutierrez, Edison Duarte, Luiz Alberto Pilatti and Claudia Tania Picinin Universidade Estadual de Campinas – UNICAMP	doab	2025-04-07T04:13:04.695713	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 30 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.31	Quality of Life Assessment in People Living with HIV/AIDS: Clarifying the WHOQOL-HIV and WHOQOL-HIV-Bref Instruments Bruno Pedroso, Gustavo Luis Gutierrez, Edison Duarte, Luiz Alberto Pilatti and Claudia Tania Picinin Universidade Estadual de Campinas – UNICAMP Brazil #### 1. Introduction 162 Global View of HIV Infection Venkatachalam, Mao, C., Uckun, F.M. et al. (2004).Effect of stereochemistry on the anti-HIV Vig, R., Mao, C., Venkatachalam, T. K. et al. (1998). Rational design and synthesis of Wang, C. & Hickey, A.J. (2010). Isoxyl particles for pulmonary delivery: In vitro cytotoxicity World Health Organization. (2010a). Global tuberculosis control: WHO Report 2010, WHO World Health Organization. (2010b). Treatment of tuberculosis: guidelines (4th ed.), WHO No.12, pp.4275–4284, ISSN 0968-0896. press, ISBN 978 92 4 156406 9, Geneva, Switzerland. Press, ISBN 978 92 4 154783 3, Geneva, Switzerland. pp.1789-1797, ISSN 0968-0896. 0378-5173. activity of chiral thiourea compounds. Bioorganic & Medicinal Chemistry, vol.12, phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase. Bioorganic & Medicinal Chemistry, vol.6, No.10, and potency. International Journal of Pharmaceutics, vol.396, No.1-2, pp. 99–104, ISSN Assessing the quality of life (QoL) of people living with HIV/AIDS has become increasing. From 1995 to 2003, more than 300 papers on the subject were published. This fact encourages researchers to question the existence of suitable assessment instruments. Virtually all existing instruments until 2003 had been developed in the USA (Skevington & O'Connell, 2003). To apply these instruments in countries in which English is not the vernacular language, the instruments were subjected to literal translations, without the worry of a cultural adaptation. In this wise, came the proposal to develop an instrument from sundry centers, located in different countries (Skevington & O'Connell, 2003). The fact that there is no consensus on the QoL concept is a major problem in developing instruments to assess the QoL, while it is not possible to state clearly what elements these instruments are assessing (Fleck, 2008). From this premise, the starting point to build the instrument for QoL assessment of the World Health Organization (WHO) was to conceptualize QoL. In the concept adopted, QoL is understood as "individuals' perceptions of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns" (The WHOQOL Group, 1998a, p. 25). In face of this concept, WHO embarked on building the World Health Organization Quality of Life (WHOQOL) instruments, which assess QoL globally, e.g. WHOQOL-100 and WHOQOL-bref, and due to specific aspects, e.g. WHOQOL-HIV, WHOQOL-OLD, and WHOQOL-SRPB. One of these instruments, the WHOQOL-HIV, used to assess the QoL of HIV carriers, is the object of this study. Starting from the fact that 95% of people infected with HIV did not live in the USA but in developing countries of Asia, Latin America, and sub-Saharan Africa, WHO has developed a tool to assess the QoL directed to such audience. The instrument was designed based on the premise that a multidisciplinary approach, involving centers in several countries, would allow for greater dissemination of the developed instrument (O'Connell, 2003). The WHOQOL-HIV is a complementary module for WHOQOL-100 instrument, and was also translated into other languages and validated in sundry studies, among which are a part of Starace et al. (2002), Zimpel & Fleck (2007), Saddki et al. (2009), Canavarro et al. (2011) and Mweemba et al. (2011). Quality of Life Assessment in People 2.1 WHOQOL-100 scores calculation have at least three valid items; instrument items). be an inversion of that facet to proceed the calculation; 2.2 Questions and facets response scale conversion remain the same in both normal and inverted scales. same scale of facets. The results are also expressed on a scale from 0 to 100. areas where such facets are found, the score of the latter is converted. Living with HIV/AIDS: Clarifying the WHOQOL-HIV and WHOQOL-HIV-Bref Instruments 165 The results of the WHOQOL-100 implementation are expressed through the scores of each facet and domain. The WHOQOL-100 scoring procedure presents the following logic: - Verification of all those 100 questions completed with values between 1 and 5; The WHOQOL-100 results are expressed in two scales, a variant scale between 4 and 20 points, due to the fact that the facets scores calculation is achieved by multiplying the average of questions that constitute each facet by four. Once each domain is calculated by the simple arithmetic average of facets that composes it. The results are expressed on the The conversion of questions is used in order to standardize all the answers of the instrument, so that the most positive response is 5. Therefore, the most negative response must be 1. Thus, all questions of each facet are converted to the same scale, where the gradual increase in In cases where all four questions that constitute a facet are arranged in inverted scale, that same logic is used, but only in the domain calculation. That is, the result of these facets is expressed in the original scale: without inversion (the closer to 1, the more positive the result; the closer to 5, the more negative the result). However, when calculating the scores of For the conversion of the response scale of questions, the minimum value of the inverted scale question should be replaced by the maximum value of the normal scale question, and the maximum value of the inverted scale question should be replaced by a minimum value of the normal scale question. The same should occur with intermediate values, following this same logic. Thus, the only value that remains unchanged is the central value, which will It is necessary to be attentive to this fact, because when comparing the results between the facets, the score of a facet with inverted scale cannot be directly compared to the score of a response is equivalent in the same proportion to the increase in the result of the facet. Notwithstanding the significant diffusion of the WHOQOL, questions concerning the calculation and analysis of the results of those instruments constitute a limitation for its use. In this context, we aimed here at clarifying the mechanism predetermined by the WHOQOL-HIV Group to calculate the WHOQOL-HIV and WHOQOL-HIV-bref instrument scores. Additionally, we proposed an alternative way to perform such calculations.	doab	2025-04-07T04:13:04.703355	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 31 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.32	2. WHOQOL-100 The development of an instrument for evaluation of quality of life purposed by WHO was conducted in 15 centers simultaneously, based in 14 countries. After developing the project WHOQOL, new centers were built. Currently WHOQOL instruments are available in over 50 languages (WHO Field Center for Quality of Life of Bath, 2008). The development methodology of WHOQOL was sectioned into four major stages: clarifying the concept of quality of life, qualitative pilot study, development of a pilot and finally, field implementation. For the integrated centers, after the completion of the instrument, a protocol was established which consisted in its translation, preparation of the test pilot, development of the response scales and administration of the pilot (The WHOQOL Group, 1998a). All questions of WHOQOL-100 are closed. It was used a five-point Likert scale, ranging from 1 to 5. These extremes represent 0% and 100%, respectively. There are four different types of response scales, as can be seen in Table 1: Source: Adapted from The WHOQOL Group (1998b) Table 1. Response scale of WHOQOL-100 WHOQOL-100 aims at measuring the quality of life globally through six domains: Physical, Psychological, Level of independence, Social relationships, Environment e Spiritual/Religion/Personal beliefs. To obtain the results of WHOQOL instruments applications, the WHOQOL Group recommends the software Statistical Package for the Social Sciences (SPSS). #### 2.1 WHOQOL-100 scores calculation 164 Global View of HIV Infection Notwithstanding the significant diffusion of the WHOQOL, questions concerning the calculation and analysis of the results of those instruments constitute a limitation for its use. In this context, we aimed here at clarifying the mechanism predetermined by the WHOQOL-HIV Group to calculate the WHOQOL-HIV and WHOQOL-HIV-bref instrument The development of an instrument for evaluation of quality of life purposed by WHO was conducted in 15 centers simultaneously, based in 14 countries. After developing the project WHOQOL, new centers were built. Currently WHOQOL instruments are available in over The development methodology of WHOQOL was sectioned into four major stages: clarifying the concept of quality of life, qualitative pilot study, development of a pilot and finally, field implementation. For the integrated centers, after the completion of the instrument, a protocol was established which consisted in its translation, preparation of the test pilot, development of All questions of WHOQOL-100 are closed. It was used a five-point Likert scale, ranging from 1 to 5. These extremes represent 0% and 100%, respectively. There are four different SCALE 0% 25% 50% 75% 100% amount Neither poor nor good Not at all Slightly Moderately Very Extremely Very much nor dissatisfied Satisfied Very nor unhappy Happy Very happy An extreme amount satisfied Good Very good scores. Additionally, we proposed an alternative way to perform such calculations. the response scales and administration of the pilot (The WHOQOL Group, 1998a). Not at all A little A moderate dissatisfied Dissatisfied Neither satisfied unhappy Unhappy Neither happy CAPACITY Not at all A little Moderately Mostly Completely FREQUENCY Never Seldom Quite often Very often Always WHOQOL-100 aims at measuring the quality of life globally through six domains: Physical, Psychological, Level of independence, Social relationships, Environment e Spiritual/Religion/Personal beliefs. To obtain the results of WHOQOL instruments applications, the WHOQOL Group recommends the software Statistical Package for the 50 languages (WHO Field Center for Quality of Life of Bath, 2008). types of response scales, as can be seen in Table 1: Very Very Source: Adapted from The WHOQOL Group (1998b) Table 1. Response scale of WHOQOL-100 Very poor Poor 2. WHOQOL-100 INTENSITY EVALUATION Social Sciences (SPSS). The results of the WHOQOL-100 implementation are expressed through the scores of each facet and domain. The WHOQOL-100 scoring procedure presents the following logic: The WHOQOL-100 results are expressed in two scales, a variant scale between 4 and 20 points, due to the fact that the facets scores calculation is achieved by multiplying the average of questions that constitute each facet by four. Once each domain is calculated by the simple arithmetic average of facets that composes it. The results are expressed on the same scale of facets. The results are also expressed on a scale from 0 to 100. #### 2.2 Questions and facets response scale conversion The conversion of questions is used in order to standardize all the answers of the instrument, so that the most positive response is 5. Therefore, the most negative response must be 1. Thus, all questions of each facet are converted to the same scale, where the gradual increase in response is equivalent in the same proportion to the increase in the result of the facet. In cases where all four questions that constitute a facet are arranged in inverted scale, that same logic is used, but only in the domain calculation. That is, the result of these facets is expressed in the original scale: without inversion (the closer to 1, the more positive the result; the closer to 5, the more negative the result). However, when calculating the scores of areas where such facets are found, the score of the latter is converted. For the conversion of the response scale of questions, the minimum value of the inverted scale question should be replaced by the maximum value of the normal scale question, and the maximum value of the inverted scale question should be replaced by a minimum value of the normal scale question. The same should occur with intermediate values, following this same logic. Thus, the only value that remains unchanged is the central value, which will remain the same in both normal and inverted scales. It is necessary to be attentive to this fact, because when comparing the results between the facets, the score of a facet with inverted scale cannot be directly compared to the score of a Quality of Life Assessment in People Domain I – Physical Domain II – Psychological Domain IV – Environment Source: The WHOQOL Group (1998c) Table 3. Domains and facets of WHOQOL-bref Domain III – Social Relationships Living with HIV/AIDS: Clarifying the WHOQOL-HIV and WHOQOL-HIV-Bref Instruments 167 WHOQOL-100 has a facet that is not included in any domain, the facet Overall Quality of Life and General Health Perceptions (The WHOQOL Group, 1998b). This aspect deals with a self-assessment of quality of life, where the respondents express their point of view Aiming at providing a tool that demand less time to its filling out, and with satisfactory psychometric characteristics, the WHOQOL Group developed the short version of The WHOQOL-bref is composed of 26 questions - two questions on self-assessment of quality of life and 24 issues representing each facet of WHOQOL-100. To compound the questions of WHOQOL-bref, it was selected the question of each facet that present the highest correlation with the average score of all facets (The WHOQOL Group, 1998c). After the selection of issues, an analysis was conducted to see if they, factually, represented the corresponding facets. In six facets, the question selected was replaced by another question of the corresponding facet, for, under the bias of experts, there was another question that could best define these six facets (The WHOQOL Group, 1998c). The facets belonging to the domain Level of Independence were incorporated into the Physical domain and the facet belonging to the domain Spiritual / Religion / Personal Beliefs was incorporated into the Psychological domain. Thus, the WHOQOL-bref is composed by four domains: Physical, Psychological, Social Relationships and Environment, completing the configuration expressed in Table 3: 1. Pain and discomfort 2. Energy e fatigue 3. Sleep and rest 4. Mobility 5. Activities of daily living 11. Bodily image and appearance 13. Spiritual/Religion/Personal Beliefs 7. Work capacity 10. Self-esteem 8. Positive feelings 12. Negative feelings activities 24. Transport 14. Personal relationships 15. Social support 16. Sexual activity 17. Physical safety and security 18. Home environment 19. Financial resources 6. Dependence on medication or treatments 9. Thinking, learning, memory and concentration 20. Health and social care: accessibility and quality 21. Opportunities for acquiring new information and skills 22. Participation in and opportunities for recreation/ leisure 23. Physical environment (pollution/noise/traffic/climate) DOMAINS FACETS concerning their satisfaction with their lives, health and quality of life. WHOQOL-100, the WHOQOL-bref (The WHOQOL Group, 1996). 2.4 Short version of WHOQOL-100 (WHOQOL-bref) facet with normal scale. The answers 1, 2, 3, 4 and 5 are to take the values 5, 4, 3, 2 and 1, respectively. The same procedure is used in the conversion of inverted facets, where the scores 4, 8, 12, 16 and 20 are to take the values 20, 16, 12, 8 and 4, respectively. ### 2.3 WHOQOL-100 questions, domains and facets Composed by 100 questions, the WHOQOL-100 is sectioned into 24 groups of four questions each, receiving the name of "facets". The group of facets constitutes a "domain". Unlike the composition of facets, the six WHOQOL-100 domains are not constituted by the same number of facets, and may vary from one to eight. The questions that compose WHOQOL-100 are not arranged in the questionnaire in a logical sequence by domain or facet. They are grouped by type of answer scale. The distribution of WHOQOL-100 facets and areas are listed in Table 2: Source: The WHOQOL Group (1998a) Table 2. Domains and facets of WHOQOL-100 WHOQOL-100 has a facet that is not included in any domain, the facet Overall Quality of Life and General Health Perceptions (The WHOQOL Group, 1998b). This aspect deals with a self-assessment of quality of life, where the respondents express their point of view concerning their satisfaction with their lives, health and quality of life. #### 2.4 Short version of WHOQOL-100 (WHOQOL-bref) 166 Global View of HIV Infection facet with normal scale. The answers 1, 2, 3, 4 and 5 are to take the values 5, 4, 3, 2 and 1, respectively. The same procedure is used in the conversion of inverted facets, where the Composed by 100 questions, the WHOQOL-100 is sectioned into 24 groups of four questions each, receiving the name of "facets". The group of facets constitutes a "domain". Unlike the composition of facets, the six WHOQOL-100 domains are not constituted by the same The questions that compose WHOQOL-100 are not arranged in the questionnaire in a logical sequence by domain or facet. They are grouped by type of answer scale. The distribution of > 1. Pain and discomfort 2. Energy e fatigue 3. Sleep and rest 7. Bodily image and appearance 5. Thinking, learning, memory and concentration 11. Dependence on medication or treatments 19. Health and social care: accessibility and quality 20. Opportunities for acquiring new information and 21. Participation in and opportunities for recreation/ (pollution/noise/traffic/climate) 24. Spiritual/Religion/Personal Beliefs 4. Positive feelings 8. Negative feelings 12. Work capacity 14. Social support 15. Sexual activity skills 23. Transport 10. Activities of daily living 13. Personal relationships 17. Home environment 18. Financial resources leisure activities 22. Physical environment 16. Physical safety and security 6. Self-esteem 9. Mobility scores 4, 8, 12, 16 and 20 are to take the values 20, 16, 12, 8 and 4, respectively. 2.3 WHOQOL-100 questions, domains and facets number of facets, and may vary from one to eight. WHOQOL-100 facets and areas are listed in Table 2: DOMAINS FACETS Domain I – Physical Domain II – Psychological Domain III – Level of Independence Domain IV – Social Relationships Domain V – Environment Spiritual/Religion/Personal Source: The WHOQOL Group (1998a) Table 2. Domains and facets of WHOQOL-100 Domain VI – Beliefs Aiming at providing a tool that demand less time to its filling out, and with satisfactory psychometric characteristics, the WHOQOL Group developed the short version of WHOQOL-100, the WHOQOL-bref (The WHOQOL Group, 1996). The WHOQOL-bref is composed of 26 questions - two questions on self-assessment of quality of life and 24 issues representing each facet of WHOQOL-100. To compound the questions of WHOQOL-bref, it was selected the question of each facet that present the highest correlation with the average score of all facets (The WHOQOL Group, 1998c). After the selection of issues, an analysis was conducted to see if they, factually, represented the corresponding facets. In six facets, the question selected was replaced by another question of the corresponding facet, for, under the bias of experts, there was another question that could best define these six facets (The WHOQOL Group, 1998c). The facets belonging to the domain Level of Independence were incorporated into the Physical domain and the facet belonging to the domain Spiritual / Religion / Personal Beliefs was incorporated into the Psychological domain. Thus, the WHOQOL-bref is composed by four domains: Physical, Psychological, Social Relationships and Environment, completing the configuration expressed in Table 3: Source: The WHOQOL Group (1998c) Table 3. Domains and facets of WHOQOL-bref Quality of Life Assessment in People Symptoms of PLWHA Social Inclusion Forgiveness and Concerns about the Death and Dying Source: Adapted from Zimpel & Fleck (2008) Table 5. Additional questions of WHOQOL-HIV Blame Future FACETS QUESTIONS Living with HIV/AIDS: Clarifying the WHOQOL-HIV and WHOQOL-HIV-Bref Instruments 169 related to your HIV infection? problem? status? others? you when you are dead? How much do you fear the future? How much do you worry about death? destiny bother you? you would want to? health condition? How much are you bothered by any unpleasant physical problems To what extent do you feel any unpleasant physical problems prevent To what extent are you bothered by fears of developing any physical To what extent do you feel accepted by the people you know? How often do you feel you are discriminated against because of your To what extent do you feel accepted by your community? To what extent are you bothered by people blaming you for your HIV To what extent do you feel guilty when you need the help and care of To what extent are you concerned about your HIV status breaking To what extent are you concerned about how people will remember To what extent do any feelings that you are suffering from fate or How bothered are you by the thought of not being able to die the way How concerned are you about how and where you will die? How preoccupied are you about suffering before dying? How much do you feel alienated from those around you? How much do you blame yourself for your HIV infection? How guilty do you feel about being HIV positive? your family line and your future generations? To what extent do you fear possible future (physical) pain? you from doing things that are important to you? The calculation of scores of WHOQOL-bref follows the same logic of WHOQOL-100, except for the calculation of scores of facets. In WHOQOL-bref each facet is represented by a single question, and therefore the scores of facets are not calculated (The WHOQOL Group, 1996).	doab	2025-04-07T04:13:04.703829	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 32 }
ffffc5d2-b312-4a34-bf71-3ead508bdda7.33	3. WHOQOL-HIV Aiming at creating a tool for assessing the quality of life directed to people living with HIV, researchers from the Joint United Nations Program on HIV / AIDS (UNAIDS) and WHO carried out studies in people with HIV in nine different countries. The result of this study was the instrument WHOQOL-HIV, an additional module specifically designed for people with HIV or AIDS (WHO Field Center for the Study of Quality of Life of Bath, 2008). WHOQOL-HIV evaluates the quality of life from six domains and 29 facets. The domains and facets are the same as in WHOQOL-100, with the addition of five specific facets for people living with HIV/AIDS. The facet of WHOQOL-100 that evaluates the quality of life from the perspective of the assessed person, not included in any domain, remains in WHOQOL-HIV. The specific facets for people with HIV, as well as the facets from WHOQOL-100, are composed of four questions (O'Connell et al., 2004). The additional facets of WHOQOL-HIV are: The additional facets of WHOQOL-HIV are included in the domains already existent in WHOQOL-100, featuring the following configuration (Table 4): Source: Adapted from O'Connell et al. (2004) Table 4. Domains and facets exclusive of WHOQOL-HIV Based on the previously mentioned configuration, questions which constitute additional facets of WHOQOL-HIV, with inverted questions written in italics, are: The calculation of scores of WHOQOL-bref follows the same logic of WHOQOL-100, except for the calculation of scores of facets. In WHOQOL-bref each facet is represented by a single question, and therefore the scores of facets are not calculated (The WHOQOL Aiming at creating a tool for assessing the quality of life directed to people living with HIV, researchers from the Joint United Nations Program on HIV / AIDS (UNAIDS) and WHO carried out studies in people with HIV in nine different countries. The result of this study was the instrument WHOQOL-HIV, an additional module specifically designed for people with HIV or AIDS (WHO Field Center for the Study of Quality of Life of Bath, WHOQOL-HIV evaluates the quality of life from six domains and 29 facets. The domains and facets are the same as in WHOQOL-100, with the addition of five specific facets for people living with HIV/AIDS. The facet of WHOQOL-100 that evaluates the quality of life from the perspective of the assessed person, not included in any domain, remains in WHOQOL-HIV. The specific facets for people with HIV, as well as the facets from WHOQOL-100, are composed of four questions (O'Connell et al., 2004). The additional The additional facets of WHOQOL-HIV are included in the domains already existent in Based on the previously mentioned configuration, questions which constitute additional 52. Forgiveness and Blame 54. Death and Dying 53. Concerns about the Future Domain I – Physical 50. Symptoms of PLWHA Domain IV – Social Relationships 51. Social Inclusion WHOQOL-100, featuring the following configuration (Table 4): Domain VI – Spiritual/Religion/Personal Beliefs Table 4. Domains and facets exclusive of WHOQOL-HIV facets of WHOQOL-HIV, with inverted questions written in italics, are: Source: Adapted from O'Connell et al. (2004) DOMAINS FACETS Group, 1996). 2008). 3. WHOQOL-HIV facets of WHOQOL-HIV are: after HIV infection; could present; infection; dying. Source: Adapted from Zimpel & Fleck (2008) Table 5. Additional questions of WHOQOL-HIV Quality of Life Assessment in People COMPUTE Table 6. WHOQOL-HIV syntax inverted; on WHOQOL-HIV syntax. 4. WHOQOL-HIV-bref configuration: ENVIRO+TRANS)/8\4. results of the WHOQOL-HIV are presented as follows: by a division by four, being represented in a scale of 1 to 5; Source: Adapted from The WHOQOL-HIV Group (2002) being represented in a scale of 4 to 20; Living with HIV/AIDS: Clarifying the WHOQOL-HIV and WHOQOL-HIV-Bref Instruments 171 COMPUTE DOMAIN1=(PAIN+ENERGY+SLEEP+SYMPTOM)/4\4. COMPUTE DOMAIN2=(PFEEL+COG+ESTEEM+BODY+NFEEL)/5\4. COMPUTE DOMAIN3=(MOBIL+ADL+DEPEND+WORK)/4\4. COMPUTE DOMAIN4=(RELATIO+SUPPORT+SEX+INCLUSI)/4\4. DOMAIN5=(SAFE+HOME+FINANCE+CARE+INFO+LEISURE+ COMPUTE DOMAIN6=(FORGIVE+FUTURE+DEATH+SRPB)/4\4. The calculation of WHOQOL-HIV results is similar to the method used in WHOQOL-100. However, some criteria used in WHOQOL-100 were not inherited by WHOQOL-HIV. The Contrarily to WHOQOL-100, the scores of domains and facets represent the mean of these variables only when all the belonging items to these are correctly punctuated. The score of facets is calculated since these presents one or more answered question, while the score of domains is calculated since these owns at least one facet that has been scored. The scores are not converted to a 0-100 scale. The exclusion criterion for individuals who answered incorrectly or doesn't answer more than 20% of total items from instrument does not exist Under the same reason for the development of WHOQOL-bref, the WHOQOL Group developed an abbreviated version of WHOQOL-HIV. The WHOQOL-HIV-bref is based on The 26 questions of WHOQOL-bref are repeated in WHOQOL-HIV-bref, being added to these five questions that represent the additional facets of WHOQOL-HIV (The WHOQOL-HIV Group, 2002). Contrary to what occurs in WHOQOL-bref, the facets belonging to the domains Level of Independence and Spiritual/Religion/Personal Beliefs are not incorporated to the Physical and Psychological domains, having, therefore, the same configuration of the domains of WHOQOL-HIV, presenting the following WHOQOL-bref, in a way each facet is represented by one single question. STEPS WHOQOL-HIV SYNTAX COMPUTE DEATH=(F541+F542+F543+F544)/4. COMPUTE GENERAL=(G1+G2+G3+G4)/4. The syntax for calculation of WHOQOL-HIV domain and facets' score, correcting the error reported by Pedroso et al. (2010), is the following: Source: Adapted from The WHOQOL-HIV Group (2002) #### Table 6. WHOQOL-HIV syntax 170 Global View of HIV Infection The syntax for calculation of WHOQOL-HIV domain and facets' score, correcting the error RECODE F11 F12 F13 F14 F21 F22 F23 F24 F31 F32 F33 F34 F501 F502 F503 F504 F41 F42 F43 F44 F51 F52 F53 F54 F61 F62 F63 F64 F71 F72 F73 F74 F81 F82 F83 F84 F91 F92 F93 F94 F101 F102 F103 F104 F111 F112 F113 F114 F121 F122 F123 F124 F131 F132 F133 F134 F141 F142 F143 F144 F151 F152 F153 F154 F511 F512 F513 F514 F161 F162 F163 F164 F171 F172 F173 F174 F181 F182 F183 F184 F191 F192 F193 F194 F201 F202 F203 F204 F211 F212 F213 F214 F221 F222 F223 F224 F231 F232 F233 F234 F241 F242 F243 F244 F521 F522 F523 F524 F531 F532 F533 F534 F541 F542 F543 F544 G1 G2 G3 G4 RECODE F11 F12 F13 F14 F22 F24 F32 F34 F72 F73 F81 F82 F83 F84 F93 F94 F102 F104 F111 F112 F113 F114 F131 F154 F163 F182 F184 F222 F232 F234 F501 F502 F503 F504 F514 F512 F521 F522 F523 F524 F531 F532 F533 F534 F541 F542 F544 F543 (1=5) (2=4) (3=3) (4=2) (5=1) (1=5) (2=4) (3=3) (4=2) reported by Pedroso et al. (2010), is the following: Check all 120 items from assessment have a range of 1- 5 Reverse negatively phrased items Compute facet and domain scores (5=1). STEPS WHOQOL-HIV SYNTAX (1=1) (2=2) (3=3) (4=4) (5=5) (ELSE=SYSMIS). COMPUTE PAIN=(F11+F12+F13+F14)/4. COMPUTE ENERGY=(F21+F22+F23+F24)/4. COMPUTE SLEEP=(F31+F32+F33+F34)/4. COMPUTE PFEEL=(F41+F42+F43+F44)/4. COMPUTE COG=(F51+F52+F53+F54)/4. COMPUTE ESTEEM=(F61+F62+F63+F64)/4. COMPUTE BODY=(F71+F72+F73+F74)/4. COMPUTE NFEEL=(F81+F82+F83+F84)/4. COMPUTE MOBIL=(F91+F92+F93+F94)/4. COMPUTE ADL=(F101+F102+F103+F104)/4. COMPUTE DEPEND=(F111+F112+F113+F114)/4. COMPUTE WORK=(F121+F122+F123+F124)/4. COMPUTE RELATIO=(F131+F132+F133+F134)/4. COMPUTE SUPPORT=(F141+F142+F143+F144)/4. COMPUTE SEX=(F151+F152+F153+F154)/4. COMPUTE INCLUSI=(F511+F512+F513+F514)/4. COMPUTE SAFE=(F161+F162+F163+F164)/4. COMPUTE HOME=(F171+F172+F173+F174)/4. COMPUTE FINANCE=(F181+F182+F183+F184)/4. COMPUTE CARE=(F191+F192+F193+F194)/4. COMPUTE INFO=(F201+F202+F203+F204)/4. COMPUTE LEISURE=(F211+F212+F213+F214)/4. COMPUTE ENVIRO=(F221+F222+F223+F224)/4. COMPUTE TRANS=(F231+F232+F233+F234)/4. COMPUTE SRPB=(F241+F242+F243+F244)/4. COMPUTE FORGIVE=(F521+F522+F523+F524)/4. COMPUTE FUTURE=(F531+F532+F533+F534)/4. COMPUTE SYMPTOM=(F501+F502+F503+F504)/4. The calculation of WHOQOL-HIV results is similar to the method used in WHOQOL-100. However, some criteria used in WHOQOL-100 were not inherited by WHOQOL-HIV. The results of the WHOQOL-HIV are presented as follows: Contrarily to WHOQOL-100, the scores of domains and facets represent the mean of these variables only when all the belonging items to these are correctly punctuated. The score of facets is calculated since these presents one or more answered question, while the score of domains is calculated since these owns at least one facet that has been scored. The scores are not converted to a 0-100 scale. The exclusion criterion for individuals who answered incorrectly or doesn't answer more than 20% of total items from instrument does not exist on WHOQOL-HIV syntax. ## 4. WHOQOL-HIV-bref Under the same reason for the development of WHOQOL-bref, the WHOQOL Group developed an abbreviated version of WHOQOL-HIV. The WHOQOL-HIV-bref is based on WHOQOL-bref, in a way each facet is represented by one single question. The 26 questions of WHOQOL-bref are repeated in WHOQOL-HIV-bref, being added to these five questions that represent the additional facets of WHOQOL-HIV (The WHOQOL-HIV Group, 2002). Contrary to what occurs in WHOQOL-bref, the facets belonging to the domains Level of Independence and Spiritual/Religion/Personal Beliefs are not incorporated to the Physical and Psychological domains, having, therefore, the same configuration of the domains of WHOQOL-HIV, presenting the following configuration: Quality of Life Assessment in People Q30)/8 \4 HIV and WHOQOL-HIV-bref instruments* use and is not for free distribution. statistics of WHOQOL-100. Source: The WHOQOL-HIV Group (2002) Table 8. WHOQOL-HIV-bref syntax Check all 31 items from assessment have a range of 1-5 Reverse negatively phrased items Compute domain scores Living with HIV/AIDS: Clarifying the WHOQOL-HIV and WHOQOL-HIV-Bref Instruments 173 The calculation of WHOQOL-HIV-bref's score then follows a different logic regarding RECODE Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Q14 Q15 Q16 Q17 Q18 Q19 Q20 Q21 Q22 Q23 Q24 Q25 Q26 Q27 Q28 Q29 Q30 Q31 RECODE Q3 Q4 Q5 Q8 Q9 Q10 Q31 (1=5) (2=4) (3=3) (4=2) (5=1). COMPUTE Domain 5 = (Q12 + Q13 + Q16 + Q18 + Q19 + Q28 + Q29 + WHOQOL-bref instrument, consisting of the following command lines: STEPS WHOQOL-HIV-BREF SYNTAX (1=1) (2=2) (3=3) (4=4) (5=5) (ELSE=SYSMIS). COMPUTE Domain 1 = (Q3 + Q4 + Q14 + Q21)/4 \* 4 COMPUTE Domain 2 = (Q6 + Q11 + Q15 + Q24 + Q31)/5 \4 COMPUTE Domain 3 = (Q5 + Q22 + Q23 + Q20)/4 \ 4 COMPUTE Domain 4 = (Q27 +Q26 + Q25 + Q17)/4\4 COMPUTE Domain6 = (Q7 + Q8 + Q9+ Q10)/4 \4 multiplied by four, being represented in a scale of 4 to 20; number of questions higher than 20% from the total instrument items. The WHOQOL-HIV-bref syntax's textual transcription presents the following configuration: As can be realized, just as WHOQOL-HIV, the WHOQOL-HIV-bref's Syntax presents the same present fragility found in WHOQOL-HIV regarding the domains and facets score calculation, because it's not accomplished the arithmetic mean of domain items. There is not also the conversion of domains and facets score for a 0-100 scale. Lastly, and is not existing the criteria of exclusion of individuals who doesn't answer or answered incorrectly a 5. Tools for the calculation of scores and descriptive statistics of WHOQOL- To obtain the results to apply the WHOQOL instruments, WHOQOL Group recommends the use of SPSS software, a statistical software program that requires specific expertise for its Looking for the removal of such limitations, tools were built from the software Microsoft Excel, a software program for broad accessibility, to calculate scores and descriptive statistics for WHOQOL-HIV and for WHOQOL-HIV-bref. Such tools were made in the same manner as the tool developed by Pedroso et al. (2009) to calculate scores and descriptive Source: Adapted from The WHOQOL-HIV Group (2002) Table 7. Questions of WHOQOL-HIV-bref The calculation of WHOQOL-HIV-bref's score then follows a different logic regarding WHOQOL-bref instrument, consisting of the following command lines: Source: The WHOQOL-HIV Group (2002) 172 Global View of HIV Infection doing what you need to do? How much do you enjoy life? despair, anxiety, depression? daily living activities? your day-to-day life? How well are you able to concentrate? How satisfied are you with yourself? H ow well are you able to get around? How satisfied are you with your sex life? How safe do you feel in your daily life? How healthy is your physical environment? Have you enough money to meet your needs? How satisfied are you with your transport? How would you rate your quality of life? How satisfied are you with your health? How much do you fear the future? How much do you worry about death? To what extent do you feel that physical pain prevents you from How much are you bothered by any physical problems related to Do you have enough energy for everyday life? How satisfied are you with your sleep? Are you able to accept your bodily appearance? How often do you have negative feelings such as blue mood, How satisfied are you with your ability to perform your How satisfied are you with your capacity for work? To what extent do you feel accepted by the people you How satisfied are you with your personal relationships? How satisfied are you with the support you get from your How available to you is the information that you need in To what extent do you have the opportunity for leisure How satisfied are you with the conditions of your living To what extent do you feel your life to be meaningful? To what extent are you bothered by people blaming you for your How satisfied are you with your access to health services? How much do you need any medical treatment to function in your DOMAINS QUESTIONS your HIV infection? daily life? know? friends? activities? HIV status? place? Domain I - Physical Domain II - Psychological Domain III – Level of Independence Domain IV – Social Domain V - Environment Domain VI - Spiritual / Religion / Personal Beliefs Overall Quality of Life and General Health Source: Adapted from The WHOQOL-HIV Group (2002) Table 7. Questions of WHOQOL-HIV-bref Perceptions Relations Table 8. WHOQOL-HIV-bref syntax The WHOQOL-HIV-bref syntax's textual transcription presents the following configuration: As can be realized, just as WHOQOL-HIV, the WHOQOL-HIV-bref's Syntax presents the same present fragility found in WHOQOL-HIV regarding the domains and facets score calculation, because it's not accomplished the arithmetic mean of domain items. There is not also the conversion of domains and facets score for a 0-100 scale. Lastly, and is not existing the criteria of exclusion of individuals who doesn't answer or answered incorrectly a number of questions higher than 20% from the total instrument items. #### 5. Tools for the calculation of scores and descriptive statistics of WHOQOL-HIV and WHOQOL-HIV-bref instruments To obtain the results to apply the WHOQOL instruments, WHOQOL Group recommends the use of SPSS software, a statistical software program that requires specific expertise for its use and is not for free distribution. Looking for the removal of such limitations, tools were built from the software Microsoft Excel, a software program for broad accessibility, to calculate scores and descriptive statistics for WHOQOL-HIV and for WHOQOL-HIV-bref. Such tools were made in the same manner as the tool developed by Pedroso et al. (2009) to calculate scores and descriptive statistics of WHOQOL-100. Quality of Life Assessment in People 7. References 9536 0954-0121 1278, ISSN 0954-0121 ISSN 0954-0121 Living with HIV/AIDS: Clarifying the WHOQOL-HIV and WHOQOL-HIV-Bref Instruments 175 Canavarro, M.C. et al. (2011). Quality of life assessment in HIV-infection: validation of the Fleck, M.P.A. (2008). Problemas conceituais em qualidade de vida. In: A avaliação de qualidade Mweemba, P. et al. (2011). Validation of the World Health Organization Quality of Life HIV O'Connell, K. et al. (2003). Preliminary development of the World Health Organization's O'Connell, K. et al. (2004). WHOQOL-HIV for quality of life assessment among people Pedroso, B. et al. (2009). Cálculo dos escores e estatística descritiva do WHOQOL-100 Pedroso, B. et al. (2010). Quality of life assessment in people with HIV: analysis of the Saddki, N. et al. (2009). Validity and reliability of the Malay version of WHOQOL-HIV BREF Skevington, S.M. & O'Connell, K. A. (2003). Measuring Quality of Life in HIV and AIDS: A Starace, F. et al. (2002). Quality of life assessment in HIV-positive persons: application and The WHOQOL Group. (1998a). The World Health Organization Quality of Life assessment Medicine, Vol. 46, No 12, (December 1998), pp. 1569-1585, ISSN 0277-9536 The WHOQOL Group. (1998c). Development of the World Health Organization WHOQOL- The WHOQOL Group. (1996). WHOQOL-bref: introduction, administration, scoring and generic The WHOQOL-HIV Group. (2002). WHOQOL-HIV Instrument Users Manual. Geneva (February 2011), pp. 187-194, ISSN 0954-0121 ISBN 978-85-363-0947-7, Porto Alegre, Brazil (October 2004), pp. 882-889, ISSN 0954-0121 2009), pp. 23-32, ISSN 2175-0858 2002), pp. 405-415, ISSN 0954-0121 pp. 551-558, ISSN 0033-2917 version of assessment. Geneva The WHOQOL Group. (1998b). WHOQOL User Manual. Geneva Vol. 22, No 1, (February 2011), pp. 53-66, ISSN 1055-3290 European Portuguese version of WHOQOL-HIV. AIDS Care, Vol. 23, No 2, de vida: guia para profissionais da saúde, Fleck, M.P.A., et al. (Eds.), pp. 19-28. Artmed, instrument in a Zambian sample. Journal of the Association of Nurses in AIDS Care, Quality of Life HIV instrument (WHOQOL-HIV): analysis of the pilot version. Social & Science Medicine, Vol. 57, No 7, (October 2003), pp. 1259-1275, ISSN 0277- living with HIV and AIDS: results from a field test. AIDS Care, Vol 16, No 7, utilizando o Microsoft Excel. Revista Brasileira de Qualidade de Vida, Vol 1, No 1, (July WHOQOL-HIV syntax. AIDS Care, Vol. 22, No 3, (March 2010), pp. 361,372, ISSN in patients with HIV infection. AIDS Care, Vol. 21, No 10, (October 2009), pp. 1271- Review of the Recent Literature. AIDS Care, Vol. 18, No 3, (June 2003), pp. 331-350, validation of the WHOQOL-HIV, Italian version. AIDS Care, Vol. 14, No 3, (June (WHOQOL): development and general psychometric properties. Social Science & BREF Quality of Life Assessment. Psychological Medicine, Vol. 28, No 3, (May 1998), The tools proposed on this study automatically perform all calculations in the incipient syntaxes provided by the WHOQOL-HIV Group. The researchers who use it need only to fill in the specified cells the answers given by respondents. After data insertion, to use the results of theirs research, researcher may copy the individual scores for each respondent, results of descriptive statistics, and graphics; however, without changing such results. Is allowed to insert and edit values just in the area to tabulate the answers of respondents. To validate such tools, simulations were performed with real data applications of each of the WHOQOL-HIV and WHOQOL-HIV-bref instrument, comparing the results by using the proposed tools with those from SPSS. The results from both software programs were exactly the same, thus ensuring the reliability of tools, which are object of this study. The tools were tested on different versions of the Microsoft Office: 2000, XP, 2003, 2007 and 2010. It was found that they are compatible with all versions tested, without differences in the results. The tools are available for download in the website: http://www.brunopedroso.com.br/whoqol-hiv(en). html. ### 6. Conclusions Although the WHOQOL-HIV and WHOQOL-HIV-bref instruments are respectively additional modules for WHOQOL-100 and WHOQOL-bref instruments, the syntax of these instruments are not entirely derivative from its precursor syntax. Despite the widespread distribution and use of the WHOQOL-HIV and WHOQOL-HIV-bref, the difficulty to interpret the instrument syntax limits in choosing to use such tools. Additionally, the WHOQOL Group interposition in making the syntax to calculate the WHOQOL scores with SPSS (a relatively high cost software program and which requires specific expertise for use) encourages another imbroglio, restricting the use of WHOQOL instruments. Facing this struggle, we here investigate the instruments in question to facilitate their interpretation and use. Looking for the removal of the previously described limitations, the syntaxes are transcribed textually, detailing all the steps used to obtain the results from WHOQOL-HIV and WHOQOL-HIV-bref instrument. Were also built tools from Microsoft Excel 2003 software to calculate the scores and descriptive statistics of such instruments, in which the researcher is responsible only for data tabulation. The calculation is carried out automatically. The developed tools were tested and proved compatible in the versions 2000, XP, 2007 and 2010 of Microsoft Excel. The results returned by the tools were compared by using real application data of WHOQOL-HIV and WHOQOL-HIV-bref instruments, with the results returned by SPSS, following the parameters established by the WHOQOL-HIV Group. The results were identical to both instruments. We conclude that, despite being globally disseminated instruments, developed under a rigorous methodology, the instruments produced by the WHOQOL-HIV Group show limitations. Expecting to facilitate its use, was made an approach with a focus on clarifying these instruments. In this wise, we aimed to enable greater accessibility of the results promoted by the instruments, object of study here, thus expanding the investigation involving QoL empirical reality of people living with HIV/AIDS. ## 7. References 174 Global View of HIV Infection The tools proposed on this study automatically perform all calculations in the incipient syntaxes provided by the WHOQOL-HIV Group. The researchers who use it need only to After data insertion, to use the results of theirs research, researcher may copy the individual scores for each respondent, results of descriptive statistics, and graphics; however, without changing such results. Is allowed to insert and edit values just in the area to tabulate the To validate such tools, simulations were performed with real data applications of each of the WHOQOL-HIV and WHOQOL-HIV-bref instrument, comparing the results by using the proposed tools with those from SPSS. The results from both software programs were exactly The tools were tested on different versions of the Microsoft Office: 2000, XP, 2003, 2007 and 2010. It was found that they are compatible with all versions tested, without differences in the results. The tools are available for download in the website: Although the WHOQOL-HIV and WHOQOL-HIV-bref instruments are respectively additional modules for WHOQOL-100 and WHOQOL-bref instruments, the syntax of these instruments are not entirely derivative from its precursor syntax. Despite the widespread distribution and use of the WHOQOL-HIV and WHOQOL-HIV-bref, the difficulty to Additionally, the WHOQOL Group interposition in making the syntax to calculate the WHOQOL scores with SPSS (a relatively high cost software program and which requires specific expertise for use) encourages another imbroglio, restricting the use of WHOQOL Facing this struggle, we here investigate the instruments in question to facilitate their interpretation and use. Looking for the removal of the previously described limitations, the syntaxes are transcribed textually, detailing all the steps used to obtain the results from WHOQOL-HIV and WHOQOL-HIV-bref instrument. Were also built tools from Microsoft Excel 2003 software to calculate the scores and descriptive statistics of such instruments, in which the researcher is responsible only for data tabulation. The calculation is carried out The developed tools were tested and proved compatible in the versions 2000, XP, 2007 and 2010 of Microsoft Excel. The results returned by the tools were compared by using real application data of WHOQOL-HIV and WHOQOL-HIV-bref instruments, with the results returned by SPSS, following the parameters established by the WHOQOL-HIV Group. The We conclude that, despite being globally disseminated instruments, developed under a rigorous methodology, the instruments produced by the WHOQOL-HIV Group show limitations. Expecting to facilitate its use, was made an approach with a focus on clarifying these instruments. In this wise, we aimed to enable greater accessibility of the results promoted by the instruments, object of study here, thus expanding the investigation the same, thus ensuring the reliability of tools, which are object of this study. fill in the specified cells the answers given by respondents. http://www.brunopedroso.com.br/whoqol-hiv(en). html. interpret the instrument syntax limits in choosing to use such tools. involving QoL empirical reality of people living with HIV/AIDS. answers of respondents. 6. Conclusions instruments. automatically. results were identical to both instruments. WHO Field Center for the Study of Quality of Life of Bath. (2008). About the WHO Field Zimpel, R & Fleck, M.P.A. (2008). WHOQOL-HIV: desenvolvimento, aplicação e validação. (Eds.), pp. 83-92. Artmed, ISBN 978-85-363-0947-7, Porto Alegre, Brazil 20.09.2008 Available from http://www.bath.ac.uk/whoqol/about.cfm Zimpel, R. & Fleck, M.P.A. (2007) Quality of life in HIV-positive Brazilians: application and (August 2007), pp. 923-930, ISSN 0954-0121 Center for the Study of Quality of Life. In: University of Bath. Retrieved on validation of the WHOQOL-HIV, Brazilian version. AIDS Care, Vol. 19, No 7, In: A avaliação de qualidade de vida: guia para profissionais da saúde, Fleck, M.P.A., et al. Edited by Vishwanath Venketaraman Some of the topics covered in this book are: HIV infection, HIV transmission, Clinical symptoms of AIDS, AIDS and opportunistic infection, Prevention and treatment of HV, Treatment of HIV infection and immune reconstitution Photo by xrender / iStock Global View of HIV Infection Global View of HIV Infection Edited by Vishwanath Venketaraman	doab	2025-04-07T04:13:04.704564	20-4-2021 17:12	{ "license": "Creative Commons - Attribution - https://creativecommons.org/licenses/by/3.0/", "book_id": "ffffc5d2-b312-4a34-bf71-3ead508bdda7", "url": "https://mts.intechopen.com/storage/books/633/authors_book/authors_book.pdf", "author": "", "title": "Global View of HIV Infection", "publisher": "IntechOpen", "isbn": "9789533076713", "section_idx": 33 }

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