title: Naachiyaar

text: In February 2017, Bala confirmed that his next project would be a crime thriller starring Jyothika in the lead role, and chose to postpone the shoot of a proposed film featuring Yuvan and Pragathi Guruprasad. To accommodate dates for the film, Jyothika opted out of her commitments to play a role alongside Vijay in "Mersal" (2017). The film was reported to be set in the slums, with actor Sri signed to portray another leading character. Bala later replaced Sri with G. V. Prakash Kumar, who agreed to work on the film simultaneously with several other projects. Film producer Rockline Venkatesh also joined the cast to play a supporting role, after Bala spontaneously enquired about his interest in working as an actor. Malayalam actress Ivana was cast in a role after Bala had spotted a news article about her work in the film, "Anuraga Karikkin Vellam" (2016). He requested her to find a new stage name rather than use her original name of Aleena Shaji, prompting her to use Ivana. Prior to release, the media reported that the story was based on the life of psycho killer Jayaprakash, who killed nine of his relatives in the 1980s at Valasaravakkam, Chennai.


title: Naachiyaar

text: The principal shoot of the film began in March 2017, with a first look poster released featuring Jyothika and G. V. Prakash Kumar. As Prakash Kumar was working simultaneously on four other projects, he requested some time before starting the shoot. Instead of delaying the project, Bala worked solely on Jyothika's scenes to ensure the film was shot within the projected time of forty days. By the time he joined the set, Prakash Kumar reported to sets by 6 am every day, took an hour to put three layers of dark make-up and coloured his hair to a brownish-orange colour. Unlike several of Bala's previous films, "Naachiyar" completed production quickly and by early July 2017, "ninety percent" of the shoot was revealed to be over, with most scenes filmed in North Chennai and studios in the city. The shoot of the film was completed in mid-July 2017 in the Cuddalore district. Jyothika dubbed for the role herself and Bala wanted a base voice from the actress, so sat throughout the dubbing to get the desired output. Jyothika had earlier changed her diet plans by avoiding rice, wheat and bread to reduce nearly 10 kilograms for her work in "Naachiyaar".


title: Naachiyaar

text: Following the release of a teaser trailer, a man named Rajan from Mettupalayam filed legal case over the use of vulgar language in the teaser. Jyothika later stated that such outrage was only registered because a woman had spoken the dialogue and that the dialogue was a necessity in the film.


title: Naachiyaar

text: The soundtrack features one song composed by Ilaiyaraaja. As the album featured only one song, Bala opted against releasing the soundtrack of the film prior to its release.


title: Naachiyaar

text: Upon release, the film received positive response from both critics and audience. As a result the film was dubbed and released in Hindi as "Tejasvini 2" in 2020 and in Telugu as "Jhansi".


title: Small interfering RNA

text: Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation.


title: Small interfering RNA

text: Naturally occurring siRNAs have a well-defined structure that is a short (usually 20 to 24-bp) double-stranded RNA (dsRNA) with phosphorylated 5' ends and hydroxylated 3' ends with two overhanging nucleotides.


title: Small interfering RNA

text: The Dicer enzyme catalyzes production of siRNAs from long dsRNAs and small hairpin RNAs. siRNAs can also be introduced into cells by transfection. Since in principle any gene can be knocked down by a synthetic siRNA with a complementary sequence, siRNAs are an important tool for validating gene function and drug targeting in the post-genomic era.


title: Small interfering RNA

text: In 1998, Andrew Fire at Carnegie Institution for Science in Washington DC and Craig Mello at University of Massachusetts in Worcester discovered the RNAi mechanism while working on the gene expression in the nematode, "Caenorhabditis elegans". They won the Nobel prize for their research with RNAi in 2006. siRNAs and their role in post-transcriptional gene silencing(PTGS) was discovered in plants by David Baulcombe's group at the Sainsbury Laboratory in Norwich, England and reported in "Science" in 1999. Thomas Tuschl and colleagues soon reported in "Nature" that synthetic siRNAs could induce RNAi in mammalian cells. In 2001, the expression of a specific gene was successfully silenced by introducing chemically synthesized siRNA into mammalian cells (Tuschl et al.) These discoveries led to a surge in interest in harnessing RNAi for biomedical research and drug development. Significant developments in siRNA therapies have been made with both organic (carbon based) and inorganic (non-carbon based) nanoparticles, which have been successful in drug delivery to the brain, offering promising methods to deliver therapeutics into human subjects. However, human applications of siRNA have had significant limitations to its success. One of these being off-targeting. There is also a possibility that these therapies can trigger innate immunity. Animal models have not been successful in accurately representing the extent of this response in humans. Hence, studying the effects of siRNA therapies has been a challenge.


title: Small interfering RNA

text: In recent years, siRNA therapies have been approved and new methods have been established to overcome these challenges. There are approved therapies available for commercial use and several currently in the pipeline waiting to get approval.


title: Small interfering RNA

text: The mechanism by which natural siRNA causes gene silencing through repression of translation occurs as follows:


title: Small interfering RNA

text: siRNA is also similar to miRNA, however, miRNAs are derived from shorter stemloop RNA products. miRNAs typically silence genes by repression of translation and have broader specificity of action, while siRNAs typically work with higher specificity by cleaving the mRNA before translation, with 100% complementarity.


title: Small interfering RNA

text: Gene knockdown by transfection of exogenous siRNA is often unsatisfactory because the effect is only transient, especially in rapidly dividing cells. This may be overcome by creating an expression vector for the siRNA. The siRNA sequence is modified to introduce a short loop between the two strands. The resulting transcript is a short hairpin RNA (shRNA), which can be processed into a functional siRNA by Dicer in its usual fashion. Typical transcription cassettes use an RNA polymerase III promoter (e.g., U6 or H1) to direct the transcription of small nuclear RNAs (snRNAs) (U6 is involved in RNA splicing; H1 is the RNase component of human RNase P). It is theorized that the resulting siRNA transcript is then processed by Dicer.


title: Small interfering RNA

text: The activity of siRNAs in RNAi is largely dependent on its binding ability to the RNA-induced silencing complex (RISC). Binding of the duplex siRNA to RISC is followed by unwinding and cleavage of the sense strand with endonucleases. The remaining anti-sense strand-RISC complex can then bind to target mRNAs for initiating transcriptional silencing.


title: Small interfering RNA

text: It has been found that dsRNA can also activate gene expression, a mechanism that has been termed "small RNA-induced gene activation" or RNAa. It has been shown that dsRNAs targeting gene promoters induce potent transcriptional activation of associated genes. RNAa was demonstrated in human cells using synthetic dsRNAs, termed "small activating RNAs" (saRNAs). It is currently not known how conserved RNAa is in other organisms. One report in the "Aedes aegypti" mosquito has shown there is some evidence for RNAa and can be achieved by short or long dsRNAs targeting promoter regions.


title: Small interfering RNA

text: The siRNA-induced post transcriptional gene silencing is initiated by the assembly of the RNA-induced silencing complex (RISC). The complex silences certain gene expression by cleaving the mRNA molecules coding the target genes. To begin the process, one of the two siRNA strands, the guide strand (anti-sense strand), will be loaded into the RISC while the other strand, the passenger strand (sense strand), is degraded. Certain Dicer enzymes may be responsible for loading the guide strand into RISC. Then, the siRNA scans for and directs RISC to perfectly complementary sequence on the mRNA molecules. The cleavage of the mRNA molecules is thought to be catalyzed by the Piwi domain of Argonaute proteins of the RISC. The mRNA molecule is then cut precisely by cleaving the phosphodiester bond between the target nucleotides which are paired to siRNA residues 10 and 11, counting from the 5'end. This cleavage results in mRNA fragments that are further degraded by cellular exonucleases. The 5' fragment is degraded from its 3' end by exosome while the 3' fragment is degraded from its 5' end by 5' -3' exoribonuclease 1(XRN1). Dissociation of the target mRNA strand from RISC after the cleavage allow more mRNA to be silenced. This dissociation process is likely to be promoted by extrinsic factors driven by ATP hydrolysis.


title: Small interfering RNA

text: Sometimes cleavage of the target mRNA molecule does not occur. In some cases, the endonucleolytic cleavage of the phosphodiester backbone may be suppressed by mismatches of siRNA and target mRNA near the cleaving site. Other times, the Argonaute proteins of the RISC lack endonuclease activity even when the target mRNA and siRNA are perfectly paired. In such cases, gene expression will be silenced by an miRNA induced mechanism instead


title: Small interfering RNA

text: Piwi-interacting RNAs are responsible for the silencing of transposons and are not siRNAs. PIWI-interacting RNAs (piRNAs) are a recently-discovered class of small non-coding RNAs (ncRNAs) with a length of 21-35 nucleotides. They play a role in gene expression regulation, transposon silencing, and viral infection inhibition. Once considered as “dark matter” of ncRNAs, piRNAs emerged as important players in multiple cellular functions in different organisms.


title: Small interfering RNA

text: Many model organism, such as plants (Arabidopsis thaliana), yeast (Saccharomyces cerevisiae ), flies (Drosophila melanogaster) and worms (C. elegans), have been used to study small non coding RNA-directed Transcriptional gene silencing. In human cell, RNA-directed transcriptional gene silencing was observed a decade ago when exogenous siRNAs silenced a transgenic elongation factor 1 α promoter driving a Green Fluorescent Protein (GFP) reporter gene.


title: Small interfering RNA

text: The main mechanisms of transcriptional gene silencing (TGS) involving the RNAi machinery include DNA methylation, histone post-translational modifications, and subsequent chromatin remodeling around the target gene into a heterochromatic state.


title: Small interfering RNA

text: SiRNAs can be incorporated into a RNA-induced transcriptional silencing (RITS) complex. An active RITS complex will trigger the formation of heterochromatin around DNA matching the siRNA, effectively silencing the genes in that region of the DNA.


title: Small interfering RNA

text: One of the potent applications of siRNAs is the ability to distinguish the target versus non-target sequence with a single-nucleotide difference. This approach has been considered as therapeutically crucial for the silencing dominant gain-of-function (GOF) disorders,where mutant allele causing disease is differed from wt-allele by a single nucleotide (nt). These types of siRNAs with the capability to distinguish a single-nt difference, are termed as, allele-specific siRNAs.


title: Small interfering RNA

text: ASP-RNAi is an innovative category of RNAi with the objective of suppressing the dominant mutant allele while sparing expression of the corresponding normal allele with the specificity of single-nucleotide differences between the two. ASP-siRNAs are potentially a novel and better remedial alternative for the treatment of autosomal dominant genetic disorders especially in cases where wild-type allele expression is crucial for organism survival such as Huntington disease (HD),DYT1 dystonia (Gonzalez-Alegre et al. 2003, 2005), Alzheimer’s disease (Sierant et al. 2011), Parkinson’s disease (PD) (Takahashi et al. 2015), amyloid lateral sclerosis (ALS) (Schwarz et al. 2006), and Machado–Joseph disease (Alves et al. 2008). Their therapeutic potential has also been assessed for various skin disorders like epidermolysis bullosa simplex (Atkinson et al. 2011), epidermolytic palmoplantar keratoderma (EPPK) (Lyu et al. 2016), and lattice corneal dystrophy type I (LCDI) (Courtney et al. 2014).


title: Small interfering RNA

text: RNAi intersects with a number of other pathways; it is not surprising that on occasion, nonspecific effects are triggered by the experimental introduction of an siRNA. When a mammalian cell encounters a double-stranded RNA such as an siRNA, it may mistake it as a viral by-product and mount an immune response. Furthermore, because structurally related microRNAs modulate gene expression largely via incomplete complementarity base pair interactions with a target mRNA, the introduction of an siRNA may cause unintended off-targeting. Chemical modifications of siRNA may alter the thermodynamic properties that also result in a loss of single nucleotide specificity.


title: Small interfering RNA

text: Introduction of too many siRNA can result in nonspecific events due to activation of innate immune responses. Most evidence to date suggests that this is probably due to activation of the dsRNA sensor PKR, although retinoic acid-inducible gene I (RIG-I) may also be involved. The induction of cytokines via toll-like receptor 7 (TLR7) has also been described. Chemical modification of siRNA is employed to reduce in the activation of the innate immune response for gene function and therapeutic applications. One promising method of reducing the nonspecific effects is to convert the siRNA into a microRNA. MicroRNAs occur naturally, and by harnessing this endogenous pathway it should be possible to achieve similar gene knockdown at comparatively low concentrations of resulting siRNAs. This should minimize nonspecific effects.


title: Small interfering RNA

text: Off-targeting is another challenge to the use of siRNAs as a gene knockdown tool. Here, genes with incomplete complementarity are inadvertently downregulated by the siRNA (in effect, the siRNA acts as a miRNA), leading to problems in data interpretation and potential toxicity. This, however, can be partly addressed by designing appropriate control experiments, and siRNA design algorithms are currently being developed to produce siRNAs free from off-targeting. Genome-wide expression analysis, e.g., by microarray technology, can then be used to verify this and further refine the algorithms. A 2006 paper from the laboratory of Dr. Khvorova implicates 6- or 7-basepair-long stretches from position 2 onward in the siRNA matching with 3'UTR regions in off-targeted genes. The tool of siRNA off-target predition is available at http://crdd.osdd.net/servers/aspsirna/asptar.php and published as ASPsiRNA resource.


title: Small interfering RNA

text: Plain RNAs may be poor immunogens, but antibodies can easily be created against RNA-protein complexes. Many autoimmune diseases see these types of antibodies. There haven't yet been reports of antibodies against siRNA bound to proteins. Some methods for siRNA delivery adjoin polyethylene glycol (PEG) to the oligonucleotide reducing excretion and improving circulating half-life. However recently a large Phase III trial of PEGylated RNA aptamer against factor IX had to be discontinued by Regado Biosciences because of a severe anaphylactic reaction to the PEG part of the RNA. This reaction led to death in some cases and raises significant concerns about siRNA delivery when PEGylated oligonucleotides are involved.


title: Small interfering RNA

text: siRNAs transfection into cells typically lowers the expression of many genes, however, the upregulation of genes is also observed. The upregulation of gene expression can partially be explained by the predicted gene targets of endogenous miRNAs. Computational analyses of more than 150 siRNA transfection experiments support a model where exogenous siRNAs can saturate the endogenous RNAi machinery, resulting in the de-repression of endogenous miRNA-regulated genes. Thus, while siRNAs can produce unwanted off-target effects, i.e. unintended downregulation of mRNAs via a partial sequence match between the siRNA and target, the saturation of RNAi machinery is another distinct nonspecific effect, which involves the de-repression of miRNA-regulated genes and results in similar problems in data interpretation and potential toxicity.


title: Small interfering RNA

text: siRNAs have been chemically modified to enhance their therapeutic properties, Short interfering RNA (siRNA) must be delivered to the site of action in the cells of target tissues in order for RNAi to fulfill its therapeutic promise. A detailed database of all such chemical modifications is manually curated as siRNAmod in scientific literature. Chemical modification of siRNA can also inadvertently result in loss of single-nucleotide specificity.


title: Small interfering RNA

text: Given the ability to knock down, in essence, any gene of interest, RNAi via siRNAs has generated a great deal of interest in both basic and applied biology.


title: Small interfering RNA

text: One of the biggest challenges to siRNA and RNAi based therapeutics is intracellular delivery. siRNA also has weak stability and pharmacokinetic behavior. Delivery of siRNA via nanoparticles has shown promise. siRNA oligos in vivo are vulnerable to degradation by plasma and tissue endonucleases and exonucleases and have shown only mild effectiveness in localized delivery sites, such as the human eye. Delivering pure DNA to target organisms is challenging because its large size and structure prevents it from diffusing readily across membranes. siRNA oligos circumvent this problem due to their small size of 21-23 oligos. This allows delivery via nano-scale delivery vehicles called nanovectors.


title: Small interfering RNA

text: A good nanovector for siRNA delivery should protect siRNA from degradation, enrich siRNA in the target organ and facilitate the cellular uptake of siRNA. The three main groups of siRNA nanovectors are: lipid based, non-lipid organic-based, and inorganic. Lipid based nanovectors are excellent for delivering siRNA to solid tumors, but other cancers may require different non-lipid based organic nanovectors such as cyclodextrin based nanoparticles.


title: Small interfering RNA

text: siRNAs delivered via lipid based nanoparticles have been shown to have therapeutic potential for central nervous system (CNS) disorders. Central nervous disorders are not uncommon, but the blood brain barrier (BBB) often blocks access of potential therapeutics to the brain. siRNAs that target and silence efflux proteins on the BBB surface have been shown to create an increase in BBB permeability. siRNA delivered via lipid based nanoparticles is able to cross the BBB completely.


title: Small interfering RNA

text: A huge difficulty in siRNA delivery is the problem of off-targeting. Since genes are read in both directions, there exists a possibility that even if the intended antisense siRNA strand is read and knocks out the target mRNA, the sense siRNA strand may target another protein involved in another function.


title: Small interfering RNA

text: Phase I results of the first two therapeutic RNAi trials (indicated for age-related macular degeneration, aka AMD) reported at the end of 2005 that siRNAs are well tolerated and have suitable pharmacokinetic properties.


title: Small interfering RNA

text: In a phase 1 clinical trial, 41 patients with advanced cancer metastasised to liver were administered RNAi delivered through lipid nanoparticles. The RNAi targeted two genes encoding key proteins in the growth of the cancer cells, vascular endothelial growth factor, (VEGF), and kinesin spindle protein (KSP). The results showed clinical benefits, with the cancer either stabilized after six months, or regression of metastasis in some of the patients. Pharmacodynamic analysis of biopsy samples from the patients revealed the presence of the RNAi constructs in the samples, proving that the molecules reached the intended target.


title: Small interfering RNA

text: Proof of concept trials have indicated that Ebola-targeted siRNAs may be effective as post-exposure prophylaxis in humans, with 100% of non-human primates surviving a lethal dose of Zaire Ebolavirus, the most lethal strain.


title: Small interfering RNA

text: Currently, SiRNA are currently chemically synthesized and so, are legally categorized inside EU and in USA as simple medicinal products. But as bioengineered siRNA (BERAs) are in development, these would be classified as biological medicinal products, at least in EU. The development of the BERAs technology raises the question of the categorization of drugs having the same mechanism of action but being produced chemically or biologically. This lack of consistency should be adressed.


title: Small interfering RNA

text: There is great potential for RNA interference (RNAi) to be used therapeutically to reversibly silence any gene. For RNAi to realize its therapeutic potential, small interfering RNA (siRNA) must be delivered to the site of action in the cells of target tissues. But finding safe and efficient delivery mechanisms is a major obstacle to achieving the full potential of siRNA-based therapies.  Unmodified siRNA is unstable in the bloodstream, has the potential to cause immunogenicity, and has difficulty readily navigating cell membranes.  As a result, chemical alterations and/or delivery tools are needed to safely transfer siRNA to its site of action.


title: Small interfering RNA

text: In this technique siRNA first must be designed against the target gene. Once the siRNA is configured against the gene it has to be effectively delivered through a transfection protocol. Delivery is usually done by cationic liposomes, polymer nanoparticles, and lipid conjugation. This method is advantageous because it can deliver siRNA to most types of cells, has high efficiency and reproducibility, and is offered commercially. The most common commercial reagents for transfection of siRNA are Lipofectamine and Neon Transfection. However, it is not compatible with all cell types and has low in vivo efficiency.


title: Small interfering RNA

text: Electrical pulses are also used to intracellularly deliver siRNA into cells. The cell membrane is made of phospholipids which makes it susceptible to an electric field. When quick but powerful electrical pulses are initiated the lipid molecules reorient themselves, while undergoing thermal phase transitions because of heating. This results in the making of hydrophilic pores and localized perturbations in the lipid bilayer cell membrane also causing a temporary loss of semipermeability. This allows for the escape of many intracellular contents, such as ions and metabolites as well as the simultaneous uptake of drugs, molecular probes, and nucleic acids. For cells that are difficult to transfect electroporation is advantageous however cell death is more probable under this technique.


title: Small interfering RNA

text: This method has been used to deliver siRNA targeting VEGF into the xenografted tumors in nude mice, which resulted in a significant suppression of tumor growth.


title: Small interfering RNA

text: The gene silencing effects of transfected designed siRNA are generally transient, but this difficulty can be overcome through an RNAi approach. Delivering this siRNA from DNA templates can be done through several recombinant viral vectors based on retrovirus, adeno-associated virus, adenovirus, and lentivirus. The latter is the most efficient virus that stably delivers siRNA to target cells as it can transduce nondividing cells as well as directly target the nucleus. These specific viral vectors have been synthesized to effectively facilitate siRNA that is not viable for transfection into cells. Another aspect is that in some cases synthetic viral vectors can integrate siRNA into the cell genome which allows for stable expression of siRNA and long-term gene knockdown. This technique is advantageous because it is in vivo and effective for difficult to transfect cell. However problems arise because it can trigger antiviral responses in some cell types leading to mutagenic and immunogenic effects.


title: Small interfering RNA

text: This method has potential use in gene silencing of the central nervous system for the treatment of Huntington's disease.


title: Small interfering RNA

text: A decade after the discovery of RNAi mechanism in 1993, the pharmaceutical sector heavily invested in the research and development of siRNA therapy. There are several advantages that this therapy has over small molecules and antibodies. It can be administered quarterly or every six months. Another advantage is that, unlike small molecule and monoclonal antibodies that need to recognize specific conformation of a protein, siRNA functions by Watson-Crick basepairing with mRNA. Therefore, any target molecule that needs to be treated with high affinity and specificity can be selected if the right nucleotide sequence is available. One of the biggest challenges researchers needed to overcome was the identification and establishment of a delivery system through which the therapies would enter the body. And that the immune system often mistakes the RNAi therapies as remnants of infectious agents, which can trigger an immune response. Animal models did not accurately represent the degree of immune response that was seen in humans and despite the promise in the treatment investors divested away from RNAi.


title: Small interfering RNA

text: However, there were a few companies that continued with the development of RNAi therapy for humans. Alnylam Pharmaceuticals, Sirna Therapeutics and Dicerna Pharmaceuticals are few of the companies still working on bringing RNAi therapies to market. It was learned that almost all siRNA therapies administered in the bloodstream accumulated in the liver. That is why most of the early drug targets were diseases that affected the liver. Repeated developmental work also shed light on improving the chemical composition of the RNA molecule to reduce the immune response, subsequently causing little to no side effects. Listed below are some of approved therapies or therapies in pipeline.


title: Small interfering RNA

text: In 2018, Alnylam Pharmaceuticals became the first company to have a siRNA therapy approved by the FDA. Onpattro (patisiran) was approved for the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. hATTR is a rare, progressively debilitating condition. During hATTR amyloidosis, misfolded transthyretin (TTR) protein is deposited in the extracellular space. Under typical folding conditions, TTR tetramers are made up of four monomers. Hereditary ATTR amyloidosis is caused by a fault or mutation in the transthyretin (TTR) gene which is inherited. Changing just one amino-acid changes the tetrameric transthyretin proteins, resulting in unstable tetrameric transthyretin protein that aggregates in monomers and forms insoluble extracellular amyloid deposits. Amyloid buildup in various organ systems causes cardiomyopathy, polyneuropathy, gastrointestinal dysfunction. It affects 50,000 people worldwide. To deliver the drug directly to the liver, siRNA is encased in a lipid nanoparticle. The siRNA molecule halts the production of amyloid proteins by interfering with the RNA production of abnormal TTR proteins. This prevents the accumulation of these proteins in different organs of the body and helps the patients manage this disease.


title: Small interfering RNA

text: Traditionally, liver transplantation has been the standard treatment for hereditary transthyretin amyloidosis, however its effectiveness may be limited by the persistent deposition of wild-type transthyretin amyloid after transplantation. There are also small molecule medications that provide temporary relief. Before Onpattro was released, the treatment options for hATTR were limited. After the approval of Onpattro, FDA awarded Alnylam with the Breakthrough Therapy Designation, which is given to drugs that are intended to treat a serious condition and are a substantial improvement over any available therapy. It was also awarded Orphan Drug Designations given to those treatments that are intended to safely treat conditions affecting less than 200,000 people.


title: Small interfering RNA

text: Along with Onpattro, another RNA interference therapeutic drug has also been discovered (Partisiran) which has property of inhibiting hepatic synthesis of transthyretin. Target messenger RNA (mRNA) is cleaved as a result by tiny interfering RNAs coupled to the RNA-induced silencing complex. Patisiran, an investigational RNAi therapeutic drug, uses this process to decrease the production of mutant and wild-type transthyretin by cleaving on 3-untranslated region of transthyretin mRNA.


title: Small interfering RNA

text: In 2019, FDA approved the second RNAi therapy, Givlaari (givosiran) used to treat acute hepatic porphyria (AHP). The disease is caused due to the accumulation of toxic porphobilinogen (PBG) molecules which are formed during the production of heme. These molecules accumulate in different organs and this can lead to the symptoms or attacks of AHP.


title: Small interfering RNA

text: Givlaari is an siRNA drug that downregulates the expression of aminolevulinic acid synthase 1 (ALAS1), a liver enzyme involved in an early step in heme production. The downregulation of ALAS1 lowers the levels of neurotoxic intermediates that cause AHP symptoms.


title: Small interfering RNA

text: Years of research has led to a greater understanding of siRNA therapies beyond those affecting the liver. Alnylam Pharmaceuticals is currently involved in therapies that may treat amyloidosis and CNS disorders like Huntington's disease and Alzheimer's disease. They have also recently partnered with Regeneron Pharmaceuticals to develop therapies for CNS, eye and liver diseases.


title: Small interfering RNA

text: As of 2020, ONPATTRO and GIVLAARI, are available for commercial application, and two siRNAs, lumasiran (ALN-GO1) and inclisiran, have been submitted for new drug application to the FDA. Several siRNAs are undergoing phase 3 clinical studies, and more candidates are in the early developmental stage. In 2020, Alnylam and Vir pharmaceuticals announced a partnership and have started working on a RNAi therapy that would treat severe cases of COVID-19.


title: Small interfering RNA

text: Other companies that have had success in developing a pipeline of siRNA therapies are Dicerna Pharmaceuticals, partnered with Eli Lily and Arrowhead Pharmaceuticals partnered with Johnson and Johnson. Several other big pharmaceutical companies such as Amgen and AstraZeneca have also invested heavily in siRNA therapies as they see the potential success of this area of biological drugs.


title: Treehouse of Horror

text: Treehouse of Horror is an annual series of special Halloween-themed episodes of the animated sitcom "The Simpsons", with 33 anthology episodes between 1990 and 2022. Also known as The Simpsons Halloween Specials, each episode typically consists of three separate, self-contained segments. Each segment involves the Simpson family in some comical horror, science fiction, or supernatural setting; plot elements operate beyond the show's normal continuity, with segments exaggeratedly more morbid and violent than a typical "Simpsons" episode.


title: Treehouse of Horror

text: The eponymous first installment "Treehouse of Horror" aired October 25, 1990, during the second season, broadly inspired by EC Comics horror tales. In addition to parodies of horror, science fiction, and fantasy films, episodes include the recurring alien characters Kang and Kodos, unique opening sequences, and "scary" pseudonyms in the credits. "Treehouse of Horror" episodes have earned high ratings and broad popularity, spawning a steady stream of merchandise.


title: Treehouse of Horror

text: "Treehouse of Horror" episodes typically consist of four parts: an opening and Halloween-themed version of the credits, followed by three segments. These segments usually have a horror, science fiction or fantasy theme and quite often are parodies of films, novels, plays, television shows, "Twilight Zone" episodes, or old issues of EC Comics. Although they are sometimes connected by "wraparounds", the three segments rarely have any kind of continuing connection within the episode. Some have recurring elements, such as "Treehouse of Horror V", in which Groundskeeper Willie is killed by an axe in a similar fashion in all three segments. The episodes are considered to be non-canon, which means they always take place outside the normal continuity of the show, since each character appears to be fine afterwards.


title: Treehouse of Horror

text: From "Treehouse of Horror" to "Treehouse of Horror XIII" and resuming with Treehouse of Horror XXXIII all three segments were written by different writers. In some cases there was a fourth writer who wrote the opening and wraparound segments. For the original "Treehouse of Horror", there were three different directors for the episode. Starting with season 15's "Treehouse of Horror XIV", however, only one writer has been credited with writing each "Treehouse of Horror" episode.


title: Treehouse of Horror

text: On occasion, the episodes will be used to showcase special animation, such as the "Treehouse of Horror VI" segment "Homer", in which a computer-animated Homer is shown in a non-animated setting. At the time (1995), it was groundbreaking, as it was unusual for a television show to use such animation. The segment was executive producer Bill Oakley's idea and included live action directed by David Mirkin. "Treehouse of Horror XX" included the segment "There's No Business Like Moe Business", which was the first to be musically themed.


title: Treehouse of Horror

text: Every "Treehouse of Horror" episode opens with a special introductory segment. The first, second, and fifth "Treehouse of Horror" episodes open with Marge standing on a stage and warning parents about the content of the episode, advising them to put their children to bed. The warning in the first episode was put in as a sincere effort to warn young viewers, as the producers felt it was somewhat scary. The entire segment was a parody of Edward Van Sloan's pre-credits warning from the 1931 film "Frankenstein". Marge's warnings quickly became a burden to write, particularly because – as she herself noted – they were mostly ignored, so after "Treehouse of Horror V", they were dropped. The segment returned in the season 31 episode "Thanksgiving of Horror".


title: Treehouse of Horror

text: Other "Treehouse of Horror" episodes have opened with parodies; for example, "Treehouse of Horror III" had Homer introduce the episode in a manner similar to Alfred Hitchcock in "Alfred Hitchcock Presents", "Treehouse of Horror IV" had Bart introduce the episode and segments in a manner similar to "Night Gallery", and "Treehouse of Horror V" featured a parody of "The Outer Limits". The sixth and seventh episodes featured short clips with no lines because the episodes had run long, and longer segments were cut. Following "Treehouse of Horror VII", the opening has been upwards of a minute long and sometimes featured an introduction by a character, such as Mr. Burns in "Treehouse of Horror XVII" or included over-the-top violence, such as "Treehouse of Horror VIII" (which showed a Fox Network censor being brutally murdered) and "Treehouse of Horror XIV" (which showed the Simpson family killing each other).


title: Treehouse of Horror

text: In the opening segment of the first five episodes, the camera zooms through a cemetery where tombstones with humorous epitaphs can be seen. These messages include the names of canceled shows from the previous season, deceased celebrities such as Walt Disney and Jim Morrison, and a tombstone with an inscription that read "TV violence" that was riddled with bullets as the camera panned on it. They were last used in "Treehouse of Horror V", which included a solitary tombstone with the words "Amusing Tombstones" to signal this. The tombstone gags were easy for the writers in the first episode, but like Marge's warnings, they eventually got more difficult to write, so they were abandoned. Another reason they were dropped was that the tombstones would list television shows that had been canceled the previous season; after a few years, several of the shows that were canceled were produced by former "Simpsons" writers. However, after two decades, this gag made a brief comeback in "Treehouse of Horror XXIX" at the very beginning, this time appearing before the main opening sequence and title.


title: Treehouse of Horror

text: While the early "Treehouse of Horror" episodes featured a Halloween themed opening sequence, the later ones only included the title and the "created by" and "developed by" credits. Every episode between "Treehouse of Horror III" and "Treehouse of Horror X" featured a couch gag with a Halloween theme, including the Simpson family dressed as skeletons, zombies, and characters from previous Halloween episodes.


title: Treehouse of Horror

text: The first four "Treehouse of Horror" episodes had brief wraparounds that occurred before each segment and loosely tied together all three stories. "Treehouse of Horror" was the only one that actually included a treehouse as a setting. In that episode, Bart and Lisa sat in it telling stories to each other. "Treehouse of Horror II" presented all of the segments as being nightmares of Lisa, Bart and Homer; "Treehouse of Horror III" had Lisa, Bart and Grampa telling stories at a Halloween party; and "Treehouse of Horror IV" is presented by Bart in a parody of Rod Serling's "Night Gallery". After a few years, the amount of broadcast time for an episode was shortened, allowing less time to tell a proper story. There were no wraparounds for "Treehouse of Horror V" because they had been cut to make more time for the segments. Following that, the writers permanently dropped them.


title: Treehouse of Horror

text: Two characters that are virtually exclusive to the "Treehouse of Horror" series are Kang and Kodos, a pair of large green space aliens who were introduced in the "Hungry are the Damned" segment of "Treehouse of Horror". Kang and Kodos have since appeared in every "Treehouse of Horror" episode, sometimes as important parts of a story, but often just for brief cameos. In some episodes, they only appear in the opening segment, but often they will make a cameo appearance in the middle of a different story. For example, a story about zombies attacking the town briefly cuts to them in their space ship, watching the events and laughing maniacally at the Earthlings' suffering. The action then switches back to the actual story. The unofficial rule is that they must be in every episode, although quite often they will be forgotten and are added at the last moment, resulting in only a brief appearance. Their scene in "Treehouse of Horror VIII" nearly did not make the final cut of the episode, but David X. Cohen managed to persuade the producers to leave the scene in.


title: Treehouse of Horror

text: Kang and Kodos were prominent characters in the 2015 episode "The Man Who Came to Be Dinner," which was not Halloween themed.


title: Treehouse of Horror

text: Beginning with "Treehouse of Horror II", the producers decided to give the cast and crew of the show "scary names" in the opening and closing credits. Although the names quickly became more silly than scary, there have been a wide variety of special credits, from simple names like "Bat Groening" or "Chains Hell Brooks" to complex ones like "David²+S.²=Cohen²". Sam Simon, who left the show during the fourth season, still receives "developed by" and "executive producer" credits, and until "Treehouse of Horror XXII", he had been listed in "Treehouse of Horror" episodes as "Sam 'Sayonara' Simon" and between "Treehouse of Horror XXII" and "Treehouse of Horror XXV" as "simonsam@TWITterror". However, following his death in March 2015, he has simply been credited as "Sam Simon" starting from "Treehouse of Horror XXVI".


title: Treehouse of Horror

text: The idea for "scary names" came from executive producer Al Jean, who was inspired by EC Comics because some of the issues also used "scary" alternate names. The "scary names" became such a burden to write that they were cut for "Treehouse of Horror XII" and "Treehouse of Horror XIII", but after hearing complaints from the fans, Jean decided to bring them back. Matt Groening's rule for the "scary names" is that they cannot be longer than a person's real name, but this is rarely followed by anyone else.


title: Treehouse of Horror

text: References to films, novels, plays, television shows, and other media are commonly featured, and many segments have been parodies of a specific work in the horror, science fiction, or fantasy genre. Many segments are spoofs of episodes of "The Twilight Zone", and entire segments will be based on a single episode. Some of the "Twilight Zone" episodes parodied include "A Kind of a Stopwatch", "To Serve Man", "A Small Talent for War", "Living Doll", "Nightmare at 20,000 Feet", "Little Girl Lost", and "The Little People". The "Bart's Nightmare" segment of "Treehouse of Horror II" parodies the episode "It's a Good Life" and is even presented in a format similar to an episode of "The Twilight Zone". The Halloween episodes also regularly parody horror and thriller films such as "The Exorcist", "The Amityville Horror", "King Kong", "Night of the Living Dead", "The Shining", "A Nightmare on Elm Street", "The Fly", "Paranormal Activity", and "Dead Calm". Robert Englund, who portrays Freddy Krueger in the "Nightmare on Elm street" franchise, had a cameo appearance in "Treehouse of Horror IX" as the character. Science fiction films have also occasionally been used as inspiration for segments, and in later episodes, many of the segments were based more on science fiction than horror. Science fiction works parodied include "The Omega Man", the novel "Nineteen Eighty-Four", "E.T. the Extra-Terrestrial", The Island of Doctor Moreau, and Orson Welles's "The War of the Worlds" radio broadcast. In "Treehouse of Horror", Edgar Allan Poe's poem "The Raven" is read by James Earl Jones, while the parts are acted by various characters. Recent parodies have included films and television specials in more varied genres, including "Mr. & Mrs. Smith", "It's the Great Pumpkin, Charlie Brown", "Transformers", "Sweeney Todd", the "Twilight" film series, and "Jumanji".


title: Treehouse of Horror

text: A modified version of the production logo for Gracie Films is displayed after the closing credits. The shushing sound is replaced by either a scream or another sound effect from the episode, and the jingle is played in a minor key on a pipe organ. The first three episodes did not feature the scream.


title: Treehouse of Horror

text: The first "Treehouse of Horror" installment aired in 1990 as part of the second season, and its on-screen title was "The Simpsons Halloween Special." ("Treehouse of Horror XIII" was the first to feature "Treehouse of Horror" in the on-screen title.) It was inspired by EC Comics Horror tales. Although every episode is entitled "Treehouse of Horror", the first was the only episode that actually used the treehouse motif. During production of the first episode, Matt Groening was nervous about "The Raven" segment, and felt it would be "the worst, most pretentious thing [they had] ever done."


title: Treehouse of Horror

text: The "Treehouse of Horror" episodes are difficult for both the writers and the animators. The episodes were originally written at the beginning of the production run, but in later seasons they were written at the end and aired at the beginning of the next season as holdovers, giving the animators more time to work. Part of the difficulty for the animators is that the episodes always involve many complex backgrounds, new characters and new designs. They are difficult for the writers because they must produce three stories, an opening and, in the early episodes, a wraparound. They would have to try to fit all of this into a 20–22 minute episode. The episodes often go through many last minute changes, with rewrites requiring new lines to be recorded. "Treehouse of Horror III" in particular underwent somewhere between 80 and 100 line changes in the six-week period between the arrival of the animation from Korea and the airing of the episode. By the fourth season, executive producers Al Jean and Mike Reiss were less enamored of "Treehouse of Horror" episodes and considered dropping them, but the other writers insisted that they be kept.


title: Treehouse of Horror

text: Part of the attraction for the writers is that they are able to break the rules and include violence that would not make a regular episode. In some cases, the writers will have an idea that is too violent and far-fetched or too short for a normal episode, but can be used as a segment in the seasonal special. Several of the writers, former executive producer Mirkin among them, believe that the episodes should be scary and not just funny. "Treehouse of Horror V" has been described by Mirkin as being one of "the most intense, disturbing Halloween show ever" as it was filled with violence and gore in response to new censorship rules. Earlier installments began with Marge issuing a disclaimer that "if you have sensitive children, maybe you should tuck them into bed early tonight instead of writing us angry letters tomorrow." However, these episodes seem mild compared to the carnage that followed in later episodes, according to Jean, who calls it "a societal thing". He points out that his 10-year-old daughter loves films like "Coraline", and that, "[in] the age of scary stories [...] appropriateness has gotten lower."


title: Treehouse of Horror

text: Although gruesome for the most part, some segments, such as "Citizen Kang" in "Treehouse of Horror VII", satirize political issues. The opening segment of "Treehouse of Horror XIX" featured Homer attempting to vote for Barack Obama but a rigged electronic voting machine instead registers a vote for John McCain. Rather than taking sides in the election, Jean says it is "mostly a comment on what many people to believe to be the irregularities in our voting system."[sic]"" In "Treehouse of Horror XVII", a segment called "The Day the Earth Looked Stupid" ends with Kang and Kodos taking over Springfield as part of a mission called "Operation: Enduring occupation". The script originally called for Kodos and Kang to look over the smoking ruins of Springfield and say "This sure is a lot like Iraq will be." The Fox network did not have any objection to the line, but it was rejected by some of the writers as too obvious and was cut from broadcast. While cut from the aired version, the line does appear in the "review" version sent to newspapers and magazines.


title: Treehouse of Horror

text: The first "Treehouse of Horror" episode was the first time that an alternate version of the theme that airs over the end credits was used. Originally, it was intended to use a theremin, but one could not be found that could hit all the necessary notes. Usually when the producers submit an episode for the Primetime Emmy Award for "Outstanding Individual Achievement in Music Composition for a Series (Dramatic Underscore)", they submit a Treehouse of Horror episode, and to date, seven episodes have been nominated. The closing of "IV" features a version of the theme that is a combination of the instruments used in "The Munsters" theme song and the harpiscord and clicking from the "Addams Family" theme song.


title: Treehouse of Horror

text: Üter Zörker is so far the only human character introduced in a "Treehouse of Horror" to make it into canon. His debut episode was "Treehouse of Horror IV" in the segment "Terror at Feet". He is an obese German exchange student obsessed with candy and was voiced by Russi Taylor until her death.


title: Treehouse of Horror

text: 2019's "Treehouse of Horror" was the 666th episode of the series. Jean stated that this was planned ever since the beginning in 1989. For the 34th season, two "Treehouse of Horror" episodes were produced, the first being a single 20-minute parody of Stephen King's novel "It" entitled "Not It".


title: Treehouse of Horror

text: Although "Treehouse of Horror" episodes are Halloween-themed, for several years new episodes premiered in November following the holiday, due to Fox's coverage of Major League Baseball's World Series. Season 12's "Treehouse of Horror XI" was the first episode to air in November. There have been several references to this in the show, such as in Season 15's "Treehouse of Horror XIV" where Kang looks at a "TV Guide" and says, "Pathetic humans. They're showing a Halloween episode... in November!" and Kodos replies "Who's still thinking about Halloween? We've already got our Christmas decorations up!" The camera then cuts to a shot of the fireplace with Christmas decorations, and festive Christmas music plays over the opening credits. Season 21's "Treehouse of Horror XX" aired October 18, before the World Series, but the following year's episode, Season 22's "Treehouse of Horror XXI", aired on November 7. Season 23's "Treehouse of Horror XXII aired on October 30, however, as the World Series (which went the maximum of seven games) had concluded on October 28. Subsequent "Treehouse of Horror" episodes have premiered in the month of October. The 31st season included a Thanksgiving-themed spinoff, "Thanksgiving of Horror". The 32nd season however pushed "Treehouse of Horror XXXI" to November 1, 2020 because the National League Championship Series went into Game 7, with the World Series that followed stretching to Game 6, resulting in Fox airing "Treehouse" after Halloween for the first time since 2010. Citytv in Canada however aired the episode as originally scheduled. "Treehouse of Horror XXXII", aired in 2021 on October 10 due to the MLB post-season running into the first week of November, and to avoid airing in November again due to the World Series overrun, and with no World Series game being played on a Sunday, "Treehouse of Horror XXXIII" aired in 2022 on October 30.


title: Treehouse of Horror

text: In past years prior to 2011, however, new shows have been known to have aired exclusively on the West Coast at the appropriate time prior to the rest of the nation’s airing after Halloween.


title: Treehouse of Horror

text: There has been a variety of merchandise based on the "Treehouse of Horror" episodes, including books, action figures, comic books, video games, DVDs and a "Treehouse of Horror" version of Hasbro's board game Monopoly. Although every "Treehouse of Horror" episode until "Treehouse of Horror XIX" has been released along with its season in a boxset, in 2003, "The Simpsons: Treehouse of Horror DVD" was released. It includes "Treehouse of Horror"s V, VI, VII and XII. A "Treehouse of Horror" comic book was published annually from 1995-2017, and collected into several books, including "The Simpsons Treehouse of Horror Fun-Filled Frightfest", "Bart Simpson's Treehouse of Horror Spine-Tingling Spooktacular", "Bart Simpson's Treehouse of Horror Heebie-Jeebie Hullabaloo" and "The Simpsons Treehouse of Horror Hoodoo Voodoo Brouhaha". Several video games based on "The Simpsons" include levels with a Halloween theme, including "" and "The Simpsons Game". In 2001, Fox Interactive and THQ released "" on Game Boy Color. The entire game has a Halloween theme as the player tries to save the Simpson family from the Treehouse of Horror.


title: Treehouse of Horror

text: Many of the special character designs featured in the episodes have become action figures. Four different playsets have been made by Playmates Toys and released as Toys "R" Us exclusives. The sets are:


title: Treehouse of Horror

text: After the Playmates Toys sets were finished, McFarlane Toys produced four "Treehouse of Horror" themed playsets including the "Ironic Punishment Box Set" released in 2004, the "In the Belly of the Boss — Homer & Marge Action Figures" released in 2005, "The Island of Dr. Hibbert Box Set" released in 2006, and a "Lard Lad Box Set" released in 2007.


title: Treehouse of Horror

text: The "Treehouse of Horror" episodes are often among the top-rated episodes of their seasons, and many of the "Treehouse of Horror"s have generally been well-received by fans. However, like "The Simpsons" itself, critics have noted a decline in the quality of the later episodes. In its first airing, "Treehouse of Horror" finished with a 15.7 Nielsen rating and a 25% audience share and would lose to "The Cosby Show". It was said that it "set a level of excellence that viewers never expected creator Matt Groening to repeat", although it was also described as "kind of stupid and unsatisfying". "Treehouse of Horror V" is considered the best episode by several critics: it finished ninth on "Entertainment Weekly"'s top 25 "The Simpsons" episode list, fifth on AskMen.com's "Top 10: Simpsons Episodes" list, and was named best episode of the sixth season by IGN.com. In 2006, James Earl Jones, who guest starred in "Treehouse of Horror" and "Treehouse of Horror V", was named seventh on IGN's "Top 25 Simpsons Guest Appearances" list.


title: Treehouse of Horror

text: In 2006, IGN.com published a list of the top ten "Treehouse of Horror" segments, and they placed "The Shinning" from "Treehouse of Horror V" at the top, saying it was "not only a standout installment of the annual Halloween episode, but of "The Simpsons", period." Rounding out the list were "Dial "Z" for Zombies", "The Devil and Homer Simpson", "Time and Punishment", "Hungry Are the Damned", "Clown Without Pity", "Citizen Kang", "If I Only Had a Brain", "Bart Simpson's Dracula", and "Starship Poopers". The third, fourth, and fifth episodes were each represented by two segments. The most recent episode on the list was "Treehouse of Horror IX", which first aired in 1998.


title: Treehouse of Horror

text: "Treehouse of Horror VII" is "Simpsons" creator Matt Groening's seventh-favorite episode, and the line he likes best is "We have reached the limit of what rectal probing can teach us." "King Homer" of "Treehouse of Horror III" is one of Matt Groening's favorite segments. "Treehouse of Horror III" is also noted for the moment where Homer shoots Ned Flanders and Bart says "Dad, you killed the Zombie Flanders!" only for Homer to reply, "He was a zombie?" It is also one of Groening's favorite lines.


title: Treehouse of Horror

text: In 1996, the "Homer³" segment of "Treehouse of Horror VI" was awarded the Ottawa International Animation Festival grand prize. In 1998, "Treehouse of Horror VIII" won a Golden Reel Award for "Best Sound Editing – Television Animated Specials"; the recipients were Robert Mackston, Travis Powers, Norm MacLeod, and Terry Greene. Bob Beecher also received a nomination for "Best Sound Editing in Television Animation – Music" for "Treehouse of Horror X".


title: Treehouse of Horror

text: The second, third, fifth, eighth, ninth, fourteenth, fifteenth, and eighteenth "Treehouse of Horror" episodes were nominated for "Outstanding Individual Achievement in Music Composition for a Series (Dramatic Underscore)" at the Primetime Emmy Awards. The second and third "Treehouse of Horror" episodes were also nominated for "Outstanding Individual Achievement in Sound Mixing for a Comedy Series or a Special". In 1996, "Treehouse of Horror VI" was submitted for the Primetime Emmy Award in the "Outstanding Animated Program (For Programming less than One Hour)" category because it had a 3D animation sequence, which the staff felt would have given it the edge. The episode failed to win, and Bill Oakley later expressed regret about submitting the episode. The twenty-third and twenty-fifth "Treehouse of Horror" episodes were nominated for the same award in 2013 and 2015 respectively.


title: Another Love (Tom Odell song)

text: "Another Love" is a song by English singer-songwriter Tom Odell, released in October 2012 as his debut single and lifted from his debut extended play, "Songs from Another Love" (2012).


title: Another Love (Tom Odell song)

text: In 2013, the song peaked at number 10 on the UK Singles Chart; the song also charted in Belgium, Ireland and the Netherlands. It became Odell's first top 10 hit in the UK after it was placed at number 10 in the single chart on 29 June 2013.


title: Another Love (Tom Odell song)

text: In 2022, the song re-appeared on the charts across Europe and Australia after becoming popular on TikTok. In August 2022, the song amassed 1 billion streams on Spotify.


title: Another Love (Tom Odell song)

text: A music video to accompany the release of "Another Love" was first released onto YouTube on 5 November 2012 at a total length of four minutes and eight seconds. It depicts Odell sitting in an armchair in front of the camera as a girl attempts to get his attention. It ends with the girl seemingly leaving Odell.


title: Another Love (Tom Odell song)

text: Another video has been released, called the "short film" version, for the song's American release. It shows Odell walking the streets and showing missing person notices for a woman he does not recognize when he finally comes across her. The video features actress Sarah Navratil.


title: Another Love (Tom Odell song)

text: Writing for "Digital Spy", Lewis Corner stated that the song "is mourning at its most hauntingly beautiful".


title: Another Love (Tom Odell song)

text: "Another Love" was adapted by the Hungarian alternative rock band Zaporozsec under the title "Azon az éjszakán" and became a number-one hit on Petőfi Rádió's Top 30 for three weeks. A music video was released onto YouTube on 2 February 2016.


title: Zanzibar City

text: Zanzibar City or Mjini District, often simply referred to as Zanzibar ("Wilaya ya Zanzibar Mjini" or "Jiji la Zanzibar" in Swahili) is one of two administrative districts of Mjini Magharibi Region in Tanzania. The district covers an area of . The district is comparable in size to the land area of Nauru. The district has a water border to the west by the Indian Ocean. The district is bordered to the east by Magharibi District. The district seat is located in Stonetown. The city is largest city on the island of Zanzibar. It is located on the west coast of Unguja, the main island of the Zanzibar Archipelago, north of the much larger city of Dar es Salaam across the Zanzibar Channel. The city also serves as the capital of the Zanzibar Urban/West Region. In 2012 its population was 223,033.


title: Zanzibar City

text: Zanzibar City comprises two main parts, Stone Town and Ng'ambo (literally: "The Other Side"); the two areas are historically divided by a creek, now marked by a large street called Creek Road. Stone Town is the historical core of the city, former capital of the Zanzibar Sultanate; because of its unique architecture and culture, it was declared a UNESCO World Heritage Site in 2000. Ng'ambo is a much larger, modern area that developed around Stone Town after the Zanzibar Revolution, with office buildings and large apartment blocks such as those of the Michenzani neighbourhood. Zanzibar City is served by a number of international and domestic airlines via Abeid Amani Karume International Airport.


title: Zanzibar City

text: In 1592, the first English ship arrived in port. In 1824, Said bin Sultan, Sultan of Muscat and Oman established the capital of his kingdom in the city. The city was a high place of slavery, one of the main ports of East Africa for the slave trade. In 1846, the island had 360,000 enslaved for 450,000 inhabitants. In 1866, the British explorer David Livingstone (1813–1873) stayed in Zanzibar to prepare his last expedition to Tanzania. In 1892, Zanzibar was declared a free port.


title: Zanzibar City

text: Zanzibar City has a tropical climate, very similar to whole Unguja island, and slightly hotter than what is found in Pemba. This climate is classified as a tropical monsoon climate (Köppen climate classification "Am"). The average temperature in Zanzibar City is . The average annual rainfall is . The monthly average temperatures are usually between . There are two rain seasons, with most rainfall coming between March and May and smaller rain season coming between November and December. Drier months are January - February, and a longer drier season between June and October.


title: Zanzibar City

text: The places of worship in the city are predominantly Muslim mosques. There are also Christian churches and temples: Roman Catholic Diocese of Zanzibar (Catholic Church), Anglican Church of Tanzania (Anglican Communion), Evangelical Lutheran Church in Tanzania (Lutheran World Federation), Baptist Convention of Tanzania (Baptist World Alliance), Assemblies of God.


title: Zanzibar City

text: For parliamentary elections, Tanzania is divided into constituencies. As of the 2010 elections the area for Zanzibar City District had ten of the nineteen constituencies in the region:


title: Ashleigh Cummings

text: Ashleigh Cummings is an Australian actress. She became known for her role as Robyn Mathers in "Tomorrow, When the War Began". The film, based on the book of the same name, earned Cummings a nomination for Best Young Actor at the 2010 Australian Film Institute Awards. Cummings is also known for her roles as Dorothy Williams in ABC1's "Miss Fisher's Murder Mysteries", as Debbie Vickers in "Puberty Blues", and Vic McQueen in "NOS4A2".


title: Ashleigh Cummings

text: Cummings was born in Jeddah, Saudi Arabia, where her Australian parents lived and worked. She moved to Australia with her family when she was 12 years old. From the age of two, Cummings trained as a ballet dancer. When she was 14 she joined the Brent Street School of Performing Arts, where she learned dance and acting. Cummings then attended Wenona School in North Sydney, where she graduated in 2010. She also attended the film and television school Screenwise. Cummings studied philosophy at university between acting roles.


title: Ashleigh Cummings

text: Cummings appeared as a dancer in Darren Ashton's "" in 2007. She went on to star as Ally Sheppard in "Green Fire Envy" a project that was produced by the Participate Film Academy. Cummings' next projects were a role in the television film "Dream Life" and a guest stint in soap opera "Home and Away".


title: Ashleigh Cummings

text: In September 2009, it was announced Cummings had joined the cast of "Tomorrow, When the War Began", a film based on the John Marsden book of the same name. Cummings learned how to ride dirt bikes and operate AK-47 assault rifles before filming began. She also sat her Year 11 exams early and missed the first part of Year 12, while shooting the film. Cummings earned a nomination for Best Young Actor at the 2010 Australian Film Institute Awards for her portrayal of Robyn Mathers.


title: Ashleigh Cummings

text: From September 2010, Cummings appeared in the Sydney Theatre Company's production of "Our Town". The actress went on to appear in episodes of "Rescue Special Ops", "" and "Dance Academy" in 2011. She was then cast as Dorothy "Dot" Williams in ABC1's "Miss Fisher's Murder Mysteries", a drama series based on Kerry Greenwood's Phryne Fisher historical mysteries. Dorothy is "a conservative working-class Catholic" who becomes Phryne's assistant and companion.


title: Ashleigh Cummings

text: In March 2012, it was announced that Cummings had been cast as Debbie Vickers in the television adaptation of "Puberty Blues". Cummings read the novel before her audition and she revealed that she was surprised at the content. Cummings stated: "In terms of the sexual nature of it, I wasn't aware of a lot of that and I've learnt so much (doing this movie)." To prepare for the role of Debbie, Cummings took surfing lessons. Cummings went overseas for three weeks to work as a volunteer in South-East Asia, before she returned to film the second series of "Miss Fisher's Murder Mysteries". For her roles in "Miss Fisher's Murder Mysteries" and "Puberty Blues", Cummings received a nomination for Most Popular Actress at the Logie Awards.


title: Ashleigh Cummings

text: Cummings recorded vocals for Dan Webb's debut album "Sandstorm", released in 2014. She also starred in Rhys Graham's first feature film "Galore" as Billie. Cummings received a nomination for Best Performance by a Young Actor at the Film Critics Circle of Australia Awards for her role in "Galore". In 2015, Cummings appeared in the television miniseries "Gallipoli" as Celia. She also stars in the remake of the 1981 film "Goodbye Pork Pie". In 2016, Cummings won the Heath Ledger Scholarship awarded by Australians in Film to study at the Stella Adler Studio of Acting and the Ivana Chubbuck Studio in Los Angeles. Cummings has a lead role in "Hounds of Love". She was also cast as Cheryl Miller in "Westside", the prequel series to "Outrageous Fortune".


title: Ashleigh Cummings

text: Cummings plays Pippa in "The Goldfinch", a film adaptation of Donna Tartt's novel of the same name. She also appears in the lead role of Vic McQueen in AMC horror series "NOS4A2".


title: Dustin Pedroia

text: Dustin Luis Pedroia (born August 17, 1983) is an American former professional baseball second baseman who played his entire Major League Baseball career for the Boston Red Sox, from 2006 to 2019. He was a four-time All-Star, and won the American League (AL) Rookie of The Year Award in 2007 and the AL Most Valuable Player and Silver Slugger Award in 2008. He has also received four Gold Glove Awards and was named AL Defensive Player of the Year in 2013.


title: Dustin Pedroia

text: Pedroia was selected by the Red Sox in the 2004 MLB draft and made his major league debut in 2006. He became a full-time player in 2007, winning the AL Rookie of the Year Award. He was a member of the Red Sox World Series championship teams in 2007 and 2013. Pedroia was the last player from the 2007 World Series team to leave the club. A knee injury late in the 2017 season marked the end of his effective play. After playing in only nine major league games over the 2018 and 2019 seasons, including missing the 2018 postseason, he also missed all of the shortened 2020 season. He announced his retirement on February 1, 2021.


title: Dustin Pedroia

text: Pedroia was a proficient contact hitter with a very low strikeout rate and "a surprising amount of power", whose defense at second base has been rated significantly above-average. Pedroia was the first Red Sox infielder to win four Gold Gloves.


title: Dustin Pedroia

text: Born and raised in Woodland, California, northwest of Sacramento, Pedroia's parents operated a tire shop where they worked 14-hour days. His mother, Debbie Pedroia, played tennis at Sacramento City College. Pedroia's older brother, Brett, played baseball as a catcher at Shasta College.


title: Dustin Pedroia

text: Pedroia attended Woodland High School and played football and baseball. His football career ended as a freshman quarterback; a hit from future All-Pro NFL linebacker Lance Briggs shattered his ankle. As a senior baseball player, Pedroia did not strike out all season, compiled a .445 batting average and was chosen as his league's most valuable player.


title: Dustin Pedroia

text: Pedroia attended Arizona State University (ASU), where he played college baseball for the Arizona State Sun Devils baseball team. He was teammates with Ian Kinsler and Andre Ethier. Kinsler and Pedroia competed for the shortstop position at ASU. Ultimately, Pedroia stayed at shortstop, while Kinsler ended up at second base before transferring to the University of Missouri. In three years at ASU, Pedroia never hit below .347 and had a career average of .384, starting all 185 games. To help ASU recruit better pitchers, Pedroia also relinquished the last two years of his athletic scholarship. He was named ASU On Deck Circle Most Valuable Player; other winners have included Ike Davis, Willie Bloomquist, Paul Lo Duca, and Barry Bonds.


title: Dustin Pedroia

text: Pedroia was drafted by the Red Sox in the second round of the 2004 MLB draft, with the 65th pick overall. Pedroia, the eighth shortstop drafted, received a $575,000 signing bonus.


title: Dustin Pedroia

text: During three seasons in Minor League Baseball, Pedroia batted .308 while playing second base and shortstop. He spent 2004 with the Class A Augusta GreenJackets and Class A-Advanced Sarasota Red Sox, part of 2005 with the Double-A Portland Sea Dogs, and parts of 2005 and 2006 with the Triple-A Pawtucket Red Sox.


title: Dustin Pedroia

text: After a brief call-up in 2006, when he hit just .191 in 89 at-bats, Pedroia became the regular second baseman for the Red Sox in 2007 replacing Mark Loretta. Pedroia suffered through an early-season hitting slump, but recovered, later putting up a 13-game hitting streak and a five-hit game against the Giants. He notably made a diving stop to preserve fellow rookie Clay Buchholz's no-hitter on September 1. Pedroia won the AL Rookie of the Year award and was selected to the 2007 Topps Major League Rookie All-Star Team.


title: Dustin Pedroia

text: The Red Sox played the Indians in the 2007 ALCS. In Game 7 of the series, Pedroia homered and doubled, collecting five RBI to secure the Red Sox' spot in the World Series, to face the Rockies. Pedroia homered in the first at bat of the series, making him only the second player, and the first rookie, to lead off the Series with a home run. The Red Sox went on to win their second World Series title in four seasons – and the first World Series championship for Pedroia.


title: Dustin Pedroia

text: Pedroia performed very well during the 2008 regular season, and received AL MVP, Gold Glove and Silver Slugger awards. He was the first-ever Red Sox second baseman to win a Silver Slugger Award, the first Red Sox second baseman to win a Gold Glove since Doug Griffin in 1972, and the first second baseman to win an American League MVP Award since Nellie Fox in 1959. He hit .326 with 17 home runs over 726 PAs, for a 127 wRC+. Pedroia was defensively great, making only six errors through 157 games, saving +9.7 runs over the season, according to UZR. 2008 was also Pedroia's most productive season on the basepaths; he stole 20 bases in 21 attempts, for baserunning worth 4.9 runs above average.


title: Dustin Pedroia

text: Pedroia's contribution in the regular season was rated 6.5 WAR by Fangraphs, a "superstar" level of performance. He became only the third player in MLB history to win Rookie of the Year and Most Valuable Player in consecutive seasons joining Cal Ripken Jr. and Ryan Howard, and later was followed by Kris Bryant.


title: Dustin Pedroia

text: Pedroia was hitless through the first three games of the 2008 ALDS, recording only an RBI double in Game 4. The Red Sox defeated the Angels in four games. In the ALCS against the Tampa Bay Rays, Pedroia collected nine hits in 26 plate appearances, including three home runs and a double. The rest of the team struggled to a .234 batting average against the Tampa pitching staff, and the Red Sox lost the series.


title: Dustin Pedroia

text: On December 3, 2008, Pedroia signed a six-year contract extension worth $40.5 million, with an additional team option for 2015 worth $11 million.


title: Dustin Pedroia

text: Pedroia announced on December 15, 2008, that he would play for the United States team in the 2009 World Baseball Classic. He recorded the first Major League hit in Citi Field history during an April 3 exhibition game against the Mets. He hit a home run in his first at bat of the 2009 season.


title: Dustin Pedroia

text: Pedroia was selected to start for the 2009 AL All Star Team. However, Pedroia had to withdraw from the team to stay with his wife Kelli, who was experiencing pregnancy complications with the couple's first child. The same issue had caused him to miss a regular season game prior to the All Star break.


title: Dustin Pedroia

text: In 2010, MLB umpire Joe West made controversial statements regarding the speed of play between the Red Sox and Yankees, Pedroia responded by saying, "What he doesn't understand is that when we don't do well in these games against the Yankees, we get killed. If he doesn't want to do Red Sox and Yankee games, he should tell the umpires' union. Then when we're in the World Series, he'll be out of that assignment, too."


title: Dustin Pedroia

text: On June 24, 2010, Pedroia went 5 for 5, with 5 RBI, and hit three home runs in a game against the Rockies that the Red Sox won, 13–11, in the tenth inning. The next day, Pedroia fouled a ball off his foot in an at-bat versus the Giants. MRI results the next day confirmed that he had a broken bone in his foot, and he was placed on the 15-day disabled list. Pedroia was under doctor's orders not to put weight on his injured foot for two weeks, but continued to practice fielding grounders while on his knees.


title: Dustin Pedroia

text: Pedroia was named to be a reserve player on the 2010 AL All Star team, but did not participate due to this injury, and had former Arizona State teammate Ian Kinsler replace him on the roster. Pedroia returned to the lineup on August 17 against the Angels, only to be put back on the DL after playing 2 games. Pedroia would end the 2010 season having played only 75 games.


title: Dustin Pedroia

text: In 2011, Pedroia bounced back, batting .307 and slugging 21 home runs over 159 games. He won a Fielding Bible Award in 2011 as the best fielding second baseman in MLB, and had his best defensive season by ultimate zone rating, with 18.1 runs saved. In June and July, Pedroia had a 25-game hitting streak, the longest for a Red Sox second baseman. On August 16, Pedroia was involved in throwing a triple play, started by Jed Lowrie. Pedroia's 2011 season was rated at 7.6 Wins Above Replacement by Fangraphs, an "MVP-caliber" performance.


title: Dustin Pedroia

text: On September 30, 2012, Pedroia broke his left ring finger but, after being reassured the injury would not degrade with use, he made the decision to play through the pain in the following season-ending series at Yankee Stadium.


title: Dustin Pedroia

text: On July 23, 2013, Pedroia and the Red Sox agreed to an eight-year extension worth $110 million. Pedroia was represented in negotiations by Sam Levinson and Seth Levinson of ACES Inc.


title: Dustin Pedroia

text: Pedroia bounced back from his injury-affected 2012 season to become the only player on the Red Sox to play more than 150 games during the team's 2013 regular season, playing in 160 games. Pedroia posted a strong regular season performance, and was awarded his third Gold Glove, second Fielding Bible Award, and the Wilson Overall Defensive Player of the Year Award for the American League. The Red Sox won their division and went on to win the World Series.


title: Dustin Pedroia

text: In November 2013, Pedroia underwent thumb surgery to repair a torn UCL, an injury he suffered when sliding to first base on opening day.


title: Dustin Pedroia

text: In May 2014, Pedroia hit his 100th career home run and his 300th career double. Pedroia hit only four home runs before the 2014 All Star break, and his hitting productivity dropped to league average. For the season he batted .278/.337/.376. However, his fielding numbers remained strong. For his defensive performance, Pedroia was honored with the American League Gold Glove award at second base—his fourth in his nine-year career—along with his third Fielding Bible Award. This made him the first Red Sox infielder to win four Gold Gloves.


title: Dustin Pedroia

text: Pedroia began the 2015 MLB season with two home runs in the Red Sox opening game, on the road at Citizens Bank Park, Philadelphia. On June 25, 2015, the Red Sox placed him on the 15-day disabled list due to a right hamstring strain.


title: Dustin Pedroia

text: Pedroia had a strong month as a hitter in August, culminating in a streak of three games, from August 25 through 27, over which he hit safely in 11 consecutive at bats, falling one hit shy of tying the major league record of 12 consecutive at bats with a base hit (shared by three players since 1902). During the streak, Pedroia had 10 singles, one double, scored two runs and drove in three. He also walked once during the streak, thus reaching base safely over 12 consecutive plate appearances. In 154 games played, Pedroia batted .318 with 201 hits, 36 doubles, 105 runs scored, 15 home runs, and 74 RBI. He tied for second in the AL in double plays grounded into, with 24.


title: Dustin Pedroia

text: The Red Sox finished the 2016 season with a 93–69 record, clinching the AL East division, but were swept in three games by the Indians in the 2016 ALDS. On October 13, Pedroia underwent left knee surgery, a partial medial meniscectomy and chondroplasty. He won a 2016 Fielding Bible award. He also won the 2016 Wilson Defensive Player of the Year Award for second base, in all of MLB.


title: Dustin Pedroia

text: On May 30, Pedroia was placed on the 10-day disabled list due to a left wrist sprain. On August 1, he was again placed on the 10-day disabled list due to left knee soreness. On August 12, Pedroia was placed on the disabled list for the third time of the season due to soreness in the same knee. Limited to 105 games, Pedroia finished the 2017 Red Sox season with a .293 batting average, 7 home runs, and 62 RBI. On October 25, it was revealed that Pedroia underwent surgery on his knee for a complete cartilage restoration, meaning that he would miss the start of the 2018 season.


title: Dustin Pedroia

text: Following his late 2017 knee surgery, Pedroia started the 2018 Red Sox season on the disabled list. On May 14, he was optioned to the Triple-A Pawtucket Red Sox for a rehabilitation assignment. He was activated on May 26, but after three games (batting 1-for-11), he wound up back on the disabled list with left knee inflammation. On August 4, Pedroia was transferred to the 60-day disabled list. On September 7, the Red Sox announced that Pedroia would take no further part in any action for the remainder of 2018. The Red Sox finished the year 108–54 and went on to win the World Series over the Los Angeles Dodgers. Although Pedroia did not play in the postseason and was not on the team's World Series roster; he and other various personnel not on the World Series roster did receive 2018 World Series rings; as championship rings are issued by a team at their discretion.


title: Dustin Pedroia

text: On March 7, 2019, Pedroia made his spring training debut, hitting a single in his lone at bat of the game while playing in the field for two innings; it was his first game action since May 2018. He began the season on the injured list. On April 4, he was sent to the Class A Greenville Drive on a rehabilitation assignment, where he played in three games, batting 3-for-9. Pedroia was activated for Boston's home opener on April 9, appeared in six games while batting 2-for-20 (.100/.143/.100), and returned to the injured list on April 18 due to left knee irritation. He began a rehabilitation assignment with Double-A Portland on May 2. On May 11, he was scratched from a start due to knee discomfort, and his assignment with Portland was halted on May 13. He restarted his rehabilitation, first with Triple-A Pawtucket on May 17, and then with Double-A Portland on May 24. Pedroia was removed from Portland's May 24 game due to left knee soreness.


title: Dustin Pedroia

text: After being evaluated, he announced on May 27 that he was going to take some time to evaluate his future. When asked if he would ever play again, he said "I'm not sure." The same day, the Red Sox moved Pedroia to the 60-day injured list. On August 6, Pedroia underwent a left knee joint preservation surgery. In 2019, he had the slowest sprint speed of all American League second basemen, at 25.0 feet/second.


title: Dustin Pedroia

text: On January 21, 2020, it was reported that Pedroia suffered a "significant setback" with his left knee. On February 23, the team placed Pedroia on the 60-day injured list. Due to his injury, Pedroia missed the entirety of the shortened 2020 season.


title: Dustin Pedroia

text: On June 25, 2021, the Red Sox honored Pedroia in a pre-game ceremony at Fenway Park, and announced his induction to the Boston Red Sox Hall of Fame as part of the class of 2022.


title: Dustin Pedroia

text: Having last played in MLB in 2019, Pedroia will be eligible to appear on the ballot for the National Baseball Hall of Fame class of 2025, expected to be distributed to BBWAA voters in late 2024.


title: Dustin Pedroia

text: Pedroia has garnered multiple nicknames during his time in Boston, including Pedey, the Laser Show, and the Muddy Chicken. His family is of Swiss Italian and Portuguese heritage. The Red Sox officially lists Pedroia at , but he said he is in 2016. Pedroia has expressed an interest in Bigfoot, including tweeting about the show "Finding Bigfoot" from his Twitter account. Pedroia enjoys playing the game cribbage; he and former manager Terry Francona used to play together. Pedroia is a fan of the NBA's Sacramento Kings, and the NFL's San Francisco 49ers.


title: Dustin Pedroia

text: On January 9, 2009, Pedroia was named as the cover athlete of the baseball video game "", and appeared in several commercials for the game.


title: Dustin Pedroia

text: In June 2014, the couple had their third son. They owned a home in Chestnut Hill, Massachusetts, but sold it in 2020. They reside in Chandler, Arizona. Pedroia is the nephew of Carolina Panthers defensive coordinator Phil Snow.


title: Dustin Pedroia

text: In a 2009 interview given to "Boston" magazine, Pedroia criticized his home town of Woodland, California, calling it a "dump" and a city that never embraced him. This generated backlash from his hometown and his family received death threats. Pedroia later clarified his comments saying he was only joking and his comments were taken out of context. The original article's author, however, insisted that his use of the comment was not misleading. His transcript of the interview quoted Pedroia as saying "It's a dump. You can quote me on that. I don't give a shit."


title: Dustin Pedroia

text: Pedroia has authored an autobiography, and a children's book about Red Sox mascot Wally the Green Monster as a continuation of a series started by Jerry Remy:


title: Transgender hormone therapy

text: Transgender hormone therapy, also called hormone replacement therapy (HRT) or gender-affirming hormone therapy (GAHT), is a form of hormone therapy in which sex hormones and other hormonal medications are administered to transgender or gender nonconforming individuals for the purpose of more closely aligning their secondary sexual characteristics with their gender identity. This form of hormone therapy is given as one of two types, based on whether the goal of treatment is masculinization or feminization:


title: Transgender hormone therapy

text: Some intersex people may also undergo hormone therapy, either starting in childhood to confirm the sex they were assigned at birth, or later in order to align their sex with their gender identity. Non-binary people may also engage in hormone therapy in order to achieve a desired balance of sex hormones or to help align their bodies with their gender identities.


title: Transgender hormone therapy

text: The formal requirements to begin gender-affirming hormone therapy vary widely depending on geographic location and specific institution. Gender affirming hormones can be prescribed by a wide range of medical providers including, but not limited to, primary care physicians, endocrinologists, and obstetrician-gynecologists.


title: Transgender hormone therapy

text: Historically, many health centers required a psychiatric evaluation and/or a letter from a therapist before beginning therapy. Many centers now use an informed consent model that does not require any routine formal psychiatric evaluation but instead focuses on reducing barriers to care by ensuring a person can understand the risks, benefits, alternatives, unknowns, limitations, and risks of no treatment. Some LGBT health organizations (notably Chicago's Howard Brown Health Center and Planned Parenthood) advocate for this type of informed consent model.


title: Transgender hormone therapy

text: The Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People (SOC) require that patients seeking gender-affirmation hormone therapy be evaluated for gender dysphoria by either a mental health professional or hormone provider who is qualified in the area of transgender care. The Standards also require that the patient give informed consent, in other words, that they consent to the treatment after being fully informed of the risks involved. Before beginning gender-affirming hormone therapy, the patient must be evaluated for significant medical and mental health concerns. If present, these must be addressed and reasonably well-controlled.


title: Transgender hormone therapy

text: The World Professional Association for Transgender Health (WPATH) Standards of Care, 7th edition, note that both of these approaches to care are appropriate.


title: Transgender hormone therapy

text: Many international guidelines and institutions require persistent, well-documented gender dysphoria as a pre-requisite to starting gender-affirmation therapy. Gender dysphoria refers to the psychological discomfort or distress that an individual can experience if their sex assigned at birth is incongruent with that person's gender identity. Signs of gender dysphoria can include comorbid mental health stressors such as depression, anxiety, low self-esteem, and social isolation. It is important to note that not all gender nonconforming individuals experience gender dysphoria.


title: Transgender hormone therapy

text: The World Professional Association for Transgender Health (WPATH) and the Endocrine Society formulated guidelines that created a foundation for health care providers to care for transgender patients. UCSF guidelines are also used. There is no generally agreed-upon set of guidelines, however.


title: Transgender hormone therapy

text: Adolescents experiencing gender dysphoria may opt to undergo puberty-suppressing hormone therapy at the onset of puberty. The Standards of Care set forth by WPATH recommend individuals pursuing puberty-suppressing hormone therapy wait until at least experiencing Tanner Stage 2 pubertal development. Tanner Stage 2 is defined by the appearance of scant pubic hair, breast bud development, and/or slight testicular growth. WPATH classifies puberty-suppressing hormone therapy as a "fully reversible" intervention. Delaying puberty allows individuals more time to explore their gender identity before deciding on more permanent interventions and prevents the physical changes associated with puberty.


title: Transgender hormone therapy

text: The preferred puberty-suppressing agent for both individuals assigned male at birth and individuals assigned female at birth is a GnRH Analogue. This approach temporarily shuts down the Hypothalamic-Pituitary-Gonadal (HPG) Axis, which is responsible for the production of hormones (estrogen, testosterone) that cause the development of secondary sexual characteristics in puberty.


title: Transgender hormone therapy

text: Feminizing hormone therapy is typically used by transgender women, who desire the development of feminine secondary sex characteristics. Individuals who identify as non-binary may also opt-in for feminizing hormone treatment to better align their body with their desired gender expression. Feminizing hormone therapy usually includes medication to suppress testosterone production and induce feminization. Types of medications include estrogens, antiandrogens (testosterone blockers), and progestogens. Most commonly, an estrogen is combined with an antiandrogen to suppress and block testosterone. This allows for demasculinization and promotion of feminization and breast development. Estrogens are administered in various modalities including injection, transdermal patch, and oral tablets.


title: Transgender hormone therapy

text: The desired effects of feminizing hormone therapy focus on the development of feminine secondary sex characteristics. These desired effects include: breast tissue development, redistribution of body fat, decreased body hair, reduction of muscle mass, and more. The table below summarizes some of the effects of feminizing hormone therapy in transgender women:


title: Transgender hormone therapy

text: Masculinizing hormone therapy is typically used by transgender men, who desire the development of masculine secondary sex characteristics. Masculinizing hormone therapy usually includes testosterone to produce masculinization and suppress the production of estrogen. Treatment options include oral, parenteral, subcutaneous implant, and transdermal (patches, gels). Dosing is patient-specific and is discussed with the physician. The most commonly prescribed methods are intramuscular and subcutaneous injections. This dosing can be weekly or biweekly depending on the individual patient.


title: Transgender hormone therapy

text: Unlike feminizing hormone therapy, individuals undergoing masculinizing hormone therapy do not usually require additional hormone suppression such as estrogen suppression. Therapeutic doses of testosterone are usually sufficient to inhibit the production of estrogen to desired physiologic levels.


title: Transgender hormone therapy

text: The desired effects of masculinizing hormone therapy focus on the development of masculine secondary sex characteristics. These desired effects include: increased muscle mass, development of facial hair, voice deepening, increase and thickening of body hair, and more.


title: Transgender hormone therapy

text: Hormone therapy for transgender individuals has been shown in medical literature to be generally safe, when supervised by a qualified medical professional. There are potential risks with hormone treatment that will be monitored through screenings and lab tests such as blood count (hemoglobin), kidney and liver function, blood sugar, potassium, and cholesterol. Taking more medication than directed may lead to health problems such as increased risk of cancer, heart attack from thickening of the blood, blood clots, and elevated cholesterol.


title: Transgender hormone therapy

text: The Standards of Care published by the World Professional Association for Transgender Health (WPATH) summarize many of the risks associated with feminizing hormone therapy (outlined below). For more in-depth information on the safety profile of estrogen-based feminizing hormone therapy visit the feminizing hormone therapy page.


title: Transgender hormone therapy

text: The Standards of Care published by the World Professional Association for Transgender Health (WPATH) summarize many of the risks associated with masculinizing hormone therapy (outlined below). For more in-depth information on the safety profile of testosterone-based masculinizing hormone therapy visit the masculinizing hormone therapy page.


title: Transgender hormone therapy

text: Transgender hormone therapy may limit fertility potential. Should a transgender individual choose to undergo sex reassignment surgery, their fertility potential is lost completely. Before starting any treatment, individuals may consider fertility issues and fertility preservation. Options include semen cryopreservation, oocyte cryopreservation, and ovarian tissue cryopreservation.


title: Transgender hormone therapy

text: A study presented at ENDO 2019 (the Endocrine Society's conference) shows that even after one year of treatment with testosterone, a transgender man can preserve his fertility potential.


title: Transgender hormone therapy

text: Many providers use informed consent, whereby someone seeking hormone therapy can sign a statement of informed consent and begin treatment without much gatekeeping. For other providers, eligibility is determined using major diagnostic tools such as ICD-10 or the "Diagnostic and Statistical Manual of Mental Disorders" (DSM). Psychiatric conditions can commonly accompany or present similar to gender incongruence and gender dysphoria. For this reason, patients are assessed using DSM-5 criteria or ICD-10 criteria in addition to screening for psychiatric disorders. The Endocrine Society requires physicians that diagnose gender dysphoria and gender incongruence to be trained in psychiatric disorders with competency in ICD-10 and DSM-5. The healthcare provider should also obtain a thorough assessment of the patient's mental health and identify potential psychosocial factors that can affect therapy.


title: Transgender hormone therapy

text: The ICD-10 system requires that patients have a diagnosis of either transsexualism or gender identity disorder of childhood. The criteria for transsexualism include:


title: Transgender hormone therapy

text: Individuals cannot be diagnosed with transsexualism if their symptoms are believed to be a result of another mental disorder, or of a genetic or chromosomal abnormality.


title: Transgender hormone therapy

text: For a child to be diagnosed with gender identity disorder of childhood under ICD-10 criteria, they must be pre-pubescent and have intense and persistent distress about being the opposite sex. The distress must be present for at least six months. The child must either:


title: Transgender hormone therapy

text: The DSM-5 states that at least two of the following criteria must be experienced for at least six months' duration for a diagnosis of gender dysphoria:


title: Transgender hormone therapy

text: Some organizations – but fewer than in the past – require that patients spend a certain period of time living in their desired gender role before starting hormone therapy. This period is sometimes called real-life experience (RLE). The Endocrine Society stated in 2009 that individuals should either have a documented three months of RLE or undergo psychotherapy for a period of time specified by their mental health provider, usually a minimum of three months.


title: Transgender hormone therapy

text: Transgender and gender non-conforming activists, such as Kate Bornstein, have asserted that RLE is psychologically harmful and is a form of "gatekeeping", effectively barring individuals from transitioning for as long as possible, if not permanently.


title: Transgender hormone therapy

text: Gender-affirming care is health care that affirms people to live authentically in their genders, no matter the gender they were assigned at birth or the path their gender affirmation (or transition) takes. It allows each person to seek only the changes or medical interventions they desire to affirm their own gender identity, and hormone therapy (“HRT” or gender-affirming hormone therapy) may be a part of that.


title: Transgender hormone therapy

text: Some transgender people choose to self-administer hormone replacement medications, often because doctors have too little experience in this area, or because no doctor is available. Others self-administer because their doctor will not prescribe hormones without a letter from a psychotherapist stating that the patient meets the diagnostic criteria and is making an informed decision to transition. Many therapists require at least three months of continuous psychotherapy and/or real-life experience before they will write such a letter. Because many individuals must pay for evaluation and care out-of-pocket, costs can be prohibitive.


title: Transgender hormone therapy

text: Access to medication can be poor even where health care is provided free. In a patient survey conducted by the United Kingdom's National Health Service in 2008, 5% of respondents acknowledged resorting to self-medication, and 46% were dissatisfied with the amount of time it took to receive hormone therapy. The report concluded in part: "The NHS must provide a service that is easy to access so that vulnerable patients do not feel forced to turn to DIY remedies such as buying drugs online with all the risks that entails. Patients must be able to access professional help and advice so that they can make informed decisions about their care, whether they wish to take the NHS or private route without putting their health and indeed their lives in danger." Self-administration of hormone replacement medications may have untoward health effects and risks.


title: Transgender hormone therapy

text: A number of private companies have attempted to increase accessibility for hormone replacement medications and help transgender people navigate the complexities of access to treatment.


title: Gua bao

text: The gua bao (), also known as pork belly bun, ambiguously as bao, or erroneously as bao bun, is a type of lotus leaf bun () originating from Fujian cuisine. It is a popular snack in Taiwan and is commonly sold at night markets and restaurants. It is also a popular street food in Singapore, Malaysia, Philippines, and Nagasaki Chinatown in Japan.


title: Gua bao

text: It consists of a slice of stewed meat and condiments sandwiched between flat steamed bread known as lotus leaf bread (). The lotus leaf bread is typically in size, semi-circular and flat in form, with a horizontal fold that, when opened, gives the appearance that it has been sliced. The traditional filling for gua bao is a slice of red-cooked pork belly, typically dressed with stir-fried suan cai (pickled mustard greens), coriander, and ground peanuts.


title: Gua bao

text: "Gua" () means to cut by drawing the knife around in the Taiwanese language. "Bao" means "bun", so the name "bao bun" is redundant, and "bao" in the Chinese language without any qualifiers is generally used to refer to baozi.