10.14639/0392-100X-N2118
Objective. To our knowledge, the spatial access of naris to olfactory cleft has not been quantified. We aimed to study the relationship and space of middle turbinate, septum, anterior nasal spine and cribriform plate to improve topical medication delivery and drug applicators. Methods. One hundred CT scans of patients (50 males, 50 females) over the age of 18 were included. Subjects with radiographic sinonasal pathology, previous surgery, or specific variant nasal anatomy were excluded. Scans were independently reviewed and bilateral measurements on bony landmarks were taken by two blinded authors. Inter-rater reliability was analysed with intraclass correlation. Results. The average age was 46.26 years (σ = 14.0). Average distance from the anterior nasal spine to olfactory cleft was 52.3 mm (σ = 4.2 mm), and the average length of cribriform plate was 18.8 mm (σ = 3.8) with an angle relative to hard palate averaging -8.8 degrees below parallel (σ = 5.5 degree). The widths of the olfactory cleft at anterior and posterior edges of cribriform plate were 2.3 mm (σ = 0.7 mm) and 2.0 mm (σ = 0.7 mm).Conclusions. The findings suggest a 52.3 mm distance from the naris to the anterior border of cribriform plate. The average width along this path was 3.2 mm, suggesting devices narrower than this could potentiate direct drug delivery access.
text/xml
1827-675X
2118
en
Andrew Vernu Thamboo
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
computed tomography study
Spatial analysis of transnasal olfactory cleft access: a computed tomography study
Text.Serial.Journal
https://www.actaitalica.it/
43
Rhinology
2023-05-16
2022-04-08
2023-05-19
2023-05-19
197-202
1
Andrew Vernu Thamboo
2023/05/16
10.14639/0392-100X-N2118
197
Division of Otolaryngology Head and Neck Surgery, Department of Surgery, University of British Columbia, St. Paul Sinus Center, Vancouver, BC, Canada
1827-675X
computed tomography study
en
202
Spatial analysis of transnasal olfactory cleft access: a computed tomography study
https://www.actaitalica.it/article/download/2118/990
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43:197-202; doi: 10.14639/0392-100X-N2118




Rhinology


Spatial analysis of transnasal olfactory cleft access:
a computed tomography study
Analisi spaziale dell’accesso transnasale alla fessura olfattoria:
uno studio di tomografia computerizzata
Teffran Joey Chan1,2, Melissa Lee2, Andrew Vernu Thamboo1
1
 Division of Otolaryngology Head and Neck Surgery, Department of Surgery, University of British Columbia, St. Paul Sinus Center,
Vancouver, BC, Canada; 2 Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada


SUMMARY
Objective. To our knowledge, the spatial access of naris to olfactory cleft has not been
quantified. We aimed to study the relationship and space of middle turbinate, septum, an-
terior nasal spine and cribriform plate to improve topical medication delivery and drug
applicators.
Methods. One hundred CT scans of patients (50 males, 50 females) over the age of 18 were
included. Subjects with radiographic sinonasal pathology, previous surgery, or specific vari-
ant nasal anatomy were excluded. Scans were independently reviewed and bilateral meas-
urements on bony landmarks were taken by two blinded authors. Inter-rater reliability was
analysed with intraclass correlation.
Results. The average age was 46.26 years (σ = 14.0). Average distance from the anterior na-
sal spine to olfactory cleft was 52.3 mm (σ = 4.2 mm), and the average length of cribriform
plate was 18.8 mm (σ = 3.8) with an angle relative to hard palate averaging -8.8 degrees
below parallel (σ = 5.5 degree). The widths of the olfactory cleft at anterior and posterior
edges of cribriform plate were 2.3 mm (σ = 0.7 mm) and 2.0 mm (σ = 0.7 mm).
Conclusions. The findings suggest a 52.3 mm distance from the naris to the anterior border
of cribriform plate. The average width along this path was 3.2 mm, suggesting devices nar-          Received: April 8, 2022
rower than this could potentiate direct drug delivery access.                                       Accepted: November 3, 2022
KEY WORDS: olfactory cleft, trans cribriform, intranasal drug application, computed
tomography study                                                                                    Correspondence
                                                                                                    Andrew Vernu Thamboo
                                                                                                    Division of Otolaryngology Head and Neck Sur-
RIASSUNTO                                                                                           gery, Department of Surgery, University of British
Obiettivo. Per quanto di nostra conoscenza, lo spazio di accesso dalla narice alla fessura          Columbia, St. Paul Sinus Center, Providence 2nd
olfattoria non è mai stato quantificato. Il nostro obiettivo è l’analisi delle relazioni spaziali   floor, 1081 Burrard Street, Vancouver, BC, V6Z
tra turbinato medio, setto, spina nasale anteriore e lamina cribra per migliorare la sommi-         1Y6, Canada
nistrazione di farmaci topici ed i dispositivi per la loro nebulizzazione.                          Tel. +1 604-806-8353
Metodi. Le tomografie computerizzate di 100 pazienti maggiorenni (50 uomini e 50 donne)             E-mail: andrew.thamboo@gmail.com
sono state incluse nello studio. I soggetti con segni radiologici di patologia nasosinusale,
precedente chirurgia, o con specifiche varianti anatomiche sono stati esclusi. Le immagini            How to cite this article: Chan TJ, Lee M, Tham-
sono state revisionate in maniera indipendente da due autori, e le distanze tra specifici             boo AV. Spatial analysis of transnasal olfactory
punti ossei sono state misurate. L’attendibilità inter-operatore è stata analizzata con il            cleft access: a computed tomography study. Acta
coefficiente di correlazione intraclassi.                                                             Otorhinolaryngol Ital 2023;43:197-202. https://
                                                                                                      doi.org/10.14639/0392-100X-N2118
Risultati. L’età media era 46,26 anni (σ = 14,0). La distanza media tra la spina nasale ante-
riore e la fessura olfattoria è stata di 52,3 mm (σ = 4,2 mm), la lunghezza media della fessura
                                                                                                    © Società Italiana di Otorinolaringoiatria
olfattoria è stata di 18,8 mm (σ = 3,8) con un angolo relativo al palato duro di -8,8 gradi         e Chirurgia Cervico-Facciale
sotto il parallelo (σ = 5,5 gradi). Le larghezze della fessura olfattoria ai bordi anteriore e
posteriore della lamina cribra sono state di 2,3 mm (σ = 0,7 mm) e 2,0 mm (σ = 0,7 mm).
                                                                                                                   OPEN ACCESS
Conclusioni. I dati ottenuti indicano una distanza di 52,3 mm dalla narice al bordo an-
teriore della lamina cribriforme. La larghezza media lungo questo passaggio è stata di              This is an open access article distributed in accordance with
                                                                                                    the CC-BY-NC-ND (Creative Commons Attribution-Non-
3,2 mm, suggerendo che dispositivi più stretti di questa misura potrebbero favorire la di-          Commercial-NoDerivatives 4.0 International) license. The
stribuzione diretta del farmaco in questa regione.                                                  article can be used by giving appropriate credit and mentio-
                                                                                                    ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: fessura olfattoria, trans cribriforme, applicazione intranasale di                   only in the original version. For further information: https://
farmaci, tomografia computerizzata                                                                  creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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T.J. Chan et al.




Introduction                                                        Data extraction
                                                                    Two authors (TC & ML) obtained two sets of bilateral
Over the past decade, the intranasal (IN) drug delivery
                                                                    measurements of the 100 selected CT scans in a blinded
route has gained interest in research and development. IN
                                                                    fashion in accordance with a pre-established measure-
drug administration has historically been used to topically
                                                                    ment protocol (Appendix 1). Patient scans were reviewed
treat symptoms of sinonasal conditions, such as chronic
                                                                    on Phillips IntelliSpace PACS Enterprise (4.4.541.0), the
rhinosinusitis (CRS), by delivering drugs directly to the
                                                                    institutional software, and measurements were made utilis-
olfactory cleft (OC) via IN squeeze bottles, spray pumps,
powered nebulisers and breath-powered bidirectional na-             ing the software localisation mode, ruler and angle tool.
sal devices 1. Recently, the trans-cribriform delivery route        The coronal and sagittal CT sinus images were analysed to
has become more prominent as an alternative approach to             establish spatial relationships of bone structures pertaining
deliver drugs to the OC in the treatment of several condi-          to the access to the OC. The anterior nasal spine (ANS)
tions, including Parkinson’s Disease, Alzheimer’s Disease           was selected as the anterior bony landmark for the entrance
and epilepsy 2-4. This route allows medications to bypass           into the nasal cavity. Measurements were made from ANS
the blood-brain barrier and directly enter the brain through        to anterior edge of bony middle turbinate, ANS to anterior
olfactory nerves, which results in fewer systemic side ef-          edge of cribriform plate, length of cribriform plate, angle
fects and increased local drug activity 1,5. Despite these ad-      of cribriform plate relative to hard palate, width of anterior/
vances, effective deposition of IN drugs to the OC remains          posterior edge of OC and approximated narrowest space
challenging due to its anatomic seclusion, and variations in        between middle turbinate and septum (Figs. 1-3).
sinonasal anatomy, devices, drug formulations and admin-
istration techniques 6,7.                                           Statistical analysis
Development of strategies to improve targeted application of        All analyses were performed using SPSS 27. Inter-rater re-
IN drugs to the OC may result in trans-cribriform pharma-           liability between the authors TC & ML was assessed using
ceuticals becoming more economically and physiologically            intraclass correlation (ICC). Model selection was 2-way
accessible 12. To improve drug delivery into the OC, we first       mixed effect model, type selection was mean of k raters.
must understand the spatial relationships of sinonasal struc-       An official guideline was not found regarding interpreta-
tures impeding access to the OC. A literature search on Web of      tion of ICC coefficients, however, general consensus agree
Science, Embase, and PubMed was completed. To our knowl-
edge, a study examining spatial distance and angle to the OC
has not been published. Hence, the purpose of this study is to
better characterise the OC relative to other sinonasal structures
to improve topical medication delivery vehicles for the OC.

Methods                                                                                 CP

Recruitment
One hundred computed tomography (CT) sinus imaging
scans of patients (50 males, 50 females) over the age of
18, with imaging cuts less than or equal to 1.3 mm were
consecutively included into our study from the principal
investigator’s clinical encounters, in reverse chronological
fashion. This was done at a single institution in Vancou-
ver, Canada. Scans were also required to have no reported
or appreciable sinonasal pathology (i.e. polyps, CRS, tu-
mours, malignancies), congenital deformities, past sinona-                  ANS
sal surgery, or variant anatomy (concha bullosa, paradoxi-
cal middle turbinates, concha lamella).
CT scans which met eligibility criteria were reviewed by
two authors (TC & ML) in a blinded fashion, and discrep-            Figure 1. Protocol for key measurements regarding Step 1.
                                                                    ANS was identified and marked on the midline image. Subsequently, the sagit-
ancies were resolved through discussion and deliberation            tal slice 1 slice lateral to each side, visualising the olfactory cleft, was selected
with senior author (AT). This was continued until 100 CT            to measure the distance between anterior CP and ANS. ANS: Anterior Nasal
scans were selected.                                                Spine. CP: Cribriform Plate.



198
                                                                                                                Spatial analysis of transnasal olfactory cleft access




                                                                                    coefficients > 0.9 = excellent reliability, 0.75-0.89 = good
                                                                                    reliability, 0.5-0.75 = fair reliability, < 0.5 = poor reliabil-
                                                                                    ity 15. An independent t-test was utilised when testing for
                                                                                    significant variations in sex-related average distances and
                                                                                    angles pertaining to access to OC.

                                                                                    Results
                                                                                    Patients
                                                                                    A total of 323 patient charts were consecutively reviewed,
                                                                                    100 of which were excluded due to history of past sinonasal
                                                                                    surgery, on-going radiographic rhinosinusitis, or CT slice
                                                                                    thickness > 1.3 mm. In a blinded fashion, two authors (TC
                                                                                    and ML) reviewed 232 patient scans to screen for anatomic
                                                                                    variants, on-going sinonasal disease, or abnormal masses
                                                                                    or lesions.
                                                                                    CT scans that were included were obtained between 2016-
                                                                                    2021. Overall, the mean age of patients was 46.3 ± 14.1
                                                                                    (range: 20-87). The baseline demographic of the males and
                                                                                    females cohorts was similar, with mean age of men being
                                                                                    46.1 ± 15.0 years (range: 20-87) and females 46.4 ± 13.1
                                                                                    years (range: 24-74). Despite normal CT scan, symptoms
                                                                                    most commonly reported by patients included obstruction
Figure 2. Protocol for key measurements regarding Step 2.                           (55%) and congestion (51%) (Tab. I).
The coronal series was selected and the most anterior image visualising ol-
factory cleft was identified and the width was then measured at the superior
most aspect.                                                                        Key findings
                                                                                    Measurements of 100 patients were collected in tandem by
                                                                                    two authors TC & ML yielding 200 sets of measurements,
                                                                                    two per patient.
                                                                                    The analysis revealed a mean population distance between
                                                                                    the anterior nasal spine and anterior cribriform plate of
                                                                                    52.3 mm ± 4.2 with good interrater reliability, Cohen’s
                                                                                    Kappa Coefficient (CKC) of 0.846. When performing a su-
                                                                                    banalysis of the cohorts, male subjects had a mean ANS to
                                                                                    anterior CP distance of 54.3 mm while females had a mean
                                                                                    distance of 50.4 mm (95% CI, p < 0.001) with a large effect
                                                                                    size (Cohen’s D: -1.055). Males also had a significantly
                                                                                    greater distance between the ANS and anterior head of the


                                                                                    Table I. Demographic data.
                                                                                     Presenting symptom
                                                                                    Congestion                                               51%
                                                                                    Pressure                                                 2%
                                                                                    Facial pain                                              29%
Figure 3. Protocol for key measurements regarding Step 3.                           Dysosmia                                                 26%
The anterior most image visualising contiguous middle turbinate attachment to
skull base was selected. The distance between middle turbinate and septum           Anterior nasal discharge                                 44%
of most superior, inferior and midline points were measured.                        Posterior nasal discharge                                29%
(A) width at superior limit of bony middle turbinate attachment; (B) width at in-   Obstruction                                              55%
ferior limit of bony middle turbinate attachment; (C) total distance AB; (D) half
distance between AB; (G) width at half distance between AB.                         Headaches                                                2%




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T.J. Chan et al.




middle turbinate compared to females by 3.1 mm (95% CI,                                       Discussion
p < 0.001, Cohen’s D -0.9).
                                                                                              In this CT study, we characterised key anatomic distances
The mean length of the cribriform plate was 18.8 mm ± 3.8
                                                                                              and relationships impeding drug delivery to the olfactory
mm with good interrater reliability (CKC = 0.730). Fe-                                        cleft. The key aspects we wanted to explore were how far
males had a mean length of 19.2 mm, while males had                                           was the OC, how large this space is, and how difficult is it
mean length of 18.4 mm. The difference of 0.8 mm was                                          to reach the intended space.
found to be significant (95% CI, p = 0.034), but Cohen D’s                                    When examining the mean distance in the population to the
coefficient illustrated a small effect size at 0.213 as seen in                               OC, the distance between anterior nasal spine and anterior
Table II.                                                                                     edge of cribriform plate was 52.3 mm with a standard de-
Mean population width of OC was 2.2 mm ± 0.6 with fair                                        viation of 4.2 mm. The sex specific subanalysis revealed
interrater reliability (CKC of 0.654). Females had a mean                                     that males had a 3.9 mm longer distance between ANS to
width of 2.2 mm and males a mean width of 2.1 mm. Fe-                                         anterior CP and likely represents more difficult application
males had a significant greater width of 0.1 mm (95% CI,                                      of drug to this space. This might be overcome with a can-
                                                                                              nulated drug applicator device with a longer cannula. Re-
p = 0.029) with an expected small effect size (Cohen’s
                                                                                              garding the size of the targeted space, we found the average
D = 0.219).
                                                                                              width of the OC to be 2.2 mm with a standard deviation of
A comprehensive compilation of other measurements char-                                       0.6 mm. Comparison of our values with existing volumetric
acterising the access to OC can be found in Table III.                                        studies on the length and width of the OC had consistent
                                                                                              findings 16. However, sex specific data was not previously
                                                                                              compared, and we found females had a significantly wider
Table II. Gender comparison for average measurements (mm).
                                                                                              OC by 0.1 mm. The clinical significance of this finding is
                            Male Female Significance Cohen’s
                                               (2-tailed) 1 D                                 to be determined. Lastly, regarding the difficulty reach-
    ANS to anterior CP             54.3        50.4         < 0.001          -1.055
                                                                                              ing targeted space, we found the mean distance between
                                                                                              middle turbinate and septum to be 3.2 mm with a stand-
    ANS to anterior MT             36.2        33.1         < 0.001            -0.9
                                                                                              ard deviation of 0.7 mm. Unsurprisingly, we also found a
    Anterior CP to posterior CP    18.4        19.2          0.034            0.213
                                                                                              greater distance at the inferior aspects of the bony middle
    Average width of OC             2.1         2.2          0.029            0.219
                                                                                              turbinate compared to superiorly near the OC. There was
    Average distance between        3.2         3.2          0.937            0.008
    MT & Septum
                                                                                              no sex specific difference found upon subanalysis. In our
1
 Independent t-test, equal variances not assumed. ANS: Anterior Nasal Spine; MT: Mid-         study, we also examined the slope of the OC relative to the
dle Turbinate; CP: Cribriform Plate.                                                          hard palate, as we had to control for variability angulation


Table III. Measurements characterising trajectory to olfactory cleft.
                                                 Average          Standard deviation                       Max                Min          ICC: intraclass
                                                                                                                                             correlation
    ANS to anterior MT                                   34.7 mm                     3.7 mm              46.9 mm            24.4 mm            0.955
    ANS to anterior CP                                   52.3 mm                     4.2 mm              66.9 mm            29.6 mm            0.846
    Anterior CP to posterior CP                          18.8 mm                     3.8 mm              34.5 mm            10.1 mm            0.730
    Angle CP relative to hard palate                      - 8.8°                       5.5°               16.2°              -24.1°            0.572
    Width of anterior CP                                 2.3 mm                      0.7 mm              6.6 mm             0.8 mm             0.654
    Width of posterior CP                                2.0 mm                      0.7 mm              4.8 mm             0.4 mm             0.544
    Average width of OC                                  2.2 mm                      0.6 mm              4.0 mm             0.6 mm             0.608
    Superior aspect
    Distance between MT & septum                          2.1 mm                     0.6 mm               8.6 mm            0.8 mm
    Middle aspect
    Distance between MT & septum                          2.6 mm                     0.9 mm               5.5 mm            0.4 mm
    Inferior aspect
    Distance between MT & septum                          5.0 mm                     1.4 mm              10.7 mm            0.8 mm
    Average distance between MT & septum                  3.2 mm                     0.7 mm               5.5 mm            1.7 mm             0.663
ANS: Anterior Nasal Spine; MT: Middle Turbinate; CP: Cribriform Plate; °: degrees.




200
                                                                                        Spatial analysis of transnasal olfactory cleft access




and positioning of patient’s head during the CT study. With        patterns of IN drugs, they are often difficult to perform and
the assumption the hard palate represented our landmark            can result in improper application technique.
for horizontal, we found that there was an average -8.8°           The results of this study cannot be interpreted without
angle of the OC in comparison with a standard deviation            considering its limitations. Sinonasal anatomic variation
of 5.5°. Though this implies a convergent relationship in          is highly prevalent among those with sinonasal conditions
the general population, we found this was not the case in          and this was seen in our study which was as evident by the
all individuals. A small minority of subjects had naturally        high number of CT scans excluded due to anatomic vari-
divergent sinonasal anatomy.                                       ants, on-going sinonasal disease, or abnormal masses or
Current available sinonasal medication delivery vehicles           lesions. As such, this presents as a particular challenge in
are not effective in OC drug deposition. In a study by New-        characterising the OC relative to other sinonasal structures
man et al., 56% of aerosols from a hand-activated pump             and developing effective standard IN drug delivery devices
spray deposited in the anterior portion of the nasal cavity,       for the OC. Further study is needed to explore spatial access
and 44% deposited in the nasopharynx after 30 minutes 8.           within these anatomic variants and how best to administer
While one of the primary functions of the nasal cavity is          IN drugs to the OC. Moreover, while our study protocol
to filter inhaled particles, it also prevents effective delivery   included examination of the angle and distance of maximal
of drugs to the OC 9. In inflammatory sinonasal patholo-           septal deviation, unfortunately nasal trauma history was
gies, turbinate inflammation can result in distal obstruc-         not routinely elucidated. As such, we could not delineate
tion, which prevents traditional intranasal products from          natural deviations versus deviations secondary to traumatic
dispersing medication to the OC 1. Common anatomic vari-           events. Realistically, this will have implications of intro-
ations of the middle turbinate (MT), such as concha bullo-         ducing a cannulate drug delivery device to the OC. Lastly,
sa, concha lamella and paradoxical middle turbinates, can          the measurement protocol was based on bony landmarks as
also serve as obstructions preventing particle distribution        these structures are not subject to physiologic changes of
to the OC 10. Beyond the lack of clinical benefit, improper        mucosa, while it also increases inter-rater reliability. In the
application and deposition of intranasal drugs may result          future, prospectively collected data set can be performed
in deleterious effects such as mucosal dryness, epistaxis,         to account for this variable. In additions, inherent limita-
nasal crusting and drying which can negatively impact the          tions of computed tomography studies are applicable to our
quality of life 7.                                                 study, as our views are limited to axial, coronal and sagittal
Previous studies have been performed to optimise inhala-           planes when trajectories often take oblique paths. However,
tion devices parameters and administration techniques to           we believe this study is still adequate as a proof of concept
improve drug delivery to the OC. A study by Cheng and              to guide a drug delivery prototype design that would re-
colleagues reported that larger nasal spray droplets and a         quire in vivo trials to validate. Lastly, we acknowledge the
wider spray plume angle increased the deposition in the            narrowest distance between middle turbinate and septum
anterior nose 11. Smaller droplet sizes and narrower plume         is an approximation, as it is based on a single, consistently
angles yielded larger deposition past the nasal valve, in-         identified, coronal section. A more accurate approximation
creasing the probability of reaching the OC 11. Using nasal        would require importing computational analysis of a ren-
airway casts, Xi et al. showed that the majority of nasal          dered 3D model of patient’s skull to identify the narrowest
spray droplets distributed in the anterior nose, while less        spot along the oblique trajectory from ANS to OC.
than 4.6% reached the olfactory region 12. Head position           With the characterisation of the access to OC, the next steps
has also been shown to affect particle deposition of intra-        would be to utilise the present findings to create a more
nasal medication in the nasal cavity. The Mygind technique         efficient drug delivery system to deliver medication to the
recommends administration in the supine position with the          cribriform plate. To date, squeeze bottles, spray pumps,
head extended off the end of a bed, and turning the head to        powered nebulisers and breath-powered bidirectional na-
the right and left for 30 seconds in each direction 7. This        sal devices are the primary means of delivering IN medi-
technique was shown to distribute particles from the ante-         cations 17. When focusing on drug deposition in the OC,
rior to the middle turbinate in the lateral aspect of the nose,    the delivery methods currently employed are grossly inef-
which is the region of maximal inflammatory response in            ficient. Xi et al. compared subsite specific deposition frac-
sinonasal conditions 13. The Kaiteki position which rec-           tions with various market nasal sprays and nebulisers which
ommends the lateral decubitus position with the neck and           revealed up to 4.59 and 9% deposition in upper olfactory
chin tilted upwards has also been recommended to increase          regions, respectively with perfect applicator technique 12.
particle distribution to the OC more than the upright po-          In the context of trans-cribriform drug delivery, this would
sition 14. While these positions promote better deposition         equate, at best, to 90% of drug depositing outside of the



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                                                                 13
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                                                                      tion of nasal drops. J Laryngol Otol 2000;114:456-459. https://doi.
Author contributions                                                  org/10.1258/0022215001905832
TC: conceptualization, methodology, analysis, original           14
                                                                      Milk DG, Khong GC, Çam OH, et al. A comparison between Mygind and
draft preparation, review and editing; ML: methodology,               Kaiteki positions in administration of drops to the olfactory cleft. Clin Oto-
analysis, original draft preparation, reviewing and editing;          laryngol 2021;46:406-411. https://doi.org/10.1111/coa.13690
AT: conceptualization, methodology, originaly draft prepa-
                                                                 15
                                                                      Koo TK, Li MY. A Guideline of selecting and reporting intraclass cor-
                                                                      relation coefficients for reliability research. J Chiropr Med 2016;15:155-
ration, review and editing. The authors read and approved             163. https://doi.org/10.1016/j.jcm.2016.02.012
the final manuscript.                                            16
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                                                                      ume: possible risk factors for postinfectious olfactory dysfunction. La-
Ethical consideration                                                 ryngoscope 2021;131:5-9. https://doi.org/10.1002/LARY.28524
This study received ethics clearance by the University of        17
                                                                      Maaz A, Blagbrough IS, Bank PA De. In vitro evaluation of nasal aerosol
                                                                      depositions: an insight for direct nose to brain drug delivery. Pharmaceutics
British Columbia Providence Health Care Research Ethics               2021;13:1079. https://doi.org/10.3390/PHARMACEUTICS13071079
Board (UBC PHC REB), certificate H21-00083.                      18
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The research was conducted ethically, with all study pro-             the real size of nano-costs. Nanomedicine (Lond) 2019;14:1367-1370.
cedures being performed in accordance with the require-               https://doi.org/10.2217/NNM-2019-0130
ments of the World Medical Association’s Declaration of          19
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Helsinki.                                                             analysis of liposomal amphotericin B versus conventional ampho-
                                                                      tericin B in the empirical treatment of persistently febrile neutropenic
Written informed consent was obtained from each partici-              patients. J Clin Oncol 2000;18:2476-2483. https://doi.org/10.1200/
pant/patient for study participation and data publication.            JCO.2000.18.12.2476 [Erratum in: J Clin Oncol 2000;18:3064].




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