The Engage Study is a longitudinal biobehavioral cohort study of gay, bisexual and other men who have sex with men (GBM) in Toronto, Montreal, and Vancouver. Baseline data  were collected from February 2017 - August 2019 using respondent-driven sampling (RDS). Recruitment in Montreal required fewer seeds, had a much shorter recruitment period, and recruited the largest sample.To better understand why RDS recruitment was more successful in Montreal compared to other sites, we conducted an analysis to examine RDS recruitment characteristics for GBM in each of the three study sites, explore demographic characteristics and measures of homophily, that is, the tendency of individuals to recruit other study participants who are like themselves, and compared motivations for study participation.Montreal had the greatest proportion of participants over the age of 45  and the highest homophily for this age group, but homophily was high across the three cities. Montreal also reported the lowest percentage of participants with an annual income greater or equal to $60,000 , but homophily was similar across all three cities. The majority of participants indicated interest in sexual health and HIV as the main reason for participating . Financial interest as the main reason for participation was low .Taken together, although we found some differences in study demographic characteristics and homophily scores, we were unable to fully explain the different recruitment success based on the data available. Our study underlines the fact that success of RDS implementation may vary by unknown factors, and that researchers should be proactive and flexible to account for variability. Gay, bisexual, and other men who have sex with men (GBM) are disproportionately affected by HIV in Canada, with 41.4% of new diagnoses attributed to adult GBM in 2018 , clinicaThe Engage Study is a cohort study of GBM in Canada’s three largest cities  . The stuFor studies using RDS methodology, recruitment success in terms of sample size, recruitment time, and diversity of samples has varied. Where researchers have evaluated RDS methodology among GBM, many have linked sociodemographic characteristics and recruitment productivity –11. WirtUsing data from The Engage Study, we conducted an analysis to (1) examine RDS recruitment characteristics for GBM in each of the three study sites, with an emphasis on differences in the Montreal site compared with the other two sites, (2) examine homophily recruitment estimates in each of the three sites, including demographic characteristics, and (3) participant’s motivations for joining the study. Using these metrics, we aimed to analyze why RDS recruitment was more effective in Montreal compared to the other study sites.Eligibility criteria for The Engage Study included: being at least 16 years of age, identify as a man (including trans men), reporting sex with another man in the past six months, currently living in Vancouver, Toronto, or Montreal, and being able to complete the questionnaire in English or French . Seeds were mainly recruited with the assistance of our Community Engagement Committees (CEC), comprising staff from local community-based organizations focused on GBM health promotion, including AIDS service organizations and diverse GBM community members. In Toronto and Vancouver, we also used advertisements on social networking applications, such as Grindr, Growlr, and Squirt, as well as posts on Facebook and Craigslist to raise awareness of the study and recruit potential seeds . Of the Participants completed a computer-assisted self-interview (CASI) which asked questions about sexual behaviours, sexual health, substance use, and demographics. Participants also completed a nursing visit where a study nurse performed screening for sexually transmitted infections (STIs) and HIV. For further information on the specific tests, please see Hart et al. (2021) . For eacRDS process indicators included the date of first interview and the last interview date of participants, and the time difference in days between recruitment periods. We also included the number of seeds, number of productive seeds , the percentage of productive seeds among all seeds, the number of RDS coupons given to participants, chain length (the number of successive RDS recruitment waves), chain size (number of participants from an RDS branch) per RDS chain/seed, the wave at which participants were recruited , and the total number of participants in the recruitment chain that the participant is a part of (measured at the participant-level). Further, we asked participants about their main reason for participating in the study and their relationship to the person from whom they received their coupon. Sociodemographic measures included age, race/ethnicity, identification as a person of colour, annual income, education, current employment, whether participants were born in Canada, gender identity/transgender identity (based on birth sex and current gender identity) and sexual identity. These demographic characteristics were identified based on previously assessed literature exploring differential success using RDS among GBM . We alsoFor each city, we provided crude point estimates for RDS recruitment characteristics. We also illustrate the number of seeds and participants in each respective city and recruitment period . Kruskal–Wallis tests were used to compare RDS recruitment characteristics between the three cities . We also assessed sociodemographic characteristics by city and provide crude and RDS adjusted estimates (using RDS-II weights) and 95% confidence intervals. RDS-II weights were based on participant’s social network from the question: “How many men who have sex with men aged 16 years or older, including trans men, do you know who live or work in the Metro Vancouver/Toronto/Montreal area?” . Furthep = 0.001) and chain size (p = 0.001), we found significant differences between the three cities. Montreal had the greatest number of participants in their recruitment chain  compared to Vancouver  and Toronto ; p < 0.001. Full results are in Table A total of 2,449 participants were recruited: 753 GBM in Vancouver, 517 GBM in Toronto, and 1179 GBM in Montreal. Vancouver recruited 117 initial seeds of which 60.7% were productive . Toronto recruited 96 seeds of which 55.2% were productive. Montreal accounted for the smallest number of total seeds (n = 27) and had the greatest percentage of productive seeds (77.8%) compared to the other cities. Montreal obtained the largest sample size over the shortest recruitment period across the three cities (493 days). Assessing RDS process indicators, Montreal also had the largest average chain length  and chain size  per RDS chain per seed. For both chain length (Table p < 0.001). Montreal also had greater homophily for recruiting participants 45 years of age and older (0.63) compared to (0.53) for Vancouver and (0.50) for Toronto, but homophily for all three sites were substantially high. Across all three cities, the majority of GBM self-identified as having Canadian ethnicity, with 40.0% identifying as Canadian in Vancouver, 34.8% in Toronto, and 55.0% in Montreal (p < 0.001). Homophily results for ethnoracial identity reflected these differences and was substantially high in Montreal (0.42) compared to Toronto (0.21) and Vancouver (0.26). Regarding annual income, 61.3% of GBM reported an annual income of less than $30,000 in Vancouver, compared to 57.4% in Toronto, and 66.8% in Montreal. However, homophily measures were similar and low across the three cities, Montreal (-0.02), Toronto, (-0.03) and Vancouver (-0.03). Conversely, Montreal reported the lowest percentage of participants with an annual income $60,000 and greater (7.9%) compared to 13.1% in Vancouver and 10.6% in Toronto (p < 0.001). Homophily results for high income participants were similar and relatively high across the three cities, Montreal (0.28), Toronto (0.33), and Vancouver (0.30). Montreal had the highest homophily (0.16) for recruiting participants with annual incomes $30,000–59,000 compared to Toronto (0.10) and Vancouver (0.05), but all values were quite low, indicating limited impact on recruitment. For education, we found that Montreal had the highest proportion of participants who reported a high school or equivalent education (25.4%) compared to Toronto (12.1%) and Vancouver (16.5%) (p < 0.001). However, homophily results were similar and low across the three cities: 0.04 in both Montreal and Toronto, and 0.14 in Vancouver, indicating little effect on recruitment. We also found 76.8% of participants in Vancouver reported having a greater than high school education, compared to 77.2% in Toronto and 64.3% in Montreal (p < 0.001). Homophily values suggest a moderate impact of education on participant characteristics across all 3 cities, with 0.37 in Montreal, 0.46 in Toronto, and 0.32 in Vancouver. Lastly, we found 62.5% of participants in Vancouver self-reported negative HIV serostatus, compared to 65.4% in Toronto and 73.7% in Montreal (p < 0.001). Homophily results reflected these differences, as Montreal had lower homophily for recruiting HIV-negative GBM (0.24) compared to Vancouver (0.54) and Toronto (0.34), which were substantially higher. For GBM who self-identified as living with HIV, Montreal had the lowest proportion of participants (12.7%) compared to Toronto (18.4%) and Vancouver (19.4%). However, homophily results were substantially high across the three cities, Montreal (0.39), Toronto (0.42), and Vancouver (0.41). Financial strain in Vancouver (adjusted median:6) was lower compared to Toronto (adjusted median: 7) and Montreal (adjusted median: 7) (p < 0.001). Full sociodemographic results can be found in Table Overall, 45.4% of recruits in Vancouver were under age 30, compared with 50.7% under 30 in Toronto, and Montreal had the lowest proportion (36.4%). Homophily results highlight lower homophily in Toronto for participants recruited under 30 years of age (0.09), compared to Montreal (0.44) and Vancouver (0.40). Conversely, Montreal had the largest proportion of participants who were 45 years and older (29.1%), compared to 24.6% in Vancouver and 21.0% in Toronto. (p < 0.001). Homophily results for this outcome were mixed , and homophily was low overall. Full results are in Table Overall, the most reported reason for participation was being “interested in sexual health and HIV”, with 34.7% identifying this as their primary motive for study participation in Vancouver, 29.8% in Toronto, and 36.1% in Montreal. There were wide variations in homophily results between the three cities for this response . However, homophily was very low overall, signalling little effect on within group recruitment. Assessing the relationship participants had with their recruiter, participants from Montreal were more likely to indicate they were referred by an acquaintance (28.4%), compared to Toronto (11.2%) and Vancouver (19.0%)  and the highest proportion of participants aged 45 or older  across the three cities. While homophily was high across all three sites (0.50 for Toronto and 0.53 for Vancouver), homophily was greatest in Montreal (0.63) for recruiting participants 45 years or over. Homophily results imply that GBM over 45 years old from Montreal recruited from within their age group 63% of the time, and GBM from Vancouver 53% of the time, and GBM from Toronto 50% of the time. Age results possibly suggest that older recruits with closer social networks were associated with recruitment success , 29. TheRegarding income, Montreal had the highest proportion of participants with an annual income less than $30,000 and the lowest proportion with an annual income greater than $60,000. We found high homophily for participants with an annual income greater than $60,000 across all three study sites. Our findings are aligned with other research which has found that individuals with similar income levels tend to be connected with each other in social networks , 32. HowWe also cannot conclude that the financial incentive was the cause for RDS success in Montreal, as the majority of participants reported “interest in sexual health and HIV” as the main reason for their participation (36.1%), which was similar to results from Toronto and Vancouver. Furthermore, only 12.7% of participants from Montreal indicated their main interest in study participation was the financial incentive compared to 5.7% in Toronto and 10.6% in Vancouver. Homophily for the financial incentive in Montreal was also low (0.14), while homophily in Toronto was − 0.43 and in Vancouver, 0.06. To further understand the importance and impact of participant motivation, we propose expanding questions on motivations to include perceptions and experiences with the organization leading the study, having a better sense of participant ease and interest in engaging in research.We also found that Montreal had the greatest proportion of participants to self-identify their ethnicity as Canadian (55.0%), and homophily results reflected these differences, as homophily for Canadian ethnicity was highest in Montreal (0.42), whereas other sites homophily were not substantial. These ethnic identity differences are consistent with Montreal’s population demographics, where according to data from the Canadian Census, the percentage of residents who identify their racial origin as Canadian is higher compared to Toronto and Vancouver . HoweverFinally, Montreal had the lowest proportion of participants who self-reported as HIV-positive and the highest proportion of participants who were HIV-negative. Homophily for HIV-negative status was substantially lower in Montreal (0.24) compared to the other sites, but we found homophily for recruiting GBM living with HIV to be substantially high across the three cities. These findings are in contrast with previous homophily research, which found very low rates of homophily among GBM living with HIV and negative scores of homophily for HIV-negative GBM . OverallDifferences in the success of RDS may also be associated with geography and culture. Montreal has a distinct French-speaking culture with a significantly different history and identity compared to most large Canadian cities. Of note, Montreal has one of the largest gay villages  in North America . CorrespOur study findings are similar to previous research from Murill et al. (2016), which found significant differences in seed numbers, productivity of seeds and recruits in their three-city RDS study among Black and Latino GBM in New York, Los Angeles and Philadelphia. The authors suggest that differences in population characteristics may reflect each city, but suggest that differences may be due to inevitable data collection and implementation at each site . Our stuThis study has a number of strengths and limitations. First, our study only has data for those who chose to participate in our study. Ideally, we would have liked to have information on potential participants who were invited but declined participation, which was not possible. Furthermore, RDS recruitment is based on social networks, and GBM who are not connected with the lesbian, gay, bisexual, transgender, two-spirit, and queer (LGBT2Q) communities, or those who are isolated may be underrepresented. Although we attempt to address this limitation by identifying hidden subpopulations and recruiting purposeful and diverse seeds, individuals who are not “out” and unknown to researchers may have led to some selection bias and confounding. A challenge with RDS is choosing seeds who are well connected with other individuals in the population of interest, potentially excluding other hidden populations. However, starting with seeds who are less connected and harder to find may limit the RDS process of chain-referral sampling since this involves peer recruitment. Finally, a general limitation of RDS is its generalizability to the actual population of interest, which also applies to the study presented here.Despite these limitations, a major strength of this study is that we had three sites which allowed us to compare RDS characteristics between them and used the same recruitment strategies and study procedures in each city. Overall, RDS methodology is an economical and beneficial methodology for reaching hard-to-reach populations who may not be accessible at traditional venues, and who may have not participated in research on their own.Our study examined multiple factors to explain differences in recruitment success for Engage in Montreal, Toronto, and Vancouver. While we found some differences in participant characteristics and homophily, these differences were minimal and likely did not have a major impact on recruitment in Montreal. Notably, we found no differences in reported reasons for study recruitment across sites. While we support the use of RDS as a recruitment strategy for studies of GBM in different settings, our study underlines the fact that success of implementation may vary by unknown factors, and that researchers should be proactive and flexible to account for variability. Further research is needed to understand how and why RDS works well or does not work in the many settings in which it is being used.


Subjects followed a run‐in protocol prior to measurements. The coefficient of variation (CV) and intraclass correlation coefficient (ICC) were calculated for ventilation rates of O2 (VO2), CO2 (VCO2), the respiratory quotient , and RMR. Technical validation showed good validity with CVs ranging from 0.67% for VO2 to 1.00% for energy expenditure. For biological reproducibility, CVs were 2.89% for VO2; 2.67% for VCO2; 1.95% for RQ; and 2.68% for RMR. With the exception of RQ (74%), ICCs were excellent for VO2 (94%), VCO2 (96%) and RMR (95%). Excluding participants that deviated from the run‐in protocol did not alter results. In conclusion, the 7500 L WRIC is technically valid and reproducible for ventilation rates and RMR.Whole‐room indirect calorimeters (WRICs) provide accurate instruments for the measurement of respiratory exchange, energy expenditure, and macronutrient oxidation. Here, we aimed to determine the validity and reproducibility of a 7500 L WRIC for the measurement of ventilation rates and resting metabolic rate (RMR). Technical validation was performed with propane combustion tests ( Whole‐room indirect calorimetry is an accurate method for measuring metabolic rates. Here, we report that a newly built whole‐room indirect calorimeter at the Department of Nutrition, University of Oslo provides valid and reproducible measurements of resting metabolic rate. According to newly established guidelines for using and reporting WRIC facilities, it is recommended that validation and reproducibility experiments on energy expenditure (EE) and metabolic rates are performed and published  measured using the WRIC specific for RMR. This involved the determination of oxygen , carbon dioxide , and water vapor pressure  according to previously published protocols  and the respiratory quotient  of CO2, CO2, and WVP concentrations are measured by a Promethion GA3m2/FG‐250  integrated metabolic instrumentation. This instrumentation contains dual CO2, O2, and WVP sensors that alternate between measuring gas concentrations in the incurrent (baseline air from the buffer space) and excurrent air streams, thus maintaining a continuous measurement of the subject's respiratory exchange within the RMR‐WRIC.Fresh outside air is infused into the buffer spaces surrounding the WRIC by the main building's heating, ventilation, and air‐conditioning system. This system ensures a slight overpressure to prevent any outwards leaks from the WRIC and maintains an air temperature of 22°C. Air is directed from the buffer space into the WRIC at floor level. The WRIC is equipped with a heat pump unit  that maintains a temperature of 22°C and set at a low fan speed to mix respiratory gases. Air is continuously pulled from the RMR‐WRIC at a constant flow rate of 100 L/min, and ORaw data were acquired by Caloscreen 1.3.16  and processed by ExpeData 1.9.27 . This software contains a macro code for mathematically processing the data including signal preconditioning, WVP dilution correction, and conversion to standard pressure, as well as baseline drift correction from incurrent air measurements, mathematically drying the air stream, background baselining for each of the two analyzers and correcting for room response using z‐transformation   were performed in accordance with methods outlined in , smoking, chronic disease with known effects on energy expenditure, pregnancy, lactation, unstable weight the past 3 months (± 5%) and self‐reported claustrophobia. Participants gave written informed consents, and a letter of exempt was provided from the Regional Ethical Committee, as the project was considered methodological and not health research (Reference number: 368847). The project was approved by the Data Protection Services (SIKT) (Reference number: 359371).For the reproducibility/biological validation study, students and staff at the Department of Nutrition, University of Oslo were recruited for two consecutive measurements separated by 24‐h between March and June in 2022. In total, 20 participants (6 men and 14 women) were included. One participant was excluded from the analysis because of illness at measurement Day 2, bringing the final number of participants to 19 (6 men and 13 women)  prior to each measurement, participants were asked to refrain from caffeine intake  and vigorous exercise such as going to the gym or for a run. The participants were required to fast for 12 h and advised to sleep for 6 to 8 h prior to the measurement. Protocol adherence was checked by (1) a 24‐h dietary recall at the first measurement day, and (2) activity and sleep monitoring the final 24 h before measurements using SenseWear Armband Mini (BodyMedia), which has been validated for measuring physical activity and sleep in several populations ), and 24‐h recall interviews were performed immediately on arrival on Day 1. Brand names and recipe ingredients were registered. The food items were quantified by household measures and a booklet containing photographs of foods in different portion sizes Norkost, . Intake 2.62, VCO2, energy expenditure, and RQ were compared using independent t‐tests. For reproducibility, the primary outcome variables were VO2, VCO2, RMR, and RQ. Repeated measures were compared using paired t‐tests. Correlational analyses for Day 1 and Day 2 were performed using Pearson correlation. Measures of accuracy and precision included crude relative mean differences between the two measurements and the coefficient of variation  for each subject. The intraclass correlation coefficient (ICC) was derived from linear mixed regression models with the outcome variable as the dependent variable, no independent variable, and a random term for subject ID. Pearson correlation coefficients and ICCs >0.9 were defined as strong or excellent based on terminology used in a previous report , the mean (SD) amount of propane burned was 13.79 ± 2.16 g with an average burn rate of 0.2279 ± 0.037 g/min. Details from the tests are given in Table 2 to 1.32 (1.07) % for energy expenditure, whereas the CVs ranged from 0.67% for VO2 to 1.00% for energy expenditure. There was a near‐perfect correlation between expected and measured values (r > 0.99).For the propane combustion tests n = 0, the me3.2n = 6 males, n = 13 females) were on average 39.6 ± 15 years old with a BMI of 23.5 ± 2.7 kg/m2. In the 24 h before each visit, the subjects spent a median  of 1  minute doing vigorous physical activity  2102  kcal/d. Percent of energy from protein intake was 17 , carbohydrate intake was 46 , and fat intake was 33 .Of the 19 participants, one reported vigorous physical activity (biking to work) whereas five consumed caffeinated beverages −24 h before measurements. These were kept in the final analyses but excluded in sensitivity analyses reported under Sensitivity analyses and sources of RQ variability.3.32, VCO2, and RMR showed excellent reliability as assessed by ICC (94%–96%), with CVs at 2.89% for VO2, 2.67% for VCO2, and 2.68% for RMR. There were no significant differences between Day 1 and Day 2 for VO2, VCO2, and RMR. For RQ, ICC was lower at 74% with a CV of 1.95%, and there was a significant difference between Day 1 and Day 2 .Mean values, relative differences, deltas, CVs, ICCs, and correlation coefficients for each measurement day are shown in Table 2, the limits of agreement ranged from −42.1 to 30.1 L/day; for VCO2 from −25.9 to 24.1 L/day; for RQ from −0.06 to 0.03; and for RMR from −143 to 189. There was no evidence of proportional bias indicating that there were no significant changes in the individual differences with higher values of VO2, VCO2, RQ, or RMR .The Bland–Altman plots in Figure 3.4With the exception of a decrease in the ICC for RQ from 74 to 69%, all parameters were generally similar in sensitivity analyses excluding non‐compliant subjects . However, there was a significant, inverse association between VO2 residuals and RQ residuals .We and others  would also have been desirable to increase accuracy, precision and usability, and to be in line with previous validation studies (Allerton et al., 52, VCO2, and RMR with excellent reliability, whereas RQ was measured with acceptable reliability. These findings are of crucial importance for future research and clinical applications with RMR as the outcome.In conclusion, we have demonstrated that a 7500 L WRIC measures VOTO conceived the idea for the study; HBH, CH, RD, FH, SMU, and TO designed the study; HBH, CH, ARSS, DTA, EMSA, and TO collected data; RR customized the macro files used to estimate metabolic rates; ABW and RB made intellectual contributions; HBH and TO drafted the paper; All authors read, revised, and approved the final version of the paper.This project received support from Direktør Throne Holsts Fond For Ernæringsforskning and the University of Oslo.The authors declare no conflicts of interest.


Pou3f4y−/ mice based on an adeno‐associated viral (AAV) vector‐mediated gene transfer in cochlear spiral ligament fibrocytes. Among a broad range of AAV vectors, AAV7 was found to show a strong tropism for the spiral ligament. Thus, we suggest that an AAV7‐mediated delivery of Pou3f4 complementary DNA in the spiral ligament of Pou3f4y−/ mice could represent an attractive strategy to prevent fibrocyte degeneration and to restore normal cochlear functions and properties, including a positive endocochlear potential, before hearing loss progresses to profound deafness.Mutations and deletions in the gene or upstream of the gene encoding the POU3F4 transcription factor cause X‐linked progressive deafness DFNX2 and additional neurodevelopmental disorders in humans. Hearing loss can be purely sensorineural or mixed, that is, with both conductive and sensorineural components. Affected males show anatomical abnormalities of the inner ear, which are jointly defined as incomplete partition type III. Current approaches to improve hearing and speech skills of DFNX2 patients do not seem to be fully effective. Owing to inner ear malformations, cochlear implantation is surgically difficult and may predispose towards severe complications. Even in cases where implantation is safely performed, hearing and speech outcomes remain highly variable among patients. Mouse models for DFNX2 deafness revealed that sensorineural loss could arise from a dysfunction of spiral ligament fibrocytes in the lateral wall of the cochlea, which leads to reduced endocochlear potential. Highly positive endocochlear potential is critical for sensory hair cell mechanotransduction and hearing. In this context, here, we propose to develop a therapeutic approach in male  Pou3f4y−/ mice show progressive hearing loss, reduced endocochlear potential, and damaged spiral ligament. Among a broad range of AAV vectors, AAV7 shows strong tropism for the spiral ligament. Thus, we suggest that AAV7‐Pou3f4 transduction in newborn Pou3f4y−/ mice could help to restore cochlear functions and properties, including a positive endocochlear potential, before hearing loss progresses to profound deafness.Hearing loss is the most frequent congenital sensory disability. About 1–3 in 1000 children are affected at birth or during early childhood by severe hearing losswhich is defined as prelingual deafness, with at least half of all cases having a genetic origin. Mutations and deletions in the gene or upstream of the gene encoding the POU3F4 transcription factor cause X‐linked progressive deafness DFNX2 with inner ear malformations and additional neurodevelopmental disorders. Hearing and speech outcomes after cochlear implantation remain highly variable among patients.  About 1%–5% of nonsyndromic hearing loss is likely to be caused by a disease gene on the X chromosome .POU3F4 gene were first described in 1995 after its localization to the X chromosome in 1988 (Xq21 band).POU3F4 have been identified in some 20 countries, including missense, nonsense, deletion, frameshift, and extension mutations  were also reported.POU3F4 mutations, accounts for nearly 50% of all cases of X‐linked hearing loss. Although most cases are inherited from the carrier mother, a significant proportion (up to 20% in Eastern Asia) of POU3F4 mutations also occur de novo.POU3F4 gene. The relatively high frequency of de novo mutations is one reason for the rather high incidence of sporadic cases of X‐linked deafness DFNX2, meaning that it is not always possible to predict POU3F4 variants from a family history. Affected males present heterogeneous forms of deafness. Hearing loss can be purely sensorineural or mixed (±50% for both types), that is, with both conductive and sensorineural components, with a variable age of onset and rapid progression to severe hearing loss of all tones in the first decade. DFNX2 patients show anatomical abnormalities on computerized tomography of the temporal bone. Bilateral malformations of the vestibule, enlarged internal auditory canal and vestibular aqueduct, cochlear hypoplasia, and absence of modiolus  are jointly defined as incomplete partition type III  performed to correct the conductive loss often results in perilymphatic gusher and leakage of cerebrospinal fluid, which can cause dizziness and worsen hearing loss.4Pou3f4‐deficient mice recapitulate the main inner ear defects observed in DFNX2 patients, such as cochlear hypoplasia and absence of modiolus  and the positive endocochlear potential  are generated by the stria vascularis in the lateral wall of the cochlear duct. The ion composition of the endolymph resembles intracellular fluid, whereas that of the perilymph, which is contained in scalae vestibuli and tympani, corresponds to usual extracellular fluids (with ±5 mM [K+]). Electrophysiological analyses revealed that Pou3f4−/y male and Pou3f4−/− female mice show progressive hearing loss leading to profound deafness at three months of age, as well as a marked reduction in endocochlear potential.S, between amino acids 186 and 260) and a POU‐homeodomain , both of which have a helix–turn–helix pattern and determine DNA specificity and binding.S and two within the POUHD.275QGRKRKKRTS284) within the POUHD. If bipartite, the NLS would be most likely located between amino acids 277 and 303. In either case, the POUHD, rather than POUS, would be critical for nuclear localization  and that directly border the scala vestibuli. These suprastrial SLFs have a markedly reduced cytoplasmic volume, and the extracellular matrix is extremely sparse  is an effective nonpathogenic in vivo gene‐transfer vector that can be used for treating hearing loss in mouse models of human genetic deafness.SLC26A4, which encodes pendrin, cause hearing loss associated with enlargement of the vestibular aqueduct. Kim et al.Slc26a4‐deficient mice. In any case, the viral vector should be chosen to achieve the best match possible with the gene expression profile. Current knowledge suggests that, among a broad range of AAVs, AAV7 appears to be the vector that best matches with Pou3f4 expression in the cochlea. AAV7 especially shows a strong tropism for the entire spiral ligament and for the spiral limbus, whereas this vector minimally transduces the inner and outer sensory hair cells (Figure Pou3f4−/y mice represents an attractive strategy to prevent SLF degeneration and to restore normal cochlear functions before hearing loss progresses to profound deafness. Intracochlear viral transduction of AAV7‐Pou3f4‐EGFP construct should be performed in 3‐day‐old Pou3f4−/y mice, that is, as early as possible and before the presumed degeneration of SLFs begins in these animals (Figure Pou3f4−/y mice, different delivery routes could be tested to achieve the best transduction efficiency of cochlear SLFs. The most usual and successful way of delivering vectors or drugs to the inner ear is an intracochlear approach, via the round window membrane. Another attractive option might be to consider direct administration into the scala media compartment via cochleostomy. In the present case, gene therapy is not expected to reverse Pou3f4‐related inner ear malformations. Rather, the main objectives should be to examine whether Pou3f4 cDNA transfer in the spiral ligament of Pou3f4−/y mice restores long‐term cochlear functions assessed by auditory brainstem responses and measurement of endocochlear potential. Wild‐type, AAV7‐Pou3f4‐transduced Pou3f4−/y, and nontransduced Pou3f4−/y animals should be tested and compared from the age of 21 days (Figure As mentioned above, current therapeutic approaches to improve hearing and speech skills of DFNX2 patients still remain a major challenge and these strategies do not seem to be fully effective. In this context, here, we propose to develop a therapeutic approach in male Jean Defourny was involved in the conceptualization of the study and writing of the manuscript—original draft.The author declares no conflict of interest.Not applicable.


This article aims to ascertain the prevalence of loss of hearing in patients with chronic kidney disease (CKD) and also to examine potential causes of sensorineural hearing loss (SNHL) in patients suffering from CKD. It has been discovered in recent years that there is a relationship between the occurrence of SNHL and CKD. Nowadays many people are suffering from CKD. These patients deal with several otorhinolaryngological issues, such as SNHL, candidiasis, epistaxis, halitosis, dysgeusia, xerostomia, and lip and thyroid malignancies. One of the most frequent otorhinolaryngological complications is audiovestibular system impairment. There are various proposed mechanisms for the appearance of loss of hearing in people suffering from CKD. The kidney and the inner ear have multiple functional and structural similarities, which may be the cause of these problems in CKD patients. In addition, changes in the homeostasis of water and electrolytes can affect the endolymphatic fluid and result in endolymphatic hydrops. Finally, some medications, like aminoglycosides and loop diuretics, are well known for their ototoxicity and are utilized to treat patients with CKD. Only a small number of population-based research have so far been able to show a connection between CKD and audiovestibular system impairment. Some investigation has shown that CKD patients are more likely than healthy people to experience vestibular impairment.The quality of life of a patient can be reduced by hearing loss. People with hearing loss experience communication issues in daily life, which negatively affects their cognitive and psychosocial functioning. Social isolation and a poor quality of life in terms of health can all result from hearing loss. In addition, decreased renal function has also been linked to poor quality of life, hospitalization, and cognitive dysfunction. The most crucial hearing organ is the ear. It has three sections: 1) external ear, 2) middle ear, and 3) inner ear. The term "labyrinth" also refers to the inner ear. It comprises the cochlea, which is important for hearing, and the vestibular apparatus, which controls balance. Sound energy from the environment passes through the external and middle ear and is transformed into mechanical energy. The labyrinth then receives this mechanical energy. Then the labyrinth converts this mechanical energy into electrical energy. The final organ for hearing is the cochlea. The functional hearing processing unit is present inside the cochlea and is called the organ of Corti. This organ has an extreme sensitivity to the surrounding chemicals. Ototoxicity, or toxic damage to the ear, is caused by changes in the organ of Corti's physiological environment. Several factors deteriorate the labyrinth's functionality. These include aging, drugs, and some acquired and congenital disorders [The kidney is the organ that is most crucial for the removal of toxic chemicals from the body, thus it provides an ideal environment for the vital organs to work properly. Different renal disorders harm the labyrinth, it is because toxic compounds build up in the blood which impairs the inner ear’s functions. The nephron is a functioning unit of the kidney and it resembles the stria vascularis found in the inner ear both structurally and functionally. Due to this link, both organs are susceptible to the same agents and genetic alterations while still in the womb .- ions through the cell membrane is mediated by the ClC proteins [-/H+ antiporters, Cl- channels, and CLC-K channels. The essential subunit of the ClC-K channel is the barttin protein. Both the kidney and the labyrinth contain these transporters and channels [- and Na+ are absorbed again into the circulation via ClC-kb channels and Na+/K+ ATPase, respectively. Basolateral NKCC1 transporters in the stria vascularis aid in the movement of K+, Na+, and Cl- within the cells. ClC-Ks isomers and Na+/K+ ATPase, respectively, aid in the extrusion of Cl- and Na+ back into the interstitium. K+ levels rise in the endolymph due to the activity of the KCNQ1/KCNE1 channel, which is necessary for the sensory transduction of inner hair cells [The voltage-dependent movement of Clproteins . The CLCchannels -5. The nir cells . Both thir cells . They arLoss of hearing in chronic kidney diseasesThe quality of life of a patient can be reduced by hearing loss . ChronicIn people suffering from kidney failure, uremia affects almost every organ system of our body . NumerouCauses of loss of hearing in patients with CKDPeople suffering from CKD may experience hearing loss due to a variety of reasons viz, heredity, uremic problems, and pharmaceutical adverse effects  is commonly known as hereditary nephritis. It is a well-known causative factor of CKD in young people. Gradual renal failure, distinctive ocular abnormalities, and SNHL are hallmarks of AS . One in The type IV collagen α3, α4, and α5 chains are coded by the genes COL4A3, COL4A4, and COL4A5, respectively. The alterations in the above-mentioned genes result in AS . DependiAS occurs due to the mutation in the gene encoding for type IV collagen . Due to Branchio-oto-renal (BOR) syndrome: Ear and kidney problems occur simultaneously in BOR syndrome. Bilateral hypoplasia or dysplasia, bilateral renal agenesis, unilateral renal agenesis with contralateral hypoplasia or dysplasia, vesicoureteric reflux, and ureteropelvic obstruction are all examples of renal abnormalities. The glomerular filtration rate of the kidneys might be normal or severely reduced. Ear abnormalities include preauricular pits, hearing loss, and deformity in the external ear, middle ear, and labyrinth .Branchiogenic malformations , loss of hearing, and kidney problems, including congenital deformities of the kidney and urinary tract, are features of the autosomal dominant condition known as BOR syndrome . About 1+/K+ pump produces a Na+ electrochemical gradient which triggers the secondary active transport of NKCC2, which is expressed at the apical membrane, which causes sodium ion, chloride ion, and potassium ion to accumulate inside the cell. Potassium ions are returned to the lumen by ROMK K+ channels , whereas Cl- and Na+ are reabsorbed by the interstitial fluid through the ClC-Kb channels and Na+/K+ pump respectively. In the basolateral membrane of marginal cells of the stria vascularis of the labyrinth, both ClC-K isomers are expressed. The endolymph of the scala media has a higher content of potassium ions and a higher positive potential (about a hundred mV more than ordinary extracellular fluids) because of this multilayered epithelium. Both of which are crucial for hearing. In marginal cells of the stria vascularis Na+/K+ pumps and NKCC1 transporters build up potassium ions and chloride ions inside the cells. While apical KCNQ1/KCNE1 K+ channels leak excessive K+ into the endolymph and ClC-K/Barttin channels return chloride ions into the interstitial fluid [Bartter syndrome type IV: The thick ascending limb of Henle’s loop contains the majority of the ClC-Kb/Barttin protein, which is primarily used to reabsorb salt and then water . In thisal fluid .- recycling. Disruption of either the Barttin or both ClC-K channels results in deafness [Salt-losing Bartter syndrome type III is caused by a mutation in the gene encoding ClC-Kb . This sydeafness ,40.Adverse effects of medicinesMore than 451 medications are known to be harmful to the ear. These include both over-the-counter medications like NSAIDs (pain relievers) and prescription medications like cancer medications, antibiotics, antimalarials, and diuretics. In the majority of cases, this type of toxicity to the ear is often an acute, short-lived adverse effect; if the individual stops the utilization of medicine, the symptoms usually go away. This is not the case, although, aminoglycoside and derivatives of platinum are utilized for the treatment of cancer which can result in irreversible loss of hearing . The mecHigh-Ceiling Diuretics and Aminoglycoside AntibioticsFor patients suffering from chronic kidney disease, the medicines of importance in causing toxicity to the ear are the aminoglycoside antibiotics, which are frequently utilized for the control of septicemia and urinary tract infection (UTI) which are commonly seen in such individuals, and furosemide, a loop diuretic, is also utilized for management of pulmonary edema and fluid overload in the patients suffering from CKD. However, many medical professionals are aware of the ototoxic effects of aminoglycosides, lack of diagnostic resources in many hospitals around the globe prevents a thorough examination of these potential adverse effects. Many regions lack effective treatment interventions for hearing loss, which has diminished interest in testing for this adverse effect. The toxicity caused by furosemide to the ear is frequently ignored by nurses and other medical personnel. When the medication is given more quickly and as an i.v. push medication, furosemide toxicity usually occurs.Hearing loss among people receiving hemodialysisAnother category of CKD patients that experience hearing loss are those who are on hemodialysis and are in the end stage of the disease. Many articles show that people suffering from CKD have higher incidences of SNHL than the general population. It ranges from 26% to 78% ,42. HoweIn the study of Iraq, 59 patients were monitored for a year with a pure-tone audiometry (PTA) test every six months to investigate the impact of hemodialysis on the hearing threshold in adults with CKD . The stuPreventive healthcare strategies of SNHLDue to the large number of persons undergoing long-term hemodialysis treatments worldwide and the increasingly widespread hearing loss among this group, which is typically ignored ,42, it iIn clinical settings, ototoxic medications like the diuretic furosemide and the antibiotic aminoglycoside should be used with caution. When feasible, these drugs should not be given in combination. Education about the dangers of self-medication and the utilization of herbal products that might be toxic to the ear and kidneys, and also about issues such as undernourishment, overcrowding in nursery facilities, bottle feeding, inadequate housing systems, etc. is necessary. Acute respiratory infections should be better managed, noise levels should be reduced, and hearing protection should be used as necessary . ComorbiOtorhinolaryngological disorders are a common side effect of CKD and its therapy. CKD patients are more likely to experience SNHL, vestibular dysfunction, tinnitus, recurrent epistaxis, rhino-cerebral mucormycosis, oropharyngeal candidiasis, smell and taste changes, phonatory dysfunction, deep neck infections, mucosal abnormalities, halitosis, gingival hyperplasia, or xerostomia as opportunistic infections. Otorhinolaryngological dysfunctions associated with CKD are frequently chronic, challenging to manage, adversely affect the patient’s quality of life, and occasionally fatal. We concluded that CKD patients, particularly those following organ transplantation, require regular and ongoing examinations by an expert otorhinolaryngologist due to the high incidence of otorhinolaryngological problems caused by CKD itself and its treatment. It is especially important because some of these issues may be treatable if identified and treated early. Additionally, the introduction of appropriate treatment may be able to stop the advancement of some of these dysfunctions, and some dysfunctions may improve with therapeutic adjustment. Patients with CKD are predisposed to several otorhinolaryngological issues especially SNHL, and the link between SNHL and CKD has both been extensively explained, but the relationship between the remaining complications and CKD is still unknown.


Noise-induced hearing loss (NIHL) is the second most common cause of sensorineural hearing loss, after age-related hearing loss, and affects approximately 5% of the world’s population. NIHL is associated with substantial physical, mental, social, and economic impacts at the patient and societal levels. Stress and social isolation in patients’ workplace and personal lives contribute to quality-of-life decrements which may often go undetected. The pathophysiology of NIHL is multifactorial and complex, encompassing genetic and environmental factors with substantial occupational contributions. The diagnosis and screening of NIHL are conducted by reviewing a patient’s history of noise exposure, audiograms, speech-in-noise test results, and measurements of distortion product otoacoustic emissions and auditory brainstem response. Essential aspects of decreasing the burden of NIHL are prevention and early detection, such as implementation of educational and screening programs in routine primary care and specialty clinics. Additionally, current research on the pharmacological treatment of NIHL includes anti-inflammatory, antioxidant, anti-excitatory, and anti-apoptotic agents. Although there have been substantial advances in understanding the pathophysiology of NIHL, there remain low levels of evidence for effective pharmacotherapeutic interventions. Future directions should include personalized prevention and targeted treatment strategies based on a holistic view of an individual’s occupation, genetics, and pathology. Noise-induced hearing loss (NIHL) is a consequence of multifactorial damage to auditory structures following exposure to occupational, environmental, or recreational sources of loud sound. Noise has been recognized as a factor contributing to hearing loss long before rigorous data collection, sophisticated analyses, and careful experimental design became the norm. Although earplugs were patented in 1864, hearing protection devices are mentioned in ancient Greek mythology . HistoriNIHL may be unilateral (affecting one ear) or bilateral (affecting both ears), and the hearing deficits may be transient or permanent . The durThe most recent Global Burden of Disease report 2019) estimated that 1.57 billion people, or 20.3% of the world population, are affected by any kind of hearing loss, with 62% over the age of 50 years . As NIHL estimateDue to lack of public records and funding for research on NIHL, the true burden of NIHL in the developing world is unknown, although several studies in India and Africa have highlighted it ,18. For NIHL is also common among developed nations. In the US, interviews and hearing tests conducted by the Centers for Disease Control and Prevention (CDC) National Health and Nutrition Examination Survey (NHANES) led to estimates that at least 6% and up to 24% of adults have hearing loss in one or both ears due to noise exposure, with higher rates among males ,21. An eSound frequency is measured in Hertz (Hz), and intensity (loudness) is measured by sound pressure level on a logarithmic decibel (dB) scale, which ranges from safe to unsafe exposure levels . Normal The damage associated with NIHL begins when harmful sound is channeled to auditory structures from the outer ear via the auditory canal a. The unThe mammalian cochlea is a spiral-shaped structure divided into three fluid-filled chambers—the scala tympani, the scala vestibuli, and the scala media  b. In humThe cochlea’s scala media contains the organ of Corti, the cellular apparatus for transduction of sound vibration into neural signals that can be interpreted by the brain. The organ of Corti is a mosaic of sensory hair cells and non-sensory supporting cells which, in mammals, does not have the capacity to replace lost cells once damaged c. There + and Ca2+) from endolymph [While the scala vestibuli communicates with the scala tympani at the apex of the cochlea (helicotrema), the scala media is separated from both chambers by Reissner’s membrane and the basilar membrane, respectively. This separation is crucial for the maintenance of the unique ionic composition of the extracellular fluids in these chambers, generating the endocochlear potential which is essential for auditory transduction. Specifically, the scala vestibuli and scala tympani contain perilymph which is K+-poor and Na+-rich. Conversely, the scala media is filled with K+-rich and Na+-poor endolymph which is secreted by a specialized epithelium called the stria vascularis. The tips of the hair cells’ stereocilia are embedded in the flexible tectorial membrane and move in response to sound vibrations. The stereocilia bundles are also connected to each other (within the same hair cell) via extracellular tip links formed in part by cadherin 23 (CDH23) and protocadherin 15 (PCDH15) proteins . These lndolymph .While the endocochlear potential of endolymph in the scala media is +80 mV compared to perilymph , hair ceThe mechanisms by which loud noise induces hearing loss include mechanical damage of cochlear structures, reduction in blood flow, sterile inflammation, and oxidative stress and excitotoxicity due to overstimulation of hair cells and nerves . The losThe variables impacting the severity of damage include factors attributable to the sound stimulus  and the physical, mechanical, and chemical characteristics of the outer, middle, and inner ear. The damage caused by noise can cause temporary or permanent damage and associated hearing loss. Prolonged duration of exposure to hazardous noise levels or a one-time exposure to high-intensity sound levels can both cause permanent threshold shifts (PTS) ,38,58. PBecause the hair cells sit atop the basilar membrane and because their stereocilia are embedded in the tectorial membrane, they are subject to mechanical shearing forces in response to sound vibrations. This continuous mechanical stress causes damage over time and is a feature of typical age-related hearing loss. However, in the context of intense or persistent noise, the shearing forces can cause stereocilia core breakage, destruction of tip links, and ultimately premature hair cell death . At low Loss of stereocilia tip links due to excessive force, uncoupling the mechanoelectrical transduction (MET) channel, precludes mechanotransduction by the hair cell . HoweverSupporting cells may also be physically damaged by noise. Pillar cell damage has been observed both after high-level impulse (160 dB) and continuous noise (100–120 dB SPL) ,70. DietApart from their function in the Krebs cycle, the mitochondria play an essential role in apoptosis and oxidative stress. Following infection, trauma, and in this context, noise-induced trauma, cellular damage or degradation of cell connections may lead to the activation of apoptotic pathways by hair cells . ReactivSod1 to provide cellular defense, and the loss of Sod1 in knockout mice increased the susceptibility to noise-induced PTS [Peroxynitrite (ONOO–), a highly reactive nitrogen species (RNS) derived from NO and superoxide, is one of the most harmful free radicals to hair cells . Noise-iuced PTS .The stria vascularis forms the lateral wall of the cochlear duct and comprises three cell layers: marginal, intermediate, and basal. It is responsible for maintaining the endocochlear potential and has a rich blood supply ,85. HazaAdditionally, free radical formation in response to high-intensity noise can lead to vasoconstriction and reperfusion of cochlear cells, with subsequent cell death ,89,90. TNeuroinflammation, a critical component of maintaining homeostasis in the central and peripheral nervous system, has been implicated in a wide range of pathological processes, including NIHL. There is extensive evidence showing that pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukins, and chemokines  are induced in the mammalian cochlea after noise trauma ,103,104.Louder sounds cause more hair cells to depolarize, causing greater release of glutamate by IHC ribbon synapses and increased motility of OHC. Noise exposure causes a rapid reduction in the number of IHC ribbon synapses, which is irreversible after neuropathic noise exposure ,110,111.Ribbon synapses and the peripheral dendrites of afferent neurons can be damaged by noise levels that are not as high as those required to effectuate threshold shifts ,121,122.Tinnitus is the conscious perception of sound without an external auditory stimulus, often experienced as ringing or buzzing . TinnituHearing loss is present in approximately 60% of people with tinnitus ,133, sugThe vestibular system consists of the utricle and saccule, which detect gravitational forces and horizontal and vertical plane movements, respectively, as well as three perpendicular semicircular canals . The priThe vestibular labyrinth Is in proximity to and interconnected with the auditory system, and the fluids in the vestibular system have a degree of patency with the cochlea . The cocNeurophysiological studies have measured the effects of noise on the vestibular system via vestibular evoked myogenic potentials (VEMPs) ,148,149.Screening of NIHL is typically performed via taking a patient’s history of noise exposure and performing audiograms, and clinicians will distinguish sensorineural from conductive hearing loss. However, it is often difficult to precisely quantify the noise exposure of individuals, and the type of exposure may vary , leading to different patterns of damage. Thus, other tests may include the measurement of distortion product otoacoustic emissions (DPOAE), speech-in-noise testing, and auditory brainstem response (ABR), as detailed below. Each of these methods have notable strengths and limitations. Clinical assessments of signs of tinnitus and vestibular dysfunction may also be included if appropriate.PTA, which measures the lowest intensity at which sound can still be heard across a range of audible frequencies (hearing threshold), is performed as a baseline evaluation test for hearing loss . Air andA 10 dB confirmed threshold shift from the baseline PTA at 2000, 3000, and 4000 Hz is the metric used by the US Occupational Safety and Health Administration (OSHA) to determine a standard threshold shift in cases of occupational hearing loss . While nWhile PTA testing helps identify hearing loss, it does not account for the ability to discriminate sound in the presence of background noise, a primary presenting complaint of patients with NIHL . PTA is Speech-in-noise testing gives a useful baseline estimation of hearing impairment, helps to infer the degree of benefit from different assistive hearing devices, and allows the quantification of improvement . Speech-The OHCs amplify the intensity and sharpen the peak of the traveling sound wave in the cochlea via prestin-mediated elongation and contraction . The resDPOAEs are evoked via a probe placed into the ear canal which emits two sounds at designated intensity levels (L1 and L2) and frequencies (f1 and f2), while a microphone detects the otoacoustic emission . CochleaDecreased DPOAE amplitudes are typically detected in older patients, those exposed to noise, and those with cochlear pathologies ,185,186.ABR, or auditory brainstem evoked potentials, are electrical signals produced by the nervous system within the first 10–15 ms following a transient acoustic stimulus . A typicABR is not routinely used in clinical screening of NIHL but does have expanded applications for neurodiagnostic testing, intraoperative monitoring, hearing screening/audiometry, and neurophysiological research . In animThe UK utilizes Coles, Lutman, and Buffin diagnostic guidelines, which identify NIHL by a notch or downward bulge in the frequency range 3–6 kHz during PTA testing . AdditioNIHL is mostly preventable, and tangible steps to reduce the burden of the disorder can be taken via the implementation of educational programs, regulation, and legislation to raise awareness and pre-emptively mitigate the damage caused by noise. In the US, the 1972 Noise Control Act established federal noise emission standards for commercial products and required that the public be provided information about noise emission levels and ways of reducing them . Two US Environmental noise level is conventionally measured via a sound level meter. However, they are expensive for small businesses and require maintenance and calibration, thereby limiting their widespread implementation. However, smartphone applications for this purpose are now available and provide inexpensive alternatives to specialist calibrated sound meters. An evaluation of the reliability of nine applications found the NIOShH Sound Level Meter to be the most accurate . A free,Hearing protective devices (HPDs) such as earmuffs and earplugs play an important role in protection against noise exposure. Plugs need to be inserted to ensure coverage of the entire ear canal’s circumference to provide protection and minimize irritation. Noise Reduction Ratings (NRRs) are calibrations to assess the protection range of HPDs in a single attenuation value (in dB). Because NRRs are derived via laboratory-based testing, they may overestimate the actual protection provided in non-experimental environments. Therefore, the NRR is derated by 50% on a dB scale before estimating exposure protection . A CochrFinally, clinicians can actively counsel patients at risk of NIHL on hearing protection strategies and the hazards of noise exposure in the workplace or recreationally . Simple strategies outlined by the US Centers for Disease Control and Prevention include avoiding exposure to excessive noise, turning down the volume on music, moving away from sources of noise, and using HPDs to reduce exposure to safe levels .There is no cure for NIHL and, to date, no approved pharmacological treatment indicated for its treatment. Although there are currently no clinical practice guidelines specifically for NIHL management, such guidelines exist for sensorineural hearing loss in adults  , AmericaBox 1Grade of impairmentAudiometric ISO valuePerformanceRecommendationComments added to the prior classification0-None≥25 dB Can hear whispers.No or very slight hearing problem.None may have hearing problems. People with unilateral hearing  loss may have problems even if the better ear is normal.20 dB also recommended. People with 15–20 dB levels 1-Slight26–40 dB in a normal voice at 1 mCan hear and repeat words spoken  may be neededCounseling. Hearing aids  normal level of conversationSome difficulty in hearing but can usually hear 2-Moderate41–60 dB in raised voice at 1 mCan hear and repeat words spoken usually recommendedHearing aids are None3-Severe61–80 dB into better earCan hear some words when shouted  lip-reading and signing should  be taughtHearing aids needed. Otherwise  discrimination score should be notedDiscrepancies between pure-tone thresholds and speech 4-Profound≥81 dB a shouted voiceUnable to hear and understand even  words. Additional rehabilitation needed.  Lip-reading and sometimes signing are  essential.Hearing aids may help understanding  which hearing was lostSpeech is distorted, the degree depending on the age at There are myriad risk factors associated with NIHL, as listed in Box 2Older age, although all ages are at riskRepeated occupational noise exposure Repeated recreational noise exposure Intense blast or explosion exposureShooting firearms Hypertension, smokingLack of hearing protectionExposure to organic solvents, heavy metals, pesticides, asphyxiantsOccupational NIHL is the most prevalent occupational disease globally , with apHearing loss is common in the military and is particularly disabling as it relates to both safety of the personnel and that of the nation. Personnel are often exposed to continuous as well as intermittent hazardous levels of noise, including gun fire and blast exposure, and increased hearing loss is associated with solvent exposure and longer service ,236,237.Environmental factors, including ambient urban noise, also play an important role in the development of NIHL. For example, an observational study of environmental noise in Bangkok, Thailand, found that urban populations experienced greater mean hearing loss than suburban populations and found that among the occupational population in the urban monitoring sites, drivers had the highest risk of traffic-related NIHL . Per a 2Ahl1 (735A>GCdh23) in C57BL/6J mice, are more susceptible to further hearing deterioration caused by noise exposure [Ahl1  are less vulnerable to acoustic injury [Cdh23 [Pmca2 [Sod1 [Gpx1 [Trpv4 [Vasp [Hsf1 [mdx [Multiple studies have found that certain genetic and epigenetic characteristics increase the susceptibility to acoustic trauma in animal models of hearing loss ,247,248.c injury ,251,252.c injury ), and hec injury . Some ofy [Cdh23 , Pmca2 [3 [Pmca2 , Sod1 [8a2 [Sod1 , Gpx1 [2d1 [Gpx1 , Trpv4 [1 [Trpv4 , Vasp [2v4 [Vasp , Hsf1 [2sp [Hsf1 , and mdxsf1 [mdx .GSTM1, PON2, SOD2, and CAT have been associated with NIHL, and CAT was independently validated in Swedish and Polish populations [GJB1, GJB2, GJB3, GJB4, GJB6, KCNJ10, KCNQ1, KCNQ4, KCNE1, and SLC12A2 are ten genes in the potassium recycling pathway with known or suspected association with syndromic and non-syndromic hearing loss [KCNE1, KCNQ1, and KCNQ4 with NIHL [GJB1, GJB2, GJB4, KCNJ10, and KCNQ1 with NIHL [Evidence of genetic risk factors in human NIHL is still emerging, although studies have suggested heritability of hearing loss ,261,262.ulations ,264,265.ing loss . An analith NIHL , and a Pith NIHL .HSP70-1, HSP70-2, and HSP70-hom [PCDH15) and myosin 14 (MYH14) [HSPs are involved in the synthesis, folding, assembly, and intracellular transport of many other proteins. HPS expression increases during oxidative or other stress, including that caused by noise exposure, which may have a protective effect against cochlear damage via stabilization of stereocilia or enzyme regulation ,269. ThrSP70-hom ,270,271. (MYH14) . Cadheri (MYH14) ,268. In  (MYH14) ,274, his (MYH14) ,277,278, (MYH14) ,281,282.Finally, the inner ear has many glucocorticoid receptors (GR), which are affected by acoustic trauma or restraint stress at a transcriptional level ,284,285.The development of novel treatments for NIHL is an area of active research, encompassing interventions with anti-inflammatory, antioxidant, anti-excitatory, anti-apoptotic, or other effects. A search of ClinicalTrials.gov on 20 January 2023 identified 21 registered trials of interventional therapies inclusive of NIHL: one active and not recruiting (NCT05086276 (FX-322)), one not yet recruiting (NCT05511753 (acupuncture)), one recruiting (NCT04766853 (steroids)), two enrolling by invitation only (NCT04768569 and NCT04774250 (zonisamide)), one terminated (NCT02903355 (D-methionine)), one withdrawn ), three of unknown status (NCT02779192 (SPI-1005), NCT04482998 , and NCT01727492 (antioxidants)), and 13 completed (NCT02257983 (EPI-743), NCT01444846 (ebselen), NCT00808470 (micronutrients), NCT00552786 (antioxidant), NCT02951715 (zinc), NCT04120116, NCT04601909, and NCT04629664 (FX-322), NCT02259595 , NCT03834714 (near infrared light), NCT00802425 (AM-111), and NCT03878875 (sound conditioning)) . Of the Beta carotene, vitamins B, C, and E, zinc, and magnesium have antioxidant properties—particularly when combined—and have been shown to reduce vasoconstriction, cochlear cell death, and hearing loss in animal models when administered prior to noise exposure ,288,289.GSTM1 or GSTT1, which code for glutathione S-transferases  involved in cellular detoxification and nullification of carcinogens. Thus, antioxidant therapy with N-acetylcysteine may help to reduce the magnitude of noise-induced TTS among certain populations, although individuals’ genetic profiles influence the effect. D-methionine is the active form of methionine, an essential amino acid needed for tissue repair and selenium/zinc absorption. A randomized, double-blind Phase 3 trial (NCT02903355) of D-methionine administered prior to and during firearms training among US drill sergeant trainees  reported in ClinicalTrials.gov that it was not superior to placebo in preventing hearing threshold shift. A separate Phase II-like trial of N-acetylcysteine conducted among a similar US Marines Corp population prior to weapons training also failed to demonstrate superiority of treatment to placebo in preventing noise-induced TTS [N-acetylcysteine is a thiol which supplies cysteine for intracellular glutathione synthesis. It acts as a free radical scavenger of hydrogen peroxide and hydrogen radicals to promote detoxification of ROS and RNS ,298,299.uced TTS .Sound conditioning, or exposure to low-level noise prior to intense noise, is also aimed at increasing antioxidant activity in the inner ear . This beEbselen is a synthetic selenium-containing molecule that has anti-inflammatory properties and has been assessed as a treatment for various forms of SNHL . It mimiClinical trials have been conducted to assess HBOT and corticosteroids as treatments for NIHL, primarily focusing on acute acoustic trauma (AAT) . TreatmeHyperbaric oxygen has been previously used to counteract cochlear hypoxia in sudden idiopathic hearing loss , includiThis review of the literature described the etiology of and risk factors for NIHL, as well as approaches for screening, prevention, and treatment of affected patients. We also summarized the evidence from publications of experimental therapies which, although promising for prophylaxis or AAT that can be treated very quickly, have yet to address the needs of patients with long-standing or cumulative NIHL. The impact of NIHL is not limited to decreased quality of life of affected individuals but can extend to lower productivity of the workforce and impaired performance of military personnel. Further, NIHL is associated with a substantial economic burden to governments and society at large, expected to increase as the global population ages and experiences increased costs of NIHL-related healthcare and disability. Thus, the prevention of noise-induced cochlear injury, via the use of hearing protection in loud occupational and recreational settings, remains the cornerstone of reducing the enormous burden of NIHL. Governmental regulations and safety-focused organizations play essential roles in advising the public and industry on safe noise exposure levels and in implementing educational programs. For example, a cost-effectiveness analysis of a military hearing conservation program estimated a lifetime savings of USD $10,657 per person in service-related compensation on implementation of the program . Additio


Worldwide, hearing loss is a significant public health issue and one of the most common chronic health conditions experienced by older adults. Hearing loss is associated with communication difficulties, social withdrawal, isolation and lower quality of life. Although hearing aid technology has improved significantly, the workload of managing hearing aids has increased. The aim of this qualitative study is to develop a novel theory of people’s lived experience of hearing loss across the lifespan.Eligible participants will be young people and adults aged 16 years and above who have a hearing loss and carers/family members of people with a hearing loss. This study will use individual, in-depth face-to-face or online interviews. With participants’ permission, interviews will be audio-recorded and transcribed verbatim. A grounded theory approach to concurrent data gathering and analysis will develop grouped codes and categories and link these to provide a novel theory to describe the experience of hearing loss.The study was approved by the West of Scotland Research Ethics Service  and the Health Research Authority and Health and Care Research Wales Approval . The research will inform the development of a Patient Reported Experience Measure to improve the information and support given to patients. Findings will be disseminated through peer-reviewed articles and at academic conferences, as well as to our patient and public involvement groups, healthcare professionals, audiology services and local commissioners. Our qualitative interview study, informed by grounded theory approaches, will generate a novel theory on the lived experience of hearing loss across the life course.Different patient, public involvement groups will be involved throughout the project to guide the logistics of conducting the research and support data analysis procedures.Purposive sampling via different clinical sites and non-clinical routes  will help to ensure diverse experiences and views are captured.The study will be restricted to people living in the UK which may limit the applicability of the findings to other settings.This qualitative study part of a wider study that will inform the development of the first Patient Reported Experience Measure internationally to enable audiologists to identify the individualised and effective support.Hearing loss is a chronic health condition that affects an estimated 430 million adults worldwide.4 5The implications of hearing loss are well-established and far reaching. People with hearing loss may feel ashamed or frustrated about their difficulty communicating and limit their social interactions.12–14There is no permanent cure for hearing loss, and the main form of clinical intervention is wearing hearing aids. Using hearing aids has been shown to improve hearing function for mild to moderate hearing loss, as well as positively influence quality of life through enhancing communication.The illness burden of hearing loss is considerable. Hearing loss makes it hard work to communicate and increases risks in all aspects of life.The ‘burden of treatment’ theory is an increasingly useful way to consider the relative benefits of allocating health resources.In the UK, audiology services are commissioned differently in different parts of the country, with the introduction of ‘Any Qualified Provider’ (AQP) services meaning that large corporations and optical chains have been awarded NHS contracts to provide audiology services in England.It is critical that service development and delivery are grounded in experiential evidence to develop a good understanding of the daily illness and treatment burdens of hearing. Previous work shows that while there are benefits in aspects of communication from hearing aids, there are specific barriers to use that derive from social identity preservation and stigma of hearing loss (and hearing aids as a visible marker of hearing loss).35Further research is required to understand how people make the trade-offs at different life stages between living with a hearing loss and using a hearing aid to manage the hearing loss. Such research will enable audiology services to be sensitive to patient experience and promote shared decision making. Therefore, the overall goal of the current study is to provide a deeper understanding of the lived experiences of coping with hearing loss (with and without hearing aids) at different stages of life, from the perspectives of patients and their families. This study forms part of a larger study—the Hearing Loss and Patient Reported Experience study (HeLP study)—the first study of its kind to prioritise patients’ lived experience of hearing loss to inform decision-making in audiology care planning and services. The findings from this qualitative work will inform the development of potential items for a novel Patient Reported Experience Measure to be used in clinical practice to understand the work involved in living with hearing loss (‘illness work’) and hearing aids (‘treatment work’).Drawing on grounded theory methodology, the aim of this study is to develop a comprehensive novel theory that has the potential to explain variation in people’s lived experiences of hearing loss. The objectives are to:Develop a theoretical understanding of how coping with hearing loss (‘illness work’) and accessing and living with hearing aids (‘treatment work’) is experienced and negotiated alongside personal and sociocultural contexts.Understand how individuals adapt to and manage hearing aids.Explore the reasons why hearing aid non-use occurs.Explore patients’ experiences of accessing audiology services and support.This qualitative interview study will be informed by Strauss and Corbin’s pragmatic approach to grounded theory.41For reflexivity, the study team comprises two female clinician-researchers , three female researchers  and a female patient and public involvement (PPI) lead (JS) who is an expert in audiology by experience and writer. All the team either have first-hand experience of hearing loss or are closely related to someone who does.Participants will be interviewed by either HP, GB-OC, SH or SKS. At the start of each interview, the interviewers will undertake a ‘working alliance’ discussion agreeing participant and researcher roles, timing and nature of the interview. This will include the researcher’s interest and motivations in the topic.The study team will meet fortnightly to reflect on their role in shaping data collection and compare and contrast their interpretations of the data. Throughout the study, the wider HeLP research group and core PPI members will discuss interpretations of the findings for triangulation and work together to develop and link theoretical categories for the explanatory model.The Study Steering Committee will have overall oversight of the study and provide advice to the study research team, funder and sponsor. Our steering group will comprise eight independent members, including: one international collaborative representative, two experts by experience, three clinicians working in audiology in different parts of the country, one social science researcher and chaired by a health commissioner with a particular interest in person centred care. The steering group will meet every 6 months and oversee delivery milestones and reporting.The study is being conducted in the UK with participants  recruited from three clinical sites in England (Bristol and Bath) and Scotland (Tayside) and non-clinical groups .Participants are young people and adults aged 16 years and over and individuals who have experience of hearing loss directly or as a carer, partner or parent. Eligibility criteria  are inteBox 1Young adults (aged 16–29 years): transitioning from paediatric to adult services and negotiating independence. We will aim to recruit 4–6 young people, including those with additional disabilities such as learning disabilities, and up to four parents.Adults aged 30–49 years: managing hearing loss while pursuing career/work and family life; 4–6 people with diagnosed hearing loss either using or not using hearing aids, plus 2–4 partners/relatives.Adults aged 50–79 years: noticing symptoms of hearing loss for the first time; 4–6 hearing aid users and 5–8 non-hearing aid users.Adults aged 80 years to end of life: most likely to have hearing loss. Other health conditions likely and changes in living situation possible; 4–6 hearing aid users, 4–6 non-hearing aid users and 2–4 carers from residential care settings.Volunteers without close connection to or experience of hearing loss.Drawing on the principles of Strass and Corbin’s grounded theory approach, we will be using purposive sampling to provide maximum variation of cases to generate rich data from different perspectives which will allow us to target under-represented groups. We will examine the experience of different age groups and identify similarities and differences between and across the life stages This will enable us to build up an understanding of living with hearing loss (with and without hearing aids) across the life course.Potentially eligible participants will be made aware of the study through advertisements. Clinical sites will advertise the study to new and existing patients via word-of-mouth, invitation flyers or posters displayed in waiting/reception areas. Participants will also be recruited through non-clinical routes including care homes, supported living centres and community groups. Advertisements will also be distributed via leads of tinnitus groups, teachers of lip-reading classes and staff in residential care settings. Details of the study will be circulated on social media  and the study link hosted on Aston University website with the aim of recruiting participants with diverse experiences and backgrounds. In addition, our PPI collaborator in South Asian community groups and care homes will prompt snowball sampling in which word of mouth advertisement will encourage potential participants to contact the study team. In accordance with our PPI group in the South Asian community regarding recruitment of participants who are not help seekers, we will recruit participants from local mosques and women’s groups in the local area . Previous research experience informed our sample estimate of approximately 25–38 patients and 8–12 family members/carers see  to captuInterested participants will directly contact the HeLP study team via email, phone or post. The researchers will then provide potential participants with the participant information sheet . Informe10.1136/bmjopen-2022-069363.supp1Supplementary dataData will be collected using qualitative, semi-structured interviews by the study team  who are all experienced in qualitative research. Participants will have the option for the interview to take place at their preferred location including online (via Microsoft Teams), or at their home, the university or audiology department in a quiet and private space. An interview schedule been developed to explore the lived experience of managing hearing loss and hearing service use . It has Box 2Tell me a little bit about yourself?Tell me your story with your hearing and why you were interested in taking part?Can you tell me your thoughts and feelings about hearing loss?What have you found difficult about having a hearing loss?What have you done to manage your hearing loss?Decision making around hearing aid use or non-use/uptake—tell me how you came to be using/not using your assistive listening devices/hearing aids explore reasons why/why not?What is important to you when deciding whether to use hearing devices/aids?Who else is important in helping you decide?Has this changed over time?What has been helpful to you?Have you sought help from audiology services?Tell me about your experience with using audiology servicesBased on your experience—what do you think they ought to know/do that they currently do not do?Tell me what is it like for you managing hearing loss?What is difficult for you about living with someone with hearing loss?What if anything do you do differently as a result of hearing loss?Have you had any involvement with audiology services?What was that like?What is challenging about using hearing aids (if your family member/cared for person has them)?In line with Strauss and Corbin’s grounded theory procedures, data analysis and interviewing will be iterative, in which early analysis and findings will be compared with inform ongoing interviews. We will keep field notes of reflections and thoughts following interviews to support this. While the notion of data ‘saturation’ has been widely critiqued as a neo-positivist indication of a singular ‘truth’; there is recognition of the importance of capturing a range of views, based on different contexts.We will ensure credibility to the research process through transparent decision making, including incorporating PPI views. The lead investigator (HP) and coinvestigator (RS) will supervise the analysis closely and ensure consistency. They will blind code a subset of transcripts and compare coding. The HeLP qualitative research team  will develop and refine the conceptual model while interviews and analysis progress to understand the effort required to manage hearing loss and highlight the variations in patient need at each life stage. We will examine the fit of this model to previous models and existing theories, and we will encourage reflection from all researchers and PPI leads through discussion.A major component of the HeLP study is the involvement of PPI groups. Specifically, two PPI leads (a researcher with PPI responsibility and a public member) will manage and coordinate the PPI activities, working closing with the study team. Our PPI leads have experience in communicating with people with complex communication needs. PPI activities include reviewing patient information sheets and consent forms, advising on recruitment and interview questions, checking analysis procedures and addressing any uncertainties in data interpretation We will consult our PPI groups to check that our process and early findings have not omitted any aspects of the experience . Fieldnote diaries will record PPI engagement and outcomes.Certain groups are more likely to be affected by hearing loss including people from South Asia , older adults in residential care and adults with learning disabilities. Our PPI strategy reflects the diverse and heterogeneous nature of the population affected by hearing loss in the UK. We have directly targeted the following groups to expand our reach of PPI inclusion:South Asian community groups: we have interest and agreement from these groups. We have also spoken to local religious centres, including but not limited to specific local Imams to enhance access to those from Muslim backgrounds. South Asian heritage people have both a disproportionately high risk of hearing loss and are under-represented in patient populations in the UK.43 44Residential care homes: our PPI leads will meet with individuals in these settings (with whom we have existing relationships) face-to-face.Aston PPI group: people in the local community who have experience with hearing loss, a group including student members who are younger.Bath PPI group: a well-established group of older adults who support and advise on service delivery and research. They meet face-to-face or via email.Our initial PPI work informed the development of the proposal in a number of ways. First, our Aston group highlighted the need for researchers from the same culture and religious as participants to undertake PPI and research. As such, we will include a researcher with responsibility for PPI in marginalised groups and have recruited a researcher dedicated to South Asian groups. Second, our older group identified problems with hearing aids that inform the notion of ‘work’ . These issues will be explored further by targeting PPI and recruitment in residential care settings where access to audiology services can be challenging. Third, our older group noted the need to be flexible in where and how data gathering occurs and be mindful of travel and distance barriers for participants. This informed our plans to gather data in people’s homes, at clinics, university and online/telephone. Finally, our younger group advised we purchase amplifier headsets which could be sent out to participants for online/phone use, if required.This study was reviewed and approved by the West of Scotland Research Ethics Service  and the Health Research Authority and Health and Care Research Wales (HCRW) Approval .Each participant has the right to withdraw at any time during the study and information relating to all withdrawals will be recorded. If a participant wishes to discontinue, data collected up until that point will be kept and included in the analysis.All data obtained from participants will be kept confidential. Participants will be anonymised with all identifying information removed. Participants’ names will be replaced with pseudonyms.Participants may reflect on their experience of hearing loss (as a person living with hearing loss or as a carer/family member) and gain new understandings which might be empowering. Their insights will help inform how to better design audiology services and improve clinical practice and care.There is a possibility that discussing some topics will create distress. If at any point a participant feels distressed during the interview, they will be given the option to pause the recording and provide time to discuss the issue. The researcher will signpost participants to other services including patient liaison services within NHS providers. In the case of home interviews, researchers will follow the sponsor’s  lone working policy including plans to check in with another member of the research team before and after interviews.All study data will be stored on the university password protected server. Informed consent sheets (hard copies) containing personal information will be kept in a secure filing cabinet at the university only accessible to study staff and authorised personnel. Audio recordings of interviews will be conducted with encrypted digital recorders or MS Teams recording software. Once transcribed verbatim and checked for accuracy, recordings will be deleted. Data will be collected and retained in accordance with the Data Protection Act 2018 and General Data Protection Regulation standards. Once data analysis is completed, the study documents (paper and electronic) will be retained in a secure location for 5 years at Aston University. Personal data  are held on a separate Aston University Box file and are separate from research data. Besides clinicians in Participant Identification Centres sending the advertisements to home addresses we will not access personal data.We will obtain written informed consent from all interview participants at the start of an arranged interview time. Participants will have had at least a week to consider the participant information sheet and ask questions in advance. Participants who volunteer for online meetings will post their consent form back in a prepaid envelope. The researcher will record the consent process verbally at the start of the interview as well.Participation from adults with additional cognitive and communication difficulties are welcomed but will require capacity to consent for participation. In care home settings, where potential participants may experience dementia, researchers will check participants’ capacity with care staff and only consent those who are able to provide consent independently. For this, the researcher will check that participants can understand the nature of the research and be able to retain the information to make a free choice about participation, and be capable of making this decision at a time it needs to be made.We will prepare and publish articles in appropriate peer-reviewed journals and professional magazines  to ensure the findings are shared with audiology healthcare professionals and academics. Findings will be disseminated via poster and oral presentations at relevant academic and non-scientific conferences, and social media. They will also be disseminated to PPI groups, audiology services and local commissioners.