Otitis media is a recognized cause of significant hearing loss, particularly in developing countries. This study aimed to investigate the relationship between otitis media and hearing loss in Chinese adults aged 18 years and older.The survey was based on WHO Ear and Hearing Disorders Survey Protocol and 36,783 adults at the ages between 18 years and above were selected in this study. Trained local examiners performed pure tone audiometry to screen people with hearing loss, and those who were screened positively for hearing loss were referred to audiologists to make final diagnosis. All participants underwent clinical ENT check-up and otoscopic examination by doctors trained in ENT. Each participant was assigned a single middle ear diagnosis. Diagnoses were assigned as per the WHO classification of ear and hearing disorders.95%CI: 4.66, 6.90). The next two models (Model 2–3) had slight impact on ORs. The interaction of residency and otitis media was statistically significant ; otitis media patients in rural areas had higher risk of hearing loss. However, this interaction became not significant in 65 years old and above participants.Logistic regressions showed that higher prevalence of hearing loss was found in participants with otitis media, with an unadjusted odds ratio of 5.67 (Otitis media was associated with the risk of hearing loss. Compared with urban patients with otitis media, rural patients have the higher risk of hearing loss. Action to reduce the risk of hearing loss in otitis media will require attention to rural-urban disparities. As one of the most common sensory impairments, hearing loss has become a public health concern across the globe . AccordiOtitis media (OM) defined as inflammation involving the mucosal lining of middle ear cleft, which includes acute otitis media (AOM), otitis media with effusion (OME) and chronic suppurative otitis media (CSOM) . The comOM is a significant cause of preventable hearing loss, particularly in developing countries . This reUsing a cross-sectional, population-based Ear and Hearing Disorder Survey in four provinces of China, this study aimed to investigate the relationship between OM and hearing loss in Chinese adults aged 18 years and older. A better knowledge of the prevalence of AOM, CSOM, OME and their realtionships with hearing loss will fill the gaps on this topic in China, which is necessary to adequately assess the demand of interventions for hearing loss, and form the basis of a public health program in China, as well as provide data for the WHO Prevention for Blindness and Deafness 2020.We obtained data from Ear and Hearing Disorder Survey, which was a population-based study conducted in four provinces of China  between August 2014 and September 2015. The survey design was established by a technical team based on WHO Ear and Hearing Disorder Survey Protocol , which hThe sampling frame covered almost 200 million people, representing about one in seven of the total population in China. Probability proportion to size (PPS) sampling method was used to identify 144 sites from 24 counties or districts in four provinces. Each site included 100 households which had lived in the registered address for over 6 months. A total of 47,511 individuals were randomly selected and 45,052 of them participated in the survey, yielding a participation rate of 94.80% . All parAudiometry was performed by trained examiners according to the established protocols of Ear and Hearing Disorder Survey. Examiners were recruited from local primary health care institutions , and were trained by provisional technical teams in survey skills and audiological techniques. Before the household survey, examiners went to local sites to select audiometric test rooms with ambient noise levels not exceeding 40 dBA measured by sound level meters, and were equipped with MADSEN-Xeta pure tone audiometers and other required examination equipment. During the survey, noise-excluding headsets were used if the ambient noise of testing rooms exceeded 40 dB. Audiometric equipment was calibrated by a laboratory at the beginning and end if a study, and on a daily basis by team members using self-calibration against their known hearing levels. During and after the survey, a subsample with 5% of participants were rechecked and the consistency rates of rechecks both reached 90% and above .Examiners performed pure tone audiometry among people aged 18 years old and above in a selected quiet room. Both ears were tested separately at 0.5, 1, 2, and 4 kHz to obtain the hearing threshold on each frequency point. In this survey, each participant in our study has at least one ear, and all of them were tested in one or both ears. Pure tone threshold averages in the better ear were calculated to identify hearing loss and its grades. According to the standard of WHO/PDH/97.3 , hearingAll participants underwent clinical ENT check-up and otoscopic examination by doctors trained in ENT. A normal diagnosis was assigned if participants had healthy middle ear cleft bilaterally. If patients had a differing diagnosis in each ear, the most clinically serious diagnosis was taken: CSOM, followed by OME and AOM. Of these, AOM is diagnosed among patients with acute onset, presence of middle ear effusion, physical evidence of middle ear inflammation or of fever symptoms.This survey was ethically approved by China Disabled Persons' Federation (number: 2014&ZZ028). The committee board, which was composed of audiologists and epidemiologists, reviewed the study protocols and ethical situations. The authors had no access to identifying information for the study participants prior to data analysis. All participants signed the informed consent with interviewers to participate in the survey and clinical diagnosis. For those with severe hearing loss who were unable to sign the consent, family members represented them to sign the consent.The outcome variable was whether or not an adult had hearing loss. The independent variable was whether or not an adult had OM. Covariates included socioeconomic status, defined by three categorical variables: occupation , education  and income . White-collar workers in this study involved professional and governmental employees, and blue-collar workers referred to manual and services-oriented workers excluding farmers . Covaria2 test was used to examine the difference on prevalence of people with hearing loss by OM. The software Stata version 13.0 for Windows  was utilized for statistical analysis. Because location is also one of the independent variable that may affect both status of OM and hearing loss, all analyses were conducted separately by urban and rural areas.Descriptive statistics were used to present the proportion of hearing loss by various demographic characteristics and OM. Fisher exact test was conducted to compare the differences of the characteristics. Multivariate logistic regression models allowing for multiple demographic and socioeconomic covariates and stepwise approach were used to evaluate the association between OM and hearing loss. The odds ratios (ORs) with 95% confidence intervals (CIs) were presented. A P value less than 0.05 was considered statistically significant. χIn our study, out of 36,783 adults in the survey, there were 307 (0.83%) with OM and 7,360 (20.01%) had hearing loss. 0.83% adults had OM and 20.01% suffered from hearing loss. Among patients with OM, CSOM accounted for 89.44%, OM with effusion with 9.32%, and acute OM 0.62%.In patients with hearing loss, most were mild (68.72%), and moderate and severe hearing losses accounted for 21.62 and 9.66%, respectively. Compared with participants without hearing loss , more hearing loss patients had OM (2.77%). Older people, more males, more illiteracy and the lowest income per capita groups were in hearing loss groups. More details are presented in P < 0.001), similarly occurring in the 18–64 age group, with 55.97% for rural areas, and 46.34% for urban areas. However, for those 65 years old and above, the rates are almost similar with 91.30 and 93.44% in rural and urban areas, respectively.95%CI: 4.66, 6.90) ; OM patients in rural areas had higher risk of hearing loss  . The inting loss . This ining loss . Howevering loss .The association of significant hearing loss with OM is well-documented in previous literature, and its auditory consequences also recognized . HoweverOM is a major common risk of hearing loss. Possible explanation of hearing loss associated with OM have focused on the routes between middle and inner ear . FirstlyOur finding showed that the prevalence of hearing loss caused by OM was around 60% in Chinese adults, and this prevalence varied across different types of OM and increased with age. Evidence from Nigeria and Denmark reported that more than half of OM patients experienced hearing loss, which was similar to our results , 26. EviOur results showed that the association between OM and the risk of hearing impairment was stronger in residents of rural areas than indiviudals in urban areas. Geographical distribution of hearing loss due to OM is uneven, and socioecnomic conditions may account for a major part of the difference , 28. ComThis study has several limitations. First, due to the restriction of our study design, we did not include the exposure duration of OMs, which may affect the response variability. For example, OMs patients in rural areas always have a longer duration exposure to OMs than urban patients, which may widen the urban-rural disparities of OMs related hearing loss. Therefore, we need caution in interpreting our results. Furthermore, a cross-sectional study design cannot draw causal inferences. From this perspective, further studies are necessary to investigate the causality and its pathways between OM and hearing loss drawing from prospective cohort design in Chinese mainland.Despite these limitations, the strengths of this study include a large-size, population-based design in four provinces of China based on the WHO Ear and Hearing Disorder Survey Protocol, as well as hearing conditions ascertained by audiologists according to the WHO criteria. It is the first time to study the urban-rural disparity of the association between OMs and hearing loss in Chinese adults.This study investigated the association between OMs and hearing loss among Chinese adults based on a population-based study conducted in four provinces of China between August 2014 and September 2015 by using a multivariate analysis with logistic regression. Our results showed that among OM patients, 29.44, 18.78, and 12.86% was the prevalence of mild, moderate and severe hearing loss, respectively. We found that OM was associated with the risk of hearing loss. Compared with urban patients with OM, rural patients have the higher risk of hearing loss. This study contributes to the literature on ear disease and hearing loss in developing nations of a non-Western context. Action to reduce the risk of hearing loss in OM will require attention to rural-urban disparities.webmaster@crrchsi.org.cn; http://www.chinadeaf.org.The datasets presented in this article are not readily available because the acquisition of the dataset requires the consent of China Rehabilitation Research Center for Deaf Children, which is incharege of the date management. Requests to access the datasets should be directed to This survey was ethically approved by China Disabled Persons' Federation (number: 2014 & ZZ028). The patients/participants provided their written informed consent to participate in this study.YL, PH, and XW performed conceived and designed the study, data analysis, and wrote the manuscript. RG and XH participated in conducting the study and supervised data collection. XZ supervised all aspects of its implementation and contributed to writing the article. All authors contributed to the article and approved the submitted version.This work was supported by Major Project of the National Social Science Fund of China (21&ZD187), National Social Science Fund of China (21CRK014), Promotion of Initiative and Empowerment for Women (ANSO-SBA-2020-02), Beijing Social Science Foundation (Grant No. 20SRC029), and Beijing Union University Foundation (Grant No. BPHR2020DS05). The funders had no role in study design, data collection and analysis, decision to publish and preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study aimed to compare and rank the therapeutic effects of antivirals in treating hearing loss using a network meta-analysis approach.We searched the PubMed, Embase, and Cochrane Library databases to identify eligible randomized controlled trials (RCTs) through April 2022. Placebo-controlled or head-to-head RCTs of three categories of antivirals for hearing loss were included, and pooled relative risks (RRs) with 95% confidence interval (CI) were calculated using pairwise and network meta-analyses.P = 0.017), while no significant difference was observed between any two categories of antivirals. Finally, the use of antivirals did not increase the risk of adverse events compared with the use of a placebo .Six RCTs with 405 patients were included in the final analysis. The results showed that ganciclovir had relatively better effects on the incidence of hearing recovery (surface under the cumulative ranking: 88.8%) compared with other antivirals. However, pairwise comparison analyses found that the use of antivirals significantly increased the incidence of hearing recovery compared with the use of a placebo (RR: 1.27; 95% CI: 1.04–1.54; Antivirals are more efficacious than placebos for hearing recovery in patients with hearing loss, and ganciclovir is the most likely to increase the incidence of hearing recovery. Hearing loss is characterized by the deterioration of hearing acuity and is associated with an elevated hearing threshold. Studies have demonstrated that hearing loss is significantly related to physical , cognitiNowadays, the use of antivirals has not been recommended for improving hearing loss in patients with isolated SNHL or asymptomatic congenital cytomegalovirus (CMV) disease , 13. A sThis systematic review and network meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines . PlaceboThe literature search and study selection were independently conducted by two authors, and conflicts between the authors were resolved through mutual discussion. Studies were included if they met the following criteria: (1) patients: all of patients diagnosed sudden sensorineural hearing loss or congenital CMV disease and were not restricted by age ; (2) intThe following items from each trial were abstracted by two authors: first author's name, publication year, region, sample size, mean age, proportion of males, inclusion criteria, intervention, control, treatment duration, and reported outcomes. Subsequently, these two authors assessed the methodological quality of the included trials using a risk of bias approach according to the methods described by the Cochrane Collaboration, which includes seven specified domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and other . InconsiI2 and Q statistics were used to assess heterogeneity across the included trials, and significant heterogeneity was defined as I2 > 50.0% or P < 0.10 .Therapeutic effects of antivirals were assigned as continuous and dichotomous data, and pooled RRs with 95% CIs were calculated as effect estimates. Indirect and mixed comparisons in network meta-analysis were analyzed to compare different antivirals , and theP < 0.10 . The insn = 31), not being RCTs (n = 18), and having insufficient data (n = 11). Reviewing the reference lists of relevant studies yielded two potentially eligible trials, and these two trials were obtained through electronic searches. Finally, six RCTs were selected for the final quantitative analysis .–31.n = 3The baseline characteristics of the included trials and recruited patients are presented in The network of eligible comparisons of hearing recovery is shown in P = 0.017; I2 = 0.0%; P = 0.919). Moreover, subgroup analyses found that acyclovir , valacyclovir , and ganciclovir  were not associated with the incidence of hearing recovery compared with the placebo.After pooling all included trials, we noted that the use of antivirals significantly increased the incidence of hearing recovery compared with the use of a placebo . Moreover, the use of antivirals did not affect the risk of headache , nausea , stomach pain , elevated blood glucose , increased creatinine , increased total bilirubin , thrombopenia , neutropenia , and death .The summary results for adverse events are presented in To our knowledge, no previous systematic review and network meta-analysis has compared and ranked the efficacy and safety of antivirals in the treatment of hearing loss. This comprehensive, quantitative, systematic review and network meta-analysis was based on six RCTs involving 405 patients presenting with hearing loss who were randomly assigned to treatment with antivirals  or placebos. Hearing recovery and any adverse events following treatment were investigated. The study results show that ganciclovir had relatively better treatment effects on hearing recovery. However, pairwise comparison analyses indicated that the incidence of hearing recovery was not statistically significant when comparing any two types of antivirals. A traditional meta-analysis found that the use of antivirals significantly increased the incidence of hearing recovery compared with the use of a placebo. Finally, the use of antivirals did not increase the risk of adverse events compared with the use of a placebo in patients with hearing loss.Three studies reported the therapeutic effect of acyclovir on the incidence of hearing recovery , 29, 30.Two of the included trials reported the treatment effects of antiviral drugs on hearing recovery in newborns , 31. KimA traditional meta-analysis found that the use of antivirals significantly increased the incidence of hearing recovery compared with the use of a placebo. Moreover, although the incidence of hearing recovery in patients treated with ganciclovir was superior to that in patients treated with acyclovir and valacyclovir, the differences were not statistically significant. However, the result should be cautiously recommended because of a relatively high risk of bias in the methodological quality of the trial performed by Kimberlin et al. . FinallyThis study had several limitations. First, the severity of hearing loss are differing among included trials, while stratified data according to severity of hearing loss were not available. Second, the background therapies are varies across the included trials, which could affect the treatment effectiveness of antivirals. Third, the main cause of hearing loss are differing between adult and pediatric patients , whereasWe found that the use of antivirals significantly increased the incidence of hearing recovery in patients with hearing loss, and ganciclovir had relatively better effects on hearing recovery. Moreover, no significant differences were observed between any two types of antivirals, and the use of antivirals was well tolerated and did not increase the risk of adverse events compared with the use of a placebo. A large-scale RCT in the future should be conducted to directly compare the therapeutic effects of antivirals in the treatment of hearing loss.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Conception and design and administrative support: L-LX. Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, and manuscript writing: L-ML. Final approval of manuscript: L-ML and L-LX. All authors contributed to the article and approved the submitted version.


C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data  were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD.Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological  MAPT [GRN) [C9orf72) [GRN mutations are loss-of-function mutations, which introduce premature termination codons with the consequent degradation of the mutant RNA due to nonsense-mediated decay, resulting in a severe reduction in circulating progranulin, which is easily detectable by the plasma/serum dosage [GRN mutations cause a complete loss of progranulin, leading to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder which shares some neuropathological features with GRN-associated FTLD [4C2 repeats) in the first intron/promoter of the C9orf72 gene are among the most common causes of familial FTLD. Instead, intermediate expansions (12–30 hexanucleotide repeats) have a risk effect on familial/sporadic FTLD, influencing C9orf72 expression and the disease phenotype according to the age at onset and clinical subtype [Frontotemporal lobar degeneration (FTLD) is the second most common form of dementia after Alzheimer’s disease (AD) affecting people younger than 65 years old ,2. The mMAPT ,10, progPT [GRN) ,12, and C9orf72) ,14. The m dosage . Additiom dosage ,17. Homoted FTLD . The pat subtype ,14,19.CTSD gene. In the Golgi complex, it exists as a diglycosylated precursor form , and the removal of its N-terminal propeptide results in a 48 kDa single chain intermediate active form. The final maturation step requires further processing in the lysosomes, generating the mature active lysosomal protease, composed of heavy (34 kDa) and light (14 kDa) chains linked by non-covalent interactions [CTSD have been linked with the pathogenesis of, or predisposition to, neurodegenerative diseases, such as NCL, AD, and Parkinson’s disease (PD) [GRN mutation carriers [GRN mutations [GRN mutation carriers, cathepsin D activity was also significantly reduced in c9orf72−/− mice macrophages [Grn−/− mice [Grn KO primary mouse microglia compared to the wild type [Grn−/− mouse brains [Grn KO mice [GRN mutation and NCL patients [GRN/C9orf72-associated FTLD [GRN/C9orf72-associated and sporadic FTLD patients, thus suggesting that a common molecular mechanism is altered in both genetic and sporadic FTLD [Cathepsin D is a soluble lysosomal aspartic protease encoded by the ractions ,21. Cathractions . In partractions ,24,25,26ase (PD) ,28,29,30carriers  and in iutations . Furtherutations ,34. Thusutations . In agrerophages , in the −/− mice , and in ild type . In conte brains ,39,40, i KO mice , and alspatients . Endo-lyted FTLD ,44. Extrted FTLD . EVs havted FTLD ,47. In aGRN/C9orf72-genetic and sporadic FTLD, investigating, in particular, the lysosomal protease cathepsin D in the sEVs and plasma.In this study, we expanded on our studies of the endo-lysosomal pathway in both In this retrospective study, we investigated cathepsin D levels in 161 subjects (118 patients and 43 controls). In detail, patients with sporadic FTLD (n = 40), with FTLD due to C9orf72 expansion , with FTLD due to pathogenic mutations in GRN , with NCL due to pathogenic mutations in GRN , and subjects with normal cognitive function, as a control group , were included. Demographic and clinical characteristics are reported in The isolated sEVs were CD9+ (a tetraspanin), TSG101+ and Flotillin-1 + (cytosolic proteins recovered in EVs), and Calnexin negative  . The catp = 0.004) and in the Ctrl   . The sam= 0.001) . No sex-= 0.001)  or the C= 0.001) .p < 0.001, generalized linear model, adjusted for age and sex). Considering the total cathepsin D content in the sEVs , a statistically significant difference was found between the investigated groups , but there were no statistically significant differences between the pair of groups after the Bonferroni correction for multiple comparisons.The cathepsin D concentration per sEV (ng/sEV) was significantly increased in all patient groups  compared with the Ctrl (p = 0.011)  .−11 ng/sEV. ROC curves for the Ctrl vs. Genetic FTLD  and Ctrl vs. Sporadic FTLD had similar AUCs (0.83 and 0.89 respectively), using the DeLong test for the AUC comparison .To estimate the diagnostic performance of the cathepsin D concentration per sEV, ROC analyses were performed . The relp = 0.006; Ctrl r = 0.471, p = 0.002; p = 0.058, generalized linear model, adjusted for age and sex). Accordingly, the diagnostic performance of plasma cathepsin D in discriminating between the PTS and the Ctrl group was poor (AUC = 0.63), with a sensitivity of 60.2% and specificity of 64.3%, considering the cut-off point of 151.8 ng/mL   a. No sig alleles b.p = 0.004)  .Emerging data suggest the roles of endo-lysosomal dysfunctions in FTLD and in neurodegenerative diseases in general ,44,46. CIn this study, we provide evidence of an alteration in the lysosomal protease cathepsin D in both sporadic and genetic FTLD. Recent studies investigated the role of cathepsin D as a plasma biomarker of PD and AD ,51,52. IIn the present study, we assessed cathepsin D levels in the plasma and plasma sEVs of a relatively large group of FTLD patients, including sporadic patients, genetic patients , and GRN homozygous mutation carriers affected by NCL, a lysosomal storage disorder. First, we revealed a positive correlation of cathepsin D levels with age among both the patients and controls. This is in line with early studies on rats, in which cathepsin D levels were increased in aged brains ,54. Cyto−11 ng/sEV. In contrast, in our samples, the diagnostic performance of plasma cathepsin D in discriminating between the PTS and Ctrl groups was poor (AUC = 0.63), thus supporting the need for the isolation of EVs as a source of biomarkers. We have previously demonstrated that genetic and sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the sEV concentration/size ratio was high (AUC = 0.91), with a sensitivity 85.3% and a specificity 81.4% [GRN mutation and NCL patients [Grn−/− mouse brains [Examining the extracellular vesicles in the blood, we observed an increased cathepsin D sEV cargo in the sporadic and genetic FTLD groups. A significant increase in the cathepsin D concentration per sEV  was found in all patient groups compared to the controls. The diagnostic performance of the cathepsin D concentration per sEV as a parameter in discriminating between the patients and healthy controls was fairly high (AUC = 0.85), with a sensitivity of 75.4% and specificity of 76.7%, considering the cut-off point of 1.72 × 10ty 81.4% . Thus, aty 81.4% . Similarpatients , as welle brains ,39,40, se brains . MoreoveGRN/C9orf72 FTLD [Breakthrough molecular studies have suggested the roles of endo-lysosomal dysfunctions in f72 FTLD ,44, withf72 FTLD ,39. Moref72 FTLD .GRN/C9orf72-genetic FTLD patients and describing an alteration in cathepsin D trafficking that is common to both the genetic and sporadic forms.To the best of our knowledge, this is the first study reporting an alteration in the levels of plasma sEV-associated cathepsin D in The most well-established and clinically approved approach to treat lysosomal storage disorders is enzyme replacement therapy (ERT), aiming to replace the defective hydrolase with an exogenously applied recombinant protein . The theA limitation of this study is the small number of patients included in the C9orf72 Int. and GRN+ Homo. groups, which could have masked further significant differences between the investigated groups. This is a pilot study, and further validation using a larger and/or independent cohort is warranted.GRN/C9orf72 and sporadic FTLD, further highlighting the relevance of the endo-lysosomal pathway in neurodegenerative dementias.In conclusion, our study further emphasizes the common role of endo-lysosomal dysregulation in C9orf72 expansion (n = 9 C9orf72 Int. and n = 24 C9orf72 Pat.), with FTLD due to pathogenic mutations in GRN (n = 42 GRN+ Het.), with NCL due to pathogenic mutation in GRN (n = 3 GRN+ Homo.), and subjects with normal cognitive function, as a control group , were included in the present retrospective study. Patients were enrolled at the MAC Memory Clinic IRCCS Fatebenefratelli, Brescia, and at the Neurology 5/Neuropathology Unit, IRCCS Besta, Milan. The clinical diagnosis of FTLD was performed according to international guidelines [C9orf72 and GRN genetic screening was performed previously, as described [The project included a total of 161 subjects (118 patients and 43 controls). In detail, patients with sporadic FTLD (n = 40), with FTLD due to idelines . The diaescribed ,63,64. TTM, Waltham, MA, USA), following the manufacturer’s protocol. Briefly, 125 µL of plasma was centrifuged at room temperature (RT) at 2000× g for 20 min and at 10,000× g for 20 min to remove cells and debris. The supernatants were then incubated for 10 min at RT with 62.5 µL of 0.2 µM-filtered 1X phosphate-buffered saline (PBS) and 37.5 µL of exosome precipitation reagent. After 10 min of incubation at RT, the suspensions were centrifuged at 10,000× g for 5 min. The sEV pellets were lysed with 60 µL of ice-cold exosome resuspension buffer , and stored at −20 °C for the Western blotting and biochemical analyses. The nanoparticle tracking analysis (NTA) data (sEV concentration and size) were extracted from our previously published larger dataset, which is openly available in the Mendeley Data Repository (at doi:10.17632/kds9sb4z6t.2), or generated as previously described [11 ± 1.1 × 1011, C9orf72 Int. 1.5 × 1011 ± 7.1 × 1010, C9orf72 Pat. 1.1 × 1011 ± 5.3 × 1010, GRN+ Het. 9.7 × 1010 ± 4.3 × 1010, GRN+ Homo. 8.3 × 1010 ± 1.6 × 1010, and Sporadic FTLD 1.1 × 1011 ± 6.3 × 1010. Plasma sEV size (nm) values were as follows: Ctrl 115.1 ± 14.5, C9orf72 Int. 137.4 ± 31.0, C9orf72 Pat. 136.9 ± 10.0, GRN+ Het. 144.6 ± 16.2, GRN+ Homo. 136.3 ± 14.3, and Sporadic FTLD 135.1 ± 11.6.Total plasma sEV isolation was performed using plasma with the Total Exosome Isolation Kit  with MOPS SDS running buffer  and electro-transferred onto nitrocellulose membranes  for 90 min at 90 V. Incubation with primary antibodies was performed overnight at +4 °C , followed by incubation with horseradish-peroxidase-conjugated secondary antibodies, 1:10,000 , for 1 h at +37 °C. Immuno-positive bands were detected by ultra-sensitive enhanced chemiluminescence  according to the manufacturer’s instructions. The isolated sEVs were CD9+ (a tetraspanin), TSG101+ and Flotillin-1 + (cytosolic proteins recovered in EVs), and Calnexin negative  with a size of <200 nm  , following the manufacturer’s instructions. Plasma sEV samples were diluted at a ratio of 1:20 while plasma samples were diluted at 1:100. All analyses were performed in duplicate. The sEV-associated cathepsin D concentration data were normalized (or not) according to the sEV concentration .p values of pairwise comparisons. Spearman correlations were performed for the cathepsin D quantification and age/age at onset. The diagnostic performances of the cathepsin D concentration per sEV and plasma cathepsin D variables were assessed by areas under the curve (AUC), obtained by the receiver operating characteristic (ROC). The comparison of the AUC results was assessed by the DeLong test. All analyses were performed using SPSS software (V27) or R software, and the significance was set as 0.05.The normality assumption of the continuous variables was assessed by the Kolmogorov–Smirnov test. One-way ANOVA, with Bonferroni post hoc tests, was used for the comparison of the normally distributed demographic and biological variables between the groups. The Mann–Whitney test was used for the comparison of non-normally distributed variables between the two groups. The chi-square test  was used to assess the association between the categorical variables and the group variables. Generalized linear models or generalized additive linear models  with a gamma or inverse gaussian distribution were used for the comparison of the target variables between the groups (adjusting for age and sex). Moreover, Bonferroni’s correction was applied to the


Concurrent hearing and genetic screening of newborns have been widely adopted as an effective strategy in early diagnosis and intervention for hearing loss in many cities in China. Here, we aimed to firstly explore the efficacy of combining conventional hearing screening with genetic screening among the large-scale newborns in Jiangxi Province.GJB2, SLC26A4, MT-RNR1(12SrRNA), and GJB3, were screened using a BGISEQ-500 next generation sequencing platform. Whole coding regions sequencing of GJB2 and SLC26A4 were performed by Sanger sequencing and NGS, respectively. Following up of hearing for the newborns was undertaken by phone interviews.A total of 24,349 newborns from Jiangxi Maternal and Child Health Hospital were enrolled in our study from April 2021 to June 2022. Newborn hearing screening was conducted using otoacoustic emission (OAE) and automated auditory brainstem response (AABR). Meanwhile, newborn dried blood spots were collected and twenty common variants in four genes, including GJB2, 371 of SLC26A4, 189 as homoplasmic or heteroplasmic of MT-RNR1, and 61 of GJB3, indicating that GJB2 and SLC26A4 are the most common endemic deafness-associated genes among newborns in Jiangxi Province. Nineteen newborns were detected with combined heterozygous variants in different genes, with “c.235delC heterozygous and c.919-2A > G heterozygous” as the most prevalent genotype. Additionally, seven newborns were screened as homozygotes or compound heterozygotes responsible for congenital or late-onset prelingual hearing loss, including three cases with GJB2 c.235delC homozygous and one with SLC26A4 c.919-2A > G homozygous variant, one case with compound heterozygous variants for GJB2 and two with compound heterozygous variants for SLC26A4. Coding regions sequencing of GJB2 or SLC26A4 for overall 265 infants revealed that 14 individuals were identified as compound heterozygote with a second pathogenic variant not screened by our genetic panel.Among the 24,349 newborns, 7.00%  were bilaterally or unilaterally referred in their initial hearing screening, whereas 1.30%  exhibited bilateral or unilateral hearing loss in the repeated screening. Genetic screening revealed that 4.813%  of the screened newborns were positive for at least one mutant allele . A total of 1,146 individuals were identified with mutant allele in one gene, including 525 of Herein our study firstly investigated the efficacy of concurrent hearing screening and genetic screening of common hearing impairment variants among large-scale newborns in Jiangxi Province. Concurrent screening provides a more comprehensive approach for management of congenital or delayed onset prelingual hearing loss and prevention of drug-induced hearing impairment for newborns at risk as well as their maternal relatives. An insight into the molecular epidemiology for hearing loss genes among Jiangxi population will also be beneficial to the genetic counseling and birth defect prevention. Hearing loss (HL) is one of the most common human disorders, affecting nearly 1 to 3 newborns per 1,000 live births . In Chinhttps://deafnessvariationdatabase.org) up to now. Molecular mutation spectrum of hereditary HL can be distinct in different geographic areas and ethnic groups. According to previous epidemiological studies on molecular etiology analysis among Chinese population, GJB2, GJB3, SLC26A4, and MT-RNR1 have been proved to be highly prevalent and causative genes in NSHL patients  has been implemented worldwide as one of the important strategies for early identification, diagnosis and management of hearing impairment due to its feasibility and cost-efficiency , 11. Howin utero. A flow diagram of the recruited participants in our research was shown as in A total of 24,349 newborns from Jiangxi Maternal and Child Health Hospital were enrolled in our study between April 2021 and July 2022, including 13,413 males and 10,936 females. Inclusion criteria of the enrolled newborns were as follows: (1) the infants were born between April 2021 and July 2022 in our hospital; (2) the infants were healthy enough to tolerate the screening procedures; (3) the parents or guardians agreed with participating in the concurrent newborn genetic and hearing screening program. Exclusion criteria were as follows: (1) the infants' samples were unqualified for the genetic tests or (2) the infants were lost to hearing or genetic follow-up; (3) the infants underwent prenatal diagnosis with definite deafness mutations All the enrolled newborns underwent a two-step screening approach. Each newborn was initially tested on hearing using OAE within 72 h after delivery in a state of natural sleep in the maternity ward by an otolaryngologist. If the newborn failed the initial test, either unilaterally or bilaterally, which was also defined as “refer” in our study, a repeated OAE test combined with automatic auditory brainstem repose (AABR) assessment were performed by the age of 42 days. Newborns who failed the 42-day re-screening should be further evaluated with comprehensive audiological assessment by audiologists, preferably at the age of 3 months.GJB2, SLC26A4, MT-RNR1, and GJB3 . All the positive samples screened were further verified by Sanger sequencing.Three appropriate-sized heel peripheral blood spots were obtained using a customized dried blood collection card for genetic screening within 72 h of birth from all newborns. Nucleic acid was extracted from dried blood spots according to the manufacturers' instructions . Library preparation and targeted NGS were performed according to the standard operation procedure by Combined Probe-Anchored Synthesis Kit using the BGISEQ-500 platform. The genetic screening panel included 20 NGS targeted common sites in and GJB3 . GeneticGJB2 and/or SLC26A4, the presence of a second pathogenic allele in the same gene not screened by our panel was taken into consideration. Based on the principle of voluntary participation, the entire coding regions sequencing and approximately 20 bp of exon–intron boundaries of GJB2 and SLC26A4 were further conducted by respective Sanger sequencing and NGS . Primers used for direct sequencing in GJB2 were as listed in Newborns tested positive in the genetic screening were subsequently recommended to the Department of Medical Genetics for genetic counseling. For newborns screened as carriers of in trans”. Two mL of peripheral venous blood sample from both parents were obtained and subject to parental validation.Two variants inherited from both parents were regarded as compound heterozygous. Since the detection of two heterozygous variants in one gene is insufficient for a genetic diagnosis, newborns with suspected compound heterozygous variants by genetic screening or the entire coding regions sequencing were further investigated on parental validation to determine whether the two variants were inherited from both parents, which was also defined as “The statistical analysis was performed using SPSS 20.0 software. The referrals rate of hearing and genetic screening, as well as the frequency of genes and variants were represented by n%. Chi-squared tests were performed to determine the statistical significance of differences in mutation carrier rates between the current and previous studies.A total of 24,349 newborns were screened with hearing in our study. The overall hearing screening results was summarized in GJB2, GJB3 and SLC26A4), together with 189 infants  showing simple heteroplasmic or homoplasmic variant in MT-RNR1. Furthermore, 19 cases  exhibited combined variants in two genes and seven newborns  harboured compound heterozygous variants or homozygous variants in GJB2 or SLC26A4. The highest prevalence rate was found for GJB2 at a rate of 2.24% , followed by the SLC26A4 gene at 1.57% . The GJB2 c.235delC and SLC26A4 IVS7-2A > G were the most frequently detected variant in our study, with the respective carrier rate of 1.83%  and 0.98% . A genetic carrier rate of 0.25%  for GJB3 heterozygous variant was identified, with c.538C > T and c.547G > A making up almost a similar proportion. MT-RNR1 was identified with a carrier rate of 0.81%  among the newborns, with homoplasmic m.1095T > C being the most endemic variant at a rate of 0.59% . All the positive samples by genetic screening showed concordant results as verified by Sanger sequencing.The genetic screening data of the 20 NSHL-related variants in this study among 24,349 neonates was shown in GJB2, GJB3 and SLC26A4, while 75  of them were referred on the second hearing screening, and the remaining 892  infants passed. Notably, united hearing and genetic screening informed us of the risk of delayed-onset or drug-induced hearing loss even though these genetically referred infants had passed their two-step hearing screening. Accordingly, all these infants referred from the hearing screening should be further scheduled to receive diagnostic audiological tests for confirmation of hearing.A comprehensive analysis and the associations between hearing and genetic screening of the tested newborns were shown in GJB2 and 98 for SLC26A4. Results revealed that 13 infants were compound heterozygous for GJB2, with one case as GJB2 c.176_191del16/c.164C > A, two cases as GJB2 c.299_300delAT/c.109G > A, and ten cases as c.235delC/c.109G > A. GJB2 c.109G > A (p.V37I) was detected in 12 of these infants as a high frequent mutation allele. One infant was identified as c.919-2A > G/c.1615-1G > T compound heterozygote for SLC26A4. Detailed genotypes were listed as in GJB2 c.109G > A, GJB2 c.164C > A and SLC26A4 c.1615-1G > T were shown as in A total of 265 infants were subject to the entire coding regions sequencing after voluntary parental decision, including 167 for GJB2, SLC26A4, 12SrRNA and GJB3  of all the positive samples (p < 0.05). Of the four variants, GJB2 c.235delC was the most prevalent mutant allele with a frequency rate of 1.822%, which is also the most common variant in Asian population  of all the positive samples. Among the eleven variants screened, c.919-2A > G was the most common mutant allele in Jiangxi Province, while c.2168A > G mutation exhibits the highest prevalence in the Japanese   .GJB2  and 5,967 carriers for SLC26A4  can be instructed on their future pre-pregnancy or prenatal genetic counseling by genetic screening. Therefore, genetic screening in all the newborns are more cost effective than only in the patients who are at higher risk or those who failed the hearing screening in identifying late-onset or progressive or drug-induced hearing loss, as well as identifying the carriers of hearing loss mutations for the guidance of future pre-pregnancy or prenatal genetic counseling.Based on a survey by the Chinese National Bureau of Statistics, the number of births in 2021 in Jiangxi Province was 377,000, which suggests that an estimated number of 18,145 individuals may be positive for the 20 common hearing loss variants screened. In our study, we identified newborns with congenital or prelingual HL at the rate of 0.03%, indicating that almost 113 individuals may be diagnosed as congenital or prelingual HL at much earlier time by genetic screening. Besides, we detected mitochondria mutations at a rate of 0.081% in our study, which indicates that nearly 305 infants and their maternal family members can be protected from aminoglycoside-antibiotic induced HL. Assume a deafness treatment needs 500,000 Yuan, this would save a total of 20.9 million Yuan each year in Jiangxi Province. What's more, a predicted number of 8,444 carriers for GJB3 has been reported to be associated with late-onset high-frequency sensorineural HL  and c.1615-1G > T in SLC26A4 (c.919-2A > G/c.1615-1G > T) by the entire coding regions sequencing, which otherwise could be neglected only by conventional UNHS and genetic screening. The additional testing with entire coding regions sequencing assisted in elucidating the molecular etiologic of hearing loss for these two infants, facilitating early detection and intervention of congenital hearing infects.As previously reported, the heterozygous c.538C > T variant in eural HL . Neverthing loss . Further of five . Importan humans . In our TMC1, USH2A, CDH23 and MYO15A in an expanded panel in future studies. Secondly, an increased hearing loss risk in the “carrier” genotype group with only one heterozygous pathogenic variant identified in GJB2 or SLC26A4 may be attributed to the inclusion of affected individuals whose second pathogenic allele was undetectable by the screening, but only a limited number of individuals underwent the entire coding regions sequencing in our study. Thirdly, congenital HCMV infection, one of the leading causes of congenital hearing loss, was not included in this study. In addition, we haven't recorded the diagnostic audiological results of these infants referred from the second hearing screening so far. Therefore, long-term follow-up investigations of this cohort are, warranted.In spite of the strength above, several limitations were present in our study. Firstly, not all the genetic causes of hearing loss could be determined. We only genotyped the 20 frequent variants in four common genes in the present study. Further efforts are needed to analyze other frequent deafness-predisposing genes, such as In summary, this is the first study providing an insight into the effective strategy for prevention of common hereditary HL and early identification of late-onset prelingual HL by concurrent newborn hearing and genetic screening in a large cohort newborns in Jiangxi Province. The results of our study highlighted the importance of newborn genetic screening in elucidating common etiologies, identifying infants with late-onset or progressive hearing impairment, and recognizing newborns and their maternal relatives at-risk of increased susceptibility to ototoxicity undetectable by newborn hearing screening. Our study may also provide as a reference in promoting the implementation of universal concurrent newborn hearing and genetic screening in the whole area in Jiangxi Province in the future.


Several studies report that sound localization performance of acute and chronic monauralized normal-hearing listeners can improve through training. Typically, training sessions are administered daily for several days or weeks. While this intensive training is effective, it may also be that monaural localization abilities improve instantly after providing explicit top-down information about the direction dependent change in timbre and level. The aim of the present study was to investigate whether cognitive feedback  could instantly improve sound localization in naive acutely monauralized listeners. Forty-three normal-hearing listeners , divided over five different centers, were tested. Two control groups, consisting of, respectively, nine and eleven normal-hearing listeners, were tested in one center. Broadband sounds (0.5–20 kHz) were presented from visible loudspeakers, positioned in azimuth (− 90° to 90°). Participants in the experimental group received explicit information about the noticeable difference in timbre and the poor localization in the monauralized listening condition, resulting in an instant improvement in sound localization abilities. With subsequent roving of stimulus level (20 dB), sound localization performance deteriorated immediately. The reported improvement is related to the context of the localization test. The results provide important implications for studies investigating sound localization in a clinical setting, especially during closed-set testing, and indicate the importance of top-down information. The current study focuses on an underestimated monaural cue  arising from the head shadow. When a broadband (BB) sound is presented to the hearing-impaired side of a monauralized listener, the frequency-dependent attenuation provides a physical cue due to the low pass filtering by the head, characterized by a change in timbre Fig. . This chWhile many studies address the role of pinna-related spectral cues  and interaural level differences (ILDs) is heavily distorted and listeners perceive the stimuli mainly at the hearing (unplugged) side . These lights indicated the position of the correct loudspeaker or whether a response was correct or incorrect. Several studies demonstrated that feedback from other modalities than the visual system could further improve the monaural localization abilities. For example, kinesthetic cues improve monaural localization abilities when subjects pay attention to the position of sounds , and these multisensory cues are beneficial for acute monaural listeners . This might result in confounding situations, because participants might perceive sounds from directions that do not correspond with a loudspeaker position. The human neural system is continuously updating available information and unilateral plugged listeners can learn to use monaural cues and pinna-related spectral cues to optimize azimuthal localization in a monaural hearing condition  received a unilateral ear plug and horizontal sound localization was evaluated in four conditions in a within-subject experimental design. Sound localization was tested in the normal-hearing condition (condition 1), in the acute monaural hearing condition before and after receiving explicit information regarding the monaural hearing condition , and finally in a condition in which stimuli were presented at three different sound levels (condition 4).Normal-hearing participants  It was explained that they could perceive a change in timbre. (ii) It was told that their performance was poor and that they localized most of the sounds toward the unplugged ear, while stimuli were presented from all loudspeaker locations .n = 10; Clinic B, n = 10; Clinic C, n = 10; Clinic D, n = 6, Clinic E, n = 7) and all participants in the control groups  were naive to the experimental conditions and had normal-hearing bilaterally as determined by air-conduction hearing thresholds < 20 dB HL across the standard audiometric test frequencies, 250–8000 Hz. All experimental protocols adhered to the guidelines of the universities’ local ethics committees.Sixty-two adult participants  were included in the study. None of the participants reported a history of inferior hearing or neurological disease, all had normal or corrected to normal vision. Forty-three were tested while providing explicit information , nine were tested in a control condition without theoretical or practical orientation to the task, and eleven were tested without orientation to the task but with exposure to the 15 stimuli presented between condition 2 and 3. The experiment was conducted at five centers to determine the robustness of the effects, replicability and potential generalization to other sites performing localization assessments. All participants receiving cognitive feedback  and three acute unilateral-plug conditions (conditions 2–4). In the plug conditions one ear was plugged and muffed . Stimuli characteristics, including number and level of stimuli is shown in Fig. In condition 1, stimuli were randomly presented at 30, 40 or 50 dB SL from each of nine loudspeaker locations, totaling 27 stimuli , allowing the subject to perceive the change in loudness and timbre as the signal moved from one side of the head to the other. Altogether, providing participants with information and exposure to the 15 stimuli lasted approximately 5 min.Following condition 2 and immediately prior to condition 3, the experimental group received top-down information (cognitive feedback) regarding the monaural localization task. Participants were provided with information about their (inaccurate) localization performance demonstrated during the acute unilateral hearing condition (condition 2). Specifically, it was explained that they localized the stimuli, as predicted, mainly towards the side of their normal-hearing (open) ear. Using layman’s terms, participants were then informed about the acoustic head-shadow. It was explained that sounds would be perceived different in timbre when originating from different locations. The head acts as a low-pass filter resulting in head-related frequency dependent damping of stimuli originating from the plugged side. Therefore, broadband noise is more perceived like In condition 3 participants were asked to localize stimuli presented at 40 dB SL only. Sounds were presented at 40 dB only, because a change in timbre is better detectable when sound level is not roved. Twenty-five stimuli were presented at random from five loudspeaker locations (five stimuli from each loudspeaker).In condition 4, the experimental procedure of condition 3 was repeated without informing the participants that stimuli were randomly presented at 3 levels , and that the number of loudspeaker locations was increased from five back to nine see Fig. . Particin = 63) were checked for consistency and adherence to the protocol. In total, four protocol deviations were identified, resulting in a total of 39 data sets in the experimental group and 20 data sets in the control groups. Individual data were adjusted so that responses corresponded to right-ear plugging and then grouped for analysis. The mean absolute errors of the stimulus–response relations were calculated and analysis of variance (ANOVA) was used to assess the effects.The individual data  for each condition. Here, an individual participant example (upper row), and the pooled stimulus–response relationship for all 39 participants (lower row) is presented. The stimulus–response relationship for the normal-hearing condition  = 136.98, p < 0.0001. Post hoc comparisons (Table p < 0.0001). Normal-hearing localization abilities were observed across all levels as demonstrated by a high degree of stimulus–response accuracy.Figure ion Fig. A, E is cion Fig. A and 5A,g. F3, 15 = 136.98p < 0.0001). At the individual level it is visible that stimuli were not always perceived toward the hearing ear . Unlike that observed in the controls, a clear improvement and highly accurate localization performance is indicated by the diagonal orientation of the data points  with explicit top-down information about the acute monaural hearing situation, in combination with minimal exposure to 15 BB noise bursts, instantly improved monaural localization abilities. Introducing roving of sound level re-disrupted monaural localization . Only Musicant and Butler  adopted Recently, several studies showed that sensory feedback from other modalities than the visual system could further improve sound localization . However, localization for the 40 dB stimuli rarely differed between both conditions. The results demonstrate that when the level is roved, using sound level becomes an inaccurate strategy, resulting in a bias towards the open normal-hearing ear for high-level stimuli and a bias towards the plugged ear for low-level stimuli  cues are key in the reported improvements. Especially in plugged normal-hearing listeners speakers are visible, visual cues might dominate usage of ILDs and ITDs. An example is the strong ventriloquism effect  hearing-impaired patients.


Hearing loss is one of the most common clinical findings in subjects with malformations of the ear. Treatment consists of surgery and/or adapt a hearing aid amplification by bone (HA VO). Early intervention is critical to auditory stimulation and development of speech and language.To characterize the audiological profile of subjects with congenital malformation of the external ear and/or middle and evaluate the benefit and satisfaction of using HA VO.A descriptive study, subjects with bilateral congenital malformations of the external ear and/ or middle, conductive or mixed hearing loss, moderate or severe and HA VO users. Evaluation of the benefit test using sentence recognition in noise and measures of functional gain and satisfaction assessment questionnaire using international IQ - HA.13 subjects were evaluated, 61% were male and 80% with moderate conductive hearing loss or severe. There was better performance in the evaluation proposal, provided with HA when compared to the condition without HA.HA VO showed advantages for the population studied and should be considered as an option for intervention. Satisfaction was confirmed by elevated scores obtained in IQ - HA. Ear malformations occur during embryo development and may affect the outer, middle and inner ear. The more common congenital ear anomalies affect the pinna and the ear canal, involving one or both ears. Hearing loss is one of the most common findings in individuals with ear malformations and may occur in varying degrees and types, depending on the level of involvementTreatment consists of surgery and/or fitting patients with hearing aids. Early fitting of hearing aids favors auditory stimulation and the development of speech and language acquisition. Surgery is not indicated in all cases, and is usually performed in subjects aged at least six or seven yearsConventional hearing aids cannot be offered to patients with ear agenesis or ear canal stenosis, given the impossibility of using air conduction to stimulate hearingBone conduction hearing aids are designed to bypass the defective middle ear to stimulate the structures inside the cochlea. The output transducer is a bone oscillator. The vibrations of the bone oscillator must be effectively transmitted to the skull. In order to achieve proper transmission, the bone oscillator is usually mounted on one side of the head, attached to an elastic band to keep it pressed against the skull. The hearing aid may be located in the other end of the headband, or close to the user's body as in conventional hearing aidsResearch indicates that the amplification provided by bone conduction hearing aids, the headaches produced by the pressure applied by the headband against the mastoid, and the adverse psychosocial impact felt by users are some of the issues associated with wearing these devices. Complaints of headache caused by the headband and dissatisfaction with the visibility of the hearing aids are common in pre-teens and teenagers. These factors combined lead to reduced usage of hearing aidsBone-anchored hearing aids (BAHA) are an advantageous alternative to conventional bone conduction hearing aids. BAHA have been studied for over two decades and their use is well established in Europe and the USA. More than 20,000 patients have been implanted with BAHA in the worldThe decision on the choice of hearing aids to be offered must be made together with the patient and his/ her family. Bone conduction hearing aids are a practical, non-invasive option available at some public health care services.This study aims to characterize the audiological profile of individuals with congenital malformations of the ear and/or middle ear and assess the benefits and level of satisfaction achieved with bone conduction hearing aids.This study was approved by the Ethics Committee for Research with Human Beings and granted permit #018/2006. Subjects were advised of the nature of the study and asked to sign an informed consent term.The following enrollment criteria were adopted:•Age between six and 40 years•Bilateral congenital malformation involving the ear and/or middle ear•Bilateral moderate to severe conductive or mixed hearing loss•Experience wearing retroauricular bone conduction hearing aids for at least three months•No cognitive disorders.The hearing aids worn by the individuals enrolled in this study were the Unitron UE12 PPL and the Siemens™ Phoenix 213, coupled to a metal rod, a wire, and a bone oscillator of the same brand as the device.Speech recognition tests, functional gain measurements, and the IOI - HA questionnaire were used to assess the subjects.A two-channel audiometer was used in these tests, as dictated by the standards published by the American National Standards Institute . A CD player, a stereo amplifier, and two loudspeakers (one playing speech and the other noise) were connected to the audiometer.The materialThe lists comprised ten short, easily repeatable affirmative sentences ranging between four and seven words in length. The sentences in the list were similar in terms of phonetic content and structure. The lists contained 48 to 54 words and 202 to 214 characters each. The sentences were recorded by a male professional announcer.The first sentence in each list was presented at an intensity of 65 dBA to assess speech recognition thresholds in noise (SRTN). The individuals in the sample had the hearing thresholds required to perceive speech at such intensity. Noise was played at 65 dBA, in a way to start the test with a signal to noise ratio of 0 dB, as suggested by the author. When the subjects were able to correctly recognize the spoken sentence and repeat it using the same phonologic pattern, the next sentence would be played at an intensity of 4 dB less than the previous sentence. In the event of a mistake, the signal was increased in steps of 2 dB, until the individual got it right. Steps of two decibels would then be applied upwards in the event of other mistakes and downwards when the individual was successful, until all ten sentences were played.The subjects were positioned one meter away from the loudspeakers at an angle of incidence from the noise and speech source of zero degrees azimuth.The functional gain provided by hearing aids is defined by the difference in decibels between the free-field audiometry thresholds assessed with the subjects with and without hearing aids under equal testing conditions.The minimum intensity was 30 dB NPS with and without the use of hearing aids, as this is the minimum level of intensity allowed by the equipment used in the test sessions.Hearing thresholds at 6000 and 8000 Hz were not acquired, as the hearing aids worn by the subjects in this study provided less gain in these frequencies.The limit psychometric method was used to acquire hearing thresholds. The intensity of the sound stimuli was gradually reduced in steps of 10 dB until the patients could no longer respond. Then, the intensity was increased in steps of 5 dB until the subjects were able to respond again. The threshold was defined as the intensity at which patients were able to respond to 50% of the sentences presented.The Brazilian Portuguese version of the International Outcome Inventory for Hearing Aids (IOI - HA)The questionnaire contains seven questions with five possible answers each and is used to assess subject adaptation to hearing aids considering the following issues: 1 - Hearing aid daily use; 2 - Benefit; 3 - Residual activity limitations; 4 - Satisfaction; 5 - Residual participation restrictions; 6 - Impact on others; 7 - Quality of life.The questionnaire offers five possible answers graded from left to right, in a way that the first option refers to poor performance corresponding to a score of one, and the last option reflects top performance and a score of five. Caretakers/guardians were advised along with the patients to choose only one answer to characterize how well adapted the subjects were to their hearing aids.The analysis of the IOI - HA questionnaire was based on the answers provided to each question individually and as a group. The scores on each question, the total score considering the seven questions, and the scores considering factors 1 and 2 in the questionnaireStudent's t-test for paired samples was used to compare measurements with and without hearing aids. Student's t-test was used to estimate the mean scores on the questionnaire.Each of the seven questions have a minimum possible score of one and a maximum possible score of five. The total score refers to the sum of the scores given to each answer and may range from seven to 35. Scores on factor 1 may range from four to 20 points, while factor 2 can vary between three and 15 points. Higher scores indicate better outcome in regards to adaptation to hearing aids. Thirteen individuals  wearing hearing aids for a mean of three years were included in the study. Their ages ranged between six and 37 years (mean of 14 years of age) .Table 1DDescriptive and inferential statistical analysis  of the results derived from the assessment of the 13 subjects with and without hearing aids, in tests to assess speech recognition thresholds in noise (SRTN) at 65 dB A and signal to noise ratios (SNR) are presented on Comparisons between the test outcomes of the 13 individuals with and without hearing aids, in terms of free-field audiometry hearing thresholds (dB NPS) at 250 to 4000 Hz, along with the measurements of functional gain in each of the tested frequencies are presented on Eight of the 13 included subjects were males . The litAll patients included in this study had bilateral malformation, contrary to what other authors have observed. According to them, unilateral malformations were more prevalentCongenital stenosis or atresia of the ear canal may be partial or complete, and is frequently accompanied by malformations of the pinna, ossicles, middle ear cavity, and otic capsule, resulting in a vast array of types of hearing loss, ranging from moderate conductive to severe mixed hearing lossThe subjects included in this study claimed to be systematic users of hearing aids . AuthorsA study carried out with 20 children with ear malformations found that 36% of the subjects with unilateral malformations rarely used bone conduction hearing aids, and that 44% of the children with bilateral malformation always had them on. It is possible that the latter group wore hearing aids more frequently as a result of their bilateral involvementSignal to noise ratios may be presented in the form of positive or negative numbers, and are expressed in decibels (dB)Many studies have looked into speech recognition in noise tests to compare individuals wearing conventional bone conduction hearing aids and bone-anchored hearing aids. Some authors have reported better results for BAHA usersA study conducted with 122 subjects on speech recognition in noise at an SNR of + 6 dB found a mean improvement in speech recognition of 35.5% when subjects wore bone conduction hearing aids and a mean improvement of 41.8% when they wore BAHA, when compared to subjects without hearing aids. The 6.3% difference between BAHA and conventional bone conduction hearing aids was statistically significantIn Brazil, studies on the fitting of hearing aids in individuals with ear malformations are scarce. A study was carried out on two individuals with craniofacial malformations and bilateral moderate conductive hearing loss wearing conventional bone conduction hearing aids and BAHA. The author looked into free field tone thresholds and speech recognition in noise using the staggered spondaic word test, with the subjects not wearing hearing aids, with conventional bone conduction hearing aids on, and with BAHA on, to conclude that both devices yielded satisfactory levels of hearing gain. In regards to speech recognition, the BAHA outperformed the other devices, but failed to show evidences of improvement when compared to monaural and binaural fittings of the two types of hearing aids analyzedAccording to a study carried out at a high complexity care centerThe IOI - HA is a sensitive tool that can be used to detect individuals with negative experiences while wearing hearing aidsThese results have shown that the individuals included in this study were happy with their hearing aids, contrary to what was observed in other papersPatients showed improved functional gain and reported they were happy with their bone conduction hearing aids, thus showing the benefits provided to the studied population by this type of hearing aids.


COVID-19 which first raised its deadly head in December 2019, has now engulfed the entire planet with its fire and fury. Mankind has been literally held to ransom by this micro-beast which has caused so much pain, sorrow and suffering, leaving behind scores of people dead and millions sick and gasping for air  The whole world is in disarray since the past 16 months, and now a new deadly superadded fungal infection has appeared in COVID-19 patients, in parts of the Indian subcontinent; namely mucormycosis, the deadly “black fungus.” This persistent, unrelenting fungal infection which is relatively resistant to conventional anti-fungal treatment, sometimes requires radical, extensive surgical intervention in order to stem the spread of infection to vital organs such as the heart, brain, orbital spaces and spleen. mucormycosis has been increasingly seen to occur in COVID-19 patients who are immunocompromised and have uncontrolled diabetes mellitus as a comorbidity. Commonly seen forms of mucormycosis in COVID-19 patients include, Rhinocerebral mucormycosis and Pulmonary mucormycosis, with some patients also developing the cutaneous form, while some manifesting the more serious disseminated form of mucormycosis. Cunninghamella bertholletiae, Syncephalastrum species, Rhizopus species, Lichtheimia and the Apophysomyces species [Mucormycosis (popularly known as “black fungus”) is a rapidly spreading, unrelenting fungal infection which can be devastating in its intensity and reach, as is apparent in recent months, in patients combating COVID-19 infection. While more than two-thirds of the reported cases have been from the Indian sub-continent, the vast African continent too needs to be alerted about the potential devastation mucormycosis can cause in immunocompromised COVID-19 patients, who also have concomitant uncontrolled diabetes mellitus as a significant comorbidity. Mucormycosis, also known as zygomycosis is a fairly rare but devastating fungal infection, caused by a group of molds called mucormycetes. These molds are ubiquitous in our environment and live mostly in moist soil and decaying organic matter, such as compost piles, rotten wood and leaves . Fungi tClinical characteristics: mucormycosis mainly affects people who have comorbid conditions such as uncontrolled diabetes mellitus, and a weakened immune response due to the intake of medications such as corticosteroids, which lower the body´s response to infections. Other major risk factors for contracting mucormycosis include prolonged ICU stay, voriconazole therapy and underlying malignancies. Mucormycosis mainly affects the nasal and paranasal sinuses and the lungs. The mode of entry is by inhaling fungal spores from the atmosphere. It can also gain entry through the skin following an injury, a burn, a cut or an abrasion.Mucormycosis can be classified into the following categories.Rhinocerebral mucormycosis: it is a fulminanting infection in the sinuses that has the potential to spread to the brain. This form of mucormycosis is most common in people with uncontrolled diabetes mellitus and in people who have been immunocompromised in any way, such as due to intake of corticosteroids or immunosuppressants, following organ transplant [ansplant ,4. This Pulmonary (lung) mucormycosis is a very common type of mucormycosis. It is mainly seen in immunocompromised patients such as those who have had an organ transplant or those with cancer.Disseminated mucormycosis occurs when the infection gets disseminated through the bloodstream and affects distant organs such as the heart, brain, skin and spleen.Gastrointestinal mucormycosis is a condition more frequently observed in young children; especially in premature and low birth weight infants less than 1 month of age, who have had medications that lower the body´s immunity to fight disease [ disease ,6.Cutaneous mucormycosis occurs when the fungi gains entry following a break in the skin as a result of an abrasion, cuts or severe burns. This is the most common form of mucormycosis among people who do not have a compromised immunity. Symptoms of mucormycosis manifest depending on the point-of-entry of the fungus into the human body, and the site of growth and dissemination [mination ,8. Most Incidence of mucormycosis in COVID-19 patients: the rising incidence of mucormycosis which has an overall mortality rate of 50% in patients with COVID-19 infection, is strongly presumed to be due to the indiscriminate use of corticosteroids, combined with uncontrolled diabetes mellitus in severe and critically ill Covid-19 patients. Steroids reduce inflammation in the lungs in COVID-19 and appear to help stop some of the damage that can happen during a cytokine storm, when the body's immune system goes into overdrive, to ward off the coronavirus. But steroids also reduce the body´s immunity and elevate blood sugar levels in both diabetic and non-diabetic COVID-19 patients, which is now believed to be the triggering factor for the development of mucormycosis in these patients. As a result, a rising incidence of cases of rhino-orbital mucormycosis in COVID-19 patients have been observed over the last many months, on the Indian subcontinent. Six cases of COVID-19 infection with rhino-orbital mucormycosis were reported recently at a single institution [titution , reporteManagement and treatment options: in order to prevent mucormycosis it is recommended that blood glucose levels be kept under control through constant monitoring, even following post-COVID discharge, in diabetic patients. Judicious use of corticosteroids in correct dosage forms and duration is essential for prevention of this fungal disease in COVID-19 patients. It is also recommended that only clean sterile water be used in oxygen humidifiers, and antibiotics and antifungal medication be used in correct dosage forms and for the appropriate duration. Mucormycosis is a serious, unrelenting, persistent infection that needs to be treated with prescription antifungal medication such as liposomal amphotericin B (LAmB), lipid complex amphotericin B, posaconazole, or isavuconazole for at least six weeks. These medications are administered intravenously  or orally . During treatment for mucormycosis, it is recommended to insert a central catheter line for maintaining adequate systemic hydration, and for administration of the appropriate medication. The recommended starting dose of liposomal amphotericin B in mucormycosis is 3-5mg/kg/day, given intravenously over a 30-60 minutes period. The duration of therapy is usually determined on an individual case-to-case basis, but the normal duration of treatment is usually 6-8 weeks. A longer duration of treatment may be required in patients with deep-seated bone, palate and orbital infections, those on prolonged chemotherapy and in those with severe neutropenia.Prior to starting treatment with amphotericin B, a test dose of 1mg must be given intravenously over 10 minutes, and the patient must be assessed over the next 30 minutes for any severe allergic or anaphylactic reactions. If the medication is tolerated well, it can be continued. Hopefully, prompt use of the above medications, compounded with a good control of blood sugar levels and a more judicious use of corticosteroids in COVID-19 patients, will help in containing the rising incidence of mucormycosis in these patients. It should be noted that medications such as fluconazole, voriconazole, and echinocandins are ineffective against fungi that cause mucormycosis. Sadly, since mucormycosis is an unrelenting disease, more often than not, it entails radical surgery to cut away the infected tissue. This may include entire jaw removal or enucleation of an eyeball, in order to prevent further spread of the fungal infection into the brain, or disseminate to organs such as the heart, spleen and other vital organs.In conclusion, it appears that the spread of mucormycosis in COVID-19 patients is assuming alarming proportions in some parts of the world, namely, the Indian subcontinent. This is mainly seen in patients with uncontrolled diabetes mellitus who are on corticosteroids and other immunomodulating agents. Clinicians in Africa therefore need to stay alert to the possibility of this unrelenting fungal infection presenting in COVID-19 patients here. A high-index of clinical suspicion in patients presenting with typical symptoms and signs, will go a long way in promptly diagnosing and treating this potentially fatal infection.


Hearing rehabilitation with hearing aids is a complex process which requires professional expertise and the involvement of audiologists or hearing-care specialists. Professional care, however, requires extra resources, making it tempting to rely solely on technology and reduce the role of professional counselling.To reduce the out-of-pocket share for adults needing hearing rehabilitation, in 2011 the Israeli government tripled the subsidy for adult hearing aids by converting 3 years of subsidies into a triennial, enlarged fund. Regulations for providing hearing rehabilitation and a set of rules for tenders for the supply of hearing aids were issued.Auditory diagnosis and rehabilitation are included in the Israeli national health insurance system. Before 2011, the annual government-funded subsidy for hearing aids was negligible; hearing aids were expensive and bought mostly with patients’ own resources.A series of tenders for companies to supply hearing aids, aiming to control public and individual expenses, resulted in a large reduction in prices, which in turn raised the demand for hearing aids and increased public expenditure. As the price of hearing aids fell markedly, hearing rehabilitation is approaching a point of becoming limited to supplying hearing devices, while reducing the importance placed on professional elements of the rehabilitation course.Lowering out-of-pocket costs for patients should not be the only consideration in hearing rehabilitation. Our goal should be to control public expenditure but also provide affordable hearing aids with sufficient intervention of hearing-care specialists, to ensure access to advanced technologies and proper professional care. The World Health Organization (WHO) estimates that 466 million persons (more than 6.1% of the world’s population) live with disabling hearing loss.Hearing rehabilitation requires both technological devices (such as hearing aids and assistive listening devices) and professional care. Rehabilitation is a complex process in which audiologists or hearing-care specialists map the communication needs and difficulties of the individual; consider multiple factors ; choose the appropriate device; discuss the patient’s expectations; solve problems; and provide listening strategies and auditory training. This professional practice aims to support continued use of the hearing devices and gain optimal benefit from their use. Hearing aids are the most common rehabilitation technological devices for people with hearing loss, but often their high price can be an obstacle to rehabilitation. Professional care also requires financial resources, which in turn raise the cost of hearing rehabilitation, making it tempting to rely solely or mainly on technology, and reduce the role of professional care.We describe the Israeli experience, where a scheme intended to lower the out-of-pocket costs of hearing aids to patients could risk disrupting the hearing rehabilitation process.The Israeli national health insurance law stipulates a set of health-care technologies and services, including auditory diagnosis and rehabilitation, which are provided to every resident of the country by four health maintenance organizations. Until 2011, the annual refund for adult hearing aids was low: up to 12% for basic technology hearing aids, and no more than 6% for high-end devices.–,In 2011, to reduce the out-of-pocket share for adult hearing rehabilitation, the Public Committee for Health Service Basket tripled the public subsidy for hearing aids for adults aged 65 years and older by converting 3 years’ subsidies into a triennial, enlarged fund of New Israeli Shekel, NIS 3000  per ear.The reform was successful, and thousands of adults who previously could not afford to purchase hearing aids were now able to have proper hearing rehabilitation. The increased demand for hearing aids, however, raised the financial load on the health maintenance organizations, requiring an increase in the budget originally allocated for hearing rehabilitation. In 2011, during the first year after the reform, the health maintenance organizations spent more than five times the allocated budget.In attempts to control public expenses, more than a dozen tenders to companies for the supply of hearing aids were issued by the health maintenance organizations during 2011–2022. The result was intense competition among hearing aid suppliers, who greatly reduced the prices, which in turn further increased the demand for hearing aids, and consequently increased public expenditure. As the number of tenders increased, the cost of hearing aids was reduced in some of the tenders below the hearing-aid subsidy to eligible individuals. Eventually, tenders focused on the price of hearing aids but continued to require the full audiological rehabilitation and service bundle.,As the price of hearing aids fell dramatically, hearing rehabilitation is approaching a point of becoming limited to supplying hearing aids as commodities with minimal professional care. Fortunately, the right to appropriate professional care is a core element of the Israeli medical system. Health maintenance organizations, suppliers and audiologists all insist that patients will receive the best available hearing aids and the best professional care. Our concern is that the pressure to reduce prices might result in attempts to waive the role of professional care in the rehabilitation process. Indeed, there have been attempts to deprive audiologists of essential components of their professional work.The benefits of low-price hearing aids cannot be ignored, especially in low- and middle-income countries, in countries with no national health insurance or when audiology visits during hearing rehabilitation are paid for by the patient. Nevertheless, providing hearing aids at low prices, but with insufficient diagnosis, counselling and follow-up, can result in less than optimal rehabilitation and increased risk for non-use of the hearing aids.–Research has demonstrated higher satisfaction and adoption rates when hearing aids were fitted according to audiology best practice as compared with self-selection of pre-programmed hearing aids.Guidelines for hearing aids and services for developing countries, WHO acknowledged that while hearing aid costs should be kept low, the involvement of trained personnel in the course of hearing assessment and hearing aid fitting is an essential part of the rehabilitation process.Untreated hearing loss in adults is correlated with increased odds of cognitive decline, loneliness, depression, falls and low quality of life.The Israeli reform increased the affordability of hearing aids for many individuals, but an unforeseen consequence was that regulations and multiple tenders increased bureaucracy, made the purchasing of hearing aids complicated for everyone involved and put the role of professional care at risk . IsraeliBox 1Lowering the cost of hearing aids should not be the only consideration in hearing rehabilitation.Best practice in hearing rehabilitation with hearing aids should include professional care.Audiologists should be involved in decision-making when their scope of practice and professional role are discussed and decided.Cost should not be the only consideration in hearing rehabilitation. Our goal should be to control public expenditure but also keep prices reasonable to ensure access to advanced technologies and professional care. At the same time we need to ensure that proper counselling, fitting and maintenance are conducted, and that the medical conditions, and social and personal needs of patients are considered.