South Korea's National Health Insurance has provided hearing aids to registered individuals with hearing disabilities since 1989. In 2015, hearing aid subsidies increased to approximately US$1,000. This study aimed to understand hearing loss categories in Korea by analyzing patients between 2010 and 2020 and the effect of the 2015 hearing aid policy change on the prevalence of hearing loss.The participants were patients registered on the National Health Insurance Service database from 2010 to 2020 with hearing loss. A total of 5,784,429 patients were included in this study. Hearing loss was classified into conductive, sensorineural, and other categories. Patients with hearing loss were classified according to the International Classification of Diseases diagnostic code. Disability diagnosis and hearing aid prescription were defined using the National Health Insurance Disability and Hearing Aid Code.r-value of each analysis exceeded 0.95. Other hearing losses increased rapidly after the increased subsidy.The increase in hearing aid prescriptions and hearing disability registrations following the subsidy increase impacts hearing loss prevalence. Hearing aid prescription and hearing disability were found to have an effect on increasing hearing loss prevalence in univariate and multivariate analyses. The A hearing-impaired individual must be diagnosed with a hearing disability and prescribed a hearing aid to receive the subsidy. The prevalence of hearing loss was affected by increased hearing disabilities following changes in the hearing aid subsidy and the number of people prescribed hearing aids. Therefore, caution should be exercised when studying hearing loss prevalence over mid-long-term periods. The burden of hearing loss is substantial at an individual level and over a lifetime. This burden can be exacerbated by negative social attitudes and prejudices toward those who are affected . HearingThis study used data from the National Health Insurance Service (NHIS). The NHIS uses the National Health Insurance (NHI) to lessen the burden of high medical expenses on the public. The public pays insurance premiums to mitigate the risk of high medical expenses due to illness or injury. The insurance is managed and operated by the NHIS through social consensus. The NHI provides health insurance benefits to the public, meaning that risk is shared and everyone has access to necessary medical services. Data from National Health Insurance subscribers are accumulated in the NHIS database (NHIS DB). Information such as medical history, drug prescription history, and health evaluation is limited to researchers only , 11. HeaA 2015 study analyzing the prevalence of hearing loss and hearing aids in older adults  and a stThis study aimed to analyze the NHIS DB for patients treated for hearing loss by year, sex, and age and identify domestic hearing loss by type from 2010 to 2020. Moreover, the study assessed the current status of hearing aids for patients with hearing loss.South Korea's National Health Insurance covers 98% of the population. The citizens are covered for medical expenses whenever they visit a hospital . The parChanges in patients with hearing loss by year were analyzed for changes compared to other age groups by comparing increases and decreases between the relevant age group and other age groups. Age is an important variable, and it was thought that the influence would be different depending on the type of hearing loss, so an adjustment was not performed, but an adjustment was made according to the population of each statistical group. Statistical analyses were performed using SAS, version 9.4 .The data for this study were collected from the NHIS DB. The data were used to classify patients according to their category of hearing loss; the number of patients with hearing loss and disability diagnosis over 10 years was investigated . The typThe NHIS DB collects the following historical information: medical treatment, drug prescriptions, and health checkups of health insurance-registered individuals. After de-identifying the participant data, the dataset was provided for policy and academic research purposes. National health information data can be provided to health and academic medical fields  for systematic research activities related to public health. Patients with hearing loss were classified according to the International Classification of Diseases, 10th Revision (ICD-10) diagnostic code (major/minor diagnosis) based on the operational definition for each category . The resA total of 5,784,429 patients were included in this study. The distribution of hearing loss patients by age ranged from 25,553 patients under the age of 10 years in 2010 to 4,89,419 patients over 60 years in 2020 . The numLooking at the compound annual growth rate (CAGR) of hearing loss patients from 2010 to 2020, it is evident that the rate of increase is high among those in their 20s and 30s, and the incidence rate of those under 10 years has decreased significantly. However, prevalence increased in all age groups except those under 10 years. This is not a phenomenon whereby the number of patients with hearing loss increased in any age group because of a single event rather the influence of hearing loss increased in all age groups . The heaWhen the prevalence of hearing loss was confirmed, the number of hearing loss patients by age increased from 2015 onwards . From 20The prevalence of all types of hearing loss is increasing, especially in the conductive and other categories. The types of hearing loss were divided by age and examined according to the CAGR. Sensorineural, other, and sudden hearing loss showed a substantial increase in patients in their 20s and 30s . In partThe hearing aid prescription populations were compared before and after 2015. The average number of people prescribed hearing aids increased after 2015. When looking at the CAGR, the age group with the highest increase in hearing aid prescriptions was the under 10s; there was also a significant change in the teenage group. The population receiving hearing aids increased by 1.74 times in 2020 compared to 2010. This increase was 2.12 times in the total population for the same period .Hearing-disabled populations were compared before and after 2015. In general, the hearing-disabled population increased from 2010 to 2020. According to the CAGR, the age group with the highest rate of increase in hearing disability is the population over 60 years. However, significant changes were also observed in those under 10 years and those in their 20s. The overall hearing-disabled population increased by 2.06 times in 2020 compared to 2010 .We compared the hearing disability and hearing aid prescription populations before and after 2015. The hearing aid prescription population showed a clear upward trend starting in 2015. When looking at the CAGR, the increase was reflected in the under 10s population. In the case of the hearing-disabled population, there has been a clear upward trend since 2015. The age group with the greatest impact on the increase is the population over 60 years old. This is likely due to South Korea's hearing aid subsidy increase implemented in 2015. Patients who had suffered from hearing loss for an extended period had purchased a new hearing aid. Moreover, patients with hearing loss who previously could not afford a hearing aid could now afford one due to the subsidy.r-value of each analysis was high, exceeding 0.95  to expose themselves to potential infection in the overloaded medical system. However, this is not certain as it was outside the study period. If the prevalence of hearing loss continues to decrease or remains stable, these results may be interpreted differently. However, the total number of hearing loss cases increased by approximately 70% over 10 years from 1,281,169 in 2010 to 2,184,821 in 2020. The number of cases increased by 8% in 2015 and 12% in 2016, and the rate of increase in 2013 and 2014 was approximately 3%.South Korea's NHI system is operated by a single insurance company, the NHIS, per the National Health Insurance Act of 1963. The NHIS DB used in this study was obtained from South Korea's NHI system. South Korea's medical infrastructure and NHI provide some of the best coverage globally, and patient reluctance to diagnose and treat is very low . TherefoThe KHBC was established in 2020 as part of South Korea's big data platform business as an affiliate of the Korean Audiological Society. The purpose of the KHBC was to provide specialized big data on hearing to medical device industries and researchers. As of 2022, the KHBC has approximately 1,00,000 data points, including reference standard data for the hearing threshold of Koreans from the Korea Hearing Standard Reference Data Center. We are researching hearing big data through the MOU with NHIS. We are also exploring the combination of NHIS DB and KHBC data. This is the first MOU study conducted by the KHBC with the NHIS.This study has the following limitations. After the increase in the prevalence of hearing loss, it was not possible to confirm the stabilization, increase, or decrease in the prevalence of hearing loss. Furthermore, a study on post-subsidy supports that funding in July 2020 was not considered due to the short study period. Our study is not perfect in the operational definition as it thoroughly relied on the ICD-10 by the doctor when the patient visits the hospital. The solution to this is to add different definition conditions for each type of hearing loss, depending on the various causes. However, the ICD-10's other hearing loss is not well defined. Therefore, the prevalence rates in our study are estimates. The present study also covered the period during the onset of the COVID-19 pandemic, which may impact the generalizability of the study results. The study period should be extended to investigate the cause of the changes in the prevalence of hearing loss after the study period.In South Korea, it is necessary to undergo a process to receive a hearing aid subsidy. This includes the diagnosis of a hearing disability and being prescribed a hearing aid. This process affects the prevalence of hearing loss. Therefore, the 2015 increase in hearing aid subsidies impacted the prevalence of hearing loss in the medium and short term. Based on the category of hearing loss, a surge in sensorineural hearing loss and other types of hearing loss was observed after the increased hearing aid subsidies. The prevalence of hearing loss was, therefore, affected by the increase in the hearing-disabled population and hearing aid adoption due to changes in the hearing aid subsidy. Caution is needed when studying the period in the mid-long term.https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do.The data analyzed in this study was obtained from the Korean National Health Insurance Service (NHIS) the following licenses/restrictions apply: only Korean researchers can access these datasets. Requests to access these datasets should be directed to NHIS, The studies involving humans were approved by the Institutional Review Board (IRB) of Yonsei University Wonju Severance Christian Hospital (CR321338). The studies were conducted in accordance with the local legislation and institutional requirements. The Ethics Committee/Institutional Review Board waived the requirement of written informed consent for participation from the participants or the participants' legal guardians/next of kin because this study is a study using data collected retrospectively and the data collected is not data collected for research.YS: conceptualization. CY and JL: data curation and visualization. CY: formal analysis, methodology, and writing—original draft. CY, YS, and TK: project administration and writing—review and editing. All authors contributed to the article and approved the submitted version.


TIMM8A loss of function. It is characterized by sensorineural hearing loss in childhood, progressive optic atrophy in early adulthood, early onset dementia and psychiatric symptoms of variable expressivity. We present a family with 4 affected males, explore age-related and interfamilial variability and review the literature.Mohr-Tranebjaerg syndrome (MTS) is an X-linked recessive disorder caused by TIMM8A, c.45_61dup p.(His21Argfs*11), establishing the diagnosis of MTS. Genetic counseling of the family allowed the diagnosis of three other symptomatic relatives −3 nephews (11yo and two 6yo twins), children of a carrier sister. The oldest nephew had been followed since 4yo due to speech delay. Sensorineural hearing loss was diagnosed at 9yo, and hearing aids were prescribed. The two other nephews were monozygotic twins, and both had unilateral strabismus. One of the twins had macrocephaly and hypoplasia of the anterior temporal lobe, as disclosed by an MRI performed due to febrile seizures. Both had developmental delays, with the language being the most affected area. Their audiograms confirmed hearing loss. All three nephews were hemizygous for the familial TIMM8A variant.A 31 years-old male developed psychiatric symptoms at age 18 and presented early onset dementia. Sensorineural hearing loss had been diagnosed in childhood. At 28yo, he developed dysarthria, dysphonia, dysmetria, limb hyperreflexia, dystonia, and spasticity following an acute encephalopathic crisis. WES revealed a hemizygous novel likely pathogenic variant in Hearing loss, an early sign of MTS due to auditory neuropathy, can often be overlooked until more severe features of the disorder manifest. Recurrence risk is high for female carriers, and reproductive options should be offered. Early monitoring of hearing and vision loss and neurological impairment in MTS patients is mandatory since early interventions may positively impact their development. This family showcases the importance of performing a timely etiological investigation of hearing loss and its impact on genetic counseling. Mohr-tranebjaerg syndrome (MTS), also known as deafness-dystonia-optic neuronopathy, is a rare X-linked recessive neurodegenerative disease characterized by pre-lingual or post-lingual sensorineural hearing impairment in early childhood, followed by slowly progressive dystonia or ataxia and optic atrophy in adolescence or adulthood , 2.MTS is progressive, and other signs and symptoms may appear throughout the patient's life, such as pyramidal signs, cognitive decline, dementia, or psychiatric disorders –3. HowevTIMM8A or by a contiguous gene deletion at Xq22.1 encompassing TIMM8A. This gene encodes a small protein that localizes to the intermembrane space in mitochondria and is a component of the translational system for the import and assembly of mitochondrial inner membrane proteins . During the following weeks, with infection resolution, his conscious level improved, but his neurological state never fully recovered to the previous state. His neurological examination revealed a well-awake and aware patient with limited speech and typical dysarthria of the hearing impaired. Severe dysphagia was present during the following weeks after the encephalopathic period, and percutaneous gastrostomy was needed but removed in less than a year. He did not present any motor deficit but had a generalized increase in muscle tone, especially in the lower limbs, with moderate spasticity and hyperreflexia, with a spastic gait that was impossible without assistance. There was also slight right-hand dystonia but without functional limitation. Whenever he became severely ill by systemic disease, his neurologic deficits worsened, and there was a rapid functional decline during the following 5 years.The following investigation was carried out: normal metabolic, endocrine, and autoimmune panels; cerebral and spinal MRI with no focal lesions or atrophy. Electromyography revealed a slight axonal type of sensory neuropathy. Mitochondrial DNA sequencing was also negative for any pathological mutation. Ophthalmologic evaluation at age 29 was normal.TIMM8A, c.45_61dup p.(His21Argfs*11), establishing the diagnosis of Mohr-Tranebjaerg syndrome. This variant has not been described in the literature nor in the gnomAD and ClinVar databases.As the previous etiological investigation was inconclusive, whole exome sequencing was performed and revealed a hemizygous novel likely pathogenic variant in TIMM8A variant.Subsequently, the patient's family was referred for genetic counseling. The same variant was found in the mother and one of the four sisters. Genetic counseling also allowed the diagnosis of other symptomatic relatives: three nephews (cases 2–4) who were children of a carrier sister. All three nephews were hemizygous for the familial The oldest nephew was an 11-year-old boy, the first son of a non-consanguineous couple, born full-term after a supervised pregnancy. In the neonatal period, he performed otoacoustic emissions that were normal. At age 4, he was referred to a pediatric consultation due to a delay in developing expressive language. A global developmental delay was diagnosed, with the language area most severely affected. Afterward, behavioral problems were also reported. He started speech and occupational therapy with some progress and improvements.At 8 years old, he underwent a cognitive assessment  that revealed a full scale intelligence quotient (IQ) of 55, verbal IQ of 51 and performance IQ of 65.After irregular and incomplete attendance at medical appointments and diagnostic tests, sensorineural hearing loss  was diagnosed at 9 years Hearing aids were prescribed, which led to a slight improvement, but without full recovery of language delay.His neurological examination was always normal, and he had no dysmorphic features.The two other nephews were 6-year-old monozygotic twins, younger brothers of patient 2. They were born at 39 weeks, and no complications were described in the neonatal period. They performed the universal newborn hearing screening through otoacoustic emissions with a “pass” result in both ears.Both had unilateral strabismus, one with onset in the 1st months of life and the other at around 2 years of age, with follow-up in ophthalmology.One of the twins (case 3) was referred for a developmental consultation at 11 months due to macrocephaly (head circumference >99th percentile) and two simple febrile seizures at 7 and 10 months, without recurrence of seizures subsequently. In this context, he performed a cerebral MRI that only revealed an arachnoid cyst in the left middle fossa and associated hypoplasia of the anterior aspect of the temporal lobe. At 6 years of age, the other twin (case 4) had an episode of cervical dystonia.Both had behavioral problems and global developmental delays. At 5 years old, they were evaluated by the Griffiths Mental Development Scale (GMDS), which revealed a general quotient of 64 and 70 in patients 3 and 4, respectively. The language subscale had the lowest developmental quotient: 38 and 52 for cases 3 and 4, respectively. The audiograms of both seem to confirm hearing loss but are non-specific due to lack of cooperation. Brainstem auditory evoked potentials while sedated have been scheduled for both.MTS is characterized by a great phenotypic variability, including intrafamilial, as demonstrated by the description of these four clinical cases. Nevertheless, all these cases had in common a neurodevelopmental delay and hearing loss with onset in the first decade of life.The hearing impairment results from auditory neuropathy. As expected, many patients with MTS have intact otoacoustic emissions, indicating normal outer hair cells, at least in the early stages of the disease, as seen in the nephews cases 2–4) –4 2, 8)8). Heari8). HeariThe neurological features of MTS are usually characterized by progressive movement disorder that can appear either as dystonia and ataxia, or pyramidal signs as spasticity , 4. The Another characteristic of MTS is the development of neuropsychiatric symptoms. Behavioral or neuropsychiatric problems, such as mild intellectual disability, personality changes, anxiety, reduced impulse control, aggressiveness, and compromised concentration ability, may be present from childhood. Later, some patients may present paranoid psychiatric features or gradually develop dementia , 8. In tOptic neuropathy, another feature of this syndrome, may be subclinical for many years . Visual Although epilepsy has not been associated to MTS, it is a sufficient prevalent diagnosis in the general population to be a concomitant diagnosis in our index patient. Patient 3 did not develop epilepsy up to this point, having had only simple febrile seizure episodes. The authors also argue that this newly described variant could have epileptic seizures as a phenotypic manifestation. As MTS encompasses a neurodevelopment disorder, the association with epilepsy could be one to be traced in the future, as the incidence of neurodevelopmental disorders in patients with epilepsy is higher than that in the general population .Genetic diagnosis is essential as it may offer opportunities for anticipatory management. The treatment of this genetic syndrome is symptomatic, consisting in managing its manifestations . Thus, eMTS is inherited in an X-linked manner. Consequently, the recurrence risk is high for female carriers, as seen in this family. Genetic counseling should be offered to affected or at-risk individuals, including discussion of the potential risk to offspring and reproductive options. Once the pathogenic variant has been identified in the family, preimplantation genetic testing and prenatal testing are possible .In conclusion, Mohr-Tranebjaerg syndrome should be suspected in a family with male elements affected with hearing loss at a young age, associated with dystonia or behavioral or neuropsychiatric disorders. This family illustrates the importance of timely etiological investigation of hearing impairment and its impact on genetic counseling.The original contributions presented in the study are included in the article/Written informed consent was obtained from the legal guardians of the patients, for the publication of any potentially identifiable images or data included in this article.CF was the attending geneticist of the family and all MTS patients and reviewed and edited the manuscript. JR was the attending neurologist of the index patient and reviewed and edited the manuscript. NT was the initial attending geneticist of the monozygotic twin younger nephews. ES was the attending pediatrician resident. MA was the attending medical genetics resident. ES and MA drafted the manuscript. All authors revised the manuscript critically for important intellectual content and approved the final version of the manuscript.


Sensory dysfunctions and cognitive impairments are related to each other. Although a relationship between tinnitus and subjective olfactory dysfunction has been reported, there have been no reports investigating the relationship between tinnitus and olfactory test results.To investigate the relationship between tinnitus and olfactory test results, we conducted sensory tests, including hearing and visual examinations. The subjects included 510 community-dwelling individuals (295 women and 215 men) who attended a health checkup in Yakumo, Japan. The age of the subjects ranged from 40 to 91 years . The participants completed a self-reported questionnaire on subjective tinnitus, olfactory function, and hearing function, as well as their lifestyle. The health checkup included smell, hearing, vision, and blood examinations.After adjusting for age and sex, the presence of tinnitus was significantly associated with subjective olfactory dysfunction, poor olfactory test results, hearing deterioration, vertigo, and headache. Additionally, high serum calcium levels and a low albumin/globulin ratio were significantly associated with low physical activity and nutrition. Women scored higher than men in olfactory and hearing examinations, but there was no gender difference in vision examinations.Subjective smell dysfunction and poor smell test results were significantly associated with tinnitus complaints. Hearing and vision were associated even after adjusting for age and sex. These findings suggest that evaluating the mutual relationships among sensory organs is important when evaluating the influence of sensory dysfunctions on cognitive function. Many reports have described age-related sensory dysfunctions regarding vision, hearing, smell, and taste. However, there have been fewer studies investigating the relationships among these senses , 2. OlesNot only a decrease but also abnormal sensations in smell and taste function are significant complaints in some patients after COVID-19 infection. Parosmia changes the usual perception of odors, such as when the smell of something familiar is distorted or when something that usually smells pleasant starts smelling foul. Phantosmia refers to an olfactory hallucination that is not caused by an actual odor. Parosmia and phantosmia can sometimes be more troublesome than hyposmia or anosmia. Tinnitus, on the other hand, is characterized by hearing sounds that are not present in the external environment. The relationship between phantosmia and smell dysfunction is similar to that between tinnitus and auditory dysfunction. Qualitative smell/taste disorders  have not yet been fully characterized, whereas quantitative disturbances  have been widely investigated .The coexistence of olfactory dysfunction and tinnitus with or without hearing loss after having COVID-19 has been reported –8. Some Park et al.  recentlyWe sent a detailed questionnaire, including questions on health problems and lifestyles, to the participants before the health examination. To the question “Can you smell?”, the participants chose one among the following four answers: (1) “sense smell well,” (2) “sometimes hard to smell,” (3) “slightly,” and (4) “not at all.” To the question “Do you have tinnitus?” the participants chose one among the three answers: (1) “no,” (2) “sometimes,” and (3) “always.” The difficulty of conversation includes two questions: “Can you hear one-to-one conversations without a hearing aid?” and “Can you hear conversations between four or five people without a hearing aid?” The participants selected one among four answers: (1) “completely,” (2) “mostly,” (3) “not much,” and (4) “almost nothing.” The participants also selected one among three answers, (1) “no,” (2) “sometimes,” and (3) “always,” to the question “Do you have vertigo?” We also asked them about the presence or absence of chronic headaches.Dietary and lifestyle habits were investigated by the method described previously (14). Briefly, we investigated the frequency of 28 kinds of foods and drinks. (1) potatoes; (2) pumpkins; (3) carrots; (4) broccoli; (5) green leafy vegetables (green and yellow vegetables group A); (6) other green and yellow vegetables, including green peppers and snap beans (green and yellow vegetable group B); (7) cabbages; (8) radishes; (9) light-colored vegetables; (10) mushrooms; (11) seaweeds; (12) oranges and grapefruits; (13) other fruits, including strawberries, kiwis, apples, and watermelons; (14) tofus; (15) eggs; (16) chicken; (17) beef and pork; (18) hams, sausages, and bacons; (19) fish; (20) squid, shrimp, crabs, and octopuses; (21) shellfish; (22) deep-fried foods; (23) stir-fried foods; (24) miso soup; (25) milk; (26) yogurt; (27) green tea; and (28) coffee. In addition, we asked questions concerning sports and exercise per week as follows: rare, 1–2 h, 3–4 h, and 5 h or more. The answer “rare” was interpreted as having no exercise habits, while the other options were considered to have exercise habits (14).We asked the participants about the amount of alcohol consumed with six kinds of beverages: beer, whiskey, wine, Japanese rice wine (Japanese sake), shochu , and chuhai (a cocktail of shochu with fruit or soda). The amount of alcohol (g) per week was obtained from the table as follows: 20 g in 500 ml beer, 9.6 g in 30 ml whiskey single, 19.2g in 30 ml whiskey double, 11.5 g in a 120-ml glass of wine, 21.6 g in 180 ml (1 Gou) of Japanese sake, 36 g (180 ml) in a glass of shochu, and 14 g in 350 ml chuhai.The present status and history of smoking were enquired, including for heat-not-burn tobacco and electronic cigarettes (with or without nicotine). Then, we calculated the Brinkman index by multiplying the number of cigarettes smoked per day with the number of years of smoking while also incorporating the participants' conversion to the consumption of heat-not-burn tobacco. To achieve this, we utilized the questionnaire described in the Yakumo study , 15.We measured body weight, body mass index (BMI), and body fat percentage during the health checkup. We also conducted a blood test to assess the number of red and white blood cells, platelets, hemoglobin, hematocrit, mean corpuscular hemoglobin concentration (MCHC), total protein, albumin/globulin (A/G) ratio, globulin, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hemoglobin A1c, creatinine, blood urea nitrogen, uric acid, serum calcium, aspartate aminotransferase: AST (GOT), alanine aminotransferase: ALT (GPT), alkaline phosphatase: ALP, C-reactive protein: CRP, and γ-glutamyl transpeptidase (γ GTP).Of the 510 participants, 369 of them underwent the hearing test. An otolaryngologist examined the ears, nose, and throat before the hearing test. In a quiet room, we evaluated hearing levels using an audiometer . The noise level in the examination room was measured every hour using a sound level meter  to confirm the room's suitability for the hearing test. The equivalent continuous sound level ranged from 41.1 to 53.9 dB, with an average of 45.0 dB. We measured the hearing level bilaterally at 1 kHz and 4 kHz. When the participants could respond to 30 dB at 1 kHz and 4 kHz, we determined the hearing test to be acceptable, either unilateral or bilateral.Of the 369 people who underwent the hearing test, 298 hoped for the olfactory test. The Odor Stick Identification Test for Japanese  was developed as a simplified olfactory function test , which cThe best-corrected visual acuity (BCVA) was measured using an automatic vision tester  after the measurement of refractive errors . The present study used visual acuities of 1.0 (20/20) and 0.8 (20/25) on either side or both sides to classify good or bad visual acuity.p-value of < 0.05.The Chi-square tests, Mann–Whitney tests, and generalized linear model analyses were performed. A logistic regression model estimated the odds ratio (OR) and 95% confidence intervals (CIs). The calculations were conducted using Stata 15 and SPSS 26.0, and statistical significance was set at a The Ethics Committee of Nagoya University School of Medicine approved this study . All the participants approved the publication of anonymized data and provided informed consent to the participation.The participants were volunteers who attended an annual health examination in Yakumo, Hokkaido, Japan. These examinations were supported by the local government (the Yakumo study). In addition, a cross-sectional study was performed on 510 people  who attended a health checkup in 2019.p < 0.001). The questionnaire revealed that 25.4% and 8.8% of the participants reported experiencing tinnitus occasionally or constantly. The participants responded that subjective hearing in one-to-one conversations was much better than in conversations between four or five people. Two women and seven men used a hearing aid, and the answers were under status without a hearing aid.The visual acuity test result was worse in older age, but no significant sex difference was observed. In addition, the presence of tinnitus was not associated with age or sex.p = 0.0664). Additionally, after adjusting for age and sex, the participants with a visual acuity of 0.8 or higher in both eyes had significantly higher scores on the smell test.The influence of various factors on the smell test (correct answer: six or more) is shown in p < 0.1). These findings are consistent with the trend observed in p = 0.0768).The relationship between the hearing test and the visual and olfactory tests is shown in We investigated the influence of diabetes mellitus (DM), hypertension, and dyslipidemia on visual, olfactory, and auditory dysfunctions from the medical history, the drug intake, and the blood examination results, including hemoglobin A1c, triglyceride, total cholesterol, HDL, and LDL cholesterol. The logistic regression analysis revealed that medical history of DM  and anti-DM drug intake  but not hemoglobin A1c had a significant relationship with visual acuity <1.0 on both sides after adjusting for age and sex. However, we could not find the influence of DM on olfactory and hearing test results. We could not find the influence of hypertension and dyslipidemia on the results of the visual, olfactory, and hearing tests. p = 0.0469) and of <0.8 on both sides (p = 0.0230). However, we found no significant relationship between alcohol consumption and test results for visual, olfactory, and auditory perception after adjusting for age and sex.We investigated the effects of smoking on olfactory, hearing, and vision tests. p < 0.0001, broccoli, p = 0.0011), dairy products , and green tea, p = 0.0002) in total. Thus, smoking habits reduced healthy eating and drinking patterns significantly. No exercise habits were also significantly associated with a low intake of dairy products , vegetables , and fruits  ( 0.0005) . HoweverWe found a relationship between tinnitus and poor olfactory test results after adjusting for age and sex. The findings are consistent with those of a previous report based on questionnaire responses . BecauseResearch has shown that individuals can experience auditory, vestibular, olfactory, and gustatory dysfunctions for an extended time following a COVID-19 infection . AdditioHowever, the present study did not reveal a relationship between hearing and olfaction after adjusting for age and sex. However, tinnitus and auditory dysfunction were significantly associated after adjusting for age and sex. The connection between hearing loss and tinnitus is widely known. For example, vertigo, hearing loss, and tinnitus are significant symptoms of Meniere's disease , and tinp < 0.1); however, several reports have revealed that physical activity significantly reduced the risk of tinnitus  . Higher Many reports have described the influence of smoking on sensory functions, including olfactory , visual Hearing aids are helpful to compensate for hearing loss, but the percentage of hearing aid users (9/510) was low during this health checkup. The low percentage may be related to the fact that the nearest hearing aid store is ~100 km away. Many reports have described the effects of sensory dysfunctions on cognitive impairment or dementia. For example, the effects of olfactory, hearing, and visual impairment have been investigated . In addiThe limitation of this study was the relatively small sample size, and not all participants underwent sensory testing, as their participation in the health checkup was voluntary. Additionally, the participants in this study may have had higher health consciousness compared to the general population of Japan, as evidenced by the high proportion of individuals who had quit smoking (more than 70%) .To date, the relationship between tinnitus and olfactory test results has not been investigated, but a significant association between tinnitus and subjective olfactory dysfunction has been reported. We found a significant relationship between tinnitus and olfactory test results after adjusting for age and sex. In the present study, hearing and olfactory impairments were associated with visual impairment after adjusting for age, sex, and other confounding factors. Various studies have reported the persistence of tinnitus and olfactory and gustatory dysfunctions in people with long-term COVID-19. Mutual relationships among sensory dysfunctions need to be studied in future studies.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of Nagoya University School of Medicine . The patients/participants provided their written informed consent to participate in this study.NK, TY, TsN, and MiS designed this study. NK, TY, and TaN performed olfactory tests and evaluations. TY, TaN, AK, and ES performed hearing tests and evaluations. YI, TI, KG, YT, AT, and YN performed vision tests and evaluations. TY, TsN, MT, SS, YU, HS, MaS, and NS evaluated multiple sensory dysfunctions and related factors. TY, TsN, and NH performed the statistical analysis. The manuscript was written by NK, TY, TsN, YI, MT, and NH. All authors contributed to the article and approved the submitted version.


Concurrent chemoradiotherapy using weekly cisplatin remains standard of care for locally advanced cervical cancer in Sub-Saharan Africa. While cisplatin remains a popular cancer chemotherapeutic, it has an irreversible ototoxic effect on patients’ auditory system. However, there is a paucity of epidemiological information on its extent and severity during cervical cancer treatment. In a region with a high burden of cervical cancer, this has serious consequences for aural intervention and rehabilitation.2 body surface) at a tertiary level hospital in KwaZulu-Natal Province of South Africa, underwent audiological assessments at various intervals. We describe the temporal impact of cisplatin exposure on hearing loss, its combined effect with HIV-infection, and estimate ototoxicity incidence in this cohort. The median age was 52 years with Stages IIB (45%) and IIIB (35.4%) cancers being most common. Complaints of reduced hearing sensitivity increased significantly (p<0.0001). Bilateral, asymmetrical sensorineural hearing loss, with greater effect in the extended high-frequency range, was evident. Cisplatin dosage was significantly associated with ototoxicity severity at one- (p = 0.017), three- (p = 0.010), and six-month (p = 0.015) post-treatment follow-up. HIV-seropositivity (53.7%) was significantly associated with NCI-CTCAE Grading Scale at three- (p = 0.022) and six-months (p = 0.023) post-treatment. Multiple Tobit regression revealed a cumulative dose effect bilaterally, after adjustment for age and HIV status, evident from 9000Hz and above in the right ear, while a plateau effect was observed at 250mg/m2 in the left ear. The incidence was ototoxicity was 98% at a cumulative dose of 150mg/m2.Using a prospective cohort study design, 82 patients with incident cervical cancer, receiving weekly cisplatin chemotherapy (50 mg/mThe findings of this epidemiologic study highlight the temporal course and severity of ototoxicity experienced by cervical cancer patients treated with cisplatin, with greater impact in HIV-positive subgroup, thus underscores the need for audiological monitoring and timely interventions in this cohort. Cervical cancer continues to significantly burden the Sub-Saharan continent with the highest regional incidence . Based oWhile cisplatin is one of the most popular anti-cancer drugs due to its effectiveness, it is known to have a diverse toxicity profile affecting the gastro-intestinal, renal , hematolCisplatin-associated ototoxicity is characterized by a pattern of bilateral, progressive sensorineural hearing loss, with a greater influence on the high frequencies –16. The Hearing loss is also often a common occurrence of diabetes and hypertension, due to either the disease pathophysiology or the medication used in the treatment of these conditions. Diabetes-related-auditory manifestations are due to “spiral ganglion atrophy, degeneration of the vestibulocochlear myelin sheath, reduction of the number of spiral lamina nerve fibres, the thickening of the capillary walls of the stria vascularis and small arteries” . HyperteGiven the high incidence of cervical cancer in Sub-Saharan Africa, the associated comorbidities described above and the resulting poor quality of life in affected patients that may be further exacerbated by hearing loss, this prospective cohort study aimed to evaluate the extent and severity of cisplatin-associated ototoxicity experienced by cervical cancer patients in South Africa.2 body surface weekly for six cycles) in combination with dexamethasone (48 mg) and ondansetron (24 mg) offered as outpatient therapy. In some cases, the number of chemotherapy cycles was reduced due to some patients experiencing side effects i.e. severe gastrointestinal disturbances such as nausea, vomiting, and/or diarrhoea. Patients with cervix carcinoma were routinely tested for HIV during diagnostic work-up. All patients identified with reduced hearing ability were counseled regarding aural rehabilitation and referred for further interventions.Ethical clearance was obtained from the University of KwaZulu-Natal Biomedical and Research Ethics Committee (BE064/13) and the participating hospital, a tertiary level hospital, and one of the main referral centers for cancer patients housing an audiology department in KwaZulu-Natal (KZN), South Africa. Following written informed consent, 82 women diagnosed with histologically confirmed incident cervical cancer were prospectively enrolled into the study before treatment, within two years. Women presenting with profound hearing loss at baseline assessment, previous exposure to cisplatin chemotherapy, or with a history of tuberculosis, and/or malaria were excluded. Of the 82 participants, 80 attended all follow-up appointments. Attrition in the study was due to participant death. Chemotherapy consisted of cisplatin  staging system. All participants underwent audiological assessments before commencing cisplatin chemotherapy, with follow-up assessments at the beginning of the fourth cycle, and at one-, three-, and six-month post-treatment. These assessments included a case history, otoscopic examination, immittance audiometry , pure tone audiometry (including masking where required), extended high-frequency audiometry (up to 20000Hz), speech reception threshold (SRT) testing, word recognition score (WRS) testing and distortion product otoacoustic emission (DPOAE) testing, as prescribed for ototoxicity monitoring by the American Speech-Language and Hearing Association (ASHA) . The casPatient characteristics were summarized using frequencies and proportions for categorical and/or binary variables, whilst medians and interquartile ranges for asymmetric distributions. The distribution of participant’s pure-tone air conduction thresholds at the different frequencies was analysed separately for left and right ears, to avoid mixing frequencies, which have different upper cut-off limits on the audiometer. Data analysis is per ear and not per patient to prevent the effects of correlation between the ears, as ototoxic hearing loss is reported to be bilateral. For example, a higher pure tone threshold in the right ear may affect the threshold in the left ear and vice versa.Classification of hearing loss was based on frequencies in the range 125Hz– 8000Hz, as high-frequency audiometry does not have standardized results . The extThe Cochran-Armitage test for trend was used to test for trend in binomial proportions of auditory complaints over time. ASHA criteria  was used≥ 20dB decrease at any one test frequency,≥10dB decrease at any two adjacent frequencies, orloss of response at three consecutive frequencies where responses were previously obtained. Repeated Measures Analysis of Variance (ANOVA) was used to determine if the difference in mean DPOAE amplitudes between 1500Hz - 6000Hz was statistically significant at each audiological evaluation.2 versus High, 250mg/m2 and 300mg/m2) and HIV seropositivity on the severity of ototoxicity. As a result of the right censoring in pure-tone frequency threshold measurements (outcome variable), due to the upper limits of the audiometer at the various frequencies (125Hz-14000Hz), Tobit regression was employed to examine the association between the outcome variable and cumulative cisplatin dosage (mg/m2) (predictor variable). This approach was key as the number of ‘No Responses’ in the extended high-frequency range increased at each successive audiological evaluation (2) of 0.15, α = 0.05, power = 80% and 3 predictors  resulted in a sample size of 77. All statistical tests were 2-sided with statistical significance defined as p-value ≤ 0.05. All analyses were conducted in Stata version 15 .The Fisher’s exact test was used to determine the association between cisplatin dosage  while the remaining participants all received either 150 mg/m2, 200 mg/m2 or 250 mg/m2 of cisplatin, respectively. At each case history ascertainment, all participants reported no ongoing exposure to high levels of recreational and occupational noise. Furthermore, a review of the medical file and patient reports revealed normal renal function in all participants.Participant demographic and medical characteristics are presented in A summary of the self-reported audiological symptoms is presented in Abnormal otoscopic findings (in this case tympanic membrane perforation) were evident in the right ear of one participant, and the left ear of another participant at all audiological evaluations. At all audiological evaluations, 99% of the participants presented with Type A tympanograms bilaterally based on Jerger (1970)  classifiThere was a significant increase in the number of individuals presenting with abnormal DPOAEs bilaterally at each successive audiological evaluation  . DPOAEs There was a consistent decrease in the DPOAE amplitude bilaterally at each follow-up, as evidenced by the median DPOAE profiles with the decrease being more pronounced at the higher frequencies for both the right  and leftSpeech audiometry revealed that more than 79 participants (96%) presented with good SRT-PTA correlation bilaterally at each time point; therefore, validating the pure tone audiometry test results. Word recognition scores testing revealed that 75 participants (>95%) presented with excellent word recognition ability within normal conversational levels (below 60 dB HL) bilaterally at each audiological evaluation.2, an incidence of ototoxicity of 98% was recorded in this cohort.The ASHA criteria were used to determine the presence of an ototoxic shift in the patient’s hearing at each audiological evaluation. Given that any of the three criteria need to be fulfilled in the assessment for ototoxicity, 2) and high (250 & 300 mg/m2), respectively is illustrated in 2. At subsequent follow-up assessments, it becomes evident that the severity of ototoxicity is associated with treatment doses as more participants in the higher dosage group begin to show greater ototoxic change. The temporal association between cisplatin dosage and ototoxicity severity is significant at one- (p = 0.017), three- (p = 0.009) and six-month (p = 0.015) post-cisplatin treatment. At the end of the 6-month follow-up, 15/47 (32%) of patients in the high-dose group were in the Grade 2/3 category compared to only 5/33 (15%) of the patients in the low-dose group.The deterioration in hearing thresholds during cisplatin-chemotherapy treatment and their ability to guide recommendations regarding hearing amplification was explored. The temporal association in the severity of ototoxicity  and cumulative cisplatin dosage, stratified into low  in both the right and left ear, after adjustment for the effect of participant age and HIV status. Correlates of pure tone threshold measurements for the right ear revealed that significant changes were evident from 1000 Hz at a cumulative dose of 150 mg/mβ-coefficient 10.89) in hearing threshold at 200 mg/m2 cisplatin dose (p ≤ 0.05), compared to a 4-unit increase (β-coefficient 4.29) among the HIV-negative participants exposed to the same dose , despite there being a steady increase in the number of these participants presenting with hearing loss at each successive audiological evaluation.This study highlighted the adverse audiological impact of cisplatin in the course of cervical cancer treatment, with HIV-positive participants exhibiting a greater severity in hearing loss than their HIV-negative counterparts. By the end of the six-month follow up period, all of the participants (100%) presented with an ASHA  significThe percentage of significant ototoxic change in the current study, being higher than previously reported in South Africa , and othHIV and the subsequent use of ARTs aggravate cisplatin-ototoxicity, with there being a significant association by the three and six-month post treatment evaluations. The synergistic effect of ARTs and cisplatin on the auditory system may also account for a lower cumulative cisplatin dosage resulting in a more rapid range in the hearing thresholds in the HIV-positive group than the HIV-negative group. A synergistic effect on hearing, implies that the resultant hearing loss is greater than the sum of the hearing losses that occur from any one co-morbidity or ototoxic medication alone . The ototh cranial nerve, opportunistic infections associated with hearing loss and ototoxicity as a result of highly active antiretroviral treatment (HAART), and medication administered in the treatment of opportunistic infections” (p. 37). Whilst conductive hearing loss and outer/middle ear infections are common in HIV-infected individuals, the low incidence of these otologic conditions in the current study  highlights the benefits of the use of ARTs in preventing upper respiratory tract infections, which predispose affected individuals to middle ear infections and consequent conductive hearing loss. Additionally, it may indicate a lower viral load in this cohort due to the use of ARTs for a minimum of one year, which has proven to improve the impaired functioning of the immune system. However, it was not possible to identify the participants’ viral load, CD4 count, and treatment adherence in the current study, as this information was not captured in the hospital medical file due to participants receiving their ART from other decentralized local clinics. Additionally, participants were not knowledgeable of this information. As neurological testing was not conducted in the current study, no comment can be made about the direct action of HIV on the auditory nerve contributing to hearing loss.van der Westhuizen et al.  reported2 and 236.84 mg/m2 were likely to result in ototoxic hearing loss for the ototoxicity-free and ototoxicity groups, respectively, our study revealed that increasing cumulative dosages from 150mg/m2 have increasing effects in the high and extended high-frequency region bilaterally, with a plateau effect seen in the left ear at 250mg/m2, with no further change in hearing thresholds at increased dosages.Our findings on cumulative cisplatin dosage effects concur with literature , 45, 46 Our findings on progressively worsening pure-tone hearing thresholds, evident in the extended frequency range, supports previous literature , 40, 47.Deterioration of hearing thresholds in the extended high-frequency range does not generally negatively affect word recognition scores, as is evident in the current study with more than 90% of the participants presenting with excellent word recognition scores within normal conversational levels (60 dBHL) at all audiological evaluations. These findings concur with Theunissen et al. , who repThese results also, therefore, concur with the large number of participants presenting with ‘No Change’ when the NCI-CTCAE grading scale is used at the mid-cycle audiological evaluation, as this scale reflects the functional impact the ototoxic change has on the patient’s communication . As timeComplaints of tinnitus increased during treatment and thereafter steadily decreased from the one-month post-treatment assessment; thus, indicating a resolution of tinnitus post-treatment. The resolution of tinnitus is in keeping with Bokemeyer, Berger , MelamedThe reported progression of hearing loss for six months after cessation of cisplatin chemotherapy in this study is an indication of cisplatin retention in the cochlear indefinitely  and, theFurthermore, the increasing number of abnormal DPOAE findings in each ear with subsequent audiological evaluations is congruent with sensorineural hearing loss. Surprisingly, despite there being a significant decrease in the DPOAE amplitudes at all frequencies bilaterally, the number of abnormal DPOAE results are lower than would be expected when considering the increasing number of participants presenting with ototoxic hearing loss. These findings concur with Teotia et al. , who alsFactors that have been overlooked in previous studies investigating the effects of cisplatin, namely co-morbidities such as diabetes, hypertension, HIV infection, and the subsequent exposure to other ototoxic medication, have been considered in the current study as many women in South Africa present with such comorbidities . Due to The strength of this study is evident by the selection of the study design, which allowed for the prospective observation of cisplatin’s effect on hearing in individuals within the cohort over time . The useThis prospective cohort study, being the first in South Africa and the African continent, has revealed cisplatin’s detrimental effect on hearing with an even lower cumulative dosage of the treatment, possibly due to the large prevalence of HIV and subsequent use of ARTs. To prevent or avoid further deterioration in the quality of life of women with cervical cancer at a time when they are probably living in both physical and mental distress, early and effective identification of ototoxicity is crucial. Audiological monitoring should, therefore, be an essential part of the holistic management of patients receiving cisplatin chemotherapy, irrespective of cancer type, particularly in South Africa and other countries, which have a high burden of HIV. For patients who experience asymptomatic hearing loss but require continuation of cisplatin treatment, intensive audiological monitoring needs to be implemented with possible considerations of utilising oto-protective medication intra-tympanically. The findings of this current study will increase healthcare personnel’s awareness of the ototoxic effect of cisplatin and the need for comprehensive audiological monitoring with the potential of improving the quality of life for oncology patients. The potential for further investigation into chemotherapeutic regimens with minimal or no ototoxic effects is also warranted.S1 File(TIF)Click here for additional data file.S2 File(TIF)Click here for additional data file.S3 File(TIF)Click here for additional data file.S4 File(TIF)Click here for additional data file.S5 File(TIF)Click here for additional data file.S6 File(TIF)Click here for additional data file.S7 File(TIF)Click here for additional data file.S8 File(TIF)Click here for additional data file.


BackgroundCongenital sensorineural hearing loss (SNHL) is one of the most common birth defects with an incidence ratio of 1:1000 live births in India. Imaging plays an important role in the evaluation of congenital SNHL. As there is a paucity of studies in the Indian setting to determine the prevalence of inner-ear abnormalities, this study attempts to throw light on the various inner-ear anomalies that are prevalent in our setup in the Northern part of Karnataka using high-resolution computed tomography (HRCT) temporal bone scan.ObjectivesThe objectives of this study are estimation of the prevalence of inner-ear anomalies in children with congenital SNHL by employing a radiologic assessment of HRCT temporal bone scans and determination of the factors associated with the identification of these abnormalities like demographic factors and degree of hearing loss.MethodsChildren with congenital SNHL underwent clinical evaluation with history taking and general and ear examination. Otoacoustic emission (OAE) and brainstem evoked response audiometry (BERA) measurements were obtained.A radiological assessment by HRCT temporal bone scan was done. Using the classiﬁcation criteria of inner-ear malformations by Jackler and Sennaroglu as a reference, diagnostic standards were established in studying inner-ear malformations. Data were collected and entered in a Performa, which includes patient’s demography, audiological findings, and radiological findings, and the results were analyzed. Data were entered into Microsoft Excel, and statistical analysis was carried out using IBM SPSS Statistics for Windows, Version 27 . Categorical variables were presented as frequency and percentage. Then the prevalence of inner-ear anomaly was estimated. Correlation between inner-ear anomaly and other factors was calculated using the Chi-square test.ResultsThe prevalence of inner-ear anomalies identified in congenital SNHL by HRCT scan was as follows: 26.08% (12/46), 26.1% (24/92) of inner ears was anomalous, 23.9% of the cochlea was anomalous, 6.5% of the vestibule was anomalous, 5.4% of the vestibular aqueduct was anomalous, and 3.2% of the semicircular canal was anomalous.Cochlear aplasia, incomplete partition, common cavity, and cochlear hypoplasia were the anomalies found. Few cochleas had an abnormal cochlear height, though they appeared normal structurally. The dilated vestibule was the most common vestibular abnormality. There was a negative association found between the inner-ear anomaly in children with congenital SNHL who had a history of consanguineous marriage in their parents.ConclusionHigh-resolution temporal CT scanning could provide detailed information on the pathology of the inner ear in congenital SNHL, which can help in better planning the surgery for cochlear implantation and understanding the prognosis. Congenital sensorineural hearing loss (SNHL) is one of the most common birth defects with an incidence ratio of 1:1000 live births in India , and theIn the northern part of Karnataka where this study is being conducted, there are children who need cochlear implants, although the prevalence of inner-ear anomalies is not known. There is a paucity of studies in the Indian setting to determine the prevalence of inner-ear anomalies, and for this reason, we decided to conduct this study in the Indian context to evaluate the various inner-ear anomalies by HRCT scan of the temporal bone.The aim of this research is to study the distribution of different inner-ear anomalies in children with congenital SNHL. The primary objective is to estimate the prevalence of anomalous inner ear in children with congenital SNHL by radiologic assessment of HRCT temporal bone scans. The secondary objective is to determine the factors associated with identification of these anomalies, like demographic factors and the degree of hearing loss.This study was conducted among children with congenital SNHL attending the outpatient department at Karnataka Institute of Medical Science, Hubballi, which is a government setup, over a period of two years from March 2021 to February 2023. Karnataka Institute of Medical Sciences, Hubballi Ethics Committee (Reg. No. ECR/486/Inst/KA/2013/RR-16) issued approval. Informed written valid consent was taken from the parents of all the recruited cases.Inclusion criteriaChildren with congenital SNHL diagnosed with OAE and BERA were included in the study.Exclusion criteriaPatients with congenital conductive hearing loss, congenital cholesteatoma, and hearing loss due to an acquired cause like chronic otitis media are excluded.Children with congenital SNHL underwent clinical evaluation with history taking and general and ear examination. Clinical history included age at identification of hearing loss, prenatal, natal, and postnatal history, mother’s drug intake and radiation exposure during pregnancy, mother’s history of fever during pregnancy, type of delivery and duration of hospitalization, birth weight, history of NICU admission, history of neonatal jaundice, developmental history, hearing aid use, family history of hearing loss, and neurological disorders.The examination of the patient is inclusive of a general examination to look for dysmorphism and an ear, nose, and throat examination. The OAE and BERA measurements were obtained. The radiological assessment by HRCT temporal bone was done to see the status of morphology of the cochlea, cochlear height, cochlear duct length, vestibule, semicircular canal, and vestibular aqueduct. The scan parameters were 120 kV, 100 mA, thin-slice 0.6mm cuts HRCT.As sedation was often necessary, the examination was done with the assistance of pediatricians. Triclofos 5 mL = 500 mg was given with a dosage of 50-70 mg/kg of body weight. An additional 5 ml was given after an hour if still not sedated.CT scans are subjected to bone review programs for the enhancement of fine bony detail. Both axial and coronal views are studied. All images were evaluated in the RadiAnt DICOM viewer.Using the classiﬁcation criteria of inner-ear malformations by Jackler and Sennaroglu as a reference, diagnosis standards were established to study the inner ear malformations .The cochlear duct length was measured using the formula CDL = 4.16A - 3.98, where CDL means the cochlear duct length, and A was calculated by measuring the distance between the round window and the farthest point on the basal turn in the axial section. The minimum length of a normal cochlea is 25 mm. The cochlear height, defined as the measurement from the midpoint of the basal turn to the midpoint of the apical turn, was taken perpendicular to the axes of the cochlear lumens in the coronal view. Normal CHs are 5.2 mm (4.3-6.1 mm) in females and 5.3 mm (4.5-6.2 mm) in males [The vestibular aqueduct width is measured at the midpoint of its course from the vestibule to the opening (operculum) in the posterior cranial fossa. It is considered enlarged if the width is more than 1.5 mm. As the semicircular canal is studied, it can be normal, hypoplastic, absent, or enlarged. On the other hand, as the vestibule is studied, it can be absent, dilated, or normal. Cochlear aperture is measured in axial sections of the HRCT temporal bone and can be normal, hypoplastic  is less than 1.4 mm), aplastic , or wide (when the width of the BCNC is more than 3 mm) .Data were collected and entered in a Performa, including the patient’s demographic details, audiological findings, and radiological findings, and then the results were analyzed. Data were entered into Microsoft Excel, and statistical analysis was carried out using IBM SPSS Statistics for Windows, Version 27 . Categorical variables were presented as frequency and percentage. The prevalence of inner-ear anomalies was estimated. Correlation between the inner-ear anomaly and other factors was done using the chi-square test.Forty-six children with congenital SNHL were included in the study; 28 (60.9%) of the participants were males, and 18 (39.1%) of the participants were females  participants had no family history of hearing loss, and 11 (23.9%) participants reported having a family history of hearing loss with 54.5% in the second degree and 45.5% in the first degree. Consanguineous marriage was reported by 16 (34.7%) participants with 93.8% in the second degree and 6.3% in the first degree. Delay in language development was seen in all participants with hearing loss. In addition, gross motor, fine motor, and social development were also delayed in three (6.5%) of the participants.Details on birth history showed that two (4.3%) of the participant’s mothers had fever during pregnancy and no mothers had any miscarriage. Forty-three (93.5%) had term delivery, and one (2.2%) of each had an early term, post-term, and pre-term. The majority, 38 (82.6%), were of birth order one followed by five (10.9%) with second-order birth, two were third-order, and one with sixth-order birth. In addition, 38 (82.6%) had normal birth weight, six (13%) had low birth weight, and two (4.3%) had very low birth weight. With regard to the type of delivery, 38 (82.6%) had normal vaginal deliveries followed by seven (15.2%) cesarean section, and one (2.2%) had vacuum-assisted delivery. Seven (15.2%) had a history of NICU admission. The majority, 39 (84.8%) patients, showed a duration of hospital stay of < five days, four (8.7%) with > 10 days, and three (6.5%) with five to ten days.No participants reported a history of peripartal complications and jaundice. The majority, 44 (95.7%) participants, claimed to be of low socioeconomic status, which meant they were below-poverty-line cardholders. The majority of the patients had a normal general and systemic examination finding. Two (4.3%) patients had microtia-one had bilateral grade three while the other had grade three on right and left grade-four microtia.There was no child identified with any known syndrome associated with SNHL on examination. However, on further evaluation, one participant had a prolonged QT interval on the electrocardiogram test, which is known to occur in Jervell Lange Nielsen syndrome.Participants had varying degrees of hearing loss ranging from moderate to profound Table .The prevalence of anomaly in the cochlea structure is 19.5% (nine participants) Table . The anoIn females, seven (20%) cochleas had an abnormal cochlear height Table . On the The CDL was less than normal in 10 (10.9%) ears Table . The BCN The vestibule was normal in 43 93.5%) participants and dilated in 39 (6.5%) of them  right-side ears, and 44 95.6%) left-side ears, had a normal vestibular aqueduct , left, 45 (97.8%)), and one had aplasia on the right ear with a normal left ear, and one had bilateral hypoplasia  with bilateral congenital SNHL participated. Referring to the classiﬁcation criteria of inner-ear malformations by Jackler and Sennaroglu, diagnosis standards were established to study the inner-ear malformations ,8. Out oIn this study, there was no significant association between inner-ear anomalies and gender or family history or history of NICU admission or degree of hearing loss. However, a history of consanguineous marriage and the prevalence of inner-ear abnormalities were significantly negatively associated. No participants reported a history of peripartal complications and jaundice which are known risk factors associated with hearing loss.In addition, in this study, all the patients with inner-ear anomalies had cochlear anomalies. Jackler et al. found 76% cochlear abnormalities . DağkıraMoreover, three (6.5%) patients in this study had vestibular aqueduct abnormality, of which two (66.6%) patients had dilated vestibular aqueduct and one (33.3%) with absent vestibular aqueduct. Of the 46 cases, two (4.3%) patients had semicircular canal abnormalities involving all three semicircular canals. Dağkıran et al. found posterior semicircular canal malformation in 7.3% of their patients, lateral semicircular canal in 7.4%, and superior semicircular canal aplasia/hypoplasia in 5.9% of their patients .A study done by Vishal et al. showed that knowledge of radiological abnormalities in temporal bone or brain can provide reasonable help in predicting the auditory perception outcome . Hence, LimitationsThe study was done on a small population of only 46 participants. Results could have better coverage if a larger sample size was studied and for a longer duration. There are limitations in the utilization of CT in identifying an enlarged vestibular aqueduct, and MRI is the gold standard for the same procedure. Middle-ear and external-ear anomalies and other structures, like facial nerves, were not analyzed in this project. A detailed analysis of etiology for congenital SNHL like herpes, CMV, toxoplasmosis, rubella, and genetics was not done as there was no availability of laboratory tests. Finally, a detailed evaluation for the identification of syndromes via ECG/2D Echo/abdominal USG or other methods of investigation could not be done in all participants.HRCT scanning of the temporal bone could provide detailed information of pathology of the inner ear in congenital SNHL, which can help in planning better, the surgery for cochlear implantation and understanding the prognosis. The prevalence of inner-ear anomaly found in this study was approximately similar to previous studies. The unusual finding of this study is the negative correlation between the history of consanguineous marriage and inner-ear anomaly.


The aim of this study was to quantify the amount of deterioration in hearing and to document the trajectory of hearing loss in early identified children with unilateral hearing loss (UHL). We also examined whether clinical characteristics were associated with the likelihood of having progressive hearing loss.As part of the Mild and Unilateral Hearing Loss Study, we followed a population-based cohort of 177 children diagnosed with UHL from 2003 to 2018. We applied linear mixed models to examine hearing trends over time including the average amount of change in hearing. Logistic regression models were used to examine the relationship between age and severity at diagnosis, etiology, and the likelihood of progressive loss and amount of deterioration in hearing.The median age of the children at diagnosis was 4.1 months  and follow-up time was 58.9 months . Average hearing loss in the impaired ear was 58.8 dB HL (SD 28.5). Over the 16-year period, 47.5% (84/177) of children showed deterioration in hearing in one or both ears from their initial diagnostic assessment to most recent assessment including 21 (11.9%) who developed bilateral hearing loss. Average deterioration in the impaired ear ranged from 27 to 31 dB with little variation across frequencies. Deterioration resulted in a change in category of severity for 67.5% (52/77) of the children. Analysis for children who were followed for at least 8 years showed that most lost a significant amount of hearing rapidly in the first 4 years, with the decrease stabilizing and showing a plateau in the last 4 years. Age and severity at diagnosis were not significantly associated with progressive/stable loss after adjusting for time since diagnosis. Etiologic factors  were found to be positively associated with stable hearing loss.Almost half of children with UHL are at risk for deterioration in hearing in one or both ears. Most deterioration occurs within the first 4 years following diagnosis. Most children did not experience sudden “large” drops in hearing but more gradual decrease over time. These results suggest that careful monitoring of UHL especially in the early years is important to ensure optimal benefit from early hearing loss detection. Unilateral hearing loss (UHL) in children has gained increasing attention as a clinically important hearing disorder. Permanent childhood hearing loss is relatively common affecting 3–4 per 1,000 children when all degrees of bilateral and unilateral loss are considered during childhood . In contHistorically, the clinical implications of UHL were not well understood. Unlike children with bilateral hearing loss, these children have access to speech and develop spoken language without intervention. However, there is a growing consensus that UHL affects typical development of auditory pathways and auditory function with implications for communication and academic development for at least some children –10. DiffThere is some variation in NHS programs worldwide in defining hearing disorders including whether mild bilateral and UHL, historically considered to be minimal losses, are specifically targeted , 21, 22.Relatively little is known about the relationship between the clinical characteristics  of children with UHL and the risk of progression in hearing loss. Like bilateral hearing loss, etiology is related to both genetic and environmental factors. While genetics are the most common cause of bilateral hearing loss , 32, 33,The Joint Committee on Infant Hearing (JCIH) has historically identified risk indicators for late onset and progressive permanent hearing loss, which have guided screening surveillance programs , 42. OurUnderstanding the trajectory of hearing loss has implications for management practices including the need for surveillance and potential adjustments in intervention. Screening aims to improve developmental outcomes by detecting and managing hearing loss early and provides new opportunities to better understand the evolution of childhood hearing loss. Consistent with these goals, we have followed a population-based cohort of children with permanent hearing loss in one Canadian audiology center. The purpose of this study was to examine the clinical characteristics and the evolution of hearing loss in children with UHL. Specifically, the objectives were to: (1) determine the proportion of children with UHL, the amount of deterioration in hearing thresholds, and the trajectory of hearing loss; and (2) examine whether there was an association between clinical characteristics at diagnosis including etiology, age at diagnosis (related to onset), and severity of hearing loss and the likelihood of progressive hearing loss.This longitudinal study was conducted as part of a research program examining development outcomes in children with mild bilateral or UHL. As part of this project, population-level data related to diagnosis and intervention were collected prospectively on all children with permanent hearing loss followed in the Eastern Ontario region of Canada and diagnosed from 2003 to 2018. For this study on progressive hearing loss, we also extracted all post-diagnostic audiometric data from the medical records.The study was conducted at CHEO, a pediatric hospital which is the sole audiologic diagnostic center for infants in the area screened through a province-wide early hearing detection and intervention (EHDI) program. Screening targets include mild bilateral and UHL. The clinic also provides services for children who relocate to the area. Well-established clinical protocols for identification and follow-up of hearing loss are in place . ServiceThe study population included all children followed at CHEO who were identified with permanent UHL (2003–2018). UHL was determined based on the National Workshop on Mild and Unilateral Hearing Loss  definitiData collection for this study took place in two phases. In phase 1, as part of a longitudinal study on all children with hearing loss, clinical characteristics have been collected prospectively from medical records since full NHS implementation in 2003. Data were entered in a study-specific database and included child  and hearing loss details . In addition, medical records were re-examined for this study to update the child's profile with any new etiologic information from clinical areas such as genetics , infectious diseases  and ENT services . A researcher with experience in medical chart data also entered risk indicators for hearing loss based on JCIH  descriptIn addition to the audiologic data entered at diagnosis, all follow-up audiologic and hearing-related medical assessment results were retrospectively extracted from paper or electronic (after 2013) medical charts and entered into an SPSS database including audiometric thresholds and middle ear status . Category of hearing loss  was assigned based on 4-frequency 0.5, 1, 2, 4 kHz) pure-tone average (PTA) applying standard audiologic definitions shown in . All cliA definition used in our previous research , adoptedDecision rules consistent with our previous research on progressive hearing loss  were appt-tests or Mann-Whitney U tests (as appropriate) for continuous variables and chi-square tests for categorical variables.Statistical analyses were conducted using SPSS (version 26). Participant characteristics were summarized using descriptive statistics including means and standard deviations, medians and interquartile ranges, and frequency counts as appropriate. One outcome of interest was the proportion of children with progressive hearing loss. Differences in clinical characteristics  were compared for children with progressive and stable hearing levels using The amount of change in hearing loss across frequencies was calculated from first to most recent audiometric assessment. For the longitudinal analysis, the trajectory of hearing loss  was analyzed using mixed linear models (with the identity correlation matrix) that were fit with maximum-likelihood estimation techniques to evaluate the trajectory across individual frequencies (0.5–4 kHz). To control for intra-subject variability of trajectories, a random effect was added on the linear term of the model. Another random effect on the intercept was added to control for the variability between individual baseline thresholds. The time effect was modeled as linear, quadratic, and cubic factors to be able to detect a loss in hearing (linear effect) and a change in the rate of decrease over time (quadratic and cubic effects). Analyses were conducted with all available data without imputation, as estimation of parameters using the maximum-likelihood method is considered adequate to address missing data , 51.p < 0.05.Using logistic regression, we also evaluated the relationship between clinical characteristics  and status of hearing loss (stable versus progressive). Four multivariable models were also fit to evaluate the relationship between these covariates and the amount of deterioration in hearing at individual audiometric frequencies from 0.5–4 kHz. All models were adjusted for time since diagnosis. Two-tailed tests were applied for all analyses with statistical significance set at Hearing loss was determined to be congenital or early onset (<6 months) for 53.7% (95/177), late onset for 26.0% and acquired  for 4.0%. Onset was unknown for the remaining 16.4% of children due to unknown screening status and no early diagnostic assessment. Most  children presented with sensorineural (67.2%) or mixed (13.0%) hearing loss at diagnosis and the remaining 19.8% with permanent conductive  loss. The mean hearing loss at diagnosis (4-frequency PTA in the impaired ear) was 58.8 dB (SD 28.5) with 74.0% (131/177) of children having <70 dB HL (mild to severe). One or more known risk indicators for hearing loss was documented for 38.4% (68/177) of the children. Etiology was known for 55.4% (98/177) of children with the most common etiologies being external/middle ear anomalies , inner ear anomalies (7.9%), syndromes associated with hearing loss (11.9%) and hereditary/genetic causes (8.5%), together accounting for 88.7% of causes  children showed deterioration in hearing in one or both ears from initial diagnosis to most recent assessment. For 63 (35.6%) children, hearing loss remained unilateral with further deterioration in the impaired ear only, and 21 (11.9%) children developed bilateral hearing loss including 14 (7.9%) who showed deterioration in both ears since initial diagnosis and another 7 (4.0%) who developed a loss in the normal hearing ear only. For these 21 (11.9%) children, the loss in the normal hearing ear was identified at a median of 22.1 months . In summary, 27.7% (98/354) of all ears showed a drop in hearing since initial diagnosis .X2 (1) = 0.866, p = 0.352].Since this was an early identified cohort, we verified whether there was a difference in progressive hearing loss in children who were identified using objective ABR versus behavioral audiometry at baseline. At the final assessment there were 198 ears with hearing loss , 51.5% (102 of 198) were identified through ABR testing at baseline and 48.5% with behavioral audiometry. Chi-square analysis showed no significant difference in the percentage of ears with progressive hearing loss when the initial diagnostic assessment was conducted using ABR versus behavioral audiometry [p = 0.072), the children with progressive loss had more audiologic assessments (p < 0.001). As shown, more children with progressive hearing loss had congenital/early onset hearing loss (p = 0.042). Children with progressive hearing loss were diagnosed at a median age of 3.7 months  compared to 24.3 months  for those with stable hearing thresholds. It is important to note that children with late onset hearing loss are not necessarily identified at the initial onset of the loss but rather when it becomes severe enough to be noticed, therefore changes in hearing prior to diagnosis are unknown. There was no significant difference in age of diagnosis for children diagnosed with late onset hearing loss in the later 5-year period (2014–2018) compared to those diagnosed in the previous 11 years (2003–2013) (p = 0.074). Compared to children with stable hearing, children with progression had more sensorineural/mixed loss (p = 0.015) and had less severe hearing loss at diagnosis (p = 0.013). The latter finding may reflect that there were more children in the stable group with profound hearing loss at diagnosis in the impaired ear (17 vs. 6), and further deterioration may not have been captured if hearing loss had reached the limits of measured hearing thresholds. When considering only the 154 children with better than profound hearing loss, 50.6% (78/154) showed deterioration in at least one ear.The characteristics of the 84 children with progressive hearing loss and the 93 with stable hearing are shown in By definition, children with progressive loss did not show improvement in hearing levels. Of the 100 impaired ears that were coded as not progressive (stable), 3 showed >10 dB improvement (in 4-frequency PTA) from baseline to most recent assessment (range: 11.4–20.0 dB change). Two of these children had structural conductive hearing loss and all three children continued to present with hearing loss. One normal hearing ear that later developed hearing loss also showed an improvement of 13.8 dB from diagnosis to final audiogram but continued to show a mild loss.n at baseline of 48, 34, 60, and 50, for 0.5 1, 2 and 4 kHz respectively), we examined the trajectory of hearing loss in the impaired ear to document patterns of changes in hearing over time. p < 0.001 for all four frequencies). On average, the loss was estimated at 27.1 dB, 23.1 dB, 24.1 dB, and 22.5 dB at 0.5 1, 2, and 4 kHz respectively. Subsequently, the decrease in thresholds showed a statistically significant stabilization in deterioration for all frequencies (p < 0.001) followed by a plateau in the last 4 years of observation.Using the series of audiometric assessments recorded over the first 8 years of follow-up for this cohort  were not significantly associated with progressive/stable hearing loss  after adUsing the same variables and adjusting for time since diagnosis, linear regression models were fit to examine the association between clinical characteristics and the total amount of deterioration in hearing at individual frequencies 0.5–4 kHz . Age at n = 84 of 177) of children first diagnosed with UHL experienced deterioration in hearing in the impaired ear or developed a hearing loss in the normal hearing ear. While deterioration for most children was limited to the impaired ear  11.9% also developed bilateral hearing loss. We observed a trend towards a greater drop in hearing in the first 4 years after diagnosis with the decrease slowing over time and a plateau effect noted in the next 4 years.This population-based study showed that about 1 in 4 children with permanent hearing loss present with UHL at initial diagnosis. Based on a large dataset of longitudinal audiometric data, we found that almost half  and more than two thirds of the deterioration happened over the first 4 years post-diagnosis (average of over 20 dB decrease in thresholds). These are clinically important changes. For example, for the 77 children with impaired ears that showed progressive hearing loss, the drop in average hearing levels was sufficient to result in two-thirds (67.4%) of them being reclassified to a more severe category of hearing loss at last audiometric assessment. This resulted in an almost doubling of the number of children with severe or profound hearing loss, in at least one ear (39 ears vs. 18 at diagnosis). Furthermore, 11.9% of children developed bilateral hearing loss placing them at greater risk for delays in auditory and communication development. Of the 21 normal hearing ears that developed a loss, 5 showed severe or profound hearing loss by study end.n = 44) in our study compared to 10.2% at initial diagnosis. A recent review primarily based on adult UHL studies suggests that early cochlear implantation can prevent or reduce auditory deprivation in individuals with UHL  and later behavioral assessments can introduce some error. Although we used estimated behavioral thresholds (eHL) to document ABR results, the agreement with behavioral thresholds is not perfect and there is some evidence that predicted behavioral thresholds may be underestimated in children with moderate and greater degrees of hearing loss , 58. In Our study depended on clinical audiologic data and despite clear follow-up protocols, the nature of clinical management is that assessments do not always follow the planned schedule. For young children, assessment results may be incomplete or require several test sessions. Furthermore, compared to children with bilateral hearing loss, audiologic follow-up for these children may be less consistent due to less concern on the part of parents about communication development, less frequent intervention sessions, and higher levels of amplification non-use. It is possible that children are less likely to present for follow-up visits if there is no concern. In addition, children in this study were diagnosed over a 16-year period and had variable lengths of follow-up. While we controlled for time since diagnosis in the regression analyses, this resulted in a smaller sample size for the longitudinal analysis of trajectory of hearing loss and requires that these results be interpreted with caution. Finally, the lack of specific etiologic data  and the relatively small number of children in some etiology groups precluded more extensive analyses of conditions  previously reported to be associated with progressive hearing loss , 39, 41.Early identified children with UHL represent a new clinical population in the last 20–30 years since the widespread implementation of NHS. An important goal of screening is to improve developmental outcomes for children with hearing loss of any degree. Using population-level data to track the evolution of hearing loss, this study provides evidence that almost half of the children with UHL are at risk for further deterioration in hearing in the impaired ear or for bilateral loss especially in the first 4 years after diagnosis. The extent of the problem and the magnitude of the hearing deterioration, coupled with the potential impact on intervention decisions seem to justify efforts to regularly monitor these children to identify additional needs as early as possible.