Hypertension is one of the leading causes of morbidity and mortality worldwide, and has been associated with target organ damage. Effects of hypertension on the auditory system are varied and requires further investigation. This study aimed to investigate the association between hypertension and auditory deficits (hearing loss and tinnitus).This study employed a cross-sectional study including 106  hypertensive adults aged 18–55 years, and 92  non-hypertensive sex- and age-matched adults residing in South Africa. A data extraction sheet was used to obtain hypertension information from participants' medical files, and to subjectively obtain tinnitus status and characteristics among participants. Participants' hearing sensitivity—including extended high frequencies (EHF)—were measured using a diagnostic audiometer. The χ2 test determined the difference in auditory deficit prevalence between the study groups. Logistic regression was used to identify predictor variables associated with auditory deficits in the hypertensive group.P = 0.000, χ2 = 14.00) was found. The EHF pure-tone average among the hypertensive group was 44.1 ± 19.2 dB HL, and 20.0 ± 18.3 dB HL among the control group. Bilateral mild sensorineural hearing loss was the most common type of hearing loss among hypertensive adults. A higher prevalence of tinnitus (41.5%) was found in the hypertensive group compared to the control group (22.8%) . In this study, 30.3% of hypertensive adults had tinnitus without hearing loss compared to 17.7% non-hypertensive adults. Factors associated with hearing loss included being between 50 and 55 years , having grade 2 hypertension , and being on antihypertensive medication . Tinnitus was associated with grade 3 hypertension .A hearing loss prevalence of 37.4% among hypertensive adults compared to 14.1% among the non-hypertensive group (Our study showed that hypertensive adults had a higher proportion of hearing loss and tinnitus compared to non-hypertensive adults. Findings suggest an association between hypertension and auditory deficits, demonstrating a need for integration of hearing healthcare services for hypertension management. Hypertension, or high blood pressure (HBP) in the arterial walls, is an issue of global public health concern; and responsible for 8.5 million deaths due to ischaemic heart disease, stroke, renal diseases, and other vascular diseases globally , 2. HypeChronic exposure to HBP has been reported to lead to target organ damage (TOD) such as kidneys, brain, heart, and eyes –11. As aThe high prevalence of hypertension globally and its reported association with auditory deficits deems it of public health importance. There is still much debate on the association between hypertension and hearing loss. Some authors have reported a higher prevalence of hearing loss among hypertensives while others observed similar hearing sensitivities between hypertensive and non-hypertensive participants. Recently, two studies in Nigeria reported a hearing loss prevalence of 38.5 and 12.83% among hypertensives , 19. AnoThere is a plethora of literature demonstrating the association between hypertension and tinnitus . One stuGlobally, the WHO estimates that 1.5 billion people or 20% of the population is affected by hearing loss; the majority of the people affected by hearing loss (1.16 billion) have mild hearing loss . The AfrThe association between hypertension and auditory deficits has been an important subject of public health relevance globally. The prevention of auditory deficits is important as treatment is often difficult and costly. In 2019, the staggering global cost of hearing loss was estimated to be more than $981 billion . In SoutThis study employed a quantitative cross-sectional study design in order to determine the prevalence and characteristics of hearing loss and tinnitus in hypertensive adults in South Africa. The sample size estimation for this study was based on the 38.5% hearing loss prevalence among hypertensives and 13.5% hearing loss prevalence among non-hypertensives reported in a similar study conducted in Nigeria . Using tThe minimum required sample size for a two-group design (hypertensive and non-hypertensive group) with α = 0.05 and 1–β = 0.80 was estimated to be 48 in each arm . Previous similar studies have had sample sizes between 50 and 100 participants , 16, 20.inclusion criteria for the experimental group were being an adult between ages 18 and 55 years of age, having been diagnosed with hypertension by a clinician and attending the out-patient polyclinic or the medical out-patient-department at Helen Joseph hospital. For the control group, the inclusion criteria were being non-hypertensive and between the ages 18 and 55 years attending the out-patient polyclinic or the medical out-patient-department at Helen Joseph hospital. The exclusion criteria for both groups included having an air-bone gap of ≥10 dB HL indicating a middle ear condition, co-morbidities such as HIV/ AIDS and diabetes mellitus known to be risk factors for hearing loss, history of hearing aid use, history of ear surgery performed on the participant, history of occupational noise exposure, history of ototoxic drugs use, history of cigarette smoking, history of stroke or head injury, and family history of hearing loss.The This study was granted ethical approval from the University of Pretoria Health Sciences Research Ethics committee (Ethics Reference No: 287/2021). All the study methods were in compliance with relevant ethical and clinical guidelines and regulations. Prior to participation, all participants signed an informed consent.Demographic information obtained from the participants were sex and age. A data extraction sheet was created to obtain hypertension information from the study hypertension group's medical files. In this study, individuals were regarded as hypertensive if their medical records indicated a clinician-diagnosed hypertension. The items included in the data extraction sheet were, (I) the duration of hypertension diagnosis, (II) last recorded SBP and DBP, and (III) if the participant is on hypertensive medication. Each hypertensive participant's last recorded SBP and DBP were classified as per the WHO/International Society of Hypertension (ISH) grades of hypertension, which were: grade 1 (SPB = 140–159 and/or DBP = 90–99), grade 2 (SPB = 160–179 and/or DBP = 100–109), and grade 3 (SPB = ≥180 and/or DBP = ≥110) . In addiBoth the study and control participants' auditory status were evaluated and reported. In order to determine the proportion of participants with tinnitus and the tinnitus characteristics in each group, a data sheet was developed with the following items; tinnitus presence, tinnitus laterality, and tinnitus sound . A qualified clinical audiologist performed otoscopic examination and audiometric evaluation on both groups. Both participants' ears were examined during otoscopy, and any impacted cerumen was removed prior to pure tone audiometry.0.5, 1, 2, 4) was determined and used to classify the degree of hearing loss. The classification of the degree of hearing loss was arranged in accordance to the recently revised World Health Organization (WHO) hearing loss classification system as: normal hearing [ <20 decibel hearing level (dB HL)], mild hearing loss (20 to <35 dB HL), moderate hearing loss (35 to <50 dB HL), moderately severe hearing loss (50 to <65 dB HL), severe hearing loss (65 to <80 dB HL), profound hearing loss (80 to <95 dB HL), complete or total hearing loss/deafness (≥95 dB HL)  was determined between the two study groups.Hearing thresholds were measured using the Modified Hughson-Westlake threshold seeking method at octave frequencies 250–8,000 Hz, and extended high frequencies (EHF) 9,000, 10,000, 11,200, 12,500, 14,000, and 16,000 Hz for air conduction, and 500–4,000 Hz for bone conduction. The audiometer used in this study  was a calibrated diagnostic audiometer  with the capability to conduct diagnostic audiometry outside of a sound-treated booth . Nonethe5 dB HL) . All parP-values of < 0.05 were used to determine level of significance. A logistic regression model was used to determine the risk factors for auditory deficits among hypertensive adults with various hypertensive characteristics. All hypothesis tests were done using a significance level of 0.05, Odds ratios and adjusted Odds ratios  and their 95% confidence intervals were tabulated.All statistical analysis were done using the Stata version 16.0 . Descriptive statistics were used to summarize and describe participants' demographic and hypertension data such as sex, age, duration of hypertension diagnosis, and grade of hypertension. Frequency tables were used to report the distribution of auditory deficits in both study groups. The difference between the prevalence of auditory deficits in both groups were determined using the χ2 test for categorical variables; A total of 198 participants were included in this study. One hundred and six participants were hypertensives while 92 were non-hypertensive controls. Just over half (54.7 and 52.2%) of the participants were females in both the hypertensive and non-hypertensive controls, respectively. The mean ages of the hypertensive and control participants were 45.1 ± 9.3 years and 43.3 ± 8.7 years, respectively. There was no statistically significant difference between the sex and age of both the groups .All participants in this study either had normal hearing or sensorineural hearing loss (SNHL). Participants with hearing loss with a conductive component (air-bone gap ≥10 dB HL) were excluded from this study as per the exclusion criteria. The prevalence of hearing loss was 37.4% in the hypertensive group and 14.1% in the non-hypertensive control group .P = 0.000, χ2 = 14.00). Among hypertensives, 60.0% had bilateral hearing loss, whereas 53.9% of the non-hypertensive control group had bilateral hearing loss. To ascertain the degree of hearing loss, ear-specific degree of hearing loss was reported  was calculated using both participants' ears. The PTA9,10,11.2,12.5,14,16 among the hypertensive group was 44.1 ± 19.2 dB HL, and 20.0 ± 18.3 dB HL among the control group.There was a significant difference between the prevalence of hearing loss amongst the two groups . The majority of the hypertensive participants with tinnitus reported bilateral tinnitus (54.6%), whilst the majority of non-hypertensives with tinnitus reported unilateral tinnitus (52.4%). A hissing tinnitus sound was the most prevalent tinnitus sound amongst the hypertensive (43.2%) and non-hypertensive control participants (33.3%). The proportion of tinnitus cases among participants without hearing loss was determined in both groups. In this study, 20 out of 66 (30.3%) hypertensive adults had tinnitus without hearing loss compared to 14 out of 79 (17.7%) non-hypertensive adults  was found in the hypertensive group as compared to the non-hypertensive control group (22.8%) . The rese adults .P = 0.011). Having grade 2 hypertension increased the odds of having hearing loss by 4.18 . The odds of hearing loss in hypertensive adults who were on antihypertensive medication were 3.18 higher than those not on hypertensive medication .The odds ratios of auditory deficits—hearing loss and tinnitus—in adults with hypertension are shown in P = 0.033).This study aimed at examining the association between hypertension and auditory deficits (hearing loss and tinnitus) by estimating the prevalence of auditory deficits among hypertensive adults attending outpatient clinics in a tertiary hospital in South Africa. The prevalence of auditory deficits in hypertensive adults was significantly higher than in the non-hypertensive control group. This study found a hearing loss prevalence of 37.4% among hypertensive adults. Factors associated with hearing loss in this group included being between 50 and 55 years of age, having grade 2 hypertension, and being on antihypertensive medication.This study's prevalence of hearing loss among the hypertensive group was in line with previously reported prevalence of 46.8% , 36.7% , 38.5% , and 12.In this study, the most common degree of hearing loss was mild hearing loss. This is in agreement with previous findings from other studies which reported mild hearing loss as the most common hearing loss degree , 16. BotP = 0.011). Additionally, age is an uncontested risk factor for hearing loss. An ongoing cross-sectional survey with audiometric testing in the United States of America found that the odds of hearing loss were 33-fold higher (95% CI: 10–112) in the 50–59 years of age population compared to 20–29 years age group (P = 0.048). Higher hypertension grades have been shown to exacerbate hearing loss in previous findings (P = 0.045). The effects of antihypertensive medication on hearing are varied. In small studies conducted over four decades ago, furosemide - a loop diuretic, has been associated with reversible sudden sensorineural hearing loss that can be permanent in some cases . Similar findings were reported by Baiduc et al. with worse EHF hearing sensitivity in the hypertensive group compared to the non-hypertensive group (18.86 vs. 14.02 dB) (There is a dearth of research employing extended-high frequency (EHF) audiometry in evaluating the link between hypertension and hearing loss. The current study made use of EHF audiometry to compare EHF hearing sensitivity of both the hypertensive and non-hypertensive control group. Our study found more than 20 dB worse PTA4.02 dB) . These rThe current study employed diagnostic pure tone audiometry in the conventional frequencies  and in the EHF in order to assess the participants' hearing capacity. Pure tone audiometry is considered the “gold standard” of hearing function assessment and has been recommended for epidemiological use . HoweverWith respect to tinnitus, the current study found a tinnitus prevalence of 41.5% among hypertensive adults. Grade 3 hypertension was associated with tinnitus. The prevalence of tinnitus in this study was slightly lower than that of Mondelli and Lopes with a reported tinnitus prevalence of 43.7% among hypertensives . AlthougThe current research was the first non-multifactorial study dedicated to the investigation of the association between hypertension and auditory deficits in South Africa. Our study has a number of strengths that include the use of extended-high frequency audiometric measurements and the revised WHO hearing loss classification system with a strict upper limit . As such, the prevalence of hearing loss among hypertensive adults could not be underestimated. Another strength of the current study was the utilization of retrospective medical file review in order to obtain participants' medical history—this decreased the likelihood of recall bias. Lastly, to the authors knowledge, this was the first study to determine the proportion of tinnitus among hypertensive adults without hearing loss. This ensured the determination of an unconfounded association between hypertension and tinnitus. The current study had some limitations. Firstly, the study population was predominately black Africans; further investigations are required to evaluate this association in other population groups. Secondly, our study employed a cross-sectional study design collecting data at one point in time, as a result the cause-effect relationship could not be inferred. Lastly, the duration of hypertension may have been underestimated due to the asymptomatic nature of hypertension. Thus, some participants may have had hypertension longer than their date of diagnosis.Auditory deficits can be disabling; thus, the identification of potential modifiable risk factors is of public health importance. The current study found a 37.4% prevalence of hearing loss, and a 41.5% prevalence of tinnitus among hypertensive adults attending a tertiary hospital in South Africa. The prevalence of tinnitus among hypertensive adults without hearing loss was found to be 30.3%. The most common characteristic of the hearing loss was a bilateral mild sensorineural hearing loss with decreased extended-high frequency hearing sensitivity. Being between 50 and 55 years of age, having grade 2 hypertension, and being on antihypertensive medication were factors associated with increased odds of hearing loss. Furthermore, grade 3 hypertension was associated with increased tinnitus prevalence. Findings suggest an association between hypertension and auditory deficits, demonstrating a need for the integration of hearing healthcare services for hypertension management. The monitoring of hypertensive adults' hearing status using EHF audiometry offers the possibility of early hearing loss detection and intervention in order to prevent hearing loss in the conventional frequencies  or introduce timely rehabilitation.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Pretoria Health Sciences Research Ethics Committee (Ethics Reference No: 287/2021). The patients/participants provided their written informed consent to participate in this study.HR collected the data for the study and analyzed the data. HR and SP contributed to the final write up of the manuscript. All authors contributed to the idealization of the study, the protocol, and the study design. All authors contributed to the article and approved the submitted version.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.


The best protectors are those that are worn (Aram Glorig) .The story goes that, around the 8th or 7th century BCE, Ulysses, on his travel back home from the Trojan War, was to sail close to the island of the Sirens. These were dangerous creatures, which lured sailors with their enchanting music and singing voices to shipwreck on the rocky coast of their island. Ulysses wanted to listen to the Sirens without wrecking his ship. He devised a clever scheme: sailors will tie him to the mast, so he could not alter the ship’s course, but the ears of his sailors were plugged up with beeswax, so they could not hear the Siren’s songs see . Those eJust imagine: 8th century BC, beeswax earplugs that completely attenuated the signal getting into his sailor’s ears! .So, what is my point? I am not advertising the use of beeswax. All I am saying is that hearing protectors have been around for many, many years. What is relatively new is the concept of hearing conservation, a conscious effort to ensure that the hearing of working people does not deteriorate as a result of occupational noise. The concept is prominent in every Health and Safety program. Important resources are invested in assessing hazards in the workplace, in reducing them and, eventually, supplying hearing protection devices to the noise-exposed personnel. In parallel, workers are explained the danger of being exposed to high-level noise for extended periods of time and trained in the proper wear and care of the protecting devices.At present, protectors have hundreds of types and models: conventional, specialized, active, passive, and different shapes and sizes. Their attenuation is assessed using sophisticated tests, following national and international standards. In other words, there is no lack in devices for use in any kind of noise, under any circumstances. Therefore, it would appear that there is nothing that could be done to improve them!However, occupational hearing loss is still the most common worker affliction. Many workers’ compensation claims are made worldwide, and many workers end their working life with severe hearing loss.The reason for this tragedy is simple: people do not wear their protectors or do not do it properly! Not because they do not know how to do it, but because protectors ARE NOT COMFORTABLE. Given, no protective gear is comfortable. The statement applies to all protective gear, from safety shoes to respirators. However, hearing protectors are close to the top of the list of uncomfortable devices, next only to respirators. Consequently, because “ears don’t bleed”, people do not wear them or do not do it properly. Therefore, if education is not sufficient and disciplinary measures do not work, the solution to the problem has to be increased comfort.Here, we come to an interesting situation: there is no definition for the term “comfort”! Wikipedia defines this as follows: “Comfort (or being comfortable) is a sense of physical or psychological ease, often characterized as a lack of hardship”. This is a curious way of defining something, through a negative (“…lack of…”) characteristic. Therefore, we are talking about something that has no definition!We do not have methods for measuring comfort. There are no standards for measurement. The reason for this apparent desert in knowledge of comfort is the inherent individuality that makes it so personal. It is definitely a very difficult subject to deal with. However, it has to be tackled once and for all to begin working on a solution.Until we define what a comfortable protector is, and manufacture one, the “best protector ever” will, unfortunately, continue to be a pie in the sky!


Visual working memory (VWM), the core process inherent to many advanced cognitive processes, deteriorates with age. Elderly individuals usually experience defects in the processing of VWM. The dorsolateral prefrontal cortex is a key structure for the top-down control of working memory processes. Many studies have shown that repeated transcranial magnetic stimulation (rTMS) improves VWM by modulating the excitability of neurons in the target cortical region, though the underlying neural mechanism has not been clarified. Therefore, this study sought to assess the characteristics of brain memory function post-rTMS targeting the left dorsolateral prefrontal cortex. The study stimulated the left dorsolateral prefrontal cortex in elderly individuals by performing a high-frequency rTMS protocol and evaluated behavioral performance using cognitive tasks and a VWM task. Based on the simultaneously recorded electroencephalogram signals, event-related potential and event-related spectral perturbation analysis techniques were used to investigate the variation characteristics of event-related potential components' (N2PC and CDA) amplitudes and neural oscillations in elderly individuals to elucidate the effect of high-frequency rTMS. The results found that rTMS enhanced VWM performance and significantly improved attention and executive function in elderly individuals with subjective cognitive decline. We therefore speculate that rTMS enhances VWM by increasing the N2PC and CDA amplitude, alongside increasing β oscillation activity. This would improve the attention and allocation of resources in elderly individuals such as to improve an individual's VWM. With the advent of an aging society, the percentage of people with Alzheimer's disease (AD) and dementia increases with age, affecting 3% of people aged 65–74 years, 17% of people aged 75–84 years, and 32% of people aged 85 years and older  is believed to modulate brain function through methods of electromagnetic induction . As rTMSVisual working memory (VWM) represents the temporary storage and processing of visual information acquired from the environment for subsequent cognitive processing and serves as the basis for advanced cognitive processes –14. VWM Studies have shown that activating the left dorsolateral prefrontal cortex (DLPFC) contributes to the filtering of distractors and plays an important role in the storage and processing of VWM . HoweverTherefore, this study sought to enroll elderly individuals aged ≥50 years with SCD to observe the characteristics of brain memory function post-stimulus after targeting the left DLPFC with rTMS. Based on the change in amplitudes of the event-related potential (ERP) components [N2PC and contralateral delayed activity (CDA)], as well as the neural oscillation activity in each frequency band , during the neural processing related to a VWM task, we sought to assess the effects of rTMS on improving brain memory function and the neural mechanisms by which rTMS enhances the VWM of elderly individuals with SCD.The Department of Neurology of Tongji Hospital enrolled participants with memory decline as their primary complaint. We included 25 elderly patients with SCD  based on the inclusion and exclusion criteria. The Ethics Committee of the Tongji Hospital approved the study [No.  ethical review 429] on 10 Jan 2019, and all participants provided written informed consent.Age ≥ 50 years (no gender limitation)Primary school education or aboveSCD-Q9 screening questionnaire score > 5Global cognitive function and daily life ability in good conditionNormal objective memory assessmentNo other mental and neurological diseasesPatients with diagnosed dementia and a history of cerebrovascular disease.Patients with a consciousness disorder, severely impaired vision, hearing, aphasia disorder, and other physical diseases that seriously affect neuropsychological testing.Patients with severe primary diseases of the liver, kidney, hematopoietic and endocrine systems; mental illness; epilepsy; Parkinson's disease; diabetes; heavy drinking; drug abuse; and malignant tumors.Patients with rTMS contraindications with metal implantable devices, including metal clips, plates, or rods; stents and filters; implanted electrodes for deep brain procedures such as vagal stimulation and electroconvulsive therapy; pacemakers and medication pumps; hearing implants; bullets or metal fragments.All participants were required to provide written informed consent and underwent related examinations before participating in the experiment. Cognitive screening with an SCD survey of nine items; examinations including cranial computed tomography or magnetic resonance imaging (MRI); and blood biochemical assessments of folic acid, vitamin B12, thyroid function , treponema pallidum, and HIV antibodies were conducted. All participants were required to complete the Neuropsychological Test Battery, which consisted of Global cognitive function [Mini-Mental State Examination (MMSE)], memory , executive function [Shape trails test (STT)], language , and visuospatial function assessments  as well as attention (Digit span) and instrumental evaluation of daily living abilities. All participants were required to undergo Digit Symbol Coding test (DSCT), Stroop test , and Digit span test, including Digit Span Forward test (DSFT) and Digit Span Backward test (DSBT) pre-stimulation and post- stimulation. These were completed in a neuropsychological assessment room that was quiet without interruption, and participants were instructed to remain relaxed. The neuropsychological assessors were unaware of the treatment plans of the participants. The flow chart of the experiment can be seen in rTMS was performed with an active figure-8 coil  and a Mag Pro X100 stimulator with Mag Option . Resting motor threshold (RMT) was then defined as the rTMS pulse intensity producing, on average, a motor evoked potential (MEP) of a 50 μV peak-to-peak amplitude. MEP referred to the contraction potential recorded at the corresponding target tendon after rTMS stimulated the cerebral motor cortex. The measurement method was as follows: participants were seated upright and remained relaxed on a chair with their hands spread flat on the legs. The coil's center was placed tangentially above the patient's left motor cortex to trigger a single pulse stimulation. We observed the patient's right hand, and we would lower the set threshold until the patient's right hand stopped the maximum threshold for automatic movement if any involuntary movement occurred. The stimulation site was the left DLPFC, determined according to the Beam F3 system . All parThe assessment of the VWM task was conducted in a quiet clinical environment, and each participant sat about 60 cm away from the computer screen. We used the Eprime software (3.0) for the improved classical VWM task in this study . At eachElectroencephalogram (EEG) recordings were conducted in a quiet environment. A Neuroscan Acquire software using a Synamps 2 amplifier  with 64 single Ag/AgCl scalp electrodes were used to record the participants' EEG activity. Four facial electrodes were positioned adjacent to the left and right outer canthus of each eye and above and below the left orbit to measure eye movement. The data were processed in MATLAB  using EEGLAB toolbox  and custThe mean amplitude difference at the PO7/8 electrode was calculated by subtracting the mean activity on the opposite side. ERP difference waves were computed by subtracting the ERP waveforms obtained from electrodes located on the hemisphere ipsilateral to the target from the ERP waveforms acquired from symmetrical electrodes on the contralateral hemisphere. The contralateral waveform for the target was the average of the waveform from the left hemisphere electrode when the target was in the right visual field and the waveform from the right hemisphere electrode when the target was in the left visual field. Similarly, the ipsilateral waveform for the target was the average of the waveform from the left hemisphere electrode when the target was in the left visual field and the waveform from the right hemisphere electrode when the target was in the right visual field. The statistical analysis focused on the two ERP components: N2PC (170–290 ms) and CDA (400–600 ms). For N2PC, in the time window from 170 to 290 ms after stimulation, the most significant negative peaks on different waveforms were extracted pre-stimulation and post-stimulation. As for the CDA, we extracted the time windows' mean amplitude from 400 to 600 ms after stimulation.Time–frequency distributions (TFDs) of the EEG time course was obtained using a windowed fast Fourier transform with a fixed 300-ms Hanning window. For each estimated frequency, TFDs were baseline corrected using the frequency from the pre-stimulus interval (300–500 ms), according to the formula: interval . For eact-test. Electrophysiological findings consisting of the N2PC and CDA amplitudes and spectrum power of region of interest were compared with a paired t-test. A value of two-sided p < 0.05 was considered statistically significant.Statistical analyses were carried out in SPSS . Data were expressed as mean ± standard deviation values or percentages, and the demographics were described. The VWM behavioral performance as well as other related cognitive function test results, including digit span test scores, DSCT scores, and Stroop test scores, were assessed with a paired t = 2.577, p = 0.017). In addition, we compared the performance difference in the DSCT, Digit Span, and Stroop tests. The participants showed significant improvement in the DSCT performance post-stimulus . For the Stroop test, the participants took less time post-stimulus to complete this task compared with that taken pre-stimulus . However, no significant difference was observed in the performance of the Digit Span test .t = 2.27, p = 0.032).We extracted the mean value in the 400–600 ms time window and performed a statistical analysis. t-test. t = −2.182, p = 0.039). During the CDA time window (510–600 ms), the β band (22–26 Hz) demonstrated a statistically significant difference in the spectrum power value in the occipital lobe post-stimulus   in the occipital lobe during the N2PC (170–290 ms) and CDA (400–600 ms) time windows and performed a paired 006) see . HoweverIn our current study, we assessed the effects of rTMS targeting the DLPFC to enhance cognitive function, especially the VWM, of elderly individuals with SCD. We monitored the characteristics of EEG signals related to VWM tasks aiming to understand the electrophysiological mechanisms underlying VWM processing. We found that rTMS improved VWM, attention, and executive function. More importantly, rTMS also enhanced the encoding and maintenance of memory according to the findings of scalp EEG signals during the VWM process.We identified that a single rTMS application enhanced VWM. The behavioral findings indicated that targeting the DLPFC in the left brain improved performance in the VWM task mainly by shortening the reaction time, which was related to the speed of information processing. Therefore, our findings suggested that rTMS helped improve the information processing speed of elderly individuals with SCD, which was consistent with the findings of a previous study in young people . To the However, our findings indicated that rTMS did not significantly improve the memory capacity of the VMW task, which implies that rTMS improved the information processing speed rather than the memory storage ability of the elderly. The study results also suggested that rTMS did not significantly improve the accuracy of the VMW task. Some researchers believe that there is a ceiling effect in accuracy and that reaction time can have a more meaningful variation in the working memory task . VariatiWe also found that the accuracy of the DSCT significantly improved after rTMS for elderly individuals with SCD. Previous studies suggested that the DSCT was closely related to VWM, and both tasks were involved in the speed of information processing . Our finThe behavioral performance indicated that high-frequency rTMS reduced the total time taken by the participants to complete a Stroop_C task with an interference effect. However, no significant difference was seen in the total time taken for Stroop_A and Stroop_B tasks. Stroop_A test referred to the word-Stroop test, Stroop_B referred to the color-Stroop test, while Stroop_C referred to the word-color Stroop test, which assesses the ability to inhibit cognitive interference occurring when the processing of a stimulus feature affects the simultaneous processing of another attribute of the same stimulus . We specHowever, behavioral measures reflected only the results of the processing and not the details of VWM processing and its underlying neural mechanisms. The processing of VMW can be divided into different phases, including memory coding, memory retention, and memory output. We compared the N2PC and CDA components, which reflect the memory coding and retention performance during VWM processing. The results showed that the amplitude of both N2PC (264–290 ms) and CDA (510–600 ms) components in the left DLPFC were significantly increased post-stimulus compared with their pre-stimulus values.In the VWM task, N2PC is usually observed about 200–300 ms post-stimulus , 36, andThe CDA is a neuroelectric activity related to VWM coding and maintenance of visual information in the brain , 40 and Our ERP findings confirmed that the amplitudes of N2PC and CDA can still be modulated by the top-down control by rTMS in elderly individuals with SCD. By increasing the amplitudes of N2PC and CDA, the allocation of attentional resources and attentional control ability are enhanced, which improves the VWM of these individuals. We speculate that their enhanced VWM storage capacity may related to the improved allocation of attentional resources and attention control capacities.The ERP components (N2PC and CDA) reflect neural information processing according to the amplitude change of the scalp EEG signals, which are a comprehensive reflection of the activities of crowd neurons. During this process, neurons in the brain oscillate at different frequency bands. Neural oscillations in different frequency bands are fundamental to the maintenance of VWM and are associated with different cognitive processes involved in VWM . ActivitWe were interested in the role of neural oscillations in different stages of VWM tasks, especially in stages of presenting memory stimuli [such as N2PC (170–290 ms)] and maintaining stimuli [such as CDA (400–600 ms)]. We also tried to assess how high-frequency rTMS affects neural oscillations in various frequency bands. We employed a fast Fourier transform analysis technology to extract the ERSP values of the contralateral side [occipital lobe (PO8)] in different frequency bands .In a previous VWM EEG study, β-band EEG activity was found to be related to attentional modulation , and β-bWe found that in the N2PC time window (264–290 ms), the ERSP value in the β (24–28 Hz) band increased significantly compared with the pre-stimulation value, and a similar effect was noted in the CDA component. These findings indicated that rTMS increased the β activity in the occipital lobe during the N2PC time window (264–290 ms) and CDA time window (510–600 ms). An increase in β activity power may be the target of rTMS intervention.To our knowledge, this is the first study to focus on the effects of high-frequency rTMS (10 Hz) applied over the left DLPFC on VWM of elderly individuals with SCD. However, the current study still has certain limitations. First, the generalizability of the current findings may be limited by our use of a relatively small sample of elderly participants. Therefore, additional studies with larger samples are warranted. Second, the study used a conventional electrode cap (F3) to target the left DLPFC; this method is less accurate compared with the MRI-guided neuro navigation that targets a desired cortical region directly . HoweverOur research revealed that high-frequency rTMS significantly improved the reaction time, attention, ability to suppress irrelevant information, and executive function of elderly individuals with SCD when completing VWM tasks. The findings of electrophysiological studies based on ERP suggested that rTMS increased the amplitudes of N2PC and CDA, which reflect the memory coding and maintenance stages of VWM processing, in the occipital lobe. Additionally, β oscillation activity was enhanced during the N2PC and CDA time windows. We speculated that high-frequency rTMS improved the VWM ability of elderly individuals by activating the left DLPFC and modulating top-down control, aiming to increase the amplitudes of N2PC and CDA, as well as the β oscillation activity, in the occipital lobe. Our study confirmed the potential therapeutic targets for enhancing VWM in SCD to lay forth a scientific theoretical basis for future clinical applications.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by The Ethics Committee Shanghai Tongji Hospital. The patients/participants provided their written informed consent to participate in this study.ML: study design, data collection, statistical analysis, data interpretation, manuscript preparation, and literature search. Z-YN: study design, data interpretation, manuscript revision, reviewing, and editing. R-RL: data collection, statistical analysis, and literature search. WZ, J-QW, and W-XX: data collection and literature search. L-HH: manuscript revision, interpretation, reviewing, and editing. J-LZ: study design, supervision, manuscript revision, reviewing, and editing. Y-XL: study design, supervision, manuscript revision, funding acquisition, and writing (reviewing and editing). All authors contributed to the article and approved the submitted version.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.


TM Version 4.0 Generic Core Scales were used to measure HRQoL based on self and parent proxy reports in 114 adolescents aged 13–19 years, 76 with bilateral PCHL and 38 with normal hearing, recruited from a population sample that was followed up from birth to adolescence. Descriptive statistics and multivariable analyses were used to estimate the relationship between severity of PCHL and HRQoL outcomes. PCHL was associated with decrements in mean multi-attribute utility score that varied between 0.078 and 0.148 for the HUI2 (p = 0.001) and between 0.205 and 0.315 for the HUI3 (p < 0.001), dependent upon the national tariff set applied and respondent group. Multivariable analyses revealed that, after controlling for clinical and sociodemographic covariates, mean HUI3 multi-attribute utility scores were significantly lower in adolescents with moderately severe, severe and profound hearing loss than in adolescents with normal hearing. Significant differences in physical functioning, social functioning, psychosocial functioning and total PedsQLTM scores were only observed when assessments by parents were relied upon, but these dissipated in the multivariable analyses. Bilateral PCHL is associated with poorer HRQoL outcomes in adolescence. Further studies conducted are needed to understand the trajectory and underpinning mechanisms of HRQoL outcomes following PCHL.Little is known about the impact of bilateral permanent childhood hearing loss (PCHL) on health-related quality of life (HRQoL). The objective of this study was to describe preference-based and non-preference based HRQoL outcomes in adolescence, from both self and proxy perspectives, amongst participants of the Hearing Outcomes Project. The Health Utilities Index Marks II (HUI2) and III (HUI3) and the PedsQL Permanent childhood hearing loss (PCHL) is the most common sensory impairment in the early years. Bilateral PCHL of moderately severe, severe or profound severity affects approximately 1 in 750 children and is present at birth in more than 80% of affected children . The prePCHL can result in delays in communication, cognition, language, reading and social and emotional development during childhood, which in turn can result in lower educational and employment levels through adolescence and adulthood . GloballTM (PedsQLTM) revealed statistically significant and clinically important decrements relative to those of children with hearing within the normal limits  in the PedsQLTM scores of those with bilateral PCHL in the social functioning and school functioning sub-scales. Differences in the physical domain scores were statistically significant but not clinically important. We have previously reported the results of the Hearing Outcomes Project in England, which assessed HRQoL outcomes in children with bilateral PCHL of moderately severe or greater severity [Relatively little is known about the impacts of PCHL on multi-dimensional HRQoL outcomes. A recent systematic review and meta-analysis revealed that pooled estimates of these impacts are constrained by variations in the measurement method, age, hearing level and type of hearing loss amongst participants in contributing studies . An analseverity . The stuseverity . Howeverseverity , highligseverity .utility) for the health state experienced and non-preference-based measures that have scoring systems that are not preference-based. For economists and other social scientists, preference-based HRQoL measures move beyond the narrow biomedical model for evaluative research and importantly generate outputs that satisfy the requirements of decision-making bodies concerned with cost–utility comparisons [Multi-dimensional HRQoL measures provide a holistic approach to capturing the consequences of PCHL that may be of concern to the children and families affected. These measures can be divided between preference-based instruments that capture individuals’ preferences  was or was not undertaken during alternating 4–6-month periods in two pairs of hospitals, with UNHS equipment and personnel moving back and forth between the paired hospitals. The Greater London birth cohort was born in two pairs of health districts in Greater London over a 60-month period between 1992 and 1997 . Each paThe study was approved by the Southampton and SW Hampshire Research Ethics Committee. Written informed consent was obtained from the teenage participants and their principal caregivers. Full details on the tracing and recruitment procedures of the children with PCHL and children with normal hearing and the measures used to assess outcomes during adolescence are reported elsewhere ,22,23,24Severity of PCHL was categorised from the most recent audiological evaluation at audiology and cochlear implant clinics as moderately severe (40–69 dB HL), severe (70–94 dB HL) or profound (≥95 dB HL) according to four-frequency averaging of the pure-tone thresholds at 0.5, 1, 2 and 4 kHz in the better ear ,19,20. TTM Version 4.0 Generic Core Scales.In conjunction with the literacy, language, emotional and behavioural assessments, undertaken at the teenager’s home or at their school according to their expressed preference, each teenager and their principal caregiver  was independently interviewed about the teenager’s HRQoL. The interviews were conducted by a trained researcher who was unaware of the teenager’s audiological history. The HRQoL measures were the HUI and the PedsQLThe HUI is a family of preference-based, multi-attribute utility measures . The uneTM Version 4.0 Generic Core Scales were specifically designed to measure the core dimensions of health, as delineated by the World Health Organisation, as well as role (school/day care) functioning [TM scale, psychosocial and total scores, between the adolescents with PCHL and those with normal hearing, were estimated using two-sample t-tests for unequal variance. The analyses were replicated based on self or parent proxy responses. Finally, we performed separate multivariable regressions to explore the effects of severity of PCHL  on HUI2 or HUI3 multi-attribute utility scores or the PedsQLTM total scores. The multivariable analyses were replicated based on self or parent proxy responses. Covariates included in the multivariable models were informed by previous theoretical or empirical models [The PedsQLctioning . The Pedl models ,18,19,20l models .p-values of 0.05 or less were considered statistically significant.Statistical analyses were conducted by using Stata 16.0 . Of the 183 participants  followed up at primary school age, 114 teenagers and their families (76 (63.3%) with PCHL and 38 (60.3%) with normal hearing) agreed to participate in this latter phase of the research. Attrition was largely attributable to participants not responding to invitations to participate in this phase of the study ,20,21. Op < 0.05) were reported by both the teenagers and the parent proxies. However, in a further four attributes , significantly higher proportions of suboptimal levels of function were reported by the parent proxies but not by the teenagers.Comparisons of the frequency and proportion of suboptimal levels of function between the teenagers with PCHL and those with normal hearing are shown in p < 0.05), regardless of the national tariff set applied or respondent group (Appendix Ant group . This want group .p < 0.05) (p < 0.001). The difference in utility scores widened to 0.315  when parent reports were relied upon ( < 0.05) . The meaied upon .TM scale, psychosocial and total scores. Based on self reports, there were no significant differences in mean scores the PedsQLTM scale, psychosocial and total scores between the adolescents with PCHL and those with normal hearing (p = 0.009), social functioning (76.74 vs. 88.11: p = 0.003), psychosocial functioning (73.17 vs. 81.35: p = 0.022) and for the total score (76.25 vs. 84.64: p = 0.009) amongst adolescents with PCHL  and also for more subjective attributes that are less observable . Clearly, HRQoL assessments obtained from children or adolescents with hearing losses, and from their corresponding parent proxies, should be viewed as complementary, rather than necessarily interchangeable. Both sets of assessments may need to be considered in clinical practice and policy settings, including those informing cost-effectiveness-based decision-making.Differences in self and parent proxy assessments of HRQoL outcomes were observed across measures. A recent systematic review of self-reported versus proxy-reported assessments in the derivation of childhood utility values for economic evaluation revealed that parent proxies tended to generate lower utility values than child self reports . Inter-rAs expected in any population based on a sample of youth with bilateral PCHL, a substantial minority (26%) also had a medical condition that might adversely affect their HRQoL additional to their PCHL. This accounts, in large part, for the reported decrements in ambulation, dexterity and, especially, vision and will also have contributed to the decrement in cognition apparent, for example, in the HUI3 scores. The effect, in multivariable analyses, of the presence of an additional medical condition on HRQoL was smaller than the effect of any degree of PCHL and non-significant by self report, but substantial and larger than the effect of PCHL by parent-report.This study was based on a longitudinal design and population-based sample drawn from defined geographic areas rather than clinic-based populations; consequently, selection biases are unlikely to represent a major problem. It also used validated preference-based and non-preference-based measures ,28,29,31How might the results of our study be used? If confirmed by future research, the data generated by our study provide a basis for targeting services towards adolescents likely to experience unfavourable HRQoL outcomes following bilateral PCHL. In addition, the health utility data reported in this study can act as a significant new resource that can inform quality-adjusted life year (QALY) estimation within this clinical context. The use of health utility catalogues to inform QALY estimation and cost-effectiveness estimates for preventive and treatment interventions is now relatively common in other areas of health care ,42. It iSince the present study shows that the largest decrements of HRQoL associated with bilateral PCHL are associated with the presence of that hearing loss and with the decrements in speech and cognition associated with it, early intervention to correct and mitigate the effects of hearing loss, aimed in particular to be of benefit to speech and language at teen age, can reasonably be expected to improve HRQoL. Based on the reports of parents, targeting services at adolescents with not only PCHL but also another medical condition, appears justified by their associated poorer HRQoL. In children with mild and moderately severe PCHL, aiding of hearing is correlated with levels of speech and language ability at 3 and 5 years of age with longer duration of hearing aid use being most beneficial for children who had the best aided hearing . In chilIn conclusion, the results of this study reveal that bilateral PCHL is associated with poorer HRQoL outcomes in adolescence in comparison to normal hearing. It complements evidence from a sparse body of literature on this topic ,36,37,46


Background: Hearing loss remains an important global health problem that is potentially addressed through early identification of a genetic etiology, which helps to predict outcomes of hearing rehabilitation such as cochlear implantation and also to mitigate the long-term effects of comorbidities. The identification of variants for hearing loss and detailed descriptions of clinical phenotypes in patients from various populations are needed to improve the utility of clinical genetic screening for hearing loss. Methods: Clinical and exome data from 15 children with hearing loss were reviewed. Standard tools for annotating variants were used and rare, putatively deleterious variants were selected from the exome data. Results: In 15 children, 21 rare damaging variants in 17 genes were identified, including: 14 known hearing loss or neurodevelopmental genes, 11 of which had novel variants; and three candidate genes IST1, CBLN3 and GDPD5, two of which were identified in children with both hearing loss and enlarged vestibular aqueducts. Patients with variants within IST1 and MYO18B had poorer outcomes after cochlear implantation. Conclusion: Our findings highlight the importance of identifying novel variants and genes in ethnic groups that are understudied for hearing loss. SLC9A3R1, ANLN, FOXF2, TOP2B, PLS1, PISD, CLRN2, AP1B1, SCD5, GGPS1, SLC12A2, THOC1 and GREB1L were identified in patients of various ethnicities [Hearing loss remains a public health burden worldwide, with global measures of the effects of hearing disability remaining steady over the past three decades . With thnicities ,20,21,22nicities ,9,14,19.SLC26A4; superior semicircular canal dehiscence (SSCD) or posterior semicircular canal dehiscence (PSCD) and CDH23; and variable cochleovestibular anomalies in some patients with variants in GJB2, POU3F4, SOX10, CHD7, SIX1 and GREB1L [Compared to hundreds of known hearing loss genes, studies on the genetic causes of temporal bone malformations are limited, with only a few genes identified so far, to name a few: EVA and/or Mondini dysplasia and d GREB1L ,28,29. Pd GREB1L ,31. BecaSLC26A4 c.706C>G  that was associated with bilaterally enlarged vestibular aqueducts (EVA) [SLC26A4 variants, only three had inner ear anomalies, including: EVA in a patient with an EYA4 variant; and SSCD in one patient with a KCNQ4 variant, and in another patient with CHARGE syndrome due to a CHD7 variant [We previously studied a cohort of Filipino patients with hearing loss requiring CI ,33,34. Its (EVA) ,33,34. O variant ,34. On tGJB2-negative individuals included 82,853 variants, of which 74,965 passed QC filters. Variants from the entire .vcf file were annotated using ANNOVAR  [Out of our initial cohort of 30 Filipino patients, we previously identified a genetic variant as causal of hearing loss in 15 patients ,33,34. F8, 2021) . Indels 8, 2021) , howeverSingle nucleotide variants that passed QC were initially selected if they: (a) were homozygous or heterozygous in the 15 children with no known genetic etiology of hearing loss; (b) were stop, splice or missense variants; (c) had a minor allele frequency (MAF) <0.005 in any gnomAD , 1000 Genomes or Greater Middle East (GME) Variome population ,39,40; , the IntOf the 15 children studied, six had EVA, three with high jugular bulb (HJB), two with SSCD/PSCD and two with malformed cochleae ; Table 1CLDN9 variant in ID20; (2) potentially compound heterozygous variants in GDPD5, PCDH15 and/or CDH23 in three children; and (3) an X-linked variant in FLNA in male patient ID24  were first identified as a cause of AD hearing loss DFNA39 with dentinogenesis (MIM 605594) in Chinese families with dentinogenesis imperfecta 1 and adult-onset progressive sensorineural high-frequency hearing loss [DSPP [DSPP , ZNF462 , and CEP290 . Each of these three genes harbor variants previously associated with hearing loss in various syndromes (ANLN [ZNF462 [CEP290 [CEP290 variants) [DSPP variant in ID6 fits his inner ear findings.ing loss . Additioss [DSPP ,47,48. Iss [DSPP ,46,47,48PP [DSPP . AlthougPP [DSPP . Dspp isotoliths ,49,50. Hyndromes : branchi [ZNF462 ; and Jou [CEP290 . While wariants) , the othLMX1A: In addition to hearing loss, ID3 has malformed cochleae, left-sided EVA and global developmental delay  c.606G>C (p.(Leu202Phe)) and/or COL2A1  c.3569G>A (p.(Arg1190His)) (. LMX1A is known for AD or AR nonsyndromic hearing loss [COL2A1 is related to Stickler syndrome type 1 with hearing loss (MIM 108300) as well as various skeletal phenotypes [Lmx1a-mutant mice lack endolymphatic ducts and have short cochlear ducts [Lmx1a-heterozygous mice had normal hearing [LMX1A variants had mild-to-profound hearing loss of variable onset from infancy to adulthood [Col2a1-mutant mouse model had a smaller misshapen otic capsule as well as craniofacial abnormalities such as cleft palate and short mandible [USH2A  were previously ruled out due to high MAF in the general Filipino population and lack of retinitis pigmentosa after years of follow-up –ZFHX4 is one of two genes within the minimum region of overlap in patients with 8q21 microdeletions manifesting with intellectual and developmental disability, sensorineural hearing loss, craniofacial anomalies and hypotonia [NRP1–the +/−Nrp1 mouse has abnormal auditory brainstem responses (ABR), progressive hearing loss, disorganized outer spiral bundles and enlarged microvessels of the stria vascularis [ARHGAP4 , in which missense variants were previously described in children with intellectual disability [LMX1A variant is the strongest etiology of inner ear abnormalities in this patient while the ZFHX4 or ARHGAP4 variants may explain ID3’s developmental delay.al delay ; Table 1190His)) . LMX1A iing loss ,54, whilenotypes . Homozygar ducts . Howeverdulthood . On the mandible ; these lollow-up . There wollow-up : (a) hetypotonia ,60; (b) scularis ; and (c)sability ,63. ThisDMXL2: DMXL2  was recently identified to have missense variants causing AD nonsyndromic hearing loss in Chinese and Cameroonian families [DMXL2 variant c.257T>C (p.(Leu86Ser)) , www.mousephenotype.org, last accessed March 31, 2021). It is possible that the temporal bone findings are also an effect of the Dmxl2 variant in ID5′s case. Biallelic loss-of-function DMXL2 variants are also known to cause Ohtahara syndrome characterized by neurologic deficits including intellectual disability, developmental delay, hearing loss, polyneuropathy and also facial dysmorphisms [DMXL2 variant, the developmental delay may also be due to other causes, such as variants in CCDC186 , ZRF2 or MCM3AP  ) . In addiu86Ser)) . She alsu86Ser)) . In mice neurons , and Dmxorphisms . However21q22.3) .PTPRQ: PTPRQ  is a known cause of AD (MIM 617663) or AR (MIM 613391) nonsyndromic hearing loss in families and probands with multiple ethnicities, which may be variable in clinical presentation [PTPRQ  due to lack of clinically diagnosed craniofacial hallmarks of AD Treacher-Collins syndrome (MIM 154500), but upon review, we cannot rule out that the TCOF1 variant also contributes to hearing loss and temporal bone anomalies, as was previously described , a candidate gene for primary ciliary dyskinesia and lung function in cystic fibrosis  variants may be inherited in an AD manner, while digenic inheritance for PCDH15  and CDH23  were demonstrated in mice and humans [PCDH15/CDH23 variants plus a heterozygous MYO7A variant (MYO7A variant c.4921G>A (p.(Glu1461Lys)) is heterozygous in another patient ID18, who has nonsyndromic hearing loss  in ClinVar , while the PCDH15 c.3787C>T (p.(Pro1263Ser)) variant is novel.d humans . ID7 has variant . Interesing loss . This maing loss . Patientntal DNA . These CCOL11A1: ID8 has hearing loss, left-sided SSCD, and heterozygous missense variants in two genes known for AD nonsyndromic hearing loss, namely COL11A1  and TECTA  (COL11A1 c.4364A>C (p.(Lys1455Thr)) variant is rarer (gnomAD EAS MAF = 0.0004). Previous reports on COL11A1 or TECTA did not reveal inner ear abnormalities in patients with variants [11q23.3) . Of the  MIM 6025; 11q23.3variants .IST1: ID9 with profound hearing loss and left-sided EVA is heterozygous for a c.737C>G (p.(Pro246Arg)) variant in IST1 . This rare deleterious variant . In mouse cochlea, Ist1 is expressed in both hair cells and supporting cells (gEAR). Recently de novo VPS4A variants were identified to cause a multi-systemic neurodevelopmental disorder including sensorineural hearing loss due to the abnormal accumulation of IST1 protein in the limiting membrane of proband-derived fibroblasts and also in neuronal endosomes [IST1 an excellent candidate gene for nonsyndromic hearing loss. Moreover, ID9 had poor CI outcomes, such as average CI-aided hearing threshold of 74 dB and speech tests using PEACH scores at 10–21%. Identification of additional patients with IST1 variants is needed to verify these CI outcomes. variant  was singndosomes , suggestSLC12A2: ID13 who has hearing loss and global developmental delay is heterozygous for a novel stop variant c.2977G>T (p.(Glu993*)) in SLC12A2  (SLC12A2 variants have been identified in patients with AD nonsyndromic hearing loss (MIM 619081), with AD Delpire-McNeill syndrome (MIM 619083), or AR Kilquist syndrome (MIM 619080). Recently McNeill et al. identified heterozygous SLC12A2 variants in eight mostly pediatric patients with intellectual disability or developmental delay, and ~60% had bilateral sensorineural hearing loss [Slc12a2 in mice led to loss of hearing and vestibular function, collapse of Reissner’s membrane, disorganization of the organ of Corti, and loss of hair cells and supporting cells [Slc12a2 in mice resulted in early hearing loss that progressed with age despite normal inner ear morphology and histology [ 5q23.3) . SLC12A2ing loss . Previouistology .MYO18B: Two patients had variants in MYO18B . Patient ID23 with nonsyndromic hearing loss has potentially compound heterozygous CDH23 variants and also a novel heterozygous MYO18B variant c.1982G>A (p.(Trp661*))  which is characterized by nemaline myopathy, facial dysmorphisms and hearing loss in up to 60% of patients [Myo18b-knockout mice had abnormal ABR findings (IMPC), further supporting the role of heterozygous MYO18B variants in the etiology of hearing loss. Patients with hearing loss as part of Klippel-Feil syndrome were also diagnosed with inner ear dysplasias including internal acoustic canal deformities [MYO18B variants had poorer outcomes after CI, with PEACH scores whether in quiet or noise at 4–37% despite average post-CI thresholds of ~40 dB at 0.25–8 kHz. This is not unexpected given potential cochlear nerve defects [rp661*)) . The othrp661*)) . In patirp661*)) . MYO18B patients . Heterozormities , which a defects ,31 that FLNA: The same FLNA  variant c.6350A>G (p.(Asn2117Ser)) that is classified as VUS in ClinVar was identified in two children ID20 and ID24  which may explain his neonatal jaundice , Melnick-Needles syndrome (MIM 309350) and otopalatodigital syndrome (MIM 311300/304120) have been reported to include sensorineural hearing loss. ID24 has EVA in addition to the hearing loss but has no detailed assessment of additional skeletal anomalies; meanwhile temporal bone anomalies have been reported previously in a patient with Melnick–Needles syndrome [FLNA variant has additional variants as the cause of hearing loss ) in CLDN9  and heterozygous for ANKRD11   . KBG synentation . In conting loss ; this clell loss . In thisGREB1L: Previously variants in GREB1L  were associated with AD nonsyndromic hearing loss with or without cochleovestibular malformations and non-ear phenotypes [GREB1L c.3798C>G (p.(Ser1266Arg)) but has no other features in addition to profound hearing loss . Cbln3 is expressed in supporting cells and outer hair cells of the inner ear (gEAR), and also in the cerebellum and dorsal cochlear nucleus [Cbln3-mutant mice have abnormal ABR (IMPC), implying that CBLN3 is also a candidate gene for ID22′s hearing loss.enotypes ,21,22. Oing loss . She als nucleus . HeterozGDPD5: Patient 27 has two missense variants each in two genes: GDPD5  which encodes an enzyme involved in glycerol metabolism; and MADD  (Gdpd5 is expressed in hair cells and supporting cells of mouse cochlea (gEAR) and homozygous knockout mice have abnormal ABRs (IMPC). On the other hand, biallelic MADD variants cause a multisystemic neurodevelopmental disorder that includes sensorineural hearing loss in 17% of patients [GDPD5 is a candidate gene for her hearing loss.11p11.2) . Gdpd5 ipatients . Our patDSPP, LMX1A, DMXL2, PTPRQ, PCDH15, COL11A1, TECTA, SLC12A2, MYO18B, CLDN9 and GREB1L; while four variants are in candidate genes for hearing loss IST1, CBLN3 and GDPD5  semicircular canal dehiscence in carriers of DMXL2, PTPRQ and COL11A1/TECTA variants; and (3) malformed cochleae in carriers of variants in LMX1A and MYO18B  are also potentially causal of temporal bone anomalies. Factors that may have contributed to an increased rate of variant identification from the sequence data of our cohort of 30 pediatric cochlear implant recipients include: (a) a more inclusive approach for low-frequency variants, particularly if the MAF was increased in an indigenous or isolated population which has high rates of intermarriage and potentially undiagnosed hearing loss  variants have been associated with either autosomal dominant (MIM 601317) or autosomal recessive non-syndromic hearing loss (MIM 600060), as well as autosomal recessive Usher syndrome type 1B (MIM 276900). Differences in modes of inheritance may be associated with phenotypic variability, such that variants known to cause autosomal recessive hearing loss that is characterized by prelingual profound hearing loss co-exist with heterozygous variants that cause autosomal dominant forms with milder hearing loss of later onset. Additionally, with the increasing number of identified genes for hearing loss, the occurrence of multiple variants within different genes that independently predispose to hearing loss in the same individual may be more common than previously thought [G6PD variant likely explains the patient’s neonatal jaundice, while the hearing loss is potentially due to a known variant in FLNA. Continued efforts in identifying novel genes mean that patient sequence data must be periodically reanalyzed not only to resolve a potential genetic etiology, but also to identify compound phenotypes due to variants in multiple genes. If multiple genes or variants are involved, additional studies on the functional effects per variant will aid in the determination of which variant is more strongly contributing to the hearing loss phenotype.It is not unusual for the same gene to cause both autosomal dominant and autosomal recessive forms of hearing loss, e.g., A MIM 2763 variantIST1, CBLN3 and GDPD5 as potential candidate genes for hearing loss, all three of which have mouse models with abnormal ABR findings that are matched to the patient’s genotype. Our findings highlight the importance of identifying novel variants and genes in well-characterized patients from ethnic groups that are understudied for hearing loss.We identified novel variants in 11 known genes for hearing loss and neurodevelopmental phenotypes. We also present three genes


Sound localization in daily life is one of the important functions of binaural hearing. Bilateral bone conduction devices (BCDs), middle ear implants, and cartilage conduction hearing aids have been often applied for patients with conductive hearing loss (CHL) or mixed hearing loss, for example, resulting from bilateral microtia and aural atresia. In this review, factors affecting the accuracy of sound localization with bilateral BCDs, middle ear implants, and cartilage conduction hearing aids were classified into four categories: (1) types of device, (2) experimental conditions, (3) participants, and (4) pathways from the stimulus sound to both cochleae. Recent studies within the past 10 years on sound localization and lateralization by BCDs, middle ear implants, and cartilage conduction hearing aids were discussed. Most studies showed benefits for sound localization or lateralization with bilateral devices. However, the judgment accuracy was generally lower than that for normal hearing, and the localization errors tended to be larger than for normal hearing. Moreover, it should be noted that the degree of accuracy in sound localization by bilateral BCDs varied considerably among patients. Further research on sound localization is necessary to analyze the complicated mechanism of bone conduction, including suprathreshold air conduction with bilateral devices. We are surrounded by many different sounds and we can easily know where they are and how far they are from us. This ability is called “localization”. According to Moore , the terHearing loss affects sound localization and causes serious problems in daily life for the hearing-impaired. Häusler et al. (1983)  investigThe usefulness of bone conduction devices (BCDs) to assist persons with CHL, such as bone conduction hearing aids (BCHAs), was already pointed out in the early 1950s . For a lFor bone-conducted sound lateralization, Kaga et al. (2001)  found, uFurther advances in technology have led to the development of various kinds of BCDs apart from conventional BCHAs with a steel-spring headband or with framed glasses. Reinfeldt et al. (2015)  categoriSo far, research on sound localization thus has been carried out using the various kinds of devices mentioned above. Most of the studies have reported that bilaterally fitted devices showed more improved sound localization than the unilaterally fitted ones. As the basis, Zeitooni et al. (2016)  investigThe present review aimed to discuss the factors affecting sound localization or lateralization, as well as their accuracy, for persons with bilateral (simulated) CHL using bilateral devices. For the first aim, the factors affecting sound localization and lateralization were classified, and the relevant research is discussed. For the second aim, regarding the accuracy of sound localization and lateralization using a multi-loudspeaker system, rather than a questionnaire such as “The Speech, Spatial and Qualities of Hearing Scale (SSQ) , the cliFirst, the keyword search conditions in “Google Scholar” were set to exclude “Include patents” and “Include quotes”. The search resulted in 1079 hits for sound localization and 670 hits for sound lateralization. These contents were sorted in descending order of relevance. The 1000 hits of the upper limit displayed from the top for sound localization and the 670 hits for sound lateralization were investigated. After inspection of the URLs, it was found that 982 hits for sound localization and 653 hits for sound lateralization were valid for analysis, after excluding links that displayed a “Not found” or “Not connected” message. These hit numbers were set as the initial values for screening for this review. The screening process and the number of resulting hits are shown in A conventional skin-drive BCHA that vibrates the bone via the skin consists of a microphone, an amplifier, and a BC transducer (vibrator or actuator) with a soft headband (softband), a steel spring headband, or spectacles . The conThe principles and characteristics of the BCDs shown in In studies on sound localization, various kinds of devices have been used for (simulated) CHL. The devices differ in microphone type and position, transducer positions, and signal processing. These differences may affect the accuracy of sound localization. Denk et al. (2019)  investigRegarding the stimulation position of the bone-conducted sound, Stenfelt (2012)  reportedWhen sound is presented by a loudspeaker in a sound field, two methods can be mainly used to measure the ability of sound localization. One is to identify one loudspeaker’s direction from multiple loudspeakers arranged in a semicircular or circular way relative to the participant. When multiple loudspeakers are arranged in a circle  and patients with bilateral CHL.Normal-hearing participants are used to simulate bilateral CHL by blocking their ears with earplugs (and earmuffs) or earmolds. Normal-hearing participants with simulated CHL have the advantages of normally developed hearing, and the BC thresholds of the left and right ears under masking can be accurately measured. The participants thus can be assumed to be a homogeneous study group. However, there is a limit of sound insulation by earplugs and earmuffs, and the audiogram of simulated CHL depends on the sound insulation performance. For example, in an experiment to investigate the effect of simulated unilateral hearing loss on horizontal sound localization by Asp et al. (2018) , the degFor patients with bilateral CHL, it is clinically meaningful to examine their sound localization ability. The heterogeneity of the study group with respect to the duration of deafness, the degree of hearing loss, the symmetry of hearing, and the period of device use makes it difficult to generalize the results. Furthermore, there are few reports on how localization accuracy is affected by whether the CHL is congenital or acquired. In the case of congenital aural atresia and microtia, the auditory system may not always be fully developed for both ears. Kaga et al. (2016)  carried When the participants are children, their ages can affect the ability of sound localization. From measurement of ITD and ILD with a self-recording apparatus, Kaga (1992)  showed tSound localization by binaural hearing with devices is mainly mediated by two pathways: (1) the pathways from the sound source to the microphones of the bilateral devices, and (2) the pathways from the bone-conducted sound induced by both devices to both cochleae .The ITD detection threshold varies depending on the type of sound  and ranges from 9 to 28 μs . ITD reaIt is generally accepted that bone-conducted sound transmission in the human skull is linear, at least for frequencies between 0.1 and 10 kHz and up to 77 dB HL . HoweverTranscranial attenuation (TA):Stenfelt et al. (2012)  studied Transcranial delay (TD):TD between the ipsilateral and contralateral cochleae with stimulation by a BCD on one side is related to the propagation velocity of bone-conducted sound in the skull. Franke 1956)  placed t56  placeAs described above, the bone-conducted sound induced via bilateral devices can cause complicated interference for the bilateral cochleae due to TA and TD. Farrel et al. (2017)  measuredAs mentioned above, previous studies have shown that sound localization by bone-conducted sound with bilaterally fitted devices involves a greater variety of factors than sound localization by air-conducted sound. Next, a review was made to assess how much the accuracy of sound localization by bilaterally fitted devices differs from that with unilaterally fitted devices or unaided conditions for participants with bilateral (simulated) CHL and with normal hearing. The methodology of the studies is shown in Gawliczek et al. (2018a)  evaluateSnapp et al. (2020)  investigFan et al. (2020)  comparedCaspers et al. (2021)  investigDun et al. (2013)  investigNishimura et al. (2020)  evaluateAs reviewed above, most of the recent studies on sound localization and lateralization have shown that performance with bilaterally fitted devices was better than that with unilaterally fitted device for bilateral (simulated) CHL. However, the judgment accuracy was generally lower than that for normal hearing, and the localization errors tended to be larger than for normal hearing. It should also be noted that the degree of accuracy in sound localization with bilateral BCDs varied considerably among patients. Many factors such as the type of device, the experimental conditions, participants, and pathways from the stimulus sound to both cochleae can affect the results. Especially, it is unclear whether localization with bilaterally fitted devices, for which the presentation level exceeds the threshold in bilateral (simulated) conductive hearing loss, involves both air-conducted sound and bone-conducted sound. Further research on sound localization is necessary to analyze the complicated mechanism of BC, including suprathreshold air conduction with bilateral devices.


The importance of impairment in performing activities of daily living (ADL) is likely to increase in sub-Saharan Africa because few care options for affected people exist. This study investigated the prevalence of ADL impairment, the extent to which care need was met, and described characteristics of people with ADL impairment and unmet need in Burkina Faso.This study used data from the Centre de Recherche en Santé de Nouna Heidelberg Aging Study, a population-based study among 3,026 adults aged older than 40 years conducted in rural Burkina Faso. Information on 6 basic ADL items was sought, with a follow-up question asking whether care need was not met, partially met, or met. Bivariable correlations and multivariable logistic regression were used to determine sociodemographic and health characteristics associated with ADL impairment and unmet need.ADL impairment of any kind was reported by 1,202 (39.7%) respondents and was associated with older age (adjusted odds ratio: 1.05 [95% CI: 1.04–1.06]), being a woman (1.33 [1.06–1.60]), and reporting depressive symptoms (1.90 [1.65–2.18]). Among those with ADL impairment, 67.8% had at least one unmet need. Severe ADL impairment was found in 202 (6.7%) respondents, who reported a lower prevalence of unmet need (43.1%). Severe ADL impairment was associated with depressive symptoms (2.55 [2.11–3.07]) to a stronger degree than any ADL impairment.Prevalence of ADL impairment and unmet need was high in this setting. Variation in impairment across the population highlighted key groups for future interventions. Unmet need for care was highest in middle-aged adults, indicating a gap in care provision. As is the case worldwide, populations in sub-Saharan Africa (SSA) and Burkina Faso are rapidly aging. The number of people in Burkina Faso aged older than 50 is estimated to more than double in the next 50 years . UnderstThe amount of research about functional health of older people from other SSA countries such as South Africa , TanzaniPhysical, psychological, and cognitive impairments associated with aging have adverse effects on an older individual’s ability to perform everyday activities independently . ActivitThe link between activity impairment and the use of formal and informal LTC services is best approached by investigating perceived or evaluated need for care . An unmeHowever, external evaluation of unmet need for care may miss some perceived needs for care and those who receive help but have needs that are not adequately covered may be ignored . This adThis is one of the first studies in SSA to explore the gradient of unmet, partially met, and met need for care among ADL-impaired older adults and how this gradient relates to sociodemographic factors, chronic morbidities, mental health, and cognitive impairment. Our measures of need are novel for the setting—in the past, unmet need for care in SSA has been determined indirectly  or dichoThis analysis aims to investigate the prevalence and correlates of (a) impaired ability to perform ADL at different degrees of severity and (b) unmet, partially met, and met need for care in a rural, poor, older adult population in SSA. Age, being female, low socioeconomic and educational status, cardiovascular disease, cardiovascular disease risk factors, depressive symptoms, and cognitive impairment have all been shown to be associated with higher levels of activity impairment , and we The study used data from the CHAS, collected between May and July 2018. CHAS is a population-based study of adults aged 40 years and older based in a rural region in north-western Burkina Faso. It was conducted in the Nouna Health and Demographic Surveillance System , which cBetween May and July 2018, all sampled individuals were invited to participate in the study at their homes. Consenting participants completed a questionnaire on socioeconomic and demographic characteristics and their physical, cognitive, and mental health. Field workers were trained to administer the questionnaire, using French as the main language. Translations from French to the local language, Djula, were done within the training module and clearly communicated to all field workers verbally. Written Djula literacy is very limited in this setting, necessitating verbal rather than a written translation. Physical measurements such as grip strength and walk speed were measured by study staff .Data were captured on the six basic ADLs: walking across a room (mobility), bathing or showering, getting dressed, eating, getting into or out of sleeping location (transfers), and using the toilet . For theOur primary bivariable and multivariable analyses use a binary measure for whether respondents reported any impairment on one or more ADLs. Additional analyses investigated whether relationships differed among individuals reporting mild to moderate impairment or severe to extreme impairment on one or more ADLs. These separate models have been conducted to show a more detailed picture of the subgroups composing people with ADL impairment. We present the findings of the binary logistic regression model given that this reflects the way that similar analyses have been presented before and therefore conveys the key results most effectively to readers while facilitating comparison with other studies.If an individual reported any difficulty with an ADL, there was a follow-up question about whether the individual received from others: no help; some, but not enough help; or enough help for that ADL. We classified as follows: no help as an unmet need for care; some, but not enough help as a partially met need; and enough help as a met need. We then aggregated across ADLs to arrive at a summary measure. Those with any unmet need were classified as having “unmet need.” Those having no unmet need but reporting at least one partially met need were classified as having “partially met need.” Those with neither unmet nor partially met needs were classified as “met need.” We repeated the same process among the subgroup of respondents with severe to extreme ADL impairment to determine the rates of unmet need, partially met need, and met need among those most severely impaired.We considered sociodemographic and socioeconomic characteristics commonly predictive of ADLs and care need. Age was segmented into 5-year groups to illustrate the prevalence of ADL impairment and care need and used as a continuous variable in bi- and multivariable regression. A wealth index was constructed using a previously described method .First, we described baseline characteristics of the sample, calculating confidence intervals (CIs) for binomial variables using Clopper–Pearson intervals. For significance testing, in order to compare continuous variables, the independent-samples This study received ethics approval from the National Health Ethics Committee in Ouagadougou (#2018-5-053), the CRSN institutional ethics committee in Nouna (#2018-04), and the ethics committee of the medical faculty of the Ruprecht-Karls-Universität Heidelberg (#S-120/2018).Summary statistics for the sample used in the present analysis are presented in Of the 3,996 sampled individuals, 3,026 (75.7%) participants were found, consented, and completed questions on all six ADL items and the follow-up questions and were included in the analysis. There were no substantial demographic differences between the sampled and participating individuals .At least one ADL impairment of any category was reported by 1,202/3,026 (39.7% [95% CI: 38.0%–41.5%]) of all respondents .p < .001) than men (33.1% [30.7%–35.5%]). In bivariable, unadjusted analyses, which are presented in Mild to moderate ADL impairment was reported by 1,000/3,026 (33.0% [31.4%–34.8%]) of all respondents and made up 83.2%  of those reporting an ADL impairment. Prevalence of reporting any ADL impairment increased with age, from 22.8% (19.7%–26.1%) of those aged 40–44 to 78.5% (71.6%–84.4%) of those aged older than 75 . Women hAt least one severe to extreme ADL impairment was reported by 6.7% (5.8%–7.6%) of all respondents . PrevaleWhen respondents reported any difficulty in performing an ADL, more unmet need than partially met or met need for care was reported for each of the six ADL items separately . Having Of respondents with any ADL impairment, 67.8% (65.1%–70.4%) had at least one unmet need for care, 17.3% (15.2%–19.6%) had partially met need, and 14.9% (12.9%–17.0%) had all their ADL-related needs met. The proportion of unmet need was higher in younger age groups and declined with age . Among pIn people with severe to extreme ADL impairment, the percentages of unmet need for care were significantly lower than in those with any ADL impairment (43.1% [36.1%–50.2%]). At least one partially met need, but no unmet need was reported by 27.2% [21.2%–33.9%]; and 29.7% [23.5%–36.5%] reported that all their ADL-related needs were met. At higher ages, people with severe to extreme ADL impairment more often reported partially met need and met need than unmet need  althoughWhen using ordinal logistic regression to account for the natural ordering of outcome categories, the results, presented in Our analysis of a population-based representative sample of adults aged 40 years and older in a rural, poor area in Burkina Faso found that almost two out of five respondents had impaired ability to perform central ADLs. Most of these ADL limitations were mild to moderate, but one in 15 had severe or extreme ADL limitations. In a setting where care provision is largely informal and family-based , this plThe number of people with severe to extreme activity impairment found in our study (6.7%) is relatively low when compared to other studies conducted in Burkina Faso  that fouOlder women had the highest burden of ADL impairment in our sample. This confirms results from previous studies in Burkina Faso , NigeriaThird, although more conclusive evidence is necessary, biological differences between men and women at older ages may also contribute to the observed gender-specific patterns . SpecifiFourth, living with a spouse is known to protect against ADL impairment  were almost triple those seen in rural South Africa . They arAmong those with any ADL impairment, middle-aged people reported significantly higher rates of unmet need than older individuals. While older age has been found to be associated with unmet need in Nigeria  and IndiSurprisingly, being married or cohabiting was positively associated with unmet need in multivariate analysis. At first sight, this finding does not align with results from other studies that have found more unmet needs in people who live without a spouse than in those sharing their household with a spouse . HoweverIn additional sensitivity analyses, the association between being married or cohabiting and reporting unmet need for care was statistically significant for women, but not for men . This fiDepressive symptoms were less common in individuals with unmet need than in those with partially met or met need, in contrast to the positive association seen in previous studies . Prior aOur study has the strengths of being large, population-based, and representative of local adults aged 40 years and older, providing reassurance that our findings are locally valid, potentially generalizing to other rural areas in Burkina Faso and the Sahel region. The age cutoff of 40 means our overall findings are not directly comparable to the typically older cutoffs for aging studies in HICs; however, given the life expectancy at birth of Burkinabé people (61.2 years ), we belThere are, however, some important limitations to consider. First, the cross-sectional design of the study does not make it possible to draw temporal causal interpretations. Second, case numbers of ADL-impaired respondents with partially met and met need were too low to detect significant associations with explanatory variables in multivariable analysis. Third, our choices of measures are important to consider. The concept of ADL as a measure of disability is widely used in HICs as well as low- and middle-income countries and makes a comparison with the related literature possible. Our decision to present results for both “any ADL impairment,” which comprises all degrees of severity and “severe to extreme ADL impairment,” including only the most severely impaired, reflects the lack of consensus in categorizing ADL impairment. However, presenting both allows for comparison with a range of previous studies. It was necessary to align categories of severity between walking and the other ADL impairments as direct mapping of categories was not possible due to different answering options.We found a high prevalence of ADL impairment and of unmet need for care in a population-based sample of more than 3,000 older adults in a poor rural Burkina Faso setting. ADL impairment was particularly prevalent in older women, people with frailty, and people with depressive symptoms, highlighting key groups for future interventions. Importantly, unmet need was not reported mainly by those who were the most impaired, but by younger respondents with ADL impairment of any category, including those with mild or moderate impairment. Future research should focus on the investigation of the informal care system within families and peers for people with activity impairment to understand where and how care provision could help best.gbab041_suppl_Supplementary_MaterialClick here for additional data file.


The chimeric anti-CD20 antibody rituximab has demonstrated good efficacy as an off-label treatment in chronic inflammatory demyelinating polyneuropathy (CIDP), while the humanized anti-CD20 antibody ocrelizumab has been approved for treatment of multiple sclerosis (MS), whereas there is no evidence for its use in CIDP so far. We present a patient suffering from CIDP and MS, both refractory to standard treatment and both showing marked improvement on ocrelizumab. To the best of our knowledge, this is a unique report of CIDP with an almost full electrophysiological recovery on ocrelizumab which could be considered as a potential treatment option for refractory CIDP. One of these off-label treatment options which has shown good efficacy is rituximab, an anti-CD20 antibody. The humanized or full human anti-CD20 antibodies ocrelizumab and ofatumumab have been approved for treatment of other diseases such as multiple sclerosis (MS), however these biologicals have not been regularly used for treatment of CIDP so far. In MS, a chronic demyelinating autoimmune disease of the central nervous system, ocrelizumab is a highly effective therapeutic option especially in highly active disease courses. Here, we present the case of a patient with co-existing MS and CIDP who was treated with ocrelizumab which led not only to freedom of MS disease activity but also to nearly full recovery of CIDP previously fluctuating over years. To our knowledge, there is only one reported case of CIDP successfully treated with ocrelizumab.Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic autoimmune inflammatory disorder of the peripheral nervous system. First-line treatments of CIDP include intravenous immunoglobulins (IVIg), corticosteroids, and plasmapheresis. Beside these standard treatments several off-label immunomodulatory or immunosuppressive treatments are used particularly in treatment-refractory disease.Written informed consent for patient information and images to be published was provided by the patient. The patient was initially treated with plasmapheresis and intravenous immunoglobulins (IVIg), followed by a long-term therapy with oral corticosteroids due to poor response on IVIg. Under this treatment, motor deficits improved; however, he complained of persisting fluctuating sensory symptoms in both legs.In October 2017, 2 weeks after a respiratory tract infection, a 26 year old, otherwise healthy, male patient experienced slowly progressive, at the beginning slightly asymmetric, left-side dominant ascending sensory and motor deficits first in both legs, then also affecting both hands. When he was not able to walk longer distances anymore and distal and proximal motor and sensory deficits were present in all four limbs, he was admitted to a hospital in his home country in January 2018. Nerve conduction studies showed typical non-uniform features of demyelinating and motor-dominant neuropathy leading to diagnosis of CIDP according to the accepted and recently revised diagnostic criteria.) and CIDP, were confirmed by clinical, radiological  and neurographical (demyelinating neuropathy) findings. Antibodies against nodal and paranodal proteins , well characterized onconeural antibodies  as well as antibodies against PKCγ, CARPVIIII, ARHGAP26, SOX1, GAD65, AK5 and Homer3 were not detected. MOG-IgG and AQP4 antibodies were negative as well. Cerebrospinal fluid work-up showed normal findings at that time. Neurologic symptoms improved after high-dose intravenous methylprednisolone (HDMP). Because MS was the clinically leading disorder at that time with 2 relapses within 1 year, treatment with dimethylfumarate (DMF) was started in August 2019.In August 2018, the patient developed an impaired vision on his left eye. Diagnostic work-up including visual evoked potentials showed optic neuritis and typical radiologic findings of a multiple sclerosis (MS) with demyelinating white matter lesions disseminated in space and time. After migration to Austria, he presented the first time at Innsbruck Medical University in July 2019 with an acute optic neuritis on the right eye. Both diagnoses, MS  again while MS treatment with DMF was continued. In March 2020 the patient presented with multiple new neurologic symptoms such as diplopia, mild gait ataxia and worsening of sensory deficits in all extremities . Because worsening of both, MS (brain stem and cerebellar symptoms) and CIDP (sensory symptoms) occurred, HDMP in a total dosage of 3 g was administered with only partial improvement. MRI showed several new and contrast-enhancing white matter lesions  while elNeurographical findings before and after treatment start with ocrelizumab, exemplary shown in detail for the right median and ulnar nerve. Improvement or even normalization of motor and sensory amplitudes, motor latency, motor and sensory conduction velocity, and F-wave latency of both nerves is demonstrated. Compound muscle action potentials were measured from peak to base.8 One case of successful treatment of CCPD with rituximab has been published so far. Contrary to most case reports about CCPD our patient did not simultaneously develop peripheral and central demyelination so that both CIDP and MS were independently diagnosed at different time points. Both, the diagnostic criteria for CIDP and MS were fulfilled in this case. Long-term treatment strategies in MS and CIDP are fundamentally different, however, the anti-CD20 antibody rituximab has been used as an off-label treatment in both diseases. The efficacy of rituximab has particularly been reported in patients with demyelinating polyneuropathy associated with antibodies against paranodal proteins and in patients with the MADSAM  subtype, whereby the pathomechanism in these patients may be different to typical CIDP with macrophage-induced demyelination. While ocrelizumab has been approved for treatment of active relapsing-remitting (and primary progressive) MS there is no evidence for its use in CIDP. Recently, one case has been published with ocrelizumab having been successfully used in a patient with CIDP refractory to standard treatments who developed anti-rituximab antibodies. The authors were able to show improvement of neurophysiological findings following initiation of ocrelizumab. Our patient suffered from both MS and CIDP, whereby both diseases were not sufficiently controlled under standard treatments. There are no guidelines as to how to treat patients in this special situation. By introducing ocrelizumab as a potential treatment option for both diseases we observed a stabilization of MS disease course with no further relapses and substantial improvement of CIDP. Clinical symptoms related to CIDP and previously present over several years resolved completely and electrophysiological findings markedly improved during ongoing treatment with ocrelizumab.MS and CIDP are both autoimmune, demyelinating neurological diseases. Co-occurrence of both diseases is uncommon but has been reported earlier. The condition of demyelination present in the central and peripheral nervous system is also known as combined central and peripheral demyelinating disease (CCPD) with a large heterogeneity of clinical presentation and disease course.14 and in the rare case of co-occurrence with MS, it seems suitable as treatment of both diseases.We suggest that ocrelizumab could be considered as off-label treatment for CIDP, also due to lower immunogenicity than that of rituximab (26–37% anti-drug antibodies against rituximab compared to .4% against ocrelizumab),