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Deafness is the most common form of sensory impairment in humans and frequently caused by defects in hair cells of the inner ear. Here we demonstrate that in male mice which model recessive non-syndromic deafness (DFNB6), inactivation of Tmie in hair cells disrupts gene expression in the neurons that innervate them. This includes genes regulating axonal pathfinding and synaptogenesis, two processes that are disrupted in the inner ear of the mutant mice. Similar defects are observed in mouse models for deafness caused by mutations in other genes with primary functions in hair cells. Gene therapy targeting hair cells restores hearing and inner ear circuitry in DFNB6 model mice. We conclude that hair cell function is crucial for the establishment of peripheral auditory circuitry. Treatment modalities for deafness thus need to consider restoration of the function of both hair cells and neurons, even when the primary defect occurs in hair cells. Deafness is the most common form of sensory impairment in humans and frequently caused by defects in hair cells of the inner ear. Here authors demonstrate that in a mouse model for recessive non-syndromic deafness (DFNB6), inactivation of Tmie in hair cells disrupts gene expression in the neurons that innervate them, suggesting treatment modalities for deafness may require restoration of the function of both hair cells and neurons. [ABSTRACT FROM AUTHOR]

Background: Corticosteroid therapy is commonly recommended for acute facial nerve weakness; however, its effectiveness in treating traumatic nerve injuries remains controversial. This study investigated the functional recovery and cellular effects of systemic dexamethasone administration after facial nerve injury. Methods: C57BL/6 mice were assigned to two groups by intraperitoneal injection: the phosphate‐buffered saline group and the dexamethasone group. Facial nerve crush injury was induced, followed by the functional grading of recovery. Cellular effects were investigated using transmission electron microscopy, flow cytometry, immunofluorescence, and intravital imaging. Results: Macrophage infiltration into the facial nerves was significantly inhibited by systemic dexamethasone administration. However, dexamethasone group slightly delayed the functional recovery of the facial nerve compared to the PBS group. In addition, the morphological changes in the nerve were not significantly different between the two groups at 14 days post‐injury. Macrophage migration analysis in the intravital imaging also showed no difference between groups. Conclusions: In summary, systemic dexamethasone successfully inhibited leukocyte infiltration; however, functional recovery was delayed compared to the PBS control group. Clinically, these findings indicate that more evidence and research are required to use steroid pulse therapy for the treatment of traumatic facial nerve injuries. [ABSTRACT FROM AUTHOR]

Background: Alport syndrome (AS) is a genetic disorder characterized by progressive renal disease, ocular abnormalities, and sensorineural hearing loss. However, the audiological profile of patients with AS remains elusive. Thus, this study aims to evaluate the natural history of auditory function in patients with AS. Methods: Exome or targeted sequencing for deafness genes was performed to confirm the pathogenic variants in patients with AS. Results: We identified fifteen individuals with AS who carried pathogenic variants of COL4A3, COL4A4, or COL4A5. Among fifteen, twelve (80%) showed hematuria, and six (40%) showed proteinuria. The patients exhibited bilateral sensorineural hearing loss, which was progressive and symmetric. The hearing thresholds increased according to age and plateaued at the level of 53 dB HL, indicating the hearing loss did not reach the severe-to-moderate level. The auditory dysfunction showed a distinct natural history depending on the inheritance pattern, but there was no remarkable difference between males and females among X-linked AS. Conclusions: Auditory dysfunction in AS is progressive up to the level of moderate hearing loss. Precise auditory rehabilitation for patients with AS is warranted depending on the inheritance pattern and genetic predisposition. [ABSTRACT FROM AUTHOR]

Purpose: Single-sided deafness (SSD) presents significant challenges for patients, including compromised sound localization, reduced speech recognition, and often, tinnitus. These issues are typically addressed using interventions such as cochlear implantation (CI) and bone conduction implant (BCI). However, evidence regarding the efficacy of BCI in reducing tinnitus in SSD patients remains limited. This study explored the ability of a novel active transcutaneous BCI (Bonebridge BCI602) to alleviate tinnitus in SSD patients. Study design: Prospective cohort multicenter study. Setting: Tertiary referral hospitals. Methods: A prospective multicenter study of 30 SSD patients was conducted. The patients were divided into two groups: those with (n = 19) and without (n = 11) tinnitus. Audiometric assessments, subjective questionnaires including the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Bern Benefit in Single-Sided Deafness (BBSS), and tinnitus evaluations with the Tinnitus Handicap Inventory (THI) and tinnitogram were conducted before and after BCI surgery. Results: THI scores after surgery were significantly reduced in SSD patients with tinnitus. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups; however, the former group exhibited a significantly greater improvement in the APHAB questionnaire score. According to tinnitograms, the loudness of tinnitus decreased, particularly in patients with ipsilateral tinnitus. Patients with residual hearing had greater reductions in their THI scores. However, three patients without residual hearing had a relative worsening of tinnitus after surgery. Conclusion: The Bonebridge BCI602 effectively reduced tinnitus in SSD patients, particularly in those with residual hearing. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups. These findings demonstrate the therapeutic potential of BCI for managing SSD and associated tinnitus. [ABSTRACT FROM AUTHOR]

Background: Mutations in Wolfram syndrome 1 (WFS1) cause Wolfram syndrome and autosomal dominant non-syndromic hearing loss DFNA6/14/38. To date, more than 300 pathogenic variants of WFS1 have been identified. Generally, the audiological phenotype of Wolfram syndrome or DFNA6/14/38 is characterized by low-frequency hearing loss; however, this phenotype is largely variable. Hence, there is a need to better understand the diversity in audiological and vestibular profiles associated with WFS1 variants, as this can have significant implications for diagnosis and management. This study aims to investigate the clinical characteristics, audiological phenotypes, and vestibular function in patients with DFNA6/14/38. Methods: Whole-exome or targeted deafness gene panel sequencing was performed to confirm the pathogenic variants in patients with genetic hearing loss. Results: We identified nine independent families with affected individuals who carried a heterozygous pathogenic variant of WFS1. The onset of hearing loss varied from the first to the fifth decade. On a pure-tone audiogram, hearing loss was symmetrical, and the severity ranged from mild to severe. Notably, either both low-frequency and high-frequency or all-frequency-specific hearing loss was observed. However, hearing loss was non-progressive in all types. In addition, vestibular impairment was identified in patients with DFNA6/14/38, indicating that impaired WFS1 may also affect the vestibular organs. Conclusions: Diverse audiological and vestibular profiles were observed in patients with pathogenic variants of WFS1. These findings highlight the importance of comprehensive audiological and vestibular assessments in patients with WFS1 mutations for accurate diagnosis and management. [ABSTRACT FROM AUTHOR]

KCNQ4 is a voltage-gated K+ channel was reported to distribute over the basolateral surface of type 1 vestibular hair cell and/or inner surface of calyx and heminode of the vestibular nerve connected to the type 1 vestibular hair cells of the inner ear. However, the precise localization of KCNQ4 is still controversial and little is known about the vestibular phenotypes caused by KCNQ4 dysfunction or the specific role of KCNQ4 in the vestibular organs. To investigate the role of KCNQ4 in the vestibular organ, 6-g hypergravity stimulation for 24 h, which represents excessive mechanical stimulation of the sensory epithelium, was applied to p.W277S Kcnq4 transgenic mice. KCNQ4 was detected on the inner surface of calyx of the vestibular afferent in transmission electron microscope images with immunogold labelling. Vestibular function decrease was more severe in the Kcnq4p.W277S/p.W277S mice than in the Kcnq4+/+ and Kcnq4+/p.W277S mice after the stimulation. The vestibular function loss was resulted from the loss of type 1 vestibular hair cells, which was possibly caused by increased depolarization duration. Retigabine, a KCNQ activator, prevented hypergravity-induced vestibular dysfunction and hair cell loss. Patients with KCNQ4 mutations also showed abnormal clinical vestibular function tests. These findings suggest that KCNQ4 plays an essential role in calyx and afferent of type 1 vestibular hair cell preserving vestibular function against excessive mechanical stimulation. [ABSTRACT FROM AUTHOR]

Background: The vestibular phenotypes of patients with genetic hearing loss are poorly understood. Methods: we performed genetic testing including exome sequencing and vestibular function tests to investigate vestibular phenotypes and functions in patients with genetic hearing loss. Results: Among 627 patients, 143 (22.8%) had vestibular symptoms. Genetic variations were confirmed in 45 (31.5%) of the 143 patients. Nineteen deafness genes were linked with vestibular symptoms; the most frequent genes in autosomal dominant and recessive individuals were COCH and SLC26A4, respectively. Vestibular symptoms were mostly of the vertigo type, recurrent, and persisted for hours in the genetically confirmed and unconfirmed groups. Decreased vestibular function in the caloric test, video head impulse test, cervical vestibular-evoked myogenic potential, and ocular vestibular-evoked myogenic potential was observed in 42.0%, 16.3%, 57.8%, and 85.0% of the patients, respectively. The caloric test revealed a significantly higher incidence of abnormal results in autosomal recessive individuals than in autosomal dominant individuals (p = 0.011). The genes, including SLC26A4, COCH, KCNQ4, MYH9, NLRP3, EYA4, MYO7A, MYO15A, and MYH9, were heterogeneously associated with abnormalities in the vestibular function test. Conclusions: In conclusion, diverse vestibular symptoms are commonly concomitant with genetic hearing loss and are easily overlooked. [ABSTRACT FROM AUTHOR]

Objective: To investigate the safety and efficacy of a novel active transcutaneous bone conduction implant (BCI) device for patients with single‐sided deafness (SSD). Study Design: Prospective cohort study. Setting: Tertiary referral hospitals. Methods: This prospective multicenter study was conducted at 15 institutions nationwide. Thirty adult (aged ≥19 years) SSD patients were recruited. They underwent implantation of an active transcutaneous BCI device (Bonebridge BCI602). Objective outcomes included aided pure‐tone thresholds, aided speech discrimination scores (SDSs), and the Hearing in Noise Test (HINT) and sound localization test results. The Bern Benefit in Single‐Sided Deafness (BBSS) questionnaire, the Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire, and the Tinnitus Handicap Inventory (THI) were used to measure subjective benefits. Results: The mean aided pure‐tone threshold was 34.2 (11.3), mean (SD), dB HL at 500 to 4000 Hz. The mean total BBSS score was 27.5 (13.8). All APHAB questionnaire domain scores showed significant improvements: ease of communication, 33.6 (23.2) versus 22.6 (21.3), P =.025; reverberation, 44.8 (16.6) versus 32.8 (15.9), P =.002; background noise, 55.5 (23.6) versus 35.2 (18.1), P <.001; and aversiveness, 36.7 (22.8) versus 25.8 (21.4), P =.028. Moreover, the THI scores were significantly reduced [47.4 (30.1) versus 31.1 (27.0), P =.003]. Congenital SSD was a significant factor of subjective benefit (−11.643; 95% confidence interval: −21.946 to −1.340). Conclusion: The BCI602 active transcutaneous BCI device can provide functional hearing gain without any adverse effects and is a feasible option for acquired SSD patients with long‐term deafness. [ABSTRACT FROM AUTHOR]

Suggested several decades ago, the nine-step test is an intuitive test of Eustachian tube function. However, studies employing the nine-step test to assess the results of Eustachian tube balloon dilation (EBD) are limited. We aimed to objectively evaluate the efficacy of EBD in opening failure patients with decreased maximal peak pressure difference (MPD) using the nine-step test. Patients who had MPD values ≤ 13 daPa in the nine-step test were enrolled. The patients were categorized into two groups according to treatment decisions after discussion with a clinician: an EBD group (N = 26) and a medication group (N = 30). One month after treatment, the seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ7) and the nine-step test were administered to all participants and subgroups of symptomatic participants (ETDQ7 > 15). MPD improved (increased) in both the EBD group and the medication group. ETDQ7 values improved (decreased) in the EBD group, but not in the medication group. In subgroup analysis, MPD and ETDQ7 values improved only in the symptomatic EBD group. According to the nine-step test, EBD can normalize 53.8% of decreased MPD. Posttreatment MPD and ETDQ7 scores were significantly better in the EBD group than in the medication group. However, EBD in patients with abnormal nine-step test results seemed less efficacious when the treatment results of the medication group were considered. [ABSTRACT FROM AUTHOR]

Genetic hearing loss is the most common hereditary sensorial disorder. Though more than 120 genes associated with deafness have been identified, unveiled causative genes and variants of diverse types of hearing loss remain. Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration. CEP250 encodes C-Nap1 protein belonging to the CEP protein family, comprising 30 proteins that play roles in centrosome aggregation and cell cycle progression. The nonsense variant in CEP250 led to the early truncating protein of C-Nap1, which hindered centrosome localization; heterologous expression of CEP250 (c.3511C>T) in NIH3T3 cells within cilia expression condition revealed that the truncating C-Nap1 (p.Gln1171Ter) was not localized at the centrosome but was dispersed in the cytosol. In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells. Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response. In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice. [ABSTRACT FROM AUTHOR]

Purpose: Facial nerve decompression surgery is performed on patients with immediate, complete traumatic facial palsy. However, the clinical advantage of the surgical treatment has weak evidence because of lack of control groups in previous studies. Therefore, this study compared facial function outcomes between the patients who underwent surgery and those who did not. Furthermore, in cases of bilateral traumatic facial palsy, the outcomes of the surgical and nonsurgical sides were also discussed. Methods: A retrospective medical chart review of immediate and severe (House–Brackman [HB] grade V and VI) traumatic facial palsy was conducted. Twenty-five ears from the surgical group and eight ears from the conservative treatment group were enrolled. Among the patients, three with immediate and severe bilateral facial palsy underwent unilateral surgery. Results: The average HB grade after 1-year follow-up was 1.7 in the surgical group and 1.5 in the nonsurgical group. Four patients who have definite facial canal disruption in the imaging study have recovered to HB grades I–III without surgical intervention. In patients with bilateral facial palsy, the nonsurgical side showed the same or better facial functions than the surgical side. Conclusions: Compared with nonsurgical conservative treatment, facial nerve decompression surgery did not show superior outcomes in immediate HB grade V–VI traumatic facial palsy. The clinical advantage of facial nerve decompression is questionable and should be re-evaluated in a prospectively designed study. [ABSTRACT FROM AUTHOR]

Intracellular accumulation of mutant proteins causes proteinopathies, which lack targeted therapies. Autosomal dominant hearing loss (DFNA67) is caused by frameshift mutations in OSBPL2. Here, we show that DFNA67 is a toxic proteinopathy. Mutant OSBPL2 accumulated intracellularly and bound to macroautophagy/autophagy proteins. Consequently, its accumulation led to defective endolysosomal homeostasis and impaired autophagy. Transgenic mice expressing mutant OSBPL2 exhibited hearing loss, but osbpl2 knockout mice or transgenic mice expressing wild-type OSBPL2 did not. Rapamycin decreased the accumulation of mutant OSBPL2 and partially rescued hearing loss in mice. Rapamycin also partially improved hearing loss and tinnitus in individuals with DFNA67. Our findings indicate that dysfunctional autophagy is caused by mutant proteins in DFNA67; hence, we recommend rapamycin for DFNA67 treatment. Abbreviations: ABR: auditory brainstem response; ACTB: actin beta; CTSD: cathepsin D; dB: decibel; DFNA67: deafness non-syndromic autosomal dominant 67; DPOAE: distortion product otoacoustic emission; fs: frameshift; GFP: green fluorescent protein; HsQ53R-TG: human p.Q53Rfs*100-transgenic: HEK 293: human embryonic kidney 293; HFD: high-fat diet; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NSHL: non-syndromic hearing loss; OHC: outer hair cells; OSBPL2: oxysterol binding protein-like 2; SEM: scanning electron microscopy; SGN: spiral ganglion neuron; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TG: transgenic; WES: whole-exome sequencing; YUHL: Yonsei University Hearing Loss; WT: wild-type. [ABSTRACT FROM AUTHOR]

Although the cleft palate is regarded as a contraindication for Eustachian tube ballooning, the presence of submucosal cleft palate may be overlooked while diagnosing Eustachian tube dysfunction. Therefore, we aimed to determine the incidence of the presence of a hard palate bony notch and vomer defect, which indicate the presence of submucosal cleft palate in patients with Eustachian tube dysfunction. In the Eustachian tube dysfunction group (n = 28), 4 patients (14.3%) exhibited a hard palate bony notch and a concurrent vomer defect. Three of them exhibited the presence of occult submucosal cleft palate, which had not been diagnosed previously. None of the control group (n = 39) showed any of these findings. The hard palate length of patients in the Eustachian tube dysfunction group was significantly lesser than that of those in the control group (34.2 ± 5.6 mm vs. 37.2 ± 2.1 mm, P = 0.016). Patients with Eustachian tube dysfunction have a high incidence of submucosal cleft palate and its occult variant, which are challenging to diagnose without any preexisting suspicion. Clinicians should evaluate the hard palate and vomer to exclude the presence of occult submucosal cleft palate while diagnosing Eustachian tube dysfunction. [ABSTRACT FROM AUTHOR]

Cochlea macrophages regulate cochlea inflammation and may harbors the potentials to protect hearing function from injury, including acoustic overstimulation. Cochlea macrophage numbers increase at 3–7 days after acoustic stimulation. However, the exact timing of macrophage infiltration and maturation from inflammatory monocytes is unclear. Furthermore, neutrophils may also be involved in this process. Therefore, in this study, we investigated time-dependent immune cell infiltration, macrophage transformation, and neutrophil involvement following acoustic stimulation. Flow cytometry and immunofluorescence were conducted in C-X3-C motif chemokine receptor 1 (CX3CR1)+/GFP mice after acoustic overstimulation (at baseline and at 1, 2, 3, and 5 days after exposure to 120 dB for 1 h) to identify inflammatory monocytes in the cochlea. RNA-sequencing and quantitative polymerase chain reaction were performed to identify differentially expressed genes. Inflammatory monocytes infiltrated into the lower portion of the lateral wall within 2 days after acoustic overstimulation (dpn), followed by transformation into macrophages at 3–5 dpn via CX3CR1 upregulation and Ly6C downregulation. In addition, inflammatory monocytes were aggregated inside the collecting venule only at 1 dpn. Neutrophils were not a major type of phagocyte during this response. The gene encoding C-C motif chemokine ligand 2 gene was significantly upregulated as early as 3 h after acoustic overstimulation. Given these results, treatment to control immune response after a noise-induced hearing loss should be applied as soon as possible. [ABSTRACT FROM AUTHOR]

Autosomal dominant hearing loss (ADHL) manifests as an adult-onset disease or a progressive disease. MYO7A variants are associated with DFNA11, a subtype of ADHL. Here, we examined the role and genotype–phenotype correlation of MYO7A in ADHL. Enrolled families suspected of having post-lingual sensorineural hearing loss were selected for exome sequencing. Mutational alleles in MYO7A were identified according to ACMG guidelines. Segregation analysis was performed to examine whether pathogenic variants segregated with affected status of families. All identified pathogenic variants were evaluated for a phenotype–genotype correlation. MYO7A variants were detected in 4.7% of post-lingual families, and 12 of 14 families were multiplex. Five potentially pathogenic missense variants were identified. Fourteen variants causing autosomal dominant deafness were clustered in motor and MyTH4 domains of MYO7A protein. Missense variants in the motor domain caused late onset of hearing loss with ascending tendency. A severe audiological phenotype was apparent in individuals carrying tail domain variants. We report two new pathogenic variants responsible for DFNA11 in the Korean ADHL population. Dominant pathogenic variants of MYO7A occur frequently in motor and MyTH4 domains. Audiological differences among individuals correspond to specific domains which contain the variants. Therefore, appropriate rehabilitation is needed, particularly for patients with late-onset familial hearing loss. [ABSTRACT FROM AUTHOR]

Ski-slope hearing loss (HL), which refers to increased auditory threshold at high frequencies, is common in adults. However, genetic contributions to this post-lingual HL remain largely unknown. Here, we prospectively investigated deafness-associated and novel candidate genes causing ski-slope HL. We analyzed 192 families with post-lingual HL via gene panel and/or exome sequencing. With an overall molecular diagnostic rate of 35.4% (68/192) in post-lingual HL, ski-slope HL showed a lower diagnostic rate (30.7%) compared with other conditions (40.7%). In patients who showed HL onset before the age of 40, genetic diagnostic probability was significantly lower for ski-slope HL than for other conditions. Further analysis of 51 genetically undiagnosed patients in the ski-slope HL group identified three variants in delta-like ligand 1 (DLL1), a Notch ligand, which presented in vitro gain-of-function effects on Notch downstream signaling. In conclusion, genetic diagnostic rates in post-lingual HL varied according to audiogram patterns with age-of-onset as a confounding factor. DLL1 was identified as a candidate gene causing ski-slope HL. [ABSTRACT FROM AUTHOR]

This phenotype–genotype study aimed to investigate the extent of audioprofile variability related to cochlin major domains and to identify potential ethnic-specific differences associated with COCH-related hearing loss. Eight Korean families (26 cases) were diagnosed with COCH-related hearing loss by exome sequencing. Audiometric test results were combined with those from nine published East Asian families (20 cases) and compared with those from 38 European-descent families (277 cases). Audioprofiles were created by grouping audiometric test results into age ranges by age at testing and then averaging hearing loss thresholds by frequency within age ranges. The functional impact of the identified variants was assessed in vitro by examining the intracellular trafficking, secretion, and cleavage of cochlin. In both East Asian and European-descent families segregating COCH-related hearing loss, deafness-associated variants in non-LCCL domains of cochlin were associated with hearing loss that was more severe earlier in life than hearing loss caused by variants in the LCCL domain. Consistent with this phenotypic difference, functional studies demonstrated distinct pathogenic mechanisms for COCH variants in a domain-dependent manner; specifically, a cytotoxic effect was observed for the p.Phe230Leu variant, which is located in the vWFA1 domain. No ethnic-specific differences in hearing loss progression were observed, except for those attributable to an overrepresentation of presymptomatic cases in the European-descent cohort. [ABSTRACT FROM AUTHOR]

This study investigated the relationship of tinnitus with mental health and health-related quality of life (QoL) in older people. Data source included 5,129 community-dwelling men and women ≥60 years old from the Korean National Health and Nutrition Examination Survey. Tinnitus was categorized into three groups: normal, tolerable tinnitus, and annoying tinnitus. Mental health and health-related QoL were assessed according to three dimensions (depressive mood, psychological distress, and suicidal ideation) and five domains (impaired mobility, impaired self-care, impaired usual activities, pain/discomfort, and anxiety/depression). The odds ratios (ORs) and 95% confidence intervals (CIs) of mental health and health-related QoL were calculated using multiple logistic regression analyses. Annoying tinnitus was positively and independently associated with deteriorated mental health and health-related QoL, suggesting comprehensive care is needed in older people with annoying tinnitus. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cell transplantation (HSCT) may dramatically alter the immunity of a recipient. Transient immunodeficiency that occurs before and after HSCT could be associated with the development of sudden sensorineural hearing loss (SSNHL), which is presumed to be often due to viral aetiology. We found an incidence of SSNHL of 29.4 per 10,000 person‐years in patients receiving HSCT, 12‐fold higher than reported for background population incidence. Development of SSNHL tended to cluster early after diagnosis of haematological malignancies, rather than around date of treatment with HSCT. Increased risk of unilateral SSNHL in patients with haematological malignancy may relate to underlying disease rather than treatment [ABSTRACT FROM AUTHOR]

To investigate the effect of choline alfoscerate (CA) on hearing amplification in patients with age related hearing loss, we performed a prospective case-control observational study from March 2016 to September 2020. We assessed patients with bilateral word recognition score (WRS) <50% using monosyllabic words. The patients were 65–85 years old, without any history of dementia, Alzheimer's disease, parkinsonism, or depression. After enrollment, all patients started using hearing aids (HA). The CA group received a daily dose of 800 mg CA for 11 months. We performed between-group comparisons of audiological data, including pure tone audiometry, WRS, HA fitting data obtained using real-ear measurement (REM), and the Abbreviated Profile of Hearing Aid benefit scores after treatment. After CA administration, the WRS improved significantly in the CA group (4.2 ± 8.3%), but deteriorated in the control group (−0.6 ± 8.1%, p = 0.035). However, there was no significant between-group difference in the change in pure tone thresholds and aided speech intelligibility index calculated from REM. These findings suggest that the difference in WRS was relevant to central speech understanding rather than peripheral audibility. Therefore, administering oral CA could effectively enrich listening comprehension in older HA users. [ABSTRACT FROM AUTHOR]

Introduction: Patients with postlingual deafness usually depend on visual information for communication, and their lipreading ability could influence cochlear implantation (CI) outcomes. However, it is unclear whether preoperative visual dependency in postlingual deafness positively or negatively affects auditory rehabilitation after CI. Herein, we investigated the influence of preoperative audiovisual per-ception on CI outcomes. Method: In this retrospective case-comparison study, 118 patients with postlingual deafness who underwent unilateral CI were enrolled. Evaluation of speech perception was performed under both audiovisual (AV) and audio-only (AO) conditions before and after CI. Before CI, the speech perception test was performed under hearing aid (HA)-assisted conditions. After CI, the speech perception test was performed under the CI-only condition. Only patients with a 10% or less preoperative AO speech perception score were included. Results: Multivariable regression analysis showed that age, gender, residual hearing, operation side, education level, and HA usage were not correlated with either postoperative AV (pAV) or AO (pAO) speech perception. However, duration of deafness showed a significant negative correlation with both pAO (p = 0.003) and pAV (p = 0.015) speech perceptions. Notably, the preoperative AV speech perception score was not correlated with pAO speech perception (R2 = 0.00134, p = 0.693) but was positively associated with pAV speech perception (R2 = 0.0731, p = 0.003). Conclusion: Preoperative dependency on audiovisual information may positively influence pAV speech perception in patients with postlingual deafness. [ABSTRACT FROM AUTHOR]

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Introduction: Fluctuating hearing loss is a distinctive feature caused by SLC26A4 variants. We investigated whether cochlear implantation had protective or deleterious effect on hearing fluctuation in patients with biallelic SLC26A4 variants.Methods: Patients with biallelic SLC26A4 variants (N = 16; age = 10.24 ± 9.20 years) who had unilateral cochlear implantation and consecutive postsurgical, bilateral pure-tone audiograms more than 3 times were selected. We retrospectively reviewed the patients' medical records from 2008 to 2019 obtained from a tertiary medical center and used the auditory threshold change (Shift) over time as a marker of hearing fluctuation. Fluctuation events were counted, and the Shift of the implanted and contralateral ears was compared using logistic regression with a generalized estimating equation and linear mixed model. A total of 178 values were included.Results: The odds of fluctuating hearing frequency were 11.185-fold higher in the unimplanted ears than in the implanted ears postoperatively (p = 0.001). The extent of fluctuation at 250 and 500 Hz was also significantly lower in the implanted ears than in the unimplanted ears after adjusting for every other effect (p = 0.003 and p < 0.001, respectively). Notably, higher residual hearing was rather associated with lesser fluctuation in frequency and the extent of fluctuation at 500 Hz, indicating residual hearing function is not the positive predictor for hearing fluctuation.Conclusion: In patients with biallelic SLC26A4 variants, cochlear implantation may reduce the frequency and extent of hearing fluctuations. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: To investigate the efficacy of direct implantation of a Vibrant Soundbridge (VSB) implant in the oval window (OW) without the use of an OW coupler in patients with severe mixed hearing loss. Study Design Retrospective chart review Methods: A total of 62 patients underwent VSB implantation between July 2016 and December 2018 at Severance Hospital in Seoul, South Korea. Among them, eight patients (nine ears) with moderate‐to‐severe mixed hearing loss were implanted with a VSB directly in the OW. A floating mass transducer (FMT) was attached to the stapes footplate and covered with tragal cartilage. The outcomes were evaluated using pure‐tone audiogram and speech audiogram preoperatively and postoperatively. Word recognition score (WRS; % correct) were measured at the most comfortable loudness (MCL) level to evaluate speech perception. Results: All cases posed difficulty with round window vibroplasty during surgery, and eventually, an FMT was appropriately placed in the OW without a coupler. Preoperative and postoperative bone conduction thresholds were not different. VSB‐aided threshold improved in terms of functional and effective gains. Interestingly, four cases showed improved air conduction thresholds without the use of a VSB. In addition, MCL level with a VSB was significantly lower than that with a hearing aid, and VSB‐aided WRS improved over time. Conclusions: Direct implantation of a VSB in the OW without the use of a coupler showed favorable hearing outcomes, and the OW vibroplasty was safe. Direct OW vibroplasty without a coupler is a reliable procedure and can be a good option for hearing rehabilitation in patients with severe mixed hearing loss. Level of Evidence: 4 Laryngoscope, 2020 [ABSTRACT FROM AUTHOR]

Objectives: The investigation of cochlear hair cells and lateral wall is a time‐consuming and labor‐intensive process. However, it is a mandatory experiment in audiology research. Here we suggest a novel method for investigating the inner ear microstructures from intact cochleae using two‐photon laser scanning microscopy (TPLSM). This technique guarantees fewer artifacts and technical simplicity. Methods: Using TPLSM, we investigated the whole mount cochleae, decalcified cochleae, and cleared cochleae of wild type C57BL/6 mice. CX3CR1+/GFP mice were used to investigate the feasibility of visualizing cellular structures in the cochlear spiral ligament. All samples were investigated without staining. Results: Endogenous fluorescence emission from the outer hair cells was strong enough to be distinguished from the other structures in all samples. From the single apical view, 50 and 90% of the whole hair cells of the decalcified cochleae and cleared cochleae, respectively, could be visualized without staining using TPLSM. Capillary structure of stria vascularis and spiral ligament could be visualized by endogenous fluorescence without staining. Conclusion: We successfully investigated the hair cells and lateral wall of mouse cochleae using TPLSM without using staining or any destructive procedures. This method is easier, faster, and more reliable than conventional methods. [ABSTRACT FROM AUTHOR]

Many anion channels, frequently referred as Cl− channels, are permeable to different anions in addition to Cl−. As the second-most abundant anion in the human body, HCO3− permeation via anion channels has many important physiological roles. In addition to its classical role as an intracellular pH regulator, HCO3− also controls the activity and stability of dissolved proteins in bodily fluids such as saliva, pancreatic juice, intestinal fluid, and airway surface liquid. Moreover, HCO3− permeation through these channels affects membrane potentials that are the driving forces for transmembrane transport of solutes and water in epithelia and affect neuronal excitability in nervous tissue. Consequently, aberrant HCO3− transport via anion channels causes a number of human diseases in respiratory, gastrointestinal, genitourinary, and neuronal systems. Notably, recent studies have shown that the HCO3− permeabilities of several anion channels are not fixed and can be altered by cellular stimuli, findings which may have both physiological and pathophysiological significance. In this review, we summarize recent progress in understanding the molecular mechanisms and the physiological roles of HCO3− permeation through anion channels. We hope that the present discussions can stimulate further research into this very important topic, which will provide the basis for human disorders associated with aberrant HCO3− transport. [ABSTRACT FROM AUTHOR]

The article discusses a study to examine predictive factors for the rehabilitation of patients with unilateral deafness, including single¿sided deafness (SSD) and asymmetric hearing loss (AHL) through bone¿anchored hearing implants (BAHI) implantation. Topics discussed include the audiological performance of pBAHIs, transcutaneous BAHIs (tBAHIs) without percutaneous abutments and subjective satisfaction in CROS¿tBAHI.

Objectives/hypothesis: To identify the clinical characteristics of patients with bilateral Meniere's disease (MD) in an Asian population.Study Design: Cross-sectional retrospective study.Methods: We compared the clinical features of bilateral MD (BMD) and unilateral MD (UMD) in 320 Asian patients with single ethnicity. Demographic variables; age of onset; inner ear function; the coexistence of related disorders such as vestibular migraine, delayed MD, systemic autoimmune diseases, and familial MD; and prognoses were analyzed and compared.Results: The overall prevalence of BMD was 5.6%. The mean age of disease onset was 40.3 ± 14.8 and 47.0 ± 14.1 years for patients with BMD and UMD, respectively (P = .07). Demographic variables were not significantly different between patients with BMD and UMD (P > .05). Inner ear function, evaluated by hearing thresholds, caloric tests, and cervical vestibular evoked myogenic potentials, was significantly more deteriorated in the first involved ear of patients with BMD than in the second involved ear or the affected side of patients with UMD (P < .05). Among the comorbid conditions, only the prevalence of delayed MD was significantly higher in patients with BMD than in patients with UMD. Systemic autoimmune disease was found in only three patients with UMD. There was no significant prognostic difference between patients with UMD and BMD (P > .05).Conclusions: A low prevalence of BMD, a higher frequency of delayed MD in BMD patients, and a low frequency of systemic autoimmune diseases in both UMD and BMD patients are significant findings in an Asian population.Level Of Evidence: 4 Laryngoscope, 129:1191-1196, 2019. [ABSTRACT FROM AUTHOR]

Mutations in potassium voltage‐gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to nonsyndromic hearing loss (NSHL), deafness nonsyndromic autosomal dominant 2 (DFNA2). To identify causative mutations of hearing loss in 98 Korean families, we performed whole exome sequencing. In four independent families with NSHL, we identified a cosegregating heterozygous missense mutation, c.140T>C (p.Leu47Pro), in KCNQ4. Individuals with the c.140T>C KCNQ4 mutation shared a haplotype flanking the mutated nucleotide, suggesting that this mutation may have arisen from a common ancestor in Korea. The mutant KCNQ4 protein could reach the plasma membrane and interact with wild‐type (WT) KCNQ4, excluding a trafficking defect; however, it exhibited significantly decreased voltage‐gated potassium channel activity and fast deactivation kinetics compared with WT KCNQ4. In addition, when co‐expressed with WT KCNQ4, mutant KCNQ4 protein exerted a dominant‐negative effect. Interestingly, the channel activity of the p.Leu47Pro KCNQ4 protein was rescued by the KCNQ activators MaxiPost and zinc pyrithione. The c.140T>C (p.Leu47Pro) mutation in KCNQ4 causes progressive NSHL; however, the defective channel activity of the mutant protein can be rescued using channel activators. Hence, in individuals with the c.140T>C mutation, NSHL is potentially treatable, or its progression may be delayed by KCNQ activators. KQNQ4 is a voltage‐gated potassium channel and essential for outer hair cell function in the inner ear. Its mutations lead to nonsyndromic hearing loss. In this study, we identified a recurrent mutation c.140T>C (p.Leu47Pro) in KCNQ4 from four Korean families with hearing loss. The resulting mutant protein p.Leu47Pro exhibited reduced potassium channel activity; however, this defective channel activity was rescued by KCNQ activators, suggesting the possibility of medical intervention for hearing loss resulting from c.140T>C (p.Leu47Pro) KCNQ4 mutation. [ABSTRACT FROM AUTHOR]

Background: Anoctamin (ANO)/transmembrane member 16 (TMEM16) proteins mediate diverse physiological and pathophysiological functions including cancer cell proliferation. The present study aimed to identify the role of ANOs in pancreatic cancer.Methods: In an initial screen of ANOs, ANO9/TMEM16J was overexpressed in pancreatic cancer cells, and its role in the pathogenesis of pancreatic cancer was evaluated using an integrated in vitro and in vivo approach. To determine clinical relevance of the experimental findings, the prognostic value of ANO9 was evaluated in patients with pancreatic cancer.Results: The ANO9 mRNA and protein levels were increased in pancreatic cancer-derived cells. Exogenous expression of ANO9 in PANC-1 cells significantly increased cell proliferation in cell cultures and in mice. In contrast, knockdown of ANO9 in AsPC-1, BxPC-3, and Capan-2 cells strongly inhibited cell proliferation. Mechanistic analysis suggested that physical association of ANO9 with epidermal growth factor receptor (EGFR) underlies ANO9-induced cell proliferation. Knockdown of ANO9 augmented the effects of the EGFR inhibitor and the cytotoxic agent on pancreatic cancer cell proliferation. In addition, high ANO9 expression is a poor prognostic factor in patients with pancreatic cancer.Conclusions: The ANO9/TMEM16J appears to be a clinically useful prognostic marker for pancreatic cancer and a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: We compared the audiologic benefits of active middle ear implants with those of passive middle ear implants with hearing aids in mixed hearing loss, and also compared the outcomes of stapes vibroplasty with those of round window vibroplasty.Study Design: Retrospective chart review.Methods: Thirty-four patients with mixed hearing loss due to chronic otitis media were treated with a middle ear implant. Of these, 15 were treated with a passive middle ear implant (conventional ossiculoplasty with a partial ossicular replacement prosthesis), nine with an active middle ear implant coupling to the stapes, and 10 with an active middle ear implant coupling to the round window. Patients underwent pure-tone/free-field audiograms and speech discrimination tests before surgery and 6 months after surgery, and the results of these tests were compared.Results: The active middle ear implant resulted in better outcomes than the passive middle ear implant with hearing aids at mid to high frequencies (P < .05). Patients who received either a stapes vibroplasty or a round window vibroplasty showed comparable hearing gain except at 8,000 Hz (48.9 dB vs. 31.0 dB, P < .05). Patients who received a stapes vibroplasty showed an improvement even in bone conduction at 1,000 Hz and 2,000 Hz (both P < .05).Conclusions: Active middle ear implantation could be a better option than treatment with passive middle ear implants with hearing aids for achieving rehabilitation in patients with mixed hearing loss. Vibroplasty via either oval window or round window stimulation shares similar good results.Level Of Evidence: 4 Laryngoscope, 127:1435-1441, 2017. [ABSTRACT FROM AUTHOR]

Objective: We performed the video head impulse test (vHIT) and caloric test in patients with enlarged vestibular aqueducts (EVA). We compared the results with those found in Ménière's disease (MD) and acute vestibular neuritis to clarify the characteristics of vestibular dysfunction in EVA and to suggest reasons for the discrepancy between the vHIT and caloric tests in endolymphatic hydrops.Study Design: Retrospective analysis.Methods: Ten patients with EVA and confirmed biallelic SLC26A4 genetic mutations were enrolled. The results of video head impulse and caloric tests were analyzed and compared with those of patients diagnosed with MD (n = 76) or acute vestibular neuritis (n = 19).Results: Among patients with EVA, 40% showed unilateral caloric weakness and 30% had recurrent episodes of vertigo. All patients with recurrent vertigo had caloric weakness. However, only 25% of patients with abnormal caloric test results had abnormal vHIT results. The discrepancy between the caloric test and vHIT results was also found in patients with MD, but not in patients with acute vestibular neuritis (abnormal vHIT results in 47.3% and 94.7% of patients with unilateral caloric weakness, respectively).Conclusion: Unilateral vestibular dysfunction was identified in 40% of patients with EVA by the caloric test, but caloric test results were not correlated with vHIT results. This finding was similar in patients with MD. Hence, it is possible that endolymphatic hydrops, a common pathologic feature of both EVA and MD, could cause the discrepancy, and that vestibulopathy in endolymphatic hydrops might be restricted to the low-frequency range.Level Of Evidence: 4. Laryngoscope, 127:921-926, 2017. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: The purpose of this study was to evaluate the audiologic limitations of the Vibrant Soundbridge (VSB) implant and the benefits of contralateral hearing aid (HA) fitting in VSB recipients.Study Design: Retrospective study.Methods: Twenty-three patients with symmetrical sensorineural or mixed hearing loss were enrolled in this study. The patients underwent VSB implantation in one ear and HA fitting in the other. Aided pure-tone audiometry was performed to measure the functional gains of each device. The Korean version of the Hearing in Noise Test (K-HINT) was used to determine the sentence speech perception in a quiet environment and the signal-to-noise ratio (SNR) in a noisy environment.Results: VSB implantation resulted in hearing gains comparable to that of conventional HAs at high frequencies, whereas the functional gains at low frequencies were not satisfactory in the mixed hearing loss group. In these patients, the contralateral HA sufficiently amplified the low frequencies. The results of the K-HINT of the SNR in the VSB-aided ear were not significantly improved when compared to HA-aided contralateral ear. However, binaural fitting of a VSB and HA resulted in substantially improved SNR when compared to the unaided condition. This improvement of the SNR strongly correlated with functional gains at low frequencies in the contralateral HA-aided ear.Conclusions: Although unilateral VSB implantation is limited in terms of low-tone enhancement and speech perception in noisy environments, contralateral HA fitting can overcome these limitations and increase the efficacy of hearing rehabilitation.Level Of Evidence: 4 Laryngoscope, 126:2116-2123, 2016. [ABSTRACT FROM AUTHOR]

Key points Cellular stimuli can modulate the ion selectivity of some anion channels, such as CFTR, ANO1 and the glycine receptor (GlyR), by changing pore size., Ion selectivity of CFTR, ANO1 and GlyR is critically affected by the electric permittivity and diameter of the channel pore., Pore size change affects the energy barriers of ion dehydration as well as that of size-exclusion of anion permeation., Pore dilatation increases the bicarbonate permeability ( [ABSTRACT FROM AUTHOR]

ABSTRACT DFNA9 is an autosomal dominant disorder characterized by late-onset, non-syndromic hearing loss, and vestibular dysfunction. Mutations in the COCH (coagulation factor C homology) gene encoding cochlin are etiologically linked to DFNA9. Previous studies have shown that cochlin is cleaved by aggrecanase-1 during inflammation in the spleen and that the cleaved LCCL domain functions as an innate immune mediator. However, the physiological role of cochlin in the inner ear is not completely understood. Here, we report that cochlins containing DFNA9-linked mutations (p.P51S, p.V66G, p.G88E, p.I109T, p.W117R, p.V123E, and p.C162Y) demonstrate reduced cleavage by aggrecanase. Notably, in families affected with DFNA9, we found a novel COCH mutation causing p.V123E substitution in cochlin, which significantly reduced protein susceptibility to cleavage by aggrecanase (to about 20.5% of the wild-type). These results suggest that the impaired post-translational cleavage of cochlin mutants may be associated with pathological mechanisms underlying DFNA9-related sensorineural hearing loss. [ABSTRACT FROM AUTHOR]