Given the inconsistent evidence regarding hearing aid use and reduced dementia risk, this study evaluates whether hearing aid use, particularly effective use, is associated with lower probable dementia risk among hearing-impaired older adults. Using harmonized longitudinal data from 61,089 hearing-impaired participants (aged 55+ years) from seven cohorts (CHARLS, KLOSA, SHARE, ELSA, TILDA, HRS, and MHAS), we employ IPTW-corrected Cox models stratified by country income. Over a 6.5-year average follow-up (8,911 events), hearing aid use is associated with reduced dementia risk (hazard ratio [HR] = 0.91, 95% confidence interval [CI] 0.88-0.94). This association is confined to participants reporting effective hearing improvement (HR = 0.86, 95% CI 0.80-0.93), whereas those reporting poor hearing improvement show no reduced risk (HR = 0.98, 95% CI 0.90-1.07). The association is stronger in middle-income countries (HR = 0.76) and among subgroup populations, including those aged <70 years, women, those who are unmarried, and those with lower education. Quality hearing rehabilitation is a potential public health priority for addressing the dementia burden.

Damage to cochlear spiral ganglion neurons (SGNs) causes irreversible sensorineural hearing loss (SNHL), yet the underlying degenerative mechanisms remain elusive, impeding targeted therapies. Here, we established an auditory neuropathy model using the ototoxic drug ouabain to induce selective SGN injury. Transcriptomic profiling revealed a ferroptosis-linked gene signature, with functional assays confirming ferroptotic damage in SGNs. Pharmacological inhibition of ferroptosis mitigated SGN loss and hearing impairment. Lipidomics demonstrated dysregulated fatty acid metabolism with an elevated saturated-to-monounsaturated fatty acid ratio, accompanied by downregulation of stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme for monounsaturated fatty acid synthesis. Restoring SCD1 activity through SCD1 overexpression or monounsaturated fatty acid supplementation mitigated ouabain-induced ferroptosis in SGN and preserved auditory function, whereas genetic ablation of SCD1 aggravated degeneration. Bioinformatic screening and chromatin immunoprecipitation-PCR identified microphthalmia-associated transcription factor (MITF) as a direct upstream transcriptional regulator of SCD1. MITF overexpression restored SCD1 expression, suppressed ferroptosis, and improved SGN survival, while disruption of the MITF-SCD1 axis abrogated these protective effects, which were further validated in a cisplatin ototoxicity model. Collectively, these findings reveal a MITF-SCD1 lipid metabolic axis that safeguards SGNs against ferroptosis by sustaining SCD1-dependent lipid desaturation, highlighting a promising therapeutic target for SNHL.

OBJECTIVES:Listening effort and listening-related fatigue are clinically important yet rarely assessed in routine audiology. This study culturally adapted the Effort Assessment Scale (EAS) into Chinese and psychometrically evaluated the Chinese EAS (C-EAS) and the 10-item Vanderbilt Fatigue Scale for Adults-10 (C-VFS-A-10) in Chinese-speaking adults. Associations with better-ear pure-tone average (PTA), tinnitus, and key demographic factors were also examined. DESIGN:A two-phase study was conducted. Phase 1 followed established guidelines to translate and culturally adapt the EAS. Phase 2 was a cross-sectional validation in 701 adults recruited from a tertiary hospital in China (normal hearing, n = 180; unilateral hearing loss, n = 22; bilateral hearing loss, n = 499). A subsample of 85 participants with hearing loss completed repeat testing over 7 to 21 days to assess test-retest reliability. All participants completed the C-EAS, C-VFS-A-10, the Hearing Handicap Inventory for the Elderly/Adults-Screening version (HHIE/A-S), and pure-tone audiometry. Psychometric evaluation included internal consistency, test-retest reliability, factor analyses, convergent validity with PTA and HHIE/A-S, and item response theory (IRT) modeling, alongside ANCOVA and multivariable regression. RESULTS:Both scales showed excellent internal consistency and high short-interval stability. Scale-specific confirmatory factor analyses supported essential unidimensionality adequate for total-score use. Convergent validity was supported by moderate associations with better-ear PTA and HHIE/A-S ( ρ = 0.47 to 0.63). Item-level diagnostics indicated localized local dependence for both instruments. For the C-EAS, item-level IRT parameter estimates were unstable under local dependence, supporting the use of summed total scores. For the C-VFS-A-10, a graded-response testlet model produced stable item parameters and high measurement precision across the range where most respondents fell. Scores on both measures increased with hearing-loss severity. In multivariable models, higher better-ear PTA and tinnitus independently predicted higher effort and fatigue scores, while age showed a small additional association with effort only. CONCLUSIONS:The C-EAS and C-VFS-A-10 are reliable, culturally adapted measures of listening effort and listening-related fatigue for Chinese-speaking adults. Associations with better-ear PTA and tinnitus support clinical relevance.

Hearing loss is a widespread global disability, commonly treated using dexamethasone (Dex). However, targeted delivery of Dex to the inner ear remains a significant challenge due to the blood-perilymph barrier (BLB), which limits its therapeutic efficacy. In this study, we aimed to develop a strategy to enhance Dex delivery to the inner ear and improve its treatment outcome by the noninvasive intranasal approach. Also, poly(ethylene glycol) (PEG)─liposomal nanoparticles were used as a drug carrier and loaded with Dex (PLN-Dex). For intranasal delivery, a thermosensitive hydrogel was fabricated by methylcellulose. The PLN-Dex nanocomposite was incorporated into the hydrogel to obtain PLN-Dex@Gel. PLN-Dex@Gel could be administrated intranasally and their transport pathway from olfactory mucosa to the cochlea was explored. In vivo magnetic resonance and fluorescence microscopy showed that drugs delivery into the olfactory mucosa reached the inner ear by dispersive transport via the brain. Interestingly, we found that beyond the cochlear duct, the cochlear axis may serve as a crucial pathway for the transportation of drugs from the brain to the inner ear. In guinea pig models of LPS-induced and noise-induced hearing loss, intranasal PLN-Dex@Gel treatment significantly reduced auditory brainstem response thresholds, ameliorated cochlear blood flow, and protected hair cells and synapses. Our findings underscore the potential of intranasal Dex delivery as a noninvasive and effective strategy for treating hearing loss. The target drug delivery to the inner ear, combined with the enhanced formulation of Dex-loaded liposomal hydrogels, offers promising prospects for future research in the treatment of inner ear disorders, with potential for clinical translation. This study expands the understanding of delivery route from nose to inner ear and suggests a method for utilizing intranasal administration as a strategy for treating hearing loss.

OBJECTIVE:To evaluate clinical features of unilateral sudden sensorineural hearing loss (SSNHL) in patients with autoimmune disease and identify factors influencing the prognosis of such patients. STUDY DESIGN:Retrospective, case-control study. SETTING:A single tertiary referral center. METHODS:Patients diagnosed with both unilateral SSNHL and autoimmune disease (n = 46) who were hospitalized between January 2018 and October 2023 were included in the autoimmune disease group. A control group propensity score matched for sex, age, and initial pure-tone average (n = 183) comprised hospitalized patients with unilateral SSNHL but without autoimmune disease. The two groups were compared regarding clinical symptoms, audiological evaluations, vestibular function assessments, laboratory blood test results, and hearing outcomes. Prognostic factors were analyzed using binary logistic regression. RESULTS:Autoimmune disease and non-autoimmune disease groups differed significantly in terms of the monocyte-to-lymphocyte ratio, total bilirubin, and indirect bilirubin (P < .05) levels. Univariate analysis identified significant associations between hearing prognosis and the time from disease onset to treatment and final pure-tone average, monocyte-to-lymphocyte ratio, indirect bilirubin, and high-density lipoprotein levels (P < .05). Multivariate analysis further confirmed that time from disease onset to treatment and monocyte-to-lymphocyte ratio and indirect bilirubin levels were independent prognostic predictors in the autoimmune disease group. CONCLUSION:Patients with unilateral SSNHL with autoimmune disease exhibited elevated levels of monocyte-to-lymphocyte ratio and reduced total bilirubin and indirect bilirubin levels as compared with those without autoimmune disease. Time from disease onset to treatment, monocyte-to-lymphocyte ratio, and indirect bilirubin levels were strongly associated with prognosis in this patient population.

Melanocytes are important components of the inner-ear cellular architecture. However, limited morphological research hinders our understanding of inner-ear function. Here, we characterize the morphology of inner-ear melanocytes and cells often misidentified as melanocytes. Immunofluorescence, smart-seq, transmission/field emission scanning electron microscopy, and immunoelectron microscopy are used. Cells previously referred to as “perivascular macrophage-like melanocytes” are not observed in the stria vascularis and are actually macrophages; along with melanocytes, they constitute intermediate cells. Cells with a “black ball” appearance in the vestibule are identified as macrophages. We examine variation in melanocytes or macrophages with age, strain, and cisplatin injury. Kir4.1 expression and the greater noise resistance observed in pigmented mice suggest melanocyte functions. Based on melanin distribution in Pou3f4y/- mice, we hypothesize that melanocytes migrate from the modiolus along Reissner’s membrane area to the stria vascularis, following a base-to-apex gradient. These findings provide novel ultrastructural and immunological insights into inner-ear function. Electron microscopy and single-cell RNA sequencing analysis help distinguish melanocytes and macrophages in the inner ear, which are often misidentified.

Ménière's disease (MD), a chronic inflammatory disorder with age-related increased incidence, exhibits poorly understood pathogenesis and limited therapeutic options. Here, we demonstrate that cellular senescence, marked by mitochondrial damage, reactive oxygen species accumulation, and senescence-associated secretory phenotype (SASP), is prevalent in the vestibular tissue of MD patients and an endolymphatic hydrops mouse model. The transcription factor GATA4 is upregulated in MD and mice, and its genetic deletion in hair cells alleviates LPS-induced audio-vestibular dysfunction and cellular senescence in mice and HEI-OC1 cells. Mechanistically, HDAC6 interacts with GATA4 and restrains its nuclear transport, while RNA-seq and ChIP-seq identify HtrA1, a serine protease, as a direct transcriptional target of GATA4. Inhibition of HDAC6 or AAV-mediated HtrA1 overexpression exacerbates MD-like symptoms, whereas inhibition of HtrA1 by Galegenimab ameliorates these phenotypes in mice. In aged mice, GATA4 deletion reduces age-related audio-vestibular deficits and senescence markers. Collectively, our findings establish GATA4 as a critical regulator of cellular senescence and inflammaging in inner ear pathologies, providing promising therapeutic targets for MD and age-related audio-vestibular disorders.

BACKGROUND:Sensorineural hearing loss is the most common sensory disorder, and more than 50% of congenital cases are genetic. For decades, clinical management has relied largely on prosthetic devices such as hearing aids and cochlear implants, which improve audibility but do not restore native cochlear biology. AIMS:To review how advanced biological therapies-especially inner-ear gene therapy-have evolved from animal proof-of-concept to first-in-human trials. To summarize the progression of therapeutic strategies (gene replacement, antisense oligonucleotides, genome/RNA editing) and the technological hurdles that had to be cleared. MATERIAL AND METHODS:We surveyed preclinical studies in rodents and non-human primates and analyzed advances in delivery vectors high-efficiency AAVs for various inner-ear cell types, and surgical administration routes validated in adult and primate models. We also review published clinical data from AAV-mediated OTOF gene therapy trials. RESULTS:Highly efficient viral vectors can now transduce multiple cell types in the cochlea. Safe, increasingly standardized surgical routes have been established in the primate inner ears. Novel platforms for dominant mutations and oversized genes are maturing. Critically, AAV-OTOF gene therapy has restored hearing in congenitally deaf children with DFNB9. CONCLUSIONS AND SIGNIFICANCE:Inner-ear gene therapy has moved from an experimental concept to a clinically validated treatment. AAV-OTOF success opens the door to extending gene therapy to a broad spectrum of auditory and vestibular disorders, heralding a new era of restorative medicine for deafness.

To explore associations of vestibular disorders with all‐cause and cause‐specific dementia and underlying biological mechanisms/neuroimaging changes. A population‐based cohort study of 406,348 UK Biobank participants was conducted. Inverse probability of treatment weighting (IPTW) balanced baseline covariates, and Cox proportional hazards models estimated hazard ratios (HRs) for dementia outcomes. Inflammatory markers, plasma metabolites, and brain structure changes were analyzed. During 13.9 (SD 2.1) years of follow‐up, 6702 dementia cases occurred. Vestibular disorders were linked to higher risks of all‐cause dementia (HR 1.86 and 95% CI 1.04–3.30), Alzheimer's disease (AD, 2.36, and 1.01–5.51), and vascular dementia (VD, 3.35, and 1.48–7.59). Eight metabolites (e.g., VLDL cholesterol, and histidine) mediated the vestibular disorder‐dementia association. Vestibular disorders also correlated with alterations in dementia‐related brain structures (cortex, subcortical regions, and white matter tracts). Vestibular disorders increase all‐cause and cause‐specific dementia risk. This modifiable factor should be incorporated into dementia prevention initiatives.

Background Genetic diagnosis plays a critical role in enhancing the identification and clinical management of pediatric hearing loss, ultimately improving both physiological outcomes and social-emotional development. As one of the most prevalent sensory disorders characterized by substantial genetic heterogeneity, hearing loss requires the implementation of efficient diagnostic approaches to inform targeted clinical interventions and personalized care strategies. Methods Here, we recruited 3353 Han Chinese children with nonsyndromic hearing loss, including 598 multiplex cases with family history. We employed SNPscan, targeted panel sequencing (TPS), and whole-exome sequencing (WES) to delineate the mutation landscape. Findings Utilizing a tiered genomic testing strategy, we performed SNPscan for all 3353 participants, TPS for 675 cases, and WES for 204 multiplex cases. We achieved an overall diagnostic yield of 48.3% (1620/3353) in this cohort. Our analysis identified 87 previously unreported variants across 24 genes, including a de novo FOXI1 mutation (c.479_481del) linked to Mondini malformation and enlarged vestibular aqueduct, validated through knock-in mouse models. Additionally, we discovered NEU4 as a candidate gene related to hearing loss, with knockout mice and cellular models demonstrating its role in auditory dysfunction via disrupted neuraminidase activity and axonal development. These findings enrich the spectrum of deafness-related genes and provide a new theoretical foundation for diagnosing hearing loss. Interpretation This study not only expands the genetic spectrum of hearing loss but also underscores the clinical utility of advanced sequencing in guiding precision therapies and early syndromic surveillance. This study offers a detailed characterization of the genetic landscape of pathogenic variants associated with hearing loss in the Han Chinese population, which will contribute to the design of a cost-effective genetic screening scheme, and also provides valuable insights that contribute to the global understanding of the genetics of hearing loss. Funding This work was supported by the Key Program of National Natural Science Foundation of China, the National Key Research and Development Program of China, the National Natural Science Foundation of China and the Major Fundamental Research Program of the Natural Science Foundation of Shandong Province, China.

Background The relationship between cognitive function and hip fracture risk among middle-aged and older adults in China remains unclear, with limited longitudinal evidence. Objective To investigate the association between cognitive function and hip fracture risk among Chinese middle-aged and elderly adults. Study design Prospective longitudinal study. Methods We analyzed 8257 participants (aged ≥45) from China Health and Retirement Longitudinal Study (CHARLS). The present analysis used Wave 3 (2015) as the study entry and followed participants through Wave 5 (2020). Cognitive function was assessed across four domains: orientation, memory, calculation and drawing. All cognitive z-scores were standardized to the metrics of Wave 3. The calculation formula involved subtracting the Wave 3 average score from each participant’s test score per wave, followed by division using the Wave 3 standard deviation. Hip fracture status served as the outcome measure. Potential confounding effects stemming from demographic attributes and other covariates were controlled for during the analysis. Longitudinal logistic regression was used to analyze the relationship between the cognitive z-scores and their dimensions and hip fracture incidence at two follow-up surveys. Results Participants (mean age 56.62 ± 8.92 years; 53.8% male) were followed for up to 5 years. Each standard deviation decrease in global cognitive z-scores was associated with increased hip fracture risk at Wave 4 (odds ratio [OR] = 0.71, 95% CI:0.57–0.89) and Wave 5 (OR = 0.72, 95% CI:0.58–0.87). Decline in orientation demonstrated consistent associations (Wave 4: OR = 0.82, 95% CI:0.70–0.96; Wave 5: OR = 0.82, 95% CI:0.68–0.99). Declines in calculation were associated with hip fracture at Wave 4 only, while declines in memory and drawing showed such an association only at Wave 5. Conclusion Independent associations exist between impaired global cognitive function, weakened orientation and increased hip fracture risk in this Chinese middle-aged and older population. These findings highlight the need to integrate cognitive assessments with fracture risk evaluations.

Background/Objectives: The study was aiming to determine the test-retest repeatability of DEX or CH as single sedative agents on ABR indices by analyzing data from initial test and retest. We also preliminarily explored the correlation between sleep deprivation and onset time of sedation in group DEX and group CH, respectively. Methods: We collected data from two groups of children sedated with either DEX (n = 20, 40 ears) or CH (n = 20, 40 ears). Paired- samples t-tests and Bland-Altman plots were used to evaluate repeatability between the initial test and retest. Pearson correlation analysis was used to measure the relationship between the average onset time of sedation and the average duration of sleep deprivation in both groups. Results: Within each sedative group, no significant differences were observed in ABR indices between the initial test and retest. Additionally, in group DEX, the mean onset time was 12.15 ± 4.40 min and the mean sleep deprivation duration was 442.80 ± 85.91 min, with no correlation between them (r = 0.01, p = 0.96). In group CH, the mean onset time was 27.55 ± 15.70 min and the mean sleep deprivation duration was 455.10 ± 90.94 min, showing a significant negative correlation (r = -0.97, p = 0.00). Conclusions: ABR indices exhibited high repeatability when DEX and CH were used as a sedative in pediatric ABR examinations. The choice of sedative agent in clinical practice should be individualized, taking into account institutional protocols and clinical requirements.

Importance: Evidence regarding the diagnosis of patulous Eustachian tube (PET) remains a challenge. This study employed compliance-over-time (COT) testing with different breathing patterns to reflect tympanic membrane (TM) “respiration” and its oscillatory movement, which is beneficial for the development of diagnostics of PET. Objective: To summarize the clinical characteristics of patients with PET and to assess the diagnostic efficiency of COT testing under single breathing patterns and the COT protocol. Design: Retrospective observational study. Setting: Clinical audiology center in a tertiary-care hospital, December 2018 to October 2024. Participants: One hundred thirty-eight PET patients (189 ears) and 102 healthy controls (204 ears). Exposures: Data were collected on clinical symptoms, pure-tone audiometry, tympanometry, otoscopy, and COT testing. Main Outcome Measures: Positivity rates of otoscopic, COT under the protocol, and COTs under single breathing patterns were compared. Agreements between COT under the protocol and COTs under single breathing patterns were examined. Results: Clinical characteristics of PET included autophony (86.8%), fullness (82.0%), aerophony (91.0%), and symptomatic alleviation after posture changing (76.2%) or sniffing (66.1%). Respiratory fluctuation of the TM was observed in 55.0% of PET ears. 96.3% of PET ears had a positive response in the COT protocol. Among COTs under different breathing tasks, COT under ipsilateral nostril deep breathing exhibited the highest diagnostic accuracy, closely mirroring the sensitivity and specificity of the COT protocol. Conclusion: The COT protocol is a practical and reliable test with high sensitivity and specificity for diagnosing PET in routine clinical settings. Additionally, COT under ipsilateral nostril deep breathing is expected to be a rapid screening method for diagnosing PET. Relevance: The investigated approach holds potential to improve diagnostic efficiency. It may expand diagnostic options for patients with PET.

Noise exposure is a known cause of hearing loss, and only a few effective preventive drugs are available. Therefore, in this study, we aimed to investigate the protective effects of brimonidine on noise-induced inner ear hearing impairment in mice and explore its underlying mechanisms and long-term outcomes. Mice were randomly divided into control, noise exposure, and brimonidine groups. A 62-week follow-up was conducted after noise exposure. Brimonidine inhibited the noise-induced increase in inner ear glutamate concentration and downregulated inflammatory factors and immunoglobulins. Brimonidine decreased glutaminase and VGLUT2/3 expression and reduced glutamate synthesis and vesicle transport without affecting its clearance, thereby decreasing glutamate excitotoxicity and protecting synapses and spiral ganglion neurons long term. Mice exposed to noise could temporarily restore their hearing thresholds; however, their auditory function in old age remained significantly worse than those that received brimonidine-mediated cochlear protection in youth. These findings highlight the importance of enhancing noise protection from an early age.

Auditory neuropathy (AN) is a hearing disorder that is often overlooked due to its hidden cochlear activity and hearing loss profiles. Diphtheria toxin (DT) is commonly used to induce deafness in conditional gene knockout mouse models, but its ototoxic targets in wild-type animals remain controversial. This study aimed to characterize the pathogenic effects of DT on the cochlea of wild-type mice and establish a reliable model of AN. Adult CBA/CaJ mice of both sexes (n = 81) were administered by DT for three consecutive days. AN was confirmed by electrophysiological profiles: abnormal auditory brainstem response (ABR) with preserved distortion product otoacoustic emissions (DPOAE), followed by histopathological evaluation of the cochlear auditory pathway. DT induced a characteristic AN-characteristic hearing loss in mice. It initiated with ribbon synapse degeneration in inner hair cells (IHCs) within 24 h, coinciding with a significant reduction in ABR amplitude peak I. By post-injection day 3, extensive damage was observed, including IHC loss, degeneration of type I spiral ganglion neurons (SGNs), and demyelination of their axons. Despite a minimal loss of OHCs ( 2.1

Background Ménière disease (MD) is a chronic inner ear disorder of unknown etiology. Although an immune-inflammatory link is suspected, the upstream triggers and cellular mechanisms connecting psychosocial stress to inner ear pathology remain poorly defined. This study aimed to investigate the role of stress-related, myeloid cell-derived inflammation in the progression of MD. Methods This multi-cohort study involved 384 MD patients (62.5% female); and 138 healthy controls (HCs) (46.4% female). Perceived stress was evaluated in 110 MD patients and 65 HCs. Transcriptional profiles were characterized using RNA sequencing on peripheral whole blood (4 MD, 6 HC) and on sorted CD11b + myeloid cells versus CD11b-non-myeloid cells (8 MD, 6 HC). In a larger cross-sectional cohort (239 MD patients, 35 HCs), the association between serum inflammatory cytokines and audio-vestibular function was examined, with a subset (n = 42) followed up. Finally, in vitro experiments explored the regulatory effects of catecholamines and glucocorticoids on myeloid cells isolated from 23 MD patients and 26 HCs. Results MD patients reported significantly higher levels of perceived stress compared to controls. RNA sequencing of peripheral blood revealed a distinct pro-inflammatory transcriptional signature in MD patients. Further analysis identified CD11b + myeloid cells as the primary source of this inflammation, showing significant upregulation of pro-inflammatory genes. Clinically, elevated serum levels of the myeloid-derived cytokine G-CSF were associated with poorer baseline audio-vestibular function, and a follow-up increase in G-CSF levels correlated with functional deterioration. Mechanistically, MD patients exhibited elevated plasma norepinephrine and increased β1-adrenergic receptor mRNA in myeloid cells. In vitro, blockade of the β-adrenergic-cAMP pathway attenuated pro-inflammatory cytokine production in these cells. Although systemic cortisol levels remained unchanged, the glucocorticoid receptor sensitivity of myeloid cells in MD patients was altered. Conclusion Our study elucidates a potential pathophysiological axis in MD, where perceived psychosocial stress is linked to sympathetic nervous system overactivity. This, in turn, primes circulating myeloid cells for a pro-inflammatory response via the β-adrenergic pathway. The resultant systemic inflammation is closely associated with the severity and progression of audio-vestibular dysfunction. These findings suggest that targeting the stress-neuroendocrine-immune interface may offer novel therapeutic strategies for MD.

Ménière’s disease (MD) is a disabling inner-ear disorder. Although the key pathologic alteration of MD is characterized as endolymphatic hydrops (EH), the underlying pathogenic mechanism remains unclear, and no definitive curative treatments are available. Emerging evidence implicates oxidative stress and innate immunity as key contributors to MD pathogenesis. Human vestibular end organs were collected to characterize the reactive oxygen species (ROS) levels and the STING signaling activation, findings that were further corroborated in an LPS-induced EH mouse model. Transfection and transwell co-culture were performed to investigate the feedback loop between sensory epithelial cells and macrophages in vitro. Molecular biology experiments were performed to elucidate the underlying regulatory mechanisms. Additionally, STING and CUL4B deficiency mice were used to explore potential therapeutic targets in vivo. The oxidative stress, cytoplasmic dsDNA leakage, and STING activation were elevated in both MD patients and LPS-induced EH mouse model. The dsDNA released from ROS-damaged hair cells activates STING in vestibular macrophages. STING-specific knockout in macrophages alleviates EH, audio-vestibular dysfunction, and interferon-stimulated genes expression in mouse model. The CUL4B-DDB1-ROC1 complex ubiquitinates STING at K370, promoting its degradation and inhibiting activation. Notably, CUL4B deficiency exacerbates LPS-induced EH, audio-vestibular dysfunction, and interferon-stimulated genes (ISG) upregulation, while double conditional knockout reverses these effects. Our study demonstrates that STING activation in vestibular macrophages contributes to audio-vestibular dysfunction and modulating this pathway has promising beneficial effects on audio-vestibular function in EH mice model, which is a potential therapeutic strategy for MD.

OBJECTIVES:To evaluate cochlear nerve responsiveness to electrical stimulation in prelingually deafened adults with late cochlear implantation by analyzing electrically evoked compound action potentials (eCAPs), and to compare their neural status with that of postlingually deafened adults. DESIGN:Participants were divided into two groups: prelingually deafened adults (Prelingual) group (n = 15) and postlingually deafened adults (Postlingual) group (n = 11). All participants used Cochlear Nucleus cochlear implants. The input/output function of the eCAP under inter-phase gap (IPG) conditions of 7 and 35 µsec, and refractory recovery functions under the 7 µsec IPG condition, were recorded at basal, middle, and apical electrodes for each participant. Dependent variables included eCAP input/output function slope, maximum amplitude, threshold, N1 latency, IPG effect on these measurements, absolute refractory period (t0), and relative refractory recovery time (τ). A linear mixed-effects model was used to analyze the effects of groups, electrode locations, and IPGs on these dependent variables. RESULTS:Prelingually deafened adults exhibited significantly shallower eCAP input/output function slopes compared with postlingually deafened adults, while the maximum amplitudes, thresholds, and N1 latencies did not differ significantly between groups. For IPG effects, the Postlingual group demonstrated significantly larger IPG-induced increases in maximum amplitude than the Prelingual group, whereas IPG effects on slope and N1 latency did not differ between groups. The t0 and τ were comparable across groups. Electrode-specific analyses revealed reduced eCAP amplitudes and shallower slopes at basal electrodes compared with middle or apical electrodes in the postlingual group, whereas these electrode-related differences in amplitude and slope were not significant in the Prelingual group. CONCLUSIONS:Despite prolonged auditory deprivation, prelingually deafened adults generally retain substantial cochlear nerve function, although neural recruitment appears reduced. This preserved cochlear nerve function is crucial for processing electrical stimulation signals.

Degeneration of cochlear spiral ganglion neurons (SGNs) leads to irreversible sensorineural hearing loss (SNHL), as SGNs lack regenerative capacity. Although cochlear glial cells (GCs) have some neuronal differentiation potential, their specific identities remain unclear. This study identifies a distinct subpopulation, Frizzled10 positive (FZD10+) cells, as an important type of GC responsible for neuronal differentiation in mouse cochlea. FZD10 + cells can differentiate into various SGN subtypes in vivo, adhering to natural proportions. Wnt signaling enhances the ability of FZD10 + cells to function as neural progenitors and increases the neuronal excitability of the FZD10-derived neurons. Single-cell RNA sequencing analysis characterizes FZD10-derived differentiating cell populations, while crosstalk network analysis identifies multiple signaling pathways and target genes influenced by Wnt signaling that contribute to the function of FZD10 + cells as neural progenitors. Pseudotime analysis maps the differentiation trajectory from proliferated GCs to differentiating neurons. Further experiments indicate that glypican 6 (GPC6) may regulate this neuronal lineage, while GPC6 deficiency diminishes the effects of Wnt signaling on FZD10-derived neuronal differentiation and synapse formation. These findings suggest the critical role of Wnt signaling in the neuronal differentiation derived from cochlear FZD10 + cells and provide insights into the mechanisms potentially involved in this process.

BACKGROUND:Menière's disease (MD) can lead to disabling vertigo attacks with hearing loss. Triple semicircular canal plugging (TSCP) surgery is a new treatment for MD, but high-quality evidence is scarce. This study aimed to assess the long-term efficacy and safety of TSCP. METHODS:In a single-center, open-label, randomized non-inferiority trial, MD patients were assigned to either TSCP or intratympanic gentamicin injections, with 24 months of follow-up. The primary outcome measure was the effective vertigo control rate. Secondary outcome measurements included the mean and median number of vertigo attacks post-intervention, audiovestibular symptom scale scores, audiovestibular test results, and time to balance recovery. RESULTS:A total of 66 patients (33 TSCP and 33 gentamicin) were randomized. The effective vertigo control rate in the TSCP group (97%) was non-inferior to the gentamicin group (85%) (p value = 0.012,95% CI = -2.8% to 27.1%). The TSCP group showed more improvement in audiovestibular symptoms compared to the gentamicin group, regarding the VSS (5.7, 95% CI = 0.30-11.0, p value = 0.038), DHI (10.7, 95% CI = 3.1-18.3, p value = 0.006), and FLS (0.5, 95% CI = 0.1-1.0, p value = 0.025). Semicircular canal function was significantly reduced in TSCP, as measured by video Head Impulse Testing (p value = 0.001) and the caloric test (p value < 0.001). Otolith responses were more preserved in the TSCP group. The TSCP group demonstrated a significantly shorter median time to balance recovery (p value < 0.001). CONCLUSION:The effective vertigo control rate in the TSCP group is non-inferior to intratympanic gentamicin, with a higher vertigo control rate. TRIAL REGISTRATION:ChiCTR1900023606 LEVEL OF EVIDENCE: 2.