Background Allergic rhinitis (AR) is a common chronic inflammatory disorder that can adversely affect both middle and inner ear function through Eustachian tube dysfunction (ETD) and cochlear involvement. Despite increasing evidence of auditory complications, hearing impairment among adults with AR remains under-recognized in routine clinical practice. This study aimed to estimate the prevalence of hearing impairment and identify sociodemographic and clinical factors independently associated with hearing impairment among adults with allergic rhinitis attending a tertiary care centre in Tiruvannamalai district of Tamil Nadu, India. Materials and methods A hospital-based cross-sectional study was conducted among 136 adults with clinically diagnosed allergic rhinitis attending the Otorhinolaryngology outpatient department of a tertiary care medical college and hospital in Tamil Nadu. Audiological assessment included pure-tone audiometry (PTA), tympanometry, and otoacoustic emissions (OAE). Data were analysed using IBM SPSS Statistics for Windows, version 26 (IBM Corp., Armonk, New York, United States). Descriptive statistics were expressed as frequencies, percentages, and mean ± SD. Independent samples t-test, one-way ANOVA, paired t-test, Pearson's correlation, and multivariable logistic regression were used to identify factors associated with hearing impairment. A p-value <0.05 was considered statistically significant. Results The mean age of the study participants was 32.51 ± 10.77 years, and 57.4% were female. Abnormal OAE findings, interpreted alongside tympanometry and PTA, were identified in 20 (14.7%) participants, suggesting possible cochlear dysfunction, while 28 (20.6%) had hearing impairment on PTA and 14 (10.3%) demonstrated Type C tympanograms indicating ETD in at least one ear. Mean PTA thresholds increased significantly with age, longer symptom duration, antihistamine use, congested nasal mucosa, abnormal OAE findings, and Type C tympanograms. Septal deviation showed an ear-specific association. In multivariable analysis, female sex was associated with lower odds of hearing impairment, whereas longer symptom duration and previous antihistamine use were associated with higher odds. Age and duration of symptoms also showed significant positive correlations with PTA thresholds. Conclusion Adults with allergic rhinitis demonstrated a considerable burden of audiological abnormalities. Female sex, prolonged symptom duration, and previous antihistamine use were independently associated with hearing impairment in the multivariable model. Routine audiological evaluation using PTA, tympanometry, and OAE should be considered in patients with persistent allergic rhinitis to facilitate early detection and appropriate management of auditory dysfunction.

Biallelic pathogenic FDXR variations were identified in 2017 as being responsible for sensorial neuropathies. The first reported patients suffered from auditory and optic sensorineural impairments (ANOA, MIM #617717). Since then, many publications have described various phenotypes including peripheral and central nervous systems impairments (MMDS9B, MIM #620887). This is consistent with the role of the encoded protein ferredoxin reductase (FDXR) as one of the actors of iron-sulfur proteins synthesis in mitochondria. Ophthalmologic and neurologic symptoms have often been reported, but little is known about the associated inner ear disabilities, although hearing loss was described in the early clinical reports. Firstly, we would like to characterize inner ear abnormalities, sharing our observations of five new patients' hearing and the outcome after rehabilitation. Thereafter, considering the increasing numbers of publications about FDXR, it appeared useful to provide an overview of literature, analyzing how molecular data may correlate with clinical symptoms. We analyzed the clinical and molecular findings in patients reported from 2017 until March 2025. Data included 89 cases from 79 unrelated families. Protein changes were mostly located in the FAD binding domain, whereas those in NADPH binding domains seem to be less prevalent but more related to severe cases with earlier onset symptoms. These data, combined with current knowledge about FDXR catalytic function and its interaction with FDX and/or cytochrome P450 proteins, could help to understand potential phenotype-genotype correlations.

Postmortem human temporal bones provide an irreplaceable resource for studying the cochlea and vestibular labyrinth in their native anatomic context, as the tissues of these organs cannot be non-destructively biopsied. However, temporal bone procurement using an intracranial circular saw blade remains technically challenging, with intermittent blade fractures despite iterative optimization of blade materials and design. Because specimens are rare, efficient collection of biologic materials, including perilymph, further increases the value of each autopsy. We qualitatively assessed modifiable and non-modifiable factors contributing to blade fracture risk during five postmortem temporal bone collections by three operators and evaluated refinements for perilymph collection. Potential contributors, based on direct observation and operator-reported experience, included irregular middle cranial fossa (MCF) topography, angle of saw blade engagement with bone, cortical scoring technique, and operator body mechanics. Modifiable factors included maintaining an orthogonal saw axis relative to the MCF, performing cortical scoring before complete osteotomy, and repositioning of the operator to improve ergonomic alignment with the saw axis. Non-modifiable factors included the irregular surface of the MCF, temporal bone asymmetry, and physical constraints limiting orthogonal saw alignment. These observations informed a refined saw blade design intended to accommodate non-modifiable anatomic and ergonomic constraints. Perilymph workflow refinements enabled timely recovery of low-volume samples before temporal bone fixation. After optimization, trainee procurement duration averaged 8.0 ± 2.5 min across five serial sessions, whereas experienced operators retrospectively self-reported ~5 min per temporal bone. These refinements are intended to improve the robustness, reproducibility, speed, and accessibility of postmortem temporal bone collection for human otopathology studies.

The cochlear dimensions relevant to hearing capability generally follow a pattern of allometric scaling with body mass in mammals. Nevertheless, humans exhibit cochlear dimensions larger than expected from the body mass, and it has been proposed that this is related to encephalization. In this study, we investigate whether the link between brain mass and cochlear morphology is unique to humans and whether cranial features other than brain mass impinge on the cochlear morphology in catarrhine primates that exhibit considerable variation in brain mass. Cochlear and cranial dimensions (cochlear length, oval window area, endocranial volume, cranial size, and interaural distance) were measured on three-dimensional surface models for 30 hominoid individuals (humans, chimpanzees, gorillas, orangutans, and gibbons) and 20 cercopithecine individuals (Japanese macaques, mandrills, and baboons). Relations between cochlear and cranial variables were evaluated using generalized linear mixed model (GLMM) and phylogenetic generalized least squares (PGLS) analyses. The endocranial volume better predicts cochlear morphology than the other cranial measurements in catarrhines. Specifically, the average cochlear length per turn exhibits a strong correlation, while the oval window area exhibits a weaker correlation with the endocranial volume in both GLMM and PGLS. Humans do not deviate from the common allometric pattern of cochlear length against endocranial volume in the catarrhine primates studied here. It appears that humans do not necessarily represent an exceptional cochlear morphology in catarrhine primates after accounting for the cranial dimensions and phylogeny. Our data thus indicate that the link between endocranial volume and cochlear morphology could be a more general pattern for catarrhine primates than previously recognized.

Pathogenic variants in the SLC26A4 gene (solute carrier family 26, member 4) are a common cause of inherited hearing loss. The SLC26A4 gene encodes the transmembrane protein pendrin, a member of the SLC26 anion transporter family, with predominant expression in the inner ear, thyroid, and kidney tissues. Pathogenic SLC26A4 variants cause nonsyndromic recessive hearing loss (DFNB4) and Pendred syndrome (sensorineural hearing loss and thyroid dysfunction). In many studies analyzing the SLC26A4 gene, along with patients who have two recessive pathogenic SLC26A4 variants (M2 patients) and an accurate molecular genetic diagnosis can be made, a group of patients with only one pathogenic SLC26A4 variant (M1 patients) is often identified, which creates a diagnostic problem. The presence of M1 patients may reflect copy number variations (CNVs, deletions/duplications) in the SLC26A4 gene that are not detected by routine diagnostic methods. The aim of the study is to search for deletions/duplications in the SLC26A4 gene using the MLPA (Multiplex Ligation-dependent Probe Amplification) method in thirteen patients belonging to the indigenous people of the Tyva Republic (Southern Siberia), in whom only one pathogenic SLC26A4 variant (M1 patients) was identified during the study of the etiology of hereditary hearing loss. As a result of MLPA analysis and molecular cloning in DNA samples of three M1 patients from two related Tuvinian families, a novel variant was revealed - tandem duplication of twelve nucleotides (c.1185_1196dup) in exon 10 of the SLC26A4 gene. This variant is an in-frame insertion resulting in the inclusion of four additional amino acid residues Gly-Phe-Phe-Ser (p.(Gly396_Ser399dup)) in a highly conserved region of the pendrin protein. Most predictive programs predict the damaging effect of the c.1185_1196dup variant on the structure and function of the pendrin protein. The pathogenicity of the c.1185_1196dup variant is supported by its segregation with hearing pathology in the pedigree of patients in whom it was found in a compound heterozygous state with pathogenic SLC26A4 variants, as well as its absence in a control sample of Tuvinians and in the world genomic databases. Functional in vitro studies are needed to confirm the potentially deleterious effects of the novel c.1185_1196dup (p.(Gly396_Ser399dup)) variant and its association with hearing pathology.

Hearing loss affects over 1.5 billion people worldwide and has substantial social, educational, and economic consequences. Although genetic studies have identified numerous hearing-loss-associated genes, the molecular changes accompanying noise-induced hearing loss (NIHL) remain incompletely understood. We characterized the adult mouse cochlear proteome following damaging noise exposure using nano-LC-MS/MS and an integrative bioinformatics workflow. Comparative profiling of normal-hearing and NIHL cochleae identified 1742 proteins and an 80-protein NIHL-associated signature comprising 49 quantitatively defined differentially abundant proteins and 31 condition-specific proteins. These proteins were organized into five functional groups encompassing metabolic and mitochondrial function, protein synthesis and ribonucleoprotein complexes, structural and synaptic organization, cell polarity and cytoskeletal remodeling, and regulatory and stress-responsive functions. Representative alterations included reduced HSPA9, a mitochondrial chaperone involved in protein homeostasis; changes in the RNA-associated proteins PRMT1 and CIRBP; reduced HAPLN1, associated with extracellular matrix organization; and altered MAP2K2, a signaling protein related to cell polarity; and increased SYNJ2. Comparison with an independent cochlear proteomic data set identified 39 of the 80 proteins as dysregulated, with 22 showing concordant directional changes. Single-cell transcriptomic mapping provided cellular context for 74 of the 80 protein-associated genes, while human genetic and disease annotations supported the prioritization of selected proteins associated with hearing or ear phenotypes. Together, these findings define a proteomic landscape of the noise-exposed cochlea and identify molecular candidates and cellular processes for further investigation of NIHL.

Many falls and balance disorders in older adults originate in the otolith organs, the gravity sensors of the inner ear. These sensors maintain upright posture through otoconia, calcium carbonate crystals that mass-load the sensory maculae. Otoconia dislodgement causes the most common form of vertigo, and their age-related loss reduces gravity sensation and undermines balance. Yet the cellular mechanisms of otoconia formation and maintenance-and how they fail in disease- remain unknown. Using mineral-preserving histology, crystal-sensitive imaging, volume electron microscopy, and immunolabeling in human and animal otolith organs, we found otoconia biogenesis-related proteins and early crystallization at the pole opposing the macula, the roof domain. We discovered filigree extracellular matrix scaffolds bridging roof and macula, loaded with nascent otoconia, suggesting scaffold-guided transport across the organ. Single-cell transcriptomics nominated a specialized roof mesenchyme, signaling to the roof epithelium, as a driver of otoconia and scaffold production. In guinea pigs with endolymphatic hydrops, fluid expansion of the organs ruptured the otoconia-trafficking scaffolds as roof and macula separated, followed by a decline in macular otoconial mass. We propose a new disease model for common vertigo and balance disorders in which disruption of the otoconia-generating and -trafficking epithelial-mesenchymal roof niche leads to displacement and depletion of otoconia.

Peripheral vestibular vertigo requires surgical management in 10 to 20 % of patients, who present persistent symptoms despite conservative treatment. The main indications include Ménière's disease, superior semicircular canal dehiscence, benign paroxysmal positional vertigo, and perilymphatic fistulas. Non-ablative interventions aim to control vertigo while preserving inner ear function. They include endolymphatic sac surgery, semicircular canal occlusion, and perilymphatic fistula repair.

Voltage-gated potassium channel KCNQ1 (Kv7.1) underpins cardiac repolarization, epithelial ion transport, and inner ear function. Its versatility arises from interactions with KCNE proteins, calmodulin (CaM), and the lipid phosphatidylinositol 4,5-bisphosphate (PIP2), yet the molecular basis of PIP2 regulation remains incompletely understood. Here, we present the Stepwise Integrated Multi-scale Dynamics and Advanced Analysis (SIMDA) framework, which integrates coarse-grained and all-atom molecular dynamics, well-tempered metadynamics, and clustering and energy analyses. Over 2,000 µs of simulations across eight functional states find six recurrent PIP2 sites (C0-C5), each complex populating three to four. Sites C1 and C3 agree with experimental densities, whereas C0, C4, and C5 are forward predictions. KCNE3 stabilizes the primary C1 site by amplifying a C-terminal twist motion, while CaM tunes binding at C4 and C5. Interconnected transfer pathways form a dynamic circular route among sites. SIMDA thus provides a generalizable strategy for dissecting lipid-protein dynamics.

Age-related hearing loss (ARHL) is a prevalent sensory disorder in the elderly, yet the molecular mechanisms underlying cochlear aging remain incompletely understood. While insulin-like growth factor 1 (IGF-1) has been implicated in ARHL, its role in the stria vascularis, particularly in pericyte-mediated blood-labyrinth barrier (BLB) regulation, is poorly defined. We performed transcriptomic analysis of FACS-purified pericytes from young and aged mouse stria vascularis. Functional studies were conducted using primary pericyte cultures, lentiviral gene modulation, and AAV-mediated in vivo delivery. Auditory function was assessed by auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE). Molecular changes were evaluated via qPCR, western blot, immunofluorescence, flow cytometry, and transmission electron microscopy (TEM). Transcriptomics revealed significant downregulation of Igf1 and Slc25a33 in aged pericytes, with enrichment of the TGF-β signaling pathway. IGF-1 deficiency suppressed SLC25A33 expression in vitro, leading to mitochondrial ROS (mtROS) accumulation, activation of TGF-β/Smad2 signaling, and pericyte phenotypic switching, characterized by increased α-SMA and decreased E-cadherin. In vivo, suppression of IGF-1 or SLC25A33 activated TGF-β/Smad2 signaling in the stria vascularis, disrupted BLB ultrastructure, and exacerbated hearing loss. Conversely, exogenous IGF-1 or SLC25A33 overexpression attenuated these effects and partially restored auditory function. Our findings identify a novel IGF-1/SLC25A33-TGF-β/Smad2 axis that regulates pericyte activation and BLB integrity in the aging cochlea. This pathway provides mechanistic insight into ARHL pathogenesis and highlights a potential therapeutic target for preserving hearing in older adults.

The mammalian vestibular system has two types of sensory receptor hair cells (HCs), each with different neurotransmission mechanisms. Type II HCs use ribbon synapses to transmit neurotransmitters like glutamate to bouton terminals of afferent neurons. Type I HCs are nearly engulfed by a calyceal afferent ending. They regulate afferent activity through both quantal and non-quantal transmission (NQT), the latter faster than classic neurotransmitter release and potentially key to stabilizing vision and balance during rapid head movements. Here, we describe a novel striated contact, present only in the mouse type I HC and its calyceal afferent ending. Electron tomography reveals periodic striations on both the HC and calyx plasma membranes. These contact sites are intimately associated with a plasma membrane mitochondria contact site on the type I HC side of the synapse. Given that mitochondrion-plasma membrane contact sites in other systems regulate local ion homeostasis, this distinctive arrangement has the potential to serve or modulate NQT at the type I HC-calyx synapse.