Biosafety and potency of high-molecular-weight hyaluronic acid with intratympanic dexamethasone delivery for acute hearing loss.

Objective: This study evaluated the potential of high-molecular-weight hyaluronic acid (HHA) as an intratympanic (IT) drug delivery vehicle for dexamethasone (D) in treating acute hearing loss. We compared the efficacy, safety, and residence time of HHA to the standard-of-care IT drug delivery method. Methods: Endoscopic examinations were used to track tympanic membrane (TM) healing post-IT injection. Micro-computed tomography (CT) was used to gauge drug/vehicle persistence in the bulla air space. Histological analyses covered the middle ear, TM, and hair cell counts. Auditory brainstem responses (ABR) were used to measure hearing thresholds, while high-performance liquid chromatography (HPLC) was employed to quantify cochlear perilymph dexamethasone concentrations. Results: The HHA + D group had a notably prolonged drug/vehicle residence time in the bulla (41 ± 27 days) compared to the saline + D group (1.1 ± 0.3 days). Complete TM healing occurred without adverse effects. Histology revealed no significant intergroup differences or adverse outcomes. Hearing recovery trends favored the HHA + D group, with 85.0% of ears showing clinically meaningful improvement. D concentrations in cochlear perilymph were roughly double in the HHA group. Conclusion: HHA is a promising vehicle for IT drug delivery in treating acute hearing loss. It ensures extended residence time, augmented drug concentrations in targeted tissues, and safety. These results highlight the potential for HHA + D to excel beyond existing standard-of-care treatments for acute hearing loss.

Electrically Evoked Auditory Brainstem Response Using Extracochlear Stimulation at Different Cochlear Sites: A Comparison With Intracochlear Stimulation.

Objectives: The distribution and extent of excitable spiral ganglion neurons (SGNs) have been investigated using electrically evoked auditory brainstem response (EABR) during either pre- or perioperative period. In this study, we investigated the EABR with extracochlear stimulation (eEABR) as a preoperative testing tool to estimate these factors. Methods: Sixteen male Sprague-Dawley rats were used in this study. Experiments were conducted in 9 rats with normal hearing and 7 rats that were partially deafened with ouabain treatment. Each experiment involved the following steps in common: (1) The extracochlear stimulating electrode placement at three different sites along the axis of the cochlea and eEABR recordings. (2) Cochleostomies and 4-channel intracochlear array implantation. Then, EABR recordings with various electrode pair combinations. (3) After electrophysiological measurements, cochleae harvesting for histopathological evaluation. The slope characteristics of the amplitude growth function measured from eEABR and EABR, frequency-specific auditory thresholds, and the density of SGNs were compared. Results: There were similar trends in slope changes on different sites of stimulation with both types of stimulation in normal hearing animals, a monotonically increasing slope with increasing distance between bipolar pairs. In addition, eEABR slopes showed significant correlations with EABR slopes when the expected cochlear regions of stimulation were similar in normal hearing animals. In partial-deaf animals, the auditory thresholds at several frequencies had a significant correlation to the eEABR slopes of each extracochlear electrode at the apical, middle, and basal cochlear positions. It showed that increasing stimulating regions of the cochlea revealed a differential effect on eEABR slopes according to the neural conditions. Conclusion: Our Results indicated that eEABR slopes showed significant spatial correlations to the functionality of the auditory nerve. Therefore, eEABR tests at various cochlear positions possibly can be used for estimating the extent of excitable SGNs in cochlear implant candidates prior to implantation.

Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions.

BACKGROUND: TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations. METHODS: In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity. RESULTS: We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability. CONCLUSIONS: This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.

Allelic hierarchy for USH2A influences auditory and visual phenotypes in South Korean patients.

When medical genetic syndromes are influenced by allelic hierarchies, mutant alleles have distinct effects on clinical phenotypes. Genotype-phenotype correlations for Usher syndrome type 2 (USH2) suggest that the USH2A gene exhibits an allelic hierarchy. Here, we analyzed the phenotypes and genotypes of 16 South Korean patients with USH2A biallelic variants to investigate an allelic hierarchy from audiological and ophthalmological perspectives. Using whole exome and genome sequencing, 18 mutant alleles, including 4 novel alleles, were identified and implicated in USH2A-related disorders. Truncated alleles were linked to earlier onset of subjective hearing loss and more severe thresholds; biallelic truncated alleles had more severe effects. Truncated alleles were also associated with retinal structure degeneration and severe functional deterioration. However, younger patients (aged < 16 years) did not exhibit overt retinitis pigmentosa even when they had biallelic truncated alleles, suggesting that USH2A-related USH2 can mimic nonsyndromic hearing loss. For truncated alleles, there was a clear correlation between mean hearing threshold and 30-Hz flicker electroretinography implicit time. This study provides the first evidence of an USH2A-related allelic hierarchy among South Korean patients; our data yield valuable insights concerning the natural courses of clinical phenotypes and how genotype-based therapies may be used.

Assessing the manufacturable 32-channel cochlear electrode array: evaluation results for clinical trials.

Reliability evaluation results of a manufacturable 32-channel cochlear electrode array are reported in this paper. Applying automated laser micro-machining process and a layer-by-layer silicone deposition scheme, authors developed the manufacturing methods of the electrode array for fine patterning and mass production. The developed electrode array has been verified through the requirements specified by the ISO Standard 14708-7. And the insertion trauma of the electrode array has been evaluated based on human temporal bone studies. According to the specified requirements, the electrode array was assessed through elongation & insulation, flexural, and fatigue tests. In addition, Temporal bone study was performed using eight fresh-frozen cadaver temporal bones with the electrode arrays inserted via the round window. Following soaking in saline condition, the impedances between conducting wires of the electrode array were measured over 100 kΩ (the pass/fail criterion). After each required test, it was shown that the electrode array maintained the electrical continuity and insulation condition. The average insertion angle of the electrode array inside the scala tympani was 399.7°. The human temporal bone studies exhibited atraumatic insertion rate of 60.3% (grade 0 or 1). The reliability of the manufacturable electrode array is successfully verified in mechanical, electrical, and histological aspects. Following the completion of a 32-channel cochlear implant system, the performance and stability of the 32-channel electrode array will be evaluated in clinical trials.

Feasibility of a Smartphone-Based Hearing Aid App for Mild-to-Moderate Hearing Loss: Prospective Multicenter Randomized Controlled Trial.

Background: Hearing loss is a growing health concern worldwide. Hearing aids (HAs) are the treatment of choice for hearing rehabilitation in most cases of mild-to-moderate hearing loss. However, many patients with hearing loss do not use HAs due to their high cost, stigma, and inaccessibility. Since smartphones are widely used, many apps that mimic the amplification function of HAs have been introduced. Smartphone-based HA apps (SHAAs) are affordable and easy to access. However, the audiological benefit of SHAAs has not been determined. Objective: We compared the audiological performance between an SHAA and a conventional HA in a prospective, multicenter randomized controlled trial. Methods: Patients with mild-to-moderate hearing loss were prospectively enrolled from 2 tertiary hospitals and randomly assigned to either an SHAA (Petralex; IT4YOU Corp LLC) or a conventional HA (Siya 1 miniRITE; Oticon A/S). For the cross-over study design, participants used the alternate device and repeated the same 2-month trial. Audiological measurements were obtained using hearing tests, real-ear measurements, and the hearing-in-noise test (HINT). Subjective satisfaction was evaluated using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and International Outcome Inventory for Hearing Aids (IOI-HA). Results: Overall, 63 participants were screened and 38 completed the study. In sound-field audiometry testing, the SHAA showed a 20- to 60-dB gain in the low-to-high frequencies of the hearing threshold level. The HA provided adequate gain in the middle-to-high frequencies (55, 65, and 75 dB in real-ear measurements), which is the sound level for most speaking volumes. However, the SHAA could not improve word recognition at 50 dB. The HA showed better audiological performance than the SHAA in both quiet and noisy conditions in the HINT. The IOI-HA scores were significantly improved by both the HA and SHAA versus unaided conditions. Among the SHAA users, 37% (14/38), 42% (16/38), 24% (9/38), and 32% (12/38) showed improvement in APHAB scores for ease of communication, reverberation, background noise, and aversiveness of sounds, respectively. There were no differences in adverse events between the 2 study groups. Conclusions: The HA showed better performance than the SHAA in word recognition and the HINT. However, the SHAA was significantly better than unaided hearing in terms of amplification. The SHAA may be a useful hearing assistance device for patients with mild-to-moderate hearing loss when listening to soft sounds in quiet conditions. The SHAA demonstrated poorer performance than the HA in the mid- to high-frequency sounds that are important for word recognition, sound quality, and hearing in noisy conditions. Further development of the signal technology of SHAAs is needed to improve the sound quality of mid- to high-frequency sounds and overcome noisy environments.

A situational analysis of ear and hearing care in South Korea using WHO ear and Hearing Care Situation Analysis tool.

Objectives: The WHO emphasizes lifelong management of hearing diseases such as hearing loss and advocates for prevention. The Ear and Hearing Care Situation Analysis (EHCSA) tool was designed by the WHO for assessment and quality improvement of state-led management of hearing loss prevention and management programs. The purpose of this study was to use the EHCSA to assess the ear and hearing management program in Korea and to establish goals consistent with best practices for improving policies and services related to ear and hearing care. Methods: The EHCSA was used as a need assessment of the ear and hearing management services in the country. The EHCSA consists of two sections. Section 1 consists of 41 questions to evaluate health policies and support services. Section 2 consists of 203 questions to evaluate human resources and services of the ear and hearing management sector. Results: There are an estimated 800,000 people with hearing loss in Korea. Policies such as hearing aid support are in place, and outreach services such as free hearing tests are also being actively conducted. In all medical institutions, ear and hearing management treatment and medication prescriptions could be received without barriers. Workers in the fields of ear and hearing management, such as audiologists, language therapists, special education teachers, and sign language interpreters, are specialized and have well-established guidelines for training. Conclusion: Overall, the domestic ear and hearing management sector has confirmed that policies and services are well-prepared in comparison with advanced countries such as the United States, Iran, and China. The use of the EHCSA was functional in collecting data on the current state of domestic ear and hearing management policies and services in Korea, can be used for continuous quality improvement and expansion of medical services, and can be used as a reporting mechanism to the WHO.

Phenotypic and molecular basis of SIX1 variants linked to non-syndromic deafness and atypical branchio-otic syndrome in South Korea.

Branchio-oto-renal (BOR)/branchio-otic (BO) syndrome is a rare disorder and exhibits clinically heterogenous phenotypes, marked by abnormalities in the ear, branchial arch, and renal system. Sporadic cases of atypical BOR/BO syndrome have been recently reported; however, evidence on genotype-phenotype correlations and molecular mechanisms of those cases is lacking. We herein identified five SIX1 heterozygous variants (c.307dupC:p.Leu103Profs*51, c.373G>A:p.Glu125Lys, c.386_391del:p.Tyr129_Cys130del, c.397_399del:p.Glu133del, and c.501G>C:p.Gln167His), including three novel variants, through whole-exome sequencing in five unrelated Korean families. All eight affected individuals with SIX1 variants displayed non-syndromic hearing loss (DFNA23) or atypical BO syndrome. The prevalence of major and minor criteria for BOR/BO syndrome was significantly reduced among individuals with SIX1 variants, compared to 15 BOR/BO syndrome families with EYA1 variants. All SIX1 variants interacted with the EYA1 wild-type; their complexes were localized in the nucleus except for the p.Leu103Profs*51 variant. All mutants also showed obvious but varying degrees of reduction in DNA binding affinity, leading to a significant decrease in transcriptional activity. This study presents the first report of SIX1 variants in South Korea, expanding the genotypic and phenotypic spectrum of SIX1 variants, characterized by DFNA23 or atypical BO syndrome, and refines the diverse molecular aspects of SIX1 variants according to the EYA1-SIX1-DNA complex theory.

Molecular Genetic Etiology and Revisiting the Middle Ear Surgery Outcomes of Branchio-Oto-Renal Syndrome: Experience in a Tertiary Referral Center.

OBJECTIVES: To explore the phenotypes and genotypes of patients with branchio-oto-renal (BOR) and branchio-otic (BO) syndrome, and to analyze the middle ear surgery outcomes qualitatively and quantitatively, proposing a factor usefully prognostic of surgical outcomes. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Eighteen patients with BOR/BO syndrome in 12 unrelated Korean families. INTERVENTION: Middle ear surgery, including either stapes surgery or ossicular reconstruction. MAIN OUTCOME MEASURE: Clinical phenotypes, genotypes, and middle ear surgery outcomes. RESULTS: Eight probands (66.7%) were confirmed genetically; the condition segregated as a dominant or de novo trait. Six EYA1 heterozygous variants were identified by exome sequencing and multiplex ligation-dependent probe amplification. All variants were pathogenic or likely pathogenic based on the ACMG/AMP guidelines. Two novel EYA1 frameshift variants (p.His373Phefs*4 and p.Gln543Asnfs*90) truncating a highly conserved C-terminal Eya domain were identified, expanding the genotypic spectrum of EYA1 in BOR/BO syndrome. Remarkably, middle ear surgery was individualized to ensure optimal audiological outcomes and afforded significant audiological improvements, especially in BOR/BO patients without enlarged vestibular aqueducts (EVAs). A significant difference in air-bone gap closure after middle ear surgery was noted between the two groups even after adjusting for confounders: -20.5 dB in ears without EVAs (improvement) but 0.8 dB in ears with EVAs (no change or deterioration). Furthermore, the success rate was significantly associated with the absence of EVA. CONCLUSIONS: The results of this study were against the notion that middle ear surgery is always contraindicated in patients with BOR/BO syndrome, and an EVA could be a negative prognostic indicator of middle ear surgery in BOR/BO patients. This may aid to determine the strategy of audiological rehabilitation in patients with BOR/BO syndrome.

Intraoperative zoom lens calibration for high magnification surgical microscope.

BACKGROUND AND OBJECTIVES: An augmented reality (AR)-based surgical guidance system is often used with high-magnification zoom lens systems such as a surgical microscope, particularly in neurology or otolaryngology. To superimpose the internal structures of relevant organs on the microscopy image, an accurate calibration process to obtain the camera intrinsic and hand-eye parameters of the microscope is essential. However, conventional calibration methods are unsuitable for surgical microscopes because of their narrow depth of focus at high magnifications. To realize AR-based surgical guidance with a high-magnification surgical microscope, we herein propose a new calibration method that is applicable to the highest magnification levels as well as low magnifications. METHODS: The key idea of the proposed method is to find the relationship between the focal length and the hand-eye parameters, which remains constant regardless of the magnification level. Based on this, even if the magnification changes arbitrarily during surgery, the intrinsic and hand-eye parameters are recalculated quickly and accurately with one or two pictures of the pattern. We also developed a dedicated calibration tool with a prism to take focused pattern images without interfering with the surgery. RESULTS: The proposed calibration method ensured an AR error of < 1 mm for all magnification levels. In addition, the variation of focal length was within 1% regardless of the magnification level, and the corresponding variation with the conventional calibration method exceeded 20% at high magnification levels. CONCLUSIONS: The comparative study showed that the proposed method has outstanding accuracy and reproducibility for a high-magnification surgical microscope. The proposed calibration method is applicable to various endoscope or microscope systems with zoom lens.

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome.

BACKGROUND: Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review. METHODS: We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review. RESULTS: One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7-9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI. CONCLUSIONS: We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.

Significance of cytomegalovirus tests after three weeks of life in children with hearing loss.

BACKGROUND: To determine the diagnostic role of viral markers for cytomegalovirus (CMV) when tested after the diagnostically critical period (postnatal 3 weeks) in children with sensorineural hearing loss (SNHL). METHODS: A retrospective review of 104 subjects who underwent CMV diagnostic tests after the critical period of 3 postnatal three weeks but before 24 months of age. Infants included had not passed universal newborn hearing screening tests in at least one ear and thus underwent obligatory follow up audiology testing as well as either exome sequencing or magnetic resonance imaging in cases of SNHL. Our cohort was classified into four subgroups depending on the results from audiological and etiologic diagnostic tests (genetic and radiological tests): congenital CMV (cCMV)-related SNHL (Group 1, n = 9), SNHL with another clear etiology (Group 2, n = 34), and SNHL classified as neither Group 1 nor 2 (Group 3, n = 18). We added age-matched, normal-hearing children (Group 4, n = 43) as a control group. CMV related viral metrics were compared among these four groups. RESULTS: CMV PCR positivity, PCR titers, and culture positivity successfully differentiated Group 1 from Groups 2 and 4. Group 3 showed values of these parameters that were significantly different from Groups 2 and 4, while being more similar to those in Group 1, suggesting that a substantial portion of Group 3 truly had cCMV deafness. A hypothetical formula was developed to predict cCMV infections using logistic regression analysis. CONCLUSION: This is the first study to propose the clinical significance of CMV test results obtained after 3 weeks post-birth in children with SNHL and to suggest how we can utilize them.

Association of Central Auditory Processing Dysfunction With Preclinical Alzheimer's Disease.

OBJECTIVE: To investigate whether central auditory processing dysfunction measured by the dichotic digit test-1 digit (DDT1) is present in preclinical Alzheimer's disease (AD) individuals who are cognitively normal (CN) older adults with the cerebral beta-amyloid (Aß) deposition and to explore the potential of the DDT1 as a screening test for preclinical AD. STUDY DESIGN: Cross-sectional design. SETTING: A prospective observational cohort study. METHODS: CN older adults with a global clinical dementia rating score of 0 were included. The hearing test battery including pure-tone audiometry, speech audiometry, distortion product otoacoustic emission, and DDT1 was administered to participants. RESULTS: Fifty CN older adults were included. Among them, 38 individuals were included in the Aß deposition negative (AN) group and 12 were included in the Aß deposition positive (AP) group. The DDT1 scores of both the better and worse ears were significantly lower in the AP group than in the AN group (p = .008 and p = .015, respectively). No significant differences were observed between the groups in tests of the peripheral auditory pathways. In multivariable logistic regression analysis adjusted for apolipoprotein E4 positivity, the DDT1 better ear score predicted the AP group (p = .036, odds ratio = 0.892, 95% confidence interval: 0.780-0.985) with relatively high diagnostic accuracy. CONCLUSION: Our findings suggest that Aß deposition may affect the central auditory pathway even before cognitive decline appears. DDT1, which can easily be applied to the old-age population, may have the potential as a screening tool for preclinical AD.

Effect of closing material on hearing rehabilitation in stapedectomy and stapedotomy: A finite element analysis.

Stapedotomy or stapedectomy operations are often performed to treat otosclerosis. During the operation, the space created by bone removal is usually filled with a closing material such as fat or fascia. In this study, the effect of the Young's modulus of the closing material on the hearing level was investigated through the 3D finite element model of a human head including auditory periphery. The Young's moduli of the closing material used to implement stapedotomy and stapedectomy conditions in the model were varied from 1 kPa to 24 MPa. The results showed that the hearing level improved when the closing material was more compliant after stapedotomy. Therefore, when the stapedotomy was performed using fat whose Young's modulus is lowest among the potential closing materials, the hearing level recovered the best among all simulated cases. On the other hand, in stapedectomy, the Young's modulus did not have the linear relationship between the hearing level and the compliance of the closing material. Hence, the Young's modulus causing the best hearing rehabilitation in stapedectomy was found not at the end of the investigated range of Young's modulus but somewhere in the middle of the given range.

Structural analysis of pathogenic TMPRSS3 variants and their cochlear implantation outcomes of sensorineural hearing loss.

TMPRSS3, a type II transmembrane serine protease, is involved in various biological processes including the development and maintenance of the inner ear. Biallelic variants in TMPRSS3 typically result in altered protease activity, causing autosomal recessive non-syndromic hearing loss (ARNSHL). Structural modeling has been conducted to predict the pathogenicity of TMPRSS3 variants and to gain a better understanding of their prognostic correlation. The mutant-driven changes in TMPRSS3 had substantial impacts on neighboring residues, and the pathogenicity of variants was predicted based on their distance from the active site. However, a more in-depth analysis of other factors, such as intramolecular interactions and protein stability, which affect proteolytic activities is yet to be conducted for TMPRSS3 variants. Among 620 probands who provided genomic DNA for molecular genetic testing, eight families with biallelic TMPRSS3 variants that were segregated in a trans configuration were included. Seven different mutant alleles, either homozygous or compound heterozygous, contributed to TMPRSS3-associated ARNSHL, expanding the genotypic spectrum of disease-causing TMPRSS3 variants. Through three-dimensional modeling and structural analysis, TMPRSS3 variants compromise protein stability by altering intramolecular interactions, and each mutant differently interacts with the serine protease active site. Furthermore, the changes in intramolecular interactions leading to regional instability correlate with the results of functional assay and residual hearing function, but overall stability predictions do not. Our findings also build on previous evidence indicating that most recipients with TMPRSS3 variants have favorable cochlear implantation (CI) outcomes. We found that age at CI was significantly correlated with speech performance outcomes; genotype was not correlated with these outcomes. Collectively, the results of this study contribute to a more structural understanding of the underlying mechanisms of ARNSHL caused by TMPRSS3 variants.

Intratympanic steroid treatment can reduce ROS and immune response in human perilymph investigated by in-depth proteome analysis.

Intratympanic (IT) steroid treatment is one of the most widely used and effective treatments for inner ear disorders such as sudden sensorineural hearing loss (SNHL). However, a clear mechanism of IT steroids in inner ear recovery has not yet been revealed. Therefore, we investigated proteome changes in extracted human perilymph after steroid treatment. In this study, we applied a tandem mass spectrometry (MS/MS)-based proteomics approach to discover global proteome changes by comparing human perilymph after steroid treatment with non-treated perilymph group. Using liquid chromatography-MS/MS analysis, we selected 156 differentially expressed proteins (DEPs) that were statistically significant according to Student's t-test. Functional annotation analysis showed that upregulated proteins after steroid treatment are related to apoptosis signaling, as well as reactive oxygen species (ROS) and immune responses. The protein-protein interaction (PPI) clusters the proteins associated with these processes and attempts to observe signaling circuitry, which mediates cellular response after IT steroid treatments. Moreover, we also considered the interactome analysis of DEPs and observed that those with high interaction scores were categorized as having equivalent molecular functions (MFs). Collectively, we suggest that DEPs and interacting proteins in human perilymph after steroid treatment would inhibit the apoptotic and adaptive immune processes that may lead to anti-inflammatory effects.

Increased Resting-State Positron Emission Tomography Activity After Cochlear Implantation in Adult Deafened Cats.

OBJECTIVES: Cochlear implants are widely used for hearing rehabilitation in patients with profound sensorineural hearing loss. However, Cochlear implants have variable. RESULTS: and central neural plasticity is considered to be a reason for this variability. We hypothesized that resting-state cortical networks play a role in conditions of profound hearing loss and are affected by cochlear implants. To investigate the resting-state neuronal networks after cochlear implantation, we acquired 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) images in experimental animals. METHODS: Eight adult domestic cats were enrolled in this study. The hearing threshold of the animals was within the normal range, as measured by auditory evoked potential. They were divided into control (n=4) and hearing loss (n=4) groups. Hearing loss was induced by co-administration of ethacrynic acid and kanamycin. FDG-PET was performed in a normal hearing state and 4 and 11 months after the deafening procedure. Cochlear implantation was performed in the right ear, and electrical cochlear stimulation was performed for 7 months (from 4 to 11 months after the deafening procedure). PET images were compared between the two groups at the three time points. RESULTS: Four months after hearing loss, the auditory cortical area's activity decreased, and activity in the associated visual area increased. After 7 months of cochlear stimulation, the superior marginal gyrus and cingulate gyrus, which are components of the default mode network, showed hypermetabolism. The inferior colliculi showed hypometabolism. CONCLUSION: Resting-state cortical activity in the default mode network components was elevated after cochlear stimulation. This suggests that the animals' awareness level was elevated after hearing restoration by the cochlear implantation.

Endolymphatic hydrops asymmetry distinguishes patients with Meniere's disease from normal controls with high sensitivity and specificity.

Background: Many endolymphatic hydrops (EH) MRI studies in the literature do not include a normal control group. Consequently, it remains unclear which outcome measure in EH MRI can most effectively distinguish between MD patients and normal controls. Methods: Gadolinium-enhanced EH imaging was performed to quantitatively evaluate the extents of hydrops in MD patients and age-/sex-matched normal controls. Four hours after intravenous injection of contrast agent, MRI was performed using a 3-T MR platform fitted with a 32-channel phased-array coil receptor. MR images (10-15 slices) covering an inner ear were 3D-stacked. Analyses of all images that included the vestibule or the cochlea yielded the volumes (in µL) of the endolymphatic and perilymphatic spaces. Results: For the vestibule, they were significantly greater EH% in ipsilateral (52.4 ± 12.5) than in contralateral MD ears (40.4 ± 8.5, p = 0.001) and in ipsilateral MD ears than in control ears (42.4 ± 13.7, p = 0.025). For the cochlea, the values were slightly higher EH% in ipsilateral MD ears (49.7 ± 10.4, p = 0.061) but did not significantly differ from contralateral (41.3 ± 12.6) or control ears (39.6 ± 18.9, p = 0.858). In the MD group, the EH asymmetries were 12.0 ± 10.2% (vestibule) and 8.4 ± 8.6% (cochlea), significantly larger than those of controls. Conclusion: Compared to conventional semiquantitative grading or quantitative EH% analysis, EH asymmetry may better distinguish MD patients from normal controls. Quantitative hydrops volumetric analysis yields clinically relevant information on inner ear function.

Synaptic Remodeling of the Auditory Cortex Following Bilateral Blindness: Evidence of Cross-modal Plasticity.

We aimed to evaluate structural dynamic changes of neurons in the auditory cortex after visual deprivation. We longitudinally tracked dendritic spines for 3 weeks after visual deprivation in vivo using a two-photon microscope. GFP-labeled dendritic spines in the auditory cortex were serially followed after bilateral enucleation. The turnover rate, density, and size of the spines in the dendrites were evaluated 1, 2, and 3 weeks after visual deprivation. The turnover rate of the dendritic spines in the auditory cortex increased at 1 week (20.1±7.3%) after bilateral enucleation compared to baseline (12.5±7.9%); the increase persisted for up to 3 weeks (20.9±11.0%). The spine loss rate was slightly higher than the spine gain rate. The average spine density (number of spines per 1 µm of dendrite) was significantly lower at 2 weeks (2W; 0.22±0.06 1/µm) and 3 W (0.22±0.08 1/µm) post-nucleation compared to baseline (0.026±0.09 1/µm). We evaluated the change of synaptic strength in the stable spines at each time point. The normalized spine size in the auditory cortex was significantly increased after bilateral blindness at 1 W postoperatively (1.36±0.92), 2 W postoperatively (1.40±1.18), and 3 W postoperatively (1.36±0.88) compared to baseline. Sensory deprivation resulted in remodeling of the neural circuitry in the spared cortex, via cross-modal plasticity in the direction of partial breakdown of synapses, and enhanced strength of the remaining synapses.

Patterns of vestibular function in patients with dizziness after COVID-19 vaccination; dual tertiary referral center study.

BACKGROUND: Although dizziness is a common symptom after vaccination, the mechanism, and prognosis are not well understood. AIMS/OBJECTIVES: This study aimed to investigate patients with dizziness after COVID-19 vaccination by analyzing objective information. METHODS: A retrospective study of patients who visited the outpatient clinics of two institutes with a complaint of dizziness occurring within 72 h after a COVID-19 vaccination. RESULTS: In most cases, patients experienced only a single event of dizziness, and the subjective symptom was relieved after a few weeks. All patients decreased gain of vestibular ocular reflex (VOR). The vestibular function test results showed signs of central vestibulopathy in some cases. We separated patients into two groups; the direction-fixed nystagmus (DFN) group and the direction-changing nystagmus (DCN) group. All patients showed decreased gain on the rotational chair test (RCT). The DFN group showed an 80% decrease in video head impulse test (vHIT) gain, whereas the DCN group only showed a decrease of 25%. In RCT, 66% of the DFN group showed asymmetry compared to 20% showing asymmetry in the DCN group. CONCLUSION AND SIGNIFICANCE: The patients who suffered from dizziness after the COVID-19 vaccination exhibited decreased VOR gain and in some cases signs of central vestibulopathy.