Novel Variant of FDXR as a Molecular Etiology of Postlingual Post-synaptic Auditory Neuropathy Spectrum Disorder via Mitochondrial Dysfunction: Reiteration of the Correlation between Genotype and Cochlear Implantation Outcomes.

OBJECTIVES: FDXR encodes mitochondrial ferredoxin reductase, which is associated with auditory neuropathy spectrum disorder (ANSD) and optic atrophy. To date, only two studies have described FDXR-related hearing loss. The auditory rehabilitation outcomes of this disease entity have not been investigated, and the pathophysiological mechanisms remain incompletely understood. Here we report a hearing-impaired individual with co-segregation of the FDXR variant and post-synaptic type ANSD, who underwent cochlear implantation (CI) with favorable outcomes. We suggest a possible pathophysiological mechanism of adult-onset ANSD involving mitochondrial dysfunction. METHODS: A 35-year-old woman was ascertained to have ANSD. Exome sequencing identified the genetic cause of hearing loss, and a functional study measuring mitochondrial activity was performed to provide molecular evidence of pathophysiology. Expression of FDXR in the mouse cochlea was evaluated by immunohistochemistry. Intraoperatively, electrically evoked compound action potential (ECAP) responses were measured, and the mapping parameters were adjusted accordingly. Audiological outcomes were monitored for over 1 year. RESULTS: In lymphoblastoid cell lines (LCLs) carrying a novel FDXR variant, decreased ATP levels, reduced mitochondrial membrane potential, and increased reactive oxygen species levels were observed compared to control LCLs. These dysfunctions were restored by administering mitochondria isolated from umbilical cord mesenchymal stem cells, confirming the pathogenic potential of this variant via mitochondrial dysfunction. Partial ECAP responses during CI and FDXR expression in the mouse cochlea indicate that FDXR-related ANSD is post-synaptic. As a result of increasing the pulse width during mapping, the patient's CI outcomes showed significant improvement over 1-year post-CI. CONCLUSION: A novel FDXR variant associated with mitochondrial dysfunction and post-synaptic ANSD was first identified in a Korean individual. Additionally, 1-year post-CI outcomes were reported for the first time in the literature. Excellent audiologic. RESULTS: were obtained, and our. RESULTS: reiterate the correlation between genotype and CI outcomes in ANSD.

The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Clinical characteristics and hearing loss etiology of cochlear implantees undergoing surgery in their teens, 20s, and 30s.

PURPOSE: This study aimed to investigate the etiology of hearing loss, including genetic variants, in individuals who underwent cochlear implantation (CI) in their teens to thirties. It also sought to analyze post-CI speech performance and identify prognostic factors affecting CI outcomes in this age group. METHODS: We conducted a retrospective review of 421 cochlear implant patients at Seoul National University Bundang Hospital, focusing on 63 subjects aged 10-39 years who underwent their first CI by a single surgeon between July 2018 and June 2022. The study included audiologic evaluation, molecular genetic testing, and analysis of speech performance post-CI. Statistical analyses were performed using SPSS 25 and GraphPad Prism 7. RESULTS: Among 63 participants (M:F, 24:39), nine underwent CI in their teens, 24 in their 20 s, and 30 in their 30 s. Most of them (40, 63.5%) had postlingual deafness. The study found that 65.2% (40/63) of subjects received a genetic diagnosis, with DFNB4 being the most common etiology (37.5%, 15/40). Post-CI speech evaluation showed an average sentence score of 80% across all subjects. Factors such as the onset of hearing loss, duration of deafness (DoD), and preoperative Speech Intelligibility Rating (SIR) significantly influenced CI outcomes. Notably, longer DoD was associated with poorer CI outcomes, but this did not affect individuals with postlingual hearing loss as much. CONCLUSION: The study concludes that in individuals aged 10-39 undergoing CI, the onset of hearing loss and preoperative SIR are critical predictors of postoperative outcomes. CI is recommended for those with postlingual hearing loss in this age group, irrespective of the DoD. The study highlights the importance of genetic factors especially DFNB4 in hearing loss etiology and underscores the value of the relatively easy-to-evaluate factor, preoperative SIR in predicting CI outcomes.

Efficacy of vestibular rehabilitation and its facilitating and hindering factors from real-world clinical data.

Background and purpose: Customized vestibular rehabilitation improved dizziness and imbalance in several randomized controlled trials. In the present study, we determined the efficacy of customized vestibular rehabilitation using real-world observational data. Methods: In this retrospective observational study, we recruited 64 patients (median age = 60, interquartile range = 48-66.3) who completed the customized vestibular rehabilitation from January to December 2022. The outcomes of rehabilitation were evaluated using the dizziness handicap inventory (DHI) or vestibular disorders activities of daily living scale (VADL). The factors associated with outcomes were assessed with a generalized linear model, of which covariates included patients' age, sex, duration of illness, type of vestibular disorders, initial DHI and VADL scores, exercise compliance, and initial hospital anxiety and depression scale (HADS) scores. Results: After the median of 6 (4-6) weeks of rehabilitation, DHI and VADL scores significantly improved in patients with either peripheral or central vestibular disorders (Wilcoxon signed-rank test, p < 0.05). The initial DHI and VADL scores showed a positive while the sum of HADS scores showed a negative correlation with the outcome. In contrast, the age, sex, duration of illness, types of vestibular disorders, and exercise compliance did not affect the outcome. Discussion and conclusion: Customized vestibular rehabilitation is effective for central as well as peripheral disorders, especially when the symptoms are severe and the psychological distress is mild.

Selection of speech processor in cochlear implant patients: experience in a tertiary hospital.

BACKGROUND: There are two types of speech processors used in CI devices: behind-the-ear (BTE) and off-the-ear (OTE). OBJECTIVES: This study aimed to investigate the characteristics of patients and revision cases in relation to the type of speech processors. MATERIALS AND METHODS: A retrospective review of 452 ears that underwent CI was performed. RESULTS: Children with severe inner ear anomalies (91.7%) more frequently preferred BTE speech processors than those without severe inner ear anomalies (p = .000). The magnet strength used in OTE speech processor users was significantly higher than in BTE speech processor users (p = .002). In cochlear implantees who underwent surgery before 12 months of age, the magnet strength in the revision group was greater than in the non-revision group (p = .025). CONCLUSIONS AND SIGNIFICANCE: Overall, our findings suggest factors to consider when choosing the type of speech processor and modifying the magnet strength of the implant device. The choice between BTE and OTE speech processors led to different required magnet strengths, contributing to the occurrence of skin flap inflammation.

Early Postoperative Benefits in Receptive and Expressive Language Development After Cochlear Implantation Under 9 Months of Age in Comparison to Implantation at Later Ages.

OBJECTIVES: The recent expansion of eligibility for cochlear implantation (CI) by the U.S. Food and Drug Administration (FDA) to include infants as young as 9 months has reignited debates concerning the clinically appropriate cut-off age for pediatric CI. Our study compared the early postoperative trajectories of receptive and expressive language development in children who received CI before 9 months of age with those who received it between 9 and 12 months. This study involved a unique pediatric cohort with documented etiology, where the timing of CI was based on objective criteria and efforts were made to minimize the influence of parental socioeconomic status. METHODS: A retrospective review of 98 pediatric implantees recruited at a tertiary referral center was conducted. The timing of CI was based on auditory and language criteria focused on the extent of delay corresponding to the bottom 1st percentile of language development among age-matched controls, with patients categorized into very early (CI at <9 months), early (CI at 9-12 months) and delayed (CI at 12-18 months) CI groups. Postoperative receptive/expressive language development was assessed using the Sequenced Language Scale for Infants receptive and expressive standardized scores and percentiles. RESULTS: Only the very early CI group showed significant improvements in receptive language starting at 3 months post-CI, aligning with normal-hearing peers by 9 months and maintaining this level until age 2 years. During this period (<2 years), all improvements were more pronounced in receptive language than in expressive language. CONCLUSION: CI before 9 months of age significantly improved receptive language development compared to later CI, with improvements sustained at least up to the age of 2. This study supports the consideration of earlier CI, beyond pediatric Food and Drug Administration labeling criteria (>9 months), in children with profound deafness who have a clear deafness etiology and language development delays (<1st percentile).

Hearing preservation after stereotactic radiosurgery for sporadic intracanalicular vestibular schwannomas classified as Koos grade 1.

INTRODUCTION: The mechanism of hearing loss following stereotactic radiosurgery (SRS) for vestibular schwannomas (VSs) remains unclear. There is conflicting evidence regarding cochlear nerve damage by transient volume expansion of VSs after radiosurgery and radiation-induced cochlear damage. This study aimed to investigate whether there is a specific patient population that can achieve definite hearing preservation after SRS for VSs. METHODS: A total of 37 consecutive patients with sporadic unilateral intracanalicular VSs and serviceable hearing (Gardner-Roberson [G-R] class I or II) were treated with SRS from 2009 to 2023. This is a retrospective study. Survival analysis with Cox regression for hearing deterioration was performed. RESULTS: The median age was 55 years old. The median tumor volume was 0.089 cm3 , and the median marginal dose was 12.0 Gy. Nonserviceable hearing deterioration occurred in 9 patients (24.3%), with a median onset of 11.9 months after SRS. The actuarial rates of serviceable hearing preservation were 86%, 82%, and 70% at 1, 2, and 3 years after SRS, respectively. In a multivariate analysis, only baseline pure tone average > 30 dB increased the risk of nonserviceable hearing deterioration with significant hazard ratio. There were 13 patients with petit VSs whose tumor volume was smaller than 0.05 cm3 , and 11 of them were treated by a 4-mm single shot with a marginal dose of 12 Gy. None of the 13 patients had nonserviceable hearing deterioration. CONCLUSIONS: Petit VSs that can be treated with 4-mm single or double shots with a marginal dose of 12 Gy may achieve hearing preservation after SRS.

Comparing pronunciation challenges in South Korean preschoolers with unilateral single-sided deafness due to cochlear nerve deficiency to a norm-referenced standard.

This study aimed to compare the development of pronunciation in South Korean preschoolers with unilateral cochlear nerve deficiency (CND) to that of age-matched preschoolers with normal hearing, a topic that has not been explored previously. In a retrospective analysis, 25 preschoolers with unilateral CND who had undergone a speech evaluation battery, including a pronunciation and vocabulary test, were enrolled. Utilizing the Urimal Test of Articulation and Phonation and customized language ability tests, pronunciation and vocabulary were assessed. The subjects' speech evaluation scores were converted into age-adjusted z-scores using normal controls' data. While vocabulary performance was within normal limits, their average pronunciation z-score was -2.90, significantly lower than both the zero reference point and their vocabulary z-scores. None of the subjects scored above average in pronunciation. Thirteen patients were recommended for articulation therapy, seven were considered as potential candidates for this therapy, and the remaining five were within normal limits. There was no observed correlation between the development of pronunciation and vocabulary. Notably, some subjects' pronunciation scores did not improve, even after serial follow-up during their preschool years. Despite typical vocabulary development, preschoolers with unilateral CND exhibit significant delays in pronunciation. These findings emphasize the necessity for vigilant monitoring of their language development.

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.

Improving the Accuracy of Otitis Media with Effusion Diagnosis in Pediatric Patients Using Deep Learning.

Otitis media with effusion (OME), primarily seen in children aged 2 years and younger, is characterized by the presence of fluid in the middle ear, often resulting in hearing loss and aural fullness. While deep learning networks have been explored to aid OME diagnosis, prior work did not often specify if pediatric images were used for training, causing uncertainties about their clinical relevance, especially due to important distinctions between the tympanic membranes of small children and adults. We trained cross-validated ResNet50, DenseNet201, InceptionV3, and InceptionResNetV2 models on 1150 pediatric tympanic membrane images from otoendoscopes to classify OME. When assessed using a separate dataset of 100 pediatric tympanic membrane images, the models achieved mean accuracies of 92.9% (ResNet50), 97.2% (DenseNet201), 96.0% (InceptionV3), and 94.8% (InceptionResNetV2), compared to the seven otolaryngologists that achieved accuracies between 84.0% and 69.0%. The results showed that even the worst-performing model trained on fold 3 of InceptionResNetV2 with an accuracy of 88.0% exceeded the accuracy of the highest-performing otolaryngologist at 84.0%. Our findings suggest that these specifically trained deep learning models can potentially enhance the clinical diagnosis of OME using pediatric otoendoscopic tympanic membrane images.

TMTC4 is a hair cell-specific human deafness gene.

Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a deafness gene in mice. Tmtc4-KO mice have rapidly progressive postnatal hearing loss due to overactivation of the unfolded protein response (UPR); however, the cellular basis and human relevance of Tmtc4-associated hearing loss in the cochlea was not heretofore appreciated. We created a hair cell-specific conditional KO mouse that phenocopies the constitutive KO with postnatal onset deafness, demonstrating that Tmtc4 is a hair cell-specific deafness gene. Furthermore, we identified a human family in which Tmtc4 variants segregate with adult-onset progressive hearing loss. Lymphoblastoid cells derived from multiple affected and unaffected family members, as well as human embryonic kidney cells engineered to harbor each of the variants, demonstrated that the human Tmtc4 variants confer hypersensitivity of the UPR toward apoptosis. These findings provide evidence that TMTC4 is a deafness gene in humans and further implicate the UPR in progressive hearing loss.

Two Discrete Types of Tip Fold-Over in Cochlear Implantation Using Slim Modiolar Electrodes: Influence of Cochlear Duct Length on Tip Fold-Over.

OBJECTIVE: Precise electrode positioning is crucial for achieving optimal audiological outcomes in cochlear implantation. The slim modiolar electrode (SME), a thin, flexible, and precurved electrode, exhibits favorable modiolar proximity. However, tip fold-over can affect optimal electrode placement. Herein, we share our experiences with tip fold-over in SMEs and present an analysis of conditions that may predispose to tip fold-over. STUDY DESIGN: Retrospective medical record review. PATIENTS: In total, 475 patients (671 ears) underwent cochlear implantation using SMEs (Nucleus CI532 or CI632 from Cochlear) performed by a single surgeon at a tertiary center between June 14, 2018, and December 1, 2022. INTERVENTIONS: Intraoperative x-ray scans (cochlear view), operative records, and cochlear duct length (CDL) were reviewed. MAIN OUTCOME MEASURES: Tip fold-over patterns on plain x-ray images (proximal versus distal). RESULTS: Electrode tip fold-over was observed in 18 (2.7%) of the 671 ears with SMEs. This fold-over occurred more frequently in cases with long CDL (>36 mm). Among the 14 cases with available initial x-rays before correction of the tip fold-over, half were classified as proximal and the other half as distal. A predilection for proximal tip fold-over was found in those with a CDL of 36 mm or longer, and longer CDLs were observed for proximal cases than for distal cases. Our pilot data suggest that identifying the type of tip fold-over can aid in correcting it more efficiently. CONCLUSIONS: Tip fold-over of SME does not occur uniformly and is more common in ears with long CDL. This tendency is particularly pronounced for the proximal type of tip fold-over. Therefore, preoperative measurement of the CDL and meticulous examination of intraoperative imaging are essential for customized correction.

Ramifications of POU4F3 variants associated with autosomal dominant hearing loss in various molecular aspects.

POU4F3, a member of the POU family of transcription factors, commonly causes autosomal dominant deafness. Exome sequencing was used to identify four novel variants in POU4F3 (NM_002700.2), including c.564dupA: p.Ala189SerfsTer26, c.743T > C:p.Leu248Pro, c.879C > A:p.Phe293Leu, and c.952G > A:p.Val318Met, and diverse aspects of the molecular consequences of their protein expression, stability, subcellular localization, and transcriptional activity were investigated. The expression of three mutant proteins, encoded by missense variants, was reduced compared to the wild-type protein, demonstrating that the mutants were unstable and vulnerable to degradation. Additionally, all the mutant proteins had distinct subcellular localization patterns. A mutant protein carrying p.Ala189SerfsTer26, in which both mono- and bi-partite nuclear localization signals were disrupted, showed abnormal subcellular localization. Resultantly, all the mutant proteins significantly reduced the transcriptional activity required to regulate the downstream target gene expression. Furthermore, we identified the altered expression of 14 downstream target genes associated with inner ear development using patient-derived lymphoblastoid cell lines. There was a significant correlation of the expression profile between patient-derived cells and the cochlear hair cells, which provided a breakthrough for cases where the collection of human cochlear samples for transcriptome studies was unfeasible. This study expanded the genotypic spectrum of POU4F3 in DFNA15, and further refined the molecular mechanisms underlying POU4F3-associated DFNA15.

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.

Audiogram Configuration, Molecular Etiology, and Outcome of Cochlear Implantation in Postlingual Auditory Neuropathy Spectrum Disorder.

OBJECTIVE: To explore the diverse molecular etiologies of postlingual auditory neuropathy spectrum disorder (ANSD) and report on the electrically evoked compound action potential (ECAP) thresholds and the outcome of cochlear implantation (CI). METHODS: Patients with late-onset, progressive hearing loss who went through molecular genetic testing were enrolled. Type of sensorineural hearing loss (SNHL) was classified as flat, reverse-slope, midfrequency, downsloping, or ski slope. We identified postlingual ANSD subjects through diagnostic tracts applied differently depending on the degree of SNHL. For CI recipients, individual ECAP thresholds, postoperative speech perception abilities, and the genetic cause were analyzed. RESULTS: The detection rate of ANSD among patients with postlingual SNHL was 5.1% (15/293 probands). Diverse genetic etiologies were identified in 7 (46.6%) of the 15 postlingual ANSD subjects, the genetic cause being found exclusively in subjects with reverse-slope SNHL. The pattern of intraoperative ECAP responses was also diverse and showed some correlation with the genetic etiology. Despite the diverse molecular etiology and ECAP responses, CI in postlingual ANSD patients, including those with features involving the postsynaptic component, yielded significant improvements in speech understanding. CONCLUSIONS: This study proposes a differentiated diagnostic approach that focuses on both poor speech discrimination and reverse-slope hearing loss for the diagnosis of ANSD. Based on the improvement of speech understanding from all cochlear implantees with ANSD as well as the correlation between the genetic etiology and ECAP thresholds, we suggest that CI can significantly benefit ANSD subjects even those with unknown etiologies unless there is overt peripheral neuropathy.

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.

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.

Healthcare consumption among subjects with otitis media undergoing middle ear surgery-analysis of cost drivers.

PURPOSE: To map healthcare utilized by subjects with chronic otitis media, with or without cholesteatoma and perform a cost analysis to determine key drivers of healthcare expenditure. METHODS: A registry study of 656 adult subjects with chronic otitis media that underwent a middle ear surgery between 2014 and 2018. Healthcare contacts related to all publicly funded specialist ENT care, audiological care and primary care for a disease of the ear and mastoid process were extracted. The data are extracted from the Swedish National Patient Registry on subjects that reside in western Sweden. RESULTS: Subjects made 13,782 healthcare contacts at a total cost 61.1 million SEK (6.0 million EUR) between 2014 and 2018. The mean cost per subject was 93,075 SEK (9071 EUR) and ranged between 3971 SEK (387 EUR) and 468,711 SEK (45,683 EUR) per individual. In the most expensive quartile of subjects, mean cost was 192,353 SEK (18,747 EUR) over the 5-year period. These subjects made 3227 ENT contacts (roughly four each year) and 60% of total costs were associated with in-patient ENT care. CONCLUSION: Patients with chronic otitis media are associated with high ENT resource utilization that does not diminish after surgical intervention and the disease places a long-term burden on healthcare systems. Significant costs are attributed to revision surgeries, indicating that these patients could be managed more effectively. In many such cases, reoperation cannot be avoided, especially due to recurrence of cholesteatoma. However, in some patients, when the indication for subsequent surgery is only hearing improvement, alternative options, such as hearing aids or implants, should also be considered. This is especially true in difficult cases, where revision ossiculoplasty is likely.

A comparative study of audiological outcomes and compliance between the Osia system and other bone conduction hearing implants.

PURPOSE: To examine the subjective and objective audiological benefits of the Osia system compared to devices commonly implanted prior to the introduction of this system. METHODS: Osia recipients with either conductive hearing loss (CHL/MHL) (n = 9) or single-sided deafness (SSD) (n = 8) who underwent surgery from February 2021 to March 2022 were prospectively recruited. The audiological outcomes and usage rate of Osia implantees were compared with those of retrospectively recruited patients implanted with other devices (n = 50). The subjective satisfaction of the Osia implantees was also evaluated through questionnaires. RESULTS: All users of the Osia system were classified as regular users. In the CHL/MHL group, the effective gain of the Osia system (11.1 ± 14.9 dB) surpassed that of the Baha and Bonebridge (- 2.7 ± 12.6 dB) at 2 kHz (p = 0.01, Mann-Whitney U test). Among the devices, the Osia system tended to tolerate the worst bone conduction thresholds, up to the level of 61 dB. In the SSD group, the functional gain of Osia at 4 kHz (37.5 ± 3.1 dB) was higher than that of the Baha and Bonebridge group (26.9 ± 3.0 dB) (p = 0.05, Mann-Whitney U test). CONCLUSION: The Osia system yielded larger audiological gain than the Baha Attract and Bonebridge devices, especially at high frequencies, leading to substantially higher compliance. The Osia system tended to have the strongest tolerance to aggravated bone conduction thresholds among the available transcutaneous bone conduction hearing implants. Therefore, the Osia system could potentially be a good option for CHL/MHL patients with bone conduction thresholds of 50 dB HL or more, as well as patients with SSD.