Exome variant prioritization in a large cohort of hearing-impaired individuals indicates IKZF2 to be associated with non-syndromic hearing loss and guides future research of unsolved cases.

Although more than 140 genes have been associated with non-syndromic hereditary hearing loss (HL), at least half of the cases remain unexplained in medical genetic testing. One reason is that pathogenic variants are located in 'novel' deafness genes. A variant prioritization approach was used to identify novel (candidate) genes for HL. Exome-wide sequencing data were assessed for subjects with presumed hereditary HL that remained unexplained in medical genetic testing by gene-panel analysis. Cases in group AD had presumed autosomal dominantly inherited HL (n = 124), and in group AR, presumed autosomal recessive HL (n = 337). Variants in known and candidate deafness genes were prioritized based on allele frequencies and predicted effects. Selected variants were tested for their co-segregation with HL. Two cases were solved by variants in recently identified deafness genes (ABHD12, TRRAP). Variant prioritization also revealed potentially causative variants in candidate genes associated with recessive and X-linked HL. Importantly, missense variants in IKZF2 were found to co-segregate with dominantly inherited non-syndromic HL in three families. These variants specifically affected Zn2+-coordinating cysteine or histidine residues of the zinc finger motifs 2 and 3 of the encoded protein Helios. This finding indicates a complex genotype-phenotype correlation for IKZF2 defects, as this gene was previously associated with non-syndromic dysfunction of the immune system and ICHAD syndrome, including HL. The designed strategy for variant prioritization revealed that IKZF2 variants can underlie non-syndromic HL. The large number of candidate genes for HL and variants therein stress the importance of inclusion of family members for variant prioritization.

Long-Term Outcomes of Cochlear Implantation in Usher Syndrome.

OBJECTIVES: Usher syndrome (USH), characterized by bilateral sensorineural hearing loss (SNHL) and retinitis pigmentosa (RP), prompts increased reliance on hearing due to progressive visual deterioration. It can be categorized into three subtypes: USH type 1 (USH1), characterized by severe to profound congenital SNHL, childhood-onset RP, and vestibular areflexia; USH type 2 (USH2), presenting with moderate to severe progressive SNHL and RP onset in the second decade, with or without vestibular dysfunction; and USH type 3 (USH3), featuring variable progressive SNHL beginning in childhood, variable RP onset, and diverse vestibular function. Previous studies evaluating cochlear implant (CI) outcomes in individuals with USH used varying or short follow-up durations, while others did not evaluate outcomes for each subtype separately. This study evaluates long-term CI performance in subjects with USH, at both short-term and long-term, considering each subtype separately. DESIGN: This retrospective, observational cohort study identified 36 CI recipients (53 ears) who were categorized into four different groups: early-implanted USH1 (first CI at ≤7 years of age), late-implanted USH1 (first CI at ≥8 years of age), USH2 and USH3. Phoneme scores at 65 dB SPL with CI were evaluated at 1 year, ≥2 years (mid-term), and ≥5 years postimplantation (long-term). Each subtype was analyzed separately due to the significant variability in phenotype observed among the three subtypes. RESULTS: Early-implanted USH1-subjects (N = 23 ears) achieved excellent long-term phoneme scores (100% [interquartile ranges {IQR} = 95 to 100]), with younger age at implantation significantly correlating with better CI outcomes. Simultaneously implanted subjects had significantly better outcomes than sequentially implanted subjects ( p = 0.028). Late-implanted USH1 subjects (N = 3 ears) used CI solely for sound detection and showed a mean phoneme discrimination score of 12% (IQR = 0 to 12), while still expressing satisfaction with ambient sound detection. In the USH2 group (N = 23 ears), a long-term mean phoneme score of 85% (IQR = 81 to 95) was found. Better outcomes were associated with younger age at implantation and higher preimplantation speech perception scores. USH3-subjects (N = 7 ears) achieved a mean postimplantation phoneme score of 71% (IQR = 45 to 91). CONCLUSIONS: This study is currently one of the largest and most comprehensive studies evaluating CI outcomes in individuals with USH, demonstrating that overall, individuals with USH benefit from CI at both short- and long-term follow-up. Due to the considerable variability in phenotype observed among the three subtypes, each subtype was analyzed separately, resulting in smaller sample sizes. For USH1 subjects, optimal CI outcomes are expected with early simultaneous bilateral implantation. Late implantation in USH1 provides signaling function, but achieved speech recognition is insufficient for oral communication. In USH2 and USH3, favorable CI outcomes are expected, especially if individuals exhibit sufficient speech recognition with hearing aids and receive ample auditory stimulation preimplantation. Early implantation is recommended for USH2, given the progressive nature of hearing loss and concomitant severe visual impairment. In comparison with USH2, predicting outcomes in USH3 remains challenging due to the variability found. Counseling for USH2 and USH3 should highlight early implantation benefits and encourage hearing aid use.

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.

Surgical Treatment for Troublesome Mastoid Cavities: Canal Wall Reconstruction With Bony Obliteration Versus Subtotal Petrosectomy.

INTRODUCTION: A chronically discharging modified radical mastoid cavity may require surgical intervention. We aim to explore two techniques. OBJECTIVE: To compare outcomes of subtotal petrosectomy (STP) and canal wall reconstruction with bony obliteration technique (CWR-BOT). STUDY DESIGN: Retrospective cohort study. SETTING: A tertiary referral center. PATIENTS: All patients with a chronically discharging mastoid cavity surgically treated at the Radboud University Medical Center by STP or CWR-BOT in 2015 to 2020, excluding patients with preoperative cholesteatoma. MAIN OUTCOME MEASURES: Dry ear rate, audiometry, and rehabilitation. SECONDARY OUTCOME MEASURES: Healing time, number of postoperative visits, complications, cholesteatoma, and need for revision surgeries. RESULTS: Thirty-four (58%) patients underwent STP, and 25 (42%) CWR-BOT. A dry ear was established in 100% of patients (STP) and 87% (CWR-BOT). The air-bone gap (ABG) increased by 12 dB in STP, and decreased by 11 dB in CWR-BOT. Postoperative ABG of CWR-BOT patients was better when preoperative computed tomography imaging showed aerated middle ear aeration. ABG improvement was higher when ossicular chain reconstruction took place. Mean follow-up time was 32.5 months (STP) versus 40.5 months (CWR-BOT). Healing time was 1.2 months (STP) versus 4.1 months (CWR-BOT). The number of postoperative visits was 2.5 (STP) versus 5 (CWR-BOT). Cholesteatoma was found in 15% (STP) versus 4% (CWR-BOT) of patients. Complication rate was 18% (STP) and 24% (CWR-BOT) with a need for revision in 21% (STP) and 8% (CWR-BOT), including revisions for cholesteatoma. CONCLUSION: STP and CWR-BOT are excellent treatment options for obtaining a dry ear in patients with a chronically discharging mastoid cavity. This article outlines essential contributing factors in counseling patients when opting for one or the other. Magnetic resonance imaging with diffusion-weighted imaging follow-up should be conducted at 3 and 5 years postoperatively.

Remote Cochlear Implant Assessments: Validity and Stability in Self-Administered Smartphone-Based Testing.

OBJECTIVES: The stability of remote testing in cochlear implant care was studied by testing the influence of time-of-day, listener fatigue, and motivation on the outcomes of the aided threshold test (ATT) and digit triplets test (DTT) in cochlear implant (CI) recipients using self-tests at-home on a smartphone or tablet. DESIGN: A single-center repeated measures cohort study design (n = 50 adult CI recipients). The ATT and DTT were tested at-home ten times, with nine of these sessions planned within a period of eight days. Outcomes were modeled as a function of time-of-day, momentary motivation, listeners' task-related fatigue, and chronotype (i.e., someone's preference for morning or evening due to the sleep-wake cycle) using linear mixed models. Additional factors included aided monosyllabic word recognition in quiet, daily-life fatigue, age, and CI experience. RESULTS: Out of 500 planned measurements, 407 ATTs and 476 DTTs were completed. The ATT determined thresholds and impedances were stable across sessions. The factors in the DTT model explained 75% of the total variance. Forty-nine percent of the total variance was explained by individual differences in the participants' DTT performance. For each 10% increase in word recognition in quiet, the DTT speech reception threshold improved by an average of 1.6 dB. DTT speech reception threshold improved, on average by 0.1 dB per repeated session and correlated with the number of successful DTTs per participant. There was no significant time-of-day effect on auditory performance in at-home administered tests. CONCLUSIONS: This study is one of the first to report on the validity and stability of remote assessments in CI recipients and reveals relevant factors. CI recipients can be self-tested at any waking hour to monitor performance via smartphone or tablet. Motivation, task-related fatigue, and chronotype did not affect the outcomes of ATT or DTT in the studied cohort. Word recognition in quiet is a good predictor for deciding whether the DTT should be included in an individual's remote test battery. At-home testing is reliable for cochlear implant recipients and offers an opportunity to provide care in a virtual hearing clinic setting.

The Effectiveness of the Interventions to Reduce Sound Levels in the ICU: A Systematic Review.

Excessive noise is ubiquitous in the ICU, and there is growing evidence of the negative impact on work performance of caregivers. This study aims to determine the effectiveness of interventions to reduce noise in the ICU. DATA SOURCES: Databases of PubMed, EMBASE, PsychINFO, CINAHL, and Web of Science were systematically searched from inception to September 14, 2022. STUDY SELECTION: Two independent reviewers assessed titles and abstracts against study eligibility criteria. Noise mitigating ICU studies were included when having at least one quantitative acoustic outcome measure expressed in A-weighted sound pressure level with an experimental, quasi-experimental, or observational design. Discrepancies were resolved by consensus, and a third independent reviewer adjudicated as necessary. DATA EXTRACTION: After title, abstract, and full-text selection, two reviewers independently assessed the quality of each study using the Cochrane's Risk Of Bias In Nonrandomized Studies of Interventions tool. Data were synthesized according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, and interventions were summarized. DATA SYNTHESIS: After screening 12,652 articles, 25 articles were included, comprising either a mixed group of healthcare professionals (n = 17) or only nurses (n = 8) from adult or PICU settings. Overall, the methodological quality of the studies was low. Noise reduction interventions were categorized into education (n = 4), warning devices (n = 3), multicomponent programs (n = 15), and architectural redesign (n = 3). Education, a noise warning device, and an architectural redesign significantly decreased the sound pressure levels. CONCLUSIONS: Staff education and visual alert systems seem promising interventions to reduce noise with a short-term effect. The evidence of the studied multicomponent intervention studies, which may lead to the best results, is still low. Therefore, high-quality studies with a low risk of bias and a long-term follow-up are warranted. Embedding noise shielding within the ICU-redesign is supportive to reduce sound pressure levels.

Genotype and Phenotype Analyses of a Novel WFS1 Variant (c.2512C>T p.(Pro838Ser)) Associated with DFNA6/14/38.

The aim of this study is to contribute to a better description of the genotypic and phenotypic spectrum of DFNA6/14/38 and aid in counseling future patients identified with this variant. Therefore, we describe the genotype and phenotype in a large Dutch-German family (W21-1472) with autosomal dominant non-syndromic, low-frequency sensorineural hearing loss (LFSNHL). Exome sequencing and targeted analysis of a hearing impairment gene panel were used to genetically screen the proband. Co-segregation of the identified variant with hearing loss was assessed by Sanger sequencing. The phenotypic evaluation consisted of anamnesis, clinical questionnaires, physical examination and examination of audiovestibular function. A novel likely pathogenic WFS1 variant (NM_006005.3:c.2512C>T p.(Pro838Ser)) was identified in the proband and found to co-segregate with LFSNHL, characteristic of DFNA6/14/38, in this family. The self-reported age of onset of hearing loss (HL) ranged from congenital to 50 years of age. In the young subjects, HL was demonstrated in early childhood. At all ages, an LFSNHL (0.25-2 kHz) of about 50-60 decibel hearing level (dB HL) was observed. HL in the higher frequencies showed inter-individual variability. The dizziness handicap inventory (DHI) was completed by eight affected subjects and indicated a moderate handicap in two of them (aged 77 and 70). Vestibular examinations (n = 4) showed abnormalities, particularly in otolith function. In conclusion, we identified a novel WFS1 variant that co-segregates with DFNA6/14/38 in this family. We found indications of mild vestibular dysfunction, although it is uncertain whether this is related to the identified WFS1 variant or is an incidental finding. We would like to emphasize that conventional neonatal hearing screening programs are not sensitive to HL in DFNA6/14/38 patients, because high-frequency hearing thresholds are initially preserved. Therefore, we suggest screening newborns in DFNA6/14/38 families with more frequency-specific methods.

Genetic Hearing Loss Affects Cochlear Processing.

The relationship between speech recognition and hereditary hearing loss is not straightforward. Underlying genetic defects might determine an impaired cochlear processing of sound. We obtained data from nine groups of patients with a specific type of genetic hearing loss. For each group, the affected cochlear site-of-lesion was determined based on previously published animal studies. Retrospectively obtained speech recognition scores in noise were related to several aspects of supra-threshold cochlear processing as assessed by psychophysical measurements. The differences in speech perception in noise between these patient groups could be explained by these factors and partially by the hypothesized affected structure of the cochlea, suggesting that speech recognition in noise was associated with a genetics-related malfunctioning of the cochlea. In particular, regression models indicate that loudness growth and spectral resolution best describe the cochlear distortions and are thus a good biomarker for speech understanding in noise.

Computational Audiology: New Approaches to Advance Hearing Health Care in the Digital Age.

The global digital transformation enables computational audiology for advanced clinical applications that can reduce the global burden of hearing loss. In this article, we describe emerging hearing-related artificial intelligence applications and argue for their potential to improve access, precision, and efficiency of hearing health care services. Also, we raise awareness of risks that must be addressed to enable a safe digital transformation in audiology. We envision a future where computational audiology is implemented via interoperable systems using shared data and where health care providers adopt expanded roles within a network of distributed expertise. This effort should take place in a health care system where privacy, responsibility of each stakeholder, and patients' safety and autonomy are all guarded by design.

Cortical Tonotopic Map Changes in Humans Are Larger in Hearing Loss Than in Additional Tinnitus.

Neural plasticity due to hearing loss results in tonotopic map changes. Several studies have suggested a relation between hearing loss-induced tonotopic reorganization and tinnitus. This large fMRI study on humans was intended to clarify the relations between hearing loss, tinnitus, and tonotopic reorganization. To determine the differential effect of hearing loss and tinnitus, both male and female participants with bilateral high-frequency hearing loss, with and without tinnitus, and a control group were included. In a total of 90 participants, bilateral cortical responses to sound stimulation were measured with loudness-matched pure-tone stimuli (0.25-8 kHz). In the bilateral auditory cortices, the high-frequency sound-evoked activation level was higher in both hearing-impaired participant groups, compared with the control group. This was most prominent in the hearing loss group without tinnitus. Similarly, the tonotopic maps for the hearing loss without tinnitus group were significantly different from the controls, whereas the maps of those with tinnitus were not. These results show that higher response amplitudes and map reorganization are a characteristic of hearing loss, not of tinnitus. Both tonotopic maps and response amplitudes of tinnitus participants appear intermediate to the controls and hearing loss without tinnitus group. This observation suggests a connection between tinnitus and an incomplete form of central compensation to hearing loss, rather than excessive adaptation. One implication of this may be that treatments for tinnitus shift their focus toward enhancing the cortical plasticity, instead of reversing it.SIGNIFICANCE STATEMENT Tinnitus, a common and potentially devastating condition, is the presence of a "phantom" sound that often accompanies hearing loss. Hearing loss is known to induce plastic changes in cortical and subcortical areas. Although plasticity is a valuable trait that allows the human brain to rewire and recover from injury and sensory deprivation, it can lead to tinnitus as an unwanted side effect. In this large fMRI study, we provide evidence that tinnitus is related to a more conservative form of reorganization than in hearing loss without tinnitus. This result contrasts with the previous notion that tinnitus is related to excessive reorganization. As a consequence, treatments for tinnitus may need to enhance the cortical plasticity, rather than reverse it.

Tinnitus- and Task-Related Differences in Resting-State Networks.

We investigated tinnitus-related differences in functional networks in adults with tinnitus by means of a functional connectivity study. Previously it was found that various networks show differences in connectivity in patients with tinnitus compared to controls. How this relates to patients' ongoing tinnitus and whether the ecological sensory environment modulates connectivity remains unknown.Twenty healthy controls and twenty patients suffering from chronic tinnitus were enrolled in this study. Except for the presence of tinnitus in the patient group, all subjects were selected to have normal or near-normal hearing. fMRI data were obtained in two different functional states. In one set of runs, subjects freely viewed emotionally salient movie fragments ("fixed-state") while in the other they were not performing any task ("resting-state"). After data pre-processing, Principal Component Analysis was performed to obtain 25 components for all datasets. These were fed into an Independent Component Analysis (ICA), concatenating the data across both groups and both datasets, to obtain group-level networks of neural origin, each consisting of spatial maps with their respective time-courses. Subject-specific maps and their time-course were obtained by back-projection (Dual Regression). For each of the components a mixed-effects linear model was composed with factors group (tinnitus vs. controls), task (fixed-state vs. resting state) and their interaction. The neural components comprised the visual, sensorimotor, auditory, and limbic systems, the default mode, dorsal attention, executive-control, and frontoparietal networks, and the cerebellum. Most notably, the default mode network (DMN) was less extensive and shows significantly less connectivity in tinnitus patients than in controls. This group difference existed in both paradigms. At the same time, the DMN was stronger during resting-state than during fixed-state in the controls but not the patients. We attribute this pattern to the unremitting engaging effect of the tinnitus percept.

A diffusion tensor imaging study on the auditory system and tinnitus.

Tinnitus is an auditory percept in the absence of an external sound source. Mechanisms in the central nervous system are believed to be key in the pathophysiology of tinnitus. Diffusion tensor imaging (DTI) is an MR imaging technique that allows in vivo exploration of white matter tissue in the human brain. Using a probabilistic DTI approach, we determined the characteristics of fiber tracts from the inferior colliculus to the medial geniculate body up to the primary auditory cortex. We also investigated the connections between the auditory system and the amygdala, which may be involved in some forms of tinnitus. White matter tracts were characterized by three quantities: the mean fractional anisotropy, the weighted mean fractional anisotropy and the path strength. All these quantities are measures of the patency of white matter tracts. The most important finding is an increased patency of the white matter tracts between the auditory cortex and the amygdala in tinnitus patients as compared to healthy controls.