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.

Cohort profile: Netherlands Longitudinal Study on Hearing (NL-SH).

PURPOSE: The Netherlands Longitudinal Study on Hearing (NL-SH) was set up to examine associations of hearing ability with psychosocial, work and health outcomes in working age adults. PARTICIPANTS: Inclusion started in 2006 and is ongoing. Currently the sample comprises 2800 adults with normal and impaired hearing, aged 18-70 years at inclusion. Five-year follow-up started in 2011, 10-year follow-up in 2016 and 15-year follow-up in 2021. All measurements are web-based. Participants perform a speech-in-noise recognition test to measure hearing ability and fill out questionnaires about their hearing status, hearing aid use, self-reported hearing disability and coping, work status and work-related outcomes (work performance, need for recovery), physical and psychosocial health (depression, anxiety, distress, somatisation, loneliness), healthcare usage, lifestyle (smoking, alcohol), and technology use. FINDINGS TO DATE: The NL-SH has shown the vast implications of reduced hearing ability for the quality of life and health of working-age adults. A selection of results published in 27 papers is presented. Age-related deterioration of hearing ability accelerates after the age of 50 years. Having a history of smoking is associated with a faster decline in hearing ability, but this relationship is not found for other cardiovascular risk factors. Poorer hearing ability is associated with increased distress, somatisation, depression and loneliness. Adults with impaired hearing ability are more likely to be unemployed or unfit for work, and need more time to recuperate from work effort. FUTURE PLANS: Participant data will be linked to a national database to enable research on the association between hearing ability and mortality. Linking to environmental exposure data will facilitate insight in relations between environmental factors, hearing ability and psychosocial outcomes. The unique breadth of the NL-SH data will also allow for further research on other functional problems, for instance, hearing ability and fall risk. TRIAL REGISTRATION NUMBER: NL12015.029.06.

Factors Associated With the Development of Tinnitus and With the Degree of Annoyance Caused by Newly Developed Tinnitus.

OBJECTIVES: Tinnitus is highly prevalent, but only a few risk factors for developing tinnitus are known and little is known about factors associated with the degree of annoyance of new-onset tinnitus. Longitudinal analysis can reveal risk factors associated with the development of tinnitus and might lead to targeted prevention. The aim of this study is twofold. (1) To identify risk factors that are longitudinally associated with the odds of developing tinnitus 5 years later. (2) To identify factors that are cross-sectionally associated with tinnitus annoyance in adults with new-onset tinnitus. METHODS: Baseline, 5-year, and 10-year follow-up data of participants in the Netherlands Longitudinal Study on Hearing (NL-SH) were used. The NL-SH is a web-based prospective cohort study, which started in 2006 and includes both normal hearing and hearing-impaired adults aged 18 to 70 years at baseline. The NL-SH uses an online digit-triplet speech-in-noise test to asses speech recognition ability in noise, and online questionnaires on various aspects of life. At follow-up, participants are asked (1) if they suffer from tinnitus and (2) to rate tinnitus annoyance on a 0 to 100 numeric rating scale. We investigated whether demographic (age, sex, living arrangement, educational level), lifestyle (history of tobacco smoking, alcohol use), health (asthma, severe heart disease, hypertension, history of stroke, osteoarthritis, rheumatoid arthritis, epilepsy, multiple sclerosis, and migraine), hearing (speech recognition ability in noise, hyperacusis, and occupational noise exposure), and psychological variables (distress, somatization, depression, and anxiety) were potential risk factors for new-onset tinnitus, or associated with annoyance caused by new-onset tinnitus. Generalized estimating equations were used to longitudinally analyze the association between potential risk factors and new-onset tinnitus measured 5 years later. A multivariable association model was constructed using a forward selection procedure with p < 0.05 for model entry. Linear regression analysis was used to cross-sectionally analyze the association between potential factors and tinnitus annoyance in new-onset tinnitus. For this purpose, a multivariable association model was constructed using a forward selection procedure with p <0.05 for model entry. RESULTS: In total, 734 participants without tinnitus at baseline were included, from which 137 participants reported to suffer from new-onset tinnitus 5 or 10 years later. Risk factors for new-onset tinnitus were history of smoking (odds ratio 1.5, 95% confidence interval [CI] 1.0 to 2.2, p = 0.027) and higher levels of somatization (odds ratio 2.0, 95% CI 1.2 to 3.3, overall p = 0.024). Factors associated with the degree of tinnitus annoyance were increased levels of anxiety (ß = 11.6, 95% CI 2.3-20.8, overall p = 0.035) and poor speech recognition ability in noise (ß = 13.5, 95% CI, 4.4 to 22.6, overall p = 0.014). CONCLUSIONS: Higher levels of somatization and a history of smoking were found to be risk factors for new-onset tinnitus 5 years later. Anxiety and poor speech recognition ability in noise were associated with higher degrees of tinnitus annoyance in new-onset tinnitus. Somatization deserves to be addressed in future research and clinical practice as it might provide part of a model for the development of chronic tinnitus.

Association of beta blocker use and hearing ability in adults: a cross-sectional study.

OBJECTIVES: To investigate the potential association between beta blocker use and hearing ability in adults and to discern whether this effect is dose-dependent. DESIGN: Cross-sectional analyses. Multiple linear regression was performed with hearing ability as the dependent variable and beta blocker use as the independent variable. The independent variable was classified into three dose categories for secondary analysis. Adjustments were made for age, gender, educational level, and tobacco smoking status. STUDY SAMPLE: 1636 adults, 75 of whom reported being on beta blockers, from the internet-based Netherlands Longitudinal Study on Hearing (NL-SH). RESULTS: No significant association was found between beta blocker use and hearing ability in noise. In the adjusted regressions, beta blocker use changed the speech reception threshold in noise (SRT) by -0.04 dB signal-to-noise ratio (SNR) (95%CI [-0.67 to 0.58], p = 0.890). Medium dose beta blocker use changed SRT by -0.42 dB SNR (95%CI [-1.38 to 0.71], p = 0.433), while a high dose changed it by -0.26 dB SNR (95%CI [-1.74 to 1.4], p = 0.767). CONCLUSIONS: No evidence was found for beta blocker-induced changes in hearing ability. Future studies on this topic should favour case-control and cohort study designs, while focussing on a hypertensive population to minimise confounding by indication.

Association between Speech Recognition in Noise and Risk Factors of Cardiovascular Disease.

INTRODUCTION: Risk factors for cardiovascular disease (CVD) are associated with sensorineural hearing loss. CVD risk factors are known to cluster and interact, thereby increasing the cumulative risk for CVD. Previously, using the database of the Netherlands Longitudinal Study on Hearing (NL-SH), an association was found between a history of smoking and an increased decline in speech recognition in noise over 10 years of follow-up. Prospectively limited data are available on the association between CVD risk factors, interactions of these risk factors, and hearing loss. In this study, data from the NL-SH were used to study the association between CVD risk factors and speech recognition in noise longitudinally. METHODS: Baseline, 5-year, and 10-year follow-up data of the NL-SH were included. The NL-SH is a web-based prospective cohort study which started in 2006. Participants were aged 18-70 years at baseline. Speech recognition in noise was determined with an online digit-triplet speech-in-noise test. In addition, participants completed online questionnaires on demographic, lifestyle, and health-related characteristics. The association of the ability to recognize speech in noise with CVD risk factors (i.e., obesity, rheumatoid arthritis [RA], hypertension, diabetes mellitus, and dyslipidemia) was analyzed longitudinally. We also analyzed the interaction between these risk factors (including age, sex, and history of smoking) and speech recognition in noise. RESULTS: None of the CVD risk factors or interactions of 2 CVD risk factors was significantly associated with a decline in SRT over time. Obesity (p = 0.016), RA (p = 0.027), and hypertension (p = 0.044) were associated with overall higher (more unfavorable) SRTs. No overall interactions between CVD risk factors were found. CONCLUSION: Obesity, RA, and hypertension were overall associated with a higher SRT, but no longitudinal associations between these or other CVD factors with SRTs were found. Also, no interactions between 2 CVD risk factors and SRTs were found. Although no longitudinal associations between CVD risk factors and decline in SRTs were found, clinicians should be alert about the concurrent association between CVD risk factors and hearing loss.

Spontaneous Tegmen Tympani Dehiscence: Causes and Treatment of Conductive Hearing Loss.

OBJECTIVE: Conductive hearing loss (CHL) commonly arises in patients with spontaneous dehiscence of the tegmen of the temporal bone with meningoencephalocele (SME). The aim of this study was to further investigate 1) the potential mechanisms for CHL in this setting; 2) hearing outcomes following surgery to address SME, and 3) the possible causes of persistent CHL following surgery. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS AND INTERVENTION: Seven patients (six female; nine ears) who underwent middle cranial fossa repair of SME and were found to have a tegmen tympani dehiscence from October 2010 to September 2014 were included in the study. MAIN OUTCOME MEASURES: Pre- and postoperative pure-tone audiometry. RESULTS: Eight of nine ears (89%) had audiometric hearing loss at presentation. Seven ears (78%) had an air bone gap of ≥15 dB; all of these had an encephalocele traversing the tegmen tympani defect, four had a middle ear effusion, and three had a simultaneous superior semicircular canal dehiscence (SSCCD). The CHL resolved postoperatively in four of seven ears. Two of the three ears with persistent CHL had SSCCD. Attic ossicular fixation was identified in the other patient and the CHL resolved after ossiculoplasty. CONCLUSIONS: CHL associated with SME can be attributed preoperatively to ossicular chain fixation and synchronous SSCCD as well as the more commonly cited cerebrospinal fluid effusion and prolapse of meningoencephalocele onto the ossicular chain. Persistent postoperative CHL can also occur due to SSCCD and ossicular fixation by adhesions.

10-Year Follow-Up Results of The Netherlands Longitudinal Study on Hearing: Trends of Longitudinal Change in Speech Recognition in Noise.

OBJECTIVES: Previous findings of longitudinal cohort studies indicate that acceleration in age-related hearing decline may occur. Five-year follow-up data of the Netherlands Longitudinal Study on Hearing (NL-SH) showed that around the age of 50 years, the decline in speech recognition in noise accelerates compared with the change in hearing in younger participants. Other longitudinal studies confirm an accelerated loss in speech recognition in noise but mostly use older age groups as a reference. In the present study, we determined the change in speech recognition in noise over a period of 10 years in participants aged 18 to 70 years at baseline. We additionally investigated the effects of age, sex, educational level, history of tobacco smoking, and alcohol use on the decline of speech recognition in noise. DESIGN: Baseline (T0), 5-year (T1), and 10-year (T2) follow-up data of the NL-SH collected until May 2017 were included. The NL-SH is a web-based prospective cohort study which started in 2006. Central to the NL-SH is the National Hearing test (NHT) which was administered to the participants at all three measurement rounds. The NHT uses three-digit sequences which are presented in a background of stationary noise. The listener is asked to enter the digits using the computer keyboard. The outcome of the NHT is the speech reception threshold in noise (SRT) (i.e., the signal to noise ratio where a listener recognizes 50% of the digit triplets correctly). In addition to the NHT, participants completed online questionnaires on demographic, lifestyle, and health-related characteristics at T0, T1, and T2. A linear mixed model was used for the analysis of longitudinal changes in SRT. RESULTS: Data of 1349 participants were included. At the start of the study, the mean age of the participants was 45 years (SD 13 years) and 61% of the participants were categorized as having good hearing ability in noise. SRTs significantly increased (worsened) over 10 years (p < 0.001). After adjustment for age, sex, and a history of tobacco smoking, the mean decline over 10 years was 0.89 dB signal to noise ratio. The decline in speech recognition in noise was significantly larger in groups aged 51 to 60 and 61 to 70 years compared with younger age groups (18 to 30, 31 to 40, and 41 to 50 years) (p < 0.001). Speech recognition in noise in participants with a history of smoking declined significantly faster during the 10-year follow-up interval (p = 0.003). Sex, educational level, and alcohol use did not appear to influence the decline of speech recognition in noise. CONCLUSIONS: This study indicated that speech recognition in noise declines significantly over a 10-year follow-up period in adults aged 18 to 70 years at baseline. It is the first longitudinal study with a 10-year follow-up to reveal that the increased rate of decline in speech recognition ability in noise already starts at the age of 50 years. Having a history of tobacco smoking increases the decline of speech recognition in noise. Hearing health care professionals should be aware of an accelerated decline of speech recognition in noise in adults aged 50 years and over.

Surgical Management of a Persistent Stapedial Artery: A Review.

OBJECTIVE: To evaluate the outcome and per- and postoperative complications of the surgical management of patients with a persistent stapedial artery (PSA). METHODS: A systemic literature search for reports on patients treated for pulsatile tinnitus and/or conductive hearing loss caused by a PSA was conducted of the PubMed and Embase databases using the terms "stapedial" and "artery." Inclusion criteria were adequate description of the intervention and pre- and postoperative signs and symptoms. In addition, one case of a PSA, treated at VU University Medical Center Amsterdam, The Netherlands, was included in this series. INTERVENTION: Middle ear surgery consisting of stapedotomy or stapedectomy, and/or transection of the PSA. MAIN OUTCOME MEASURES: Pre- and postoperative hearing levels, pre- and postoperative pulsatile tinnitus, and per- and postoperative complications. RESULTS: Seventeen patients and 18 operated ears were evaluated (16 patients described in 14 articles and our case). Twelve out of 14 ears in which a stapedotomy or stapedectomy was initiated experienced improvement in hearing. In four cases pulsatile tinnitus was described pre- and postoperatively. In all four, pulsatile tinnitus subsided after transection of the PSA. Peroperative bleeding from the PSA was described in four patients, which could be controlled during the procedure. No significant postoperative sequelae were reported. CONCLUSIONS: In case of a PSA, improvement of conductive hearing loss is best achieved by stapes surgery, while pulsatile tinnitus is effectively treated with transection of the PSA. To date no long-term postoperative complications have been reported.

Atherosclerotic tissue characterization in vivo by optical coherence tomography attenuation imaging.

Optical coherence tomography (OCT) is rapidly becoming the method of choice for assessing arterial wall pathology in vivo. Atherosclerotic plaques can be diagnosed with high accuracy, including measurement of the thickness of fibrous caps, enabling an assessment of the risk of rupture. While the OCT image presents morphological information in highly resolved detail, it relies on interpretation of the images by trained readers for the identification of vessel wall components and tissue type. We present a framework to enable systematic and automatic classification of atherosclerotic plaque constituents, based on the optical attenuation coefficient mu(t) of the tissue. OCT images of 65 coronary artery segments in vitro, obtained from 14 vessels harvested at autopsy, are analyzed and correlated with histology. Vessel wall components can be distinguished based on their optical properties: necrotic core and macrophage infiltration exhibit strong attenuation, mu(t)>or=10 mm(-1), while calcific and fibrous tissue have a lower mu(t) approximately 2-5mm(-1). The algorithm is successfully applied to OCT patient data, demonstrating that the analysis can be used in a clinical setting and assist diagnostics of vessel wall pathology.