National Institute on Deafness and Other Communication Disorders

Emerging evidence in animal models and humans suggests that statins may provide partial protection against noise-induced and drug-induced hearing loss. However, evidence for protection against age-related hearing loss (ARHL) is mixed, and longitudinal studies in large adult cohorts from the general population are limited. This study examined the association between statin use and ARHL in a diverse, community-based longitudinal cohort of adults across the lifespan. The 1239 participants, aged ≥ 55 years, are from the MUSC Longitudinal Cohort Study of Age-Related Hearing Loss (1988-present). Following a comprehensive baseline examination, participants attended annual examinations during which audiometric and statin use data were collected. Multivariable linear regression models were performed on baseline data for cross-sectional analyses, and general linear mixed models were performed on longitudinal data to assess the association between statin use, two types of statins, and hearing over time. Hearing outcomes include four pure-tone averages (PTA): narrow (0.5, 1.0, 2.0, and 4.0 kHz), low frequency (0.25, 0.5, and 1.0 kHz), broad (0.5, 1.0, 2.0, 3.0, 4.0, 6.0, and 8.0 kHz), and high frequency (2.0, 3.0, 4.0, 6.0, and 8.0 kHz). Missing covariate data were imputed with multiple imputation using chain equations (MICE). Statin use (versus no use) was associated with better hearing at baseline for the broad and high-frequency PTAs for adults aged 55-64 and 65-74 years. However, this statin benefit was not observed for the 75+-year age group and for all participants when hearing was examined over time. Without age stratification, similar results were observed for atorvastatin use but not for simvastatin use. Overall, the findings suggest statin benefits for mid-to-high frequency hearing for middle-aged to older adults at early stages of ARHL. On the basis of evidence suggesting that some statins have beneficial effects on hearing, well-controlled clinical trials are needed to examine effects of statin use and statin types on ARHL in the general population.

ObjectiveForce platforms are widely used to assess postural stability and fall risk in older adults. However, traditional parameters often capture overlapping phenomena and fail to fully reflect underlying control mechanisms. This study evaluated combining of six partly independent parameters to distinguish sex and age-related differences in postural control among community-dwelling elderly.MethodsA total of 4,588 adults aged 65–95 years were assessed using static posturography under non-visual conditions. Six time-domain parameters, reflecting torque control, positional control and anticipatory control of the center point of force. Romberg’s quotient was included for comparison.ResultsFemales exhibited greater stability, whereas males relied more on corrective force moments and showed larger sway amplitudes. Classification trees predicted sex with 71% accuracy using three parameters. Aging was associated with increased anteroposterior sway amplitude and a reduction in the critical time for transition between open- and closed-loop control. Additional age-sensitive parameters included mediolateral velocity zero-crossing rate and steady-phase duration. Age could be predicted within ±5 years for both sexes. Romberg’s quotient could discriminate age in 30% and sex differences in 60% of participants, only.ConclusionPostural stability is influenced by both sex and age. The identified combination of parameters provides a framework for estimating the “biological age” of postural control and investigate balance impairments. Age-related decline appears consistent within a 5-year range, bur does not exclude the effect of lifestyle or comorbid factors. This study demonstrates that use of multidimensional data vectors with the implementation of AI-modeling can improve the predictive accuracy and clinical applicability of posturography.

Background:Few studies have evaluated ototoxic effects of in utero antiretroviral (ARV) exposure on hearing in children HIV-exposed uninfected (CHEU). Concerns have been identified for some ARVs: tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), lamivudine (3TC), zidovudine (ZDV), and atazanavir (ATV). The aims are to describe hearing outcomes in 5-year-old CHEU in the Surveillance Monitoring for ART Toxicities study and evaluate their association with in utero ARV exposures.Methods:Hearing evaluations including pure tone thresholds and distortion product otoacoustic emissions (DPOAEs) were completed in CHEU at 5 years. Log-binomial regression models were fit to assess associations of maternal ARV exposures with risk of sensorineural hearing loss (SNHL) and incomplete DPOAE responses.Results:Among 1078 CHEU, 13% had SNHL. Among those exposed <13 weeks gestation, there was 28% higher risk (95% CI: −37%, 158%) of SNHL with TDF/FTC with ATV and 38% lower risk (95% CI: −68%, 19%) with ZDV/3TC without ATV than for regimens containing TDF/FTC without ATV. There was a higher risk of incomplete DPOAE responses for ZDV/3TC without ATV and lower risk for TDF/FTC with ATV. For CHEU with first ARV exposure at 13-26 weeks gestation, those exposed to TDF/FTC with ATV or ZDV/3TC without ATV had lower risk for SNHL compared to TDF/FTC without ATV. Despite nontrivial relative risks, all confidence intervals were wide.Conclusion:While SNHL was relatively common, there were no consistent associations between in utero ARV exposure and SNHL or incomplete DPOAEs. Further research is needed on ARV exposures and other hearing measures in CHEU.

BACKGROUNDCisplatin is often the cytotoxic drug of choice for chemoradiation therapy (CRT) for head and neck squamous cell carcinoma (HNSCC), but it can lead to irreversible hearing loss. There may be similar oncologic outcomes but different toxicity profiles depending on whether cisplatin is given at 75–100 mg/m2 every 3 weeks or 30–40 mg/mg2 weekly. This study compares cisplatin-induced hearing loss in patients with HNSCC receiving similar cumulative doses of cisplatin administered either on higher-dose or lower-dose treatment schedules.METHODSUsing the Enhancing Cancer Hearing Outcomes (ECHO) dataset from 5 academic centers, we conducted a multicenter retrospective cohort study of adults (≥18 years) with HNSCC receiving cisplatin-based CRT. Participants were grouped by cisplatin dose schedule: every 3 weeks (≥75 mg/m²) or weekly (<75 mg/m²). Hearing loss was assessed using American Speech-Language-Hearing Association (ASHA) and Common Terminology Criteria for Adverse Events (CTCAE) v5.0 threshold shift criteria based on audiograms obtained ≤120 days before and after treatment. Risk differences and predictors of hearing loss were evaluated using χ2 analyses and multivariate regression. Kaplan-Meier curves assessed overall and disease-free survival.RESULTSAmong 564 participants (1,127 ears), lower-dose weekly cisplatin was associated with significantly lower incidence of hearing loss (ASHA criteria: 57% vs. 82%; CTCAE criteria: 39% vs. 69%). CTCAE grade ≥2 hearing loss occurred in 18% of the weekly group versus 50% of the 3-week group. Multivariate analysis confirmed treatment schedule as an independent predictor of ototoxicity. Two-year survival outcomes did not differ between groups.CONCLUSIONSWeekly low-dose cisplatin significantly reduced the incidence and severity of hearing loss without compromising survival, supporting its broader use in CRT for HNSCC.

During development, inner hair cells (IHCs) in the mammalian cochlea are unresponsive to acoustic stimuli but instead exhibit spontaneous activity. During this same period, neurons originating from the medial olivocochlear (MOC) complex transiently innervate IHCs, regulating their firing pattern which is crucial for the correct development of the auditory pathway. Although the MOC-IHC is a cholinergic synapse, previous evidence indicates the widespread presence of gamma-aminobutyric acid (GABA) signaling markers, including presynaptic GABAB receptors (GABABR). In this study, we explore the source of GABA by optogenetically activating either cholinergic or GABAergic fibers. The optogenetic stimulation of MOC terminals from GAD;ChR2-eYFP and ChAT;ChR2-eYFP mice (of either sex) evoked synaptic currents in IHCs, which were blocked by α-bungarotoxin. This suggests that GABAergic fibers release acetylcholine (ACh) and activate α9α10 nicotinic acetylcholine receptors (nAChRs). Additionally, MOC cholinergic fibers release not only ACh but also GABA, as the effect of GABA on ACh response amplitude was prevented by applying a GABABR blocker. Using optical neurotransmitter detection and calcium imaging techniques, we examined the extent of GABAergic modulation at the single synapse level. Our findings suggest heterogeneity in GABA modulation, as only 15 out of 31 recorded synaptic sites were modulated by applying the GABABR specific antagonist, CGP 35348 (100-200 µM). In conclusion, we provide evidence indicating that GABA and ACh are co-released from at least a subset of MOC terminals. In this circuit, GABA functions as a negative feedback mechanism, locally regulating the extent of cholinergic inhibition at certain efferent→IHC synapses during an immature stage.

Laboratory-based word learning research demonstrates that retrieval-based practice supports learning and retention more than passive training strategies. The goal of the current study was to determine whether incorporating retrieval-based practice into an interactive book reading intervention contributed to better learning and retention for children with developmental language disorder (DLD) than a more passive version. Kindergarten children with DLD (N = 37) completed the intervention administered twice a week for a total of 15 sessions. The between-participants conditions varied in the proportion of retrieval opportunities (high, mid, low). Learning of word forms and meanings were assessed throughout training, immediately after training, and after 4-, 8-, and 12-week delays. The proportion of retrieval opportunities did not relate to learning or retention. Children who started the intervention with more language knowledge and skills produced more forms and meanings correctly during and after treatment. Few factors related to the learning and forgetting rates. Maternal education related positively to learning rate of forms. Children who produced more definitions during training and females, as opposed to males, demonstrated a shallower forgetting rate of definitions. Both the more passive version and the retrieval-based version of the intervention were effective to support word learning in children with DLD. Overall, pretreatment characteristics did not provide a good indication of children's learning rate or posttraining forgetting rate. Thus, it is likely that frequent assessments during training are the best indicator of intervention effectiveness for a given child. Additionally, retention should be periodically assessed post-intervention to monitor forgetting. https://doi.org/10.23641/asha.29696552.

ABSTRACTMethionine sulfoxide reductases (MSRs) are enzymes responsible for catalyzing the reduction of methionine sulfoxides. We previously demonstrated that variants in human MSRB3, an MSR family member, are associated with profound autosomal recessive prelingual non-syndromic deafness, DFNB74. To better understand the role of MSRB3 in the auditory pathway, we generated complete Msrb3 gene knockout mice. The Msrb3-deficient mice showed profound deafness by postnatal day 16, which was accompanied by morphological abnormalities including altered stereocilia bundle shape and cuticular plate degeneration, followed by hair cell apoptotic death. Although the absence of MSRB3 primarily affected the actin cytoskeleton, rootlets were present, and the localization of major F-actin stereocilia-core proteins was unaltered. Biochemical assays demonstrated that wild-type MSRB3, but not MSRB3 harboring p.Cys89Gly, the same variant reported for DFNB74, can repolymerize oxidized actin. Consistent with these results, we observed a decreased ratio of reduced/total actin in the inner ears of Msrb3 knockout mice. These data suggest a protective role for MSRB3 in the maintenance and maturation of stereocilia and hair cells, a conserved mechanism aimed at maintaining actin redox dynamics in these sensory cells.

Pathogenic variants in the gene TMPRSS3 are a common cause of hearing loss in humans, although the causal mechanisms remain unknown. Previous work has shown that Tmprss3Y260X/Y260X mice exhibit normal hair cell development, mechanosensory transduction, and spiral ganglion patterning, but experience rapid hair cell death from P12 to P14 at the onset of hearing. Here, we demonstrate that Tmprss3Y260X/Y260X mice display an early and temporary spike in endocochlear potential (EP) prior to the onset of hair cell death. In vitro experiments with cochlear explants from Tmprss3Y260X/Y260X mice and in vivo studies with Tmprss3Y260X/Y260X mice crossed with 2 different mutant models that lacked EP generation promoted hair cell survival. Furthermore, systemic administration of furosemide, a drug that reduces EP in vivo, reduced hair cell death in Tmprss3Y260X/Y260X mice. These findings suggest that extracellular factors, including EP, play a role in TMPRSS3-related hair cell survival and hearing loss, and suggest that modulating EP could be a therapeutic strategy.

Abstract Sensory cells in the retina and inner ear rely on specialized ribbon synapses for neurotransmission. Disruption of these synapses is linked to visual and auditory dysfunction, but it is unclear how these unique synapses form. Ribbon synapses are defined by a presynaptic density called a ribbon. Using live imaging in zebrafish hair cells, we find that numerous small ribbon precursors are present throughout the cell early in development. As development progresses, fewer large ribbons remain, and localize at the presynaptic active zone (AZ). Using tracking analyses, we show that ribbon precursors exhibit directed motion along an organized microtubule network to reach the presynaptic AZ. In addition, we show that ribbon precursors can fuse together on microtubules. Using pharmacology, we find that microtubule disruption interferes with ribbon motion, fusion, and normal synapse formation. Overall, this work demonstrates a dynamic series of events that underlies the formation of a critical synapse required for sensory function.

Abstract Chronic pain is a global epidemic that disproportionately affects Black, Indigenous, and other people of color as well as individuals of lower socioeconomic status. Unfortunately, the mechanisms that cause and sustain disparities in pain outcomes remain underexamined. This review highlights recent insights into epigenetics as a uniquely suited biological mechanism linking environmental stressors and pain disparities. Emerging evidence suggests that epigenetic modification of genes in pathways involved in stress dysregulation and neuroinflammation may play a central role in racial pain disparities and internalized stigma. These findings indicate that differential environmental exposure (ie, chronic stress) induces epigenetic changes (mediators) that explain pain disparities. Another putative mechanism by which differential epigenetic modifications contribute to pain disparities is epigenetic age acceleration. Emerging evidence suggests that epigenetic age acceleration mediates the relationship between lower socioeconomic status (household income, food insecurity, and neighborhood deprivation) and worse pain outcomes. Epigenetic modifications are dynamic and reversible, leaning toward pharmacological and nonpharmacological interventions. Logically, these will contribute to tailored interventions for pain management and equity in pain management. Finally, we cannot ignore that social and structural forces are the root causes of pain disparities. Thus, there is a need for policy changes addressing these forces.