Clinical, Biomarker, and Research Tests Among US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: Since 2015, US government and related personnel have reported dizziness, pain, visual problems, and cognitive dysfunction after experiencing intrusive sounds and head pressure. The US government has labeled these anomalous health incidents (AHIs). Objective: To assess whether participants with AHIs differ significantly from US government control participants with respect to clinical, research, and biomarker assessments. Design, Setting, and Participants: Exploratory study conducted between June 2018 and July 2022 at the National Institutes of Health Clinical Center, involving 86 US government staff and family members with AHIs from Cuba, Austria, China, and other locations as well as 30 US government control participants. Exposures: AHIs. Main Outcomes and Measures: Participants were assessed with extensive clinical, auditory, vestibular, balance, visual, neuropsychological, and blood biomarkers (glial fibrillary acidic protein and neurofilament light) testing. The patients were analyzed based on the risk characteristics of the AHI identifying concerning cases as well as geographic location. Results: Eighty-six participants with AHIs (42 women and 44 men; mean [SD] age, 42.1 [9.1] years) and 30 vocationally matched government control participants (11 women and 19 men; mean [SD] age, 43.8 [10.1] years) were included in the analyses. Participants with AHIs were evaluated a median of 76 days (IQR, 30-537) from the most recent incident. In general, there were no significant differences between participants with AHIs and control participants in most tests of auditory, vestibular, cognitive, or visual function as well as levels of the blood biomarkers. Participants with AHIs had significantly increased fatigue, depression, posttraumatic stress, imbalance, and neurobehavioral symptoms compared with the control participants. There were no differences in these findings based on the risk characteristics of the incident or geographic location of the AHIs. Twenty-four patients (28%) with AHI presented with functional neurological disorders. Conclusions and Relevance: In this exploratory study, there were no significant differences between individuals reporting AHIs and matched control participants with respect to most clinical, research, and biomarker measures, except for objective and self-reported measures of imbalance and symptoms of fatigue, posttraumatic stress, and depression. This study did not replicate the findings of previous studies, although differences in the populations included and the timing of assessments limit direct comparisons.

Neuroimaging Findings in US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: US government personnel stationed internationally have reported anomalous health incidents (AHIs), with some individuals experiencing persistent debilitating symptoms. Objective: To assess the potential presence of magnetic resonance imaging (MRI)-detectable brain lesions in participants with AHIs, with respect to a well-matched control group. Design, Setting, and Participants: This exploratory study was conducted at the National Institutes of Health (NIH) Clinical Center and the NIH MRI Research Facility between June 2018 and November 2022. Eighty-one participants with AHIs and 48 age- and sex-matched control participants, 29 of whom had similar employment as the AHI group, were assessed with clinical, volumetric, and functional MRI. A high-quality diffusion MRI scan and a second volumetric scan were also acquired during a different session. The structural MRI acquisition protocol was optimized to achieve high reproducibility. Forty-nine participants with AHIs had at least 1 additional imaging session approximately 6 to 12 months from the first visit. Exposure: AHIs. Main Outcomes and Measures: Group-level quantitative metrics obtained from multiple modalities: (1) volumetric measurement, voxel-wise and region of interest (ROI)-wise; (2) diffusion MRI-derived metrics, voxel-wise and ROI-wise; and (3) ROI-wise within-network resting-state functional connectivity using functional MRI. Exploratory data analyses used both standard, nonparametric tests and bayesian multilevel modeling. Results: Among the 81 participants with AHIs, the mean (SD) age was 42 (9) years and 49% were female; among the 48 control participants, the mean (SD) age was 43 (11) years and 42% were female. Imaging scans were performed as early as 14 days after experiencing AHIs with a median delay period of 80 (IQR, 36-544) days. After adjustment for multiple comparisons, no significant differences between participants with AHIs and control participants were found for any MRI modality. At an unadjusted threshold (P < .05), compared with control participants, participants with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala. The structural MRI measurements were highly reproducible (median coefficient of variation <1% across all global volumetric ROIs and <1.5% for all white matter ROIs for diffusion metrics). Even individuals with large differences from control participants exhibited stable longitudinal results (typically, <±1% across visits), suggesting the absence of evolving lesions. The relationships between the imaging and clinical variables were weak (median Spearman ρ = 0.10). The study did not replicate the results of a previously published investigation of AHIs. Conclusions and Relevance: In this exploratory neuroimaging study, there were no significant differences in imaging measures of brain structure or function between individuals reporting AHIs and matched control participants after adjustment for multiple comparisons.

Evaluating Quality, Credibility, and Readability of Online Over-the-Counter Hearing Aid Information.

OBJECTIVE: With over-the-counter hearing aids being recently approved by the United States Food and Drug Administration, the accuracy and usefulness of online information has not yet been examined. This study evaluates the quality, credibility, readability, and accessibility of online over-the-counter hearing aids education materials. METHODS: Google was queried using the search term "over-the-counter hearing aids". The top 50 results were categorized into healthcare versus non-healthcare authored resources. The Flesch Reading Ease Score (FRES) and Flesch-Kincaid Grade Level (FKGL) tests were utilized to assess readability, whereas the Currency, Relevance, Authority, Accuracy, and Purpose (CRAAP) test and DISCERN instruments were used to assess quality and credibility. The number of clicks taken to access relevant information on each website was used to assess accessibility. RESULTS: There was no significant difference in FRES or FKGL readability scores between healthcare and non-healthcare authored websites (p = 0.5548, p = 0.5981, respectively), but both readability scores were higher than that of the recommended reading level for patient education materials. There was no significant difference in CRAAP and DISCERN scores between both groups (p = 0.5746, p = 0.1699, respectively). The number of clicks did not significantly differ between healthcare and non-healthcare authored resources (p = 0.4932). CONCLUSION: This study highlights poor readability and accessibility of virtual healthcare information regarding OTC hearing aids. Although credibility in articles authored by healthcare and non-healthcare professionals was adequate, readability was greatly compromised due to the written information exceeding the recommended United States reading level. Accessibility posed a similar issue, as many sites required multiple clicks to access product information. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3302-3309, 2024.

Molecular differences between neonatal and adult stria vascularis from organotypic explants and transcriptomics.

Summary: The stria vascularis (SV), part of the blood-labyrinth barrier, is an essential component of the inner ear that regulates the ionic environment required for hearing. SV degeneration disrupts cochlear homeostasis, leading to irreversible hearing loss, yet a comprehensive understanding of the SV, and consequently therapeutic availability for SV degeneration, is lacking. We developed a whole-tissue explant model from neonatal and adult mice to create a robust platform for SV research. We validated our model by demonstrating that the proliferative behaviour of the SV in vitro mimics SV in vivo, providing a representative model and advancing high-throughput SV research. We also provided evidence for pharmacological intervention in our system by investigating the role of Wnt/ß-catenin signaling in SV proliferation. Finally, we performed single-cell RNA sequencing from in vivo neonatal and adult mouse SV and revealed key genes and pathways that may play a role in SV proliferation and maintenance. Together, our results contribute new insights into investigating biological solutions for SV-associated hearing loss. Significance: Hearing loss impairs our ability to communicate with people and interact with our environment. This can lead to social isolation, depression, cognitive deficits, and dementia. Inner ear degeneration is a primary cause of hearing loss, and our study provides an in depth look at one of the major sites of inner ear degeneration: the stria vascularis. The stria vascularis and associated blood-labyrinth barrier maintain the functional integrity of the auditory system, yet it is relatively understudied. By developing a new in vitro model for the young and adult stria vascularis and using single cell RNA sequencing, our study provides a novel approach to studying this tissue, contributing new insights and widespread implications for auditory neuroscience and regenerative medicine. Highlights: - We established an organotypic explant system of the neonatal and adult stria vascularis with an intact blood-labyrinth barrier. - Proliferation of the stria vascularis decreases with age in vitro , modelling its proliferative behaviour in vivo . - Pharmacological studies using our in vitro SV model open possibilities for testing injury paradigms and therapeutic interventions. - Inhibition of Wnt signalling decreases proliferation in neonatal stria vascularis.- We identified key genes and transcription factors unique to developing and mature SV cell types using single cell RNA sequencing.

Variability in Perioperative Steroid Therapy Regimen for Cochlear Implantation as It Relates to Hearing Preservation.

HYPOTHESIS: We aimed to identify practice trends and association between physician training and administration of perioperative steroids for cochlear implantation (CI) as it relates to hearing preservation. BACKGROUND: Perioperative steroid therapy regimens are postulated to protect residual hearing and improve hearing preservation outcomes in CI. METHODS: A 27-question online survey was developed by the senior authors using the Qualtrics Survey Tool, then distributed via email from September to November 2022 to otolaryngologists specializing in otology or neurotology and who practice in the United States or Canada. RESULTS: The survey was sent to 463 physicians, 162 (35.0%) of whom completed the survey. One hundred forty-four (31.1%) responses underwent analysis. All physicians administering preoperative steroids (n = 31) prefer preoperative oral prednisone. Of 143 physicians administering intraoperative steroids, 54.5% prefer intraoperative intravenous dexamethasone. More than half (77.6%) of 85 physicians administering postoperative steroids prefer postoperative oral prednisone. Postoperative steroid administration (p < 0.006) and taper utilization (p < 0.041) were greater among physicians who complete greater than 40 CIs annually (n = 47 [71.2%]; n = 30 [49.2%]) than physicians who complete up to 40 CIs annually (n = 37 [48.7%]; n = 20 [31.3%]), respectively. Physicians practicing for 5 to 20 years after residency are more prevalent in using postoperative steroid tapers than physicians practicing for fewer than 5 years after and more than 20 years after residency (n = 37 [51.4%] versus n = 14 [25.5%], p < 0.001). CONCLUSION: Consensus is needed about the optimal steroid treatment for CI patients. LEVEL OF EVIDENCE: 4.

Transgenic Tg(Kcnj10-ZsGreen) fluorescent reporter mice allow visualization of intermediate cells in the stria vascularis.

The stria vascularis (SV) is a stratified epithelium in the lateral wall of the mammalian cochlea, responsible for both endolymphatic ion homeostasis and generation of the endocochlear potential (EP) critical for normal hearing. The SV has three layers consisting predominantly of basal, intermediate, and marginal cells. Intermediate and marginal cells form an intricate interdigitated network of cell projections making discrimination of the cells challenging. To enable intermediate cell visualization, we engineered by BAC transgenesis, reporter mouse lines expressing ZsGreen fluorescent protein under the control of Kcnj10 promoter and regulatory sequences. Kcnj10 encodes KCNJ10 protein (also known as Kir4.1 or Kir1.2), an ATP-sensitive inwardly-rectifying potassium channel critical to EP generation, highly expressed in SV intermediate cells. In these transgenic mice, ZsGreen fluorescence mimics Kcnj10 endogenous expression in the cochlea and was detected in the intermediate cells of the SV, in the inner phalangeal cells, Hensen's, Deiters' and pillar cells, in a subset of spiral ganglion neurons, and in glial cells. We show that expression of the transgene in hemizygous mice does not alter auditory function, nor EP. These transgenic Tg(Kcnj10-ZsGreen) mice allow live and fixed tissue visualization of ZsGreen-expressing intermediate cells and will facilitate future studies of stria vascularis cell function.

Deafness DFNB128 Associated with a Recessive Variant of Human MAP3K1 Recapitulates Hearing Loss of Map3k1-Deficient Mice.

Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many mutant genes causing rare forms of deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic deafness in two sibships were studied using microarrays and exome sequencing. A 1.2 Mb locus (DFNB128) on chromosome 5q11.2 encompassing six genes was identified. In one of the two sibships of this family, a novel homozygous recessive variant NM_005921.2:c.4460G>A p.(Arg1487His) in the kinase domain of MAP3K1 co-segregated with nonsyndromic deafness. There are two previously reported Map3k1-kinase-deficient mouse models that are associated with recessively inherited syndromic deafness. MAP3K1 phosphorylates serine and threonine and functions in a signaling pathway where pathogenic variants of HGF, MET, and GAB1 were previously reported to be associated with human deafness DFNB39, DFNB97, and DFNB26, respectively. Our single-cell transcriptome data of mouse cochlea mRNA show expression of Map3k1 and its signaling partners in several inner ear cell types suggesting a requirement of wild-type MAP3K1 for normal hearing. In contrast to dominant variants of MAP3K1 associated with Disorders of Sex Development 46,XY sex-reversal, our computational modeling of the recessive substitution p.(Arg1487His) predicts a subtle structural alteration in MAP3K1, consistent with the limited phenotype of nonsyndromic deafness.

MRI Screening in Vestibular Schwannoma: A Deep Learning-based Analysis of Clinical and Audiometric Data.

Objective: To find a more objective method of assessing which patients should be screened for a vestibular schwannoma (VS) with magnetic resonance imaging (MRI) using a deep-learning algorithm to assess clinical and audiometric data. Materials and Methods: Clinical and audiometric data were collected for 592 patients who received an audiogram between January 2015 and 2020 at Duke University Health Center with and without VS confirmed by MRI. These data were analyzed using a deep learning-based analysis to determine if the need for MRI screening could be assessed more objectively with adequate sensitivity and specificity. Results: Patients with VS showed slightly elevated, but not statistically significant, mean thresholds compared to those without. Tinnitus, gradual hearing loss, and aural fullness were more common in patients with VS. Of these, only the presence of tinnitus was statistically significant. Several machine learning algorithms were used to incorporate and model the collected clinical and audiometric data, but none were able to distinguish ears with and without confirmed VS. When tumor size was taken into account the analysis was still unable to distinguish a difference. Conclusions: Using audiometric and clinical data, deep learning-based analyses failed to produce an adequately sensitive and specific model for the detection of patients with VS. This suggests that a specific pattern of audiometric asymmetry and clinical symptoms may not necessarily be predictive of the presence/absence of VS to a level that clinicians would be comfortable forgoing an MRI.

In Silico Localization of Perilymph Proteins Enriched in Menier̀e Disease Using Mammalian Cochlear Single-cell Transcriptomics.

Hypothesis: Proteins enriched in the perilymph proteome of Menier̀e disease (MD) patients may identify affected cell types. Utilizing single-cell transcriptome datasets from the mammalian cochlea, we hypothesize that these enriched perilymph proteins can be localized to specific cochlear cell types. Background: The limited understanding of human inner ear pathologies and their associated biomolecular variations hinder efforts to develop disease-specific diagnostics and therapeutics. Perilymph sampling and analysis is now enabling further characterization of the cochlear microenvironment. Recently, enriched inner ear protein expression has been demonstrated in patients with MD compared to patients with other inner ear diseases. Localizing expression of these proteins to cochlear cell types can further our knowledge of potential disease pathways and subsequent development of targeted therapeutics. Methods: We compiled previously published data regarding differential perilymph proteome profiles amongst patients with MD, otosclerosis, enlarged vestibular aqueduct, sudden hearing loss, and hearing loss of undefined etiology (controls). Enriched proteins in MD were cross-referenced against published single-cell/single-nucleus RNA-sequencing datasets to localize gene expression to specific cochlear cell types. Results: In silico analysis of single-cell transcriptomic datasets demonstrates enrichment of a unique group of perilymph proteins associated with MD in a variety of intracochlear cells, and some exogeneous hematologic and immune effector cells. This suggests that these cell types may play an important role in the pathology associated with late MD, suggesting potential future areas of investigation for MD pathophysiology and treatment. Conclusions: Perilymph proteins enriched in MD are expressed by specific cochlear cell types based on in silico localization, potentially facilitating development of disease-specific diagnostic markers and therapeutics.

Cochlear Implantation in Noonan Syndrome With and Without Multiple Lentigines: A Case Report and Systematic Review.

Objectives: To describe outcomes after bilateral cochlear implantation (CI) in a patient with a pathologic PTPN11 variant associated with Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML). Additionally, to assess the utility of CI in this specific population based on our outcome and previous reports. Study Design: Retrospective case report with literature review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Patients: A young boy with various multiorgan abnormalities, speech and language delay, and persistent hearing loss who was found to have a heterozygous PTPN11 gene mutation at age 2. Interventions: Bilateral tympanostomy tube placement, diagnostic imaging, and eventual staged bilateral CI. Main Outcome Measures: Objective audiometric testing and developmental milestone attainment. Results: Bilateral CI was successfully completed over a 2-month period. The patient illustrated significant improvement in objective audiologic measurement. However, he continues to sign as his main form of communication without significant speech progression. Conclusions: Early diagnostic and therapeutic intervention in patients with NS/NSML can help improve long-term audiologic and speech development. Given the heterogeneity of NS/NSML, a multidisciplinary approach is needed for optimal outcomes.

Cochlear Implantation and Perioperative Management in Autoimmune Inner Ear Disease: A Systematic Review and Meta-Analysis.

Objective: To assess outcomes in autoimmune inner ear disease (AIED) after cochlear implantation (CI) through systematic review and meta-analysis. Databases Reviewed: PubMed, MedLine, Embase, and CINAHL. Methods: Databases were queried for inclusion of AIED patients who underwent CI with outcomes recorded ≥3 months postoperatively. We examined demographics, pure-tone average (PTA), speech perception, preoperative imaging, intraoperative management, and postoperative complications. Results: Twenty-six articles encompassing 124 patients met inclusion criteria. Mean implantation age was 26.2 years (range 4-65 years) with average length of follow-up at 28.2 months (range 3-120 months). Meta-analysis demonstrated significant improvement in speech perception following CI. There was a statistically significant improvement in speech recognition score (SRS) (standard mean difference [SMD] = 6.5, 95% confidence interval [CI], 4.8-8.0, P < 0.0001) as well as word recognition score (WRS) (SMD = 5.5, 95% CI, 4.2-6.8, P < 0.0001) after CI. Anomalous preoperative radiologic manifestations were reported by 57.7% (15/26) studies. Disease activity-related intraoperative adjustment was noted in 57.7% (15/26) studies; common consequences were cochlear drill-out (53.3%), difficult round window insertion (26.7%), and scala vestibuli insertion (26.7%). Frequent postoperative complications noted in 26.9% (7/26) studies included systemic AIED flares (71.4%) and wound healing delay (42.9%). Conclusion: Findings of this systematic review of AIED cochlear implant literature demonstrate a lack of consistent reporting standards for PTA and speech perception as well as a lack of long-term follow-up. Despite these findings, meta-analysis suggests that CI is a viable treatment for improving speech perception in AIED patients.