Risk of Hearing Loss in Neonates and Toddlers with in Utero Exposure to SARS-CoV-2.

OBJECTIVE: Given the prevalence of neonatal hearing loss (HL) associated with intrauterine viral exposures, the goal of this study is to provide information on neonatal HL in the context of the COVID-19 pandemic. METHODS: Data were drawn from the COVID-19 Mother Baby Outcomes (COMBO) Initiative. 1007 participants completed the newborn hearing screen as part of routine clinical care (COMBO-EHR cohort) and 555 completed the National Survey of Children's Health (NSCH) at 2 and/or 3 years of age for research purposes (COMBO-RSCH cohort). Maternal SARS-CoV-2 infection status during pregnancy was determined through electronic health records and maternal-reported questionnaires. RESULTS: In adjusted multivariate logistic regression models covarying for newborn age at assessment, mode of delivery, and gestational age at delivery, there was no significant association between intrauterine SARS-CoV-2 exposure and newborn hearing screening failure (OR = 1.05, 95% CI = 0.39-2.42, p = 0.91) in the COMBO-EHR cohort. In the COMBO-RSCH cohort, there were similar non-significant associations between intrauterine exposure to SARS-CoV-2 and maternal-reported concern for HL on the NSCH (OR = 1.19 [95% CI = 0.30-4.24], p = 0.79). CONCLUSION: There is no association between intrauterine exposure to SARS-CoV-2 and failed hearing screen in neonates. Similarly, based on the NSCH, there is no association between intrauterine exposure to SARS-CoV-2 and maternal-reported concern for hearing in toddlers. These results offer reassurance given the widespread nature of this pandemic with tens of millions of fetuses having a history of intrauterine exposure. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 2024.

Microneedle-Mediated Delivery of siRNA via Liposomal-Based Transfection for Inner Ear Gene Therapy.

HYPOTHESIS: Microneedle-mediated intracochlear injection of siRNA-Lipofectamine through the round window membrane (RWM) can be used to transfect cells within the cochlea. BACKGROUND: Our laboratory has developed 100-µm diameter hollow microneedles for intracochlear injection through the guinea pig RWM. In this study, we test the feasibility of microneedle-mediated injection of siRNA and Lipofectamine, a commonly used reagent with known cellular toxicity, through the RWM for cochlear transfection. METHODS: Fluorescently labeled scramble siRNA was diluted into Lipofectamine RNAiMax and OptiMEM. One microliter of 5 µM siRNA was injected through the RWM of Hartley guinea pigs at a rate of 1 µl/min (n = 22). In a control group, 1.0 µl of Lipofectamine, with no siRNA, was diluted into OptiMEM and injected in a similar fashion (n = 5). Hearing tests were performed before and either at 24 hours, 48 hours, or 5 days after injection. Afterward, animals were euthanized, and cochleae were harvested for imaging. Control cochleae were processed in parallel to untreated guinea pigs. RESULTS: Fluorescence, indicating successful transfection, was observed within the basal and middle turns of the cochlea with limited distribution in the apex at 24 and 48 hours. Signal was most intense in the organ of Corti, spiral ligament, and spiral ganglion. Little to no fluorescence was observed at 5 days post-injection. No significant changes in auditory brainstem response (ABR) were noted post-perforation at 5 days, suggesting that siRNA-Lipofectamine at low doses does not cause cochlear toxicity. CONCLUSIONS: Small volumes of siRNA and Lipofectamine can be effectively delivered to cochlear structures using microneedles, paving the way for atraumatic cochlear gene therapy.

Speech Quality Perception in Unilateral Cochlear Implant Users With Single-Sided Deafness.

OBJECTIVE: Cochlear implant (CI) users frequently complain about speech quality perception (SQP). In patients undergoing cochlear implantation for single-sided deafness, there is concern that poor SQP from the implanted ear will negatively impact binaural (CI + normal hearing [NH]) SQP. In this study, we investigate if binaural SQP is measurably different than unimplanted NH alone. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care center. METHODS: Fifteen unilateral CI users with NH in the contralateral ear completed the validated Columbia Speech Quality Instrument. This instrument consists of 9 audio clips rated across 14 specific speech qualities using a 10-point visual analog scale. SQP was assessed in 3 conditions: CI only, NH only, and CI + NH. RESULTS: Median speech quality scores were worse in the CI only condition compared to the NH only (50.0 vs 72.6, P = .0003) and binaural (50.0 vs 71.0, P = .007) conditions. Median speech quality scores were not significantly different between the NH only and binaural conditions (72.6 vs 71, P = .8). Compared to NH, CI speech quality sounded less clear, less natural, and more mechanical. CONCLUSION: Compared to NH, SQP is poorer with a CI alone. However, in contrast to expectation, there is no significant difference between NH and binaural SQP. This suggests poorer CI speech perception does not negatively impact binaural SQP in patients undergoing cochlear implantation for single-sided deafness.

Exploring Inner Ear and Brain Connectivity through Perilymph Sampling for Early Detection of Neurological Diseases: A Provocative Proposal.

Recent evidence shows that it is possible to identify the elements responsible for sensorineural hearing loss, such as pro-inflammatory cytokines and macrophages, by performing perilymph sampling. However, current studies have only focused on the diagnosis of such as otologic conditions. Hearing loss is a feature of certain neuroinflammatory disorders such as multiple sclerosis, and sensorineural hearing loss (SNHL) is widely detected in Alzheimer's disease. Although the environment of the inner ear is highly regulated, there are several communication pathways between the perilymph of the inner ear and cerebrospinal fluid (CSF). Thus, examination of the perilymph may help understand the mechanism behind the hearing loss observed in certain neuroinflammatory and neurodegenerative diseases. Herein, we review the constituents of CSF and perilymph, the anatomy of the inner ear and its connection with the brain. Then, we discuss the relevance of perilymph sampling in neurology. Currently, perilymph sampling is only performed during surgical procedures, but we hypothesize a simplified and low-invasive technique that could allow sampling in a clinical setting with the same ease as performing an intratympanic injection under direct visual check. The use of this modified technique could allow for perilymph sampling in people with hearing loss and neuroinflammatory/neurodegenerative disorders and clarify the relationship between these conditions; in fact, by measuring the concentration of neuroinflammatory and/or neurodegenerative biomarkers and those typically expressed in the inner ear in aging SNHL, it could be possible to understand if SNHL is caused by aging or neuroinflammation.

Physiologic Effects of Microneedle-Mediated Intracochlear Dexamethasone Injection in the Guinea Pig.

OBJECTIVES: Oral or intratympanic corticosteroids are commonly used to treat sudden sensorineural hearing loss (SSHL), tinnitus, and Meniere disease. Direct intracochlear delivery has been proposed to overcome the variability in bioavailability and efficacy of systemic or middle ear delivery. In this study, we aim to characterize the physiologic consequences of microneedle-mediated direct intracochlear injection of dexamethasone through the round window membrane (RWM). METHODS: In Hartley guinea pigs (n = 5), a post-auricular incision followed by bullostomy was made to access the round window membrane. Using 100 µm diameter hollow microneedles, 1.0 µl of 10 mg/ml dexamethasone was injected through the RWM over 1 min. Compound action potential (CAP) and distortion product otoacoustic action emissions (DPOAE) were measured before perforation, at 1 h, and at 5 h following injection. CAP hearing thresholds were measured from 0.5 to 40 kHz, and DPOAE f2 frequencies ranged from 1.0 and 32 kHz. Repeated measures ANOVA followed by pairwise t-tests were used for statistical analysis. RESULTS: ANOVA identified significant CAP threshold shifts at four frequencies (4, 16, 36, and 40 kHz) and differences in DPOAE at 1 frequency (6 kHz). Paired t-tests revealed differences between the pre-perforation and 1 h time point. By 5 h post injection, both CAP hearing thresholds and DPOAE recover and are not significantly different from baseline thresholds. CONCLUSION: Direct intracochlear delivery of dexamethasone via microneedles results in temporary shifts in hearing thresholds that resolve by 5 hours, thus supporting microneedle technology for the treatment of inner ear disorders. LEVEL OF EVIDENCE: NA Laryngoscope, 134:388-392, 2024.

Community Health Worker Intervention for Newborns Not Passing Initial Universal Hearing Screening.

BACKGROUND: Universal newborn hearing screening (UNHS) is effective in identifying newborns with possible hearing loss (HL). Outpatient follow-up for newborns referred after hospital-based screening remains a potential area of improvement. In this study, we evaluate the efficacy of a community health worker (CHW) intervention in promoting adherence to outpatient rescreening for newborns referred after initial UNHS. METHODS: A mixed prospective-retrospective cohort study was performed to evaluate a CHW intervention at an academic medical center. Caregivers of referred newborns were contacted by CHWs prior to discharge and educated about HL and the importance of follow-up screening. The CHW outreach intervention was performed for 297 referred newborns between May 2020 and June 2021 and compared to a cohort of 238 newborns without the CHW intervention between March 2019 and June 2021. Statistical analyses were conducted using 2 × 2 Chi-square tests, two-tailed unpaired t-tests, multinomial logistic regression, and multiple linear regression. RESULTS: In the intervention group, 236 of 297 newborns (79.5%) completed their outpatient follow-up rescreening; in the comparison group, 170 of 238 newborns (71.4%) completed their follow-up rescreening (P = .031, OR = 1.55 with regression P = .04). In the intervention group, the average time to follow-up was 13.4 days versus 12.5 days for the comparison group (P = .449, multiple R2 = .02 with P = .78). CONCLUSIONS: CHW outreach intervention may increase adherence to outpatient follow-up rescreening for newborns referred after initial, hospital-based UNHS. Expansion of nursery teams to include CHWs may thus improve completion of recommended follow-up hearing screens.

The Association of Hearing Loss With Active Music Enjoyment in Hearing Aid Users.

OBJECTIVE: Hearing aids (HAs) are designed for speech rather than music listening. The impact of HAs on music enjoyment is poorly studied. We examine the effect of HAs on active music enjoyment in individuals with varying levels of hearing loss (HL). STUDY DESIGN: Cross-sectional study. SETTING: Tertiary medical center and community. METHODS: Adult (≥18 years) bilateral HA users and normal hearing (NH) controls actively listened to musical stimuli and rated their enjoyment across 3 measures (pleasantness, musicality, naturalness) with and without HAs using a visual analog scale. Multivariable linear regression was used to assess the association between HL (measured by a pure-tone average [PTA] and word recognition score [WRS] of the better ear) and music enjoyment with and without HAs, adjusting for covariates. Music enjoyment was compared between HA users and NH controls, and HA users with and without their HAs. RESULTS: One hundred bilateral HA users (mean age 66.0 years, 52% female, better ear mean [SD] PTA 50.2 [13.5] dBHL, mean WRS 84.5 [16.5]%) completed the study. Increasing severity of HL (PTA) was independently associated with decreased music enjoyment (pleasantness, musicality, naturalness) with and without HAs (p < .05). HA usage increased music enjoyment (musicality) in those with moderate to moderately severe HL. Music enjoyment in NH controls (n = 20) was significantly greater across all measures compared to HA users. CONCLUSION: Increased severity of HL is associated with decreased music enjoyment that can be enhanced with HA usage. Thus, HA usage can positively enhance both speech and music appreciation.

Microneedles Facilitate Small-Volume Intracochlear Delivery Without Physiologic Injury in Guinea Pigs.

HYPOTHESIS: Microneedle-mediated intracochlear injection through the round window membrane (RWM) will facilitate intracochlear delivery, not affect hearing, and allow for full reconstitution of the RWM within 48 hours. BACKGROUND: We have developed polymeric microneedles that allow for in vivo perforation of the guinea pig RWM and aspiration of perilymph for diagnostic analysis, with full reconstitution of the RWM within 48 to 72 hours. In this study, we investigate the ability of microneedles to deliver precise volumes of therapeutics into the cochlea and assess the subsequent consequences on hearing. METHODS: Volumes of 1.0, 2.5, or 5.0 µL of artificial perilymph were injected into the cochlea at a rate of 1 µL/min. Compound action potential (CAP) and distortion product otoacoustic emission were performed to assess for hearing loss (HL), and confocal microscopy was used to evaluate the RWM for residual scarring or inflammation. To evaluate the distribution of agents within the cochlea after microneedle-mediated injection, 1.0 µL of FM 1-43 FX was injected into the cochlea, followed by whole mount cochlear dissection and confocal microscopy. RESULTS: Direct intracochlear injection of 1.0 µL of artificial perilymph in vivo , corresponding to about 20% of the scala tympani volume, was safe and did not result in HL. However, injection of 2.5 or 5.0 µL of artificial perilymph into the cochlea produced statistically significant high-frequency HL persisting 48 hours postperforation. Assessment of RWMs 48 hours after perforation revealed no inflammatory changes or residual scarring. FM 1-43 FX injection resulted in distribution of the agent predominantly in the basal and middle turns. CONCLUSION: Microneedle-mediated intracochlear delivery of small volumes relative to the volume of the scala tympani is feasible, safe, and does not cause HL in guinea pigs; however, injection of large volumes induces high-frequency HL. Injection of small volumes of a fluorescent agent across the RWM resulted in significant distribution within the basal turn, less distribution in the middle turn, and almost none in the apical turn. Microneedle-mediated intracochlear injection, along with our previously developed intracochlear aspiration, opens the pathway for precision inner ear medicine.

Anatomic, physiologic, and proteomic consequences of repeated microneedle-mediated perforations of the round window membrane.

BACKGROUND: We have developed 3D-printed microneedle technology for diagnostic aspiration of perilymph and intracochlear delivery of therapeutic agents. Single microneedle-mediated round window membrane (RWM) perforation does not cause hearing loss, heals within 48-72 h, and yields sufficient perilymph for proteomic analysis. In this study, we investigate the anatomic, physiologic, and proteomic consequences of repeated microneedle-mediated perforations of the same RWM at different timepoints. METHODS: 100-µm-diameter hollow microneedles were fabricated using two-photon polymerization (2PP) lithography. The tympanic bullae of Hartley guinea pigs (n = 8) were opened with adequate exposure of the RWM. Distortion product otoacoustic emissions (DPOAE) and compound action potential (CAP) were recorded to assess hearing. The hollow microneedle was introduced into the bulla and the RWM was perforated; 1 µL of perilymph was aspirated from the cochlea over the course of 45 s. 72 h later, the above procedure was repeated with aspiration of an additional 1 µL of perilymph. 72 h after the second perforation, RWMs were harvested for confocal imaging. Perilymph proteomic analysis was completed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Two perforations and aspirations were performed in 8 guinea pigs. In six, CAP, DPOAE, and proteomic analysis were obtained; in one, only CAP and DPOAE results were obtained; and in one, only proteomics results were obtained. Hearing tests demonstrated mild hearing loss at 1-4 kHz and 28 kHz, most consistent with conductive hearing loss. Confocal microscopy demonstrated complete healing of all perforations with full reconstitution of the RWM. Perilymph proteomic analysis identified 1855 proteins across 14 samples. The inner ear protein cochlin was observed in all samples, indicating successful aspiration of perilymph. Non-adjusted paired t-tests with p < 0.01 revealed significant changes in 13 of 1855 identified proteins (0.7%) between the first and second aspirations. CONCLUSIONS: We demonstrate that repeated microneedle perforation of the RWM is feasible, allows for complete healing of the RWM, and minimally changes the proteomic expression profile. Thus, microneedle-mediated repeated aspirations in a single animal can be used to monitor the response to inner ear treatments over time.

Instrumented insoles for assessment of gait in patients with vestibular schwannoma.

Background: Imbalance and gait disturbances are common in patients with vestibular schwannoma (VS) and can result in significant morbidity. Current methods for quantitative gait analysis are cumbersome and difficult to implement. Here, we use custom-engineered instrumented insoles to evaluate the gait of patients diagnosed with VS. Methods: Twenty patients with VS were recruited from otology, neurosurgery, and radiation oncology clinics at a tertiary referral center. Functional gait assessment (FGA), 2-minute walk test (2MWT), and uneven surface walk test (USWT) were performed. Custom-engineered instrumented insoles, equipped with an 8-cell force sensitive resistor (FSR) and a 9-degree-of-freedom inertial measurement unit (IMU), were used to collect stride-by-stride spatiotemporal gait parameters, from which mean values and coefficients of variation (CV) were determined for each patient. Results: FGA scores were significantly correlated with gait metrics obtained from the 2MWT and USWT, including stride length, stride velocity, normalized stride length, normalized stride velocity, stride length CV, and stride velocity CV. Tumor diameter was negatively associated with stride time and swing time on the 2MWT; no such association existed between tumor diameter and FGA or DHI. Conclusions: Instrumented insoles may unveil associations between VS tumor size and gait dysfunction that cannot be captured by standardized clinical assessments and self-reported questionnaires.

Inner Ear Diagnostics and Drug Delivery via Microneedles.

OBJECTIVES: Precision medicine for inner ear disorders has seen significant advances in recent years. However, unreliable access to the inner ear has impeded diagnostics and therapeutic delivery. The purpose of this review is to describe the development, production, and utility of novel microneedles for intracochlear access. METHODS: We summarize the current work on microneedles developed using two-photon polymerization (2PP) lithography for perforation of the round window membrane (RWM). We contextualize our findings with the existing literature in intracochlear diagnostics and delivery. RESULTS: Two-photon polymerization lithography produces microneedles capable of perforating human and guinea pig RWMs without structural or functional damage. Solid microneedles may be used to perforate guinea pig RWMs in vivo with full reconstitution of the membrane in 48-72 h, and hollow microneedles may be used to aspirate perilymph or inject therapeutics into the inner ear. Microneedles produced with two-photon templated electrodeposition (2PTE) have greater strength and biocompatibility and may be used to perforate human RWMs. CONCLUSIONS: Microneedles produced with 2PP lithography and 2PTE can safely and reliably perforate the RWM for intracochlear access. This technology is groundbreaking and enabling in the field of inner ear precision medicine.

Hearing Aids Enhance Music Enjoyment in Individuals With Hearing Loss.

OBJECTIVE: To investigate music appreciation in hearing aid (HA) users with varying levels of hearing loss (HL). STUDY DESIGN: Cross-sectional, within-subjects design. SETTING: Tertiary medical center, community. PATIENTS: Adults (≥18 yr) bilateral HA users. INTERVENTIONS: HA usage. MAIN OUTCOME MEASURES: Outcome variables included self-reported music enjoyment measures (pleasantness, musicality, naturalness) with and without HAs assessed with visual analogue scales (10 indicates highest level of enjoyment, 0 the least). Exposure variables include HL (better ear pure-tone average) and speech discrimination (word recognition scores [WRS]). Demographic information was collected. RESULTS: One hundred nine bilateral HA users completed the study. Mean (standard deviation) age was 66.6 years (16.8 yr); 52.3% were female patients. Mean (standard deviation) better ear pure-tone average was 51.1 dB (16.3 dB) HL. Increased severity of HL and worse WRS were associated with decreased music enjoyment ( p < 0.05) across all measures without HAs, adjusting for sex, age, education, race, HA type, age of HL diagnosis, duration of HL, duration of HA use, musical preference, and musical experience. However, these associations were attenuated or no longer significant with HA usage. Moreover, among all subjects, HAs (vs. no HAs) provided increased music enjoyment in pleasantness (HA, 6.94, no HA, 5.74; p < 0.01), musicality (HA, 7.35; no HA, 6.13, p < 0.01), and naturalness (HA, 6.75; no HA, 6.02; p = 0.02). CONCLUSION: HA users report increased music enjoyment with HAs compared with without HAs. Increased severity of HL and worse WRS were independently associated with decreased unaided music enjoyment. HA usage seems to mitigate this effect, particularly for those with worse HL.

Histopathology of Labyrinthitis Ossificans From an Intralabyrinthine Surgical Specimen.

OBJECTIVE: Histologic characterization of labyrinthitis ossificans (LO) has mostly been limited to postmortem samples. In this report, we describe the histology of LO from a surgical specimen obtained from a patient undergoing labyrinthectomy with simultaneous cochlear implantation. PATIENT: A 38-year-old woman initially presenting to the emergency room with acute vertigo, left-sided hearing loss, tinnitus, and aural fullness. INTERVENTIONS: Contrast-enhanced magnetic resonance imaging (MRI) and computerized tomography (CT) were performed for the patient before labyrinthectomy and cochlear implantation. Audiometric testing was performed before and after surgical intervention. Histologic analysis was performed on a specimen obtained from the left lateral semicircular canal (SCC) during surgery. MAIN OUTCOME MEASURES: Preoperative CT and MRI findings, preoperative and postoperative hearing thresholds via air conduction and bone conduction, hematoxylin and eosin (H&E) stain of the surgical sample, and CD45 immunostain of the surgical sample. RESULTS: Preoperative CT and MRI confirmed the diagnosis of isolated LO of the left lateral SCC. Audiometric testing revealed significant improvement in hearing after labyrinthectomy and cochlear implantation. H&E stain demonstrated fibrosis and ossification in the left lateral SCC, and CD45 immunostain was negative. CONCLUSIONS: Histopathology of LO based on a surgical sample is comparable to heterotopic ossification (HO) seen in other human tissue. Given the similarities between LO and HO, agents effective in preventing HO may have utility in preventing LO.

Pyrolyzed Ultrasharp Glassy Carbon Microneedles.

Polymeric microneedles fabricated via two-photon polymerization (2PP) lithography enable safe medical access to the inner ear. Herein, the material class for 2PP-lithography-based microneedles is expanded by pyrolyzing 2PP-fabricated polymeric microneedles, resulting in glassy carbon microneedles. During pyrolysis the microneedles shrink up to 81% while maintaining their complex shape when the exposed surface-area-to-volume ratio (SVR) is 0.025 < SVR < 0.04, for the temperature history protocol used herein. The derived glassy carbon is confirmed with energy-dispersive X-ray spectroscopy and Raman spectroscopy. The pyrolyzed glassy carbon has Young's modulus 9.0 GPa. As a brittle material, the strength is stochastic. Using the two-parameter Weibull distribution, the glassy carbon has Weibull modulus of 3.1 and characteristic strength of 710 MPa. The viscoelastic response has characteristic time scale of about 10000 s. In vitro experiments demonstrate that the glassy carbon microneedles introduce controlled perforations across the guinea pig round window membrane (RWM) from the middle ear space into the inner ear, without damaging the microneedle. The resultant controlled perforation of RWM is known to enhance diffusion of therapeutics across the RWM in a predictable fashion. Hence, the glassy carbon microneedles can be deployed for mediating inner ear delivery.

Integrating community health workers into a community hearing health collaborative to understand the social determinants of health in children with hearing loss.

BACKGROUND: Children with hearing loss (HL) require coordination of care to navigate medical and social services. Strong evidence supports the role of community health workers (CHWs) to identify and address social barriers. OBJECTIVE: The goal of this study was to evaluate the impact of integrating CHWs into the medical teams of children with HL and identify the social needs associated with their caregivers at a large urban hospital center. METHODS: A retrospective chart review was conducted for 30 children with HL whose caregivers enrolled in a CHW program between August 1, 2017 and December 31, 2019. Baseline demographic data were collected, including social circumstances such as food and housing insecurity, status of social security supplemental income (SSI), and need for referral to early intervention (EI) or preschool/school services. Caregivers were assessed for confidence in self-management; baseline distress level was measured via a distress thermometer. RESULTS: Of the 30 charts reviewed, 93% demonstrated social needs including food insecurity (24%) and educational service needs (45%). Eighty-seven percent of caregivers reported a sense of control over the child's condition, yet 73% reported a stress level of four or greater on the distress thermometer scale. At 3 months follow-up, 70% of patients completed referrals; a significant number of patients had obtained hearing aids and cochlear implants compared to baseline (p = 0.017). CONCLUSIONS: Caregivers of children with HL face multiple social obstacles, including difficulties connecting to educational and financial resources. CHWs are instrumental in identifying social needs and connecting caregivers to services.