Differences in Hearing Devices and Speech Therapy Utilization Between Children With Permanent Unilateral Versus Bilateral Hearing Loss.

OBJECTIVES: In this study, we aimed to describe differences in diagnosis and both auditory and speech/language intervention utilization between children with permanent unilateral hearing loss as compared with bilateral hearing loss. DESIGN: A retrospective cohort study was performed of children evaluated in a multidisciplinary hearing loss clinic at a tertiary care pediatric hospital. Children aged 0 to 18 years with either permanent unilateral or bilateral hearing loss were included. RESULTS: One hundred fourteen children with unilateral hearing loss and 268 children with bilateral hearing loss were studied for a total of 382 children. There were no demographic differences between children with permanent unilateral versus bilateral hearing loss. Rates of newborn hearing screening and referred screening results were similar between those with unilateral and bilateral hearing loss. Despite similar rates of referred newborn hearing screening, those with bilateral hearing loss were diagnosed at a younger age (mean 3.6 years, SD 3.8 years) as compared with those with unilateral hearing loss (mean 5.0 years, SD 4.2 years). Children with unilateral hearing loss had similar severity of hearing loss in their poorer hearing ear as compared with children with bilateral hearing loss, yet they were significantly less likely to be fitted with hearing devices (53% versus 78%) or receive speech/language therapy (36% versus 54%) as compared with children with bilateral hearing loss. Multivariate analysis found that bilateral hearing loss and earlier age of hearing loss diagnosis were associated with hearing device use. CONCLUSIONS: Early diagnosis and intervention for childhood hearing loss have a significant impact on a child's educational success and social relationships. However, little is known about differences in diagnosis and resource utilization between children with permanent unilateral hearing loss versus bilateral hearing loss. Children with unilateral hearing loss were diagnosed at a later age and were less likely to utilize hearing devices or speech/language therapy compared with those with bilateral hearing loss, despite having similar severity of hearing loss in the poorer hearing ear. There is a strong body of evidence that children with unilateral hearing loss have improved hearing outcomes with hearing devices, which suggests there is room for improvement in identifying unilateral hearing loss and providing adequate services to optimize educational success. However, speech therapy is generally implemented in response to language delays. Therefore, children with unilateral loss may have lower rates of language delays as compared with those with bilateral hearing loss, thereby explaining differences in speech therapy utilization.

Barriers to Meeting National Early Hearing Detection and Intervention Guidelines in a Diverse Patient Cohort.

OBJECTIVES: To determine our audiology clinics status in meeting the Joint Committee on Infant Hearing recommended 1-3-6 benchmarks for identification and intervention for congenital sensorineural hearing loss and identify those factors contributing to delay in identification and intervention. DESIGN: This is a retrospective case series. Children with sensorineural hearing loss who underwent auditory brainstem response (ABR) testing, hearing aid evaluation, or cochlear implant mapping at our tertiary pediatric medical center between January 2018 and December 2021 were included. Simple and multiple linear regression analyses were used to identify social, demographic, and health factors associated with primary outcomes, defined as age at hearing loss identification, age at intervention (here defined as amplification start), and interval between identification and intervention. RESULTS: Of 132 patients included, mean age was 2.4 years, 48% were male, and 51% were Hispanic. There was significant association between each Hispanic ethnicity ( p = 0.005, p = 0.04, respectively), insurance type ( p = 0.02, p = 0.001, respectively), and later age at identification and intervention. In multivariable analyses, Hispanic ethnicity was significantly associated with both delays in identification and intervention ( p = 0.03 and p = 0.03, respectively), and public insurance was associated with delays in intervention ( p = 0.01). In addition, the total number of ABRs was significantly associated with both older age of identification and intervention ( p < 0.001, p < 0.001, respectively). Mediator analysis demonstrated that the effect of ethnicity on age at identification is mediated by the total number of ABRs performed. CONCLUSIONS: A significant association between total number of ABRs and age at identification and intervention for children with hearing loss exists. Hispanic ethnicity was associated with delays in meeting milestones, further mediated by the number of ABRs, providing a potential avenue for intervention in addressing this disparity.

Racial and ethnic disparities in genetic testing for hearing loss: a systematic review and synthesis.

Racial/ethnic disparities in the diagnostic efficacy of genetic testing for hearing loss have been described. These disparities may relate to differences in variant classification between different racial/ethnic groups, which may, in turn, derive from disparate representation of these groups in the published literature. We sought to quantify racial/ethnic disparities in the published literature on the human genetics of hearing loss. We conducted a search of PubMed for articles describing single-gene, multiple-gene, or whole-exome sequencing for individuals with sensorineural hearing loss. Data on the included subjects, including race/ethnicity and/or region of origin, a number of subjects tested, and method of testing, were extracted. 1355 populations representing 311,092 subjects from 1165 studies were included. Overall, subjects of European and Asian ancestry were equivalently represented, but those of Latino American, African, and indigenous North American ancestry were significantly underrepresented; over 96% of all subjects in the published literature were European or Asian. Within populations, the majority of subjects derived from a small subset of countries. The observed disparity was greater for multiple-gene and whole-exome sequencing than for single-gene sequencing. These findings illustrate the large disparity in the published literature on the genetics of hearing loss, and demonstrate the need for increased representation of Latino American, African, and indigenous North American populations.

Racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing for sensorineural hearing loss.

Understanding racial and ethnic disparities in diagnostic rates of genetic testing is critical for health equity. We sought to understand the extent and cause of racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing (CGT) for sensorineural hearing loss (SNHL). We performed a retrospective cohort study at two tertiary children's hospitals on a diverse cohort of 240 consecutive pediatric patients (76% publicly insured, 82% non-White) with SNHL of unknown etiology who underwent CGT. Definite and possible genetic diagnoses were assigned for each patient, representing the likelihood of a genetic cause of hearing loss. Associations between diagnostic rates were examined. 3.8 ± 2.1 variants were detected per patient; this frequency did not vary between White/Asian and Hispanic/Black cohorts. Overall, 82% of variants were variants of uncertain significance (VUS). Compared with White and Asian subjects, variants identified among Hispanic and Black children were less likely to be classified as pathogenic/likely pathogenic (15% vs. 24%, p < 0.001), and Hispanic and Black children were less likely to have a definite genetic diagnosis (10% vs. 37%, p < 0.001). The adjusted odds ratio for definite genetic diagnosis in Black and Hispanic children compared with White and Asian children was 0.19. Expanding genetic diagnostic criteria to include predicted deleterious VUSs reduced these disparities between White/Asian and Hispanic/Black children, with comparable molecular diagnostic rates (41% vs. 38%, p = 0.72). However, in silico predictions are insufficiently valid for clinical use. Increased inclusion of underrepresented groups in genetic hearing-loss studies to clinically validate these variants is necessary to reduce racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing.

Prevention and management of hearing loss in patients receiving ototoxic medications.

Following the efforts of patient advocates, the World Health Organization published updated guidelines for management of multidrug-resistant tuberculosis in 2018 that advised against the routine use of ototoxic second-line injectable drugs (amikacin, capreomycin and kanamycin). Although hearing loss is no longer considered an unavoidable harm for patients with multidrug-resistant tuberculosis, ototoxic medications continue to be used for several infectious and oncological disorders around the world. These drugs contribute to more than a half a million cases of hearing loss worldwide annually. Currently, there are no international standards for preventing and managing hearing loss associated with ototoxic medications. We present recent data on the prevention and management of hearing loss related to these drugs and highlight the variability in care across settings. More importantly, we aim to provide an evidence-based framework for evaluating, screening and preventing ototoxicity. Finally, we identify avenues for future research so that patients no longer have to choose between hearing loss and a disease cure. There remain significant gaps in our understanding about optimal screening and treatment of ototoxic hearing loss. Here we aim to inspire future international guidelines to address gaps in ototoxicity care and establish research agendas for eliminating ototoxic medications.

Sous l'impulsion des défenseurs des droits des patients, l'Organisation mondiale de la Santé a publié une version actualisée des lignes directrices relatives à la prise en charge de la tuberculose multirésistante en 2018, qui déconseille l'usage systématique de médicaments ototoxiques injectables de deuxième intention (amikacine, capréomycine et kanamycine). Bien que la perte auditive ne soit plus considérée comme un risque inévitable chez les patients atteints de tuberculose multirésistante, les médicaments ototoxiques continuent à être largement employés pour traiter de nombreuses maladies infectieuses et oncologiques à travers le monde. Ces médicaments sont impliqués chaque année dans plus de la moitié des cas de déficience auditive dans le monde. Il n'existe actuellement aucune norme internationale consacrée à la prévention et à la prise en charge de la perte auditive causée par des médicaments ototoxiques. Dans le présent document, nous exposons les données récentes à ce propos et soulignons la variabilité des soins prodigués d'une région à l'autre. Nous tentons surtout d'établir, à partir d'éléments concrets, un cadre dédié à l'évaluation, au dépistage et à la prévention de l'ototoxicité. Enfin, nous dégageons des pistes pour de futures études, afin que les patients n'aient plus à choisir entre une perte auditive et un remède. D'importantes lacunes subsistent dans notre compréhension du dépistage et du traitement de la perte auditive d'origine ototoxique. Nous espérons inspirer de futures lignes directrices internationales afin d'y remédier et de développer des programmes de recherche pour supprimer les médicaments ototoxiques.

Tras los esfuerzos de los defensores de pacientes, la Organización Mundial de la Salud publicó en 2018 unas directrices actualizadas para el tratamiento de la tuberculosis multirresistente en las que se desaconsejaba el uso rutinario de medicamentos inyectables de segunda línea ototóxicos (amikacina, capreomicina y kanamicina). Aunque la pérdida de audición ya no se considera un daño inevitable para los pacientes con tuberculosis multirresistente, los medicamentos ototóxicos se siguen administrando para varios trastornos infecciosos y oncológicos en todo el mundo. Estos fármacos contribuyen a más de medio millón de casos de pérdida de audición en todo el mundo cada año. En la actualidad, no existen estándares internacionales para prevenir y tratar la pérdida de audición asociada a los medicamentos ototóxicos. En este documento, se presentan datos recientes sobre la prevención y el tratamiento de la pérdida de audición relacionada con estos fármacos y se destaca la variabilidad de la atención en los distintos entornos. Además, se pretende ofrecer un marco basado en la evidencia para evaluar, detectar y prevenir la ototoxicidad. Por último, se identifican las vías de investigación futura para que los pacientes no tengan que elegir entre la pérdida de audición y la cura de la enfermedad. Siguen existiendo importantes deficiencias en el conocimiento del cribado y el tratamiento óptimos de la pérdida de audición ototóxica. En este sentido, se pretende inspirar futuras directrices internacionales para abordar las deficiencias en la atención a la ototoxicidad y establecer programas de investigación para eliminar los medicamentos ototóxicos.

Disparities in Speech and Language Delay Among Children With Aural Atresia.

OBJECTIVE: To describe risk factors for speech and language delay in a diverse population of children with aural atresia. METHODS: Retrospective chart review was performed from 2012 to 2020 at UCSF Benioff Children's Hospital to identify children with aural atresia evaluated for speech, language, or auditory skills delays. Ninety-five children with aural atresia, conductive hearing loss, and assessment of speech, language, or auditory skills delay were included. Demographic and clinical data were analyzed to identify predictors of speech and language delay. Cohort and case-control analyses were performed to determine risk factors for delayed intervention, and for ultimate delays in speech, language, or auditory skills. RESULTS: Children exhibited a wide diversity of race/ethnicity, primary home language, geography, and insurance status. Eighty-nine percent had unilateral aural atresia. Forty-eight percent had delays in speech, language, or auditory skills. Most children used hearing aids (84%), had educational accommodations (84%), and received speech therapy (63%). In a univariate retrospective cohort analysis, public-insured ( p = 0.004), non-English speaking ( p = 0.002) and non-white/non-Hispanic children ( p = 0.007) were found to be significantly less likely to be fit with hearing aids in infancy. Children with delays were fit with hearing aids at later ages. In a multivariate case-control analysis, primary home language was a significant predictor for presence of delays [OR, 3.9 (95% CI: 1.2-13.2), p = 0.03]. CONCLUSIONS: Disparities due to insurance type, primary language, and race/ethnicity are associated with delays in hearing aid fitting for children with aural atresia. Earlier, hearing amplification is correlated with reduced risk for speech, language, and auditory skills delay. These findings can help identify at-risk children for targeted support.

Medical Home Care for Children with Deafness and Hearing Problems.

BACKGROUND AND OBJECTIVES: Since 2001, the American Academy of Pediatrics (AAP) has advocated for improving the effectiveness of early hearing screening, diagnosis, and intervention (EHDI) and reducing hearing health disparities through the medical home model of care (MHMOC). However, the scope of the MHMOC and its components and potential disparities among US children with deafness or hearing problems (DHH) have not been identified. METHODS: Data from the 2016 to 2020 National Survey of Children's Health (N = 174 551) were analyzed, including 12 121 children with DHH, 171 523 children without DHH, and 38 722 with other special health needs (SHCN). Univariable statistics and multivariable logistic regression were used to analyze the association of hearing problems with medical home composite and components and cohort disparities. RESULTS: After adjusting for sociodemographic characteristics, medical home care was less likely for children with DHH (adjusted odds ratio: 0.74; 95% confidence interval: 0.56-0.97) compared with children without DHH. Children with DHH and SHCN were also less likely to receive medical home care compared with other SHCN children (adjusted odds ratio: 0.71; 95% confidence interval: 0.55-0.92). Specific medical home components significantly less prevalent among children with DHH included family-centered care, ease of referrals, and effective care coordination, whereas a usual source for sick care was more prevalent, although not statistically significant. CONCLUSIONS: Despite over two decades of efforts to improve EHDI through the medical home, rates of the MHMOC for children with DHH remain disparately low. Systems-level quality improvement efforts supporting the medical home will be necessary to allow the MHMOC to support early hearing detection and intervention (EHDI) systems.

Sociodemographic Disparities in Educational Services in Children who are Deaf or Hard of Hearing.

OBJECTIVE: Examine the association between sociodemographic factors and Individualized Education Program (IEP) establishment. DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. METHODS: Participants included deaf or hard-of-hearing children who were eligible for an IEP with "deafness" or "hard of hearing" as a primary or secondary disability. Primary outcome measures were time intervals between initial referral for services and parental consent; parental consent to determination of eligibility; and initial referral to eligibility (the sum of the previous 2 intervals). Student's t tests and linear regression were used to examine the association between sociodemographic factors and the primary outcome variables. RESULTS: Of the 88 participants, 51 (58%) were male, 45 (51%) were from underrepresented minority (URM) groups, 35 (40%) spoke a primary language other than English, and 53 (60%) utilized public insurance. IEP establishment was significantly delayed in participants who required an English-language interpreter. Most of the delay occurred in the time between the initial referral and parental consent (mean: 115 vs 37 days, P = .02). There were also significant delays from the time of referral for services to eligibility in URM participants (mean: 159 vs 85 days, P = .04). Significant delays were also associated with Minority Status and Language within social vulnerability index percentile rankings. CONCLUSION: This study found that IEP establishment was delayed in both URM participants and those who required an English-language interpreter. These results highlight the importance of clear communication between the school system and caregivers in the IEP establishment process, particularly with families who require an English-language interpreter or identify as URM.

Disparities in Newborn Hearing Screening Outcomes in the United States From 2007 to 2017.

OBJECTIVE: Establishing timely language intervention for children who are deaf or hard of hearing is crucial for their cognitive and language development. Newborn hearing screening (NBHS) programs are now commonplace, but disparities in receipt of support may exist. This study seeks to investigate if states with more diverse populations, less educated mothers, fewer resources, and no legislative mandate of screening have lower rates of milestone completion. STUDY DESIGN: This is a cross-sectional study. SETTING: Data describing screening, identification, and intervention rates from individual state NBHS programs were aggregated by the Centers for Disease Control and Prevention from 2007 to 2017. METHODS: Regression models were fitted to assess associations between these outcomes and state demographic and policy variables. Forest plots from meta-analyses were used to obtain nationwide pooled estimates of the relative risk (RR) of maternal predictors from individual state data. RESULTS: State averages of maternal education level, age, and race/ethnicity were found to be significantly associated with various outcomes. The presence of program funding and legislative state mandate were associated with multiple improved outcomes. Meta-analyses identified increased RRs for most outcomes based on maternal education less than high school, age 19 and below, and non-White race/ethnicity. CONCLUSION: There is evidence of disparities in access to and timing of screening, identification testing, and intervention by various demographic and policy factors at the state level. More research is needed to further explore these relationships and determine how to address existing disparities in order to provide more equitable care.

Risk Factors Associated with Delays in Hearing Loss Identification in Pediatric Patients.

OBJECTIVE: To identify sociodemographic factors associated with pediatric late-identified hearing loss (LIHL) and classify novel subgroups within the LIHL population. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary children's hospital. METHODS: Our cohort included children with permanent hearing loss (HL) between 2012 and 2020 (n = 1087). Patients with early-identified HL were compared to patients with LIHL (>6 months of age at diagnosis), and 3 subgroups: (1) late-identified congenital HL: failed NHS but had a diagnostic audiogram >6 months old; (2) late-onset HL: passed NHS and identified with HL after 6 months old; (3) late-identified, unknown-onset: unknown NHS results, identified after 6 months old. Geospatial analysis was performed using ArcGIS Pro. RESULTS: Compared with early-identified children, children with LIHL were more likely to have more comorbidities (odds ratio [OR] = 1.12, [1.01, 1.23]), be an under-represented minority (URM) (OR = 1.92, [1.27, 2.93]) and have a higher social vulnerability index (SVI) (adjusted odds ratio [AOR] = 2.1, [1.14, 3.87]). However, subgroups in the LIHL cohort had variable associations. Children with late-identified unknown onset hearing loss were uniquely associated with a primarily non-English speaking household (AOR = 1.84, [1.04, 3.25]), whereas children with late-onset hearing loss were less likely to have public insurance (AOR = 0.47, [0.27, 0.81]. There were no significant associations for children with late-identified congenital hearing loss. Neighborhood disadvantage, as measured by SVI, had an increased association with late-identified unknown onset HL (AOR = 4.08, [2.01, 8.28]) and a decreased association with late-onset HL (AOR = 0.40, [0.22, 0.72]). CONCLUSION: Sociodemographic factors serve as proxies for health care access, and these factors vary across LIHL pathways. Understanding the risk factors associated with each LIHL subgroup may help address disparities in pediatric HL identification.

Synaptic ribbon dynamics after noise exposure in the hearing cochlea.

Moderate noise exposure induces cochlear synaptopathy, the loss of afferent ribbon synapses between cochlear hair cells and spiral ganglion neurons, which is associated with functional hearing decline. Prior studies have demonstrated noise-induced changes in the distribution and number of synaptic components, but the dynamic changes that occur after noise exposure have not been directly visualized. Here, we describe a live imaging model using RIBEYE-tagRFP to enable direct observation of pre-synaptic ribbons in mature hearing mouse cochleae after synaptopathic noise exposure. Ribbon number does not change, but noise induces an increase in ribbon volume as well as movement suggesting unanchoring from synaptic tethers. A subgroup of basal ribbons displays concerted motion towards the cochlear nucleus with subsequent migration back to the cell membrane after noise cessation. Understanding the immediate dynamics of synaptic damage after noise exposure may facilitate identification of specific target pathways to treat cochlear synaptopathy.

Teletherapy to address language disparities in deaf and hard-of-hearing children: study protocol for an inclusive multicentre clinical trial.

INTRODUCTION: Children who are deaf or hard-of-hearing (DHH) are at risk for speech and language delay. Language outcomes are worse in DHH children from lower socioeconomic backgrounds, due in part to disparities in access to specialised speech-language therapy. Teletherapy may help improve access to this specialised care and close this language gap. Inclusion of diverse DHH children in prospective randomised clinical trials has been challenging but is necessary to address disparities and pursue hearing health equity. Stakeholder input regarding decisions on study design elements, including comparator groups, masking, assessments and compensation, is necessary to design inclusive studies. We have designed an inclusive, equitable comparativeness effectiveness trial to address disparities in paediatric hearing health. The specific aims of the study are to determine the effect of access to and utilisation of speech-language teletherapy in addressing language disparities in low-income children who are DHH. METHODS AND ANALYSIS: After stakeholder input and pilot data collection, we designed a randomised clinical trial and concurrent longitudinal cohort trial to be conducted at four tertiary children's hospitals in the USA. Participants will include 210 DHH children aged 0-27 months. 140 of these children will be from lower income households, who will be randomised 1:1 to receive usual care versus usual care plus access to supplemental speech-language teletherapy. 70 children from higher income households will be simultaneously recruited as a comparison cohort. Primary outcome measure will be the Preschool Language Scales Auditory Comprehension subscale standard score, with additional speech, language, hearing and quality of life validated measures as secondary outcomes. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Boards of the participating sites: the University of California, San Francisco (19-28356), Rady Children's Hospital (804651) and Seattle Children's Hospital (STUDY00003750). Parents of enrolled children will provide written informed consent for their child's participation. Professional and parent stakeholder groups that have been involved throughout the study design will facilitate dissemination and implementation of study findings via publication and through national and regional organisations. TRIAL REGISTRATION NUMBER: NCT04928209.

Geographic, Sociodemographic, and Clinical Factors Associated With Parental Self-Efficacy in Pediatric Patients With Hearing Loss.

OBJECTIVE: To identify geographic, sociodemographic, and clinical factors associated with parental self-efficacy in a diverse cohort of deaf or hard-of-hearing (DHH) children. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary children's hospital. METHODS: Four hundred forty parents of DHH children aged 0 to 17 completed the 25-item Scale of Parental Involvement and Self-Efficacy (SPISE) survey from 2014 to 2022. Residential addresses were geocoded and assigned Area Deprivation Index and Social Vulnerability Index rankings, and univariable and multivariable analyses were conducted using sociodemographic and clinical variables, including sex, race/ethnicity, insurance type, survey language, age at the survey, comorbidities, newborn hearing screening results, and hearing loss laterality and severity. RESULTS: Compared to English and Spanish-speaking parents, Chinese-speaking parents were associated with overall lower parental self-efficacy and involvement (regression coefficient = -0.518, [-0.929, -0.106]), Cohen's d = 0.606) and lower scores on items related to their ability to affect multiple aspects of their child's development and expression of thoughts as well as competency in checking and putting on their child's sensory device. Across univariable and multivariable analyses, besides Chinese language, all other sociodemographic, clinical, and geographic variables were not associated with SPISE score. CONCLUSION: To achieve the best patient outcomes, care teams can use the SPISE to evaluate parental self-efficacy and provide targeted support to parents at risk for having lower knowledge and confidence scores about critical skills necessary to facilitate their child's auditory access and language development. Notably, this study found similar reports of parental efficacy across various sociodemographic, clinical, and geographic variables but significantly lower SPISE scores in Chinese-speaking families.

Modulating the unfolded protein response with ISRIB mitigates cisplatin ototoxicity.

Cisplatin is a commonly used chemotherapy agent with a nearly universal side effect of sensorineural hearing loss. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate (STS), while beneficial when used in standard risk hepatoblastoma, is associated with reduced survival in disseminated pediatric malignancy, highlighting the need for more specific drugs without potential tumor protective effects. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo, and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin, and UPR marker gene expression and cell death measured. Treatment with ISRIB (Integrated Stress Response InhIBitor), a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested for its ability to reduce apoptosis in HEK cells, hair-cell death in cochlear cultures, and hearing loss using an in vivo mouse model of cisplatin ototoxicity. Finally, to evaluate whether ISRIB might interfere with cisplatin chemoeffectiveness, we tested it in head and neck squamous cell carcinoma (HNSCC) cell-based assays of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact cisplatin's cytotoxic effects on HNSCC cell viability, unlike STS. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.

Probing versus primary nasal endoscopy for the treatment of congenital dacryocystoceles.

PURPOSE: To compare outcomes and complications of three surgical techniques for the treatment of congenital dacryocystoceles: nasolacrimal probing and irrigation (P+I), P+I plus nasal endoscopy (NE) with intranasal cyst marsupialization, and primary NE with intranasal cyst marsupialization. METHODS: The medical records of children ≤2 years of age at a single academic center with a diagnosis of dacryocystocele from 2012 to 2022 were retrospectively identified and reviewed. The primary outcome was resolution of the dacryocystocele (ie, elimination of the medial canthal mass and resolution of tearing or discharge) after a single procedure ("primary success"). Surgical techniques were compared using exact logistic regression. RESULTS: Of 54 patients, 21 (39%) underwent P+I, 23 (43%) underwent P+I plus nasal endoscopy, and 10 (18%) underwent primary NE. Primary success was 76% for P+I and 100% for the other two cohorts. Most patients (89%) who underwent P+I received general anesthesia compared with none who underwent primary nasal endoscopy. Most complications were related to the use of general anesthesia, with a complication rate of 10% for P+I, 48% for P+I plus NE, and 0% for primary NE. Most P+I procedures required hospital admission compared to half of primary NE procedures. CONCLUSIONS: In our study cohort, primary NE provided good outcomes and was associated with a lower complication rate than P+I with or without NE.

Noise induces intercellular Ca 2+ signaling waves and the unfolded protein response in the hearing cochlea.

Exposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response, have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways has been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice. We used a genetically encoded calcium indicator mouse model in which GcAMP is expressed specifically in hair cells or supporting cells under control of Myo15Cre or Sox2Cre, respectively. We performed live calcium imaging and UPR gene expression analysis in 8-week-old mice exposed to levels of noise that cause cochlear synaptopathy (98 db SPL) or permanent hearing loss (106 dB SPL). UPR activation occurred immediately after noise exposure and was noise dose-dependent, with the pro-apoptotic pathway upregulated only after 106 dB noise exposure. Spontaneous calcium transients in hair cells and intercellular calcium waves in supporting cells, which are present in neonatal cochleae, were quiescent in mature-hearing cochleae, but re-activated upon noise exposure. 106 dB noise exposure was associated with more persistent and expansive ICS wave activity. These findings demonstrate a strong and dose-dependent association between noise exposure, UPR activation, and changes in calcium homeostasis in hair cells and supporting cells, suggesting that targeting these pathways may be effective to develop treatments for noise-induced hearing loss.

Hearing Impairment and School Engagement Outcomes in US Children.

Importance: Ensuring appropriate school engagement for deaf or hard of hearing (DHH) children in the US is important for improving their long-term outcomes as they grow into adults. Objective: To examine the associations between hearing loss (HL), its sequelae (speech and/or language disorders, behavioral and/or conduct problems, and neuropsychiatric and/or learning disorders), and various school engagement measures among school-aged children in the US. Design, Setting, and Participants: This cross-sectional study combined data from the nationally representative 2016-2021 National Survey of Children's Health. A total of 155 178 randomly selected children (weighted, approximately 49 340 700 children) aged 6 to 17 years with a parent or caregiver who responded to an address-based survey by mail or online were included. All analyses were weighted to account for the probability of selection and nonresponse and to reflect population-based estimates representative of all noninstitutionalized school-aged US children and adolescents residing in housing units. Main Outcomes and Measures: Diverse school engagement measures, including extracurricular participation in sports, clubs, paid work, volunteer work, and organized lessons, as well as educational performance variables, including missed school days, not caring about doing well in school, not doing required homework, grade repetition, and parent or guardian contacted by school. Results: Of the estimated 49 340 700 children aged 6 to 17 years (41.1% aged 6-10 years; 51.1% male; 54.7% without underrepresented minority status), an estimated 1.4% (95% CI, 1.2%-1.5%) were reported by their parent or guardian to have deafness or hearing problems. Having DHH status was associated with significantly worse outcomes on 8 of 10 school engagement measures (eg, participation in sports: adjusted odds ratio [AOR], 0.75 [95% CI, 0.60-0.93]; missed school days: AOR, 2.98 [95% CI, 2.21-4.00]), even after adjustment for age, sex, underrepresented minority status, highest educational level of parent or guardian, federal poverty level of the household, and primary language in the household. Moreover, although subgroup analyses of DHH children with and without HL sequelae revealed significant differences (speech and/or language disorder: AOR, 5.83 [95% CI, 4.31-7.89]; behavioral and/or conduct problem: AOR, 2.75 [95% CI, 2.10-3.60]; neuropsychiatric and/or learning disorder: AOR, 3.06 [95% CI, 2.39-3.91]), HL sequelae only partially mediated the associations between these disparities. Conclusions and Relevance: In this cross-sectional study, DHH status itself may have been the primary factor directly associated with school engagement disparities. These findings suggest the need for greater emphasis on educational accommodations and support for hearing status itself, independent of the presence or absence of HL sequelae.

Impact of Genetic Testing on Hearing Interventions.

OBJECTIVE: Clinical guidelines recommend genetic testing when evaluating congenital and late-onset sensorineural hearing loss (SNHL). Genetic diagnoses can provide parents additional information regarding anticipated hearing loss progression, comorbid conditions, and family planning. Additionally, obtaining a genetic diagnosis may increase parental acceptance of hearing loss and subsequent pursuit of intervention. This study evaluates the association between genetic diagnoses and hearing loss intervention. METHODS: We included children ages 0-18 years with SNHL who were hearing aid or cochlear implant candidates but non-users and underwent hearing-loss gene panel testing prior to initiating intervention. Univariate analyses were performed to identify predictors of hearing aid fitting or cochlear implantation. Multivariate logistic regression evaluated the impact of demographic and clinical factors on subsequent intervention. RESULTS: Of the 385 children with SNHL who underwent hearing loss gene panel testing, 111 were included. Median age was 7.5 years. 56% were underrepresented minorities, 71% were non-White, and 71% were publicly insured. Those found to have a genetic diagnosis were 4.6 times as likely to subsequently undergo intervention (p = 0.035). Additionally, bilateral hearing loss and earlier age of genetic testing were associated with increased likelihood of intervention. CONCLUSION: Up to half of children with SNHL are suspected to have an underlying genetic etiology. Children diagnosed with a genetic diagnosis are significantly more likely to subsequently utilize hearing aids or cochlear implantation. This provides additional support for clinical guidelines recommending genetic testing not only due to the impact of prognostication but also on treatment decision-making. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1982-1986, 2023.

Impact of Sociodemographic Disparities on Language Outcomes After Cochlear Implantation in a Diverse Pediatric Cohort.

OBJECTIVE: We examined how sociodemographic and audiologic factors affect receptive and expressive language outcomes in children with cochlear implantation. STUDY DESIGN: Retrospective cohort study. SETTING: A hearing loss (HL) clinic at a tertiary center. METHODS: Sociodemographic variables, HL characteristics, age at implantation, and receptive language scores (Preschool Language Scale and the Clinical Evaluation of Language Fundamentals) were collected from patients with congenital HL who received their first implant by 4 years old after January 1, 2007. t Tests, linear regression, Mann-Whitney, Cohen's d, and mediation analysis were used for descriptive statistics and hypothesis testing. RESULTS: Among 79 patients, 42 (53%) were females, 44 (56%) under-represented minorities, and 56 (71%) had public insurance. At least 1 year after implantation, the median receptive language score was 69 (range 50-117). Females (p = .005), having private insurance (p = .00001), having a Cochlear Implant Profile score below 4 (p = .0001), and receiving their implant at or before 12 months of age (p = .0009) were significantly associated with improved receptive language outcomes. Insurance type had a significant effect on receptive language outcomes, independent from age at first implantation (total effect: coef = -13.00, p = .02; direct effect: coef = -12.26, p = .03; indirect effect: coef = -0.75, p = .47). Sociodemographic variables had large effect sizes, with the Cochlear Implant Profile score having the largest effect size (d = 1.3). CONCLUSION: Sociodemographic factors have a large impact on receptive language outcomes. Public insurance is associated with worse receptive language, not mediated by later age at implantation, suggesting that other factors primarily impact language outcomes in publicly insured children with cochlear implants.

Modulating the Unfolded Protein Response with ISRIB Mitigates Cisplatin Ototoxicity.

Cisplatin is a common chemotherapy drug with a nearly universal side effect of ototoxicity. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate, is associated with reduced survival in disseminated hepatoblastoma, highlighting the need for more specific drugs. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo , and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin and UPR-modulating drugs, and UPR marker gene expression and cell death measured. Treatment with ISRIB, a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested in an in vivo mouse model of cisplatin ototoxicity and well as a head and neck squamous cell carcinoma (HNSCC) cell-based assay of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact cisplatin's cytotoxic effects on HNSCC cell viability. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.