Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model.

Autosomal recessive genetic forms (DFNB) account for most cases of profound congenital deafness. Adeno-associated virus (AAV)-based gene therapy is a promising therapeutic option, but is limited by a potentially short therapeutic window and the constrained packaging capacity of the vector. We focus here on the otoferlin gene underlying DFNB9, one of the most frequent genetic forms of congenital deafness. We adopted a dual AAV approach using two different recombinant vectors, one containing the 5' and the other the 3' portions of otoferlin cDNA, which exceed the packaging capacity of the AAV when combined. A single delivery of the vector pair into the mature cochlea of Otof-/- mutant mice reconstituted the otoferlin cDNA coding sequence through recombination of the 5' and 3' cDNAs, leading to the durable restoration of otoferlin expression in transduced cells and a reversal of the deafness phenotype, raising hopes for future gene therapy trials in DFNB9 patients.

Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G.

Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensitivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected.

A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records.

Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0x10-11), 52Kb 3' of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8x10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9x10-6). We also tested variants within exons of 132 other previously-identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2x10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI.

Spiral ganglion degeneration and hearing loss as a consequence of satellite cell death in saposin B-deficient mice.

Saposin B (Sap B) is an essential activator protein for arylsulfatase A in the hydrolysis of sulfatide, a lipid component of myelin. To study Sap B's role in hearing and balance, a Sap B-deficient (B(-/-)) mouse was evaluated. At both light and electron microscopy (EM) levels, inclusion body accumulation was seen in satellite cells surrounding spiral ganglion (SG) neurons from postnatal month 1 onward, progressing into large vacuoles preceding satellite cell degeneration, and followed by SG degeneration. EM also revealed reduced or absent myelin sheaths in SG neurons from postnatal month 8 onwards. Hearing loss was initially seen at postnatal month 6 and progressed thereafter for frequency-specific stimuli, whereas click responses became abnormal from postnatal month 13 onward. The progressive hearing loss correlated with the accumulation of inclusion bodies in the satellite cells and their subsequent degeneration. Outer hair cell numbers and efferent function measures (distortion product otoacoustic emissions and contralateral suppression) were normal in the B(-/-) mice throughout this period. Alcian blue staining of SGs demonstrated that these inclusion bodies corresponded to sulfatide accumulation. In contrast, changes in the vestibular system were much milder, but caused severe physiologic deficits. These results demonstrate that loss of Sap B function leads to progressive sulfatide accumulation in satellite cells surrounding the SG neurons, leading to satellite cell degeneration and subsequent SG degeneration with a resultant loss of hearing. Relative sparing of the efferent auditory and vestibular neurons suggests that alternate glycosphingolipid metabolic pathways predominate in these other systems.

The Impact of Visual Abstracts Compared to Automated Tweets on Social Media in Otology & Neurotology.

OBJECTIVE: To analyze the effect of visual abstracts versus automated tweets on social media participation in Otology & Neurotology . PATIENTS: N/A. INTERVENTIONS: Introduction of visual abstracts developed by the social media editorial team to established automated tweets created by the dlvr.it computer program on the Otology & Neurotology Twitter account. MAIN OUTCOME MEASURES: Twitter analytics including the number of new followers per month, impressions per tweet, and engagements per tweet. The Kruskal-Wallis analysis of variance test was used to compare means. RESULTS: From October 2016 to October 2017 (average of 20 new followers per month), 101 automated tweets averaged 536 impressions and 16 engagements per tweet. The visual abstract was introduced in November 2017. From November 2017 to November 2020 (average of 39 new followers per month), 447 automated tweets averaged 747 impressions and 22 engagements per tweet, whereas 157 visual abstracts averaged 1977 impressions and 78 engagements per tweet. Automated tweets were discontinued in December 2020. From December 2020 to December 2022 (average of 44 new followers per month), 95 visual abstracts averaged 1893 impressions and 103 engagements per tweet. With the introduction of the visual abstract, the average number of followers, impressions per tweet, and engagements per tweet significantly increased (all p -values <0.01; all large effect sizes of 0.16, 0.47, and 0.47, respectively). CONCLUSIONS: Visual abstracts created by a social media editorial team have a positive impact on social media participation in the field of otology and neurotology. The impact is greater than that of social media content generated by Twitter automation tools.

Bell's Palsy and Its Semantic Change over Time.

BACKGROUND: From 1821 to 1829, Sir Charles Bell presented cases of facial paralysis from infection, trauma, and unknown causes. As such, "Bell's palsy" initially referred to facial palsy of any etiology. Today, the term is reserved for idiopathic peripheral facial palsy. The objectives of this analysis were to establish when the eponym came to vogue and delineate the semantic shift from its original definition to its current one. METHODS: Extensive review of available 19th and 20th century literature mentioning "Bell's palsy" and "Bell's paralysis." RESULTS: Historical accounts have eponymously attached Bell's name to facial paralysis as early as the 1840s-Bell's palsy was first used to describe cases of facial palsy of any cause. In 1886, Gowers characterized Bell's palsy as a "neuritis usually within the Fallopian Canal," distinguishing it as a separate etiology. Over the next decades, the definition narrowed to peripheral facial paralysis from cold exposure or unknown causes. By the 1940s, its natural history was well described-an acute, unilateral, idiopathic, and usually self-limited peripheral facial palsy. CONCLUSION: The semantic change of a word over time can tell us a remarkable story of its history and origins. Absence of a discrete lesion, lack of proven treatment, and good prognosis without intervention distinguished Bell's palsy from other causes of facial paralysis. Over time, the definition has narrowed from a facial palsy of any cause to an idiopathic peripheral facial palsy. Recent evidence supporting Bell's palsy as a viral mononeuritis may have driven its recent semantic change toward this specific etiology.

Reporting of Sociodemographic Data in Cochlear Implant Clinical Trials: A Systematic Review.

OBJECTIVE: The purpose of this study was to systematically evaluate the literature on the frequency of reporting of sociodemographic data (gender, race, ethnicity, education status, health insurance status, geographic location of residence, and socioeconomic status) among interventional clinical trials involving cochlear implant patients. DATABASES REVIEWED: A systematic search was performed in PubMed, Cochrane Database of Systematic Reviews, Web of Science, and SCOPUS to identify peer reviewed research. METHODS: A systematic review was performed, which included original prospective clinical trial research studies involving cochlear implantation and/or interventional trials involving cochlear implant patients. Collected data included funding type, level of evidence, race reporting, ethnicity reporting, socioeconomic status reporting, education level reporting, type of insurance, geographic location, and gender of patients. RESULTS: A total of 644 articles were included for review. Gender was the most reported sociodemographic factor (70% of included studies). Reporting of other data among included studies was low: educational level (6%), socioeconomic status (2%), race (1%), ethnicity (1%), insurance status (0.3%), and geography (1%). The odds of reporting gender (odds ratio [OR] = 1.51), education (OR = 1.81), and geography (OR = 2.72) increased with each subsequent publication date decade; however, this trend was not seen for reporting of race, ethnicity, socioeconomic status, or insurance. The reporting of gender was less likely to be reported in studies with the pediatric participants (OR = 0.62), level II evidence (OR = 0.14), and device programming interventional studies (OR = 0.26). CONCLUSION: Reporting of sociodemographic data, other than gender, is low among prospective clinical trials involving cochlear implant patients. The lack of reporting of this key data may limit research rigor and generalizability. Clinical researchers are advised to prospectively collect these data to promote equity in cochlear implant research and clinical care.

Two-Year Outcomes After Pediatric In-Office Tympanostomy Using Lidocaine/Epinephrine Iontophoresis and an Automated Tube Delivery System.

OBJECTIVE: Evaluate 2-year outcomes after lidocaine/epinephrine iontophoresis and tympanostomy using an automated tube delivery system for pediatric tube placement in-office. STUDY DESIGN: Prospective, single-arm. SETTING: Eighteen otolaryngology practices. METHODS: Children age 6 months to 12 years indicated for tympanostomy were enrolled between October 2017 and February 2019. Local anesthesia of the tympanic membrane was achieved via lidocaine/epinephrine iontophoresis and tympanostomy was completed using an automated tube delivery system (the Tula® System). An additional Lead-In cohort of patients underwent tube placement in the operating room (OR) under general anesthesia using only the tube delivery system. Patients were followed for 2 years or until tube extrusion, whichever occurred first. Otoscopy and tympanometry were performed at 3 weeks, and 6, 12, 18, and 24 months. Tube retention, patency, and safety were evaluated. RESULTS: Tubes were placed in-office for 269 patients (449 ears) and in the OR for 68 patients (131 ears) (mean age, 4.5 years). The median and mean times to tube extrusion for the combined OR and In-Office cohorts were 15.82 (95% confidence interval [CI]: 15.41-19.05) and 16.79 (95% CI: 16.16-17.42) months, respectively. Sequelae included ongoing perforation for 1.9% of ears (11/580) and medial tube displacement for 0.2% (1/580) observed at 18 months. Over a mean follow-up of 14.3 months, 30.3% (176/580) of ears had otorrhea and 14.3% (83/580) had occluded tubes. CONCLUSION: In-office pediatric tympanostomy using lidocaine/epinephrine iontophoresis and automated tube delivery results in tube retention within the ranges described for similar grommet-type tubes and complication rates consistent with traditional tube placement in the OR.

Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.

The expression of unconventional vesicular glutamate transporter VGLUT3 by neurons known to release a different classical transmitter has suggested novel roles for signaling by glutamate, but this distribution has raised questions about whether the protein actually contributes to glutamate release. We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway. The early degeneration of some cochlear ganglion neurons in knockout mice also indicates an important developmental role for the glutamate released by hair cells before the onset of hearing. In addition, the mice exhibit primary, generalized epilepsy that is accompanied by remarkably little change in ongoing motor behavior. The glutamate release conferred by expression of VGLUT3 thus has an essential role in both function and development of the auditory pathway, as well as in the control of cortical excitability.

Cochlear gene therapy.

PURPOSE OF REVIEW: This review highlights recent advances in cochlear gene therapy over the past several years. Cochlear gene therapy has undergone tremendous advances over the past decade. Beginning with some groundbreaking work in 2005 documenting hair cell regeneration using virally mediated delivery of the mouse atonal 1 gene, gene therapy is now being explored as a possible treatment for a variety of causes of hearing loss. RECENT FINDINGS: Recent advances in cochlear gene therapy include improved methods of gene delivery with a better delineation of viral vectors that are suitable for this purpose, additional improvements in hair cell regeneration, and directed research toward autoimmune hearing loss, ototoxicity, spiral ganglion survival, and genetic forms of hearing loss. SUMMARY: If successful, cochlear gene therapy will dramatically alter our ability to treat a variety of forms of acquired and genetic hearing loss.

Tissue-specific calibration of extracellular matrix material properties by transforming growth factor-ß and Runx2 in bone is required for hearing.

Physical cues, such as extracellular matrix stiffness, direct cell differentiation and support tissue-specific function. Perturbation of these cues underlies diverse pathologies, including osteoarthritis, cardiovascular disease and cancer. However, the molecular mechanisms that establish tissue-specific material properties and link them to healthy tissue function are unknown. We show that Runx2, a key lineage-specific transcription factor, regulates the material properties of bone matrix through the same transforming growth factor-ß (TGFß)-responsive pathway that controls osteoblast differentiation. Deregulated TGFß or Runx2 function compromises the distinctly hard cochlear bone matrix and causes hearing loss, as seen in human cleidocranial dysplasia. In Runx2+/⁻ mice, inhibition of TGFß signalling rescues both the material properties of the defective matrix, and hearing. This study elucidates the unknown cause of hearing loss in cleidocranial dysplasia, and demonstrates that a molecular pathway controlling cell differentiation also defines material properties of extracellular matrix. Furthermore, our results suggest that the careful regulation of these properties is essential for healthy tissue function.

From a Slave to a Surgeon: David Kearney McDonogh, the First Black Otolaryngologist.

David McDonogh, born into chattel slavery in Louisiana in the early 1800s, accomplished the unfathomable by becoming the first Black otolaryngologist in the United States of America. With tireless determination and profound intellect, Dr McDonogh surmounted immeasurable adversity along his improbable journey to freedom and success as an eye, ear, nose, and throat doctor in New York. His doctorate in medicine was posthumously awarded to his great-great-granddaughter in 2018 by the Columbia University Vagelos College of Physicians and Surgeons. In this History of Otolaryngology piece, we share his extraordinary story.

Impact of COVID-19 on Otolaryngology Literature.

OBJECTIVES/HYPOTHESIS: To understand the effect of the COVID-19 pandemic on the volume, quality, and impact of otolaryngology publications. STUDY DESIGN: Retrospective analysis. METHODS: Fifteen of the top peer-reviewed otolaryngology journals were queried on PubMed for COVID and non-COVID-related articles from April 1, 2020 to March 31, 2021 (pandemic period) and pre-COVID articles from the year prior. Information on total number of submissions and rate of acceptance were collected from seven top-ranked journals. RESULTS: Our PubMed query returned 759 COVID articles, 4,885 non-COVID articles, and 4,200 pre-COVID articles, corresponding to a 34% increase in otolaryngology publications during the pandemic period. Meta-analysis/reviews and miscellaneous publication types made up a larger portion of COVID publications than that of non-COVID and pre-COVID publications. Compared to pre-COVID articles, citations per article 120 days after publication and Altmetric Attention Score were higher in both COVID articles (citations/article: 2.75 ± 0.45, P < .001; Altmetric Attention Score: 2.05 ± 0.60, P = .001) and non-COVID articles (citations/article: 0.03 ± 0.01, P = .002; Altmetric Attention Score: 0.67 ± 0.28, P = .016). COVID manuscripts were associated with a 1.65 times higher acceptance rate compared to non-COVID articles (P < .001). CONCLUSIONS: COVID-19 was associated with an increase in volume, citations, and attention for both COVID and non-COVID articles compared to pre-COVID articles. However, COVID articles were associated with lower evidence levels than non-COVID and pre-COVID articles. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1364-1373, 2022.

Role of the copper transporter, CTR1, in platinum-induced ototoxicity.

The goal of this study was to determine the role of an influx copper transporter, CTR1, in the ototoxicity induced by cisplatin, a potent anticancer platinum analog used in the treatment of a variety of solid tumors. As determined through reverse transcriptase-PCR (RT-PCR), quantitative RT-PCR, Western blot, and immunohistochemistry, mouse CTR1 (Ctr1) was found to be abundantly expressed and highly localized at the primary sites of cisplatin toxicity in the inner ear, mainly outer hair cells (OHCs), inner hair cells, stria vascularis, spiral ganglia, and surrounding nerves in the mouse cochlea. A CTR1 substrate, copper sulfate, decreased the uptake and cytotoxicity of cisplatin in HEI-OC1, a cell line that expresses many molecular markers reminiscent of OHCs. Small interfering RNA-mediated knockdown of Ctr1 in this cell line caused a corresponding decrease in cisplatin uptake. In mice, intratympanic administration of copper sulfate 30 min before intraperitoneal administration of cisplatin was found to prevent hearing loss at click stimulus and 8, 16, and 32 kHz frequencies. To date, the utility of cisplatin remains severely limited because of its ototoxic effects. The studies described in this report suggest that cisplatin-induced ototoxicity and cochlear uptake can be modulated by administration of a CTR1 inhibitor, copper sulfate. The possibility of local administration of CTR1 inhibitors during cisplatin therapy as a means of otoprotection is thereby raised.

Price Differences Between Otic and Ophthalmic Drops.

OBJECTIVE: Otic drops are one of the most frequently prescribed medications in otolaryngology. However, some forms of these drops can be very expensive, and ophthalmic formulations are sometimes used by practitioners to decrease the cost for their patients. The goal of this study is to determine the cost differential between otic and ophthalmic drops. METHODS: Pharmacies in New York City, Chicago, and Portland were surveyed in the span of 6 weeks by telephone to evaluate the current prices of various otic and ophthalmic drops commonly prescribed by otolaryngologists. RESULTS: A total of 83 pharmacies were surveyed. Surveyed drugs included ciprofloxacin/dexamethasone (cip/dex) otic, neomycin/polymyxin B sulfates/hydrocortisone (neo/poly/HC) otic, acetic acid (AA) otic, acetic acid/hydrocortisone (AA/HC) otic, ofloxacin otic, ofloxacin ophthalmic, and tobramycin/dexamethasone (tob/dex) ophthalmic. Per milliliter, cip/dex otic was consistently the most expensive, with a median price of $38.00 per milliliter. Among the antibiotic drops, neo/poly/HC otic was the least expensive formulation with a median price of $11.60 per milliliter. Ofloxacin ophthalmic was significantly less expensive than the otic formulation, at $11.00 and $31.00 per milliliter, respectively (adjusted p < 0.001). In general, otic and ophthalmic formulations were not significantly different according to manufacturing information, although ophthalmic drops were more often packaged in a sterile fashion and with less abrasive ingredients for use in the more sensitive tissue of the eye. CONCLUSION: Significant and meaningful price differences exist between otic and ophthalmic drops. Given the safety of ophthalmic drops used in the ears, they may be a more cost-effective alternative to traditionally prescribed otic drops when clinically appropriate.

Sexual and Gender Minority Curriculum Within Otolaryngology Residency Programs.

Purpose: Otolaryngologists are uniquely situated to provide sexual and gender minority (SGM) care, including gender-affirmation (voice/communication, facial surgery) and HIV/AIDS-related conditions. Yet, no research has characterized otolaryngology residency program directors' attitudes toward SGM-related curricula, nor opportunities for supporting training in SGM-related care. Methods: An anonymous cross-sectional e-mail survey was disseminated to 116 otolaryngology residency program directors in July-September 2019. Information collected included current/future curriculum in and attitudes toward SGM care, and program demographics. Data were categorical and analysis utilized chi-square test. Results: The 65 complete responses (56% rate) were nationally representative. Overall, 17% of programs include no SGM-related education. Subjective importance of SGM training ranged from not important at all (3%) to absolutely essential (11%), with mode of average importance (47%); this varied significantly by program geographic setting and population, and program size. The mean percentage of curriculum dedicated to SGM care was 1.0% for didactics and 0.7% for clinical. Curricula include HIV/AIDS-related conditions (58%), facial gender-affirming procedures (50%), culturally informed care (42%), changes with gender-affirming hormones (voice/communication: 48%, facial: 22%), and cancer in SGM patients (42%). Frequently reported barriers were insufficient experienced faculty (52%) and time (42%). Program directors deemed visiting expert lectures (66%), small-group discussion (39%), and online modules (27%) the best ways to incorporate SGM education. Conclusions: More than 80% of otolaryngology residency curricula in a representative national survey include SGM-related education, which represents a limited portion of total curriculum. These results highlight the opportunity for expert lectures and discussion-based and online tool development to facilitate standardized SGM education in otolaryngology residencies.

Comparison of Cochlear Implant Device Fixation-Well Drilling Versus Subperiosteal Pocket. A Cost Effectiveness, Case-Control Study.

OBJECTIVE: To compare surgical characteristics and complications between well drilling (WD) and subperiosteal pocket techniques (SPT) for receiver/stimulator (R/S) fixation of cochlear implant (CI), and conduct cost-effectiveness analysis. STUDY DESIGN: Retrospective clinical study, decision-analysis model. SETTING: Tertiary referral center. PATIENTS: Three-hundred and eighty-eight CI recipients with a minimum of 6-months follow-up. INTERVENTIONS: CI surgery using either WD or SPT for R/S fixation. A decision-analysis model was designed using data from a systematic literature review. MAIN OUTCOME MEASURES: Surgical operation time, rates of major and minor long-term complications were compared. Incremental cost-effectiveness was also estimated, comparing the two methods of fixation. RESULTS: We compared 179 WD with 209 SPT. Surgery time was significantly shorter in SPT (148 versus 169 min, p = 0.001) and remained significant after adjustment for possible confounders. Higher rates of major complications requiring surgical intervention were found with SPT (10.5% versus 4.5%, p = 0.042), however, the difference was not significant after adjusting for follow-up time (47.8 versus 32.5 months for SPT, WD respectively; p < 0.001). The incremental cost-effectiveness ratio for WD (compared with SPT) was $48,795 per major complication avoided, which was higher than the willingness-to-pay threshold of $47,700 (average cost of 2 h revision surgery). CONCLUSIONS: SPT was found to be faster but potentially risks more complications, particularly relating to device failure. Further long-term studies are required to validate these differences. Based on data from the current literature, neither of the methods is compellingly cost-effective over the other, and surgeons can base their choice on personal preference, comfort, and previous training.