Selection of viral capsids and promoters affects the efficacy of rescue of Tmprss3-deficient cochlea.

Adeno-associated virus (AAV)-mediated gene transfer has shown promise in rescuing mouse models of genetic hearing loss, but how viral capsid and promoter selection affects efficacy is poorly characterized. Here, we tested combinations of AAVs and promoters to deliver Tmprss3, mutations in which are associated with hearing loss in humans. Tmprss3tm1/tm1 mice display severe cochlear hair cell degeneration, loss of auditory brainstem responses, and delayed loss of spiral ganglion neurons. Under the ubiquitous CAG promoter and AAV-KP1 capsid, Tmprss3 overexpression caused striking cytotoxicity in vitro and in vivo and failed to rescue degeneration or dysfunction of the Tmprss3tm1/tm1 cochlea. Reducing the dosage or using AAV-DJ-CAG-Tmprss3 diminished cytotoxicity without rescue of the Tmprss3tm1/tm1 cochlea. Finally, the combination of AAV-KP1 capsid and the EF1α promoter prevented cytotoxicity and reduced hair cell degeneration, loss of spiral ganglion neurons, and improved hearing thresholds in Tmprss3tm1/tm1 mice. Together, our study illustrates toxicity of exogenous genes and factors governing rescue efficiency, and suggests that cochlear gene therapy likely requires precisely targeted transgene expression.

Attention-deficit/hyperactivity disorder in children with hearing loss.

OBJECTIVE: To evaluate rates of Attention-Deficit/Hyperactivity Disorder (AD/HD) diagnosis among pediatric patients with normal hearing (NH) and hearing loss (HL) with and without comorbidities. STUDY DESIGN: Retrospective cohort study of NH and HL patients following chart review of all pediatric patients with a history of tympanostomy tube placement treated at the Cleveland Clinic Foundation between 2019 and 2022. METHODS: Patient demographic information, hearing status (type of HL, laterality, severity), and comorbidities including prematurity, genetic syndromes, disorders with neurological impairment, and autism spectrum disorder (ASD) were collected. Rate of AD/HD amongst HL and NH cohorts with and without comorbidities were compared using Fisher's exact test. Covariate-adjusted analysis was also completed (sex, current age, age at tube placement, and OSA). The primary outcome of interest was rates of AD/HD among children with NH and HL, and the secondary outcome of interest was the impact of comorbidities on rates of AD/HD diagnosis in these cohorts. RESULTS: Of the 919 screened patients between 2019 and 2022, there were 778 NH patients and 141 HL patients (80 bilateral, 61 unilateral). HL ranged from mild (n = 110) to moderate (n = 21) to severe/profound (n = 9). Overall, the rate of AD/HD was significantly higher in HL children (12.1% HL vs 3.6% NH, p < 0.001). Of the 919 patients, 157 had comorbidities. In children without comorbidities, HL children still had significantly higher rates of AD/HD compared to NH children (8.0% vs 1.9%, p = 0.02), but there was loss of significance after covariate adjustment (p = 0.72). CONCLUSION: The rate of AD/HD among children with HL (12.1%) is higher than the rate of AD/HD in NH children (3.6%), consistent with previous findings. After excluding patients with comorbidities and adjusting for covariates, there are similar rates of AD/HD between HL and NH patients. Given high rates of comorbidities and AD/HD in HL patients and potential for augmented developmental challenges, clinicians should have a low threshold to refer children with HL for neurocognitive testing, particularly those with any of the comorbidities or covariates described in this study.

The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans.

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

Surgical Approach for Rapid and Minimally Traumatic Recovery of Human Inner Ear Tissues From Deceased Organ Donors.

OBJECTIVE: To develop a surgical approach for rapid and minimally traumatic recovery of inner ear tissue from human organ and tissue donors to provide fresh tissue for use in inner ear research. STUDY DESIGN: Exploration of novel surgical methodology and evaluation of the steps necessary for obtaining specimens from donors during the procurement of organs for transplantation. SETTING: Donor procurement locations across multiple local hospitals and tissue processing at the microsurgical temporal bone laboratory. PATIENTS TISSUE SOURCE: Human organ and tissue donors. INTERVENTIONS: Dissection and procurement of the inner ear tissue. MAIN OUTCOME MEASURES: Development of rapid and minimally traumatic inner ear tissue recovery. Primarily, establishing an efficient process which includes collaboration with transplant network, implementing a consent protocol, developing and training an on-call recovery team, and designing a portable surgical kit suitable for use in a variety of settings. RESULTS: The extraction procedure is described in three consecutive steps: the trans-canal exposure, the approach to the vestibule with extraction of the vestibular organs; and the approach to extract inner ear tissues from the cochlear duct. CONCLUSIONS: Organ and tissue donors are a promising and underutilized resource of inner ear organs for purposes of research and future translational studies. Using our modified technique through the trans-canal/trans-otic approach, we were able to extract tissues of the vestibular and auditory end organs in a timely manner.

Selection Criteria Optimal for Recovery of Inner Ear Tissues From Deceased Organ Donors.

OBJECTIVE: To identify optimal conditions for recovering viable inner ear tissues from deceased organ donors. SETTING: Tertiary recovery hospitals and Donor Network West Organ Recovery Center. INTERVENTIONS: Recovering bilateral inner ear tissues and immunohistological analysis. MAIN OUTCOME MEASURES: Immunohistochemical analysis of utricles from human organ donors after brain death (DBD) or donors after cardiac death (DCD). RESULTS: Vestibular tissues from 21 organ donors (39 ears) were recovered. Of these, 18 donors (33 utricles) were examined by immunofluorescence. The sensory epithelium was present in seven utricles (two from DBD and five from DCD). Relative to DBD utricles, DCD organs more commonly displayed dense populations of hair cells and supporting cells. Relative to DBD, DCD had significantly shorter postmortem interval time to tissue recovery (<48 h). Compared to donors with no sensory epithelium, donors with intact and viable sensory epithelium (both DCD and DBD) had significantly shorter lag time to resuscitation prior to hospital admission (6.4 ±â€Š9.2 vs 35.6 ±â€Š23.7 min, respectively) as well as a shorter time between pronouncements of death to organ recovery (22.6 ±â€Š30.4 vs 64.8 ±â€Š22.8 h, respectively). CONCLUSIONS: Organ donors are a novel resource for bilateral inner ear organs. Selecting tissue donors within defined parameters can optimize the quality of recovered inner ear tissues, thereby facilitating future research investigating sensory and nonsensory cells.

Influence of electrode to cochlear duct length ratio on post-operative speech understanding outcomes.

OBJECTIVE: To assess whether the pre-operative electrode to cochlear duct length ratio (ECDLR), is associated with post-operative speech recognition outcomes. STUDY DESIGN: A retrospective chart review study. SETTING: Tertiary referral center. PATIENTS: The study included sixty-one adult CI recipients with a pre-operative computed tomography scan and a speech recognition test 12 months after implantation. INTERVENTIONS: The average of two raters' cochlear duct length (CDL) measurements and the length of the recipient's cochlear implant electrode array formed the basis for the electrode-to-cochlear duct length ratio (ECLDR). Speech recognition tests were compared as a function of ECDLR and electrode array length itself. MAIN OUTCOME MEASURES: The relationship between ECDLR and percent correct on speech recognition tests. RESULTS: A second order polynomial regression relating ECDLR to percent correct on the CNC words speech recognition test was statistically significant, as was a fourth order polynomial regression for the AzBio Quiet test. In contrast, there was no statistically significant relationship between speech recognition scores and electrode array length. CONCLUSIONS: ECDLR values can be statistically associated to speech-recognition outcomes. However, these ECDLR values cannot be predicted by the electrode length alone, and must include a measure of CDL.

Long-Term Health Utilization and Outcomes in Chronic Suppurative Otitis Media.

OBJECTIVE: To report health utilization patterns and outcomes of medical and surgical management in patients with chronic suppurative otitis media (CSOM). STUDY DESIGN: Retrospective cohort. SETTING: Academic otology clinic. METHODS: This study included 175 patients with CSOM with a first clinic visit at our institution between March 2011 and November 2016. All patients displayed a diagnosis of CSOM by International Classification of Diseases code, had at least 1 episode of active CSOM (defined as perforation with otorrhea), and had a documented history of chronic ear infections. The mean age was 49.5 ± 1.5 years, 53% were female, and mean follow-up time was 3.5 ± 0.3 years. RESULTS: Patients had an average of 9.5 ± 0.5 otology visits, 4.7 ± 0.4 prescriptions, and 1.7 ± 0.1 surgeries, with estimated per patient cost ranging from $3927 to $20,776. Under medical management, 69% of patients displayed recurrence of disease, with a median time to recurrence of 4 months. For tympanoplasty and tympanomastoidectomy, median time to recurrence was similar at 5 and 7 years, respectively (P = .73). At the most recent visit, the prevalence of all patients with CSOM displaying moderate or worse sensorineural hearing loss (SNHL) was 41%. CONCLUSIONS: CSOM represents a major public health issue with high health care utilization and associated costs. Surgery is superior to medical therapy for achieving short- to medium-term inactive disease. Patients with CSOM display a high SNHL burden.

Tumor Control Following Stereotactic Radiosurgery in Patients with Vestibular Schwannomas - A Retrospective Cohort Study.

BACKGROUND: To better counsel vestibular schwannoma patients, it is necessary to understand the tumor control rates of stereotactic radiosurgery (SRS). OBJECTIVES: To determine tumor control rates, factors determining control and complication rates following SRS. METHODS: Tertiary hospital retrospective cohort. RESULTS: 579 tumors (576 patients) were treated with SRS. 477 tumors (474 patients, 82%) had ≥1 year follow up and 60% (344) ≥3 years follow up. 88% of tumors had primary SRS and 6.7% salvage SRS. Median follow up time was 4.6 years. At 3 years, the tumor control rate of primary SRS was 89% (258 of 290) in sporadic tumors compared to 43% in Neurofibromatosis type II (3 of 17) (p < 0.01). Our bivariable survival data analysis showed that Neurofibromatosis type II, documented pre-SRS growth, tumor measured by maximum dimension, SRS given as nonprimary treatment increased hazard of failure to control. There was one case of malignancy and another of rapid change following intra-tumoral hemorrhage. For tumors undergoing surgical salvage (25 of 59), 56% had a total or near-total resection, 16% had postoperative CSF leak, with 12% new facial paralysis (House-Brackmann grade VI) and worsening of facial nerve outcomes (House-Brackmann grade worse in 59% at 12 mo). CONCLUSIONS: Control of vestibular schwannoma after primary SRS occurs in the large majority. Salvage surgical treatment was notable for higher rates of postoperative complications compared to primary surgery reported in the literature.

The risk of ergonomic injury across surgical specialties.

Lack of ergonomic training and poor ergonomic habits during the operation leads to musculoskeletal pain and affects the surgeon's life outside of work. The objective of the study was to evaluate the severity of ergonomic hazards in the surgical profession across a wide range of surgical subspecialties. We conducted intraoperative observations using Rapid Entire Body Assessment (REBA) score system to identify ergonomic hazards. Additionally, each of the ten surgical subspecialty departments were sent an optional 14 question survey which evaluated ergonomic practice, environmental infrastructure, and prior ergonomic training or education. A total of 91 surgeons received intraoperative observation and were evaluated on the REBA scale with a minimum score of 0 (low ergonomic risk <3) and a maximum score of 10 (high ergonomic risk 8-10). And a total of 389 surgeons received the survey and 167 (43%) surgeons responded. Of the respondents, 69.7% reported suffering from musculoskeletal pain. Furthermore, 54.9% of the surgeons reported suffering from the highest level of pain when standing during surgery, while only 14.4% experienced pain when sitting. Importantly, 47.7% stated the pain impacted their work, while 59.5% reported pain affecting quality of life outside of work. Only 23.8% of surgeons had any prior ergonomic education. Both our subjective and objective data suggest that pain and disability induced by poor ergonomics are widespread among the surgical community and confirm that surgeons rarely receive ergonomic training. Intraoperative observational findings identified that the majority of observed surgeons displayed poor posture, particularly a poor cervical angle and use of ergonomic setups, both of which increase ergonomic risk hazards. This data supports the need for a comprehensive ergonomic interventional program for the surgical team and offers potential targets for future intervention.

Assessment of Inter- and Intra-Rater Reliability of Tablet-Based Software to Measure Cochlear Duct Length.

OBJECTIVE: The objective of this study is to build upon previous work validating a tablet-based software to measure cochlear duct length (CDL). Here, we do so by greatly expanding the number of cochleae (n = 166) analyzed, and examined whether computed tomography (CT) slice thickness influences reliability of CDL measurements. STUDY DESIGN: Retrospective chart review study. SETTING: Tertiary referral center. PATIENTS: Eighty-three adult cochlear implant recipients were included in the study. Both cochleae were measured for each patient (n = 166). INTERVENTIONS: Three raters analyzed the scans of 166 cochleae at 2 different time points. Each rater individually identified anatomical landmarks that delineated the basal turn diameter and width. These coordinates were applied to the elliptic approximation method (ECA) to estimate CDL. The effect of CT scan slice thickness on the measurements was explored. MAIN OUTCOME MEASURES: The primary outcome measure is the strength of the inter- and intra-rater reliability. RESULTS: The mean CDL measured was 32.84 ±â€Š2.03 mm, with a range of 29.03 to 38.07 mm. We observed no significant relationship between slice thickness and CDL measurement (F1,164 = 3.04; p = 0.08). The mean absolute difference in CDL estimations between raters was 1.76 ±â€Š1.24 mm and within raters was 0.263 ±â€Š0.200 mm. The intra-class correlation coefficient (ICC) between raters was 0.54 and ranged from 0.63 to 0.83 within raters. CONCLUSIONS: This software produces reliable measurements of CDL between and within raters, regardless of CT scan thickness.

Ambient Pressure Tympanometry Wave Patterns in Patients With Superior Semicircular Canal Dehiscence.

Importance: Superior semicircular canal dehiscence (SSCD) is a treatable condition, but current diagnostic modalities have numerous limitations. Clinicians would benefit from an additional tool for diagnostic workup that is both rapid and widely available. Objective: To assess the utility of ambient pressure tympanometry (APT) in the diagnostic workup of SSCD by determining the sensitivity and specificity of APT for SSCD in comparison to other diagnostic modalities. Design: Retrospective cohort study of patients who underwent APT and temporal bone computerized tomography (CT) scans from May 2017 to July 2018. Setting: Tertiary referral center. Participants: APT was performed as part of routine audiological testing on adult patients. We retrospectively analyzed all patients who received both APT and temporal bone CT scans, and divided ears into SSCD and non-SSCD groups based on the presence or absence of radiographic SSCD. Ears with other radiographic findings that could affect tympanic membrane compliance were excluded. Exposures: All patients in this study underwent APT and temporal bone CT scans. Some patients also underwent pure tone audiometry and vestibular evoked myogenic potentials (VEMPs). Main Outcomes and Measures: The primary outcome measures were sensitivity, specificity, and risk ratio of APT for SSCD. Secondary outcome measures include sensitivity of VEMPs and supranormal hearing thresholds. Results: We describe 52 patients (70 ears) who underwent APT and CT imaging (mean age 47.1 years, 67.1% female). APT detected SSCD with 66.7% sensitivity and 72.1% specificity. In symptomatic patients, sensitivity was 71.4% and specificity was 75%. VEMPs performed best at detecting SSCD when defining a positive test as oVEMP amplitude >17 µV, with a sensitivity of 68.2%, similar to APT (p > 0.99). The combination of APT and VEMPs increased sensitivity to 88.9%, better than APT alone (p = 0.031) and trending toward better than VEMPs alone (p = 0.063). Conclusions and Relevance: Rhythmic wave patterns on APT are associated with SSCD and may raise suspicion for this condition in conjunction with consistent results on other diagnostic modalities. Although clinical utility requires confirmation in a larger prospective study, APT is a simple, rapid, and widely available tool warranting further study.

Speech Perception Changes in the Acoustically Aided, Nonimplanted Ear after Cochlear Implantation: A Multicenter Study.

In recent years there has been an increasing percentage of cochlear implant (CI) users who have usable residual hearing in the contralateral, nonimplanted ear, typically aided by acoustic amplification. This raises the issue of the extent to which the signal presented through the cochlear implant may influence how listeners process information in the acoustically stimulated ear. This multicenter retrospective study examined pre- to postoperative changes in speech perception in the nonimplanted ear, the implanted ear, and both together. Results in the latter two conditions showed the expected increases, but speech perception in the nonimplanted ear showed a modest yet meaningful decrease that could not be completely explained by changes in unaided thresholds, hearing aid malfunction, or several other demographic variables. Decreases in speech perception in the nonimplanted ear were more likely in individuals who had better levels of speech perception in the implanted ear, and in those who had better speech perception in the implanted than in the nonimplanted ear. This raises the possibility that, in some cases, bimodal listeners may rely on the higher quality signal provided by the implant and may disregard or even neglect the input provided by the nonimplanted ear.

What Genes Can Tell: A Closer Look at Vestibular Schwannoma.

OBJECTIVE: Comprehensive molecular profiling of radioresistant and cystic vestibular schwannoma (VS) subtypes. STUDY DESIGN: Our study utilized whole-exome sequencing (WES), RNA-sequencing (RNAseq), and correlated clinical data from 12 samples (2 samples of solid sporadic subtype, 8 with cystic changes, and 2 previously irradiated). SETTING: Academic medical center. PATIENTS: Patients diagnosed with VS who required surgical treatment. Inclusion: Cystic and radioresistant tumors matched to age and tumor volume, with solid sporadic VS samples as control; Exclusion: NF-2 patients. INTERVENTION(S): WES using custom probes for copy number analysis. A modified version of the Agilent Human Whole Exome sequencing hybrid capture system was used to process samples. Recurrent variants were identified and compared between groups. Leukocyte-derived DNA was utilized as internal control to reduce false-positives. MAIN OUTCOME MEASURE(S): Analysis of genetic landscape of VS subtypes (naive solid VS, cystic VS, and previously irradiated VS) by performing deep next-generation sequencing. RESULTS: WES data achieved a mean coverage of 202X and RNAseq generated an average of 74 million total reads. As a group, 25% of samples had 22q loss. Somatic analysis identified previously reported genes and multiple novel mutations across samples. Differential expression analysis of RNAseq data found significantly mutated genes such as COL6A3, CLMP, ART4, Lumican that were shared by both cystic VS and irradiated VS, but not seen in sporadic VS. CONCLUSIONS: Using WES we were able to demonstrate that cystic and irradiated samples are subtypes of VS with an increased mutation burden and a unique genetic fingerprint. We identified differences between the genomic and molecular profile of cystic VS and radioresistant VS. Our results help advance the understanding of the pathophysiology of these tumor subtypes and suggest possible molecular targets for novel treatment strategies.

Advances in Inner Ear Therapeutics for Hearing Loss in Children.

Purpose of review: Hearing loss is a common congenital sensory disorder with various underlying causes. Here, we review and focus on genetic, infectious, and ototoxic causes and recent advances in inner ear therapeutics. Recent findings: While hearing aids and cochlear implantation are the mainstay of treatment for pediatric hearing loss, novel biological therapeutics are being explored. Recent preclinical studies report positive results in viral-mediated gene transfer techniques and surgical approaches to the inner ear for genetic hearing loss. Novel pharmacologic agents, on the other hand, show promising results in reducing aminoglycoside and cisplatin ototoxicity. Clinical trials are underway to evaluate the efficacy of antivirals for cytomegalovirus-related hearing loss, and its pathogenesis and other potential therapeutics are currently under investigation. Summary: Individualized therapies for genetic and infectious causes of sensorineural hearing loss in animal models as well as pediatric patients show promising results, with their potential efficacy being active areas of research.

History of Cranial Nerve-Implanted Stimulators in Otolaryngology.

This article aims to clearly understand the historical development of cranial nerve-implanted stimulators in otolaryngology. The authors also discuss cranial nerve history; initial theory of the functional concept of animal spirit; electrical nerve impulse theory; first electrical otolaryngology cranial nerve stimulation devices; and the development of implanted stimulators.

Dye Tracking Following Posterior Semicircular Canal or Round Window Membrane Injections Suggests a Role for the Cochlea Aqueduct in Modulating Distribution.

The inner ear houses the sensory epithelium responsible for vestibular and auditory function. The sensory epithelia are driven by pressure and vibration of the fluid filled structures in which they are embedded so that understanding the homeostatic mechanisms regulating fluid dynamics within these structures is critical to understanding function at the systems level. Additionally, there is a growing need for drug delivery to the inner ear for preventive and restorative treatments to the pathologies associated with hearing and balance dysfunction. We compare drug delivery to neonatal and adult inner ear by injection into the posterior semicircular canal (PSCC) or through the round window membrane (RWM). PSCC injections produced higher levels of dye delivery within the cochlea than did RWM injections. Neonatal PSCC injections produced a gradient in dye distribution; however, adult distributions were relatively uniform. RWM injections resulted in an early base to apex gradient that became more uniform over time, post injection. RWM injections lead to higher levels of dye distributions in the brain, likely demonstrating that injections can traverse the cochlea aqueduct. We hypothesize the relative position of the cochlear aqueduct between injection site and cochlea is instrumental in dictating dye distribution within the cochlea. Dye distribution is further compounded by the ability of some chemicals to cross inner ear membranes accessing the blood supply as demonstrated by the rapid distribution of gentamicin-conjugated Texas red (GTTR) throughout the body. These data allow for a direct evaluation of injection mode and age to compare strengths and weaknesses of the two approaches.

Ergonomic hazards in otolaryngology.

OBJECTIVES/HYPOTHESIS: To evaluate the presence of postural-related strain and musculoskeletal discomfort, along with the level of ergonomics training and the availability of ergonomic equipment among otolaryngology surgeons. STUDY DESIGN: Intraoperative observations and survey study. METHODS: Using the Rapid Entire Body Assessment score system to identify ergonomic hazards, we conducted intraoperative observations assessing operating room personnel during different otolaryngological subspecialty procedures. Based on these findings, otolaryngology surgeons at a single academic institution in the United States were sent a survey that evaluated ergonomic practice, environmental infrastructure, and prior ergonomic training or education. RESULTS: A response rate of 69% was obtained from 70 surgeons, with 72.9% of responding surgeons suffering from some level of back pain, with cervical spine pain being the most common. Interestingly, residents were equally affected when compared to more senior surgeons both in subjective survey reports and from observational risk analysis. Furthermore, 43.8% of surgeons reported suffering from the highest level of pain when standing, whereas only 12.5% experienced pain when sitting. Importantly, 10% stated that pain impacted their work. Only 24% of surgeons had any prior ergonomic training or education. CONCLUSIONS: Our data suggest that pain and disability induced by poor ergonomics are widespread among the otolaryngology community and confirm that surgeons rarely receive ergonomic training in the surgical context. Additionally, intraoperative observational findings identified that the majority of observed surgeons display poor posture, particularly a poor cervical angle and use of ergonomic setups, both of which increase ergonomic risk hazard. These data provide guidance for future interventional studies. LEVEL OF EVIDENCE: NA Laryngoscope, 129:370-376, 2019.