Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs.

Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.

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.

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.

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.

A case report of two different skull base pathologies causing hearing loss in the same ear: vestibular schwannoma and superior semicircular canal dehiscence.

Vestibular schwannoma and superior semicircular canal dehiscence are both uncommon entities, especially when present in the same ear. Here we illustrate how both of these pathologies can be repaired through the same surgical exposure, of the middle cranial fossa, with complete preservation of the cochlear nerve function and relief of symptoms caused by canal dehiscence.