Formation of left-handed helices by C2'-fluorinated nucleic acids under physiological salt conditions.

Recent findings in cell biology have rekindled interest in Z-DNA, the left-handed helical form of DNA. We report here that two minimally modified nucleosides, 2'F-araC and 2'F-riboG, induce the formation of the Z-form under low ionic strength. We show that oligomers entirely made of these two nucleosides exclusively produce left-handed duplexes that bind to the Zα domain of ADAR1. The effect of the two nucleotides is so dramatic that Z-form duplexes are the only species observed in 10 mM sodium phosphate buffer and neutral pH, and no B-form is observed at any temperature. Hence, in contrast to other studies reporting formation of Z/B-form equilibria by a preference for purine glycosidic angles in syn, our NMR and computational work revealed that sequential 2'F…H2N and intramolecular 3'H…N3' interactions stabilize the left-handed helix. The equilibrium between B- and Z- forms is slow in the 19F NMR time scale (≥ms), and each conformation exhibited unprecedented chemical shift differences in the 19F signals. This observation led to a reliable estimation of the relative population of B and Z species and enabled us to monitor B-Z transitions under different conditions. The unique features of 2'F-modified DNA should thus be a valuable addition to existing techniques for specific detection of new Z-binding proteins and ligands.

Disparities in polysomnography referral in a high-risk cardiac population.

PURPOSE: Obstructive sleep apnea (OSA) is associated with metabolic, cardiovascular, and cerebrovascular comorbidities. Appropriate diagnosis and treatment of OSA might mitigate these comorbidities. This retrospective review sought to assess the impact of sex, age, race, ethnicity, and insurance status on polysomnography (PSG) referral rates. METHODS: An institutional STOP-Bang database of 299,320 patients was filtered for patients admitted to the hospital with an acute cardiac diagnosis between 2015-2020. A cohort of 4,735 patients were risk stratified by STOP-Bang (SB) score and correlations were made between PSG referrals and demographic and clinical variables (sex, age, race, ethnicity, and insurance status). RESULTS: Of the 25.3% of the cohort with high SB scores (5-8) only 21.3% were referred for PSG. Age and female sex were negatively associated with sleep study referrals (p < 0.001). No correlation was found between sleep study referral rates and race or ethnicity. No correlation was found between sleep study referrals and insurance provider. Admitting cardiac diagnosis significantly influenced sleep study referrals with diagnoses of arrhythmias and myocardial infarction being associated with an increased rate of PSG referrals compared to heart failure patients (p < 0.002). CONCLUSIONS: Our study found no significant correlation between PSG referral rates and race, ethnicity, or insurance provider. However, we found low overall rates of PSG referral, with negative correlations between older age and female sex and a high-risk cardiac population. This represents a substantial missed opportunity to identify patients at risk for OSA, obtain a diagnosis, and provider adequate treatment.

Duration of effectiveness of coblation for recurrent epistaxis in hereditary hemorrhagic telangiectasia.

INTRODUCTION: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease leading to recurrent epistaxis, telangiectasias, and/or visceral arteriovenous malformations. Multiple treatment methods, including both pharmacologic and surgical, are described to be effective in managing symptomatic HHT. Few report the duration of symptom improvement for each of these treatment methods. This study aims to analyze the duration of effectiveness of coblation treatment for recurrent epistaxis in those with HHT. METHODS: Retrospective single-center chart review was completed for patients diagnosed with HHT who underwent coblation treatment by the same otolaryngologist from December 2009 to November 2021. Demographic information was collected along with whether local Bevacizumab was used during each treatment. Months between treatment coblation sessions was used as a surrogate for duration of treatment effectiveness. Descriptive statistics were used for analysis alongside quantitative statistical analysis. RESULTS: Over the course of 12 years, 57 patients (24 female, 42.11%) with HHT underwent a total number of 150 coblation treatments. The average age at initial coblation was 59 years (29-88) with an average follow-up time of 5 years (1-12 years). Of the 150 coblations, 30 treatments (20%) included bevacizumab injections into the nasal cavity. The average duration of treatment effectiveness across all 150 treatment sessions was 24.5 months (1-87 months). Of the 26 patients (46%) that underwent multiple coblation treatments, the overall average duration of coblation effectiveness was 16.4 months (1-72 mos). When Bevacizumab was utilized, the average duration of effectiveness was 18.3 months (3-62 mos), while the average duration of effectiveness for treatments without Bevacizumab was 15.7 months (1-87 mos, p > 0.251). Further, there was no correlation between duration of treatment effectiveness and age, sex, and race; yet,there was a significant negative correlation between the use of tobacco and duration of coblation effectiveness (p = 0.0202). CONCLUSIONS: Coblation is an effective treatment option for the management of epistaxis in patients with HHT with duration of benefit lasting approximately 2 years. The use of Bevacizumab did not add to the duration of treatment benefit. Further, the duration of benefit was negatively impacted by smoking history.

Medial orbital wall decompression: Demographics influencing surgical follow-up and complications: Impacts on follow-up and complications.

OBJECTIVE: Identify the impact of demographics and social determinants of health on surgical follow-up and complications after medial orbital wall decompression (MOWD) secondary to thyroid associated orbitopathy (TAO). METHODS: Demographics and social determinants of health (age, sex, race, insurance status) for 46 patients undergoing MOWD secondary to TAO were correlated with post-operative compliance and surgical complications by chi-square analyses. RESULTS: Among 46 patients, 23 were compliant with follow-up. There was no statistically significant difference between compliance and non-compliance based on age (60.25 vs 56.4, p = .41), sex (71.9 % female vs 85.7 % female, p = .31), race (65.6 % white vs 71.4 % white, p = .70) or insurance status (59.4 % private vs 42.9 % private, p = .30). Complications were noted in 50 % of patients of which sinus infection was most common (47.8 % of complications) and epistaxis rare (4.3 % of complications). No correlation was noted between development of complications and compliance (p = .20). Likewise, age, race and insurance status did not correlate with complications. CONCLUSION: For patients undergoing MOWD, no correlations with compliance or complication rate were noted with age, sex, race, or insurance status. A larger cohort may be indicated to identify such patterns. The overall complication rate was 50 % and the increased number of visits may have economic impact. KEY POINTS: This study provides a unique chance to assess demographic correlates of compliance and complication while controlling for surgeon preference. There was no association between sociodemographics and compliance or complications.

Abnormal hearing patterns are not associated with endothelium-dependent vasodilation and carotid intima-media thickness: The Framingham Heart Study.

INTRODUCTION: Prior data suggest associations between hearing loss, cardiovascular (CV) risk factors, and CV disease. Whether specific hearing loss patterns, including a strial pattern associated with inner ear vascular disease, are associated with systemic endothelial dysfunction and carotid intima-media thickness (IMT) remains unclear. METHODS: We evaluated participants without prevalent CVD in the Framingham Offspring Study who underwent formal audiogram testing and brachial and carotid artery ultrasounds. Audiograms were categorized as normal or as belonging to one of four abnormal patterns: cochlear-conductive, low-sloping, sensorineural, or strial. Endothelial function as measured by brachial artery flow-mediated dilation (FMDmm and FMD%). Internal and common intima-media thicknesses (icIMT and ccIMT, respectively) were compared between audiogram patterns. RESULTS: We studied 1672 participants (mean age 59 years, 57.6% women). The prevalence of each hearing pattern was as follows: 43.7% normal; 20.3% cochlear-conductive; 20.3% sensorineural; 7.7% low-sloping; and 8.0% strial. Strial pattern hearing loss was nearly twice as prevalent (p = 0.001) in those in the highest quartile of ccIMT and nearly 50% higher in those in the highest icIMT quartile (p = 0.04). There were no statistically significant differences between the prevalence of the strial pattern comparing the lowest quartiles of FMDmm and FMD% with the upper three quartiles. Age- and sex-adjusted linear regression models did not show significant associations between the vascular measures and hearing patterns. CONCLUSION: Abnormal hearing patterns were not significantly associated with impaired brachial FMD and increased carotid IMT after adjusting for age and sex effects, which may reflect age and sex-related distributional differences based on hearing loss pattern.

Safety, tolerability and pharmacokinetics of oral nafithromycin (WCK4873) after single or multiple doses and effects of food on single-dose bioavailability in healthy adult subjects.

Nafithromycin (WCK 4873), a novel lactone-ketolide, was administered to healthy adult subjects in 2 randomized, double-blind, placebo-controlled, Phase 1 studies. In the first-in-human study, single-ascending oral doses of nafithromycin (100 to 1200 mg) were administered to subjects under fasted or fed condition, with effects of food on bioavailability of nafithromycin studied at the dose levels of 400 and 800 mg. In the second study, multiple-ascending oral doses of 600, 800, or 1000 mg of nafithromycin were administered once daily for 7 days under a fed condition. Nafithromycin was generally well tolerated at all doses. No serious or severe adverse events were observed. The mean maximum plasma concentration (Cmax) ranged from 0.099 to 1.742 mg/L, and the area under the concentration-time curve from time zero to time t (AUC0-t ) ranged from 0.54 to 22.53 h⋅mg/L. Nafithromycin plasma AUC0-t increased approximately 1.2-fold under fed compared to fasted condition. In the multiple-dose study, the Day 7 nafithromycin Cmax ranged from 1.340 to 2.987 mg/L and the AUC over the final dosing interval (AUC0-24) ranged from 13.48 to 43.46 h⋅mg/L. The steady state was achieved after 3 days for the 600 mg and 800 mg dose cohorts and after 4 days for the 1000 mg cohort. Under both single- and multiple-dosing regimens, plasma exposure to nafithromycin appeared to increase more than dose-proportionally. Nafithromycin showed moderate accumulation on Day 7 of dosing. The human pharmacokinetic profile, safety and tolerability data support further development of nafithromycin.

Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer.

BACKGROUND: Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non-small cell lung cancer. METHODS: In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways. RESULTS: Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08). CONCLUSIONS: Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936-44. © 2017 American Cancer Society.

Improving Conduct and Feasibility of Clinical Trials to Evaluate Antibacterial Drugs to Treat Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team.

BACKGROUND: The etiology of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is often multidrug-resistant infections. The evaluation of new antibacterial drugs for efficacy in this population is important, as many antibacterial drugs have demonstrated limitations when studied in this population. HABP/VABP trials are expensive and challenging to conduct due to protocol complexity and low patient enrollment, among other factors. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development by streamlining HABP/VABP clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with HABP/VABP protocol complexity. The Project Team developed potential solutions to streamline HABP/VABP trials using a Quality by Design approach. RESULTS: CTTI recommendations focus on 4 key areas to improve HABP/VABP trials: informed consent processes/practices, protocol design, choice of an institutional review board (IRB), and trial outcomes. Informed consent processes should include legally authorized representatives. Protocol design decisions should focus on eligibility criteria, prestudy antibacterial therapy considerations, use of new diagnostics, and sample size. CTTI recommends that sponsors use a central IRB and discuss trial endpoints with regulators, including defining a clinical failure and evaluating the impact of concomitant antibacterial drugs. CONCLUSIONS: Streamlining HABP/VABP trials by addressing key protocol elements can improve trial startup and patient recruitment/retention, reduce trial complexity and costs, and ensure patient safety while advancing antibacterial drug development.

Failure in HiRes Ultra Series Recall Devices Does Not Necessarily Lead to Decrement in Performance.

OBJECTIVE: To understand the impact on speech perception for patients experiencing Advanced Bionics V1 series Ultra and Ultra 3D cochlear implant failure. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic center. PATIENTS: Adult patients implanted with V1 series devices. INTERVENTIONS: Device integrity and speech perception testing. MAIN OUTCOME MEASURES: consonant-nucleus-consonant and AzBio in quiet speech recognition scores. RESULTS: At our institution, 116 V1 series cochlear implants were placed in 114 patients. Thirteen devices in prelingual patients were excluded, leaving 103 (89%) for final analysis. Forty-eight (46.6%) devices were considered as failed using the company provided EFI analysis tool. There were 36 (65.5%) of the remaining 55 devices that consistently tested within normal range; the remainder lost to follow-up with unknown status. Among the 48 device failures, 29 were revised and 19 patients were not revised. Among those not revised, 11 self-opted for observation (57.9%). Observed patients, despite impedance changes meeting failure criteria, had no subjective or objective changes in speech perception. Sentence testing scores for failure patients who elected observation (82.9 ± 11.4%) were significantly higher at failure compared with those opting for revision (55 ± 22.8%, p = 0.006). For those undergoing revision surgery, significant improvement in post-activation scores was noted as compared with time of failure with a mean improvement of 12.9% (p = 0.002, n = 24) for consonant-nucleus-consonant word scores and 17.2% (p = 0.001, n = 19) for AzBio in quiet scores. CONCLUSIONS: Proactive monitoring using EFI identifies a higher rate of Ultra Series V1 device failure than previously reported. However, about 20% of these patients may not have subjective change in hearing or objective decline in test scores and could be observed. Should performance worsen, reimplantation provides significant improvement in speech recognition.

The Impact of Sociodemographic Factors on Rates of Tympanostomy Tube Placement for Pediatric Otitis Media.

Objective: To identify the impact of race, ethnicity, and socioeconomic status (SES) on the rate of tympanostomy tube placement. Study Design: Retrospective medical review and population-level analyses. Setting: Tertiary referral center. Methods: Demographic and population-level characteristics (age, gender, race, insurance status, and ZIP code) compared to the regional, health system, and otolaryngology clinic demographics. Results: Among 38,461 children diagnosed with otitis media (OM) 61.4% were white, 27.4% were black, 32.7% had private insurance, and 18.2% were Hispanic. Among patients seen in the pediatric ear, nose, and throat (ENT) clinics, 70.0% were white, 20.0% were black, 46.6% had private insurance, and 14.9% were Hispanic. Further disparity was noted among those receiving tympanostomy tubes: 75.6% white, 15.6% black, 61.9% private insurance, and 11.7% Hispanic. Higher rates of tube placement were noted for those of white race [odds ratio, OR: 1.96, (95% confidence interval, CI: 1.85-2.04), <.001] and non-Hispanic ethnicity [OR: 1.67, (95% CI: 1.56-1.75), <.001]. Geographically, rates of tube placement were significantly lower in areas with higher deprivation indices, areas with lower proportions of white residents, and areas with the lowest median incomes. These markers correlate strongly with black race and Hispanic ethnicity. Lower rates of tube placement were also seen in majority white locales with higher deprivation indices and lower median incomes. Conclusion: Rates of access to pediatric ENT clinics, and of tube placement, are significantly lower for those of Hispanic ethnicity and black race than for non-Hispanic white children. Higher rates of tube placement were noted among white children and those with private insurance. Lower rates of tube placement were seen in areas of lower SES regardless of racial demographics.

Evaluation of Social Determinants of Health on Dysphagia Care Pathways at a Tertiary Care Facility.

OBJECTIVES: Limited research exists evaluating the impact of social determinants of health in influencing care pathways for patients with dysphagia. A better understanding of whether these determinants correlate to altered care and resource utilization is essential as it relates to patient outcomes. STUDY DESIGN: Retrospective chart review. METHODS: All adult patients seen at a tertiary midwestern hospital were screened for ICD codes of dysphagia diagnoses from 2009 to 2019. Demographic information was collected from these patients with dysphagia including sex, race, ethnicity, and insurance status. Subgroup analysis was performed to assess referral pattern rates and types of diagnostic interventions ordered (none, videofluoroscopic swallow study, esophagram, and esophagogastroduodenoscopy). RESULTS: A total of 31,858 patients with dysphagia were seen at our institution during the study period, with a majority being female (56.36%), Caucasian (79.83%), and publicly insured (63.16%), at a median age of 60.35 years. There were no significant care delivery pattern differences based on geography/zip code analyses. African American patients were significantly more likely to have imaging or interventions performed (odds ratio [OR] 1.463, p = 0.005). Patients with public insurance also had higher rates of diagnostic study utilization (OR 1.53, p = 0.01). Only 3% of all patients with dysphagia were seen by laryngologists. CONCLUSION: No significant differences were seen in dysphagia evaluation modalities based on zip code analyses surrounding this tertiary care facility. African American patients and those with public insurance had significantly higher utilization of subsequent testing and intervention for dysphagia care. Further studies are necessary to delineate causes and outcome differences for these measurable differences in dysphagia care pathways. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1139-1146, 2024.

A novel otoferlin splice-site mutation in siblings with auditory neuropathy spectrum disorder.

We characterize a novel otoferlin mutation discovered in a sibling pair diagnosed with auditory neuropathy spectrum disorder and investigate auditory nerve function through their cochlear implants. Genetic sequencing revealed a homozygous mutation at the otoferlin splice donor site of exon 28 (IVS28 + 1G>T) in both siblings. Functional investigation showed that the intronic sequence between exons 28 and 29 was retained in the mutated minigenes that were expressed in 293T cells. Auditory nerve compound action potential recovery functions in the siblings demonstrated different rates of neural recovery, with sibling AN1 showing rapid recovery (1.14 ms) and AN2 showing average recovery (0.78 ms) compared to subjects with sensorineural hearing loss (average: adults 0.71 ms, children 0.85 ms). Differences in neural recovery were consistent with speech perception differences between the siblings. Genotype information may indicate site of lesion in hearing loss; however, additional, as yet, unknown factors may impact clinical outcomes and must be considered.

The Demographics of Menière's Disease: Selection Bias or Differential Susceptibility?

OBJECTIVE: To clarify whether the reported lack of racial and ethnic diversity among Menière's disease (MD) patients is representative of selection bias or disease susceptibility. STUDY DESIGN: Retrospective medical record review and population-level analyses. SETTING: Tertiary referral center. PATIENTS: Cohort of 1091 patients diagnosed with MD by the tertiary otology service. MAIN OUTCOME MEASURE: Demographic and population-level characteristics (age, sex, race, insurance status, ZIP code, median income, education level) compared with local, regional, health system, and otolaryngology clinic demographics. RESULTS: Patients seen for MD were significantly older than those seen throughout the otolaryngology clinic (median, 65.0 versus 58.8 yr) or health system (65.0 versus 50.8 yr). A majority of patients with MD were of White race (92%), compared with 2.7% Black race and 0.5% Asian. Using population-level data, median income and having medical insurance were significantly correlated with care for MD. A disproportionate rate of care for MD was seen in ZIP codes outside urban areas as compared with other otologic and otolaryngologic conditions seen in the same clinic. CONCLUSION: Patients with MD are of older age, more likely to be of White race, and disproportionately from rural locales. The demographic profile of patients diagnosed with MD by tertiary otology is better explained by differential susceptibility to MD than by selection bias.

Factors associated with delayed referral and hearing rehabilitation for congenital sensorineural hearing loss.

OBJECTIVES: To identify the impact of social determinants of health and clinical status on referral and intervention for congenital sensorineural hearing loss. STUDY DESIGN: Retrospective chart review of children with confirmed sensorineural or mixed hearing loss between 2013 and 2021 at a single academic medical institution. METHODS: Referral rates and timing for hearing rehabilitation, rates and timing of completed evaluation, and rate and timing of amplification were recorded. Patient demographics included gestational age, race, ethnicity, sex, hearing loss severity, and CMV status. RESULTS: There were 216 children with confirmed sensorineural or mixed hearing loss, of which 77 had a unilateral hearing loss and 89 a severe or profound hearing loss. Delayed referral for hearing aid evaluation was noted in premature patients (median 375 days premature, median 147 term; p < 0.01) and publicly insured patients (median 215 days, median 123 private; p = 0.04). Delayed time to hearing aid fitting was noted for non-white patients (median 325 days, median 203 white patients; p < 0.01), publicly insured patients (median 309 days, median 212 private insurance; p < 0.02), and premature patients (median 462 days, median 224 term; p = 0.03). White patients were more likely to be referred for cochlear implant (p = 0.03).Privately insured patients and patients with a positive CMV test were more likely to be referred for cochlear implant evaluation, be seen in the cochlear implant clinic, and undergo implantation (p < 0.05). Non-white patients had a delay in cochlear implantation referral (median 928 days, median 398 days white patients; p = 0.05). Prolonged interval between evaluation in cochlear implant clinic to implantation was noted for privately insured patients (median 125 days; median 78 days publicly insured; p = 0.05). CONCLUSIONS: Sociodemographic factors were significantly associated with hearing amplification referral rates and time until amplification for children with identified congenital sensorineural hearing loss. For cochlear implantation, insurance type, CMV status were significantly associated with rate and timing of cochlear implant pathway.

Impacts of Socioeconomic Status on Dentoalveolar Trauma.

INTRODUCTION: Children sustain dentoalveolar trauma and lose teeth at the same rate regardless of socioeconomic status; however, debate surrounds these rates in adults. It is known socioeconomic status plays a major role in access and treatment in health care. This study aims to clarify the role of socioeconomic status as a risk factor for dentoalveolar trauma in adults. METHODS: A single center retrospective chart review took place from January 2011 through December 2020 for patients requiring oral maxillofacial surgery consultation in the emergency department, due to either dentoalveolar trauma (Group 1) or other dental condition (Group 2). Demographic information including age, sex, race, marital status, employment status, and type of insurance were collected. Odds ratios were calculated by chi-square analysis with significance set at P < 0.05. RESULTS: Over the course of 10 years, 247 patients (53% female) required an oral maxillofacial surgery consultation, with 65 (26%) sustaining dentoalveolar trauma. Within this group, there were significantly more subjects who were Black, single, insured with Medicaid, unemployed, and 18 - 39 years old. In the nontraumatic control group, there were significantly more subjects who were White, married, insured with Medicare, and 40 - 59 years old. CONCLUSIONS: Among those seen in the emergency department requiring an oral maxillofacial surgery consultation, those with dentoalveolar trauma have an increased likelihood of being single, Black, insured with Medicaid, unemployed, and 18 - 39 years old. Further research is needed to determine causality and the most critical/influential socioeconomic status factor in sustaining dentoalveolar trauma. Identifying these factors can assist in developing future community-based prevention and educational programs.

Establishment of novel immortalized middle ear cell lines as models for otitis media.

Objective: Otitis media (OM) is among the most frequently diagnosed pediatric diseases in the US. Despite the significant public health burden of OM and the contribution research in culture models has made to understanding its pathobiology, a singular immortalized human middle ear epithelial (MEE) cell line exists (HMEEC-1, adult-derived). We previously developed MEE cultures from pediatric patients with non-inflamed MEE (PCI), recurrent OM (ROM), or OM with effusion (OME) and demonstrated differences in their baseline inflammatory cytokine expression and response to stimulation with an OM-relevant pathogen lysate and cytokines. Herein, we sought to immortalize these cultures and assess retention of their phenotypes. Methods: MEE cultures were immortalized via lentivirus encoding temperature-sensitive SV40 T antigen. Immortalized MEE lines and HMEEC-1 grown in monolayer were stimulated with non-typeable Haemophilus influenzae (NTHi) lysate. Gene expression (TNFA, IL1B, IL6, IL8, MUC5AC, and MUC5B) was assessed by qPCR. Results: Similar to parental cultures, baseline cytokine expressions were higher in pediatric OM lines than in HMEEC-1 and PCI, and HMEEC-1 cells were less responsive to stimulation than pediatric lines. Conclusion: Immortalized MEE lines retained the inflammatory expression and responsiveness of their tissues of origin and differences between non-OM versus OM and pediatric versus adult cultures, supporting their value as novel in vitro culture models for OM.

Clinical perspectives on nasopharyngeal morphology in humans.

The nasopharynx is an integral component of the upper aerodigestive tract, whose morphologic features share an intimate relationship with a vast array of clinical, functional, and quality of life conditions related to contemporary humans. Its composite architecture and central location amidst the nasal cavity, pharyngotympanic tube, palate, and skull base bears implications for basic physiologic functions including breathing, vocalization, and alimentation. Over the course of evolution, morphological modifications of nasopharyngeal anatomy have occurred in genus Homo which serve to distinguish the human upper aerodigestive tract from that of other mammals. Understanding of these adaptive changes from both a comparative anatomy and clinical perspective offers insight into the unique blueprint which underpins many clinical pathologies currently encountered by anthropologists, scientists, and otorhinolaryngologists alike. This discussion intends to familiarize readers with the fundamental role that nasopharyngeal morphology plays in upper aerodigestive tract conditions, with consideration of its newfound clinical relevance in the era of the COVID-19 pandemic.

The impact of social determinants of health and clinical comorbidities on post-tympanotomy tube otorrhea.

OBJECTIVES: To measure the impact of social determinants of health and clinical comorbidities on the incidence of post-tympanotomy tube otorrhea (PTTO). METHODS: Retrospective observational cohort study. All children between the ages of 0 and 17 having tympanotomy tube placement between 2009 and 2019. Between group comparisons entailed the calculation of odds ratios (OR) with 95% confidence intervals and associated p-values. RESULTS: Among 12,757 patients who underwent myringotomy and tube placement, 2217 (17.4%) presented with PTTO within 1 year. Race and sex did not correlate with the development of PTTO. Non-Hispanic ethnicity had a negative association with PTTO (OR: 0.80 (0.70-0.91), p < .0001). Insurance status correlated with incidence of PTTO with a higher rate noted among those with public insurance (OR: 1.12 (1.02-1.23), p = .02) and a lower rate among those with private insurance (OR: 0.84 (0.77-0.92), p < .0001). Craniofacial abnormalities had the strongest positive correlation with PTTO, particularly, cleft lip and/or cleft palate (OR>2.24, p < .0001). Immunodeficiency had similar impact on PTTO (OR: 2.38 (1.46-3.91), p < .0001). Asthma and prematurity did not significantly correlate with occurrence of PTTO. CONCLUSION: Higher rates of PTTO correlated strongest with clinical factors; particularly craniofacial abnormalities and immunodeficiency. Social determinants, including private insurance and non-Hispanic ethnicity, were associated with lower rates of PTTO. Race and sex did not show significant correlations.

Analysis of socioeconomic factors in laryngology clinic utilization for treatment of dysphonia.

OBJECTIVE: To evaluate the association between patient socioeconomic and demographic factors and tertiary care utilization for dysphonia in a localized metropolitan area of the American Midwest. METHODS: Multivariate regression analysis was used to correlate patient demographics and population level data (e.g., age, gender, race, insurance, median income, education level) with tertiary laryngology utilization for dysphonia care at our institution between 2000 and 2019. Initial analyses characterized tertiary laryngology utilization rates for all regional ZIP codes and correlated these data with census information for household income and education. Dysphonia patient demographics were compared among populations cared for in our entire academic Otolaryngology department, our health system, and the regional population. RESULTS: Among 1,365,021 patients in our health system, there were 7066 tertiary laryngology visits with a diagnosis of dysphonia. Dysphonia patients as compared to the overall health system were older (62.0 vs. 50.8 years), more likely to be female (63.7 vs. 50.2%) and more likely to have insurance (98.4 vs. 87.5%, all p < .001). Patient and population-level factors including insurance status, education, and black race showed positive correlation with laryngology utilization while median income did not. CONCLUSIONS AND RELEVANCE: Insurance status, education level, and race correlated with utilization of tertiary laryngology services for the evaluation of dysphonia in our community, while median income did not. Black patients utilized tertiary laryngology care at higher rates compared to departmental and regional population utilization data. These results underscore important demographic and disease-specific factors that may affect utilization of subspecialty care in Otolaryngology. LEVEL OF EVIDENCE: IV.

Standardization of Outcome Measures for Intratympanic Steroid Treatment for Idiopathic Sudden Sensorineural Hearing Loss.

OBJECTIVE: To identify variability in reported hearing outcomes for intratympanic (IT) steroid treatment of idiopathic sudden sensorineural hearing loss (ISSNHL) by comparing outcomes using the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guideline with other published criteria. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary otology practice. PATIENTS: Patients with ISSNHL treated with IT steroid between April 2003 and December 2020. INTERVENTIONS: IT steroid injection and audiometric evaluation. MAIN OUTCOME MEASURES: 1) Rates of full, partial, or no recovery using the AAO-HNS guideline versus other reported criteria, and 2) correlation analyses of demographic and clinical variables with response to IT steroid. RESULTS: Using AAO-HNS reporting criteria, full recovery of the pure-tone average was noted in 25.68% of patients. Applying eight other published outcomes criteria to this patient cohort classified full recovery in 14.87 to 40.54% of patients. Similarly, AAO-HNS criteria classified "no recovery" in 51.35% of our patients, whereas applying the other reported criteria showed an average rate of 62.16% no recovery and as high as 82.43% of patients without recovery. Younger age ( p = 0.003; effect size, 0.924) and IT injection within a week of onset ( p < 0.001; effect size, 1.099) positively correlated with full recovery. There was no impact of prior or concurrent oral steroids, or number of steroid injections on outcome. CONCLUSION: Great variability exists in the literature for assessment of IT steroid outcomes in ISSNHL. Standard reporting of outcomes as per the AAO-HNS SSNHL guideline is recommended to consistently characterize IT steroid efficacy and allow comparison across studies.