N95 vs Half-face Respirator Wear in Surgical Trainees: Physiologic and Psychological Effects of Prolonged Use

Objectives: As specialists of the upper airway, otolaryngologists are at high risk for COVID-19 transmission. N95 and half-face respirator (HFR) masks are commonly worn, each with advantages in functionality and comfort. In this study, physiologic and psychological parameters of prolonged N95 vs HFR wear were compared. Study Design: Prospective crossover cohort study. Setting: Single academic tertiary care hospital. Methods: A prospective crossover cohort study was performed. Healthy otolaryngology trainees and medical students (N = 23) participated and wore N95 and HFR masks continuously for 3 hours each on separate days. Various measures were analyzed: vitals, spirometry variables, scores on the State-Trait Anxiety Inventory and HIT-6 (Headache Impact Test–6), distress, and “difficulty being understood.” Results: The average age was 26.3 years (SD, 3.42). There were no significant differences in vital signs and spirometry variables between N95 and HFR wear. N95 wear was associated with decreases in oxygen saturation of approximately 1.09% more than with HFRs (95% CI, 0.105-2.077). State-Trait Anxiety Inventory scores increased more with HFR wear when compared with mean changes with N95 wear (95% CI, 1.350-8.741). There were no significant differences in HIT-6 scores or distress levels between masks. The proportions of participants reporting difficulty being understood was significantly higher with HFRs. Conclusions: Oxygen saturation decreases with prolonged N95 wear, but anxiety and difficulty being understood are greater with HFR wear. Although HFRs have less resistance to gas exchange, N95 respirators may produce less anxiety and distress in clinical situations. Further studies are warranted to evaluate the clinical significance of these differences. Level of Evidence: 2

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Changes in Single-Specialty Postoperative Opioid Prescribing Patterns in Response to Legislation: Single-Institution Analysis Over Time

Objectives To determine changes in the prescriptions of postoperative opioids in response to Florida state legislation restricting the number of days for which these medications could be prescribed to 3 days in most circumstances or 7 days at provider discretion. Study Design A retrospective review was performed for all patients undergoing 7 common outpatient otolaryngology surgical procedures. Setting Single-institution academic center in Florida. Methods Query of the state’s online prescription drug monitoring program was used to compare prescription habits 3 months before and after the law and then again 1 year later. Results A total of 561 patients were identified meeting criteria. The number of days that opioids were prescribed decreased significantly, from 6.42 to 4.48 to 3.03 days. There was a significant decrease in the proportion of patients receiving any postoperative opioid prescription, from 0.80 to 0.52 to 0.32. The total morphine milligram equivalents prescribed decreased from 28.4 before the law to 18.4 at 1 year after. Conclusions Legislative restrictions on the length of opioid prescriptions were associated with significant decreases in the proportion of patients receiving any opioids, the number of days that opioids were prescribed, and the total morphine milligram equivalents 3 months after the law went into effect, with even more dramatic changes at the 1-year time point. We opine that these changes are due to providers learning that many procedures do not require postoperative opioids and therefore increasingly considering and utilizing nonopioid alternatives in this setting

WP1066 induces cell death in a schwannomatosis patient–derived schwannoma cell line

Schwannomatosis is a rare genetic disorder that predisposes individuals to development of multiple schwannomas mainly in spinal and peripheral nerves and to debilitating chronic pain often unrelated to any schwannoma. Pathogenic variants of two genes, SMARCB1 and LZTR1 , are causal in familial cases. However, many schwannomatosis patients lack mutations in these genes. Surgery is the standard treatment for schwannomas but leaves patients with increasing neurological deficits. Pain management is a daily struggle controlled by the use of multiple analgesic and anti-inflammatory drugs. There is a need for both nonsurgical treatment to manage tumor growth and nonaddictive, nonsedative pain control. Because standard clinical trials are exceedingly difficult for patients with rare disorders, precision medicine approaches offer the possibility of bespoke therapeutic regimens to control tumor growth. As a proof of principle, we obtained a bio-specimen of paraspinal schwannoma from a schwannomatosis patient with a germline point mutation in the SMARCB1/INI gene. We created an hTERT immortalized cell line and tested the ability of targeted small molecules with efficacy in neurofibromatosis type 2–related schwannomas to reduce cell viability and induce cell death. We identified WP1066, a STAT3 inhibitor, currently in phase 2 clinical trials for pediatric and adult brain tumors as a lead compound. It reduced cell viability and STAT-3 phosphorylation and induced expression of markers for both necroptosis and caspase-dependent cell death. The results demonstrate feasibility in creating patient-derived cell lines for use in precision medicine studies

Speech Discrimination Outcomes in Adult Cochlear Implant Recipients by Primary Language and Bilingual Hispanic Patients

Abstract Objective Compare cochlear implant (CI) outcomes in English speakers, Spanish speakers, and bilingual Hispanics. Study Design Retrospective review. Setting Academic tertiary care center. Methods Eighty‐five postlingually deafened adults unilaterally implanted between January 2014 and December 2018 were stratified by primary language. Primary outcomes were: (1) English consonant‐nucleus‐consonant and Spanish bisyllables word tests in quiet, and (2) English AzBio and Latin American Hearing In Noise Test (LA‐HINT) sentence tests in quiet and in noise at multiple time‐intervals postactivation. Results In the respective languages, primary Spanish speakers (n = 24), and English speakers (n = 61) experienced the greatest increases in average scores for word and sentence tests in quiet during the first 6 months postactivation, with gradual increases in average scores over time. English speakers performed significantly worse on AzBio tests in noise, compared to quiet, while the addition of noise did not significantly affect average LA‐HINT scores in Spanish speakers across multiple time intervals. An early ceiling effect was also demonstrated for LA‐HINT. Although not significant, bilingual Hispanics (n = 12) had lower average AzBio in quiet scores than English speakers and higher average LA‐HINT in quiet scores than the Spanish speakers across multiple time intervals. Conclusion English and Spanish CI users experienced the greatest increases in speech understanding in quiet the first few months after implant activation. An early ceiling effect is demonstrated with LA‐HINT, indicating LA‐HINT is not appropriate for evaluating longitudinal CI outcomes in Spanish speakers. Bilingual Hispanics represent a unique group, and further investigations are necessary to understand speech perception patterns in both languages and develop the best CI test strategies for these individuals

The Outcomes of Cochlear Implantation in Usher Syndrome: A Systematic Review

Objective: To systematically appraise the implementation of cochlear implantation (CI) in Usher Syndrome (USH) Types 1, 2, and 3 patients, and analyze who would benefit from CI. Data Sources: A comprehensive search of PubMed, Embase, CINAHL, and Cochrane Library electronic databases from inception through June 2020 was performed. There were no language restrictions. Study Selection: The PRISMA strategy was followed. Included studies discuss USH patients who underwent CI regardless of age, nationality, or clinical subtype. All included studies report post-implantation functional, cognitive, or quality of life outcomes. Only reviews were excluded. Results: Fifteen studies met the inclusion criteria. USH patients experienced improvements in PTA and speech perception and expression outcomes after CI, as well as improvements in phonological memory and quality of life measures. Overall, patients implanted at younger ages outperformed older patients in audiological testing. Similarly, patients with prolonged auditory deprivation had relatively poor performance outcomes in sentence recognition and speech detection following CI. Conclusions: Most USH patients benefit from CI. USH patients who undergo CI at younger ages generally achieve better hearing, speech, and cognitive outcomes. CI at older ages can still prove beneficial if appropriate auditory amplification is started at the right time. Further research is warranted to fill the gap in understanding regarding the gene mutations underlying the pathophysiology of USH that have favorable CI outcomes as well as the optimal time to perform CI

Comparison of Speech Test Outcomes After Cochlear Implantation in Patients With and Without Asymmetric Hearing Loss

Determine whether asymmetric hearing loss (AHL) affects postoperative speech outcomes in cochlear implant (CI) patients. Retrospective cohort study. Tertiary care hospital. Adult English-speaking patients with unilateral CIs implanted between 2014 and 2018 were stratified into NonAHL and AHL groups based on preoperative AzBio scores in quiet from the nonimplanted ear (0-50% vs. 51-100%, respectively). CI surgery in the poorer performing ear. Postoperative consonant-nucleusconsonant (CNC) word and AzBio sentence test scores in quiet and/or noise at +5 dB signal-to-noise ratio (SNR). Of 512 patients, 33 non-AHL and 27 AHL patients were included. Average ages were 65.6 and 63.6 years, respectively. As expected, preoperative AzBio scores in quiet from the nonimplanted ear were higher in the AHL group (95% confidence interval [95%CI]: 66.4-76.4%) than the non-AHL group at baseline (95%CI: 12.3-23.6%). In both cohorts, AzBio scores in quiet from the implanted ear improved from baseline, with 24-month scores (95%CI: 73.8 - 84.9%) being higher than preoperative scores (95%CI: 13.2-23.1%). There were also significant differences in AzBio scores in quiet between cohorts overall (p  = 0.0120) on mixed model analysis, with the AHL group performing ∼6.4% better than the non-AHL group; however, differences were not significant when scores were stratified by time. In addition, there were no significant differences in CNC in quiet and AzBio scores in noise at +5 dB SNR between cohorts (p  = 0.1786 and p  = 0.6215, respectively). After CI, patients with AHL can achieve scores on word and sentence tests at least comparable to traditional CI candidates, supporting the expansion of CI candidacy to include patients with AHL

Reversal of motor-skill transfer impairment by trihexyphenidyl and reduction of dorsolateral striatal cholinergic interneurons in Dyt1 ΔGAG knock-in mice

DYT-TOR1A or DYT1 early-onset generalized dystonia is an inherited movement disorder characterized by sustained muscle contractions causing twisting, repetitive movements, or abnormal postures. The majority of the DYT1 dystonia patients have a trinucleotide GAG deletion in DYT1/TOR1A. Trihexyphenidyl (THP), an antagonist for excitatory muscarinic acetylcholine receptor M1, is commonly used to treat dystonia. Dyt1 heterozygous ΔGAG knock-in (KI) mice, which have the corresponding mutation, exhibit impaired motor-skill transfer. Here, the effect of THP injection during the treadmill training period on the motor-skill transfer to the accelerated rotarod performance was examined. THP treatment reversed the motor-skill transfer impairment in Dyt1 KI mice. Immunohistochemistry showed that Dyt1 KI mice had a significant reduction of the dorsolateral striatal cholinergic interneurons. In contrast, Western blot analysis showed no significant alteration in the expression levels of the striatal enzymes and transporters involved in the acetylcholine metabolism. The results suggest a functional alteration of the cholinergic system underlying the impairment of motor-skill transfer and the pathogenesis of DYT1 dystonia. Training with THP in a motor task may improve another motor skill performance in DYT1 dystonia

Genomics, Epigenetics, and Hearing Loss in Neurofibromatosis Type 2

In this review, we discuss current knowledge about the genetics and epigenetics of vestibular schwannoma (VS) in relation to hearing loss. A multistep and sequential genetic algorithm suitable for the identification of Neurofibromatosis Type 2 (NF2) constitutional and somatic mutations is discussed. A review was performed of the English literature from 1990 to 2019 using PubMed regarding genetics and epigenetics of vestibular schwannoma and NF2. NF2 is a genetic disorder characterized by NF2 mutations that affect the function of a tumor suppressor called merlin. In particular, individuals with NF2 develop bilateral VS that can lead to hearing loss and even deafness. Recent advances in genetic and epigenetic studies have improved our understanding of the genotype-phenotype relationships that affect hearing in NF2 patients. Specific constitutional NF2 mutations including particular truncating, deletion, and missense mutations have been associated with poorer hearing outcomes and more severe clinical manifestations. Epigenetic events, such as DNA methylation and histone modifications, also contribute to the development and progression of hearing loss in NF2 patients. Furthermore, the accumulation of multiple NF2 and non-NF2 genetic and epigenetic abnormalities at the level of the tumor may contribute to worse hearing outcomes. Understanding genetic and epigenetic signatures in individual NF2 patients and particularly in each VS will allow us to develop novel gene therapies and precision medicine algorithms to preserve hearing in NF2 individuals

Molecular and Cellular Mechanisms of Perineural Invasion in Oral Squamous Cell Carcinoma: Potential Targets for Therapeutic Intervention

The most common oral cavity cancer is squamous cell carcinoma (SCC), of which perineural invasion (PNI) is a significant prognostic factor associated with decreased survival and an increased rate of locoregional recurrence. In the classical theory of PNI, cancer was believed to invade nerves directly through the path of least resistance in the perineural space; however, more recent evidence suggests that PNI requires reciprocal signaling interactions between tumor cells and nerve components, particularly Schwann cells. Specifically, head and neck SCC can express neurotrophins and neurotrophin receptors that may contribute to cancer migration towards nerves, PNI, and neuritogenesis towards cancer. Through reciprocal signaling, recent studies also suggest that Schwann cells may play an important role in promoting PNI by migrating toward cancer cells, intercalating, and dispersing cancer, and facilitating cancer migration toward nerves. The interactions of neurotrophins with their high affinity receptors is a new area of interest in the development of pharmaceutical therapies for many types of cancer. In this comprehensive review, we discuss diagnosis and treatment of oral cavity SCC, how PNI affects locoregional recurrence and survival, and the impact of adjuvant therapies on tumors with PNI. We also describe the molecular and cellular mechanisms associated with PNI, including the expression of neurotrophins and their receptors, and highlight potential targets for therapeutic intervention for PNI in oral SCC