Making a racket in America's fastest growing sport: Evaluation of noise exposure in pickleball.

OBJECTIVE: To measure noise exposure present on pickleball courts and assess the risk of noise-induced hearing loss (NIHL) per guidelines put forward by the National Institute of Occupational Safety and Health (NIOSH). METHODS: Observational study measuring noise levels at multiple recreational pickleball courts in the Richmond, VA area, documenting LAeq, LASmax, and LCpeak at courtside and waiting areas of pickleball courts. Measurements were completed using the NIOSH SLM application on an iPhone 13 with iMM-6 Calibrated Measurement Microphone (equivalent to IEC 61672-1 Class II) that was calibrated using ND-9 Sound Level Calibrator (IEC942 Class I). RESULTS: Average sound levels recorded at waiting areas adjacent to the courts, measured in LAeq, LASmax, and LCpeak, were 69.1 dBA, 92.0 dBA, and 112.1 dBC, respectively, while courtside measurements were 69.7 dBA, 92.2 dBA, and 115.6 dBC, respectively. These measurements were within NIOSH and OSHA recommendations. CONCLUSION: The data demonstrates that randomly sampled pickleball courts have noise levels that do not increase risk for NIHL for participants or bystanders alike based on NIOSH guidelines. However, prolonged noise exposure and ambient noise pollution may have other health implications and warrant further investigations. LEVEL OF EVIDENCE: Level 2.

IL-8 correlates with nonresponse to neoadjuvant nivolumab in HPV positive HNSCC via a potential extracellular vesicle miR-146a mediated mechanism.

Therapy using anti-PD-1 immune checkpoint inhibitors (ICI) has revolutionized the treatment of many cancers including head and neck squamous cell carcinomas (HNSCC), but only a fraction of patients respond. To better understand the molecular mechanisms driving resistance, we performed extensive analysis of plasma and tumor tissues before and after a 4-week neoadjuvant trial in which HNSCC patients were treated with the anti-PD-1 inhibitor, nivolumab. Luminex cytokine analysis of patient plasma demonstrated that HPVpos nonresponders displayed high levels of the proinflammatory chemokine, interleukin-8 (IL-8), which decreased after ICI treatment, but remained higher than responders. miRNAseq analysis of tetraspanin-enriched small extracellular vesicles (sEV) purified from plasma of HPVpos nonresponders demonstrated significantly lower levels of seven miRNAs that target IL-8 including miR-146a. Levels of the pro-survival oncoprotein Dsg2, which has been to down-regulate miR-146a, are elevated with HPVpos tumors displaying higher levels than HPVneg tumors. Dsg2 levels decrease significantly following ICI in responders but not in nonresponders. In cultured HPVpos cells, restoration of miR-146a by forced expression or treatment with miR-146a-loaded sEV, reduced IL-8 level, blocked cell cycle progression, and promoted cell death. These findings identify Dsg2, miR-146a, and IL-8 as potential biomarkers for ICI response and suggest that the Dsg2/miR-146a/IL-8 signaling axis negatively impacts ICI treatment outcomes and could be targeted to improve ICI responsiveness in HPVpos HNSCC patients.

Inpatient Otolaryngology Consultations and COVID-19: The Surge and Lasting Effects at an Urban, Academic Institution.

Objective: This study aims to examine the lasting effects of the coronavirus disease 2019 (COVID-19) pandemic on inpatient otolaryngology consultations. Methods: In a retrospective analysis, inpatient otolaryngology consultations at an urban, academic tertiary care center were reviewed over the course of 2 years (Jun 2019-Jun 2021). The consultations were categorized by time period based on the local data for COVID-19 hospitalizations and deaths as follows: pre-COVID (Jun 2019-Feb 2020), Surge 1 (Mar 2020-May 2020), Surge 2 (Oct 2020-Jan 2021), and Post Surge (Mar 2021-Jun 2021). Results: A total of 897 patients undergoing an inpatient otolaryngology consultation across all 4 time periods were included for analysis. The average consultations per day was 1.67 ± 0.24 in pre-COVID times, and dropped acutely to 0.86 ± 0.33 consultations per day during Surge 1. The consultation volume was not statistically different from pre-COVID levels during Surge 2 (1.33 ± 0.35) and Post Surge (1.60 ± 0.20). Reason for consultation and procedures performed did not vary significantly between pre-COVID times and Post Surge, except that consultation for postoperative complaint was less frequent in Post Surge (4.8% vs 1.0%, P = .02). More patients had been screened with rapid antigen COVID testing in Post Surge versus Surge 1 (20.1% vs 7.6%, P = .04). Conclusions: Inpatient otolaryngology consultation volumes, indications, and procedures performed at an urban, academic institution returned to pre-COVID levels after being significantly impacted during Surge 1.

Symptomatic Lingual Thyroglossal Duct Cyst in Children: A Laryngomalacia Phenotype.

OBJECTIVES: Patients with lingual thyroglossal duct cyst (TGDC) can present as symptomatic with obstructive airway and feeding difficulties. METHODS: We present 3 cases of symptomatic lingual TGDC. RESULTS: All 3 patients were diagnosed with laryngomalacia and underwent further concurrent or delayed airway intervention, in addition to cyst removal. CONCLUSIONS: We reason that there is a phenotype of laryngomalacia in the symptomatic lingual thyroglossal duct cyst patients who present with symptoms due to disruption in laryngeal anatomy rather than the cyst itself causing obstructive symptoms. Distinguishing this phenotype, especially in comparison to other pathologies such as vallecular cysts, may better allow for planning of concurrent or delayed airway procedures and overall counseling of parents.

Multi-Institutional Study Validates Safety of Intraoperative Cesium-131 Brachytherapy for Treatment of Recurrent Head and Neck Cancer.

INTRODUCTION: Surgery is the primary treatment for resectable, non-metastatic recurrent head and neck squamous cell carcinoma (HNSCC). We explore the safety and oncologic benefit of intraoperative Cesium-131 (Cs-131) brachytherapy combined with salvage local and/or regional surgical resection. METHODS AND MATERIALS: Findings were reported from a single arm multi-institutional prospective phase 1/2 trial involving surgery plus Cs-131 (surgery + Cs-131) treatment. The results of two retrospective cohorts-surgery alone and surgery plus intensity modulated radiation therapy (surgery + ReIMRT)-were also described. Included patients had recurrent HNSCC and radiation history. Safety, tumor re-occurrence, and survival were evaluated. RESULTS: Forty-nine patients were enrolled in the surgery + Cs-131 prospective study. Grade 1 to 3 adverse events (AEs) occurred in 18 patients (37%), and grade 4 AEs occurred in 2 patients. Postoperative percutaneous endoscopic gastrostomy (PEG) tubes were needed in 10 surgery + Cs-131 patients (20%), and wound and vascular complications were observed in 12 patients (24%). No cases of osteoradionecrosis were reported in the surgery + Cs-131 cohort. We found a 49% 2-year disease-free survival at the site of treatment with a substantial number of patients (31%) developing metastatic disease, which led to a 31% overall survival at 5 years. CONCLUSIONS: Among patients with local/regional recurrent HNSCC status-post radiation, surgery + Cs-131 demonstrated acceptable safety with compelling oncologic outcomes, as compared to historic control cohorts. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifiers NCT02794675 and NCT02467738.

Laryngeal cleft: A literature review.

INTRODUCTION: Laryngeal cleft is a congenital condition in which an opening in the posterior laryngotracheal wall allows food and liquid to pass from the esophageal lumen to the airway and causes aspiration. The severity of a laryngeal cleft is measured using the Benjamin-Inglis system, and can be managed conservatively or with a variety of surgical options With increased awareness, higher suspicion among primary physicians, advanced technology and improved intensive neonatal care services, more babies with laryngeal clefts survive in the modern era. Therefore, the focus has shifted from infant survival to treatment of laryngeal clefts and the challenging, complex medical conditions they create. OBJECTIVE: To understand current laryngeal cleft management and post-operative outcomes. METHODS: Literature review of laryngeal cleft studies from 2010 to 2021. RESULTS: A total of 1033 patients were included. Based on 415 cases for whom sufficient classification data were available, the predominate symptom for patients with type I, III, and IV clefts is swallowing dysfunction, while the predominant symptoms for patients with type II clefts are stridor and aspiration. A wide variety of comorbidities involving several major organs has been reported with laryngeal clefts, which tend to impact clinical outcomes negatively. Approximately 19% of type I clefts have been treated conservatively successfully, but the majority was treated surgically. Most studies that used injection laryngoplasty for type I clefts reported highly successful repairs without complications or delays in additional procedures. Ninety-eight percent all type II clefts were treated with endoscopic repair; 87% of patients with type III clefts received endoscopic repair; and 66% of patients with type IV clefts underwent open surgery. Approximately 62% of resolved cases were reported within 12 months, while 50.87% of failed cases were reported within 6 weeks. CONCLUSIONS: There are multiple treatment approaches, each of which may be applicable depending on factors such as laryngeal cleft type, severity of presentation, and comorbidities. Conservative approaches appear to be most useful for type I clefts or in patients with mild symptoms, while surgical management can be considered for any type of laryngeal cleft. The benefit of injection laryngoplasty, endoscopic repair and open surgery can also vary, but injection laryngoplasty and endoscopic repair are used most commonly. Open surgery should be to be considered if patients present with severe cleft types or if it is unsafe to perform other surgical techniques. Familiarity with this literature review should help clinicians understand clinical characteristics, direct medical management, and guide successful resolution of laryngeal clefts.

Utility of Audiometry in the Evaluation of Patients Presenting with Dysphonia.

OBJECTIVES: Hearing loss has been implicated in dysphonia secondary to voice misuse, although the data supporting this claim are scant. Determining the prevalence of hearing loss in patients with dysphonia and correlating it with self-perception of vocal handicap may help clarify the value of audiometry in evaluation of patients with dysphonia. METHODS: This is a retrospective chart review of all new voice patients (n = 405) presenting with dysphonia to the primary investigator between 2015 and 2018. Each new patient routinely undergoes audiometric and voice objective analyses. Main outcomes measured include prevalence, severity of hearing loss, and voice handicap index-10 (VHI-10). RESULTS: Of the 405 subjects reviewed, mean age was 49.0 years (SD = 17.4). 60.7% of subjects were female and 39.3% male. Patients with hearing loss defined as >25 dB in worse ear with pure tone average (PTA) thresholds at 0.5, 1, 2, and 3 kHz (PTA-S) accounted for 18% of the total cohort. The prevalence of previously undiagnosed hearing loss in this cohort was 13.1% (53 of 405 subjects). Of these subjects, 62.3% (33 subjects) reported no perception of hearing loss while 37.7% (20 subjects) suspected they had some hearing loss, yet never sought evaluation. Only increased PTA-S, speech discrimination, Reflux Symptom Index, and female gender demonstrated a significant relationship with VHI-10 when analyzed with multivariate linear regression analysis. CONCLUSIONS: The prevalence of hearing loss in patients presenting with dysphonia in this cohort is similar to normative population data. This study has also demonstrated that the majority of these patients did not perceive any hearing loss. The reasons behind this may be a result of or associated with the patients' dysphonia. Furthermore, clinicians should consider performing audiometric evaluation in patients with abnormal VHI-10 scores in the appropriate clinical context.

Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers.

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC50 = 8.3 µM. A structure-activity relationship (SAR) study revealed that the array of tolerated substituents, on either the benzo portion of the quinolinone or the 4-phenyl, was very narrow. However, the lactam ring of the quinolinone was more amenable to modifications. For example, the quinazolinone (9a) and the benzoxazepin-2(3H)-one (19) demonstrated improved potency and efficacy for increase in SMN2 expression as compared to 2.

Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.

Small Molecules in Development for the Treatment of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease resulting from pathologically low levels of survival motor neuron (SMN) protein. The majority of mRNA from the SMN2 allele undergoes alternative splicing and excludes critical codons, causing an SMN protein deficiency. While there is currently no FDA-approved treatment for SMA, early therapeutic efforts have focused on testing repurposed drugs such as phenylbutyrate (2), valproic acid (3), riluzole (6), hydroxyurea (7), and albuterol (9), none of which has demonstrated clinical effectiveness. More recently, clinical trials have focused on novel small-molecule compounds identified from high-throughput screening and medicinal chemistry optimization such as olesoxime (11), CK-2127107, RG7800, LMI070, and RG3039 (17). In this paper, we review both repurposed drugs and small-molecule compounds discovered following medicinal chemistry optimization for the potential treatment of SMA.

Soil components mitigate the antimicrobial effects of silver nanoparticles towards a beneficial soil bacterium, Pseudomonas chlororaphis O6.

Silver nanoparticles (Ag NPs) are widely used for their antimicrobial activity and consequently the particles will become environmental contaminants. This study evaluated in sand and soil matrices the toxicity of 10nm spherical Ag NPs (1 and 3 mg Ag/L) toward a beneficial soil bacterium, Pseudomonas chlororaphis O6. In sand, both NP doses resulted in loss in bacterial culturability whereas in a loam soil, no cell death was observed. Amendments of sand with clays (30% v/v kaolinite or bentonite) did not protect the bacterium when challenged with Ag NPs. However, culturability of the bacterium was maintained when the Ag NP-amended sand was mixed with soil pore water or humic acid. Imaging by atomic force microscopy revealed aggregation of single nanoparticles in water, and their embedding into background material when suspended in pore water and humic acids. Zeta potential measurements supported aggregation and surface charge modifications with pore water and humic acids. Measurement of soluble Ag in the microcosms and geochemical modeling to deduce the free ion concentration revealed bacterial culturability was governed by the predicted free Ag ion concentrations. Our study confirmed the importance of Ag NPs as a source of ions and illustrated that processes accounting for protection in soil against Ag NPs involved distinct NP- and ion-effects. Processes affecting NP bioactivity involved surface charge changes due to sorption of Ca²âº from the pore water leading to agglomeration and coating of the NPs with humic acid and other organic materials. Removal of bioactive ions included the formation of soluble Ag complexes with dissolved organic carbon and precipitation of Ag ions with chloride in pore water. We conclude that mitigation of toxicity of Ag NPs in soils towards a soil bacterium resides in several interactions that differentially involve protection from the Ag NPs or the ions they produce.

Responses of a soil bacterium, Pseudomonas chlororaphis O6 to commercial metal oxide nanoparticles compared with responses to metal ions.

The toxicity of commercially-available CuO and ZnO nanoparticles (NPs) to pathogenic bacteria was compared for a beneficial rhizosphere isolate, Pseudomonas chlororaphis O6. The NPs aggregated, released ions to different extents under the conditions used for bacterial exposure, and associated with bacterial cell surface. Bacterial surface charge was neutralized by NPs, dependent on pH. The CuO NPs were more toxic than the ZnO NPs. The negative surface charge on colloids of extracellular polymeric substances (EPS) was reduced by Cu ions but not by CuO NPs; the EPS protected cells from CuO NPs-toxicity. CuO NPs-toxicity was eliminated by a Cu ion chelator, suggesting that ion release was involved. Neither NPs released alkaline phosphatase from the cells' periplasm, indicating minimal outer membrane damage. Accumulation of intracellular reactive oxygen species was correlated with CuO NPs lethality. Environmental deposition of NPs could create niches for ion release, with impacts on susceptible soil microbes.

Interaction of silver nanoparticles with an environmentally beneficial bacterium, Pseudomonas chlororaphis.

This study explores the potential antimicrobial mechanisms of commercial silver nanoparticles (Ag NPs) in the environmental bacterium, Pseudomonas chlororaphis O6. The 10nm size NPs aggregated in water, as demonstrated by atomic force microscopy. Solubility of the NPs at 10mg/L was 0.28 mg/L (pH 6) and 2.3mg/L (pH 7); release from 10mg/L bulk Ag was below detection. The NPs eliminated cell culturability at 3mg/L, whereas no effect was observed at 10mg/L bulk Ag. Zeta potential measurements revealed that the NPs were negatively charged; unlike Ag ions, their addition to the negatively charged cells did not change cell charge at pH 6, but showed a trend to reduce cell charge at pH 7. Isolated extracellular polymeric substances (EPS) from PcO6 was polydisperse, with negative charge that was neutralized by Ag ions, but not by the NPs. Addition of EPS eliminated Ag NP's toxicity in cells lacking EPS. Intracellular accumulation of OH was not detected in NP-treated cells; however, the use of scavengers suggested the NPs caused extracellular H(2)O(2) production. No evidence was found for loss of membrane integrity upon treatment with the NPs. Our findings indicate that growth of environmental bacteria could be impaired by Ag NPs, depending on the extent of EPS production.