Efficacy and safety of SENS-401 in sudden sensorineural hearing loss: The AUDIBLE-S randomized placebo-controlled phase IIb trial.

PURPOSE: Safety and efficacy of SENS-401, a serotonin type 3 (5-HT3) receptor antagonist and calcineurin inhibitor, in patients with acute sudden sensorineural hearing loss (SSNHL). METHODS: Multicentre randomized, double blind, placebo-controlled trial enrolled adult subjects with sudden sensorineural hearing loss (SSNHL) or unilateral/bilateral acute acoustic trauma leading to SSNHL within 96 h of disease onset. Subjects were randomly assigned to one of the three oral dose groups: 29 mg, 43.5 mg or placebo given twice daily for 28 days. The primary endpoint was the change from baseline in Pure Tone Average (PTA) in the affected ear to the end of treatment visit (day 28). Subjects were further followed up 8 weeks after the end of the treatment period (day 84). RESULTS: A total of 115 subjects were randomized. SENS-401 was well tolerated. Although the primary efficacy endpoint was not met at day 28, post-hoc analyses revealed clinically significant and meaningful efficacy outcomes with SENS-401 when compared to placebo in a substantial group of participants diagnosed with idiopathic SSNHL and who had received corticosteroid treatment. Notable improvements were observed in the PTA change from baseline, the complete hearing recovery rate, and the Word Recognition Score (WRS), particularly at day 84. The responder rate consistently favored treated subjects over those who received the placebo. CONCLUSION: While the primary endpoint was not achieved at the end of the treatment period, the study revealed consistently positive efficacy results of clinical relevance in patients with idiopathic SSNHL who received SENS-401, particularly in the 8-weeks follow-up phase after the completion of the treatment.

Disease-associated polyalanine expansion mutations impair UBA6-dependent ubiquitination.

Expansion mutations in polyalanine stretches are associated with a growing number of diseases sharing a high degree of genotypic and phenotypic commonality. These similarities prompted us to query the normal function of physiological polyalanine stretches and to investigate whether a common molecular mechanism is involved in these diseases. Here, we show that UBA6, an E1 ubiquitin-activating enzyme, recognizes a polyalanine stretch within its cognate E2 ubiquitin-conjugating enzyme USE1. Aberrations in this polyalanine stretch reduce ubiquitin transfer to USE1 and, subsequently, polyubiquitination and degradation of its target, the ubiquitin ligase E6AP. Furthermore, we identify competition for the UBA6-USE1 interaction by various proteins with polyalanine expansion mutations in the disease state. The deleterious interactions of expanded polyalanine tract proteins with UBA6 in mouse primary neurons alter the levels and ubiquitination-dependent degradation of E6AP, which in turn affects the levels of the synaptic protein Arc. These effects are also observed in induced pluripotent stem cell-derived autonomic neurons from patients with polyalanine expansion mutations, where UBA6 overexpression increases neuronal resilience to cell death. Our results suggest a shared mechanism for such mutations that may contribute to the congenital malformations seen in polyalanine tract diseases.

Hemotympanum as a Complication of a Valsalva Maneuver during Childbirth.

Background: Hemotympanum may occur due to otic barotrauma secondary to Valsalva maneuver during the second phase of labor. A pressure differential across the tympanic membrane (TM) of about five psi can cause rupture. The increased intrathoracic and intraabdominal pressure spikes repeatedly manifested by "pushing" during second-stage labor easily approach (and may exceed) this level. Clinical Presentation. This case report describes a healthy thirty-seven-year-old multipara patient admitted for the 40-weeks' gestational age routine follow-up that proceeded to active labor followed by an aural fullness and bloody otorrhea. Otoscopic examination with a light microscope confirmed the hemotympanum of the right tympanic membrane. Conclusion: Forceful Valsalva can cause hemotympanum. Investigating the benefits and disadvantages of the pushing methods could help reduce such complications in the future. A prompt evaluation of an otolaryngologist should be requested in the event of a new postpartum hearing disturbance or bloody otorrhea.

Do-It-Yourself Low-Cost Stroboscopy.

This case series tests the construction of an extremely low-cost stroboscope and assesses its strengths and weaknesses.

Oculopharyngeal muscular dystrophy mutations link the RNA-binding protein HNRNPQ to autophagosome biogenesis.

Autophagy is an intracellular degradative process with an important role in cellular homeostasis. Here, we show that the RNA binding protein (RBP), heterogeneous nuclear ribonucleoprotein Q (HNRNPQ)/SYNCRIP is required to stimulate early events in autophagosome biogenesis, in particular the induction of VPS34 kinase by ULK1-mediated beclin 1 phosphorylation. The RBPs HNRNPQ and poly(A) binding protein nuclear 1 (PABPN1) form a regulatory network that controls the turnover of distinct autophagy-related (ATG) proteins. We also show that oculopharyngeal muscular dystrophy (OPMD) mutations engender a switch from autophagosome stimulation to autophagosome inhibition by impairing PABPN1 and HNRNPQ control of the level of ULK1. The overexpression of HNRNPQ in OPMD patient-derived cells rescues the defective autophagy in these cells. Our data reveal a regulatory mechanism of autophagy induction that is compromised by PABPN1 disease mutations, and may thus further contribute to their deleterious effects.

Analysis of Prognostic Factors Impacting Pediatric Acute Mastoiditis Outcomes.

BACKGROUND: This study aimed to investigate the outcomes of pediatric patients with acute mastoiditis while examining the role of intravenous steroid therapy, patient demographics, and serum inflammatory values as prognostic factors. METHODS: This study is a single-center retrospective observational study including 73 consecutive patients treated for acute mastoiditis in the course of the 10-year study period (January 2010 to December 2019). RESULTS: Data analysis showed that patients requiring surgical treatment (14%) had a 3-fold higher C-reactive protein value at admission compared to those treated conservatively (P < .001). Receiver operating characteristic analysis revealed that a C-reactive protein cut-off of ≥98.7 had a sensitivity and specificity of 100% and 74.6%, respectively, for predicting the need for surgery (area under the curve=0.927, P < .001). The duration of symptoms before hospitalization was nearly 2 days shorter in male patients (P=.031), and the use of intravenous steroid therapy significantly shortened the length of hospitalization (P=.023), by 1.4 days on average. CONCLUSION: Intravenous steroid therapy may be useful in decreasing the length of hospital stay. Mastoiditis tends to present more severely in male patients, and monitoring C-reactive protein values during treatment correlated well with the need for surgery.

Safety of a New Sinus Irrigation Device in Rhinosinusitis: A Pilot Study.

BACKGROUND: Puncture and lavage of the paranasal sinuses, previously the primary treatment for unresponsive acute bacterial rhinosinusitis before surgery, has been abandoned due to procedural discomfort and advancements in antibiotic efficacy and endoscopic surgery. The rise in antibiotic-resistant bacteria has renewed the interest in minimally invasive sinus lavage to both avoid aggressive surgical interventions and identify appropriate antibiotic therapy. In this article, we describe the safety and feasibility of a new device in human patients and evaluate its efficacy as a treatment before the traditional sinus surgery in acute rhinosinusitis. METHODS: The device with its seeker-shaped guiding tube and rotating wire can enter the sinus cavity through the natural ostium, pulverize the inspissated mucus, and enable lavage and culture sampling without the need for sinus puncturing. It was tested in 6 patients with chronic sinusitis under general anesthesia during endoscopic sinus surgery and in additional 10 patients with maxillary acute bacterial rhinosinusitis in outpatient settings under local anesthesia. RESULTS: The device enabled rapid, efficient, and atraumatic insertion of the wire into the occluded sinuses. The rotating wire permitted pulverization of the thick mucus, which enabled irrigation without mucosal damage or adverse events. Overall, 9 of 10 patients with acute bacterial rhinosinusitis demonstrated remarkable improvements and were discharged the following day with no acute symptoms. The visual analog scale score for pain dropped from 8.9 to 0.4. The remaining one patient underwent endoscopic sinus surgery subsequently. None of the patients treated during endoscopic sinus surgery developed any adverse events.

International Consensus Statement on Obstructive Sleep Apnea.

BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. CONCLUSION: This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

Transillumination Assisted Cricopharyngeal Myotomy.

Abstract: Cricopharyngeal muscle myotomy (CPM) is a common intervention for relief of dysphagia in patients with Oculo-pharyngeal muscular dystrophy (OPMD). Because of difficulties in approaching and dissecting cricopharyngeal muscle in these patients, we used transillumination for the myotomy (TA-CPM). Transillumination is a simple technique to improve the guidance and navigation of the surgeon in determining the location and depth of myotomy. The purpose of this study is to evaluate the efficacy and safety of transillumination in CPM in OPMD patients. An observational cohort of patients with OPMD who underwent CPM due to dysphagia at one medical center between 2010 and 2019. Two groups of patients are included, according to whether transillumination was used during their surgery. Patients were evaluated before and after surgery (1 week and 1 month) for their dysphagia score with a standardized questionnaire. The surgical team preferences, experience and complexity with and without transillumination were evaluated. Ten OPMD patients (8 heterozygotes, 2 homozygotes for the commonmutation) underwent CPM for relieving dysphagia symptoms at medium size medical center in Israel between 2010 and 2019. Five patients had TA-CPM and the 5 patients had CPM without transillumination. All patients showed an improvement at follow-up examinations, 1 week and 1 month postoperative, including a decrease in dysphagia score and in choking and aspiration events, compared to their preoperative state. TA-CPM improved the surgical approach, reduced the difficulty of CPM and was preferred by the surgical team. From the patients' point of view, TA-CPM was as good as a non-transillumination approach in improving dysphagia. TA-CPM is a cheap, fast and simple technique to improve the surgical outcomes in CPM for patients with OPMD. TA-CPM navigates the surgeon, helps with anatomical orientation, improve the surgeon's comfortable, may shorten the duration of surgery and reduces potential errors. Improvement in dysphagia score was similar in both groups. This technique may improve myotomy procedures for dysphagia of other etiologies. Level of evidence: IV. Case series (with or without comparison). Endoscopic transillumination assisted myotomy.

Clinical Efficacy of Topical Nasal Pomegranate Fruit Extract for Chronic Rhinitis and Chronic Rhinosinusitis.

Objective: To evaluate the clinical efficacy of topical nasal Pomegranate Fruit Extract (PFE) for Chronic Rhinitis (CR), Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP), and Chronic Rhinosinusitis without Nasal Polyposis (CRSsNP). Methods: Prospective, double-blinded, randomized study including 111 consecutive patients, between April 2012 and January 2017, afflicted by CRSwNP, CRSsNP, and CR. Patients from each group were randomly assigned to either PFE treatment or placebo twice daily for 30 days. Therapeutic efficacy was assessed by Ear Nose and Throat, blood and tomographic examinations, and the SNOT-20 questionnaire. Results: CR patients treated with PFE suffered significantly less from thick nasal discharge, difficulty falling asleep, reduced productivity, reduced concentration, and sadness (P = .004, P = .02, P = .03, P = .007 and P = .02, respectively). Conclusions: Topical nasal PFE was found to have some benefits for CR patients, however, not for CRS with or without Nasal Polyposis.