Objectives The aim of this study was to evaluate the association between physical activity and changes in levels of highly sensitive troponin T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP), and the subsequent risk of the development of heart failure (HF) in community-dwelling older adults. Background Higher baseline levels of cTnT and NT-proBNP and increases over time correlate with the risk of HF in older adults. Factors modifying these levels have not been identified. Methods NT-proBNP and cTnT were measured at baseline and 2 to 3 years later in adults 65 years of age and older free of HF participating in the Cardiovascular Health Study. Self-reported physical activity and walking pace were combined into a composite score. An increase was prespecified for NT-proBNP as a >25% increment from baseline to ≥190 pg/ml and for cTnT as a >50% increment from baseline in participants with detectable levels (≥3 pg/ml). Results A total of 2,933 participants free of HF had NT-proBNP and cTnT measured at both time points. The probability of an increase in biomarker concentrations between baseline and follow-up visits was inversely related to the physical activity score. Compared with participants with the lowest score, those with the highest score had an odds ratio of 0.50 (95% confidence interval: 0.33 to 0.77) for an increase in NT-proBNP and an odds ratio of 0.30 (95% confidence interval: 0.16 to 0.55) for an increase in cTnT, after adjusting for comorbidities and baseline levels. A higher activity score associated with a lower long-term incidence of HF. Moreover, at each level of activity, an increase in either biomarker still identified those at higher risk. Conclusions These findings suggest that moderate physical activity has protective effects on early heart failure phenotypes, preventing cardiac injury and neurohormonal activation.

During nervous system development, axons often undergo elaborate changes in branching patterns before circuits have achieved their mature patterns of innervation. In the auditory system, type I spiral ganglion neurons (SGNs) project their peripheral axons into the cochlear epithelium and then undergo a process of branch refinement before forming synapses with sensory hair cells. Here, we report that Semaphorin-5B (Sema5B) acts as an important mediator of this process. During cochlear development in mouse, immature hair cells express Sema5B, whereas the SGNs express both PlexinA1 and PlexinA3, which are known Sema5B receptors. In these studies, genetic sparse labeling and three-dimensional reconstruction techniques were leveraged to determine the morphologies of individual type I SGNs after manipulations of Sema5B signaling. Treating cultured mouse cochleae with Sema5B-Fc (to activate Plexin-As) led to type I SGNs with less numerous, but longer terminal branches. Conversely, cochleae from Sema5b knockout mice showed type I SGNs with more numerous, but shorter terminal branches. In addition, conditional loss of Plxna1 in SGNs (using Bhlhb5 Cre) led to increased type I SGN branching, suggesting that PlexinA1 normally responds to Sema5B in this process. In these studies, mice of either sex were used. The data presented here suggest that Sema5B-PlexinA1 signaling limits SGN terminal branch numbers without causing axonal repulsion, which is a role that distinguishes Sema5B from other Semaphorins in cochlear development.

Despite the known importance of the transcription factors ATOH1, POU4F3 and GFI1 in hair cell development and regeneration, their downstream transcriptional cascades in the inner ear remain largely unknown. Here, we have used Gfi1cre;RiboTag mice to evaluate changes to the hair cell translatome in the absence of GFI1. We identify a systematic downregulation of hair cell differentiation genes, concomitant with robust upregulation of neuronal genes in the GFI1-deficient hair cells. This includes increased expression of neuronal-associated transcription factors (e.g. Pou4f1) as well as transcription factors that serve dual roles in hair cell and neuronal development (e.g. Neurod1, Atoh1 and Insm1). We further show that the upregulated genes are consistent with the NEUROD1 regulon and are normally expressed in hair cells prior to GFI1 onset. Additionally, minimal overlap of differentially expressed genes in auditory and vestibular hair cells suggests that GFI1 serves different roles in these systems. From these data, we propose a dual mechanism for GFI1 in promoting hair cell development, consisting of repression of neuronal-associated genes as well as activation of hair cell-specific genes required for normal functional maturation.

Objectives/Hypothesis Recurrent respiratory papillomatosis (RRP) is a rare, potentially life‐threatening, disease that impacts the voice, breathing, and quality of life of patients. Frequent surgical interventions may be needed to control symptoms. We examined the safety and efficacy of utilizing parenteral bevacizumab in the management of severe RRP in adults. Study Design This is a retrospective review of clinical management approaches in a group of patients with severe RRP defined as having a high disease burden, frequent need for debridement, and/or tracheobronchial disease. Patients were initially treated with 15 mg/kg of bevacizumab at 3‐week intervals. Bevacizumab dosing and frequency was then individually titrated down. Results Fourteen adults received a median of 8.5 (range 2–17) bevacizumab infusions over approximately 24 months. All had a history of laryngeal RRP with 6/14 having additional tracheobronchial lesions. Patients required a median of 4 (range 2–11) procedures in the year prior to treatment. Only 3/10 (30%) patients who continued therapy required any additional procedures. Bevacizumab administration was generally well tolerated, with four patients discontinuing therapy. Medical reasons included severe epistaxis and hypertension and thrombocytopenia in an individual with systemic lupus erythematosus. Common side effects included hypertension (grade 2), headache (grades 1–2), elevated creatinine (grades 1–2), and epistaxis (grade 3). Conclusions Intravenous bevacizumab for the primary treatment of severe RRP in adults appears clinically effective and safe. Expected and typically mild side effects related to bevacizumab were observed. Continued investigation of bevacizumab through a prospective clinical trial is warranted. Level of Evidence 4. Laryngoscope, 131:E921–E928, 2021

Pediatric jaw tumors are rare lesions most commonly presenting with a swelling or mass. Patients can be asymptomatic with the lesion identified on routine imaging. Certain clinical features such as age, location of tumor, and presence or absence of bone and soft tissue can narrow the differential diagnosis and identify tumors that may be malignant. Incisional biopsy is an important first step. A majority of jaw tumors are benign but require surgical intervention for eradication of disease. Multiple procedures, including reconstruction, may be required for certain lesions prior to cure.