Importance DNL343 is a brain-penetrant small molecule that acts as an activator of eukaryotic translation initiation factor 2B (eIF2b), designed to inhibit the integrated stress response. A prior phase 1B trial of DNL343 in amyotrophic lateral sclerosis (ALS) provided evidence of a favorable safety profile, central nervous system penetrance, and target engagement based on integrated stress response biomarkers in blood and cerebrospinal fluid. Objectives To evaluate the safety and efficacy of a 200-mg formulation of DNL343 given once daily in individuals living with ALS. Design, Setting, and Participants DNL343 was evaluated as a regimen of the HEALEY ALS Platform Trial, a double-blind, multiregimen, placebo-controlled randomized clinical trial conducted at 74 centers in the US between May 24, 2023, and May 22, 2025. Eligible participants were randomized in a 3:1 ratio to receive DNL343 or matching placebo, with both groups enrolling concurrently. The analysis included shared randomized participants receiving placebo from an additional regimen. Intervention The study drug was administered for a placebo-controlled duration of 24 weeks. Main Outcomes and Measures The primary analysis was a bayesian shared parameter model of function and survival that provided an integrated estimate of the relative rate of disease progression among participants receiving DNL343 relative to placebo. The model had components for function and survival linked through an integrated estimate of disease slowing in treatment relative to controls across the 2 outcomes (denoted as the disease rate ratio [DRR]). Several safety, secondary, and exploratory end points were also evaluated. Results A total of 259 screenings were completed in this regimen; 249 participants met eligibility and were randomized to DNL343 (n = 186) and regimen-specific placebo (n = 63), with an additional 76 participants from a concurrent regimen receiving placebo included for a total of 139 shared placebo participants (325 participants, with 196 (60.3%) male and mean [SD] age of 59.3 [11.5] years). The estimated median DRR common to the ALS Functional Rating Scale–Revised and survival was 1.04 (95% credible interval, 0.83-1.32; probability of DRR <1, 0.37). Secondary outcome measures were not statistically different between the DNL343 and placebo groups. Overall, the incidence rates of adverse events were similar in participants receiving DNL343 and placebo. Conclusions and Relevance In this randomized clinical trial, despite the relevance of the eIF2b activation pathway in ALS disease biology and supporting evidence of proof of mechanism and optimal dose selection in a prior phase 1B ALS clinical trial, 200-mg/d DNL343 did not show evidence of slowing disease progression in ALS, highlighting the need for alternative therapeutic approaches. Trial Registration ClinicalTrials.gov Identifier: NCT05842941
OBJECTIVES:Although nasal breathing is the preferred pathway for quiet respiration, up to 30% of the population are habitual mouth breathers. This systematic review investigates the association between mouth breathing and musculoskeletal outcomes. DATA SOURCES:A literature search was conducted on Medline, Embase, CINAHL, Web of Science, and Scopus from inception to August 8, 2025. REVIEW METHODS:Eligible studies included adults and investigated the association between chronic or induced mouth breathing (or relevant proxies such as nasal obstruction or induced nasal obstruction) and outcomes of musculoskeletal pain, temporomandibular joint dysfunction (TMD), changes in posture or muscle activity/electromyography (EMG). Outcome data were summarized using a narrative synthesis due to heterogeneity in included studies. GRADE was used to assess evidence certainty. RESULTS:Studies evaluated the impact of chronic mouth breathing (n = 4) or induced mouth breathing (n = 8) on posture, TMD, masticatory muscle activity, and efficiency. No study evaluated the direct relationship between chronic or induced mouth breathing and pain. Compared to nasal breathers, mouth breathers had a higher prevalence of TMD, adopted a head forward posture and increased lumbar lordosis, demonstrated reduced chewing efficiency, and had reduced masseter and temporalis, and increased suprahyoid EMG activity. Certainty of evidence was very low. CONCLUSIONS:This review found very low certainty evidence that chronic or induced mouth breathing may negatively impact posture, temporomandibular joint function, masticatory muscle activity, and efficiency. However, there is no data on whether there is an impact on pain. Due to the very low certainty of evidence, caution is recommended when interpreting the current literature. LEVEL OF EVIDENCE:N/A.
BACKGROUND:Severe mitral annular calcification (MAC) carries significant risk. Safe and effective transcatheter options are needed for patients with MAC. OBJECTIVES:The goal of this study was to evaluate the safety and effectiveness of the Tendyne Transcatheter Mitral Valve System (Abbott Structural Heart) in symptomatic patients with mitral disease due to severe MAC. METHODS:This analysis reports results from the severe MAC cohort of the SUMMIT (Safety and Effectiveness of Using the Tendyne Transcatheter Mitral Valve System for the Treatment of Symptomatic Mitral Regurgitation) study, which was the first prospective clinical trial designed to assess the use of the Tendyne system for severe MAC. All patients had severe MAC with significant mitral valve dysfunction and were at high surgical risk. An echocardiography core laboratory performed independent assessments of mitral disease. Adverse events were adjudicated by an independent clinical events committee. The primary endpoint was freedom from all-cause mortality and heart failure hospitalization at 12 months' postindex procedure. RESULTS:Overall, 103 patients (mean age 78.0 ± 6.5 years; 55% female) with severe MAC and mitral regurgitation or stenosis underwent treatment with Tendyne. Mitral regurgitation was present in nearly all patients at baseline (ie, 97% of patients with grade ≥2+). Technical success was achieved in 94.2%, with a 30-day mortality of 6.8%. The primary endpoint was met: freedom from all-cause mortality and heart failure hospitalization was 60.4% at 12 months (performance goal: 43%; P = 0.0002). Heart failure symptoms improved significantly (NYHA functional class I/II: 30.6% vs 87.5% [paired baseline vs 12 months]; P < 0.0001) and quality of life improved significantly (mean paired increase in the Kansas City Cardiomyopathy Questionnaire Overall Summary: 18.7 ± 24.4 points; P < 0.0001). CONCLUSIONS:In this first report of the primary outcomes of the SUMMIT-MAC clinical trial, transcatheter mitral valve replacement with Tendyne led to successful treatment of mitral valve disease due to MAC and significant improvements in heart failure symptoms and quality of life.
