Citations

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

Abstract Rationale Seralutinib is an investigational, first-in-class tyrosine kinase inhibitor designed for inhalation and selective for PDGFRα, PDGFRβ, CSF1R, and cKIT, targeting proliferation, inflammation, and fibrosis ─ three core drivers of pulmonary vascular remodeling in PAH. The phase 2 TORREY trial of seralutinib added to standard-of-care treatment in adults with PAH WHO FC II or III met its primary endpoint of a statistically significant reduction in pulmonary vascular resistance (PVR) vs. placebo at 24 weeks. Methods PROSERA (NCT05934526), a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, evaluated the efficacy and safety of inhaled seralutinib in PAH patients treated for up to 48 weeks. Eligible patients (WHO Group 1 PH, FC II or III; REVEAL Lite 2 Risk Score ≥5 or NT-proBNP ≥300 ng/L or PVR ≥800 dyne•s/cm5) on standard background therapy were randomized 1:1 to seralutinib 90 mg or placebo delivered by dry powder inhaler twice daily. The primary endpoint was change in six-minute walk distance (6MWD) from baseline to week 24 in the seralutinib treatment group vs. placebo. Key secondary endpoints included: time to clinical worsening (TTCW), proportion of patients with clinical improvement at week 24, change in NT-proBNP from baseline to week 24, and proportion of patients with ≥1-point decrease from baseline in REVEAL Lite 2 Risk Score at week 24. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs). Patients who completed blinded treatment could be eligible to participate in an open-label extension study. Preliminary Blinded Results 390 patients were randomized at 132 sites worldwide. At baseline, mean age was 50.0 years. PAH etiologies included 61.0% idiopathic, 9.7% heritable, and 22.3% associated with connective tissue disease. 25.6% of patients were WHO FC II and 74.4% FC III. Mean time from diagnosis was TBD years. Most patients were receiving 2 (39.2%) or ≥ 3 (54.6%) PAH medications, 29.2% were receiving parenteral prostacyclin. Baseline PVR was 798.4 dyne•s/cm5, 6MWD was 373.7 m, and NT-proBNP was 986.8 ng/L. The difference in 6MWD from baseline to week 24 between seralutinib and placebo was TBD [SD] m (p=TBD). Secondary endpoints of TTCW, clinical improvement, NT-proBNP, and REVEAL Lite 2 Risk Score will be reported. The most common AEs were TBD (x%) and TBD (y%). SAEs and discontinuations related to AE will be reported. Conclusions The PROSERA study demonstrates⋯ [to be updated following unblinding of the data]. Funding Gossamer Bio, Inc. This abstract is funded by: Gossamer Bio, Inc.

ABSTRACT Background The Academy for Women in Academic Emergency Medicine (AWAEM) within the Society for Academic Emergency Medicine was established to advance the recruitment, promotion, retention, and career satisfaction of women in academic emergency medicine (AEM). Despite progress, persistent gender disparities remain in several areas, including compensation, promotion, and leadership representation. Objective To better assess and evaluate current AWAEM programming, we developed a logic model to visually and systematically map AWAEM activities and initiatives with current and future metrics for evaluation. Methods The logic model was guided by AWAEM’s strategic plan and developed through an iterative process involving feedback from AWAEM members and leaders. Results The model outlines key inputs, describes activities categorized across five thematic areas, and identifies tangible outputs with corresponding metrics for those activities. The model concludes with short‐, intermediate‐, and long‐term outcomes that speak to the likely impact of AWAEM’s programming. Discussion The proposed logic model serves as a practical framework to align AWAEM’s efforts to outcomes while also embedding evaluation into ongoing programming. It provides a visual tool for identifying gaps and incorporating data‐driven modifications, as well as facilitating collaboration across the academy. While there are limitations to this logic model, it provides an initial roadmap and foundation for strategic planning and evaluation. It also provides an opportunity to periodically revise the model as AWAEM’s needs evolve to ensure continued relevance and alignment with the needs of the entire membership. Additionally, this model can serve as a framework for other professional development groups, academies, and societies external to SAEM.

The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type–specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional KO (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity, yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal potentially novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.

Background The wide reach and unique short audiovisual nature of TikTok make it a potential modality for disseminating information about orthopaedic surgery to both patients and medical professionals. However, only a few recent studies have assessed the purpose and creators of orthopaedic surgery content on TikTok. Methods The top 100 most-liked TikTok videos about orthopaedic surgery topics were included for analysis. Data reflecting video and creator account characteristics were collected. Video validity was determined by three reviewers according to the DISCERN criteria and Kruskal-Wallis H tests were performed to correlate validity to creator and video type. Results The majority of videos were created by orthopaedic surgeons (n=57/100) and for entertainment purposes (n=82/100). Orthopaedic surgeons had the highest DISCERN score (34.7) and greater video reliability compared to all other creator types (H = 59.0-67.1, all p<0.001). Videos made for educational and procedural purposes had the highest DISCERN scores (38.9 and 40.5, respectively) while entertainment videos had lower reliability (H=-56.7 to -113.5, all p<0.05). Conclusion The most popular orthopaedic surgery-related videos on the TikTok platform are primarily being created by orthopaedic surgeons for entertainment purposes. Less frequently were videos made to educate, describe procedures, and explain the lifestyle of an orthopaedic surgeon. Potential applications of utilizing the platform by orthopaedic surgeons include case or research discussions, educational videos on different pathologies, recruitment of prospective students to the field, and entertainment highlighting a day in the life of an orthopaedic surgeon.

Abstract Background Sleep disturbances are common in Alzheimer's disease and have been reported in its preclinical stage. A detailed characterization of sleep disruption across the Alzheimer’s disease continuum is required to clarify its role as a potential therapeutic target and to evaluate the utility of sleep-related biomarkers. Methods Sleep architecture was characterized through detailed spectral and temporal analysis of the slow-wave activity using polysomnography across the Alzheimer’s disease continuum . Participants included: cognitively unimpaired individuals without abnormal Alzheimer’s disease biomarkers (n = 30), cognitively unimpaired individuals with abnormal Alzheimer’s disease biomarkers (n = 45), and individuals with mild cognitive impairment or mild dementia due to Alzheimer’s disease (n = 41). Associations between slow-wave features and longitudinal cognitive performance were tested in cognitively unimpaired participants. Sex differences were also explored. Results A stepwise increased wake after sleep onset and latency to rapid eye movement sleep was observed, alongside reduced spectral power of slow-wave activity and a progressive flattening of slow-waves across the Alzheimer’s disease continuum in both sexes. In cognitively unimpaired individuals, higher slow-wave slope and greater peak-to-peak amplitude were associated with better cognitive trajectories over time. Conclusions Sleep macro- and microarchitecture are altered early and progressively deteriorate across the Alzheimer’s disease continuum . Slow-wave features relate to cognitive trajectories in preclinical Alzheimer’s disease, with exploratory analyses suggesting stronger associations in men. These findings support slow-wave morphology as a candidate non-invasive marker for future sleep-based intervention studies.

Abstract INTRODUCTION Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS We used three datasets: [18F]flortaucipir positron emission tomography (PET) in 157 former professional American football players and 53 controls (DIAGNOSE CTE); cortical myelin water fractions (MWF) in 50 healthy individuals (Myelin Water Atlas); and white matter (WM) tract MWF and functional connectivity (FC) in 100 healthy individuals (Human Connectome Project). We tested associations between tau‐PET uptake and covariance in football players and typical cortical gray matter (GM) MWF, WM tract MWF, and FC. RESULTS Cortical regions with lower typical GM MWF showed higher tau‐PET uptake ( β = −0.399, p = 0.001). WM tracts with lower typical MWF were associated with higher tau‐PET covariance ( β = −0.238, p < 0.001). Higher typical FC was associated with higher tau‐PET covariance ( β = 0.447, p < 0.001). DISCUSSION In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.