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Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Cancer outcomes vary widely between individual patients, each accumulating an irregular record of treatments, diagnoses, measurements, and complications. Current prognostic models reduce this complexity into a single snapshot, focus on narrow clinical settings, and rarely generalize across hospitals. Here we introduce Chronicle , an explainable transformer that learns from entire patient trajectories to predict diverse clinical outcomes throughout the disease course while capturing both short- and long-term temporal dependencies. Trained on 53.7 million longitudinal data points from 51,711 patients spanning 67 cancer types, Chronicle operates natively on irregular data without imputation and jointly predicts eight endpoints within a flexible framework adaptable to additional outcomes. Chronicle outperformed cross-sectional models for overall survival prediction (C-index 0.84 vs 0.76-0.79), stratified patients more accurately than established prognostic systems, including TNM stage, and predicted seven adverse event and transfusion endpoints (AUC 0.80-0.92). Applied without retraining to 69,341 patients in Germany, Switzerland, and the United States, Chronicle generalized across healthcare systems and improved further with local fine-tuning. Integrated explainability traced each risk update to patient-specific clinical factors, revealing distinct temporal persistence of prognostic information, with relevance half-lives ranging from weeks for therapies to nearly one year for baseline characteristics. These findings demonstrate that learning from hospital-wide patient trajectories enables interpretable and continuously updated predictions, providing a scalable framework to support individualized treatment decisions.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

PURPOSE To compare mortality risk among long-term survivors of high-grade serous ovarian cancer (HGSOC) with that of the general US population and to examine how mortality and recurrence trends have evolved under changing treatment approaches. MATERIALS AND METHODS This is a retrospective cohort study including patients with histologically confirmed HGSOC treated at a single referral cancer center from 1991 to 2022. Mortality risk, expressed as standardized mortality ratios (SMRs, ratio of observed deaths in the study population to expected deaths in an age-matched US population), was assessed at diagnosis and yearly on patients without events (disease persistence, recurrence, or death from any cause). RESULTS A total of 2,074 consecutive patients were included. The median follow-up was 12.5 years (IQR, 11.7-13.8). Most patients were stage III (1,396, 69.2%), 1,299 (62.8%) underwent primary cytoreductive surgery, and 1,688 (87.4%) received platinum-taxane as first-line therapy. At diagnosis, the mortality rate was 7.40 times higher than that in the general population (95% CI, 7.04 to 7.77). By 7 event-free years, the 95% CI for the SMR included 1 for the first time, and at 10 years, the SMR was 1.05 (95% CI, 0.72 to 1.49), indicating no statistically significant excess mortality compared with the general population. In those event-free at 10 years, the 5-year cumulative incidence of ovarian cancer–related deaths (8.2% [95% CI, 4.2 to 16.0]) was comparable with that of non–ovarian cancer–related deaths (6.3% [95% CI, 2.9 to 13.8]). CONCLUSION In this cohort, mortality risk steadily declined for patients who remained event-free, approaching that of the general population by 7 years after diagnosis. These results emphasize the importance of individualized, long-term follow-up to address both recurrence risk and survivorship needs.

Abstract Chimeric antigen receptor (CAR) T-cell therapy enriched for a memory-like phenotype may persist and function longer than a nonenriched product, thereby improving duration of response (DOR). We conducted a phase I study with bb21217 (NCT03274219), an anti–B-cell maturation antigen CAR T-cell therapy manufactured in the presence of the phosphoinositide 3-kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype, in patients with relapsed/refractory multiple myeloma (N = 72). No new safety concerns were raised with bb21217 therapy (three cases each of grade ≥3 cytokine release syndrome and grade ≥3 neurotoxicity were observed). The objective response rate was 69.4% and the median DOR was 23.8 (95% confidence interval, 16.8–34.8) months. Analysis of the drug product established an association between early memory phenotype and robust expansion and depth of response. Examination of baseline characteristics indicated that tumor burden and prior therapies influenced DOR. The data indicate that generation of CAR T cells early in a disease course when tumor burden is lower and source material exhibits a more naïve phenotype may maximize the clinical benefit potential of the drug product.

BACKGROUND: End colostomy reversal with colorectal anastomosis (Hartmann’s reversal) is a technically challenging procedure associated with significant morbidity due to adhesions and distorted anatomy after the index surgery. OBJECTIVE: To compare perioperative outcomes of open, laparoscopic, and robotic approaches for Hartmann’s reversal. DESIGN: Retrospective analysis of prospectively maintained data. SETTINGS: High-volume tertiary referral center with specialized colorectal surgery expertise. PATIENTS: A total of 218 patients who underwent Hartmann’s reversal between May 2018 and April 2023. MAIN OUTCOME MEASURES: Primary outcomes included hospital length of stay and rate of conversion. Secondary outcomes included overall complication rates and time to return of bowel function. RESULTS: Of 218 patients, 139 (63.8%) underwent open surgery, 48 (22.0%) underwent laparoscopic surgery, and 31 (14.2%) underwent robotic surgery. Robotic surgery had the lowest estimated blood loss (median 77.5 vs 100 mL laparoscopic and 150 mL open, p < 0.0001). Conversion to open surgery occurred in 16.1% of robotic cases compared with 35.4% of laparoscopic cases ( p = 0.0618). Minimally invasive approaches were associated with shorter hospital length of stay (median 3.0 vs 4.0 days, p < 0.0001) and faster return of bowel function (median 2.0 vs 3.0 days, p = 0.0095) compared to open surgery. Overall 30-day morbidity was 23.4%, with no significant difference among approaches ( p = 0.30). The temporal trend showed increasing adoption of robotic techniques, from 0% in 2018 to 53.8% in 2023, and a decrease in the proportion of cases approached by open surgery, from 76.9% in 2018 to 23.1% in 2023. LIMITATIONS: Retrospective design and single-institution experience with limited follow-up duration. CONCLUSIONS: Minimally invasive approaches to Hartmann’s reversal are associated with improved short-term outcomes compared to open surgery. The robotic approach shows promise in reducing conversion rates, potentially extending the benefits of minimally invasive surgery to more patients undergoing this challenging procedure. See Video Abstract . COMPARACIÓN DE LOS ENFOQUES ABIERTO, LAPAROSCÓPICO Y ROBÓTICO PARA LA REVERSIÓN DE HARTMANN: LA EXPERIENCIA DE LA CLÍNICA MAYO ANTECEDENTES: La reversión de la colostomía terminal con anastomosis colorrectal (reversión de Hartmann) es un procedimiento técnicamente complejo asociado a una morbilidad significativa debido a las adherencias y la distorsión anatómica tras la cirugía inicial. OBJETIVO: Comparar los resultados perioperatorios de los abordajes abiertos, laparoscópicos y robóticos para la reversión de Hartmann. DISEÑO: Análisis retrospectivo de datos mantenidos prospectivamente. ENTORNO: Centro terciario de referencia de gran volumen con experiencia especializada en cirugía colorrectal. PACIENTES: Un total de 218 se sometieron a la reversión de Hartmann entre mayo de 2018 y abril de 2023. PRINCIPALES MEDIDAS DE RESULTADOS: Los resultados primarios incluyeron la duración de la estancia hospitalaria y la tasa de conversión. Los resultados secundarios incluyeron las tasas generales de complicaciones y el tiempo de recuperación de la función intestinal. RESULTADOS: De los 218 pacientes, 139 (63,8 %) se sometieron a cirugía abierta, 48 (22,0 %) a cirugía laparoscópica y 31 (14,2 %) a cirugía robótica. La cirugía robótica tuvo la menor pérdida de sangre estimada (mediana, 77,5 ml frente a 100 ml en laparoscopia y 150 ml en cirugía abierta, p < 0,0001). La conversión a cirugía abierta se produjo en el 16,1 % de los casos robóticos frente al 35,4 % de los casos laparoscópicos ( p = 0,0618). Los abordajes mínimamente invasivos se asociaron con una estancia hospitalaria más corta (mediana de 3,0 días frente a 4,0 días, p < 0,0001) y un retorno más rápido de la función intestinal (mediana de 2,0 días frente a 3,0 días, p = 0,0095) en comparación con la cirugía abierta. La morbilidad global a los 30 días fue del 23,4 %, sin diferencias significativas entre los distintos enfoques ( p = 0,30). La tendencia temporal mostró un aumento en la adopción de técnicas robóticas, del 0 % en 2018 al 53,8 % en 2023, y una disminución en la proporción de casos abordados mediante cirugía abierta, del 76,9 % en 2018 al 23,1 % en 2023. LIMITACIONES: Diseño retrospectivo y experiencia de una sola institución con una duración de seguimiento limitada. CONCLUSIONES: Los enfoques mínimamente invasivos para la reversión de Hartmann se asocian con mejores resultados a corto plazo en comparación con la cirugía abierta. El enfoque robótico es prometedor para reducir las tasas de conversión, lo que podría ampliar los beneficios de la cirugía mínimamente invasiva a más pacientes que se someten a este procedimiento tan complejo. ( AI-generated translation ).

Abstract Introduction: Indolent systemic mastocytosis (ISM) is a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases and is associated with symptoms of mast cell activation and tissue infiltration. It can cause chronic, debilitating symptoms − including life-threatening anaphylaxis and impaired bone health. While historically most patients have relied on symptom-directed best supportive care (BSC) therapies, avapritinib is used as a new standard of care targeting KIT D816V, the primary driver for SM. Avapritinib is an oral, potent, selective KIT D816V inhibitor, and the first and only approved targeted therapy for adult patients with ISM in the USA and the EU. Approval was based on results from the phase 2 PIONEER trial. Here, we present the findings from ~3.5-year long-term follow-up. Methods: Adults with centrally confirmed ISM and uncontrolled moderate-to-severe symptoms who completed the randomized dose-finding (Part 1), or randomized, double-blind, placebo-controlled (Part 2) portions of PIONEER (NCT03731260) rolled over to the open-label, long-term extension (Part 3). This cumulative analysis includes patients who initiated avapritinib at the recommended dose of 25 mg once daily (QD) in either Parts 1, 2, or 3. All patients received BSC. Per investigator discretion and based on disease burden, dose titration up to 50 mg QD of avapritinib was permitted in Part 3. Long-term efficacy was assessed by measuring changes in symptoms and QoL, using the ISM-Symptom Assessment Form (ISM-SAF; ©2018 Blueprint Medicines, a Sanofi Company) and the Mastocytosis Quality-of-Life Questionnaire (MC-QoL). Safety was also assessed. Results: Overall, 226 patients initiated avapritinib 25mg QD across Parts 1, 2, and 3. This longer-term analysis is inclusive of 65 patients who dose titrated from 25 mg to 50 mg QD in Part 3. Median (range) treatment duration was 40.0 months (0.7‒67.2) as of February 21, 2025. Longer-term efficacy data with ~3.5 years of follow-up demonstrated sustained disease-related symptom improvements. The mean change (standard deviation [SD]) in total symptom score (TSS, per ISM-SAF), was −19.80 (19.81) at Week 144 (Month 33) and −20.43 (20.57) at Week 168 (Month 39) from a baseline of 48.08 (19.47). Additionally, avapritinib-treated patients demonstrated durable improvement in their most severe symptoms (mean change [SD] from baseline of −3.35 [3.02] at Month 33 and −3.47 [3.19] at Month 39) per ISM-SAF. Sustained responses were observed across all individual symptom domains (0–30) with mean changes (SD) at Month 33 and Month 39 of −3.77 (5.52) and −3.84 (6.05) for the gastrointestinal domain, −8.21 (7.70) and −8.20 (7.85) for the skin domain, and −4.66 (6.24) and −4.87 (6.51) for the neurocognitive domain. The mean percent change (SD) in MC-QoL was −34.67 (40.16) at Month 33 and −40.72 (33.24) at Month 39 from a baseline of 54.24 (18.32). Treatment with avapritinib was well tolerated, and its safety profile was similar to the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were Grades 1–2, and 7% of patients experienced Grade ≥3 TRAEs of which diarrhea, neutrophil count decrease, and weight increase occurred in &gt;1 patient. No Grade ≥3 TRAEs of increase in transaminases were observed. Edema (peripheral and periorbital), the most frequently reported TRAE, was mostly Grade 1 and occurred most frequently during the first 3–4 months of treatment. Three patients (1%) experienced serious adverse events assessed as treatment related. However, none led to treatment discontinuation and no trends were observed. After approximately 3.5 years of follow-up, low rates of treatment discontinuations (n=7, 3%) due to TRAEs were observed. Conclusion: Longer follow-up of patients with ISM treated on the PIONEER trial, including some on avapritinib for up to 5 years, demonstrates that prolonged avapritinib therapy continues to be effective and well tolerated. Additional prospective analyses will be needed to determine effects of selective KIT D816V-inhibition on anaphylaxis. These data support a favorable benefit-risk profile of avapritinib as a chronic treatment for adult patients with ISM.

Abstract Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C&gt;T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P&lt;0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P&lt;0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.

Abstract Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson’s disease. Using functional MRI, optimal DBS response networks have been characterized. However, neural activity associated with Parkinsonian symptoms is magnitudes faster than what can be resolved by this method. Although both spatial and temporal domains of these networks appear crucial, no single study has yet investigated both domains simultaneously. Here, we aimed at closing this gap by analysing electrophysiological data from a total of n = 127 hemispheres. Using subthalamic local field potentials that were recorded concurrently alongside whole-brain magnetoencephalography in a multi-centre cohort of patients who underwent subthalamic DBS for the treatment of Parkinson’s disease (n = 100 hemispheres), we analysed the DBS response network in both spatial and temporal domains. In every cortical vertex, cortico-subthalamic coupling was correlated with stimulation outcomes. This network spatially resembled functional MRI-based findings (R = 0.40, P = 0.039) and explained significant amounts of variance in clinical outcomes (βstd = 0.30, P = 0.002), whereas theta–alpha and low beta coupling did not show significant associations with DBS response (theta–alpha: βstd = −0.02, P = 0.805; low beta: βstd = −0.08, P = 0.426). The ‘optimal’ high beta coupling map was robust when subjected to various cross-validation designs (10-fold cross-validation: R = 0.29, P = 0.009; split-half design: R = 0.31, P = 0.026) and was able to predict outcomes across DBS centres [R = 0.74; P(1) = 8.9 × 10−5]. We identified a DBS response network that resembles the previously defined MRI network and operates in the high beta band. Maximal connectivity to this network was associated with optimal DBS outcomes and was able to cross-predict clinical improvements across DBS surgeons and centres.