Citations

Background & Aims: Multi-target stool DNA (mt-sDNA) is an established stool-based colorectal cancer screening test, yet long-term performance is not well-described. We evaluated follow-up colonoscopy rates & quality, neoplasia yield, and repeat-testing adherence over 10 years with an integrated screening program. Methods: We assembled a retrospective cohort of mt-sDNA tests (September 2014–July 2025) within a multi-site health system. A validated large-language-model pipeline extracted colonoscopy, pathology, and quality endpoints from free-text reports. Detection outcomes (adenoma detection rate, advanced neoplasia, modified advanced adenoma, sessile serrated lesion (SSL), and negative exams) were calculated among high-quality exams; adenocarcinoma, bowel preparation adequacy, and cecal intubation rate (CIR) used all screening exams. We assessed colonoscopy completion ≤1 year after positive mt-sDNA, follow-up colonoscopy findings, findings by time-to-colonoscopy, and adherence to repeat mt-sDNA after negative result. Results: Among 148,624 tests in 110,410 individuals, positivity was 13.6%. Of 19,506 positives, 65.1% completed colonoscopy within 12 months (median 82 days). Colonoscopy after a positive mt-sDNA had high yield: advanced adenoma diagnosis was 30.7%; adenocarcinoma was 1.3%. Of patients who had colonoscopy within 3 years of a negative mt-sDNA test, 45.2% had adenoma/serrated lesion, 9.3% had advanced adenoma and 0.5% had colon cancer. Adenoma detection rate after positive mt-sDNA (>50%) exceeded specialty society quality benchmarks and increased over time; Longer intervals (>6 months) to colonoscopy after a positive test were associated with higher advanced adenoma (trend P=0.001).After an initial negative mt-sDNA, only 35.3% were screened again by mt-sDNA testing within 3 years. Conclusions: Over a decade,mt-sDNA screening achieved high colonoscopy qualitybut revealed critical gaps in the care cascade. One-third of positive tests lacked timely follow-up and nearly two-thirds of negative tests were not repeated on schedule, suggesting opportunities for system-level interventions.

Background Diastolic dysfunction is common in patients with aortic stenosis and may influence outcomes following surgical aortic valve replacement. We aimed to examine the association of preoperative artificial intelligence (AI)‐generated diastolic function grades with early and late outcomes following aortic valve replacement and how postoperative progression influence prognosis. Methods We identified 5503 patients undergoing aortic valve replacement between 2000 and 2023. Diastolic function was assessed using a validated deep‐learning AI model applied to 12‐lead ECGs done preoperatively and on postoperative follow‐up. Diastolic grades were classified by AI into Grades 1 to 3. Longitudinal trend analyses and multivariable regression models were used to assess study end points. Results Among 5503 patients (mean age 72.4±10.8 years; 39% female), higher AI ECG diastolic grades were associated with greater comorbidity burden, including diabetes, renal disease, and heart failure. AI ECG diastolic Grade 3 was independently associated with higher in‐hospital mortality (odds ratio, 2.5; P =0.007) and other complications. At 5‐year follow‐up, patients with Grade 3 showed the least improvement in diastolic function by both ECG and echocardiography. Grades 2 and 3 diastolic function at baseline were independently associated with increased late mortality (hazard ratio, 1.3 and 2.45, respectively; both P <0.001). Additionally, lack of improvement in AI ECG diastolic grade by 1 year was also independently associated with late mortality. Conclusions AI ECG–derived diastolic function grades strongly correlates with early complications and long‐term mortality and diastolic progression after aortic valve replacement. AI ECG provides a powerful, noninvasive tool for risk stratification and longitudinal monitoring of patients with aortic stenosis.

Importance Timely identification of aortic stenosis (AS) is essential for appropriate clinical management, yet screening remains limited by dependence on comprehensive echocardiography and trained imaging personnel. Objective To develop and validate a deep learning algorithm for detection of moderate or greater AS and prospectively evaluate its performance using artificial intelligence (AI)–guided focused cardiac ultrasound (FoCUS) acquired by novice operators. Design, Setting, and Participants This diagnostic study included retrospective algorithm development and validation and prospective evaluation of AI-guided FoCUS across Mayo Clinic sites in the Midwest, Arizona, and Florida. The model was developed using 6753 patients and evaluated in internal validation (n = 852), internal test (n = 844), and validation (n = 1912) cohorts. Performance was assessed on FoCUS acquired by experienced sonographers (n = 602) and prospectively by novice operators (n = 1302). The retrospective model development and validation cohorts comprised studies performed from January 2005 through September 2022. Prospective study was conducted in 2 enrollment periods from June to August 2024 and from June to September 2025. Participants from both periods were combined to comprise the final prospective cohort. Exposure AI-guided FoCUS acquisition and automated deep learning–based assessment for detection of moderate or greater AS. Main Outcomes and Measures Detection of moderate or greater AS. Performance was assessed using area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and positive predictive value. Results The model demonstrated excellent discrimination in the internal test cohort (AUROC, 0.99; 95% CI, 0.98-1.00) and geographically distinct validation cohorts in Arizona (AUROC, 0.99; 95% CI, 0.97-1.00) and Florida (AUROC, 0.99; 95% CI, 0.96-1.00). Among FoCUS examinations acquired by experienced sonographers, sensitivity was 95% (95% CI, 82-99) and specificity was 97% (95% CI, 95-98). In the prospective novice-operator cohort, 1258 of 1302 examinations (96.6%) were suitable for automated analysis. Sensitivity was 93% (95% CI, 82-99) and specificity was 96% (95% CI, 95-97). Expert review of AI-positive and uninterpretable examinations increased the positive predictive value from 49.4% to 91.1%, with sensitivity of 85.4%. Conclusions and Relevance A deep learning algorithm accurately detected moderate or greater AS across validation cohorts in this study. In prospective evaluation, novice operators were able to acquire AI-guided FoCUS examinations that enabled accurate detection of moderate or greater AS. These findings support a scalable strategy that may expand access to AS detection in settings with limited echocardiography resources.

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

Importance Recent case reports suggest that B antigen–containing blood products may be associated with anaphylactic transfusion reactions in recipients with preformed immunoglobulin E to galactose- α -1,3-galactose (alpha-gal). Objective To test the association of local alpha-gal syndrome (AGS) prevalence and allergic transfusion reaction (ATR) in patients with blood type O. Design, Setting, and Participants In this international, multicenter, retrospective cohort study at academic medical centers, sites were assigned to AGS high- or low-prevalence clusters based on the known geographic distribution of AGS. Data were collected on platelet or plasma transfusions and ATRs during 2020 to 2024. Consecutive patients receiving platelet or plasma transfusions were included. Exposures Patients with blood type O who received B or AB units and patients with blood type O who received O units (reference group) in AGS high- and low-prevalence clusters were compared. Main Outcomes and Measures Before data collection, the hypothesis was that if transfusion-related alpha-gal syndrome (TRAGS) is a true clinical entity, excess ATRs to group B or AB units would be detected in AGS high-prevalence regions exclusively. The main measure was the overall risk ratio (RR) for ATRs to B or AB plasma or platelets in AGS high- vs low-prevalence clusters. Results In total, 558 823 platelet and plasma transfusions at 40 sites in 5 countries were analyzed, of which ATRs occurred in 1744 transfusions (0.3%). In the US AGS high-prevalence cluster (9 sites), significantly more ATRs of any severity occurred among patients with blood type O who received B or AB units vs patients with blood type O who received O units (overall RR, 3.93; 95% CI, 2.96-5.21; P &amp;lt; .001). In contrast, in the primary analysis of the AGS low-prevalence cluster (15 sites), excess ATRs to B or AB units were not detected. In subgroup analyses among patients with blood type O receiving B units, the RR for moderate to severe ATRs was 9.14 (95% CI, 5.39-15.52; P &amp;lt; .001) in the AGS high-prevalence cluster vs 2.15 (95% CI, 1.34-3.47; P = .002) in the AGS low-prevalence cluster. Outside the US, a signal consistent with TRAGS was not detected. Conclusions and Relevance This cohort study provides provocative epidemiologic evidence that TRAGS may be a unique manifestation of AGS and a previously unrecognized risk associated with transfusion. In AGS high-prevalence regions, blood collectors and hospital transfusion services should consider approaches to preventing severe ATRs from B or AB plasma or platelet units.

Alcohol-associated liver disease (ALD) is a growing global health concern, with alcohol-associated hepatitis (AH) leading to the highest morbidity and mortality. Available therapies are limited and often inadequate. Platelets contribute in a variety of ways to liver disease pathogenesis, but their role in AH remains largely unexplored. In this study, we addressed the hypothesis that platelets contribute to pathological inflammation in AH. Using patient samples and a multiomics approach, we found that platelets undergo proinflammatory transcriptomic and proteomic changes in AH, with 2 alarmins, S100A8 and S100A9, being among the top upregulated genes/proteins. Additionally, the abundance of platelet-derived microparticles containing S100A8 and S100A9 in AH patient plasma was increased and correlated with disease severity (assessed by model for end-stage liver disease sodium [MELD-Na]) and endotheliopathy (assessed by ICAM1, CXCL8, and vWF). We mechanistically linked S100A9 with endotheliopathy via crosstalk between primary human liver sinusoidal endothelial cells and primary human monocytes. We also demonstrated that IL-6 upregulates S100A9 in megakaryocytic cells in a JAK/STAT-dependent manner, modeling changes occurring in the bone marrow in patients with AH. Our studies establish proinflammatory platelets as important contributors to AH pathology. Moreover, antiplatelet agents — or, more specifically, S100A9 targeted drugs — are potential therapeutic strategies in AH.

Abstract Objective To assess the efficacy and safety of fenfluramine in patients with Dravet syndrome (DS) stratified by age, number of previously attempted antiseizure medications (ASMs), and SCN1A pathogenic variant status. Methods In this post hoc analysis, data from three randomized controlled trials (RCTs) in patients with DS (2–18 years) were pooled and stratified by age (<4; ≥4 years), number of previous ASMs (1–3; 4–6; ≥7), and SCN1A pathogenic variant status ( SCN1A +; SCN1A −). Stratified groups were assessed and compared with the pooled placebo group (change in monthly convulsive seizure frequency [MCSF], longest convulsive seizure‐free interval, and Clinical Global Impression–Improvement [CGI–I] scale scores rated by parents/caregivers and investigators), and safety (treatment‐emergent adverse events [TEAEs]: frequency, days to onset, and proportion resolved). Results Among 348 patients included in the RCTs, 216 were randomized to fenfluramine (0.7 mg/kg/day, n = 88; 0.4 mg/kg/day [with stiripentol], n = 43; 0.2 mg/kg/day, n = 85) and 132 to placebo. Compared with placebo, fenfluramine treatment (all doses combined) resulted in greater MCSF reductions, greater increases in longest convulsive seizure‐free intervals, and a higher proportion of parents/caregivers and investigators reporting clinically meaningful improvement (“Much Improved”, “Very Much Improved”) on CGI–I scores across all stratified groups. CGI–I scores were consistent across fenfluramine doses in most stratified groups, but patients with the fewest number of previous ASMs had the greatest frequency of clinically meaningful improvement on investigator‐rated CGI–I scores. Safety outcomes were similar across all strata. Most TEAEs resolved by end‐of‐study. Significance Fenfluramine treatment was associated with improved seizure outcomes and global functioning compared with placebo regardless of age, number of previous ASMs, and SCN1A status in patients with DS. Fenfluramine was well‐tolerated; no new safety signals were identified. Further studies with larger sample sizes (including adults) and a priori inferential analyses of stratified groups are warranted. Plain Language Summary Patients with Dravet syndrome struggle with seizures and everyday life. In three studies, patients aged 2–18 years received fenfluramine or placebo (sugar pill). Fenfluramine lowered seizures without many side effects. Researchers combined results from these studies to see how fenfluramine worked in different patient groups based on age, number of previous medications, and a gene called SCN1A . They looked at seizure reduction and whether doctors felt patients had improved. In all groups, fenfluramine worked better than placebo, with similar side effects. Researchers believe fenfluramine helped these patients, but some groups were small, so these results need to be confirmed.

ABSTRACT Background and Objectives Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, but the contribution of nonbiological factors to long‐term survival is unclear. We evaluated demographic, socioeconomic, clinical, treatment, and care‐delivery factors associated with 3‐year survival and whether these associations persisted at 5 years. Methods National Cancer Database patients with stage I–III PDAC diagnosed from 2012 to 2022 were analyzed using multivariable logistic regression adjusted for treatment pathway. Results Among 57,053 patients, 51,071 were eligible for a 3‐year analysis, and 12,205 (23.9%) survived. Compared with chemotherapy alone, surgery with chemotherapy (OR, 7.12; 95% CI, 6.64–7.63) and surgery alone (OR, 3.84; 95% CI, 3.49–4.23) had the strongest associations with survival. Younger age, lower comorbidity, Asian race, Spanish/Hispanic ethnicity, private insurance, lower grade, body or tail location, and lower nodal burden were independently associated with survival. Black race and treatment timing were not significant after adjustment. Findings were directionally consistent at 5 years. Conclusion Demographic, socioeconomic, and clinical factors independently influence 3‐year survival in PDAC. These findings underscore the need to complement biologic and therapeutic advances with structural interventions, such as insurance expansion and improved access to high‐quality centers, to mitigate disparities and improve outcomes in this highly lethal cancer.