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INTRODUCTION: Despite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk of progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB)—particularly when TB < 0.6 times the upper limit of normal (× ULN)—is associated with improved outcomes compared with ALP reduction to < 1.5 × ULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC. METHODS: We compared complication-free survival in patients achieving an ALP > ULN and < 1.5 × ULN (adequate response) with those with an ALP ≤ ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained. RESULTS: Patients achieving normal ALP and/or TB ≤ 0.6 × ULN demonstrated significantly improved complication-free survival compared with those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI: 0.56, 2.11; P = 0.001) for ALP normalization alone, 3.7 years (95% CI: 3.11, 4.29; P < 0.001) for TB ≤ 0.6 × ULN, and 4.51 years (95% CI: 4.13, 4.88; P < 0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (hazard ratio [HR] 0.34; 95% CI: 0.15, 0.80; P = 0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI: 0.09, 0.55; P = 0.001), or both (HR 0.14; 95% CI: 0.05, 0.38; P < 0.001). High-risk patients, defined by liver stiffness measurement ≥ 10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit. DISCUSSION: Achieving normal ALP and TB ≤ 0.6 × ULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management.

Abstract Endoscopic sleeve gastroplasty (ESG) facilitates 13.6%–16.2% total body weight loss (TBWL) at 12 months, but falls short of that seen with surgical vertical sleeve gastrectomy, in part owing to the retention of the gastric fundus. In adults with obesity, gastric fundal mucosal ablation (GFMA) reduces fasting plasma ghrelin (FPG), hunger, cravings, and accommodation. Combined GFMA-ESG could improve TBWL. This study aimed to evaluate the effectiveness and safety of sequential GFMA followed by ESG in adults with obesity, building on previously published 6-month results of GFMA alone. This was a prospective, first-in-human, two-phase clinical trial. Ten participants underwent GFMA, followed by ESG at month 6, and were followed for 12 months post-ESG (18 months total). GFMA was performed using hybrid argon plasma coagulation to lift and ablate the entire gastric fundal mucosa. ESG was performed using standard full-thickness endoscopic suturing of the gastric body. The primary end point was TBWL; secondary end points were safety and changes in FPG, maximum tolerated volume (MTV), and validated appetite questionnaires. Mean TBWL was 22.5% (SD 8.3%) at month 18. Hunger-related behaviors and eating self-efficacy showed sustained improvements. FPG was decreased at month 6 and returned toward baseline by month 18, while MTV remained suppressed. No serious adverse events occurred. Sequential GFMA-ESG is safe and induces substantial weight loss, reduced MTV of ingested nutrients, and improved behavioral measures. This combination approach builds on prior traditional ESG and GFMA-only results and may represent a promising advancement of endoscopic therapeutic options for weight loss.

Abstract Associations of Alzheimer’s disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier versus later an individual’s progression on plasma and PET Alzheimer’s disease biomarkers is associated with earlier versus later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed-effects models to estimate how much earlier versus later each individual progresses on plasma phosphorylated tau (p-tau)217, amyloid PET, tau PET and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cut-off points, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R = 0.38–0.47) in the MCSA and stronger (R = 0.74–0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET Alzheimer’s disease biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer’s disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer’s disease co-pathologies.

ABSTRACT Background Concomitant atrial fibrillation (AF) and gastrointestinal (GI) bleeding present a clinical challenge due to recurrent bleeding risk associated with anticoagulation for AF‐associated stroke prevention. Left atrial appendage occlusion (LAAO) offers an alternative stroke prevention strategy, but its impact on recurrent GI bleeding remains unknown. Methods This retrospective, multicenter cohort study used the TriNetX database to identify adults with AF on oral anticoagulation and a history of GI bleeding. Patients were stratified by treatment with or without LAAO. 1:1 propensity score matching (PSM) was employed. The primary outcome was recurrent GI bleeding. Cox regression analysis was used to generate hazard ratios (HRs) with 95% confidence intervals (CIs). Odds ratios (ORs) were used to evaluate effect sizes between groups. Kaplan–Meier curves were used for time‐to‐event analyses. Results After PSM, 9259 patients were compared in each group. Odds of recurrent GI bleeding were consistently lower in patients undergoing LAAO than without LAAO across all follow‐up intervals: at 3 months (OR 0.84; 95% CI 0.78–0.91), 6 months, 1 year, 3 years, and 5 years (OR 0.87; 95% CI 0.82–0.92). Kaplan–Meier analysis demonstrated significantly lower risk of recurrent GI bleeding with LAAO (HR 0.80; 95% CI 0.76–0.84; p < 0.01). Conclusion In patients with AF and prior GI bleeding, LAAO was associated with a significantly lower risk of recurrent GI bleeding at short‐term and long‐term time intervals.

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Objectives: To summarize recent high-quality trials and provide an update to the original 2022 American College of Radiology Appropriate Use Criteria for Treatment of Locoregional Gastric Adenocarcinoma. This multi-specialty-led committee included gastrointestinal radiation and medical oncology, gastroenterology, radiology, and surgical oncology. Methods: Using the population, intervention, comparator, outcome, timing, and study design framework, the evidence was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included prospective Phase II/II trials and select retrospective studies published between 5/1/2020 and 8/1/2025 in the Embase, Medline, and Pubmed databases. Study type and quality were assessed. Well-established RAND-UCLA consensus methodology (modified Delphi) was used to rate the appropriateness of the treatment options. Results: ARS AUC recommendations include adjuvant FLOT chemotherapy for localized gastric adenocarcinoma after neoadjuvant FLOT and surgery, poCT or perioperative chemoimmunotherapy for localized gastric adenocarcinoma, adjuvant chemotherapy +/− CRT for localized gastric adenocarcinoma that undergoes upfront surgery, and systemic therapy alone for localized gastric adenocarcinoma in a medically inoperable patient. Conclusions: This updated ARS AUC summary provides guidelines for the multimodality treatment of resectable gastric adenocarcinoma.