American Journal of Gastroenterology

IntroductionVonoprazan, a new oral potassium-competitive acid blocker (PCAB), has shown promise in terms of superior acid suppression when compared to Proton-pump inhibitors (PPIs). We evaluated the efficacy of PCABs versus PPIs in preventing rebleeding in high-risk peptic ulcer patients after endoscopic hemostasis. MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search for relevant studies across Medline, Embase, Web of Science, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov, from inception till March 25, 2025. The primary outcome of interest was peptic ulcer rebleeding rate. Pooled risk ratios (RR) and mean difference (MD) with the corresponding 95% confidence intervals (CIs) were calculated. ResultsThree studies with 54,410 patients receiving endoscopic hemostasis for peptic ulcer bleeding were included in our analysis. The mean age of included participants was 71 {+/-} 1.83 years. There was no significant difference in rebleeding rates between patients receiving PPIs and PCABs (RR 0.827; 95 % CI: 0.5 -1.3). We observed a significant reduction in length of hospital stay in the PCAB group when compared to the PPI group (MD: -0.44, 95% CI: -0.72 - -0.17), but no significant difference in all-cause mortality between both groups (RR: 0.90, 95% CI: 0.79 - 1.04). ConclusionsOur study demonstrates comparable efficacy of PPIs and PCABs in preventing rebleeding in patients with high-risk peptic ulcers after successful endoscopic hemostasis. However, there was a significant reduction in hospital length of stay favoring PCABs. Research in ContextO_ST_ABSWhat is already known on this topicC_ST_ABSBleeding from peptic ulcers is considered one of the major reasons for mortality and hospitalization, and the standard treatment after endoscopic hemostasis is the administration of high-dose proton pump inhibitors (PPIs). Potassium competitive acid blockers (PCABs), such as vonoprazan, have been reported to have more potent and faster onset of action than PPIs in the treatment of acid-related diseases, but their efficacy in the prevention of post-endoscopic peptic ulcer rebleeding has not been well established in the literature in the form of a dedicated meta-analysis. What this study addsIn the present study, the efficacy and safety of PCABs in the prevention of post-endoscopic rebleeding and mortality in 54,410 patients with high-risk peptic ulcer bleeding were investigated in the context of a systematic review and meta-analysis. PCABs were found to have similar efficacy to PPIs in the prevention of mortality and rebleeding in the context of endoscopic hemostasis, and the use of PCABs was also observed to reduce the length of stay in the hospital to a significant extent. How this study might affect research, practice or policyThese findings indicate that PCABs are a reasonable alternative to PPIs in post-endoscopic management of high-risk peptic ulcer bleeding and may be particularly useful in situations where early discharge and optimization of resources are critical. Additional large-scale studies in different populations are required to validate these findings and create guidelines

BackgroundPatients with chronic immune-mediated disorders (IMIDs), including inflammatory bowel disease (IBD), are at increased risk of cardiovascular disease. While advanced therapies show cardioprotective effects in other IMIDs, their impact on major adverse cardiovascular events (MACE) in IBD remains unclear. We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating MACE risk with advanced therapies in IBD. MethodsSystematic search of PubMed, Embase and Cochrane Central identified 43 high-quality studies (36 RCTs,7 observational studies) published between 2002 and 2024. Primary analyses estimated odds ratios (OR) for MACE comparing advanced therapy to placebo, with secondary analyses stratified studies by drug class and length of follow-up. ResultsPlacebo-controlled RCTs showed a nonsignificant trend toward reduced MACE risk (OR: 0.60; 95% CI: 0.24-1.51), with similar findings after continuity correction for zero-event studies (OR: 0.87; 95% CI: 0.45-1.68). Class-specific trends suggested lower MACE risk with IL-12/IL-23 inhibitors (OR: 0.35; 95% CI: 0.05-2.21), JAK inhibitors (OR: 0.57; 95% CI: 0.16-2.06), and a potential increase with anti-TNF agents (OR: 3.04; 95% CI: 0.31-29.47), though none reached statistical significance. Long-term follow-up studies showed consistent findings. Observational studies suggested lower MACE risk for anti-TNF therapies (OR: 0.29; 95% CI: 0.21-0.40), but not for IL-12/IL-23 (OR: 4.41; 95% CI: 0.49-39.28) or JAK inhibitors (OR: 1.57; 95% CI: 0.86-2.84). ConclusionAdvanced therapies did not demonstrate a clear increase or decrease in cardiovascular risk in IBD. The discrepancies between RCTs and observational studies underscore the urgent need for rigorous-designed observational research with long-term follow-up to evaluate the real-world impact of advanced therapies on MACE risk. SummaryThis study evaluated cardiovascular safety of advanced therapies in inflammatory bowel disease. Findings showed no clear signal of decreased major cardiovascular risk compared with conventional treatment, highlighting the need for continued monitoring through long-term and real-world evidence. Key MessagesO_LIWhat is already known? Patients with IBD are at increased risk of cardiovascular events, and the impact of advanced therapies on this risk remains uncertain. C_LIO_LIWhat is new here? This meta-analysis integrates data from randomized and observational studies and found no significant association between advanced therapies and MACE. C_LIO_LIHow can this study help patient care? Findings show no clear signal of decreased cardiovascular risk with advanced IBD therapies, though continued evaluation is warranted. C_LI

BackgroundAnti-tumor necrosis factor (anti-TNF), particularly infliximab, have transformed inflammatory bowel disease (IBD) management, but their high cost imposes a significant economic burden. Infliximab biosimilars were introduced to reduce the unmet needs. Despite the approval of infliximab biosimilars, real-world evidence of cardiovascular safety and effectiveness of infliximab biosimilars is lacking among patients with IBD. In this trial emulation, we compared the effectiveness and cardiovascular safety between patients who initiated infliximab reference product (IFX-RP) and biosimilars (IFX-BP). MethodsUsing the Merative Marketscan Research database (2011-2023), we conducted a retrospective cohort study to emulate the target trial where biologic-naive adults were randomly assigned to initiate IFX-RP or IFX-BP. Primary outcomes included healthcare resource utilization (HRU), and incidence of major adverse cardiovascular events (MACE) over one year. Propensity score matching was applied to mimic the randomization. Both intention-to-treat and per-protocol effects were estimated. ResultsAfter matching, 850 patients (425 per group) were included. HRU was comparable between IFX-RP and IFX-BP groups across outpatient visits, hospitalizations, surgeries, and emergency visit. During follow-up, MACE events were more frequent in the IFX-BP group (9 vs. 3), with an incidence rate ratio (IRR) of 3.04 (95% CI: 0.82-11.23). Although the difference was not statistically significant, consistent directional trends were observed across analyses. Sensitivity analyses supported primary results. ConclusionOur study found comparable effectiveness between IFX-RP and IFX-BP in routine clinical care. While cardiovascular events were infrequent, the potential signal suggesting increased MACE risk associated with infliximab biosimilars warrants further investigation. Continued pharmacovigilance is essential to ensure the cardiovascular safety of biosimilars. SummaryInfliximab biosimilars, introduced to reduce the economic burden of anti-TNF therapy in IBD, demonstrated comparable real-world effectiveness to the infliximab reference product in a target trial emulation using Merative MarketScan data, while a potential signal of increased cardiovascular risk underscores the need for ongoing pharmacovigilance and further investigation. Key MessagesO_LIWhat is known? Infliximab biosimilars demonstrate comparable efficacy and safety to the reference product in IBD, but cardiovascular outcomes remain underexplored. C_LIO_LIWhat is new here? This U.S. real-world study emulating a target trial found similar effectiveness between infliximab reference and biosimilar products, with a possible trend toward increased cardiovascular risk in biosimilar users. C_LIO_LIHow can this study help patient care? Findings highlight the need for continued pharmacovigilance and cardiovascular monitoring when prescribing infliximab biosimilars to optimize safety in IBD management. C_LI

ObjectivesGastric cancer (GC) is a leading cause of cancer mortality in the United States (U.S.), yet no routine screening strategy exists. Opportunistic upper endoscopy (EGD) performed during screening colonoscopy (EGD-SC) may provide a practical early detection approach. We evaluated the feasibility, acceptability, patient perspectives, and diagnostic yield of EGD-SC. MethodsThis single-center, open-label, single-arm prospective trial enrolled adults aged 45-80 years scheduled for colonoscopy without prior EGD in the past five years. Feasibility was assessed by enrollment, added procedural time, and safety. Acceptability, patient beliefs, motivators, barriers, and satisfaction were assessed using pre- and post-procedure surveys. Gastric biopsies evaluated for precancerous lesions. ResultsOf individuals contacted, 51.6% expressed interest and 26.6% enrolled (n=50; median age 56; 48% male; 68% high-risk). Median added time was 17 minutes (range 9-26), with no complications. All participants rated EGD-SC as satisfactory (100%) and 90% as acceptable; most preferred the combined procedure (97.5%) and would recommend it to family or friends (92.5%). Knowledge gaps were common: nearly half lacked awareness of GC risk factors; although 72% viewed screening as beneficial, only 23.3% perceived GC as severe, and none considered themselves highly susceptible. EGD found H. pylori infection (32%), atrophic gastritis (14%), and intestinal metaplasia (12%), with higher prevalence among high-risk participants. ConclusionsEGD-SC is feasible, safe, and highly acceptable, with strong patient endorsement and meaningful detection of GC precursor lesions. These findings support risk-stratified EGD-SC as a promising and pragmatic strategy for GC prevention and early detection in the U.S.

BackgroundEndoscopic resection is the standard treatment for rectal neuroendocrine tumors (r-NETs) [&le;]10 mm, yet the optimal technique remains controversial. Modified endoscopic mucosal resection (m-EMR) has emerged as a potential alternative compared to endoscopic submucosal dissection (ESD), but existing evidence is largely retrospective and the results of recent randomized controlled trials (RCTs) are inconclusive. AimsTo compare the efficacy and safety of m-EMR versus ESD for r-NETs [&le;]10 mm. MethodsWe systematically searched CENTRAL, PubMed, Embase, and WanFang from January 1st, 1970 to December 23, 2025 for RCTs comparing m-EMR with ESD in r-NETs [&le;]10 mm. The GRADE framework assessed evidence certainty, while trial sequential analysis (TSA) controlled random errors and evaluated conclusion validity. ResultsSix RCTs involving 440 patients were analyzed. No significant difference between m-EMR and ESD was found in histologic complete resection (RR = 1.00, 95% CI 0.97-1.03; I2 = 0%), en bloc resection rates (P = 0.75) and procedure-related complications (P = 0.94). And m-EMR was associated with a significantly shorter procedure time (P<0.00001) and lower hospitalization cost (P<0.00001). The evidence was of moderate certainty; TSA confirmed its reliability, and both cumulative and sensitivity analyses supported the robustness. ConclusionsModerate-certainty evidence indicates m-EMR achieves oncologic outcomes comparable to ESD while offering clear advantages in procedural efficiency and cost for r-NETs [&le;]10 mm, supporting m-EMR possibly as a preferred endoscopic strategy in clinical practice.

BackgroundAcute appendicitis (AA) is a common surgical emergency. Observational studies have reported associations between obesity-related anthropometric traits and AA, but these associations may be affected by confounding and reverse causation. We used Mendelian randomization (MR) to investigate the potential causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on AA risk. Methods and FindingsWe obtained genome-wide association study (GWAS) summary statistics for BMI (ukb-b-19953), WHR (ieu-a-73), and AA (finn-b-K11_APPENDACUT) from the IEU Open GWAS database. We conducted single-variable MR (SVMR) and multivariable MR (MVMR) analyses. The primary estimator was inverse-variance weighted (IVW) MR, complemented by MR-Egger, weighted median, weighted mode, and simple mode methods. Instrument strength was assessed using the variance explained and F-statistics. Sensitivity analyses included Cochrans Q for heterogeneity, MR-Egger intercept and MR-PRESSO global test for horizontal pleiotropy, leave-one-out analysis, and Steiger directionality testing. We mapped instrumental variants to cis-eQTL genes (eQTLGen) and performed GO and KEGG enrichment analyses. In SVMR, genetically predicted BMI (OR 1.145, P = 0.0006) and WHR (OR 1.336, P = 0.0040) were associated with higher AA risk. Instruments were strong (BMI: [Formula]; mean/min F-statistic= 64.15/29.76; WHR: [Formula]; mean/min F-statistic= 48.41/29.75). Sensitivity analyses did not show strong evidence of heterogeneity or directional pleiotropy, and Steiger tests supported the hypothesized direction (exposure -> outcome). In MVMR including both traits, WHR remained associated with AA risk (OR 1.374, P = 0.0110), whereas BMI was not (P = 0.8000). Enrichment analyses suggested WHR-mapped genes were enriched in pathways related to adipocyte differentiation, while BMI-mapped genes were enriched in terms including nuclear envelope and endocytosis-related pathways. ConclusionsThese MR analyses are consistent with a potential causal relationship between obesity-related traits and AA risk, with WHR showing an association independent of BMI in multivariable models. Further work in diverse populations and with additional sensitivity analyses is warranted to assess robustness to pleiotropy and generalizability.

BackgroundSeveral colorectal cancer (CRC) screening modalities are guideline-recommended in the United States, yet they vary considerably in screening interval and real-world adherence. As a result, single-round test performance may not reflect cumulative effectiveness over time. This study compared the 10-year longitudinal outcomes of two CRC screening strategies-- triennial next-generation multitarget stool DNA testing (ng mt-sDNA) and decennial screening colonoscopy. MethodsThis study used the validated, microsimulation-based Colorectal Cancer and Adenoma Incidence and Mortality (CRC-AIM) model to estimate 10-year cumulative outcomes for two guideline-recommended screening strategies: triennial ng mt-sDNA and decennial colonoscopy. Model inputs included test-specific performance and real-world adherence. Outcomes included CRC and precancerous lesions detected, CRC mortality reductions, and life-years gained (LYG). Sensitivity analyses examined the effects of varying both screening adherence and follow-up colonoscopy adherence. ResultsOver 10 years per 1,000 individuals offered screening, the ng mt-sDNA screening test detected 13% more precancerous lesions and 11% more CRC cases than colonoscopy, with a greater proportion of CRCs identified through screening rather than symptomatic detection. ng mt-sDNA resulted in greater CRC mortality reduction (33% vs 20%) and 62% more life-years gained, with consistent findings across sensitivity analyses. ConclusionsWith real-world adherence, screening with triennial ng mt-sDNA demonstrates superior cumulative effectiveness compared with decennial colonoscopy, driven by higher adherence and favorable longitudinal performance. These findings support the expanded use of noninvasive stool-based screening to reduce CRC mortality and alleviate capacity constraints associated with colonoscopy-based screening. Broader adoption of ng mt-sDNA may enhance population-level CRC prevention by increasing participation and improving early detection across the screening eligible population. Plain language summaryColorectal cancer screening tests are recommended at different time intervals and completed at different adherence rates in clinical practice. The analysis used a validated simulation model to compare 10-year outcomes of triennial next-generation multi-target stool DNA test (ng mt-sDNA) with a single colonoscopy, accounting for real-world screening and follow-up colonoscopy adherence. Our findings indicate that repeated ng mt-sDNA provides greater cumulative screening effectiveness than colonoscopy over a 10-year period.

BackgroundChronic gastroduodenal symptoms are challenging to diagnose and treat. Body surface gastric mapping provides non-invasive biomarkers of gastric function, but the requirement of a standard meal for postprandial assessment can be difficult for severely symptomatic patients. AimsTo assess the impact of reduced meal sizes and fasting on body surface gastric mapping metrics to determine clinical interpretability under non-standard nutritional loads. MethodsHealthy controls (n=60) underwent a 4.5-hour Gastric Alimetry test. Three age, sex, and BMI-matched groups (n=20 each) were compared: Standard Meal (482 kCal), Nutrient bar + Water (250 kcal), and Fasted (no meal). Principal Gastric Frequency, Gastric Alimetry Rhythm Index, BMI-Adjusted Amplitude, and fed:fasted Amplitude Ratio were analyzed against normative intervals. ResultsMeal status significantly affected amplitude-based metrics; the Standard Meal group exhibited higher BMI-Adjusted Amplitude (p<0.001) and fed:fasted Amplitude Ratio (p=0.001) than Fasted and Bar + Water groups. Frequency and rhythm-based metrics were resilient; Principal Gastric Frequency (p=0.245) and Gastric Alimetry Rhythm Index (p=0.336) showed no significant differences across conditions. While amplitude deviations were common in the Fasted group (20% fell below the normative range), Gastric Alimetry Rhythm Index and Principal Gastric Frequency remained within normal reference ranges for 95% of participants across all conditions. ConclusionsWhile consuming <50% of the standard meal significantly reduces gastric amplitude, gastric rhythm remains stable. Principal Gastric Frequency and Gastric Alimetry Rhythm Index function as reliable biomarkers of gastric myoelectrical function regardless of nutritional state.

IntroductionPrevious studies have shown that Aquamin(R), a multi-mineral extract from red marine algae, enhances barrier integrity proteins in the human colon. These findings prompted further investigation into Aquamin(R)s effects on gastrointestinal barrier function and permeability. MethodsSubjects with mild or in remission ulcerative colitis (UC) and healthy controls were enrolled in an open-label trial and received Aquamin(R) capsules (800 mg calcium/day) for 90 days. Intestinal permeability was evaluated before and after the 90-day intervention by urinary mannitol excretion after ingestion of a 5 g mannitol solution, with collections across several time intervals (pre-drink, 0-2 h, 2-8 h, and 8-24 h). The primary outcome was the change in mannitol excretion. Serum samples were also collected to assess liver and renal function. ResultsIn this pilot study (NCT04855799), which included UC patients and healthy controls (n = 8 per group), baseline urine mannitol levels in the 0-2 h sample were 54% higher in UC patients compared to healthy subjects (p = 0.006). Following 90 days of Aquamin(R) supplementation, urinary mannitol levels in UC patients decreased by 28%, 26%, and 41% at the 0-2 h, 2-8 h, and 8-24 h timepoints, respectively; the reduction at the 0-2 h interval reached statistical significance (p = 0.015). Overall, Aquamin(R) supplementation reduced total post-intervention mannitol excretion by 29% (p = 0.024). Aquamin(R) was well tolerated, with no serious adverse events reported. The serum metabolic panel revealed a modest but statistically significant reduction in alkaline phosphatase levels after 90 days of intervention. ConclusionThese results provide preliminary evidence that Aquamin(R) supplementation beneficially modulates gut barrier function and supports epithelial integrity in UC patients. These findings support further investigation of Aquamin(R) as a safe and promising adjunct to current UC management strategies, with potential utility as a barrier therapy in UC. SummaryAquamin(R) supplementation for 90 days reduced intestinal permeability in ulcerative colitis patients, as measured by urinary mannitol excretion. The intervention was well tolerated, suggesting Aquamin(R) may be a safe, promising adjunct for enhancing gut barrier function in UC management.

BackgroundFood-related gastrointestinal (GI) symptoms are highly prevalent in patients with IBS. Although dietary components may trigger symptoms through luminal mechanisms, cognitive expectations may also shape symptom perception within the gut-brain axis. No validated instrument currently exists to measure food-related symptom expectations. Hence, we developed and validated the Food Expectation Questionnaire (FEX-Q). MethodsThe FEX-Q was developed using a stepwise process including focus group interviews and face-to-face validation to ensure content validity. The finalized digital questionnaire presents 44 food images with six items rated on a visual analogue scale (VAS; 0-100), including the core item assessing food-related symptom expectation ("How severe GI symptoms do you expect after eating this food?"). Additional domains assess taste preference, willingness to eat, perceived healthiness, and perceived fat and carbohydrate content. The finalized FEX-Q was administered in a nationwide online validation survey of adults with IBS and non-IBS controls in Sweden. Participants also completed validated questionnaires including GI symptom severity (combined GSRS), psychological distress (HADS), food-related quality of life (FR-QOL), and a screening tool for food avoidance (NIAS). ResultsTwenty adults with IBS and non-IBS controls participated in the face-to-face validation, resulting in a final version of the FEX-Q comprising 44 food images, which were properly identified and provided a range of macronutrient distributions and trigger foods. In the nationwide online study including 134 patients with IBS and 126 non-IBS controls, the FEX-Q demonstrated strong known-groups validity (mean symptom expectation 18.4 in controls vs 50.1 in IBS), strong construct validity (perceived vs actual fat content r=0.78, p<0.001 and carbohydrate content r=0.59, p<0.001), significant convergent validity with GI symptom severity and food-related quality of life, and high internal consistency (split-half reliability Spearman-Brown corrected r=0.88). ConclusionThe FEX-Q can capture individual food-related symptom expectations to distinct food images. This reliable measurement can be useful to reveal the mechanism of food-related symptom expectations and provide clinically relevant insights for personalized dietary management

Background and AimsAvoidance of symptom-related situations is common in chronic gastrointestinal (GI) conditions, contributing to greater symptom severity, psychological distress, and reduced quality of life. However, no validated measure exists to comprehensively assess GI-specific avoidance. We developed and validated the GI-specific Avoidance Scale (GIAS), a self-report instrument measuring behavioral and cognitive avoidance specific to GI symptoms. MethodsFollowing literature review and multidisciplinary input, an initial pool of 58 items was generated and refined through expert and patient ratings, yielding 37 items. A sample of 102 adults (mean age 40.8 years) with medically diagnosed GI conditions completed the GIAS and validated measures of avoidance, psychological flexibility, illness shame, GI symptoms, distress, and quality of life. Exploratory factor analysis was used to determine factor structure. Internal consistency, convergent validity, incremental validity, and mediation analyses were conducted. ResultsFactor analysis supported a 20-item, three-factor solution: General Avoidance, Food Avoidance, and Intimacy/Body Exposure Avoidance. Internal consistency was excellent for the total scale ( = .94) and good-to-excellent for subscales ( = .82-.94). GIAS scores correlated positively with illness shame, GI symptoms, and distress, and negatively with psychological flexibility, self-compassion, and quality of life. GIAS showed incremental validity over a general illness avoidance measure (IBAS) in predicting GI symptoms and anxiety. Moreover, mediation models suggested that GI-specific avoidance partially mediates bidirectional associations between GI symptoms and psychological distress. ConclusionsThe GIAS is a novel, psychometrically robust, and multidimensional self-report questionnaire of GI-specific avoidance. It holds potential for clinical assessment, treatment planning, and evaluation of intervention mechanisms in GI populations.

ImportanceCannabinoid Hyperemesis Syndrome (CHS) is an emerging condition among those with heavy cannabis use characterized by persistent and severe nausea and vomiting. However, very little is known about the national prevalence of CHS, outside of healthcare settings, and among those who use cannabis frequently. ObjectiveTo determine the national prevalence of CHS symptoms, diagnosis, and associated characteristics. DesignA cross-sectional, nationally representative survey of US adults. SettingThe National Firearms, Alcohol, Cannabis, and Suicide survey was conducted in 2025. Participants7,034 US adults over 18 years old provided survey data. ExposuresNot applicable. Main Outcome and MeasuresItems were included that assess symptoms of CHS, along with multiple measures of cannabis use and problem use. ResultsThe prevalence of those reporting daily cannabis use in the past 5 years was 15.2%, corresponding to an estimated over 40 million US adults. Among those who used cannabis daily, 17.8% reported CHS-like symptoms (i.e., severe nausea, vomiting, or abdominal pain), which translates to an estimated 7.2 million US adults, or a 2.7% national prevalence rate. Only 11.5% of those with a symptom prolife consistent with CHS reported receiving a CHS diagnosis from a medical provider. Respondents reporting CHS symptoms were younger, more likely to be female and non-White race, lower income, less educated, and endorsed more cannabis use problems relative to those who used cannabis daily or less frequently. Conclusions and RelevanceA small but significant number of US adults with daily cannabis use reported symptoms consistent with CHS. Beyond patterns of cannabis use, those with CHS symptoms had fewer economic resources and endorsed more cannabis-related problems, even when compared to others with daily cannabis use. Most people reporting CHS symptoms were not diagnosed by a medical provider, suggesting that there may be a substantial cohort who is experiencing CHS symptoms but is not seeking medical treatment or having their condition recognized by medical providers. As cannabis use increases, it is likely that CHS will also become more common, underscoring the importance of expanded research on this condition. KEY POINTSO_ST_ABSQuestionC_ST_ABSHow frequently do people who use cannabis daily experience symptoms of Cannabinoid Hyperemesis Syndrome (CHS)? FindingsIn this nationally representative survey, 17.8% of those with daily cannabis use reported CHS-like symptoms (severe nausea, vomiting, or abdominal pain), which translates to over 7 million US adults. Those reporting CHS symptoms were younger, more likely to be female and non-White race, lower income, less educated, and endorsed more cannabis use problems relative to those who used cannabis daily and those who used less frequently. MeaningA significant proportion of those who use cannabis daily report symptoms consistent with CHS.

PurposeHirschsprung-associated enterocolitis remains a major postoperative complication of Hirschsprungs disease (HD), and impaired epithelial barrier integrity has been proposed as a contributing factor. In this study, we investigated whether 12-hydroxyheptadecatrienoic acid (12-HHT), an endogenous leukotriene B4 receptor 2 (BLT-2) agonist, enhances the epithelial barrier and exerts anti-inflammatory effects in patient-derived colonic organoids. MethodsNormoganglionic specimens from rectal/rectosigmoid HD at pull-through (HD-N; n = 8) and transverse colon specimens from anorectal malformation (ARM) at colostomy closure (n = 10) were used to generate colonic organoids. Epithelia were isolated using ethylenediaminetetraacetic acid and subsequently embedded in Matrigel. Baseline expression of TJP1, TJP2, F11R (encoding junctional adhesion molecule-A), JAM2, CLDN1, CLDN3, CLDN4) and LTB4R2 (encoding BLT-2) was assessed by qPCR and immunoblotting. Organoids were then treated with 12-HHT (0.4, 2, or 10 M) for 7 days, followed by qPCR. Additional experiments assessed cytokine expression (IL1B, IL6) and TJPs after 24 h with tumor necrosis factor- (TNF-, 100 ng/mL) plus phosphate buffered saline or 12-HHT. Barrier function was evaluated using FITC-dextran influx assays. ResultsHD-N and ARM organoids exhibited similar growth efficiencies. Baseline expression for F11R, JAM2, CLDN1, CLDN3, CLDN4, and LTB4R2 was significantly lower in HD-N than in ARM. TJPs were upregulated by 12-HHT at 2 and 10 M in both groups, with stronger effects in ARM. In HD-N organoids, 10 M 12-HHT suppressed TNF--induced IL1B and IL6 elevation mitigated tight junction proteins (TJPs) downregulation more effectively than 2 M. 12-HHT attenuated TNF--induced FITC-dextran influx in HD-N organoids. Conclusion12-HHT may exert anti-inflammatory effects by integrating TJPs of HD-N.

BackgroundCurrent British Society of Gastroenterology (BSG) guidelines misclassify metachronous lesion risk after polypectomy in approximately 40% of patients. Building on evidence that immune exclusion drives progression of adenomas to colorectal cancer, this study examined immune profiles in screen-detected adenomas as a predictive biomarker for metachronous lesion risk. MethodsPatients undergoing polypectomy within the Scottish Bowel Screening Programme, with surveillance colonoscopy between 6 months and 6 years were included. Chromogenic immunohistochemistry (IHC; n=2642), 6-plex multiplex immunofluorescence (mIF; n=334), and spatially resolved 6000-plex single cell transcriptomics (n=7) were applied to adenoma microarrays. Cell density and location were measured using QuPath. Hierarchical then K-means clustering was used to define immune cell density-based clusters, which were compared to future lesion events using Kaplan-Meier curves and the log rank test. ResultsAfter adjustment for age, sex, site, size and dysplasia, adenoma CD3+ T cell density was significantly associated with future colorectal neoplasia (HR 1.43, 95% CI 1.19-1.71, p<0.001). Using mIF three immune cell density clusters were identified; 1) high T cell density, low macrophage density, 2) low T cell density, low macrophage density, and 3) high T cell, macrophage and SMA density, with significant differences in future lesion risk (Cluster 1: 22%, Cluster 2: 41%, Cluster 3: 36%, p=0.032). Bulk RNAseq and spatial transcriptomic analysis revealed significant variation in T cell and macrophage co-location and gene expression profiles between clusters. ConclusionAdenoma immune contexture emerges as a determinant of future metachronous lesion risk, offering a novel biomarker to refine surveillance and reduce disease burden. SummaryWhat is already known on this topic: O_LIPost-polypectomy surveillance is currently recommended to patients with high-risk pathological features to detect metachronous lesions and cancer. However current guidelines misclassify risk in a proportion of patients, leading to unnecessary surveillance for some, whilst falsely reassuring others. C_LI What this study adds: O_LIAnalysis of this large post-polypectomy surveillance cohort reveals that adaptive immune responses within removed index adenomas predicts low risk of metachronous lesions, while an immune excluded phenotype signals higher risk, independent of pathological characteristics, and patient risk factors. C_LI How this study might affect research, practice or policy: O_LIDefining immune cell spatial distributions and interactions that drive future adenoma and cancer risk will enable more precise risk stratification for surveillance, informing surveillance guidelines and shaping targeted colorectal cancer prevention strategies. C_LI

Background and AimMASLD affects 30-38% of Indian adults, yet the contribution of genetic risk variants to disease susceptibility and fibrosis progression remains poorly characterised. We investigated the association of 12 candidate SNPs with MASLD susceptibility and fibrosis severity in North Indian patients, benchmarking allele frequencies against IndiGenomes and global populations. MethodsSixty-nine MASLD patients (75.4% male; median BMI 29.8 kg/m{superscript 2}) from a tertiary care liver clinic in New Delhi were genotyped for 12 SNPs using Illumina custom BeadChip array and Sanger sequencing. Patients were stratified by liver stiffness measurement (LSM): significant fibrosis ([&ge;]8 kPa, n=38) versus no significant fibrosis (<8 kPa, n=31). Allele frequencies were compared with IndiGenomes ([~]1,020 Indian individuals) and 1000 Genomes populations. ResultsPNPLA3 rs738409 G allele was the strongest within-cohort predictor of significant fibrosis (allelic OR 2.89, 95% CI 1.35-6.19, P=0.006; dominant model OR 3.94, P=0.008), with carriers demonstrating higher LSM (median 15.6 vs. 7.5 kPa, P=0.005). SAMM50 rs3761472 (OR 2.12, P=0.065) and FTO rs9939609 (OR 2.08, P=0.089) showed non-significant trends. In the population-level comparison, APOC3 rs2854116 T allele was the only variant significantly enriched after Bonferroni correction (64.0% vs. 47.9%; OR 1.93, 95% CI 1.35-2.77, P<0.001), followed by PNPLA3 (33.3% vs. 24.1%, OR 1.57, P=0.019) and SAMM50 (31.2% vs. 22.6%, OR 1.55, P=0.028). Notably, APOC3 showed no association with fibrosis (OR 0.96, P=1.000), suggesting a role in susceptibility rather than progression. All SNPs were in Hardy-Weinberg equilibrium. ConclusionsThis study reveals a dissociation between genetic determinants of MASLD susceptibility and fibrosis progression in North Indian patients. APOC3 rs2854116 predisposes to MASLD at the population level, while PNPLA3 rs738409 drives fibrosis severity within established disease, underscoring the need for ancestry-specific genetic risk stratification. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/26347059v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@a07808org.highwire.dtl.DTLVardef@12882adorg.highwire.dtl.DTLVardef@9b33a1org.highwire.dtl.DTLVardef@15aa5e8_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundGestational exposures may contribute to the newborns lifetime risk of inflammatory bowel disease (IBD). While gestational influences are associated with IBD onset, the causality and confounding of such exposures are difficult to ascertain. The neonatal metabolome provides a metabolic snapshot of gestational influences. ObjectiveWe tested the neonatal metabolomes ability to predict future IBD, to assess whether gestational exposures are reflected in early molecular precursors of the disease. MethodsWe profiled dried blood spots from 520 newborns who later developed IBD and matched controls using high-resolution untargeted mass spectrometry metabolomics (1,350 QC-passing metabolites). Genotyping was available for 1,009 of these individuals. PERMANOVA confirmed assay sensitivity to gestational exposures, gradient boosting was used for prediction. ResultsThe neonatal metabolome significantly captured maternal smoking, birth weight, and gestational age (p < 0.001), but explained minimal variance in IBD status (R2 = 0.09%, p = 0.390) and showed no predictive power for IBD (AUC = 0.51, 95% CI 0.50-0.52, p = 0.585). Stratifying by disease subtype and age of onset did not improve performance. In contrast, genetic risk scores were modestly predictive (CD: AUC = 0.64, p < 5.11x10-14; UC: AUC = 0.63, p < 7.65x10-{superscript 1}{superscript 2}), but uncorrelated with neonatal metabolomic profiles (CD: p = 0.650; UC: p = 0.970), suggesting a later-age effect. ConclusionsUsing a large, comprehensively profiled cohort, we demonstrate that neonatal metabolomic profiles sensitively capture gestational signatures, but not the overall future IBD risk. Our findings suggest that most IBD risk accumulates later in life, beyond gestational molecular imprints.

Background: Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC. Methods: A retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens. Results: Overall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. Conclusion: Among CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.

Background and AimsCholedocholithiasis (CDL) is a common condition that can lead to serious complications, requiring effective risk stratification for timely intervention. While current guidelines use clinical predictors, imaging, and laboratory markers for risk assessment, the role of glutamate dehydrogenase (GLDH) in CDL remains poorly understood. This study aims to evaluate its potential as a clinical biomarker for identifying patients with CDL. MethodsThis single-center cohort study identified 23,103 patients who presented to the emergency department of the University Medical Center Hamburg-Eppendorf and underwent routine abdominal laboratory testing between May 2021 and December 2023. Patients were classified into CDL and other diagnoses. To assess the predictive value of age, sex and laboratory markers for CDL, we developed a random forest machine learning model, conducted a backward stepwise logistic regression and performed receiver operating characteristic (ROC) analysis. Results152 patients were diagnosed with CDL and 22,951 with other diagnoses. In the random forest machine learning model, GLDH emerged as the most significant feature for predicting CDL. ROC analysis revealed that GLDH had the highest area under the curve of 0.93 among laboratory markers. At the upper limit of normal, GLDH demonstrated the best sensitivity (92%) compared to aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin. High GLDH levels exceeding 150 U/L demonstrate the highest specificity (99%) for CDL, outperforming AST, ALT and bilirubin. ConclusionGLDH outperforms AST, ALT and bilirubin as a screening and predictive marker for CDL, supporting its inclusion in clinical guidelines for risk stratification.

Background and ObjectivesBariatric surgery is a highly effective obesity treatment, yet it may predispose individuals to alcohol-related liver injury. While altered ethanol metabolism following procedures like Roux-en-Y gastric bypass (RYGB) is well described, the long-term hepatic consequences, particularly the risk of portal hypertension in patients who develop alcohol-related hepatitis (AH,) remain poorly defined. MethodsUsing the TriNetX US Collaborative Network, we identified adult patients diagnosed with AH or alcohol-related cirrhosis. We compared outcomes between patients with a history of RYGB or sleeve gastrectomy (SG) who subsequently developed AH (Bariatric+AH group) and those with AH and no history of bariatric surgery (AH-only group). Propensity score matching was performed on over 44 demographic, clinical, and laboratory variables. Cox proportional hazards models and Kaplan-Meier survival curves were used to estimate the risk of clinically significant portal hypertension (PH) events, liver transplantation, and all-cause mortality at three-, five-, and seven-year follow-ups. ResultsAfter matching, 772 patients were included in each cohort. At 7 years post-index event, the Bariatric + AH group exhibited a significantly higher risk of PH-related complications compared to the AH-only group (HR 1.519; 95% CI, 1.15-2.005; p = 0.003). No significant differences were observed in liver transplantation (HR 1.412; 95% CI, 0.850-2.346; p = 0.181) or all-cause mortality (HR 1.085; 95% CI, 0.904-1.303; p = 0.381). These findings were consistent across all follow-up intervals. ConclusionBariatric surgery is associated with an increased long-term risk of portal hypertension in patients who develop alcohol-related hepatitis despite similar mortality and transplantation rates. These findings underscore the need for targeted postoperative counseling, liver-focused surveillance strategies, and integration of hepatologic risk assessment into metabolic surgery care pathways.

BackgroundComprehensive data on the prevalence of Helicobacter pylori infection and its associated risk factors among patients with gastrointestinal symptoms remain limited. Generating this evidence would help inform clinical management and improve antibiotic stewardship. H. pylori infection affects a substantial proportion of the global population, with prevalence varying widely across regions. In Uganda, previous studies have documented the presence of H. pylori infection. However, data specific to symptomatic patients are scarce. This study therefore aimed to determine the prevalence of H. pylori infection and associated factors among patients with gastrointestinal symptoms attending Mulago National Referral Hospital in Kampala, Uganda. MethodsA cross-sectional study was conducted among 353 patients with gastrointestinal symptoms attending Mulago Hospital. Data on socio-demographic characteristics, lifestyle and dietary habits, and medical history were collected using a semi-structured questionnaire. H. pylori infection status was determined using stool antigen tests. Proportions were used to determine the prevalence of H. pylori, and associated factors analyzed using STATA version 14 software by performing bivariate and multivariate analyses. ResultsAmong the 353 participants, majority were between 16 and 25 years old (69%), female (58%), and residing in peri-urban areas (74%). The prevalence of H. pylori infection in this population was 308 (87.3%). Multivariate analysis showed that H. pylori infection was significantly associated with having more than five income dependents (aPRR = 1.104, 95% CI: 1.025-1.189, p = 0.008), a history of previous H. pylori treatment (aPRR = 3.459, 95% CI: 2.138-5.595, p < 0.001), and a family history of H. pylori infection or gastrointestinal ulcers (aPRR = 1.135, 95% CI: 1.055-1.221, p = 0.001). ConclusionThis study demonstrated a high prevalence of Helicobacter pylori infection among patients presenting with gastrointestinal symptoms, with nearly nine out of ten individuals testing positive. The high burden observed suggests that routine screening for H. pylori, or carefully guided empirical treatment, may be clinically justified in symptomatic patients. These findings underscore the need for integrated clinical and public health strategies to improve diagnosis, treatment, and prevention of H. pylori infection in this setting.