Despite the significant gastrointestinal (GI) disease burden in rural America, prior research has highlighted persistent disparities in access to care for GI diseases for patients in non-metropolitan regions. In the study by Cwalina et al. [5], the authors analyze gastroenterologist data from the Physician Compare Database collected from 2014 to 2025, finding that while the absolute number of rural gastroenterologists increased, the proportion practicing rurally remained stable at approximately 7.7%. Late career stage and the Midwest region were associated with increased odds of rural practice, whereas female sex, hepatology subspecialization, academic affiliation, and both small and large practice sizes were associated with decreased odds. These findings reveal a workforce that has grown numerically, but has not kept sufficient pace with the access needs of rural patients, thereby highlighting two intersecting vulnerabilities: an aging rural GI workforce and a rising proportion of women in gastroenterology who face structural barriers to rural practice. This commentary contextualizes these findings, calling for proactive, patient-centered strategies to sustain rural gastroenterology care.
Endoscopic injection sclerotherapy with ligation (EISL) is a combined endoscopic treatment that involves endoscopic injection sclerotherapy (EIS) and endoscopic variceal ligation. This study aimed to compare the efficacy of conventional EIS and EISL in treating esophageal varices and the usefulness of EISL. A total of 104 cases treated with conventional EIS and 44 cases treated with EISL for esophageal varices were included in the study. The procedure duration, intra-injection volume, and para-injection volume, the success rate of intravascular injection based on variceal type, recurrence-free survival, and post-treatment adverse events were assessed. The procedure duration was significantly shorter in the EISL group (13.1 ± 7.2 min) than in the conventional EIS group (20.7 ± 8.0 min; p < 0.0001). Additionally, the para-injection volume per session was lower in the EISL group (0.7 ± 1.0 mL) than in the conventional EIS group (1.2 ± 1.1 mL; p = 0.0426). The intravascular injection success rate was higher in the EISL group for all variceal morphologies, particularly for F1/F2 esophageal varices. In terms of post-treatment adverse events, the frequency of fever was lower in the EISL group than in the conventional EIS group (p = 0.008). There was no significant difference in recurrence-free survival between the conventional EIS and EISL groups. Compared with conventional EIS, EISL required shorter procedure times and reduced paravariceal leakage of the injected sclerosant. EISL also demonstrated higher success rates, particularly for small varices, and fewer post-treatment adverse events.
In 2024, a comprehensive framework for the screening, diagnosis, and management of metabolic dysfunction-associated steatotic liver disease (MASLD) was incorporated in the EASL-EASD-EASO clinical practice guidelines. However, physicians often face barriers applying these recommendations in routine clinical care, especially in the Southeastern Europe, Middle East, and Africa (SEEMEA) region. As a multidisciplinary group of physicians involved in MASLD and metabolic dysfunction-associated steatohepatitis (MASH) management, our objective is to provide a practice-oriented roadmap including practical and educational considerations beyond the hepatology field that could improve patient care and support implementation of clinical guidance within the SEEMEA region. This work is informed by a narrative review and expert input obtained through structured discussions, to examine the status quo and identify key gaps in the MASLD/MASH management, unravelling the patient journey from screening and diagnosis to treatment and follow-up. Furthermore, we advise on priorities on screening triggers and, considering the limited availability of vibration-controlled transient elastography (VCTE), discuss alternative approaches to achieve accurate and timely diagnosis. Finally, following the approval of resmetirom and semaglutide 2.4 mg for MASH treatment, we review the evolving pharmacotherapy landscape and propose a "blueprint" for a specialised MASLD clinic, suggesting mandatory and optional facilities for optimised care.
Functional gastrointestinal disorders (FGIDs) are prevalent among teenagers, yet understanding of them is limited. This study aimed to evaluate adolescents' awareness of FGIDs, identify factors influencing this awareness, and assess adolescents' health education needs, thereby providing evidence for targeted health education strategies. A nationwide cross-sectional survey conducted from June to August 2024 assessed 1,612 adolescents aged 10-19 years. Despite the survey's broad scope, only 4.7% exhibited a systematic understanding of FGIDs, and merely 3.7% reported high familiarity, underscoring a pronounced knowledge deficit in this population. The majority of respondents (39.8%) were only familiar with it, while 25% had not heard of it. Marked disparities in awareness were identified based on growth environment, level of education, boarding status, caregiver type, personality traits, participation in social activities, and the experience of FGIDs by respondents or their contacts (P < 0.05). The results demonstrate that teenagers typically possess limited awareness of FGIDs. It is advisable to formulate tailored health education tactics based on age, educational attainment, and living conditions to enhance knowledge dissemination, deepen comprehension, and elevate adolescents' disease awareness and self-management skills.
Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder, primarily associated with mutations in the SMAD4 and BMPR1A genes[1]. It is characterized by the development of multiple juvenile polyps throughout the gastrointestinal tract, most commonly located in the rectum and sigmoid colon. Cases of JPS with ossification are exceedingly uncommon, and the underlying pathogenesis remains unclearly. Several mechanisms have been implicated in ectopic ossification, including sensory neuron activation, lymphocytic infiltration, mast cell degranulation, skeletal muscle cell necrosis, and endothelial-to-mesenchymal transition.The presence of ossification may indicate an increased risk of disease progression, underscoring the importance of regular endoscopic surveillance in affected patients.
Evidence on the relationship between phytoestrogen exposure and hyperuricemia remains limited and inconsistent. We investigated the associations of urinary phytoestrogens with serum uric acid concentrations and hyperuricemia risk in a nationally representative U.S. population and explored the potential effect modification by smoking status. This study included 8,160 participants aged 20 years and older from the 1999-2010 National Health and Nutrition Examination Survey (NHANES). Urinary concentrations of phytoestrogens were determined using high-performance liquid chromatography-tandem mass spectrometry and adjusted for urinary creatinine. Multivariable linear and logistic regression models were employed to evaluate associations with serum uric acid levels and hyperuricemia risk, while restricted cubic splines were applied to examine nonlinear dose-response relationships. Following multivariable adjustment, higher urinary concentrations of total phytoestrogens, isoflavones, lignans, and several specific compounds were linked to a lower risk of hyperuricemia. The strongest associations were exhibited for microbial metabolites, including equol [OR (95% CI) for quartile 4 vs. 1: 0.46 (0.35, 0.59)], enterolactone [0.60 (0.49, 0.74)], and O-desmethylangolensin (O-DMA) [0.64 (0.51, 0.79)]. These inverse associations were more pronounced among current smokers (p-interaction for total phytoestrogens and isoflavones = 0.019) and largely followed L-shaped dose-response patterns. This study suggested that elevated urinary phytoestrogen levels were associated with a reduced risk of hyperuricemia in U.S. adults, particularly among current smokers. If confirmed by prospective studies, phytoestrogen-rich diets may represent a promising strategy for hyperuricemia prevention.
Fatigue is a common and debilitating symptom in inflammatory bowel disease (IBD), yet it remains under-recognised in clinical practice. This study aimed to quantify fatigue among Australian patients with IBD and examine associations with disease control, psychological distress and quality of life (QoL). We conducted a cross-sectional study of adult patients with IBD at a tertiary centre. Participants completed four validated questionnaires: Functional Assessment of Chronic Illness Therapy-Fatigue, IBD-Control 8, Short Inflammatory Bowel Disease Questionnaire and Hospital Anxiety and Depression Scale. Associations between fatigue and other patient-reported outcomes were analysed, and multivariate regression identified independent predictors of fatigue. Of 1179 patients invited, 327 (28%) participated; 166 (51%) had Crohn disease, 152 (46%) ulcerative colitis and nine (3%) IBD-unclassified. Severe fatigue was reported in 46% of participants. Depression and anxiety were present in 29% and 41% of patients respectively. Fatigue was significantly associated with poorer disease control and QoL (P < 0.0001). On multivariate analysis, independent predictors of fatigue included depressive symptoms (β = -1.03, P < 0.0001), anxiety (β = -0.41, P = 0.003), reduced disease control (β = 0.70, P < 0.0001) and lower QoL (β = 0.23, P = 0.0006). Notably, in a subgroup of 55 patients (17%) with well-controlled disease, fatigue remained strongly linked with psychological distress and impaired QoL. Fatigue is highly prevalent in IBD and persists even among patients with good disease control. Psychological distress, poor disease control and reduced QoL are independently associated with fatigue, underscoring the need for routine screening and multidisciplinary management.
Lipid peroxidation triggers ferroptosis, a type of regulated cell death that is iron-dependent. Owing to its important role in tumor suppression, ferroptosis represents an extremely promising therapeutic target for cancer. QD394, a quinazolinone-based compound, was recently identified as a novel redox regulator with demonstrated cytotoxic and proapoptotic effects in pancreatic and breast cancer models. Preliminary RNA sequencing analysis suggested potential associations between QD394 treatment and ferroptosis, mitogen-activated protein kinase (MAPK) signaling, and angiogenic pathways. Cell Counting Kit-8 (CCK-8), colony formation assay, and 5-ethynyl-2'-deoxyuridine (EdU) assays, as well as annexin V/PI staining, revealed that QD394 inhibited cell proliferation and induced apoptosis. Microtubule assembly, chick chorioallantoic membrane (CAM), and scratch assays demonstrated that QD394 suppressed angiogenesis. Notably, QD394-treated colorectal cancer (CRC) cells exhibited decreased levels of glutathione (GSH), solute carrier family 7 member 11 (xCT), and glutathione peroxidase 4 (GPX4), and increased levels of malondialdehyde (MDA) and lipid reactive oxygen species (ROS), suggesting that QD394 induces ferroptosis. Mechanistically, QD394 treatment reduced specific protein 1 (SP1) levels through ubiquitin-mediated proteolysis. Notably, overexpression of SP1 counteracted QD394-induced ferroptosis. Moreover, QD394 treatment significantly increased the ratio of p-JNK to total JNK in CRC cells, whereas SP1 overexpression effectively reversed this effect. In a xenograft model, QD394 significantly inhibited tumor growth and decreased tumor weight, and the expression of Ki-67, GPX4, and SP1. In contrast, 4-hydroxynonenal (4-HNE) and p-JNK levels were markedly elevated. Collectively, our findings reveal that QD394 triggers ferroptosis in CRC through the SP1/JNK signaling axis, highlighting its potential as a novel anticancer agent.
A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) has been implicated in arthritis and lung fibroblast activation; however, its role in liver homeostasis and fibrogenesis remains largely unexplored. Here, we investigated the functional significance of ADAMTS4 in liver fibrosis. We found that hepatic ADAMTS4 mRNA expression was significantly elevated in patients with fibrotic steatohepatitis. In mouse models of liver fibrosis, genetic deletion of ADAMTS4 protected against liver fibrogenesis, accompanied by a marked reduction in the recruitment of myeloid-derived infiltrating macrophages. Mechanistically, ADAMTS4-mediated cleavage of versican generated versikine, which promoted macrophage migration and differentiation toward a pro-inflammatory phenotype in vitro. In addition, tumor necrosis factor (TNF)α significantly increased both the mRNA expression and protein secretion of ADAMTS4. Furthermore, ADAMTS4 directly induced collagen accumulation through activation of signal transducer and activator of transcription 3 (STAT3) in LX2 cells. To explore the potential genetic regulation of ADAMTS4 expression, we performed response-eQTL analysis in patients with metabolic dysfunction-associated steatotic liver disease and identified a single-nucleotide polymorphism associated with increased ADAMTS4 expression in a subset of patients carrying a specific genotype. Collectively, our findings identify ADAMTS4 as a critical regulatory factor that promotes the recruitment of myeloid-derived infiltrating macrophages and collagen accumulation during liver fibrogenesis, suggesting that targeting ADAMTS4 may represent a potential therapeutic strategy for liver fibrosis.
Metabolic syndrome substantially elevates venous thromboembolism (VTE) risk, increasing health care burdens. The Metabolic Score for Visceral Fat (METS-VF) offers a novel, simplified approach to assess visceral fat. This study evaluates METS-VF's association with VTE risk and its utility for risk stratification in patients with metabolic syndrome. Using UK Biobank data, we included 118 619 participants with metabolic syndrome free of VTE at baseline. Time-dependent area under the curve analysis with bootstrap validation identified the strongest VTE predictor. Multivariable Cox models assessed associations of METS-VF, a VTE-specific polygenic risk score, and their combination with incident VTE. Mediation analysis evaluated potential mediators. Robustness was assessed through subgroup and sensitivity analyses, including competing risk of death. Over a median 12-year follow-up, 5162 participants developed VTE. METS-VF demonstrated stronger association with VTE than traditional metabolic indicators. Highest quartile participants showed significantly increased risks of VTE (hazard ratio [HR], 1.46 [95% CI, 1.33-1.61]), pulmonary embolism (HR, 1.50 [95% CI, 1.33-1.70]), deep vein thrombosis (HR, 1.52 [95% CI, 1.34-1.73]), and lower-extremity deep vein thrombosis (HR, 1.59 [95% CI, 1.38-1.82]). Stratified analysis revealed synergistic interaction between METS-VF and genetic susceptibility. CRP (C-reactive protein) and estimated glomerular filtration rate significantly mediated the METS-VF-VTE association. METS-VF is a significant, independent risk indicator for VTE in patients with metabolic syndrome, demonstrating synergistic effects with genetic risk. The CRP- and estimated glomerular filtration rate-mediated association supports METS-VF's clinical utility in VTE risk stratification.
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Inguinal hernia repair is one of the most common surgical procedures worldwide and is frequently performed as day-case surgery. Postoperative pain may delay recovery and occasionally necessitate unplanned hospital admission. Regional anesthesia techniques, including transversus abdominis plane (TAP) and rectus sheath (RS) blocks, have shown promise in improving analgesia. However, their combined efficacy in open inguinal hernia repair has not been established in randomized trials. The PRO-RSTAP trial is a prospective, double-blind, four-arm randomized controlled trial conducted at three hospitals in Finland. The study evaluates the individual and combined effects of TAP and RS blocks in adults undergoing elective open inguinal hernia repair. Two hundred patients are randomized equally into four groups: (1) placebo TAP + placebo RS, (2) active TAP + placebo RS, (3) active RS + placebo TAP, and (4) active TAP + active RS. All patients receive standardized sedation and multimodal analgesia, including paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), and rescue opioids. The primary outcome is cumulative perioperative opioid consumption from block administration until hospital discharge, expressed as intravenous morphine equivalents. Secondary outcomes include pain scores, conversion to general anesthesia, postoperative nausea and vomiting, time to discharge, and unplanned admissions or emergency visits within 7 days. The planned sample size provides 80% power to detect a clinically meaningful reduction in opioid use (two-sided α = 0.05). Analyses follow the intention-to-treat principle. The first participant was enrolled in September 2025, and the trial is ongoing. No interim efficacy analysis is planned. Safety is monitored continuously throughout the study. This randomized controlled trial is designed to determine whether combining TAP and RS blocks improves postoperative analgesia and recovery after open inguinal hernia repair. The results will contribute to evidence-based optimization of regional anesthesia strategies in ambulatory surgery. EU Clinical Trials Information System (CTIS): 2024-513406-59-00; ClinicalTrials.gov identifier: NCT07423910.
Avoidant/restrictive food intake disorder (ARFID) is an eating disorder characterized by persistent avoidant/restrictive eating unrelated to body image. Sex differences in clinical phenotypes and neurobiology of ARFID are understudied. We hypothesized that females with ARFID would have a greater frequency of the lack of interest and fear of aversive consequences phenotypes, higher levels of anorexigenic hormones, and greater fMRI activation in brain regions associated with cognitive control during a food cue paradigm. We further hypothesized that males with ARFID would have a greater frequency of the sensory sensitivity profile, higher levels of orexigenic hormones, and greater fMRI activation in reward processing brain regions. We recruited 96 children and adolescents with ARFID and sub-threshold ARFID (49% female) from two studies on the neurobiology of ARFID and low weight eating disorders from 2016 to 2022. We analyzed ARFID clinical phenotypes; appetite-regulating hormones, ghrelin, cholecystokinin (CCK), peptide YY (PYY), and oxytocin; and fMRI activation of cognitive control and reward-related brain regions during a food cue paradigm using frequentist and Bayesian statistical analysis. Contrary to our hypothesis, there were no sex differences in frequency of ARFID clinical phenotypes, appetite-regulating hormone levels, or brain activation. This is the first study to provide empirical evidence that ARFID has a similar clinical and neurobiological presentation in males and females.
Despite its clinical significance, pharmacological treatment options for alcohol use disorder (AUD) remained limited, which highlights the need for novel therapeutic targets. The ghrelin system has emerged as an important regulator of alcohol craving and intake. Liver-expressed antimicrobial peptide 2 (LEAP2) has recently been identified as an endogenous ghrelin receptor (GHSR) antagonist that influences metabolic and reward-related pathways. As a secondary analysis of five different clinical trials, we measured LEAP2 concentrations in the collected blood samples and examined their association with alcohol craving and the effects of both acute and chronic alcohol use on LEAP2. In addition, we complemented these clinical trial analyses by conducting preclinical experiments in wild-type and GHSR-KO Wistar rats to investigate the effects of alcohol and ghrelin on LEAP2 concentrations. In humans, LEAP2 concentrations negatively correlated with both priming- and cue-induced alcohol craving. Acute alcohol administration reduced LEAP2 concentrations 90min after oral alcohol intake, a response that was attenuated by co-administration of the GHSR inverse agonist PF-5190457. An intraperitoneal alcohol administration after a pre-treatment with ghrelin reduced LEAP2 concentrations in wild-type but not GHSR-KO Wistar rats. In contrast to acute alcohol administration, LEAP2 concentrations did not differ between people with alcohol use disorder and healthy controls and were unaffected by evidence of hepatocyte injury and alcohol abstinence. These results enhance our understanding of the ghrelin system, particularly LEAP2, with regard to alcohol craving and consumption. This work may inform the development of novel interventions for alcohol use disorder.
The early-life intestinal microenvironment plays a pivotal role in shaping immune cell development. Here, we identify a colonic Wnt4-expressing stromal cell, enriched during early-life, that promotes iNKT cell proliferation via BMP-MAPK signaling. These stromal cells are spatially associated with iNKT cells and macrophages and exhibit high Bmp2 expression during the neonatal period. Depletion of BMP2 in Wnt4+ stromal cells during, but not after, this time window leads to long-lasting reductions in iNKT cells. These stromal cells are shaped by microbial signals, as germ-free and early-life antibiotic-treated mice exhibit increased Wnt4+ stromal cell abundance and elevated Bmp2 expression, with excessive iNKT cell accumulation that lasts into adulthood. These persistent changes in iNKT cells due to early-life perturbations are associated with altered susceptibility to later-life mucosal disorders. Importantly, similar stromal cells are present in fetal and neonatal human colon, and human rBMP2 promotes iNKT cell growth. Together, our findings reveal a neonatal colonic stromal niche, orchestrated by microbial cues, that regulates colonic immune homeostasis in later-life.
Achalasia is an esophageal motility disorder that may lead to severe esophageal dilation and food impaction in advanced stages. We report a 54-year-old man with known achalasia who presented with massive esophageal food impaction. Initial endoscopic management failed to achieve complete disimpaction despite prolonged attempts. A multidisciplinary approach was undertaken, performing a transgastric retrograde endoscopic access combined with pneumatic dilation of the lower esophageal sphincter. This strategy enabled complete removal of the impacted material and subsequent esophageal clearance. The patient had a favorable clinical outcome and was scheduled for definitive surgical treatment. Massive food impaction in advanced achalasia is rare and may be refractory to conventional endoscopic techniques. Combined endoscopic-surgical approaches may offer an effective alternative in selected cases.
Inflammatory bowel disease (IBD) is a stigmatized and impairing chronic disease frequently diagnosed during adolescence. Adolescents with IBD may benefit greatly from psychosocial support, with early literature indicating effectiveness of formal mentorship programs for mentee-related outcomes. However, limited research has examined the mentor experience within IBD populations. The present study qualitatively examined the perspectives of young adult mentors participating in a peer mentorship program for adolescents with IBD. Young adults with IBD participated as mentors in the virtual iPeer2Peer © mentorship program across three tertiary pediatric centers. Twelve mentors participated in the present study through two focus groups. Interviews were analyzed following reflexive thematic analysis. Three themes were developed: (1) program delivery, (2) perceived value of participating in the program, and (3) membership dynamics. Mentors discussed logistical aspects of program implementation, including training needs, challenges in working with adolescent mentees, and factors shaping the in-call experience. The personal value of mentoring others was underscored, including growth within mentors' own IBD journey, enhanced interpersonal qualities, and perceptions of making a difference. Finally, mentors highlighted the importance of a strong mentorship relationship and factors which supported growth over time. Present results underscore the benefit of peer mentorship in IBD, highlight the importance of incorporating lived experience in patient care, and provide important avenues for improvement of mentorship programs within the healthcare context. Further research is needed to continue to advance understanding of peer mentorship in IBD and its implementation within clinical care.
Atezolizumab plus bevacizumab (Atezo/Bev) is administered for unresectable hepatocellular carcinoma (HCC), with bevacizumab dosed by body weight, which may not adequately reflect body composition. This study evaluated the association between BSA-adjusted bevacizumab dosing, expressed as the bevacizumab-BSA index (BBI), and outcomes. This retrospective study included 1,507 unresectable HCC patients treated with Atezo/Bev at 30 Japanese institutions. BBI was the ratio of actual to standard dose per BSA. Restricted cubic spline analyses identified the optimal BBI range. Outcomes were compared among BBI groups. Spline analysis revealed a nonlinear association between BBI and overall survival (OS), with an optimal BBI range of 106-121%. Accordingly, the patients were classified into Under (n=924), Target (n=522), and Over (n=61) groups. The median progression-free survival (PFS) was significantly longer in the Target group than in the non-Target group (10.3 vs. 6.5 months, p<0.001), and the median OS was prolonged (24.9 vs. 19.2 months, p=0.008). Multivariable analysis demonstrated that the Target BBI group was independently associated with improved PFS (hazard ratio [HR], 0.807; 95% confidence interval [CI], 0.715-0.910; p<0.001) and OS (HR, 0.850; 95% CI, 0.733-0.985; p=0.031). The objective response rate was significantly higher in the Target group (p=0.023), while treatment-related adverse event rates were comparable across the BBI groups, with no significant differences in proteinuria, hypertension, or other toxicities. BSA-adjusted bevacizumab dosing was associated with improved efficacy without increased toxicity in patients with unresectable HCC treated with Atezo/Bev.
The advent of oral vaccines (OVs) in the mid-twentieth century led to dramatic reductions in the global burden of gut and gut-acquired infectious diseases such as polio, rotavirus, cholera, and typhoid. Paradoxically, OVs have been less effective in low- and middle-income countries (LMICs) where morbidity and mortality from these diseases are highest. This so-called tropical barrier does not reflect intrinsic defects of OV platforms but rather the influence of adverse host and environmental conditions more prevalent in LMIC settings. Among these, nutritional status stands out as a key modifiable determinant of OV performance. The collision of undernutrition and poor sanitation in LMIC contexts fosters repeated exposure to enteropathogens via contaminated food, water, and living environments; proinflammatory gut microbiota; disrupted intestinal mucosal architecture and barrier function; and profoundly altered immune development. Together, these factors hinder the replication and take of OVs. Micronutrient deficiencies-particularly in zinc, vitamin A, vitamin D, and iron-further compromise intestinal epithelial homeostasis, antigen presentation, and antibody responses to undermine OV efficacy. This review synthesizes recent advances in our understanding of how human nutrition shapes OV immunogenicity. By integrating epidemiologic evidence, field interventions, and mechanistic insights, we outline pathways linking diet, gut health, and vaccine response and strategies to close global gaps in OV performance.