Abstract: OBJECTIVES:Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic adenocarcinoma. Artificial intelligence (AI) is a mathematical concept whose implementation automates learning and recognizing data patterns. The aim of this study was to investigate whether AI via deep l

Abstract: INTRODUCTION:Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC) Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as se

Abstract: OBJECTIVES:The primary aim of this study was to investigate the value of attenuation imaging (ATI), a novel ultrasound technique for detection of steatosis, by comparing the results to that obtained with controlled attenuation parameter (CAP) and by using MRI-derived proton density fat fraction (PDF

Abstract: The Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis and Obstructive (TIGAR-O) Pancreatitis Risk/Etiology Checklist (TIGAR-O_V1) is a broad classification system that lists the major risk factors and etiologies of recurrent acute pancreatitis, chronic pancreatitis, and overlapping pancreatic disorders with or without genetic, immunologic, metabolic, nutritional, neurologic, metaplastic, or other features. New discoveries and progressive concepts since the 2001 TIGAR-O list relevant to understanding and managing complex pancreatic disorders require an update to TIGAR-O_V2 with both a short (S) and long (L) form. The revised system is designed as a hierarchical checklist for health care workers to quickly document and track specific factors that, alone or in combinations, may contribute to progressive pancreatic disease in individual patients or groups of patients and to assist in treatment selection. The rationale and key clinical considerations are summarized for each updated classification item. Familiarity with the structured format speeds up the completion process and supports thoroughness and consideration of complex or alternative diagnoses during evaluation and serves as a framework for communication. The structured approach also facilitates the new health information technologies that required high-quality data for accurate precision medicine. A use primer accompanies the TIGAR-O_V2 checklist with rationale and comments for health care workers and industries caring for patients with pancreatic diseases.

Abstract: Fecal microbiota transfer (FMT) aims at introducing a new gut microbiota to the gastrointestinal system of a patient. It is found to be a safe, highly successful treatment in recurrent Clostridium difficile infection with cure rates of 90% and higher (1,2). Also, other diseases in which the gut microbiota plays a role became of interest for treatment with FMT. Placebo-controlled clinical studies in inflammatory bowel disease have shown that FMT leads to remission in 24%–30% of patients with ulcerative colitis (3–5). Similarly, studies in metabolic syndrome have shown that healthy donor FMT can improve insulin sensitivity (6,7). Due to the increasing evidence that a disturbed gut microbiota also plays a role in the pathophysiology of irritable bowel syndrome (IBS), FMT has been suggested as a potential treatment to improve symptoms in this study population. A recent randomized placebo-controlled clinical trial has studied the effect of FMT administered by colonoscopy on symptoms in 90 patients with IBS (8). More patients in the treatment group (65%) showed a decrease in IBS-severity scoring system (IBS-SSS) score of more than 75 points compared with the placebo group (43%) after 3 months; however, this was not significant anymore after 12 months (56% vs 36%). In an additional recent randomized clinical trial, the effect of FMT administered by capsules in 52 IBS patients was investigated. Although intake of the capsules over 12 days resulted in changes to the gut microbiota of the IBS patients in the treatment group, the symptom improvement after 3 months was larger in the placebo compared with the treatment group (9). Nowadays, typical characteristics of a healthy gut microbiota are still not known. In IBS patients, butyrate-producing bacteria in fecal samples seem to be reduced compared with healthy subjects (10). Butyrate is a short-chain fatty acid produced in the large intestine by microbial fermentation of undigested dietary carbohydrates. It is the main energy source for colonocytes and has shown to have anti-inflammatory, anticarcinogenic and barrier-protecting properties (11). Butyrate enemas have shown to decrease visceral sensitivity in healthy volunteers and might decrease inflammation in inflammatory bowel disease (12,13). Previous studies demonstrated that the amount of butyrate-producing bacteria could be increased by FMT (7). Here, we describe the outcome of a controlled study investigating FMT in IBS, in which we included donors with a high abundance of butyrate-producing bacteria in their fecal samples and IBS patients with a low abundance of butyrate-producing bacteria. Apart from studying the effect of FMT on the symptoms of IBS patients, also its effect on the patients' visceral sensitivity and on the compositional changes in fecal and mucosa-adherent microbiota were assessed in order to propose mechanistic explanations for the observed responses.

Abstract: Chronic pancreatitis (CP) is an inflammatory disorder involving injury and scarring of the pancreatic exocrine gland, which can also affect endocrine components. It has a global incidence of 10 per 100,000 population (1). CP results in a variety of signs and symptoms, including abdominal pain, weight loss, bloating, steatorrhea, malabsorption, and diarrhea. CP complications include pancreatic exocrine insufficiency (PEI), postpancreatitis diabetes mellitus (DM), and pancreatic cancer. Management of CP is challenging with multiple modalities targeting symptoms and malnutrition through pain management, pancreatic enzyme replacement therapy (PERT), and, in severe cases, surgery including total pancreatectomy. Despite advancements in CP treatment, 43% of patients do not respond to conventional therapy (2). Recent evidence suggests that pancreatic exocrine dysfunction is a major determinant of intestinal microbiota (3). Changes in the gut microbial composition have been linked to a wide array of disorders spanning infectious (4), autoimmune (5), functional (6), neoplastic (7), and gastrointestinal (GI) pathologies. Multiple reports have linked CP to microbial dysbiosis, mainly small intestinal bacterial overgrowth (SIBO). SIBO has classically been linked to blind-loop–producing GI surgeries; the resulting combination of altered anatomy, altered motility, hypochlorhydria, and exposure to colonic contents creates a favorable environment for bacterial proliferation (8). SIBO is associated with inflammatory bowel disease (9,10), neurological disorders (11,12), celiac disease (13), and irritable bowel syndrome (14). SIBO symptoms include abdominal pain, bloating, diarrhea, and malabsorption, which overlap with CP and make the diagnosis and management of SIBO in CP all the more difficult. Although Capurso et al. (15) showed in 2016 that SIBO affects 36% of patients with CP, we noted a high level of heterogeneity in the reported SIBO prevalence. In addition, their review lacked an analysis of SIBO's response to treatment or of risk factors for SIBO in CP. Moreover, we found that 3 additional studies (16–18) had been published on this subject since then. Therefore, we performed a comprehensive systematic review and meta-analysis employing rigorous statistical analysis using meta-regression models to explain heterogeneity, determine factors affecting disease prevalence, and response to treatment of SIBO in CP.

Abstract: OBJECTIVES:Pancreatic ductal adenocarcinoma (PDAC) presents the lowest survival rate of all cancers because only 6% of patients reach five-year survival. Alterations in the expression of several microRNAs (miRNAs) occur in the tumor of PDAC and in preneoplastic lesions as the called intraductal papi

Abstract: Introduction:Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to

Abstract: Pancreatitis, a complex disease influenced by both genetic and environmental factors, often leads to metabolic sequelae (such as exocrine pancreatic dysfunction and new-onset diabetes). Several trillion micro-organisms inhabit the gastrointestinal tract, and this community plays an important role in the regulation of functions of not only the gut but also the pancreas. Studies to parse the underlying contributions of the gut microbiota to metabolic sequelae of pancreatitis will offer important translational insights with a view to preventing exocrine pancreatic dysfunction and new-onset diabetes after pancreatitis.

Abstract: OBJECTIVES:Celiac disease (CD) is a chronic enteropathy characterized by an autoimmune reaction in the small intestine of genetically susceptible individuals. The underlying causes of autoimmune reaction and its effect on host metabolism remain largely unknown. Herein, we apply lipidomics to elucida

Abstract: OBJECTIVES:Circulating tumor cells (CTCs) in the blood have been used as diagnostic markers in patients with colorectal cancer (CRC). In this study, we evaluated a CTC detection system based on cell size to assess CTCs and their potential as early diagnostic and prognostic biomarkers for CRC.METHODS

Abstract: Functional dyspepsia (FD) is defined by the Rome IV criteria as bothersome postprandial fullness, early satiation, epigastric pain, and/or epigastric burning experienced for the previous 3 months with symptom onset at least 6 months prior to the diagnosis in the absence of structural disease (1). Clinically, patients may also present with upper abdominal bloating. Most patients with FD report intermittent symptoms, experiencing asymptomatic periods followed by episodes of symptom relapse (2). According to the Rome IV criteria, FD is divided into 2 subgroups: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) (1). No medication is currently approved by the FDA for the treatment of FD, although proton pump inhibitors, histamine type-2 receptor antagonists, antidepressants, and prokinetics are commonly used “off-label” to treat affected patients (3,4). Unfortunately, these medications offer only a modest therapeutic gain over placebo, often require continuous dosing, and may be associated with adverse events. The high prevalence of FD, coupled with the lack of effective medications, indicates that there is a substantial unmet medical need for patients suffering from this condition. Previous studies have shown that peppermint oil and caraway oil (primarily composed of approximately equal parts D-carvone and L-limonene), either alone or in combination, may possess gastroprotective (5–8), analgesic (9), prokinetic (10,11), and anti-inflammatory (12,13) properties, all of which might benefit patients with FD. Peppermint oil and caraway oil have demonstrated synergistic peripheral analgesic activity in preclinical studies (14). Several clinical trials, which assessed a combination of peppermint oil and caraway oil in patients with FD, exhibited significant efficacy vs placebo (10,15–18). However, no studies have evaluated the efficacy of these agents in patients categorized using Rome III criteria. Furthermore, no studies have tested a multiparticulate system, such as microspheres, designed for duodenal release for FD. We sought to test a novel combination of Caraway Oil and L-Menthol, the key active ingredient of peppermint oil, with microsphere-based Site-Specific Targeting (FDgard) to the duodenum. This site was targeted primarily due to the mounting evidence that gastroduodenal mucosal integrity and low-grade inflammation play a role in FD (19). Furthermore, studies have shown that caraway oil and peppermint oil act on the duodenum to induce smooth muscle relaxation (11), and that L-menthol has anti-inflammatory effects (12). Since the combination of caraway oil and L-menthol is an oil, it has not been possible to deliver this combination reliably and quickly to the duodenum, with the historical oil in enteric-coated capsule formulations. Pharmacodynamic studies done with enteric-coated capsules containing peppermint oil and caraway oil showed that “The activity of the enteric-coated capsules is strongly influenced by the gastric emptying of these preparations. Particles larger than 1 mm in diameter pass the pylorus during the interdigestive phase III activity of the MMC” (10). The caraway oil and L-menthol using microsphere-based Site-Specific Targeting (COLM-SST) microsphere delivery system, with an average particle size of approximately 1 mm, is anticipated to have their effect during the first migrating motor complex after administration for rapid onset of action. We developed a novel method of converting this oil-based combination into a solid state by the use of microcrystalline cellulose. This solid state was then converted into microspheres with extrusion and then spheronization, and triple-coated in fluid beds. The aims of this study were to evaluate the efficacy of COLM-SST in reducing Global Overall Symptom (GOS) scores compared with placebo in patients with EPS and PDS, to assess the efficacy of COLM-SST in reducing key individual FD symptoms, and to assess the safety and tolerability of COLM-SST in patients with FD in a real-world setting where they were allowed to take concomitant medications for their FD symptoms.

Abstract: The effectiveness of fecal immunochemical test (FIT) screening for colorectal cancer depends on timely colonoscopy follow-up of positive tests, although limited data exist regarding effective system-level strategies for improving follow-up rates. Using a mixed-methods design (qualitative and quantitative), we first identified system-level strategies that were implemented for improving timely follow-up after a positive FIT test in a large community-based setting between 2006 and 2016. We then evaluated changes in time to colonoscopy among FIT-positive patients across 3 periods during the study interval, controlling for screening participant age, sex, race/ethnicity, comorbidity, FIT date, and previous screening history. Implemented strategies over the study period included setting a goal of colonoscopy follow-up within 30 days of a positive FIT, tracking FIT-positive patients, early telephone contact to directly schedule follow-up colonoscopies, assigning the responsibility for follow-up tracking and scheduling to gastroenterology departments (vs primary care), and increasing colonoscopy capacity. Among 160,051 patients who had a positive FIT between 2006 and 2016, 126,420 (79%) had a follow-up colonoscopy within 180 days, including 67% in 2006-2008, 79% in 2009-2012, and 83% in 2013-2016 (P < 0.001). Follow-up within 180 days in 2016 varied moderately across service areas, between 72% (95% CI 70-75) and 88% (95% CI 86-91), but there were no obvious differences in the pattern of strategies implemented in higher- vs lower-performing service areas. The implementation of system-level strategies coincided with substantial improvements in timely colonoscopy follow-up after a positive FIT. Intervention studies are needed to identify the most effective strategies for promoting timely follow-up.

Abstract: Although commercial enteral formulas have been available on the market for several decades, a cultural shift toward consuming unprocessed foods with minimally added sugar has sparked interest in the preparation of home blenderized tube feedings for enteral feeding-dependent patients. Recent surveys, however, indicate lack of clinical awareness or familiarity in the management of this method of nutrition support. This article aims to equip the gastroenterologist with a guide for initiation, monitoring, and evaluation of a blenderized tube feedings regimen, and provides insights into an opportunity for greater partnership between the gastrointestinal provider and registered dietitian.

Abstract: Objectives To assess the efficacy and safety of vonoprazan on heartburn symptoms in patients with nonerosive reflux disease (NERD) (ClinicalTrials.gov: NCT02954848). Methods This phase 3, double-blind, placebo-controlled study included Japanese patients aged 20 years and older with grade N/M NERD and recurrent heartburn. Patients received placebo (n = 245) or vonoprazan 10 mg (n = 238) for 4 weeks. The primary efficacy outcome was frequency of heartburn experienced by patients during the treatment period (proportion of days without heartburn). Other outcomes included cumulative improvement rates of heartburn, proportion of patients with complete heartburn resolution in the fourth week of treatment, and safety. Results Compared with placebo, the proportion of days without heartburn was not significantly higher in the vonoprazan group in the full analysis (primary end point, 72.55% vs 61.50%, vonoprazan vs placebo, P = 0.0643) but was significantly higher in the per-protocol-set sensitivity analysis (P = 0.0341). Early onset of response and significantly greater cumulative improvement rates of heartburn were observed in the vonoprazan group (P = 0.0003). In a post hoc analysis, a greater proportion of patients with complete heartburn resolution in the fourth week of treatment were reported in the vonoprazan group (P = 0.0023). Incidence of treatment-emergent adverse events was similar between treatment groups (23.5% vs 23.3%); most treatment-emergent adverse events were mild in severity. Discussion Although vonoprazan 10 mg was not superior to placebo with respect to proportion of days without heartburn in Japanese patients with NERD, vonoprazan had a significantly higher cumulative rate of heartburn resolution and was well tolerated.

Abstract: Objectives Alcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery. Methods MR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively. Results At baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-α, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-γ, and tumor necrosis factor α). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%). Discussion We showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities.

Abstract: INTRODUCTION Defecation is a complex process that can be easily disturbed. Defecatory disorders may be diagnosed using specialized investigation, including anorectal manometry (ARM) and the balloon expulsion test (BET). Recently, we developed a simulated stool named Fecobionics that integrates several tests and assesses pressures, orientation, and bending during evacuation. The aim was to evaluate the feasibility and performance of Fecobionics for assessing defecatory physiology in normal subjects. METHODS Physiological expulsion parameters were assessed in an interventional study design. The 10-cm-long Fecobionics probe contained pressure sensors at the front and rear and inside a bag and 2 motion processor units. The bag was distended in the rectum of 20 presumed normal subjects (15 female/5 male) until urge to defecate. ARM-BET was also performed. Three subjects used +2 minutes to evacuate BET, and 1 subject had a high fecal incontinence score. Therefore, the normal group consisted of 16 subjects (13 female/3 male aged 25-78 years). RESULTS All subjects reported that Fecobionics evacuation was similar to normal defecation. Fecobionics expulsion pressure signatures demonstrated 5 phases, reflecting rectal pressure, anal relaxation, and anal passage. Preload-afterload loop diagrams demonstrated clockwise contraction cycles. The expulsion duration for BET and Fecobionics was 16 ± 2 and 23 ± 5 seconds (P > 0.2), respectively. The duration of the Fecobionics and BET expulsions was associated (P < 0.001). The change in bending of Fecobionics during defecation was 40 ± 3°. DISCUSSION Fecobionics obtained reliable data under physiological conditions. Agreement was found for comparable variables between ARM-BET and Fecobionics but not for other variables. The study suggests that Fecobionics is safe and effective in evaluation of key defecatory parameters.

Abstract: OBJECTIVES:A healed intestinal mucosa is the aim of therapy in acute ulcerative colitis (UC). Disruption of mucosal wound healing may lead to severe complications including intestinal fibrosis. This study examined mucosal gene expression in the healing process of acute UC with a special focus on kno

Abstract: OBJECTIVES:Biliary tract cancer (BTC) is an aggressive malignant tumor, and biomarker-based clinical trials for this cancer are currently ongoing. Endoscopic ultrasound–guided fine needle aspiration (EUS-FNA) is a safe procedure and enables pathological diagnoses; however, it is uncertain whether a

Abstract: Author(s): Sue, Megan J; Lee, Edward W; Saab, Sammy; McWilliams, Justin P; Durazo, Francisco; El-Kabany, Mohamed; Kaldas, Fady; Busuttil, Ronald W; Kee, Stephen T | Abstract: OBJECTIVES:To investigate the safety profile and diagnostic efficacy of transjugular liver biopsy (TJLB), with a focus on patients with severe coagulopathies and with multiple biopsies. METHODS:Clinical, laboratory, and demographic information was collected on 1,321 TJLBs in 932 patients (mean age 43.5 ± 23.2 years) performed between January 2009 and May 2017 to determine the diagnostic success rate and incidence of both major and minor complications in the 3-day and 30-day period post-biopsies. These outcomes were also analyzed for severely coagulopathic patients and a subgroup of patients who underwent multiple biopsies. RESULTS:The overall success rate (diagnostic yield) of the TJLB procedure was 97.7% (1,291/1,321). Overall, the major and minor complication rates were 1.0% (13/1,321) and 9.5% (126/1,321), respectively. In patients with multiple biopsies, the overall complication rate was similar to the entire study cohort, which was 10.4% (57/550). Patients were also stratified according to the platelet counts of 0-50, 51-100, 101-200, 201-300 and g300 × 10 platelets/μL. The overall complication rates were 8.0% (10/124), 11.6% (36/310), 9.9% (54/547), 11.9% (28/235), and 14.3% (11/77), respectively, and these were not statistically significant from each other. Patients were also stratified by international normalized ratio into 0-1, 1.1-2, 2.1-3, and g3. The overall complication rates of these patients were 8.0% (19/237), 11.8% (113/954), 16.3% (7/43), and 0% (0/9), respectively, and were not statistically significant from each other. DISCUSSION:TJLB is a highly efficacious, well-tolerated and safe procedure. It can be safely performed multiple times in the same patient or in critically ill, severely coagulopathic patients with no significant increase in the rate of complication while maintaining an extremely favorable diagnostic yield.

Abstract: Author(s): Fozouni, Laila; Wang, Connie W; Lai, Jennifer C | Abstract: ObjectivesFrailty is prevalent in patients with cirrhosis and is hypothesized to result in part from sarcopenia, but the precise contribution of sarcopenia to frailty in this population is poorly understood.MethodsIncluded were patients with cirrhosis from 2011 to 2014 who had an ambulatory frailty assessment and abdominal computed tomography scan within 3 months. Logistic regression assessed the associations between frailty (=Liver Frailty Index ≥4.5), and sarcopenia (=skeletal muscle index of l39 cm/m for women and l50 cm/m for men).ResultsTwo hundred ninety-one participants were included: 33% were female. The median (interquartile range) Liver Frailty Index was 3.7 (3.3-4.2); 19% were frail. The median (interquartile range) skeletal muscle index was 49 cm/m (31-69); 36% had sarcopenia. Among the 54 frail participants, 48% had sarcopenia. In univariable logistic regression, sarcopenia was associated with a 1.86× increased odds of being frail (95% confidence interval [CI], 1.02-3.38). After adjusting for sex, etiology, hepatocellular carcinoma, MELDNa, ascites, encephalopathy, and hypertension, sarcopenia was associated with a 2.38× increased odds of being frail (95% CI, 1.17-4.85). After stratifying by sex and adjusting for MELDNa, sarcopenia among males was associated with a significantly increased odds of frailty (odds ratio 2.81, 95% CI, 1.19-6.67), whereas sarcopenia among females was not (odds ratio 1.38; 95% CI, 0.45-4.25).DiscussionIn patients with cirrhosis, sarcopenia was associated with a nearly 2-fold increased odds of being frail. Two-thirds of frail men displayed sarcopenia compared with only one-quarter of frail women. Contributors to the frail phenotype may differ by sex and support the need for sex-specific strategies to reduce frailty in this population.

Abstract: Crohn's disease (CD) is a chronic, relapsing, and progressive inflammatory disease of the gastrointestinal tract (1,2). Although the inflammatory phenotype is predominant at diagnosis among patients with CD, more than half of patients will experience progressive bowel damage over time, culminating in intestinal complications and surgery (3,4). The concept of disabling disease was first introduced in 2006 (5). Although this definition fairly varies between authors, in CD, the term “disabling disease” denotes a progressive disease with burdening health-related events (4–7). To our knowledge, there is no validated definition of “disabling disease” in any consensus or guideline of CD to date. As CD features mucosal chronic inflammation and ulceration, mucosal healing (MH) is the reconstruction and repair of mucosa in the bowel. There is no consensus on the definition of MH to date; however, MH features a regression or disappearance of endoscopic lesions in CD (8). Understanding the importance of MH has led to the introduction of the “treat to target” strategy, where MH is set as the goal for therapy, with the aim of altering the disease's natural history (9). This strategy has been widely accepted by physician experts in inflammatory bowel disease (10). Moreover, MH has been used as an important indicator of therapeutic success in the latest guideline (11) and the primary endpoint in clinical trials, such as the recently published effect of tight control management on CD study (12). In a Norwegian population-based prospective cohort study, the achievement of MH led to significantly less endoscopic inflammation and decreased future steroid treatment in the long term (13). Moreover, a study demonstrated that MH was associated with a lower need for abdominal surgery in CD patients receiving infliximab treatment (14). Other studies also noted the effect of MH on higher steroid-free remission rates and lower rates of hospitalization and surgery (15,16). Nevertheless, evidence is still limited regarding whether achieving MH can reduce disability in CD. We, therefore, aimed to evaluate the probability of disabling disease in Chinese CD patients and to investigate the association between MH and disabling disease in CD. Here, we hypothesize that MH might be negatively associated with disabling disease in CD.

Abstract: Introduction Aquaporin (AQP) channels are involved in regulating fluid homeostasis in the colon. Several AQP channels were detected in human colon epithelial cells. In a previous study, rats fed 1% (wt/wt) sodium cholate had increased AQP3, 7, and 8 levels, suggesting AQP involvement in bile acid diarrhea (BAD). Our aim was to compare AQP expressions in rectosigmoid mucosal (RSM) biopsies from patients with irritable bowel syndrome-diarrhea (IBS-D) (divided into those with normal or high fecal BA excretion) and in patients with IBS-constipation (IBS-C) compared with healthy controls. Methods In RSM biopsies from 44 patients with IBS-D (with normal ( 2,337 μmol/48 hours (BAD)) fecal BA excretion), 10 patients with IBS-C, and 17 healthy controls, we measured expressions of AQP1, 3, 7, and 8, with RT-PCR (housekeeper gene GAPDH). We analyzed RNA for expression by RT-PCR assays, with expression calculated using 2-based fold-change. Comparisons of IBS groups were corrected for false detection rate (Bonferroni correction for 12 comparisons; P Results In RSM from patients with IBS-D (but not IBS-C), mRNA expression of AQP3 was decreased, and AQP7 and 8 were increased relative to controls. Fold differences were not different in IBS-D with or without BAD. Western blots confirmed increased expression of AQP7 and 8 and decreased AQP3 proteins in biopsies from patients with IBS-D compared with controls. Conclusions Increased AQP7 and 8 and decreased AQP3 expressions in RSM suggest that further studies on AQPs' potential role in the pathophysiology of diarrhea in IBS-D are warranted.Open access This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Abstract: Introduction The role of reproductive factors in the development of chronic hepatitis B (CHB) remains unknown. We assessed the potential contributions of gender, menopausal status, and menarche age to liver fibrosis in CHB. Methods A cross-sectional prospective study included 716 women and 716 age-matched men with CHB who were not currently receiving antiviral therapy. Liver stiffness measurement using transient elastography was used to stage liver fibrosis as F0-F1 ( Results Of the 716 women, 121 (16.9%) were postmenopausal, and 80 (11.2%) had advanced liver fibrosis. Multivariate logistic regression analysis showed that the postmenopausal status compared with the premenopausal status (odds ratio [OR] = 3.65-8.83; P 14 years compared with 0.05). Longitudinal data analysis showed that postmenopausal women (n = 31) were significantly less likely to undergo regression of liver fibrosis after antiviral treatment vs premenopausal women (n = 19) (26.3% vs 74.2%, respectively; P Discussion Menopause and late menarche aggravated liver fibrosis in untreated CHB, besides menopause delayed fibrosis regression under antiviral therapy. The protective effect of female gender against fibrosis was lost for postmenopausal women. Translational impact It is important to consider menopausal status and age at menarche in establishing surveillance strategies among CHB females. Postmenopausal estrogen therapy may be considered for the prevention or treatment of liver fibrosis.

Abstract: Introduction Fecal incontinence (FI) is a common complaint and is often associated with diarrhea and urgency. Foods high in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAP) cause symptoms of diarrhea and urgency. Therefore, this study assesses the impact of a low FODMAP diet on the occurrence of FI due to loose stool. Methods This study is a retrospective chart review of patients with FI seen in the Michigan Bowel Control Program clinic between August 2012 and December 2017. Patients who had FI with loose stool without red flag signs and who were recommended a low FODMAP diet and underwent formal dietary instruction with a Michigan Medicine dietician were included. Results Sixty-five patients with FI who underwent formal dietary teaching were included in this study. Eighty-eight percent of the patients were white, and 87% were women with a mean age of 62 years (±14 years). Additionally, the chart review showed that 35% of the patients had FI daily, 21.5% had FI weekly, and 5% had FI monthly. About 64.6% of the patients (42) had reported a reduction in their FI symptoms with the low FODMAP diet. There was no demographic or clinical characteristic that predicted the response to a low FODMAP diet. Discussion In this case series, dietary manipulation with a low FODMAP diet was a useful tool to treat patients who suffer from FI due to loose stool. Further confirmatory, prospective randomized controlled trials are required to see the true efficacy of a low FODMAP diet in patients who suffer with FI.

Abstract: Objectives Acute kidney injury (AKI) is a common complication in hospitalized patients with cirrhosis which contributes to morbidity and mortality. Improved prediction of AKI in this population is needed for prevention and early intervention. We developed a model to identify hospitalized patients at risk for AKI. Methods Admission data from a prospective cohort of hospitalized patients with cirrhosis without AKI on admission (n = 397) was used for derivation. AKI development in the first week of admission was captured. Independent predictors of AKI on multivariate logistic regression were used to develop the prediction model. External validation was performed on a separate multicenter cohort (n = 308). Results In the derivation cohort, the mean age was 57 years, the Model for End-Stage Liver Disease score was 17, and 59 patients (15%) developed AKI after a median of 4 days. Admission creatinine (OR: 2.38 per 1 mg/dL increase [95% CI: 1.47-3.85]), international normalized ratio (OR: 1.92 per 1 unit increase [95% CI: 1.92-3.10]), and white blood cell count (OR: 1.09 per 1 × 10/L increase [95% CI: 1.04-1.15]) were independently associated with AKI. These variables were used to develop a prediction model (area underneath the receiver operator curve: 0.77 [95% CI: 0.70-0.83]). In the validation cohort (mean age of 53 years, Model for End-Stage Liver Disease score of 16, and AKI development of 13%), the area underneath the receiver operator curve for the model was 0.70 (95% CI: 0.61-0.78). Discussion A model consisting of admission creatinine, international normalized ratio, and white blood cell count can identify patients with cirrhosis at risk for in-hospital AKI development. On further validation, our model can be used to apply novel interventions to reduce the incidence of AKI among patients with cirrhosis who are hospitalized.

Abstract: Objectives Inflammation-associated microsatellite alterations (also known as elevated microsatellite alterations at selected tetranucleotide repeats [EMAST]) result from IL-6-induced nuclear-to-cytosolic displacement of the DNA mismatch repair (MMR) protein MSH3, allowing frameshifts of dinucleotide or longer microsatellites within DNA. MSH3 also engages homologous recombination to repair double-strand breaks (DSBs), making MSH3 deficiency contributory to both EMAST and DSBs. EMAST is observed in cancers, but given its genesis by cytokines, it may be present in non-neoplastic inflammatory conditions. We examined ulcerative colitis (UC), a preneoplastic condition from prolonged inflammatory duration. Methods We assessed 70 UC colons without neoplasia, 5 UC specimens with dysplasia, 14 UC-derived colorectal cancers (CRCs), and 19 early-stage sporadic CRCs for microsatellite instability (MSI) via multiplexed polymerase chain reaction capable of simultaneous detection of MSI-H, MSI-L, and EMAST. We evaluated UC specimens for MSH3 expression via immunohistochemistry. Results UC, UC with dysplasia, and UC-derived CRCs demonstrated dinucleotide or longer microsatellite frameshifts, with UC showing coincident reduction of nuclear MSH3 expression. No UC specimen, with or without neoplasia, demonstrated mononucleotide frameshifts. EMAST frequency was higher in UC-derived CRCs than UC (71.4% vs 31.4%, P = 0.0045) and higher than early-stage sporadic CRCs (66.7% vs 26.3%, P = 0.0426). EMAST frequency was higher with UC duration >8 years compared with ≤8 years (40% vs 16%, P = 0.0459). Discussion Inflammation-associated microsatellite alterations/EMAST are prevalent in UC and signify genomic mutations in the absence of neoplasia. Duration of disease and advancement to neoplasia increases frequency of EMAST. MSH3 dysfunction is a potential contributory pathway toward neoplasia in UC that could be targeted by therapeutic intervention.

Abstract: Introduction Cold snare polypectomy (CSP) is a safe and effective method for removing polyps ≤10 mm. The aim of this study was to compare the risk of clinically significant bleeding and thromboembolic events after CSP between stopping and continuing thienopyridines in patients taking dual antiplatelet therapy (DAPT). Methods The study was a single-center, noninferiority, and randomized controlled study involving patients who received colonoscopy from October 2015 to October 2016. Patients receiving DAPT with polyps ≤10 mm were randomly assigned to either the DAPT group (patients continued DAPT) or the aspirin group (patients discontinued thienopyridines for 1 week). Primary outcome was clinically significant bleeding. Secondary outcomes included intraprocedural bleeding, nonsignificant hematochezia, and occurrence of thromboembolic events. Results Forty-two patients with 104 eligible polyps were allocated to the DAPT group, and 45 patients with 101 eligible polyps were allocated to the aspirin group. Patient demographic characteristics including size, location, shape, and pathology of the removed polyps were similar in the 2 groups. Intraprocedural bleeding and nonsignificant hematochezia rates were also similar between the 2 groups (4.8% vs 2.2%, P = 0.608; 19.0% vs 8.9%, P = 0.170). No thromboembolic event occurred in either group. Only 1 patient (2.4%) in the DAPT group showed clinically significant bleeding. No significant bleeding was found in the aspirin group. Discussion Clinically significant bleeding rate after CSP for polyps ≤10 mm in patients continuing to take DAPT was 2.4%. Therefore, CSP is a safe method for removing small polyps even in patients taking DAPT (ClincialTrials.gov number, NCT02865824).

Abstract: Colorectal cancer is the second and third most common cancer among men and women worldwide, respectively (age-standardized incidence rates per 100,000: 20.6 in men and 14.3 in women) (1), with approximately 1,360,000 new cases and 690,000 deaths per year (2). Colorectal cancer is also ranked among the top 20 causes of death globally, and this rank is expected to rise in the coming decades (3). Known environmental risk factors for colorectal cancer include consumption of red meat and processed meat, smoking, alcohol consumption, low physical activity, obesity, and type 2 diabetes (review by Kuipers et al. (1)). Genetic factors have also been found to play an important role in the development of colorectal cancer (4). Different susceptibility genes for colorectal cancer have been identified, including Kirsten rat sarcoma viral oncogene homolog, B-Raf murine sarcoma viral oncogene homolog, p53, and in microsatellite-containing genes vulnerable to mismatch repair defects (5). It is also commonly believed that many common but low penetrance genetic variants collectively explain a substantial proportion of colorectal cancer burden in general populations (6). Telomeres are repeated TTAGGG sequences at the ends of chromosomes and are coated by shelterin proteins, involved in the process of telomere length homeostasis to maintain chromosomal integrity and stability (7). Telomerase is the enzyme that lengthens telomeres and therefore is the primary positive regulator of telomere length. In human telomerase, the telomerase RNA component serves as a template for the catalytic component, and telomerase reverse transcriptase adds telomeric repeats (8). Both telomeres and telomerase play important roles in genomic stability because they protect chromosome ends from degradation, fusion, and abnormal recombination (9,10). Although the human telomeres are approximately 10–15 kb long, they shorten by approximately 30–200 bp after each cycle of cell division (11). In addition to age being a strong predictor of telomere length, different genetic and environmental factors (i.e., smoking, diabetes, obesity, or physical activity) are also predictors of telomere length (12,13). In normal circumstances, the incomplete replication of linear DNA molecules at the end of each chromosome results in telomere shortening, leading to cell senescence or apoptosis (9). On the other hand, if the cells bypass senescence due to dysfunctional checkpoint pathways, the telomeres will continue to shorten, driving chromosome fusions and genomic instability. Survivors of this telomere crisis then maintain telomeres, a cancer hallmark, by upregulating telomerase in most cases (14). Thus, these surviving cells with longer telomeres have a replicative advantage (15) and consequently undergo more cell divisions before telomere crisis, resulting in the increase of likelihood for acquiring mutations that drive malignant transformation (16). Previous epidemiologic studies (16–21) produced inconsistent results on the associations between leukocyte telomere length and risk of colorectal cancer. Some studies found that shorter, while others reported longer, leukocyte telomeres were significantly associated with higher risks of colorectal cancer (16,17,20,21). In addition, other studies (18,19) reported a null association. This inconsistency prompted us to investigate the association between telomere length and colorectal cancer risk in the Singapore Chinese Health Study, a prospective study of more than 60,000 middle-aged or older Chinese men and women in Singapore.