OBJECTIVES: Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with constipation-predominant irritable bowel syndrome (IBS-C). METHODS: In this phase 3, double-blind study (ClinicalTrials.gov identifier NCT02621892), patients with IBS-C were randomized to tenapanor 50 mg b.i.d. or placebo b.i.d. for 12 weeks followed by a 4-week randomized withdrawal period. The primary efficacy variable was the proportion of patients who reported a reduction in average weekly worst abdominal pain of ≥30.0% and an increase of ≥1 complete spontaneous bowel movement from baseline, both in the same week, for ≥6 weeks of the 12-week treatment period. RESULTS: Of the 629 randomized patients with IBS-C, 606 (96.3%) were included in the intention-to-treat analysis set (tenapanor: n = 307; placebo: n = 299) and 533 (84.7%) completed the 12-week treatment period. In the intention-to-treat analysis set (mean age 45 years, 81.4% women), a significantly greater proportion of patients treated with tenapanor met the primary endpoint than patients treated with placebo (27.0% vs 18.7%, P = 0.020). Abdominal symptoms and global symptoms of IBS also improved with tenapanor (P < 0.05 vs placebo). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in 6.5% and 0.7% of patients receiving tenapanor and placebo, respectively, during the 12-week treatment period. DISCUSSION: Tenapanor 50 mg b.i.d. improved IBS-C symptoms and was generally well tolerated, offering a potential new treatment option for patients with IBS-C. Correspondence: William D. Chey, MD, AGAF, FACG, RFF. E-mail: wchey@umich.edu. Received June 21, 2019 Accepted December 05, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

Immune checkpoint inhibitors have revolutionized treatment and overall survival for several different types of cancer. Antibodies to cytotoxic T-lymphocyte-associated protein 4 and to programmed cell death protein 1 and its ligand enhance cytotoxic T-cell survival, thus augmenting antitumor action and consequently inducing immune-related adverse events, of which the most relevant is diarrhea and colitis. This review compiles recent data on pathophysiology, clinical manifestations, and treatment of immune-mediated colitis (IMC). The pathogenesis of IMC is not completely understood, but recent studies have focused on the role of regulatory T cells and interactions with the gut microbiome. While sharing similarities with inflammatory bowel disease, IMC is considered a distinct form of colitis with acute onset and rapid progression leading to potential complications including bowel perforation and death. Prompt recognition and management of IMC is imperative for optimal outcomes. Although prospective clinical trials are lacking to guide therapy, recent guidelines recommend early endoscopic evaluation to establish the diagnosis and prompt initiation of corticosteroids. Response to first-line therapy should be assessed early to determine the need of escalation to biologic agents. With treatment, most patients will experience full resolution of symptoms, and subsequent rechallenge with anti–programmed cell death protein 1 or anti–programmed death-ligand 1 inhibitors can be considered. Correspondence: Emanuelle Bellaguarda, MD. E-mail: emanuelle.bellaguarda@northwestern.edu. Received July 24, 2019 Accepted November 15, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

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Esophageal adenocarcinoma (EA) incidence is 4–8 times higher in men compared with women, yet this imbalance cannot be explained by known risk factors. This issue of The American Journal of Gastroenterology features results from only the second prospective study to assess whether prediagnostic sex steroid hormones underlie sex differences in EA. Xie et al. report that higher concentrations of testosterone and luteinizing hormone were associated with decreased EA risk. While contrary to the long-standing hypothesis that testosterone increases EA risk, these important results lay a foundation for additional studies to further elucidate this intuitive, intriguing, and evolving hypothesis. Correspondence: Michael B. Cook, PhD. E-mail: cookmich@mail.nih.gov Received November 14, 2019 Accepted December 05, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

Small intestinal bacterial overgrowth is defined as the presence of excessive numbers of bacteria in the small bowel, causing gastrointestinal symptoms. This guideline statement evaluates criteria for diagnosis, defines the optimal methods for diagnostic testing, and summarizes treatment options for small intestinal bacterial overgrowth. This guideline provides an evidence-based evaluation of the literature through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process. In instances where the available evidence was not appropriate for a formal GRADE recommendation, key concepts were developed using expert consensus. Correspondence: Mark Pimentel, MD, FRCP(C), FACG. E-mail: pimentelm@cshs.org. Received February 13, 2019 Accepted November 12, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

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OBJECTIVES: Successful biliary cannulation is a prerequisite and important component of endoscopic retrograde cholangiopancreatography, but conventional cannulation methods (CCMs) have a postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) rate of 14.1% in patients at high risk for PEP. The aim of this study was to evaluate the effectiveness and safety of needle-knife fistulotomy (NKF), compared with a CCM, when used for primary biliary access in patients at high risk for developing PEP. METHODS: A total of 207 patients with one or more risk factors for PEP were prospectively enrolled. The patients were randomly allocated to one of 2 groups according to the primary biliary cannulation technique (NKF or CCM). We compared biliary cannulation success rates, cannulation and procedure times, and the incidence of adverse events, including PEP, between the groups. RESULTS: The mean number of PEP risk factors was similar between the groups (NKF, 2.2 ± 1.0; CCM, 2.2 ± 0.9). PEP occurred in 8 patients in the CCM group and in no patients in the NKF group (9.2% vs 0%, P < 0.001). The rates of other adverse events did not differ between the groups. The biliary cannulation success rate was high in the NKF group, but relatively low in the CCM group, possibly because of the stringent failure criteria aimed at reducing PEP. However, the mean cannulation and total procedural times were longer in the NKF group than in the CCM group. DISCUSSION: NKF is an effective and safe procedure to gain primary biliary access in patients at high risk for developing PEP. ClinicalTrials.gov, NCT02916199. Correspondence: Seok Jeong, MD. E-mail: inos@inha.ac.kr. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B333, http://links.lww.com/AJG/B342, http://links.lww.com/AJG/B343 Received April 29, 2019 Accepted October 22, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

OBJECTIVES: Mast cells (MCs) are increased in eosinophilic esophagitis (EoE). Endoscopic abnormalities, symptoms, and epithelial changes can persist after treatment despite a reduction of esophageal eosinophilia. It is unknown whether this could be due to persistent MC infiltration. We aimed to determine whether patients with histologically inactive (HI) EoE (defined as <15 eosinophils per high-powered field) with persistent symptoms, endoscopic, or epithelial abnormalities after treatment have increased MCs. METHODS: Secondary analysis of prospective data from 93 children with EoE undergoing post-treatment endoscopy between 2011 and 2015. Thirty-five non-EoE controls were included. Immunohistochemistry for tryptase, an MC marker, was performed on mid and distal esophageal biopsies. Total and degranulated intraepithelial MCs per high-powered field (MC/hpf) were quantified. Symptoms and endoscopic findings were recorded at time of endoscopy. MC/hpf were compared between HI-EoE and control, and among HI-EoE based on endoscopic and histologic findings, and symptoms. Nine clinical remission (CR) patients were identified, with absence of endoscopic abnormalities and symptoms. RESULTS: MC/hpf were increased in HI-EoE compared with control (17 ± 11 vs 8 ± 6, P < 0.0). Patients with persistent endoscopic abnormalities had increased total (20 ± 12 vs 13 ± 10, P = 0.001) and degranulated (8 ± 6 vs 5 ± 4, P = 0.002) MC/hpf, with no difference in eosinophils. MC/hpf predicted furrowing (odds ratio = 1.06, P = 0.01) and rings (odds ratio = 1.05, P = 0.03) after controlling for treatment type, proton-pump inhibitor, eosinophils, and duration of therapy. Patients with persistent basal zone hyperplasia and dilated intercellular spaces had increased MC/hpf. Eosinophils were weakly correlated with MC/hpf in the mid (r = 0.30, P < 0.001) and distal (r = 0.29, P < 0.001) esophagus. Clinical remission patients had lower MC/hpf compared with patients with persistent symptoms and/or endoscopic abnormalities. DISCUSSION: MC density is increased in patients with endoscopic and epithelial abnormalities, as well as a few symptoms, despite resolution of esophageal eosinophilia after treatment. This association warrants further study to ascertain whether MCs play an eosinophil independent role in EoE. Correspondence: Joshua B. Wechsler, MD. E-mail: JWechsler@luriechildrens.org. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B325, http://links.lww.com/AJG/B344 Received April 29, 2019 Accepted November 08, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

INTRODUCTION: Abdominal pain is a cardinal feature of irritable bowel syndrome (IBS); however, differences in abdominal pain among IBS subtypes remain unknown. We aimed to characterize abdominal pain symptoms among established IBS subtypes using data from the National Gastrointestinal (GI) Survey. METHODS: Individuals participating in the National GI Survey completed National Institutes of Health GI Patient-Reported Outcomes Measurement Information System (GI-PROMIS) questionnaires. Adults meeting modified Rome III IBS criteria and reporting abdominal pain in the previous 7 days were eligible. Outcomes included abdominal pain severity, bothersomeness, interference with daily activities, frequency, and location. Results were stratified by subtype (diarrhea [IBS-D], constipation [IBS-C], and mixed [IBS-M]). Regression models adjusted for demographics and comorbidities. RESULTS: One thousand one hundred fifty-eight individuals (245 IBS-D, 232 IBS-C, and 681 IBS-M) with active IBS symptoms (defined as abdominal pain in the past 7 days) were included. Demographics were similar among the subtypes except for age, race/ethnicity, education, and marital status. The GI-PROMIS score was lower for IBS-D (percentile score of 68.6, SD = 25.1; P = 0.001) and IBS-M (69.1, SD = 25.1; P < 0.001) compared with IBS-C (75.5, SD = 20.7). Abdominal pain was more bothersome (P = 0.001), caused more interference with daily activities (P = 0.03), and was more frequent (P = 0.047) for individuals with IBS-C compared with individuals with IBS-D. No differences in these domains were seen between individuals with IBS-D and IBS-M. Individuals with IBS-C and IBS-M had more widespread pain compared with those with IBS-D. DISCUSSION: In this population-based study, we found that abdominal pain characteristics differ between the IBS subtypes. Namely, individuals with IBS-C experience more bothersome, frequent, and diffuse abdominal pain compared with those with IBS-D. Correspondence: William D. Chey, MD, AGAF, FACG, FACP, RFF. E-mail: wchey@umich.edu. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B353 Received August 09, 2019 Accepted October 22, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

INTRODUCTION: We conducted a systematic review and meta-analysis to compare the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with irritable bowel syndrome (IBS) and controls. METHODS: Electronic databases were searched up to December 2018 for studies reporting SIBO prevalence in patients with IBS. Prevalence rates, odds ratios (ORs), and 95% confidence intervals (CIs) of SIBO in patients with IBS and controls were calculated. RESULTS: We included 25 studies with 3,192 patients with IBS and 3,320 controls. SIBO prevalence in patients with IBS was significantly increased compared with controls (OR = 3.7, 95% CI 2.3–6.0). In studies using only healthy controls, the OR for SIBO in patients with IBS was 4.9 (95% CI 2.8–8.6). With breath testing, SIBO prevalence in patients with IBS was 35.5% (95% CI 33.6–37.4) vs 29.7% (95% CI 27.6–31.8) in controls. Culture-based studies yielded a SIBO prevalence of 13.9% (95% CI 11.5–16.4) in patients with IBS and 5.0% (95% CI 3.9–6.2) in controls with a cutoff value of 105 colony-forming units per milliliter vs 33.5% (95% CI 30.1–36.9) in patients with IBS and 8.2% (95% CI 6.8–9.6) in controls with a cutoff value of 103 colony-forming unit per milliliter, respectively. SIBO prevalence diagnosed by lactulose breath test is much greater in both patients with IBS (3.6-fold) and controls (7.6-fold) compared with glucose breath test. Similar difference is seen when lactulose breath test is compared with culture methods. OR for SIBO in patients with IBS-diarrhea compared with IBS-constipation was 1.86 (95% CI 1.83–2.8). Methane-positive breath tests were significantly more prevalent in IBS-constipation compared with IBS-diarrhea (OR = 2.3, 95% CI 1.2–4.2). In patients with IBS, proton pump inhibitor was not associated with SIBO (OR = 0.8, 95% CI 0.5–1.5, P = 0.55). DISCUSSION: This systematic review and meta-analysis suggests a link between IBS and SIBO. However, the overall quality of the evidence is low. This is mainly due to substantial “clinical heterogeneity” due to lack of uniform selection criteria for cases and controls and limited sensitivity and specificity of the available diagnostic tests. Correspondence: Gerald J. Holtmann, MD, PhD, MBA, FRACP, FRCP, FAHMS. E-mail: g.holtmann@uq.edu.au. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B355 * For AGIRA (Australian Gastrointestinal Research Alliance). Received March 29, 2019 Accepted November 15, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

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Article Title: ACG Clinical Guideline: Disorders of the Hepatic and Mesenteric Circulation

Article Title: Chronic Pancreatitis: Managing a Difficult Disease

Disorders of the mesenteric, portal, and hepatic veins and mesenteric and hepatic arteries have important clinical consequences and may lead to acute liver failure, chronic liver disease, noncirrhotic portal hypertension, cirrhosis, and hepatocellular carcinoma. Although literature in the field of vascular liver disorders is scant, these disorders are common in clinical practice, and general practitioners, gastroenterologists, and hepatologists may benefit from expert guidance and recommendations for management of these conditions. These guidelines represent the official practice recommendations of the American College of Gastroenterology. Key concept statements based on author expert opinion and review of literature and specific recommendations based on PICO/GRADE analysis have been developed to aid in the management of vascular liver disorders. These recommendations and guidelines should be tailored to individual patients and circumstances in routine clinical practice.

Chronic unexplained gastrointestinal symptoms impact more than 1 in 5 Americans and their families; these disorders include the irritable bowel syndrome (IBS) and functional dyspepsia (FD), currently classified by Rome IV as functional gastrointestinal disorders. By definition, IBS and FD have no established pathology, but emerging evidence suggests this paradigm may need revision. Immune activation and, in subsets, subtle intestinal pathology have been identified in FD (most notably, postprandial distress syndrome) and IBS-diarrhea. A disease model is proposed that accounts for all of the intestinal and extraintestinal symptoms, relationship to food and infection, and the overlap with gastroesophageal reflux disease. It is speculated that antigen presentation to the mucosa (e.g., microbial antigens or food proteins after acute gastroenteritis) induces, in a genetically primed host, immune activation of the intestine with low-grade intestinal inflammation and subsequently neuronal structural and functional alterations, producing regional intestinal hypersensitivity and motor dysfunction. Immune activation may explain the female predominance and fluctuations in immune activity for symptom variability over time. In the future, as further evidence accumulates, the management paradigm may potentially shift to objective pathology-based subtyping based on serological, microbiological, and clinical assessments to identify when targeted therapies should be deployed in subsets. Potential targeted interventions may include therapies to dampen down immune activation or block release of key mediators such as histamine, specific microbial targeted treatments that may reverse disease, and dietary advice to eliminate relevant food antigens after objective in vivo testing. Only by identifying causation can we eventually anticipate cure, and as the true pathology unravels in subsets, this may become a reality.

OBJECTIVE: Fecal immunochemical tests (FITs) detect the majority of colorectal cancers (CRCs), but evidence for variation in sensitivity according to the CRC stage is sparse and has not yet been systematically synthesized. Thus, our objective was to systematically review and summarize evidence on the stage-specific sensitivity of FITs. METHODS: We screened PubMed, Web of Science, Embase, and the Cochrane Library from inception to June 14, 2019, for English-language articles reporting on the stage-specific sensitivity of FIT for CRC detection using colonoscopy as a reference standard. Studies reporting stage-specific sensitivities and the specificity of FIT for CRC detection were included. Summary estimates of sensitivity according to the CRC stage and study setting (screening cohorts, symptomatic/diagnostic cohorts, and case-control studies) were derived from bivariate meta-analysis. RESULTS: Forty-four studies (92,447 participants including 3,034 CRC cases) were included. Pooled stage-specific sensitivities were overall very similar but suffered from high levels of imprecision because of small case numbers when calculated separately for screening cohorts, symptomatic/diagnostic cohorts, and case-control studies. Pooled sensitivities (95% confidence intervals) for all studies combined were 73% (65%–79%) for stage-I-CRCs and 80% (74%–84%), 82% (77%–87%), and 79% (70%–86%) for the detection of CRC stages II, III, and IV, respectively. Even substantially larger variation was seen in sensitivity by T-stage, with summary estimates ranging from 40% (21%–64%) for T1 to 83% (68%–91%) for T3-CRC. DISCUSSION: Although FITs detect 4 of 5 CRCs at stages II–IV, the substantially lower sensitivity for stage-I-CRC and, in particular, T1 CRC indicates both need and potential for further improvement in performance for the early detection of CRC.

OBJECTIVES: Esophageal cancer is a highly fatal malignant neoplasm, with 2 etiologically different histological types. A large prospective study is expected to elucidate the specific risk of the 90% subtype of esophageal cancer, esophageal squamous cell carcinoma (ESCC), with metformin therapy. This study aims to determine the association between metformin use and incident ESCC risk. METHODS: This was a nationwide population-based prospective cohort study conducted in Sweden in 2005–2015. Among 8.4 million participants identified in the cohort, 411,603 (5%) were metformin users. The users were compared with 10 times as many frequency-matched nonusers of metformin (n = 4,116,030) by age and sex. Metformin use was treated as a time-varying variate, and multivariable cause-specific proportional hazards model was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for ESCC, adjusted for age, sex, calendar year, residence area, tobacco smoking, alcohol overconsumption, and use of nonsteroidal anti-inflammatory drugs or statins. RESULTS: The incidence rates of ESCC were 3.5 per 100,000 person-years among the metformin users and 5.3 per 100,000 person-years in the nonusers. Metformin users overall were at a decreased risk of ESCC compared with nonusers (HR 0.68, 95% CI 0.54–0.85). The decrease in risk was more pronounced in new metformin users (HR 0.44, 95% CI 0.28–0.64) and participants aged 60–69 years (HR 0.45, 95% CI 0.31–0.66). DISCUSSION: Metformin use decreases the risk of developing ESCC.

Most colorectal polyps are diminutive, and malignant potential for these polyps is uncommon, especially for those in the rectosigmoid. However, many diminutive polyps are still being resected to determine whether these are adenomas or serrated/hyperplastic polyps. Resecting all the diminutive polyps is not cost-effective. Therefore, gastroenterologists have proposed optical diagnosis using image-enhanced endoscopy for polyp characterization. These technologies have achieved favorable outcomes, but are not widely available. Artificial intelligence has been used in clinical medicine to classify lesions. Here, artificial intelligence technology for the characterization of colorectal polyps is discussed in a decision-making context regarding diminutive colorectal polyps.

Chronic pancreatitis is characterized by progressive, irreversible morphologic and functional changes that are most commonly attributed to environmental insults, particularly when there is a genetic or anatomic predisposition. Heavy alcohol use and cigarette smoking are the most common environmental risk factors, but both may be absent. Antecedent episodes of acute pancreatitis occur in about half of patients. Abdominal pain is the most common symptom and requires a tailored approach depending on the anatomic changes in the pancreas. Other clinical manifestations include diabetes mellitus, exocrine pancreatic insufficiency, metabolic bone disease, pancreatic cancer, and anatomic complications. Current disease management is centered on risk factor reduction and screening for and treating disease complications. There are no current therapies to delay or retard disease progression, but there are ongoing efforts to more fully understand the natural history of chronic pancreatitis and underlying mechanisms of disease. These studies are expected to provide insights that will transform our approach to disease management and provide increased hope to patients.

OBJECTIVES: Alcoholic liver disease (ALD) prevalence, particularly the subset with advanced liver disease, is not well defined. Herein, we aim to provide a comprehensive assessment of ALD epidemiology across the spectrum of disease severity and across different settings using 3 unique US databases. METHODS: We performed a retrospective, observational study of US adults with ALD using 2001–2016 National Health and Nutrition Examination Survey (NHANES), 2007–2014 Nationwide Inpatient Sample (NIS), and 2007–2017 United Network for Organ Sharing (UNOS) registry. ALD in the NHANES was defined using clinical laboratory data and self-reported alcohol use, among which fibrosis-4 score of >2.67 defined stage ≥3 fibrosis. Alcoholic cirrhosis (AC) in the NIS was identified using International Classification of Diseases, Ninth Revision codes. ALD in the UNOS was identified using UNOS coding. RESULTS: From 2001–2002 to 2015–2016, the overall weighted ALD prevalence was stable from 8.8% to 8.1% (P = 0.102), whereas the proportion of ALD with stage ≥3 fibrosis increased from 2.2% (95% CI: 0.4–4.0) to 6.6% (95% CI: 2.0–9.9; P = 0.007) (NHANES). From 2007 to 2014, the number of hospitalizations among patients with AC per 1,000 increased by 32.8%, and the proportion of hospitalizations among the patients with AC with ≥3 cirrhosis complications increased from 11.6% in 2007 to 25.8% in 2014 (Ptrend < 0.0001) (NIS). From 2007 to 2017, the total number of adults with ALD listed for liver transplant increased by 63.4% and the proportion with concurrent hepatocellular carcinoma increased by 178% (UNOS). DISCUSSION: Among these 3 US databases, consistent observations of increasing ALD severity emphasize the urgent need for greater awareness about the consequences of unhealthy alcohol use and interventions aimed specifically at addressing alcohol use disorders.

OBJECTIVE: To identify baseline clinical and demographic characteristics associated with clinically important treatment responses in a randomized trial of nonsurgical therapies for fecal incontinence (FI). METHODS: Women (N = 296) with FI were randomized to loperamide or placebo- and manometry-assisted biofeedback exercises or educational pamphlet in a 2 × 2 factorial design. Treatment response was defined in 3 ways from baseline to 24 weeks: minimal clinically important difference (MID) of −5 points in St. Mark's score, ≥50% reduction in FI episodes, and combined St. Mark's MID and ≥50% reduction FI episodes. Multivariable logistic regression models included baseline characteristics and treatment groups with and without controlling for drug and exercise adherence. RESULTS: Treatment response defined by St. Mark's MID was associated with higher symptom severity (adjusted odds ratio [aOR] 1.20, 95% confidence interval [CI] 1.11–1.28) and being overweight vs normal/underweight (aOR 2.15, 95% CI 1.07–4.34); these predictors remained controlling for adherence. Fifty percent reduction in FI episodes was associated with the combined loperamide/biofeedback group compared with placebo/pamphlet (aOR 4.04, 95% CI 1.36–11.98), St. Mark's score in the placebo/pamphlet group (aOR 1.29, 95% CI 1.01–1.65), FI subtype of urge vs urge plus passive FI (aOR 2.39, 95% CI 1.09–5.25), and passive vs urge plus passive FI (aOR 3.26, 95% CI 1.48–7.17). Controlling for adherence, associations remained, except St. Mark's score. DISCUSSION: Higher severity of FI symptoms, being overweight, drug adherence, FI subtype, and combined biofeedback and medication treatment were associated with clinically important treatment responses. This information may assist in counseling patients, regarding efficacy and expectations of nonsurgical treatments of FI.

OBJECTIVES: Constipation is prevalent in individuals after stroke. However, the pathophysiological mechanisms of poststroke constipation remain unclear. This study was designed (i) to investigate the difference in anorectal motility and rectal sensation among stroke patients with constipation, stroke patients without constipation, and healthy controls (HC), (ii) to evaluate the impact of stroke sites on constipation and rectal sensation, (iii) to explore the role of autonomic functions, and (iv) to determine the independent risk factors for poststroke constipation. METHODS: Seventy-one stroke patients and 24 HC were recruited. General information, clinical characteristics, and relevant questionnaires were collected. Meanwhile, an anorectal manometry test was performed to assess functions of anorectal motility and rectal sensation, and an electrocardiogram was recorded to evaluate autonomic functions. RESULTS: (i) Constipation patients exhibited increased rectal sensation thresholds, compared with patients without constipation or HC (P < 0.001). Almost no difference was detected in anorectal motility parameters among 3 groups. Constipation-associated clinical characteristics, such as spontaneous bowel movements, were weakly or moderately correlated with rectal sensation thresholds (P < 0.05 to P < 0.001 for various parameters). (ii) Patients with brainstem lesions had increased prevalence of constipation and first sensation threshold, compared with patients without brainstem lesions (P = 0.045, P = 0.025, respectively). (iii) There was a weak positive correlation between sympathetic activity and stroke severity and a weak negative one between vagal activity and stroke severity. Rectal sensation thresholds were positively and weakly correlated with sympathetic activity but negatively with vagal activity. (iv) The desire of defecation threshold and the physical activity were independent risk factors for poststroke constipation (P = 0.043, P = 0.025, respectively). DISCUSSION: Poststroke constipation is characterized by elevated thresholds for rectal sensation, rather than altered anorectal motility. Patients with brainstem lesions are predisposed to constipation possibly because of the disruption of afferent pathway from the rectum to the brain. Moreover, the desire of defecation threshold and the physical activity level are factors independently associated with poststroke constipation.

OBJECTIVES: In contrast with other developed nations, life expectancy is decreasing in the United States, in part due to increasing mortality from alcohol-associated liver disease (ALD). Up-to-date estimates of ALD mortality are necessary for setting public health priorities to reverse this concerning trend. We therefore aimed to assess current (2017) estimates of ALD mortality and temporal trends from 1999 to 2017. METHODS: Using national data from the Centers for Disease Control and Prevention, we analyzed stratified ALD mortality rates between 1999 and 2017. We determined the age-adjusted death rates, stratified by sex and categorized by age, race/ethnicity, urbanization, and census region. We also identified statistically significant changes in the annual rate difference (ARD), annual percentage change (APC), and average APC in ALD mortality. RESULTS: In 2017, mortality from ALD was higher than any other year since 1999 with age-adjusted rates of 13.1 per 100,000 (95% confidence interval [CI] 12.9–13.3) in men and 5.6 per 100,000 (95% CI 5.4–5.7) in women. Mortality was highest among men and women who were middle aged, Native American, and from rural areas. Since 2006, ALD mortality has increased in almost every age group and race with the exception of non-Hispanic black men. Absolute increases in mortality rates have been particularly pronounced in Native American women (2005–2017 ARD 0.8, 95% CI 0.6–0.9), non-Hispanic/white men (2006–2017 ARD 0.4, 95% CI 0.3–0.4), and non-Hispanic/white women (2013–2017 ARD 0.4, 95% CI 0.3–0.5). DISCUSSION: Mortality from ALD is increasing over time in most demographic groups. Increased effort is needed to develop targeted public health strategies to address high and increasing ALD mortality.

OBJECTIVES: Alcohol-associated liver disease is increasing, especially hospitalizations with acute on chronic liver failure and need for liver transplant. We examined trends in prevalence, inhospital mortality, and resource utilization associated with AALD and ACLF in the young. METHODS: The National Inpatient Sample (2006–2014) was queried for hospitalizations with a discharge diagnosis of cirrhosis using the International Classification of Diseases, Ninth Edition, codes. ACLF hospitalization was defined as ≥2 organ failures and stratified by age: young (≤35 years) and older (>35 years). RESULTS: Of 447,090 AALD admissions (16,126 in young) between 2006 and 2014, ACLF occurred in 29,599 (6.6%), of which 1,143 (7.1%) were in young. Compared with older, admissions in young had more women (35% vs 29%), were obese (11% vs 7.6%), were Hispanics (29% vs 18%), have alcoholic hepatitis (AH) (41% vs 17%), and have ACLF grades 2 or 3 (34% vs 25%), P < 0.001 for all. Between 2006 and 2014, ACLF in AALD among young increased from 2.8% to 5.2%, with an AH proportion from 24% to 42%, P < 0.0001 for both. Young had more complications requiring ventilation (79% vs 76%) and dialysis (32% vs 28%), P < 0.001 for both. Compared with older, ACLF admission in young had longer hospitalization (12 vs 10 days) with higher hospital charges ($127,915 vs $97,511), P < 0.0001 for both, with 20% reduced inhospital mortality (54%–45%), P < 0.001. DISCUSSION: AALD-related hospitalizations are increasing in young in the United States, mainly because of the increasing frequency of AH. Furthermore, this disease burden in young is increasing with a higher frequency of admissions with more severe ACLF and consumption of hospital resources. Studies are needed to develop preventive strategies to reduce burden related to AALD and ACLF in young.

OBJECTIVES: The prevalence of inflammatory bowel disease (IBD) is increasing. The total direct costs of IBD have not been assessed on a population-wide level in the era of biologic therapy. DESIGN: We identified all persons with IBD in Manitoba between 2005 and 2015, with each matched to 10 controls on age, sex, and area of residence. We enumerated all hospitalizations, outpatient visits and prescription medications including biologics, and their associated direct costs. Total and per capita annual IBD-attributable costs and health care utilization (HCU) were determined by taking the difference between the costs/HCU accrued by an IBD case and their controls. Generalized linear modeling was used to evaluate trends in direct costs and Poisson regression for trends in HCU. RESULTS: The number of people with IBD in Manitoba increased from 6,323 to 7,603 between 2005 and 2015. The total per capita annual costs attributable to IBD rose from $3,354 in 2005 to $7,801 in 2015, primarily driven by an increase in per capita annual anti-tumor necrosis factor costs, which rose from $181 in 2005 to $5,270 in 2015. There was a significant decline in inpatient costs for CD ($99 ± 25/yr. P < 0.0001), but not for ulcerative colitis ($8 increase ±$18/yr, P = 0.63). DISCUSSION: The direct health care costs attributable to IBD have more than doubled over the 10 years between 2005 and 2015, driven mostly by increasing expenditures on biological medications. IBD-attributable hospitalization costs have declined modestly over time for persons with CD, although no change was seen for patients with ulcerative colitis.

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OBJECTIVES: Reliable in situ diagnosis of diminutive (≤5 mm) colorectal polyps could allow for “resect and discard” and “diagnose and leave” strategies, resulting in $1 billion cost savings per year in the United States alone. Current methodologies have failed to consistently meet the Preservation and Incorporation of Valuable endoscopic Innovations (PIVIs) initiative thresholds. Convolutional neural networks (CNNs) have the potential to predict polyp pathology and achieve PIVI thresholds in real time. METHODS: We developed a CNN-based optical pathology (OP) model using Tensorflow and pretrained on ImageNet, capable of operating at 77 frames per second. A total of 6,223 images of unique colorectal polyps of known pathology, location, size, and light source (white light or narrow band imaging [NBI]) underwent 5-fold cross-training (80%) and validation (20%). Separate fresh validation was performed on 634 polyp images. Surveillance intervals were calculated, comparing OP with true pathology. RESULTS: In the original validation set, the negative predictive value for adenomas was 97% among diminutive rectum/rectosigmoid polyps. Results were independent of use of NBI or white light. Surveillance interval concordance comparing OP and true pathology was 93%. In the fresh validation set, the negative predictive value was 97% among diminutive polyps in the rectum and rectosigmoid and surveillance concordance was 94%. DISCUSSION: This study demonstrates the feasibility of in situ diagnosis of colorectal polyps using CNN. Our model exceeds PIVI thresholds for both “resect and discard” and “diagnose and leave” strategies independent of NBI use. Point-of-care adenoma detection rate and surveillance recommendations are potential added benefits.

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OBJECTIVES: The risk of noncardia gastric cancer is increased in the presence of gastric intestinal metaplasia. We aimed to identify demographic and lifestyle factors independently associated with the risk of gastric intestinal metaplasia. METHODS: We used data from a cross-sectional study of patients attending primary care and endoscopy clinics at the Michael E. DeBakey VA Medical Center in Houston, Texas, between February 2008 and August 2013. All patients completed standardized questionnaires and underwent endoscopy with gastric mapping biopsies. Gastric intestinal metaplasia cases included patients with intestinal metaplasia on any noncardia gastric biopsy; we defined extensive gastric intestinal metaplasia as antrum and corpus involvement. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariate logistic regression models. RESULTS: We identified 423 cases with gastric intestinal metaplasia and 1,796 controls without gastric intestinal metaplasia. Older age (vs <60 years: 60–69 years AdjOR, 1.50; 95% CI, 1.17–1.93; ≥70 years AdjOR, 2.12; 95% CI, 1.48–3.04), male sex (AdjOR, 2.76; 95% CI, 1.50–5.10), nonwhite race/ethnicity (vs non-Hispanic white: Hispanic, AdjOR, 2.66; 95% CI, 1.89–3.76; black, AdjOR, 2.36; 95% CI, 1.85–3.02), and current smoking status (AdjOR, 1.78; 95% CI, 1.29–2.48) were independently associated with gastric intestinal metaplasia. These risk factors remained statistically significantly associated with gastric intestinal metaplasia after adjusting for Helicobacter pylori infection, and their effect sizes were larger for associations with extensive gastric intestinal metaplasia compared with focal gastric intestinal metaplasia. DISCUSSION: Older age, male sex, nonwhite race/ethnicity, and current smoking status were the nonendoscopic factors independently associated with gastric intestinal metaplasia in a predominantly nonimmigrant US population. Correspondence: Mimi C. Tan, MD, MPH. E-mail: mc2@bcm.edu. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B350 Received July 26, 2019 Accepted November 15, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

Because of the rising incidence and lethality of esophageal adenocarcinoma, Barrett's esophagus (BE) is an increasingly important premalignant target for cancer prevention. BE-associated neoplasia can be safely and effectively treated with endoscopic eradication therapy (EET), incorporating tissue resection and ablation. Because EET has proliferated, managing patients after complete eradication of intestinal metaplasia has taken on increasing importance. Recurrence after complete eradication of intestinal metaplasia occurs in 8%–10% of the patients yearly, and the incidence may remain constant over time. Most recurrences occur at the gastroesophageal junction, whereas those in the tubular esophagus are endoscopically visible and distally located. A simplified biopsy protocol limited to the distal aspect of the BE segment, in addition to gastroesophageal junction sampling, may enhance efficiency and cost without significantly reducing recurrence detection. Similarly, research suggests that current surveillance intervals may be excessively frequent, failing to reflect the cancer risk reduction of EET. If validated, longer surveillance intervals could reduce the burden of resource-intensive endoscopic surveillance. Several important questions in post-EET management remain unanswered, including surveillance duration, the significance of gastric cardia intestinal metaplasia, and the role of advanced imaging and nonendoscopic sampling techniques in detecting recurrence. These merit further research to enhance quality of care and promote a more evidence-based approach. Correspondence: Prasad G. Iyer, MD, MSc. E-mail: iyer.prasad@mayo.edu. Received September 11, 2019 Accepted December 05, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

Assessment of endoscopist competence is an increasingly important component of colonoscopy quality assurance. In this study from the Joint Advisory Group on Gastrointestinal Endoscopy, validity evidence is provided for the use of the Direct Observation of Procedural Skills assessment tool in the formative setting during training. In this national UK dataset, overall colonoscopy competence was typically achieved after 200–249 procedures, although certain complex procedural skills (“proactive problem solving” and “loop management”) had not reached the threshold for competence even after 300 procedures. These data will help inform the development and/or refinement of certification policies and practices in jurisdictions around the world. Correspondence: Catharine M. Walsh, MD, MEd, PhD, FAAP, FRCPC. E-mail: catharine.walsh@sickkids.ca. Received October 11, 2019 Accepted November 18, 2019 © The American College of Gastroenterology 2019. All Rights Reserved.

INTRODUCTION: Long-term use of proton pump inhibitors (PPIs) has been associated with a wide variety of potentially serious adverse effects including a possible increased risk of dementia. Studies evaluating this association have reached divergent conclusions. We aimed to evaluate this proposed association further and to assess the quality of the evidence in its support. METHODS: We searched MEDLINE, EMBASE, ISI Web of Science, and Cochrane databases for studies examining a link between PPI use and dementia, up to February 2019. Studies reporting summary results as hazard ratio (HR) or odds ratio (OR) were pooled using the DerSimonian and Laird random-effects model for meta-analyses. Methodological quality of individual observational studies was assessed using the Newcastle-Ottawa scale and the overall quality of evidence rated as per the GRADE approach. RESULTS: We identified and included 11 observational studies comprising 642,949 subjects; 64% were women. Most studies were short-term ranging from 5 to 10 years. There were 158,954 PPI users and 483,995 nonusers. For studies summarizing data as adjusted HR, pooled HR for all causes of dementia was 1.10 (0.88–1.37); for Alzheimer dementia only, it was 1.06 (0.72–1.55). For studies summarizing data as adjusted OR, pooled OR for all causes of dementia was 1.03 (0.84–1.25) and for Alzheimer dementia only 0.96 (0.82–1.11). Per Newcastle-Ottawa scale assessment, 10 studies were of high quality and 1 was of moderate quality. By applying GRADE methodology, quality of evidence for both outcomes was very low. DISCUSSION: We found no evidence to support the proposed association between PPI use and an increased risk of dementia. PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk. Correspondence: Colin W. Howden, MD, FACG. E-mail: chowden@uthsc.edu. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B352 Received July 31, 2019 Accepted November 13, 2019 © The American College of Gastroenterology 2019. All Rights Reserved.

OBJECTIVES: It was suggested that normalization of serum alanine aminotransferase (ALT) levels at 1 year of antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B (CHB). However, it remains unclear whether earlier ALT normalization is associated with lower hepatocellular carcinoma (HCC) risk, independent of fatty liver or cirrhosis and on-treatment virological response (VR), in patients with CHB. METHODS: We analyzed 4,639 patients with CHB who initiated treatment with entecavir or tenofovir using landmark analysis and time-dependent Cox analysis. We defined normal ALT as ≤35 U/L (men) and ≤25 U/L (women) and VR as serum hepatitis B virus DNA <15 IU/mL. RESULTS: During a median 5.6 years of treatment, 509 (11.0%) patients developed HCC. ALT normalization occurred in 65.6% at 1 year and 81.9% at 2 years and was associated with a significantly lower HCC risk in landmark (P < 0.001) and time-dependent Cox analyses (adjusted hazard ratio [AHR] 0.57; P < 0.001). Compared with ALT normalization within 6 months, delayed ALT normalization at 6–12, 12–24, and >24 months was associated with incrementally increasing HCC risk (AHR 1.40, 1.74, and 2.45, respectively; P < 0.001), regardless of fatty liver or cirrhosis at baseline and VR during treatment. By contrast, neither earlier VR (AHR 0.93; P = 0.53) nor earlier hepatitis B e antigen seroclearance (AHR 0.91; P = 0.31) was associated with a significantly lower HCC risk. DISCUSSION: In patients with CHB treated with entecavir or tenofovir, earlier ALT normalization was independently associated with proportionally lower HCC risk, regardless of fatty liver or cirrhosis at baseline and on-treatment VR. Correspondence: Young-Suk Lim, MD, PhD. E-mail: limys@amc.seoul.kr. SUPPLEMENTARY MATERIAL accompanies this paper at https://links.lww.com/AJG/B339 Received July 09, 2019 Accepted November 08, 2019 © The American College of Gastroenterology 2019. All Rights Reserved.

OBJECTIVES: To assess the efficacy and safety of GED-0301, an antisense oligodeoxynucleotide to Smad7, in active Crohn's disease (CD). METHODS: This phase 3, blinded study randomized patients (1:1:1:1) to placebo or 1 of 3 once-daily oral GED-0301 regimens: 160 mg for 12 weeks followed by 40 mg continuously or alternating placebo with 40 or 160 mg every 4 weeks through week 52. RESULTS: In all, 701 patients were randomized and received study medication before premature study termination; 78.6% (551/701) completed week 12, and 5.8% (41/701) completed week 52. The primary endpoint, clinical remission achievement (CD Activity Index score <150) at week 12, was attained in 22.8% of patients on GED-0301 vs 25% on placebo (P = 0.6210). At study termination, proportions of patients achieving clinical remission at week 52 were similar among individual GED-0301 groups and placebo. More placebo vs GED-0301 patients achieved endoscopic response (>50% decrease from baseline Simple Score for CD) at week 12 (18.1% vs 10.1%). Additional endoscopic endpoints were similar between groups at weeks 12 and 52. More placebo vs GED-0301 patients had clinical response (≥100-point decrease in the CD Activity Index score) at week 12 (44.4% vs 33.3%); at week 52, clinical response rates were similar. Adverse events were predominantly gastrointestinal and related to active CD, consistent with lack of clinical and endoscopic response to treatment. Two deaths occurred (GED-0301 total group) due to small intestinal obstruction and pneumonia; neither was suspected by the investigator to be treatment-related. DISCUSSION: GED-0301 did not demonstrate efficacy vs placebo in active CD. Correspondence: Bruce E. Sands, MD. E-mail: bruce.sands@mssm.edu. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B341 Received July 10, 2019 Accepted November 08, 2019 © The American College of Gastroenterology 2019. All Rights Reserved.

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OBJECTIVES: As the prevalence of nonalcoholic steatohepatitis (NASH) in the elderly population increases, healthcare resource utilization (HCRU) and costs are also predicted to rise substantially. METHODS: This retrospective, observational cohort study used the Medicare 20% sample data set to evaluate the impact of NASH severity on HCRU and costs over 8 years (2007–2015). The sample included 255,681 patients with nonalcoholic fatty liver disease (NAFLD)/NASH: 185,407 (72.5%) with NAFLD/NASH and no further progression to advanced liver disease, 3,454 (1.3%) with compensated cirrhosis (CC), 65,926 (25.8%) with decompensated cirrhosis (DCC), 473 (0.2%) with liver transplant (LT), and 421 (0.2%) with hepatocellular carcinoma (HCC). RESULTS: Rates of comorbid diabetes, hypertension, hyperlipidemia, and cardiovascular disease were significantly higher in patients with CC or more severe liver disease compared with NAFLD/NASH and no progression. The annual mean number of all-cause healthcare visits increased from 32.1 for NAFLD/NASH with no progression to 37.3 for CC, 59.8 for DCC, 74.1 for LT, and 59.3 for HCC (P < 0.05). Total annual costs for inpatient, outpatient, physician, and pharmacy services rose from $19,908 in NAFLD/NASH with no progression to $129,276 for LT (P < 0.05). Generalized linear model adjusted for patient characteristics and comorbidities revealed that costs were 1.19, 3.15, 5.02, and 3.33 times significantly higher in patients diagnosed with CC, DCC, LT, or HCC, respectively, compared with NAFLD/NASH and no progression. DISCUSSION: These results confirm the substantial impact of NASH, particularly more severe disease, on HCRU and costs and identify patients who may benefit from interventions to prevent progression and subsequently reduce HCRU and costs. Correspondence: Robert Wong, MD. E-mail: rowong@alamedahealthsystem.org. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B335, http://links.lww.com/AJG/B337, and http://links.lww.com/AJG/B336 Received July 25, 2019 Accepted November 06, 2019 © The American College of Gastroenterology 2019. All Rights Reserved.

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In recent years, the therapeutic goals in ulcerative colitis (UC) have become increasingly stringent. Histological features seem to be a reliable predictor of disease outcomes after therapy, and histological remission (HR) is the new frontier in the treatment of UC. Here, we first provide a historical perspective before reviewing indexes in the era of biologics; histology as a treatment goal in UC trials; the poor correlation between symptoms, endoscopy, and histology; and the impact of histology on disease outcomes. HR seems to be a promising end point for the treatment of UC because it is typically associated with better outcomes. Two new validated indexes are available to assess histology more accurately in trials, and they may also be applicable to clinical practice. Additional interventional trials are now necessary to establish definitions of HR and its potential for disease modification. Correspondence: Laurent Peyrin-Biroulet, MD, PhD. E-mail: peyrinbiroulet@gmail.com. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B310, http://links.lww.com/AJG/B309, http://links.lww.com/AJG/B311, http://links.lww.com/AJG/B312, http://links.lww.com/AJG/B313 Received July 01, 2019 Accepted September 18, 2019 © The American College of Gastroenterology 2019. All Rights Reserved.

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Article Title: Colonic Manifestations and Complications Are Relatively Under-reported in Systemic Sclerosis: A Systematic Review

Article Title: Early Paracentesis in High-Risk Hospitalized Patients: Time for a New Quality Indicator