Search

Background: Patients treated with antithrombotic drugs are at risk of bleeding. Bleeding may be the first manifestation of underlying cancer. Methods: We examined new cancers diagnosed in relation to gastrointestinal or genitourinary bleeding among patients enrolled in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and determined the hazard of new cancer diagnosis after bleeding at these sites. Results: Of 27 395 patients enrolled (mean age, 68 years; women, 21%), 2678 (9.8%) experienced any (major or minor) bleeding, 713 (2.6%) experienced major bleeding, and 1084 (4.0%) were diagnosed with cancer during a mean follow-up of 23 months. Among 2678 who experienced bleeding, 257 (9.9%) were subsequently diagnosed with cancer. Gastrointestinal bleeding was associated with a 20-fold higher hazard of new gastrointestinal cancer diagnosis (7.4% versus 0.5%; hazard ratio [HR], 20.6 [95% CI, 15.2–27.8]) and 1.7-fold higher hazard of new nongastrointestinal cancer diagnosis (3.8% versus 3.1%; HR, 1.70 [95% CI, 1.20–2.40]). Genitourinary bleeding was associated with a 32-fold higher hazard of new genitourinary cancer diagnosis (15.8% versus 0.8%; HR, 32.5 [95% CI, 24.7–42.9]), and urinary bleeding was associated with a 98-fold higher hazard of new urinary cancer diagnosis (14.2% versus 0.2%; HR, 98.5; 95% CI, 68.0–142.7). Nongastrointestinal, nongenitourinary bleeding was associated with a 3-fold higher hazard of nongastrointestinal, nongenitourinary cancers (4.4% versus 1.9%; HR, 3.02 [95% CI, 2.32–3.91]). Conclusions: In patients with atherosclerosis treated with antithrombotic drugs, any gastrointestinal or genitourinary bleeding was associated with higher rates of new cancer diagnosis. Any gastrointestinal or genitourinary bleeding should prompt investigation for cancers at these sites. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01776424.

Summary Background Although novel therapies for irritable bowel syndrome (IBS) continue to be developed, many doctors rely on more established, traditional therapies as first-line or second-line treatment options. These therapies include soluble fibre (eg, ispaghula husk), antispasmodic drugs, peppermint oil, and gut–brain neuromodulators (including tricyclic antidepressants, selective serotonin reuptake inhibitors, or α-2-δ calcium channel subunit ligands). However, the relative efficacy of traditional treatments in patients with IBS is unclear because there have been few head-to-head randomised controlled trials (RCTs). We aimed to compare and rank the efficacy of traditional therapies in patients with IBS to help inform clinical decisions. Methods For this systematic review and network meta-analysis, we searched MEDLINE, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials from inception to week 2 of August 2019; ClinicalTrials.gov for unpublished trials or supplementary data published up to Aug 18, 2019; and gastroenterology conference proceedings for study abstracts published between 2001 and Aug 18, 2019. We included RCTs that compared any of these treatments with each other (head-to-head trials) or with placebo, in which the efficacy of soluble fibre, antispasmodic drugs, peppermint oil, or gut–brain neuromodulators was assessed in adults (aged at least 18 years) with IBS of any subtype after 4–12 weeks of treatment. Only RCTs reporting a dichotomous assessment of overall response to therapy, in terms of either improvement in global IBS symptoms or improvement in abdominal pain, were included. The efficacy and safety of all treatments were reported as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested, and treatments were ranked according to their P-score. Findings Our search identified 5863 references, of which 81 were screened for eligibility. 51 RCTs with data from 4644 patients were eligible for inclusion in our analysis, but only 13 of these trials were at low risk of bias. Based on an endpoint of failure to achieve improvement in global IBS symptoms at 4–12 weeks, peppermint oil capsules were ranked first for efficacy (RR 0·63, 95% CI 0·48–0·83, P-score 0·84) and tricyclic antidepressants were ranked second (0·66, 0·53–0·83, P-score 0·77). For failure to achieve an improvement in global IBS symptoms at 4–12 weeks, there were no significant differences between active treatments after direct or indirect comparisons. For failure to achieve improvement in abdominal pain at 4–12 weeks, tricyclic antidepressants were ranked first for efficacy (0·53, 0·34–0·83, P-score 0·87); however, this result was based on data from only four RCTs involving 92 patients. For failure to achieve an improvement in abdominal pain, none of the active treatments showed superior efficacy upon indirect comparison. Tricyclic antidepressants were more likely than placebo to lead to adverse events (1·59, 1·26–2·06, P-score 0·16). Interpretation In this network meta-analysis of RCTs of soluble fibre, antispasmodic drugs, peppermint oil, and gut–brain neuromodulators for IBS, few of which were judged as being at a low risk of bias, peppermint oil was ranked first for efficacy when global symptoms were used as the outcome measure, and tricyclic antidepressants were ranked first for efficacy when abdominal pain was used as the outcome measure. However, because of the lack of methodological rigour of some RCTs analysed in our study, there is likely to be considerable uncertainty around these findings. In addition, because treatment duration in most included trials was 4–12 weeks, the long-term relative efficacy of these treatments is unknown. Funding None.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of PPIs versus histamine‐2 receptor antagonists (H2RA) or placebo for the prevention of UGIB in adults receiving antithrombotic therapy for cardiovascular prevention, or prevention and treatment of thromboembolic disease.

Excessive intestinal permeability or intestinal barrier dysfunction as measured by various assays has been observed in various diseases. However, little is known about the factors contributing to altered gut permeability in these diseases. Our objective was to determine the genetic determinants of altered gut permeability as measured by the lactulose mannitol fractional excretion ratio (LacMan ratio) in 1075 healthy first-degree relatives of patients with Crohn’s disease (CD). In a targeted analysis of single nucleotide polymorphisms (SNPs) located in genes associated with intestinal barrier function related or not to inflammatory bowel disease, we did not find a significant association with intestinal permeability. In an untargeted genome-wide association analysis, the top 100 associations were located in 22 genomic loci, although they were not statistically significant after correction for multiple testing (raw P values [1.8 × 10–7 - 1.4 × 10–5]. The lowest P value was obtained for rs9616637 (22q13.33, C22orf34), for which the minor allele A was associated with a decreased LacMan ratio. These results suggest that host genetic background has limited contribution toward intestinal permeability. Despite this, our study is currently the largest of its kind assessing gut permeability in vivo. It remains possible that smaller genetic effect sizes on LacMan ratio are not detectable in this sized cohort. Larger studies are warranted to identify the potential genetic contribution to intestinal permeability.

We read the article by Cheung et al 1 with interest. The research question whether there is a dose-related association between proton pump inhibitors (PPIs) and gastric cancer in a country where this malignancy is highly prevalent is an important one. They report that long-term PPI therapy is associated with an increased risk of gastric cancer in patients who have received Helicobacter pylori eradication therapy. The data suggest that patients taking PPI less than once per day had a lower risk of gastric cancer than did those taking PPIs at least daily, which would support there may be a dose-related response. There are many concerns that were not adequately addressed in the paper. The paper claims that all the subjects became H. pylori negative as they had all been prescribed eradication therapy and none had received subsequent therapy. However, no data on proof of cure were provided. There …

IntroductionDiarrhoea is a frequent concern in the intensive care unit (ICU) and is associated with prolonged mechanical ventilation, increased length of ICU stay, skin breakdown and renal dysfunction. However, its prevalence, aetiology and prognosis in the critically ill have been poorly studied. The primary objectives of this study are to determine the incidence, risk factors and consequences of diarrhoea in critically ill adults. The secondary objectives are to estimate the incidence ofClostridium difficile-associated diarrhoea (CDAD) in ICU patients and to validate the Bristol Stool Chart and Bliss Stool Classification System characterising bowel movements in the ICU. Our primary outcome is the incidence of diarrhoea . Our secondary outcomes include: CDAD, ICU and hospital mortality and ICU and hospital length of stay.Methods and analysisThis international prospective cohort study will enrol patients over 10 weeks in 12 ICUs in Canada, the USA, Poland and Saudi Arabia. We will include all patients 18 years of age and older who are admitted to the ICU for at least 24 hours and follow them daily until ICU discharge. Our primary outcome is the incidence of diarrhoea based on the WHO definition, during the ICU stay. Our secondary outcomes include: CDAD, ICU and hospital mortality and ICU and hospital length of stay. We will use logistic regression to identify factors associated with diarrhoea (as defined using WHO criteria) and the kappa statistic to measure agreement on diarrhoea rates between the WHO definition and the Bristol Stool Chart and Bliss Stool Classification System.Ethics and disseminationThe protocol has been approved by the research ethics board of all participating centres. The diarrhoea interventions, consequences and epidemiology in the intensive care unit (DICE-ICU) study will generate evidence about diarrhoea and its frequency, predisposing factors and consequences, to inform critical care practice and future research.Lay summaryDiarrhoea is a frequent clinical problem for hospitalised patients including those who are critically ill in the ICU. Diarrhoea can cause complications such as skin damage, dehydration and kidney problems. It is not clear how common diarrhoea is in the ICU, the factors that cause it or the best way for clinicians to assess it. The DICE-ICU study is an international prospective observational study to examine the frequency, risk factors and outcomes of diarrhoea during critical illness.

Introduction Over half of patients with irritable bowel syndrome have either diarrhoea (IBS-D) or a mixed stool pattern (IBS-M). The relative efficacy of licensed pharmacological therapies in IBS-D and IBS-M is unclear in the absence of head-to-head trials. We conducted a network meta-analysis to resolve this uncertainty. Methods We searched MEDLINE, EMBASE, EMBASE Classic, the Cochrane central register of controlled trials, and clinicaltrials.gov through November 2018 to identify randomised controlled trials (RCTs) assessing the efficacy of licensed pharmacological therapies in adults with IBS-D or IBS-M. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all pharmacological therapies were reported as a pooled relative risk of remaining symptomatic with 95% confidence intervals (CIs) to summarise the effect of each comparison tested. Treatments were ranked according to their P-score. Results We identified 18 eligible RCTs (7 alosetron, 5 ramosetron, 2 rifaximin, 4 eluxadoline), containing 9844 patients. All were superior to placebo for the treatment of IBS-D or IBS-M at 12 weeks, according to the Food and Drug Administration (FDA)-recommended endpoint for trials in IBS (Figure 1). Alosetron 1mg twice-daily ranked first for efficacy, based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency (RR = 0.69; 95% CI 0.60 to 0.80, P-score = 0.97), effect on global symptoms of IBS, and effect on stool consistency. Ramosetron 2.5mcg once-daily was ranked first for effect on abdominal pain (RR = 0.75; 95% CI 0.65 to 0.85, P-score = 0.94). Total numbers of adverse events were significantly greater with alosetron 1mg twice-daily and ramosetron 2.5mcg, once-daily, compared with placebo. Rifaximin 550mg three times daily ranked first for safety. Constipation was significantly more common with all drugs, except rifaximin 550mg three times daily. Conclusions In a network meta-analysis of randomised controlled trials of pharmacological therapies for IBS-D and IBS-M, we found all drugs to be superior to placebo, but alosetron and ramosetron appeared to be the most effective.

Background & Aims Irritable bowel syndrome (IBS) is common but difficult to treat. Altering the gut microbiota has been proposed as a strategy for treatment of IBS, but the association between the gut microbiome and IBS symptoms has not been well established. We performed a systematic review to explore evidence for this association. Methods We searched databases, including MEDLINE, EMBASE, Cochrane CDSR, and CENTRAL, through April 2, 2018 for case–control studies comparing the fecal or colon microbiomes of adult or pediatric patients with IBS with microbiomes of healthy individuals (controls). The primary outcome was differences in specific gut microbes between patients with IBS and controls. Results The search identified 2631 citations; 24 studies from 22 articles were included. Most studies evaluated adults presenting with various IBS subtypes. Family Enterobacteriaceae (phylum Proteobacteria), family Lactobacillaceae, and genus Bacteroides were increased in patients with IBS compared with controls, whereas uncultured Clostridiales I, genus Faecalibacterium (including Faecalibacterium prausnitzii), and genus Bifidobacterium were decreased in patients with IBS. The diversity of the microbiota was either decreased or not different in IBS patients compared with controls. More than 40% of included studies did not state whether cases and controls were comparable (did not describe sex and/or age characteristics). Conclusions In a systematic review, we identified specific bacteria associated with microbiomes of patients with IBS vs controls. Studies are needed to determine whether these microbes are a product or cause of IBS.

Background Dietary factors may influence the risk of developing inflammatory bowel disease (IBD), but evidence from large, prospective studies is scarce. This study aimed to evaluate the relationship between ultra-processed food intake and the risk of developing IBD in the Prospective Urban Rural Epidemiology (PURE) cohort study. Methods This was a prospective cohort study among 21 low, middle, and high income countries across seven geographic regions of 116,087 individuals between the ages of 35–70 with at least one cycle of follow-up and complete baseline food frequency questionnaire (FFQ) data. Country-specific validated FFQs were used to document baseline dietary intake. Participants were followed prospectively at least every 3 years. The main clinical outcome for this study was development of IBD, including Crohn’s disease (CD) or ulcerative colitis (UC). Cox proportional hazard multivariable models were used to assess associations between ultra-processed food intake and risk of IBD. Results are presented as hazard ratios (HR) with 95% confidence intervals (CI). Results Participants were enrolled in the study between 2003 and 2016. During the median follow-up of 9.7 years (IQR 8.9–11.2), we recorded 467 incident cases of IBD (90 with CD and 377 with UC). Higher ultra-processed food intake was associated with a higher risk of incident IBD (HR 1.82, 95% CI 1.22 to 2.72 for ≥5 servings/day and HR 1.67, 95% CI 1.18 to 2.37, for 1–4 servings/day as compared to Conclusion Higher ultra-processed food consumption was positively associated with development of IBD. Further studies are needed to identify the potential culprits within ultra-processed foods.

SummaryBackground Clinicians are advised to refer patients with lower gastrointestinal (GI) alarm features for urgent colonoscopy to exclude colorectal cancer (CRC). However, the utility of alarm features is debated. Aims To assess whether performance of alarm features is improved by using a symptom frequency threshold to trigger referral, or by combining them into composite variables, including minimum age thresholds, as recommended by the National Institute for Health and Care Excellence (NICE). Methods We collected data prospectively from 1981 consecutive adults with lower GI symptoms. Assessors were blinded to symptom status. The reference standard to define CRC was histopathological confirmation of adenocarcinoma in biopsy specimens from a malignant-looking colorectal lesion. Controls were patients without CRC. Sensitivity, specificity, positive predictive values (PPVs) and negative predictive values were calculated for individual alarm features, as well as combinations of these. Results In identifying 47 (2.4%) patients with CRC, individual alarm features had sensitivities ranging from 11.1% (family history of CRC) to 66.0% (loose stools), and specificities from 30.5% (loose stools) to 75.6% (family history of CRC). Using higher symptom frequency thresholds improved specificity, but to the detriment of sensitivity. NICE referral criteria also had higher specificities and lower sensitivity, with PPVs above 4.8%. More than 80% of those with CRC met at least one of the NICE referral criteria. Conclusions Using higher symptom frequency thresholds for alarm features improved specificity, but sensitivity was low. NICE referral criteria had PPVs above 4.8%, but sensitivities ranged from 2.2% to 32.6%, meaning many cancers would be missed.

Fecal microbiota transplant (FMT) has emerged as an important treatment for antibiotic resistant or recurrent Clostridium difficile infection. There has been a great deal of media coverage of the efficacy of FMT, and patients with inflammatory bowel disease (IBD) understandably wonder if this approach would also work for them. There are also instructions on 'do it yourself' FMT therapy on the web. It is important to understand whether there is evidence that this approach is effective in IBD so that we can advise our patients appropriately.Systematic reviews have identified four case series involving 27 ulcerative colitis patients with a pooled remission rate of 24% (95% confidence interval (CI) = 11-45%). Two randomized controlled trials evaluating a total of 123 active ulcerative colitis patients have given conflicting results but the pooled data do suggest benefit with a number needed to treat of 6 (95% CI = 3-33). There are four case series involving 38 patients with Crohn's disease with a clinical response in 60.5% (95% CI = 28-86%). There are no randomized trials in Crohn's disease.At present there are insufficient data to recommend FMT in IBD, and patients certainly should not be administering this themselves. This remains an interesting approach to treating IBD and more studies are needed to establish the optimal method of delivery as well as randomized, placebo controlled trials to establish the efficacy of FMT.

Biological models for psychiatric disorders, such as anxiety and depression, emphasize the role of neurochemical changes in the development and maintenance of the disorders. The past decade, however, has shown increased evidence for the role of the microbiota-gut-brain axis in psychiatric disorders. Although much of this research is still in its preclinical stages and has largely been based on animal models, the findings in this area have potential implications for the conceptualization and treatment of psychiatric disorders. A number of excellent in-depth systematic and narrative reviews have been published on the topic of the microbiota-gutbrain axis and psychopathology recently (Collins, Surette & Bercik, 2012; De Angelis et al., 2015; Foster & Neufeld, 2013; Montiel-Castro et al., 2013; Wang & Kasper, 2014), many of which have been written by our research group at McMaster University. However, one of the limitations of these reviews is that they are published in basic science journals and tend to provide a very in-depth, detailed, and technical review of the basic science literature as it relates to the microbiota-gut-brain axis with limited focus on clinical implications. Therefore, the goal of the current article is to increase the visibility and accessibility of this research by providing an introduction to the topic with a strong focus on theoretical and clinical implications. Moreover, this article brings together ideas on the topic from a multidisciplinary team, including clinical psychologists, psychiatrists, gastroenterologists, and primary researchers, which highlights an interdisciplinary perspective on the topic with ideas for future research.The Gut MicrobiomeThe human body consists of a number of microbial environments that are predominantly made up of bacteria but also includes archaea, fungi, protists, and viruses. The intestinal or gut microbiome is the largest with approximately 100 trillion bacteria, most of which are located in the distal gut (Gill et al., 2006; Qin et al., 2010). The gut microbiome consists of over 1,000 distinct bacterial species (Qin et al., 2010) and its genetic material outnumbers human DNA by 10-fold. Although a core microbiome is shared by all humans, there is variability and fluctuation in the microbiota throughout the life span. This variability and fluctuation is influenced by factors such as diet, stress, infections, and antibiotic use (Cryan & O'Mahony, 2011; Forsythe, Sudo, Dinan, Taylor, & Bienenstock, 2010; Turnbaugh, Ridaura, Faith, Rey, Knight, & Gordon, 2009; Wu & Hui, 2011). The gut microbiome changes rapidly during the first 2 years of life and is influenced by a number of factors including genetics, method of birth delivery, maternal characteristics, nutrition, infections, use of antibiotics, and stress (Collado et al., 2010; Dominguez-Bello et al., 2010; Harmsen et al., 2000; Palmer et al., 2007; Penders et al., 2006).The Microbiota-Gut-Brain AxisThe microbiota-gut-brain axis is defined by the bidirectional communication between the digestive system and the central nervous system. The microbiota-gut-brain axis involves the central nervous system, the autonomic nervous system, and the enteric nervous system. The enteric nervous system consists of approximately 100 million neurons that line the gastrointestinal tract and is often referred to as the "second brain" because it can function autonomously (Pocock & Richards, 2006). Early research focused on the role of the gut-brain axis in digestion, metabolism, and immune functioning (Konturek, Konturek, Pawlik, & Brzozowski, 2004; Tache, Vale, Rivier, & Brown, 1980), with a strong focus on the role of the central nervous system in regulating these functions (i.e., a top-down model). More recently, there is growing appreciation for the bidirectional communication between the central nervous and digestive systems. The gut is not only influenced by the brain, but also influences the brain. …

Background and Aim The value of a multidisciplinary group and patient engagement in guideline groups is uncertain. We compared the recommendations of two guidelines that used the same data during the same time frame but with different participants to obtain a “real world” perspective on influence of the composition of guideline groups. Methods The Canadian Association of Gastroenterology (CAG) and the American College of Gastroenterology (ACG) recently updated their clinical practice guidelines for the management of Irritable Bowel Syndrome (IBS). Both the CAG and ACG used the same methodology and methodologist and were presented with the same data for interpretation. The ACG group consisted of predominantly academic gastroenterologists, while the CAG group also included general practitioners, a psychiatrist, a psychologist and a patient representative. The CAG group were also asked what components of the group were valuable. Results There were 14 statements with the same or similar recommendations. There were 10 statements in the CAG guideline not addressed by the ACG guideline and five recommendations where the opposite was the case. There was one statement that the two groups both addressed, but each group came to different conclusions. CAG members were in 100% agreement that involving a patient and having a multidisciplinary team was valuable and may have played a role in these differing interpretations of the same data in an IBS guideline. Conclusions There has been little uptake of patient involvement and multidisciplinary teams in guideline groups. However, this study provides a unique example of added benefit through broader group representation.

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder that is thought to be due to a disorder of brain–gut function. Drugs acting centrally, such as antidepressants, and psychological therapies may, therefore, be effective. We updated a previous systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, PsychINFO, and the Cochrane Controlled Trials Register were searched (up to July 2017). Trials recruiting adults with IBS, which compared antidepressants versus placebo, or psychological therapies versus control therapy or “usual management” were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The search strategy identified 5316 citations. Fifty-three RCTs, reported in 51 separate articles, were eligible for inclusion: 17 compared antidepressants with placebo, 35 compared psychological therapies with control therapy or “usual management”, and one compared both psychological therapy and antidepressants with placebo. Four of the trials of psychological therapies, and one of the RCTs of antidepressants, were identified since our previous meta-analysis. The RR of IBS symptoms not improving with antidepressants versus placebo was 0.66 (95% CI 0.57–0.76), with similar treatment effects for both tricyclic antidepressants and SSRIs, although with heterogeneity between RCTs of the latter (I2 = 49%, P = 0.07). The RR of symptoms not improving with psychological therapies was 0.69 (95% CI 0.62–0.76). Cognitive behavioral therapy, relaxation therapy, multi-component psychological therapy, hypnotherapy, and dynamic psychotherapy were all beneficial when data from two or more RCTs were pooled. There was significant heterogeneity between studies (I2 = 69%, P

INTRODUCTIONIrritable bowel syndrome (IBS) is the most prevalent of the functional gastrointestinal disorders (FGIDs). Current estimates are that IBS affects up to 10–12% of adults in North America [1, 2]. Although it can affect all individuals regardless of age, creed, or gender, IBS is more common

Background & Aims Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C. Methods We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score. Results We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 μg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 μg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 μg twice daily). Nausea was significantly more common in patients who received lubiprostone. Conclusions In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.

Background Fistulas occur in about 25% of patients with Crohn's disease (CD) and can be difficult to treat. The aim of this consensus was to provide guidance for the management of patients with perianal fistulizing CD. Methods A systematic literature search identified studies on the management of fistulizing CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform using a modified Delphi process, then finalized, and voted on by a group of specialists. Results The quality of evidence for treatment of fistulizing CD was generally of very low quality, and because of the scarcity of good randomized controlled trials (RCTs), these consensus statements generally provide conditional suggestions (5 of 7 statements). Imaging and surgical consultations were recommended in the initial assessment of patients with active fistulizing CD, particularly those with complicated disease. Antibiotic therapy is useful for initial symptom control. Antitumor necrosis factor (anti-TNF) therapy was recommended to induce symptomatic response, and continued use was suggested to achieve and maintain complete remission. The use of concomitant immunosuppressant therapies may be useful to optimize pharmacokinetic parameters when initiating anti-TNF therapy. When there has been an inadequate symptomatic response to medical management strategies, surgical therapy may provide effective fistula healing for some patients. Conclusions Optimal management of perianal fistulizing CD requires a collaborative effort between gastroenterologists and surgeons and may include the evidence-based use of existing therapies, as well as surgical assessments and interventions when needed. 10.1093/ibd/izy247_video1izy247.video15978518763001.

Dietary triggers such as gluten and highly fermentable oligo-, di- and monosaccharides and polyols (FODMAP)-containing foods have been associated with worsening irritable bowel syndrome (IBS) symptoms. However, the true impact of dietary restriction on IBS symptoms has remained unclear. The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) examining the efficacy of exclusion diets (we focused on low FODMAP and gluten-free diets (GFD)) in IBS. We conducted a search of the literature using the electronic databases MEDLINE (1946 to November 2017), EMBASE (1974 to November 2017), Cochrane Central Register of Controlled Trials (November 2017), and Cochrane Database of Systematic Reviews (2005 to November, 2017) for RCTs of exclusion diets in IBS. Two independent reviewers screened citations and a third reviewer resolved disagreement. Two independent reviewers performed eligibility assessment and data abstraction. For inclusion, RCTs that evaluated an exclusion diet versus an alternative or usual diet and assessed improvement in either global IBS symptoms or abdominal pain were required. Data were synthesized as relative risk of symptoms remaining using a random effects model. Quality of evidence was assessed using GRADE methodology. A total of 1726 citations were identified. After full-text screening a total of nine studies were eligible for the systematic review. There were two RCTs of a GFD, involving 111 participants. Both selected patients who responded to a GFD and then randomized them to continue the diet or have the diet “spiked” with gluten. A GFD was associated with reduced global symptoms compared with a control diet (RR = 0.42; 95% CI 0.11 to 1.55; I2 = 88%), although this was not statistically significant. There were seven RCTs comparing a low FODMAP diet with various control interventions in 397 participants. A low FODMAP diet was associated with reduced global symptoms compared with control interventions (RR = 0.69; 95% CI 0.54 to 0.88; I2 = 25%). The three RCTS that compared low FODMAP diet with rigorous control diets had the least heterogeneity between studies, but also the least magnitude of effect. The overall quality of the data was “very low” according to GRADE criteria. There is insufficient evidence to recommend a GFD to reduce IBS symptoms. There is very low quality evidence that a low FODMAP diet is effective in reducing symptoms in IBS patients.

BACKGROUND: High-resolution colonic manometry promises much deeper insight into human colon motor function and their control mechanisms than hitherto possible. One motor pattern in need of full understanding is the simultaneous pressure wave (SPW), an apparent instantaneous transient pressure development in the entire colon. AIMS: Our aim was to provide a characterization of this motor pattern, its relationship to other motor patterns and its appearance in response to a meal, balloon distension and bisacodyl in healthy subjects. METHODS: High-resolution colonic manometry (HRCM) was performed using an 84 sensor (1 cm spaced) water-perfused catheter in 16 healthy volunteers. Intraluminal pressure patterns were recorded during 90 min baseline, during balloon distension, 90 min after a meal and after luminal bisacodyl administration. Quantification was performed using software, based on Image J, developed during this study. RESULTS: SPWs, with amplitudes ranging from 2.4 to 75.2 mmHg (average 12 mmHg) and duration from 2 to 75s (average 11s), occurred throughout the entire colon or they developed at the termination of proximal High-Amplitude Pressure Waves (HAPWs). SPWs progressed into the anal canal followed by anal sphincter relaxation, even at very low amplitudes. SPWs did not obliterate haustral boundary contractions, likely the mechanism by which in vivo gas can escape while stool is retained. SPWs consisted of multiple high frequency, high velocity, pressure waves that resulted in apparent instantaneous pressure development. Balloon distension, a meal or luminal bisacodyl stimulation (10 mg) resulted in high amplitude SPWs associates with gas, water or balloon expulsion. SPWs and HAPWs also occurred independently and then did not influence each other. SPWs occurred in a rhythmic fashion on 26 occasions, including responses to all different stimuli; a distinct rhythmicity was identifiable at an average frequency of 1.8 ± 0.8 cpm, ranging from 0.3 to 4.4 cpm; 13 of the clusters were observed in response to the meal where the average frequency was 2.1 ± 0.9 cpm. CONCLUSIONS: The SPWs need to be incorporated into colonic function assessment by HRCM alongside HAPWs. It is the dominant motor pattern that allows gas expulsion and internal anal sphincter relaxation. Low- and high-amplitude SPWs are observed during baseline and are evoked by a meal, balloon distension or luminal bisacodyl. The rhythmicity of SPWs suggests the involvement of the ICC network at the submucosal border of the colon. The associated gas/liquid/balloon expulsion and anal sphincter relaxation provide potential diagnostic value. Their association with HAPWs suggest involvement in the defecation reflex. High resolution allows accurate quantification and 3-dimensional representation. FUNDING AGENCIES: CIHRHamilton Health Sciences Organization and Canadian Foundation for Innovation John Evans Leadership Fund

Summary Background Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. Methods In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. Findings Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55–0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55–1·53; p=0·76). Interpretation Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication. Funding Boehringer Ingelheim and Canadian Institutes of Health Research.

There are few data concerning the utility of symptoms and signs at first presentation in predicting a diagnosis of ulcerative colitis (UC) or Crohn's disease (CD). We conducted a study to examine this issue in secondary care.We collected complete symptom, colonoscopy, and histology data prospectively from 1,981 consecutive adult patients with lower gastrointestinal symptoms at two hospitals in Hamilton, Ontario. Assessors were blinded to symptom status. The reference standard used to define the presence of UC or CD was according to accepted histological criteria. Patients without UC or CD served as controls. Sensitivity, specificity, and positive and negative likelihood ratios (LRs) were calculated for individual items from the clinical history, as well as combinations of these.In identifying 302 patients with inflammatory bowel diseases (IBD), positive LRs for individual items ranged from 1.18 (incomplete emptying) to 2.30 (passage of stools more than four times per day at least most of the time) and negative LRs from 0.70 (bloody stools) to 0.96 (incomplete emptying). Combinations of items had a high specificity, but at the expense of sensitivity. Items that were independent predictors of IBD after logistic regression analysis were family history of IBD, younger age, passage of stools more than four times per day ≥75% of the time, urgency most of the time, and anemia.Individual items from the clinical history are not helpful in predicting a diagnosis of UC or CD. However, this may be because some items lacked sufficient detail. Combinations of symptoms and computer models had a high specificity, but overall were only modestly useful diagnostically. Future studies should evaluate biological markers in combination with symptoms to improve accuracy.

SummaryBackground Psychological factors may influence persistence and perceived severity of symptoms in irritable bowel syndrome (IBS). Literature suggests that somatisation is associated with IBS. However, the relationship between IBS subtype, symptoms of IBS and somatisation is unclear. Aim To examine this issue in a large cohort of secondary care patients. Methods Demographic and gastrointestinal (GI) symptom data were collected from 4224 adult patients via the Rome III questionnaire. Somatisation data were collected using the patient health questionnaire-12. Mean somatisation score and number of somatic symptoms were compared between IBS patients and controls with minimal GI symptoms, and between IBS subtypes using analysis of variance. Effect of level of somatisation on symptom frequency was compared according to IBS subtype using a χ2 test. Results 840 patients met Rome III criteria for IBS, controls were 2137 patients with GI symptoms without IBS. Mean somatisation scores and number of somatic symptoms were higher in IBS vs. controls (P

Celiac disease affects 1% of the North American population, with an estimated 350,000 Canadians diagnosed with this condition. The disease is triggered by the ingestion of gluten, and a lifelong, strict gluten-free diet (GFD) is the only currently available treatment. Compliance with a strict GFD is essential not only for intestinal mucosal recovery and alleviation of symptoms, but also for the prevention of complications such as anemia, osteoporotic fractures and small bowel lymphoma. However, a GFD is difficult to follow, socially inconvenient and expensive. Different approaches, such as tax reduction, cash transfer, food provision, prescription and subsidy, have been used to reduce the additional costs of the GFD to patients with celiac disease. The current review showed that the systems in place exhibit particular advantages and disadvantages in relation to promoting uptake and compliance with GFD. The tax offset system used in Canada for GFD coverage takes the form of a reimbursement of a cost previously incurred. Hence, the program does not help celiac patients meet the incremental cost of the GFD – it simply provides some future refund of that cost. An ideal balanced approach would involve subsidizing gluten-free products through controlled vouchers or direct food provision to those who most need it, independently of ‘ability or willingness to pay’. Moreover, if the cost of such a program is inhibitive, the value of the benefits could be made taxable to ensure that any patient contribution, in terms of additional taxation, is directly related to ability to pay. The limited coverage of GFD in Canada is concerning. There is an unmet need for GFD among celiac patients in Canada. More efforts are required by the Canadian medical community and the Canadian Celiac Association to act as agents in identifying ways of improving resource allocation in celiac disease.

BACKGROUND: Functional dyspepsia (FD or non‐ulcer dyspepsia) is defined as continuous or frequently recurring epigastric pain or discomfort for which no organic cause can be found. Acid suppressive therapy, including proton pump inhibitors (PPIs), has been proposed as a therapeutic option in FD, but its efficacy remains controversial. While PPIs are generally considered safe and well tolerated, they have been associated with adverse events, especially in the long term. For this reason, decisions on whether to initiate or continue PPI therapy should be made based on an appropriate clinical indication. Therefore, we conducted a systematic review to evaluate whether PPI therapy provides symptomatic relief in FD. OBJECTIVES: To determine the efficacy of proton pump inhibitors in the improvement of global symptoms of dyspepsia and quality of life compared to placebo, H2 receptor antagonists or prokinetics, in people with functional dyspepsia. SEARCH METHODS: We searched in the following electronic databases: the Cochrane Library (to May 2017), MEDLINE (OvidSP; to May 2017), Embase (OvidSP; to May 2017), and SIGLE grey literature (up to May 2017) and clinical trial registries; we handsearched abstracts from conferences up to May 2017. We screened non‐systematic reviews, systematic reviews and guidelines to identify any additional trials. We contacted trialists to obtain missing information. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing any PPI with placebo, H2 receptor antagonists (H2RAs) or prokinetics for the treatment of FD of at least two weeks' duration. Participants were adults (aged 16 years or greater) with an adequate diagnosis of FD (any validated criteria such as Rome I, II, III or Lancet Working Group). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and trial quality, and extracted data. We collected data on dyspeptic symptoms, quality of life and number of overall adverse events. Specific adverse events were beyond the scope of this review. MAIN RESULTS: We identified 25 RCTs from 27 papers (with 8453 participants) studying the effect of PPIs versus placebo, H2RAs or prokinetics for improvement of global symptoms of dyspepsia and quality of life in people with FD. Low‐dose PPIs had similar efficacy as standard‐dose PPIs, therefore we combined these subgroups for the analysis. PPI was more effective than placebo at relieving overall dyspepsia symptoms in people with FD (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.82 to 0.94; participants = 6172; studies = 18; number needed to treat for an additional beneficial outcome (NNTB) 11; moderate quality evidence). PPIs may have little or no effect compared with H2RAs (RR 0.88, 95% CI 0.74 to 1.04; participants = 740; studies = 2; low quality evidence), and may be slightly more effective than prokinetics (RR 0.89, 95% CI 0.81 to 0.99; participants = 1033; studies = 5; NNTB 16; low quality evidence) at relieving overall dyspepsia symptoms in people with FD. PPIs plus prokinetics have probably little or no effect compared with PPIs alone at relieving overall dyspepsia symptoms (RR 0.85, 95% CI 0.68 to 1.08; participants = 407; studies = 2; moderate quality evidence). There was no difference when subgrouped by Helicobacter pylori status, country of origin, or presence of reflux or Rome III subtypes. There were no differences in the number of adverse events observed between PPIs and any of the other treatments. There were fewer adverse events in the combination of PPI plus prokinetics compared to prokinetics alone (RR 0.60, 95% CI 0.39 to 0.93; participants = 407; studies = 2; moderate quality evidence). AUTHORS' CONCLUSIONS: There is evidence that PPIs are effective for the treatment of FD, independent of the dose and duration of treatment compared with placebo. PPIs may be slightly more effective than prokinetics for the treatment of FD; however, the evidence is scarce. The trials evaluating PPIs versus prokinetics are difficult to interpret as they are at risk of bias. Although the effect of these drugs seems to be small, the drugs are well tolerated.

BACKGROUND: Dyspepsia is a common condition associated with gastrointestinal (GI) disease. Prokinetics are the treatment of choice for functional dyspepsia (FD). However, the role of prokinetics in FD treatment is still controversial. OBJECTIVES: We conducted a systematic review and meta‐analysis of randomised control trials (RCTs) examining the efficacy of prokinetics in the treatment of FD. The primary outcome was overall absence of or improvement of symptoms and symptom scores at the end of treatment. We also evaluated quality of life (QoL) and adverse events as secondary outcomes. SEARCH METHODS: We performed a systematic search of MEDLINE, Embase, the Cochrane Library, and CINAHL, from 1946 until September 2017. RevMan 5.3 was used to calculate pooled risk ratios (RR) of symptoms persisting or without improved QoL or adverse events, mean difference (MD) or standardised mean difference (SMD) of post‐treatment symptoms scores, changes of symptom scores, and QoL, when appropriate with 95% confidence intervals (CI), using a random‐effects model. Quality of evidence was evaluated using GRADE methodology. SELECTION CRITERIA: We included studies that were parallel group RCTs comparing one prokinetic with either placebo or another prokinetic of the same or different class for the treatment of FD. Studies involved adults who presented with dyspepsia symptoms and who had negative or insignificant findings on endoscopy as well as no other organic and metabolic disorders. Studies only including participants with primarily reflux or heartburn symptoms were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, study quality and performed data extraction. MAIN RESULTS: From an initial 1388 citations, we identified 43 studies in 40 papers. Of those, 29 studies with 10,044 participants compared six prokinetics with placebo for the outcome of absence of symptoms or symptom improvement. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR of remaining dyspeptic = 0.81, 95% CI 0.74 to 0.89; number needed to treat for an additional beneficial outcome (NNTB) =7, very low‐quality evidence) with considerable heterogeneity; I(2) = 91% (P < 0.00001). After removing cisapride from the analysis, the effect of prokinetics in global symptom improvement still persisted, compared to placebo (RR 0.87, 95% CI 0.80 to 0.94), but was still based on very low‐quality evidence. The result showed persistence of significant improvement in subgroups of studies at unclear or at low risk of bias (RR 0.86, 95% CI 0.80‐0.92), and in subgroups by molecules of cisapride (RR 0.71, 95% CI 0.54 to 0.93; NNTB = 4), acotiamide (RR 0.94, 95% CI 0.91 to 0.98; NNTB = 20) and tegaserod(RR 0.89, 95% CI 0.82 to 0.96; NNTB = 14). Ten studies compared different types of prokinetics with each other and the most commonly used comparator was domperidone, 10 mg three times a day (eight of the 10 studies). There was a significantly better post‐treatment symptom score in other prokinetics, compared to domperidone (SMD ‐0.19, 95% CI ‐0.35 to ‐0.03, very low‐quality evidence), but no difference in reducing global symptom (RR 0.94, 95% CI 0.83 to 1.07), and mean difference symptom scores (SMD ‐0.13, 95% CI ‐0.31 to 0.05). We found five studies that assessed quality of life, but there was no benefit in improving quality of life with prokinetic treatment (SMD 0.11, 95% CI ‐0.10 to 0.33; participants = 1774). The adverse events in individual prokinetics was not different from placebo (RR 1.09, 95% CI 0.95 to 1.25; participants = 3811; studies = 17). However, when we looked at the adverse effects by each prokinetic, there were overall greater adverse effects in the active treatment group with cisapride (RR 1.31, 95% CI 1.03 to 1.65; P = 0.03). The most common side effects were diarrhoea, abdominal discomfort and nausea. The funnel plot was asymmetric (Egger's test, P = 0.02) implying reporting bias or other small‐study effects may be, in part, driving the benefit of prokinetics compared to placebo in this meta‐analysis. The GRADE assessment of the quality of the evidence in each outcome are mostly low or very low due to concerns around risk of bias in study design, unexplained heterogeneity and possible publication bias. AUTHORS' CONCLUSIONS: Due to low, or very low, quality of evidence, we are unable to say whether prokinetics are effective for the treatment of functional dyspepsia . We are uncertain which of the individual prokinetic drugs is the most effective as well as whether prokinetics can improve quality of life. Apart from cisapride, prokinetics are well‐tolerated. Good quality RCTs are needed to verify the efficacy of prokinetics.

Gastroenterology has published many seminal articles that have transformed our understanding of colorectal cancer (CRC) as well as being influential in promoting colorectal cancer screening which has saved many people from developing the disease. CRC has a hereditary component most notably highlighted in Lynch syndrome. A key paper reported that the majority of mutations in patients with hereditary nonpolyposis colorectal cancer harbored mutations in the MLH 1 or MSH 2 mismatch repair proteins. Continuing on the gene mutation theme, another paper. highlighted that serrated polyps accounted for approximately 9% of all colon polyps and the majority of these harbored BRAF mutations, a mutation rarely seen in the traditional adenoma to carcinoma sequence. The journal also published key work outlining the role of COX-2 in the development of CRC and this led to the concept that CRC may be prevented by COX-2 inhibition. Gastroenterology has published many influential guidelines to promote screening for colorectal cancer. Initially Gastroenterology guidelines emphasized the need for offering any screening modality either alone or in combination such as fecal occult blood test, flexible sigmoidoscopy, CT colography or colonoscopy. These guidelines were very influential in persuading governments around the world of the importance of CRC and now many countries in the developed world offer national CRC screening programs. More recently guidelines have emphasized the need to offer screening programs that prevent CRC as well as early detection and colonoscopy would be the gold standard approach. Gastroenterology has also led the way in developing the concept of developing quality measures. The journal has published evidence as to which measures lead to improvement in adenoma detection and reduced interval CRC rates. These papers have been instrumental in current recommendations on quality colonoscopy practice.

Proton pump inhibitors (PPIs) are effective and suppressing acid, and therefore have efficacy against gastric acid-related disorders. The long-term safety of PPIs is less clear and there have been a number of studies raising concerns regarding risk of pneumonia, fracture, Clostridium difficile, chronic renal failure, and dementia. This latter concern is addressed by a study in this issue of AJG using health care registry data and found there was no association between PPI use and Alzheimer's dementia. Furthermore, there was no increased risk of dementia with long-term use of PPIs or higher doses of PPIs. Discrepancies between studies probably relate to multiple testing and residual confounding and currently there is insufficient evidence to suggest that the association between PPIs and dementia is causal.