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Radiomics, a method used to extract large amount of data, may be useful for discriminating malignant characteristics for lung cancer staging. We aimed to critically appraise the current use of radiomics in medical imaging for determining nodal involvement in lung cancer. The literature was searched using Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Web of Science for observational studies between the databases’ inception and January 2020. All observational studies compared diagnostic tests for lung cancer in comparison to diagnostic tests with a radiomic adjunct. For each study, data were extracted for study characteristics, methodological quality, and accuracy. Discrepancies in screening and extraction were resolved by a third reviewer. Data were synthesized narratively. 15 studies were included, 13 of which were full reports, while two were conference abstracts. Overall, 3164 patients were enrolled with a total of 3379 LNs recorded (69% malignancy). Point estimate sensitivities for algorithms ranged from 52 to 99%, while specificity for the algorithms ranged from 60 to 92%. Area under the curve c-statistics were only reported for algorithms and not the clinician. Point estimate c-statistics ranged from 0.64 to 0.94, suggesting that the algorithms possessed good discrimination potentials. The current level of evidence of radiomic analysis methods for staging lung cancer is inconclusive and possesses heterogeneity in study design. Prospective external validation of these algorithms and direct comparisons using cut-off thresholds is required to determine their true predictive capability prior to implementation in clinical practice. PROSPERO ID: CRD42020162952.

Hyoscine butylbromide, also known as hyoscyamine or scopolamine, and sold under the trade name Buscopan, is an antimuscarinic agent commonly used to induce smooth muscle relaxation and reduce spasmodic activity of the gastrointestinal (GI) tract during endoscopic procedures. However, the balance between desirable and undesirable (adverse) effects is not clear when used during GI endoscopy. The Clinical Affairs Committee of the Canadian Association of Gastroenterology (CAG) conducted systematic reviews and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations for the use of Buscopan during GI endoscopy. To summarize, we recommend against the use of Buscopan before or during colonoscopy (strong recommendation, high certainty of evidence). We suggest against the use of Buscopan before or during gastroscopy (conditional recommendation, very low certainty of evidence). We suggest the use of Buscopan before or during ERCP (conditional recommendation, very low certainty of evidence). More research is needed to determine whether patients undergoing advanced procedures such as endoscopic mucosal resection or endoscopic submucosal dissection benefit from its use. Buscopan should be used with caution in patients with cardiac comorbidities. According to its product monograph, Buscopan is contraindicated in patients with tachycardia, angina, and cardiac failure. Thus, Buscopan should be used very cautiously in patients with these conditions, and only when the potential benefits of its use outweigh the potential risks in a particular case. Such patients require careful cardiac monitoring in an environment where resuscitation equipment and appropriately trained staff to use it are readily available. According to its product monograph, Buscopan is also contraindicated in patients with prostatic hypertrophy with urinary retention, and therefore, should be used very cautiously in such patients as well, and only when the potential benefits of its use outweigh the potential risks in a particular case. Obtaining a preprocedural history of glaucoma is unlikely to be of value when considering Buscopan use. However, in cases where Buscopan has been used, patients should be counselled postprocedurally and told to present to an emergency facility should they experience eye pain, redness, decreased vision, nausea and vomiting or headache.

Background and Objective Guideline development groups or other health care decision makers frequently encounter situations that require a simultaneous comparison of multiple interventions. This sometimes becomes apparent either when they identify questions of interest, before they formulate recommendations, or it may surface only when recommendations have already been formulated based on pairwise comparisons. Methods Using examples from the World Health Organization, the European Commission, and a professional society, we developed a flexible approach to developing recommendations when a multiple-intervention comparison (MC) is needed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) frameworks. We iteratively refined this approach through user testing and then included a module in GRADE's official software GRADEpro to test the approach in two real and one theoretical guideline recommendations. Results We found the approach feasible and that all EtD criteria should be considered in an MC approach. We judged that guideline development groups and other decision makers will benefit from the availability of a network meta-analyses (NMA) of intervention effects to support decisions; however, NMA supports only one of many criteria, that is, the balance of health benefits and harms, and is therefore helpful, but not essential to the approach we propose. When similar but not identical comparators are used to address MC, challenges may arise with intransitivity and the relative rankings of interventions. Conclusion We successfully applied the MC approach and software module in generating recommendations across different scenarios and identified challenges. The MC approach allows guideline groups and other decision makers to transparently and critically assess multiple options for a given health question. Application of the approach by others may lead to refinement and allow for better understanding of its impact in developing recommendations and making choices.

Background Corticosteroids (CS) have been used extensively to induce remission in Crohn’s disease (CD); however, they are associated with severe side effects. We hypothesized that the administration of an exclusive enteral nutrition (EEN) formula to CS would lead to increased CD remission rates and to decreased CS-related adverse events. We proposed to undertake a pilot study comparing EEN and CS therapy to CS alone to assess decrease symptoms and inflammatory markers over 6 weeks. Aim The overall aim was to assess study feasibility based on recruitment rates and acceptability of treatment in arms involving EEN Methods The pilot study intended to recruit 100 adult patients with active CD who had been prescribed CS to induce remission as part of their care. The patients were randomized to one of three arms: (i) standard-dose CS; (ii) standard-dose CS plus EEN (Modulen 1.5 kcal); or (iii) short-course CS plus EEN. Results A total of 2009 CD patients attending gastroenterology clinics were screened from October 2018 to November 2019. Prednisone was prescribed to only 6.8% (27/399) of patients with active CD attending outpatient clinics. Of the remaining 372 patients with active CD, 34.8% (139/399) started or escalated immunosuppressant or biologics, 49.6% (198/399) underwent further investigation and 8.8% (35/399) were offered an alternative treatment (e.g., antibiotics, surgery or investigational agents in clinical trials). Only three patients were enrolled in the study (recruitment rate 11%; 3/27), and the study was terminated for poor recruitment. Conclusion The apparent decline in use of CS for treatment of CD has implications for CS use as an entry criterion for clinical trials.

The development of anti-tumour necrosis factor (TNF) therapies has transformed the care of patients with immune-mediated diseases such as inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, psoriasis and inflammatory arthropathies, including rheumatoid arthritis and ankylosing spondylitis. For IBD patients, these biologic therapies are effective at inducing and maintaining remission (1), reducing the need for surgery (2) and improving quality of life (3). Although anti-TNF therapies are effective in several different immune-mediated disorders, individual biologics are not, necessarily, equally effective in all disorders suggesting that their actions may differ between disorders. For example, the paradox that anti-TNF drugs used to treat rheumatoid arthritis (RA) and psoriasis may yet cause joint pains and skin reactions in IBD patients, emphasizes our imperfect understanding of the mechanism of action of these biologic therapies and the need to evaluate treatment outcomes separately for different disorders. The main factors that limit the use of anti-TNF drugs are adverse events and cost. Anti-TNF therapy is associated with joint pains, dermatological disorders and transfusion reactions (4). Transfusion reactions are associated with the development of antibodies to anti-TNF agents and this may also be associated with reduced treatment efficacy (5). Anti-TNF agents are also associated with an increased risk of infection (6) and risk of lymphoma although these risks may be exacerbated, to a greater or lesser extent, by the concomitant use of azathioprine or other immunosuppressive agents (7). Anti-TNF therapies are also expensive costing up to $20,000 per year for each patient in Canada. Canada spent more on biologic therapies for all indications than on any other class of drug in 2018 accounting for 8.2% of the $33.7 billion spent on prescription medications (8). While the cost of these therapies is significant, the cost of having IBD is also expensive to society. It is estimated that the indirect cost of IBD was $1.29 billion in Canada in 2018 (9,10). Anti-TNF therapies can improve quality of life and productivity and, accounting for these societal costs, biologics may offer value for money (11). In the Canadian setting, health care is mainly funded centrally by the tax payer and the government, understandably, focuses on how biologic therapy may reduce health care costs. This is less clear cut with research using health administrative data failing to demonstrate any significant decrease in hospitalizations or surgical resections in the anti-TNF era compared to what would be expected if these drugs had not been introduced (12). Given this perspective, it is understandable that approaches to reducing the cost of these drugs are being explored. The emergence of biosimilars, also known as subsequent entry biologics have provided an opportunity for third party payers to reduce anti-TNF therapy drug costs. A biosimilar is a biological medical product that is similar to the original but manufactured by a different company once the patent for that product has expired. They are typically less expensive than the original product and therefore an obvious target in attempts to reduce biologic drug costs. Biosimilars are distinct from usual generic drugs, which are simple small molecules that are relatively straightforward to reproduce and manufacture on a large scale, and identical to the original drug. Biologic therapies are more complex proteins and require replication in living cells. The product is dependent on the type of genetically modified cell being used, the production process and purification techniques (13). The manufacturing process is considerably more expensive than standard small molecules and therefore costs of biosimilars are higher than generically produced drugs. Furthermore, the variation from the originator is greater than would normally be seen with generics. However, it is important to emphasize that even with the original manufacturer there is potential for variability between each manufacturing run due to the complexity of living organisms. The Federal Drug Agency has released documents regarding the approval process for biosimilars (14) that other regulatory authorities have largely adopted (15). Essentially biosimilars must show a high degree of similarity to the original product and have no clinically meaningful differences in safety, purity and potency (14). This is a reasonable definition in principle but the definitions of ‘high degree of similarity’ as well as ‘clinically meaningful differences in safety and potency’ need further clarification in clinical practice. The Canadian Association of Gastroenterology has previously published a position statement on biosimilars (16) but this was 6 years ago, and more data are now available. Crohn’s and Colitis Canada has published a position statement more recently (17) but the two organizations felt it was of value to release a joint position statement after a full literature review. Several positions statements have been released by various organizations (Table 1) but none has provided an explicit literature search, nor have they assessed the quality of evidence of a defined clinical question according to GRADE criteria (18). Table 1. Position statements reached by other groups on the use of biosimilars

Objective To propose a taxonomy and framework that identifies and presents actionable statements in guidelines. Study design and setting We took an iterative approach reviewing case studies of guidelines produced by the World Health Organization and the American Society of Hematology to develop an initial conceptual framework. We then tested it using randomly selected recommendations from published guidelines addressing COVID-19 from different organizations, evaluated its results, and refined it before retesting. The urgency and availability of evidence for development of these recommendations varied. We consulted with experts in research methodology and guideline developers to improve the final framework. Results The resulting taxonomy and framework distinguishes five types of actional statements: formal recommendations; research recommendations; good practice statements; implementation considerations, tools and tips; and informal recommendations. These statements should respond to a priori established criteria and require a clear structure and recognizable presentation in a guideline. Most importantly, this framework identifies informal recommendations that differ from formal recommendations by how they consider evidence and in their development process. Conclusion The identification, standardization and explicit labelling of actionable statements according to the framework may support guideline developers to create actionable statements with clear intent, avoid informal recommendations and improve their understanding and implementation by users.

This Cochrane Protocol has been withdrawn for publication as the authors are unable to complete the review and topic was deemed to be of low priority. The Cochrane Gut Editorial Team is withdrawing the protocol in agreement with the authors. There are no current plans to republish it in the future.

IntroductionEndoscopic retrograde cholangiopancreatography (ERCP) is performed to diagnose and manage conditions of the biliary and pancreatic ducts. Though effective, it is associated with common adverse events (AEs). The purpose of this study is to systematically review ERCP AE rates and report up-to-date pooled estimates.Methods and analysisA comprehensive electronic search will be conducted of relevant medical databases through 10 November 2020. A study team of eight data abstracters will independently determine study eligibility, assess quality and abstract data in parallel, with any two concordant entries constituting agreement and with discrepancies resolved by consensus. The primary outcome will be the pooled incidence of post-ERCP pancreatitis, with secondary outcomes including post-ERCP bleeding, cholangitis, perforation, cholecystitis, death and unplanned healthcare encounters. Secondary outcomes will also include rates of specific and overall AEs within clinically relevant subgroups determined a priori. DerSimonian and Laird random effects models will be used to perform meta-analyses of these outcomes. Sources of heterogeneity will be explored via meta-regression. Subgroup analyses based on median dates of data collection across studies will be performed to determine whether AE rates have changed over time.Ethics and disseminationEthics approval is not required for this study as it is a planned meta-analysis of previously published data. Participant consent is similarly not required. Dissemination is planned via presentation at relevant conferences in addition to publication in peer-reviewed journals.PROSPERO registration numberCRD42020220221.

In a recent issue, Kovacic et al. analyze data from a randomized sham-controlled trial and show that pretreatment vagal efficiency, an index related to respiratory sinus arrhythmia, is a predictor of pain improvement in adolescents with functional abdominal pain when treated with auricular percutaneous electrical nerve field stimulation. The underlying premise is the polyvagal hypothesis, an explanatory framework for the evolution of the mammalian autonomic nervous system, which proposes that functional gastrointestinal disorders can result from a chronic maladaptive state of autonomic neural control mechanisms after traumatic stress. This is an opportunity for us to stimulate physicians' interest in evolutionary medicine.

We performed systematic reviews addressing predefined clinical questions to develop recommendations with the GRADE approach regarding management of patients with overt upper gastrointestinal bleeding. We suggest risk assessment in the emergency department to identify very-low-risk patients (e.g., Glasgow-Blatchford score = 0-1) who may be discharged with outpatient follow-up. For patients hospitalized with upper gastrointestinal bleeding, we suggest red blood cell transfusion at a threshold of 7 g/dL. Erythromycin infusion is suggested before endoscopy, and endoscopy is suggested within 24 hours after presentation. Endoscopic therapy is recommended for ulcers with active spurting or oozing and for nonbleeding visible vessels. Endoscopic therapy with bipolar electrocoagulation, heater probe, and absolute ethanol injection is recommended, and low- to very-low-quality evidence also supports clips, argon plasma coagulation, and soft monopolar electrocoagulation; hemostatic powder spray TC-325 is suggested for actively bleeding ulcers and over-the-scope clips for recurrent ulcer bleeding after previous successful hemostasis. After endoscopic hemostasis, high-dose proton pump inhibitor therapy is recommended continuously or intermittently for 3 days, followed by twice-daily oral proton pump inhibitor for the first 2 weeks of therapy after endoscopy. Repeat endoscopy is suggested for recurrent bleeding, and if endoscopic therapy fails, transcatheter embolization is suggested.

Prokinetics are recommended for the treatment of functional dyspepsia (FD) but systematic reviews give conflicting results on the efficacy of these agents. We have therefore conducted an updated systematic review to support the 2017 joint ACG/CAG dyspepsia guidelines. Electronic databases, including MEDLINE, EMBASE, and CENTRAL, were searched until September 2017 for randomized controlled trials (RCTs) comparing either prokinetics and placebo or two types of prokinetics to improve FD symptoms. The primary outcome was absence or improvement of dyspeptic symptoms at the end of treatment. Double-blind eligibility assessment and data extraction was performed. Pooled risk ratios of symptoms persisting or adverse events occurring, and standardized mean difference of quality-of-life (QoL) scores with 95% CI, using a random effects model, were calculated. Quality of evidence was assessed using GRADE. The search identified 1388 citations; 38 studies in 35 papers were included. Of these, 29 trials comparing prokinetics with placebo were found. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR 0.81, 95% CI 0.74 to 0.89; I2 91%; NNT 7), regardless of FD subtype or ethnicity. When comparing two types of prokinetic, the most commonly used comparator was domperidone. There was no difference in reducing global symptoms (RR 0.94, 95% CI 0.83 to 1.07). QoL was not improved with prokinetic treatment. The adverse events with individual prokinetics were not different from placebo, except for cisapride. The GRADE assessment rated the quality of the evidence in each outcome as very low. From the current evidence, prokinetics may be effective for the treatment in all subtypes of FD, with very low quality of evidence. There was no difference between prokinetics for dyspeptic symptom improvement. High-quality RCTs with large sample sizes of FD patients are needed to verify the efficacy of prokinetics.

Background & Aims Crohn’s disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. Methods We performed a systematic review to identify published studies of the management of 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 and then finalized and voted on by a group of specialists. Results The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. Conclusions Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.

Background and aims Our aim is to review the literature and provide guidelines for the assessment of uninvestigated dysphagia. Methods A systematic literature search identified studies on dysphagia. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Statements were discussed and revised via small group meetings, teleconferences, and a web-based platform until consensus was reached by the full group. Results The consensus includes 13 statements focused on the role of strategies for the assessment of esophageal dysphagia. In patients presenting with dysphagia, oropharyngeal dysphagia should be identified promptly because of the risk of aspiration. For patients with esophageal dysphagia, history can be used to help differentiate structural from motility disorders and to elicit alarm features. An empiric trial of proton pump inhibitor therapy should be limited to four weeks in patients with esophageal dysphagia who have reflux symptoms and no additional alarm features. For patients with persistent dysphagia, endoscopy, including esophageal biopsy, was recommended over barium esophagram for the assessment of structural and mucosal esophageal disease. Barium esophagram may be useful when the availability of endoscopy is limited. Esophageal manometry was recommended for diagnosis of esophageal motility disorders, and high-resolution was recommended over conventional manometry. Conclusions Once oropharyngeal dysphagia is ruled out, patients with symptoms of esophageal dysphagia should be assessed by history and physical examination, followed by endoscopy to identify structural and inflammatory lesions. If these are ruled out, then manometry is recommended for the diagnosis of esophageal dysmotility.

BACKGROUND: Observational studies have consistently shown an increased risk of upper gastrointestinal bleeding in users of selective serotonin receptor inhibitors (SSRIs), probably explained by their inhibition of platelet aggregation. Therefore, treatment with SSRIs is often temporarily withheld in patients with peptic ulcer bleeding. However, abrupt discontinuation of SSRIs is associated with development of withdrawal symptoms in one-third of patients. Further data are needed to clarify whether treatment with SSRIs is associated with poor outcomes, which would support temporary discontinuation of treatment.AIM: To identify if treatment with SSRIs is associated with increased risk of: (1) endoscopy-refractory bleeding, (2) rebleeding or (3) 30-day mortality due to peptic ulcer bleeding.METHODS: A nationwide cohort study. Analyses were performed on prospectively collected data on consecutive patients admitted to hospital with peptic ulcer bleeding in Denmark in the period 2006-2014. Logistic regression analyses were used to investigate the association between treatment with SSRIs and outcome following adjustment for pre-defined confounders. Sensitivity and subgroup analyses were performed to evaluate the validity of the findings.RESULTS: A total of 14 343 patients were included. Following adjustment, treatment with SSRIs was not associated with increased risk of endoscopy-refractory bleeding (odds ratio [OR] [95% Confidence Interval (CI)]: 1.03 [0.79-1.33]), rebleeding (OR [95% CI]: 0.96 [0.83-1.11]) or 30-day mortality (OR [95% CI]: 1.01 [0.85-1.19]. These findings were supported by sensitivity and subgroup analyses.CONCLUSIONS: According to our data, treatment with SSRIs does not influence the risk of endoscopy-refractory bleeding, rebleeding or 30-day mortality in peptic ulcer bleeding.

The above guidance (Figure 1) reflects the current limited evidence available, but further guidance may be required as the situation rapidly evolves.CAG would like to highlight an important article by Repici et al. who had first hand experience with performing endoscopic procedures during this outbreak.1 This article discussed measures, with specific focus on patient management and risk stratification based on procedural types and patient-related risk factors, personal protection equipment (PPE) and process for wearing and removing PPE, which have been implemented in their hospitals to reduce dissemination of COVID-19 infection. It is important to note that the proposed measures are based on current limited understanding of the incubation period, mechanisms of transmission, clinical course and the duration of infectivity. As well, the evidence supporting the use of these measures is largely based on prior experience from other coronaviruses (e.g., SARS-CoV and MERS-CoV). Figure 1 summarizes CAG guidance on infection prevention and control for COVID-19 when performing endoscopic procedures (as of March 16, 2020).

Background and Aims Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. Methods We performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator and outcome questions were developed through an iterative process and were voted on by a group of specialists. Results The certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea and Crohn’s disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn’s disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review and reinvestigation for patients whose symptoms persist despite BAST. Conclusions Based on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with cholestyramine, is suggested.

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 …

Background and study aims Difficult cannulation is a risk factor for pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). The double-guidewire technique (DGT) may improve cannulation success and reduce the risk of post-ERCP pancreatitis (PEP) in patients with difficult cannulation. This systematic review compared the DGT with persistent conventional cannulation or other advanced techniques in patients with difficult cannulation. Patients and Methods CENTRAL, MEDLINE, EMBASE, and CINAHL databases and DDW and UEGW abstracts up to March 2016 were searched for randomized controlled trials (RCTs) comparing DGT with persistent conventional cannulation or other advanced techniques (precut, pancreatic duct [PD] stenting). The primary outcome was PEP. Secondary outcomes included severity of PEP, successful cannulation of the common bile duct (CBD) with the randomized technique, overall CBD cannulation success, and ERCP-related complications. Results 7 RCTs (577 patients) were included. Use of the DGT significantly increased PEP compared to other endoscopic techniques (risk ratio [RR] 1.98, 95 % confidence interval [95 %CI] 1.14 – 3.42). There was no significant difference in CBD cannulation success with the randomized technique (RR 1.04, 95 %CI 0.87 – 1.24) or in overall cannulation success (RR 1.04, 95 %CI 0.91 – 1.18) between DGT and other techniques. There was also no significant difference in the risk of other ERCP-related complications (bleeding, perforation, cholangitis, and mortality). The results were robust in sensitivity analyses. Conclusions In patients with difficult cannulation, sole use of the DGT appears to increase the risk of PEP without any superiority in achieving biliary cannulation compared to other techniques. PD stenting may reduce the risk of PEP when the DGT is used. The influence of co-intervention in the form of per-procedural nonsteroidal anti-inflammatory drug (NSAID) administration is unclear.

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.

Description: This update of the 2010 International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding (UGIB) refines previous important statements and presents new clinically relevant recommendations.Methods: An international multidisciplinary group of experts developed the recommendations. Data sources included evidence summarized in previous recommendations, as well as systematic reviews and trials identified from a series of literature searches of several electronic bibliographic databases from inception to April 2018. Using an iterative process, group members formulated key questions. Two methodologists prepared evidence profiles and assessed quality (certainty) of evidence relevant to the key questions according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Group members reviewed the evidence profiles and, using a consensus process, voted on recommendations and determined the strength of recommendations as strong or conditional.Recommendations: Preendoscopic management: The group suggests using a Glasgow Blatchford score of 1 or less to identify patients at very low risk for rebleeding, who may not require hospitalization. In patients without cardiovascular disease, the suggested hemoglobin threshold for blood transfusion is less than 80 g/L, with a higher threshold for those with cardiovascular disease. Endoscopic management: The group suggests that patients with acute UGIB undergo endoscopy within 24 hours of presentation. Thermocoagulation and sclerosant injection are recommended, and clips are suggested, for endoscopic therapy in patients with high-risk stigmata. Use of TC-325 (hemostatic powder) was suggested as temporizing therapy, but not as sole treatment, in patients with actively bleeding ulcers. Pharmacologic management: The group recommends that patients with bleeding ulcers with high-risk stigmata who have had successful endoscopic therapy receive high-dose proton-pump inhibitor (PPI) therapy (intravenous loading dose followed by continuous infusion) for 3 days. For these high-risk patients, continued oral PPI therapy is suggested twice daily through 14 days, then once daily for a total duration that depends on the nature of the bleeding lesion. Secondary prophylaxis: The group suggests PPI therapy for patients with previous ulcer bleeding who require antiplatelet or anticoagulant therapy for cardiovascular prophylaxis.

Background & aims A family history (FH) of colorectal cancer (CRC) increases the risk of developing CRC. These consensus recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on screening these high-risk individuals. Methods Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions around the effect of an FH of CRC or adenomas on the risk of CRC, the age to initiate screening, and the optimal tests and testing intervals. The GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach was used to develop the recommendations. Results Based on the evidence, the Consensus Group was able to strongly recommend CRC screening for all individuals with an FH of CRC or documented adenoma. However, because most of the evidence was very-low quality, the majority of the remaining statements were conditional (“we suggest”). Colonoscopy is suggested (recommended in individuals with ≥2 first-degree relatives [FDRs]), with fecal immunochemical test as an alternative. The elevated risk associated with an FH of ≥1 FDRs with CRC or documented advanced adenoma suggests initiating screening at a younger age (eg, 40–50 years or 10 years younger than age of diagnosis of FDR). In addition, a shorter interval of every 5 years between screening tests was suggested for individuals with ≥2 FDRs, and every 5–10 years for those with FH of 1 FDR with CRC or documented advanced adenoma compared to average-risk individuals. Choosing screening parameters for an individual patient should consider the age of the affected FDR and local resources. It is suggested that individuals with an FH of ≥1 second-degree relatives only, or of nonadvanced adenoma or polyp of unknown histology, be screened according to average-risk guidelines. Conclusions The increased risk of CRC associated with an FH of CRC or advanced adenoma warrants more intense screening for CRC. Well-designed prospective studies are needed in order to make definitive evidence-based recommendations about the age to commence screening and appropriate interval between screening tests.

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.

BACKGROUND: Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Rectal Indomethacin and prophylactic pancreatic stent placement have been shown to be effective for the prevention of post-ERCP pancreatitis. However, there remains considerable controversy regarding the usefulness of protease inhibitors (PIs) in preventing PEP. AIMS: This systematic review of randomized controlled trials (RCTs) aims to compare PIs with other pharmacological agents and/or placebo. METHODS: CENTRAL (the Cochrane library), MEDLINE, EMBASE, and CINAHL databases, and major conference proceedings from DDW, UEGW and ACG up to July 2017 were searched for RCTs examining PIs against other pharmacological agents and/or placebo. Study selection, data extraction and quality assessment were conducted independently by two authors. The primary outcome was PEP. Secondary outcomes included severity of PEP and other ERCP-related complications such as bleeding, perforation, cholangitis, cholecystitis and mortality. The outcomes were pooled into a meta-analysis using risk ratios (RR) with 95% confidence intervals (CI; Mandel-Haenszel method; random effects model). Heterogeneity was assessed by Chi(2) test (P 25%). The risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. RESULTS: 23 RCTs (7091 patients) comparing four different types of PIs with placebo were included in this review. Overall, there was a significant reduction in the risk of post-ERCP pancreatitis with PIs compared with placebo (RR 0.56, 95% CI 0.44–0.73, I(2) = 33%). Among the seven studies that compared Ulinastatin with placebo, the incidence of PEP was 3.9% in the PI group vs. 8.3% in the placebo group (RR 0.48; 95% CI 0.30–0.76; I(2) = 0%). Among the seven studies that compared Nafamostat with placebo, the incidence of PEP was 3.8% in the PI group vs. 8.2% in the control group (RR 0.43; 95% CI 0.31–0.59, I(2)=0%). There was no statistically significant difference found in the comparison between Gabexate versus placebo (RR 0.68; 95% CI 0.41–1.12; I(2) = 48%). In the one study that assessed Aprotinin versus placebo, there was no statistically significant difference (RR 1.38, 95% CI 0.66–2.86). Overall, the risks of bleeding (1.5%), perforation (0.2%), cholangitis (1.2%) and mortality (0.3%) appeared to be low. CONCLUSIONS: Protease inhibitors, specifically Nafamostat and Ulinastatin, are effective in preventing PEP. Further studies are needed to assess the optimal dose, timing and duration of PI, as well as the cost-effectiveness in different subgroups of patients. As well, the role of PIs along with prophylactic PD stent placement and rectal NSAIDs will need to be further elucidated in RCTs. FUNDING AGENCIES: None

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.

Background & Aims Altering the intestinal microbiota has been proposed as a treatment for inflammatory bowel diseases (IBDs), but there are no established associations between specific microbes and IBD. We performed a systematic review to identify frequent associations. Methods We searched the MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases, through April 2, 2018 for studies that compared intestinal microbiota (from fecal or colonic or ileal tissue samples) among patients (adult or pediatric) with IBD vs healthy individuals (controls). The primary outcome was difference in specific taxa in fecal or intestinal tissue samples from patients with IBD vs controls. We used the Newcastle-Ottawa scale to assess the quality of studies included in the review. Results We identified 2631 citations; 48 studies from 45 articles were included in the analysis. Most studies evaluated adults with Crohn's disease or ulcerative colitis. All 3 studies of Christensenellaceae and Coriobacteriaceae and 6 of 11 studies of Faecalibacterium prausnitzii reported a decreased amount of those organisms compared with controls, whereas 2 studies each of Actinomyces, Veillonella, and Escherichia coli revealed an increased amount in patients with Crohn's disease. For patients with ulcerative colitis, Eubacterium rectale and Akkermansia were decreased in all 3 studies, whereas E coli was increased in 4 of 9 studies. The microbiota diversity was either decreased or not different in patients with IBD vs controls. Fewer than 50% of the studies stated comparable sexes and ages of cases and controls. Conclusions In a systematic review, we found evidence for differences in abundances of some bacteria in patients with IBD vs controls, but we cannot make conclusions due to inconsistent results and methods among studies. Further large-scale studies, with better methods of assessing microbe populations, are needed.

There are 34 studies in almost 2 million participants that have reported on the association between proton pump inhibitor (PPI) therapy and risk of fracture. There is substantial variation between the results of each study but systematic reviews of the data suggest overall there is an association between PPI therapy and risk of fracture. The magnitude of the association is modest and is most likely due to confounding factors as patients prescribed PPI therapy tend to be more frail with more risk factors for fractures than those not given these drugs. There is no clear dose-response relationship and there is no association between PPI therapy and risk of fracture in those at highest risk. Finally, there is no clear mechanism through which PPI therapy increases the risk of fracture, as recent randomized trials show no impact of PPI therapy on calcium absorption and there is no association between PPI therapy and risk of osteoporosis. We therefore feel there is insufficient evidence to change PPI prescribing habits based on risk of fracture. Similarly, we do not recommend bone mineral density investigations for patients taking PPI therapy other than would be normally indicated. There is no evidence to support prescription of calcium and/or vitamin D in patients simply because they are taking PPI therapy. As with all medications, we only recommend prescribing PPI therapy when there is a clear indication that benefit will outweigh risk and at the lowest effective dose. Patients should be regularly assessed as to whether acid suppression is still required.

There is emerging concern that selective serotonin reuptake inhibitors (SSRIs) may be associated with an increased risk of upper gastrointestinal (GI) bleeding, and that this risk may be further increased by concurrent use of nonsteroidal anti-inflammatory (NSAID) medications. Previous reviews of a relatively small number of studies have reported a substantial risk of upper GI bleeding with SSRIs; however, more recent studies have produced variable results. The objective of this study was to obtain a more precise estimate of the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use.MEDLINE, EMBASE, PsycINFO, the Cochrane central register of controlled trials (through April 2013), and US and European conference proceedings were searched. Controlled trials, cohort, case-control, and cross-sectional studies that reported the incidence of upper GI bleeding in adults on SSRIs with or without concurrent NSAID use, compared with placebo or no treatment were included. Data were extracted independently by two authors. Dichotomous data were pooled to obtain odds ratio (OR) of the risk of upper GI bleeding with SSRIs +/- NSAID, with a 95% confidence interval (CI). The main outcome and measure of the study was the risk of upper GI bleeding with SSRIs compared with placebo or no treatment.Fifteen case-control studies (including 393,268 participants) and four cohort studies were included in the analysis. There was an increased risk of upper GI bleeding with SSRI medications in the case-control studies (OR=1.66, 95% CI=1.44,1.92) and cohort studies (OR=1.68, 95% CI=1.13,2.50). The number needed to harm for upper GI bleeding with SSRI treatment in a low-risk population was 3,177, and in a high-risk population it was 881. The risk of upper GI bleeding was further increased with the use of both SSRI and NSAID medications (OR=4.25, 95% CI=2.82,6.42).SSRI medications are associated with a modest increase in the risk of upper GI bleeding, which is lower than has previously been estimated. This risk is significantly elevated when SSRI medications are used in combination with NSAIDs, and physicians prescribing these medications together should exercise caution and discuss this risk with patients.

Background and study aims: Cannulation techniques are recognized to be important in causing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). However, considerable controversy exists about the usefulness of the guide wire-assisted cannulation technique for the prevention of PEP. This systematic review of randomized controlled trials (RCTs) aimed to compare the guide wire-assisted cannulation technique with the contrast-assisted cannulation technique. Methods: CENTRAL, MEDLINE, EMBASE, CINAHL, and abstracts from Digestive Disease Week and the United European Gastroenterology Week were searched up to February 2012 for RCTs comparing the guide wire-assisted ERCP cannulation technique with the conventional contrast-assisted ERCP cannulation technique. The risk of bias was assessed, and outcomes were pooled by meta-analysis (random-effects model). The primary outcome measure was PEP. Secondary outcome measures included severity of PEP, primary common bile duct (CBD) cannulation success, overall CBD cannulation success, precut sphincterotomy, and other ERCP-related complications. Results: In total, 12 RCTs (3450 patients) were included. The guide wire-assisted cannulation technique significantly reduced PEP compared with the contrast-assisted cannulation technique (risk ratio [RR] 0.51, 95 % confidence interval [CI] 0.32 – 0.82). In addition, the guide wire-assisted cannulation technique was associated with greater primary cannulation success (RR 1.07, 95 %CI 1.00 – 1.15), fewer precut sphincterotomies (RR 0.75, 95 %CI 0.60 – 0.95), and no increase in other ERCP-related complications. Subgroup analyses indicated that this significant risk reduction in PEP with the guide wire-assisted cannulation technique existed only in “non-crossover” trials (RR 0.22, 95 %CI 0.12 – 0.42). The results were robust in sensitivity analyses. Conclusion: Compared with the contrast-assisted cannulation technique, the guide wire-assisted cannulation technique increases the primary cannulation rate and reduces the risk of PEP, and therefore appears to be the most appropriate first-line cannulation technique.

Background & Aims Video capsule endoscopy (CE) provides a noninvasive option to assess the small intestine, but its use with respect to endoscopic procedures and cross-sectional imaging varies widely. The aim of this consensus was to provide guidance on the appropriate use of CE in clinical practice. Methods A systematic literature search identified studies on the use of CE in patients with Crohn's disease, celiac disease, gastrointestinal bleeding, and anemia. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Results The consensus includes 21 statements focused on the use of small-bowel CE and colon capsule endoscopy. CE was recommended for patients with suspected, known, or relapsed Crohn's disease when ileocolonoscopy and imaging studies were negative if it was imperative to know whether active Crohn's disease was present in the small bowel. It was not recommended in patients with chronic abdominal pain or diarrhea, in whom there was no evidence of abnormal biomarkers typically associated with Crohn's disease. CE was recommended to assess patients with celiac disease who have unexplained symptoms despite appropriate treatment, but not to make the diagnosis. In patients with overt gastrointestinal bleeding, and negative findings on esophagogastroduodenoscopy and colonoscopy, CE should be performed as soon as possible. CE was recommended only in selected patients with unexplained, mild, chronic iron-deficiency anemia. CE was suggested for surveillance in patients with polyposis syndromes or other small-bowel cancers, who required small-bowel studies. Colon capsule endoscopy should not be substituted routinely for colonoscopy. Patients should be made aware of the potential risks of CE including a failed procedure, capsule retention, or a missed lesion. Finally, standardized criteria for training and reporting in CE should be defined. Conclusions CE generally should be considered a complementary test in patients with gastrointestinal bleeding, Crohn's disease, or celiac disease, who have had negative or inconclusive endoscopic or imaging studies.

Effect of Comorbidity on Mortality in Patients With Peptic Ulcer Bleeding: Systematic Review and Meta-Analysis

Background and Aims The optimal timing of endoscopy in patients with peptic ulcer bleeding (PUB) remains unclear. The aim of this study was to examine the association between timing of endoscopy and mortality in PUB. Methods In a nationwide cohort study based on a database of consecutive patients admitted to the hospital with PUB in Denmark, patients were stratified according to the presence of hemodynamic instability at presentation and American Society of Anesthesiologists (ASA) score. Using descriptive statistics and logistic regression analyses, we identified optimal time frames for endoscopy and analyzed the association between timing of endoscopy and in-hospital mortality after adjusting for confounding factors. Results In total, 12,601 patients were included. We did not find any universal association between timing of endoscopy and mortality in hemodynamically stable patients with an ASA score of 1 to 2. In hemodynamically stable patients with an ASA score of 3 to 5, endoscopy 12 to 36 hours after admission to the hospital was associated with lower in-hospital mortality (OR, .48; 95% CI, .34-.67) compared with endoscopy outside this time frame. In patients with hemodynamic instability, endoscopy 6 to 24 hours after admission to the hospital was associated with lower in-hospital mortality (OR, .73; 95% CI, .54-.98) compared with endoscopy outside this time frame. Conclusions Timing of endoscopy is associated with mortality in patients with PUB and an ASA score of 3 to 5 or hemodynamic instability. Our findings suggest that in these patients, a period of time to optimize resuscitation and manage comorbidities before endoscopy may improve outcome.

Helicobacter pylori (H. pylori) infection is a common worldwide infection that is an important cause of peptic ulcer disease and gastric cancer. H. pylori may also have a role in uninvestigated and functional dyspepsia, ulcer risk in patients taking low-dose aspirin or starting therapy with a non-steroidal anti-inflammatory medication, unexplained iron deficiency anemia, and idiopathic thrombocytopenic purpura. While choosing a treatment regimen for H. pylori, patients should be asked about previous antibiotic exposure and this information should be incorporated into the decision-making process. For first-line treatment, clarithromycin triple therapy should be confined to patients with no previous history of macrolide exposure who reside in areas where clarithromycin resistance amongst H. pylori isolates is known to be low. Most patients will be better served by first-line treatment with bismuth quadruple therapy or concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and metronidazole. When first-line therapy fails, a salvage regimen should avoid antibiotics that were previously used. If a patient received a first-line treatment containing clarithromycin, bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options. If a patient received first-line bismuth quadruple therapy, clarithromycin or levofloxacin-containing salvage regimens are the preferred treatment options. Details regarding the drugs, doses and durations of the recommended and suggested first-line and salvage regimens can be found in the guideline.

Background Difficult cannulation is a risk factor for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). It has been postulated that the pancreatic duct guidewire (PGW) technique may improve biliary cannulation success and reduce the risk of PEP in people with difficult cannulation. Objectives To systematically review evidence from randomised controlled trials (RCTs) assessing the effectiveness and safety of the PGW technique compared to persistent conventional cannulation (CC) (contrast- or guidewire-assisted cannulation) or other advanced techniques in people with difficult biliary cannulation for the prevention of PEP. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL databases, major conference proceedings, and for ongoing trials on the ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to March 2016, using the Cochrane Upper Gastrointestinal and Pancreatic Diseases model with no language restrictions. Selection criteria RCTs comparing the PGW technique versus persistent CC or other advanced techniques in people undergoing ERCP with difficult biliary cannulation. Data collection and analysis Two review authors independently conducted study selection, data extraction, and methodological quality assessment. Using intention-to-treat analysis with random-effects models, we combined dichotomous data to obtain risk ratios (RR) with 95% confidence intervals (CI). We assessed heterogeneity using the Chi2 test (P 25%). To explore sources of heterogeneity, we conducted a priori subgroup analyses according to trial design, use of pancreatic duct (PD) stent, involvement of trainees in cannulation, publication type, and risk of bias. To assess the robustness of our results, we carried out sensitivity analyses using different summary statistics (RR versus odds ratio (OR)) and meta-analytic models (fixed-effect versus random-effects). Main results We included seven RCTs comprising 577 participants. There was no significant heterogeneity among trials for the outcome of PEP (P = 0.32; I2 = 15%). The PGW technique significantly increased PEP compared to other endoscopic techniques (RR 1.98, 95% CI 1.14 to 3.42; low-quality evidence). The number needed to treat for an additional harmful outcome was 13 (95% CI 5 to 89). Among the three studies that compared the PGW technique with persistent CC, the incidence of PEP was 13.5% for the PGW technique and 8.7% for persistent CC (RR 1.58, 95% CI 0.83 to 3.01; low-quality evidence). Among the two studies that compared the PGW technique with precut sphincterotomy, the incidence of PEP was 29.8% in the PGW group versus 10.3% in the precut group (RR 2.92, 95% CI 1.24 to 6.88; low-quality evidence). Among the two studies that compared the PGW technique with PD stent placement, the incidence of PEP was 11.7% for the PGW technique and 5.0% for PD stent placement (RR 1.75, 95% CI 0.08 to 37.50; very low-quality evidence). There was no significant difference in common bile duct (CBD) cannulation success with the randomised technique (RR 1.04, 95% CI 0.87 to 1.24; low-quality evidence) or overall CBD cannulation success (RR 1.04, 95% CI 0.91 to 1.18; low-quality evidence) between the PGW technique and other endoscopic techniques. There was also no statistically significant difference in the risk of other ERCP-related complications (bleeding, perforation, cholangitis, and mortality). The results were robust in sensitivity analyses. The overall quality of evidence for the outcome of PEP was low or very low because of study limitations and imprecision. Authors' conclusions In people with difficult CBD cannulation, sole use of the PGW technique appears to be associated with an increased risk of PEP. Prophylactic PD stenting after use of the PGW technique may reduce the risk of PEP. However, the PGW technique is not superior to persistent attempts with CC, precut sphincterotomy, or PD stent in achieving CBD cannulation. The influence of co-intervention in the form of rectal peri-procedural nonsteroidal anti-inflammatory drug administration is unclear.

*Division of Gastroenterology, and Division of Clinical Epidemiology, McGill University and the McGill University Health Centre, Montreal, Quebec, Canada; INSERM IC-P 803, CHU du Bocage, Dijon, France; Universite de Bourgogne, Dijon, France; **Department of Medicine, Division of Gastroenterology, Farncombe Family igestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Guelph General Hospital, Guelph and McMaster University, Guelph, Ontario, Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Division of Gastroenterology, Medical University Canada; f South Carlolina, Charleston, South Carolina; and the Department of Medicine, Chinese University of Hong Kong, Hong Kong, China

PPIs have become one of the most commonly used medications worldwide, as they are the treatment of choice for several acid-related gastrointestinal disorders. However, concerns have been raised about PPI therapy, including the risk of pneumonia, bone fractures and enteric infections, and a possible interaction with clopidogrel that could increase the risk of cardiovascular events. Observational studies have shown very modest associations between PPI therapy and these risks, although the association between PPI treatment and the risk of enteric infections seems to be stronger than the association with other risk factors. However, given the inherent limitations of observational studies, these associations could be attributable to bias and/or confounding factors. In addition, evidence from randomized, controlled trials does not support a clinically significant effect of PPI therapy on the risk of cardiovascular events in patients taking clopidogrel or the risk of pneumonia. Nevertheless, it is impossible to exclude the possibility that some of these associations might be causal or indeed that PPI therapy has an as yet unknown long-term adverse effect. As with any therapy, therefore, it is advisable to prescribe PPIs only to patients for whom these drugs have been proven beneficial.