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Background: Choosing Wisely Canada (CWC) recommends not to perform gastroscopy for dyspepsia in otherwise healthy adults less than 55 years of age (2014). The aim of this study was to evaluate the use of gastroscopy in a young, healthy population with uncomplicated dyspepsia., Methods: A retrospective review of gastroscopies completed during 3-month periods in 2015, 2016, and 2017 identified all patients undergoing gastroscopy for the primary indication of dyspepsia. Low-risk patients for dyspepsia were defined as adults, aged 18 to 54 years without alarm symptoms, comorbidities and/or abnormal imaging findings or laboratory values. Gastroscopy and pathology reports were reviewed to identify clinically actionable findings. Clinical outcomes were followed to December 31, 2018 including gastroenterology referrals, emergency room visitation and hospitalization., Results: Among 1358 patients having a gastroscopy for dyspepsia, 480 (35%) were low-risk patients. Sixteen patients 3.3% (16/480) had a clinically actionable result found on gastroscopy or biopsy. No malignant lesions were detected. Low-risk patients were followed up for an average of 2.75 years, 8% (39/480) visited the emergency department (ED), 1% (3/480) of patients were admitted to hospital and 12% (59/480) of patients were re-referred for a dyspepsia-related concern., Interpretation: A high rate of low yield, high cost, invasive endoscopic investigations were performed in this population of otherwise healthy patients under age 55 years. These data suggest limited uptake of current recommendations against the routine use of gastroscopy to investigate dyspepsia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

Background & Aims: The efficacy of colorectal cancer (CRC) screening is dependent on participation and subsequent adherence to surveillance. The internet increasingly is used for health information and is important to support decision making. We evaluated the accuracy, quality, and readability of online information on CRC screening and surveillance., Methods: A Website Accuracy Score and Polyp Score were developed, which awarded points for various aspects of CRC screening and surveillance. Websites also were evaluated using validated internet quality instruments (Global Quality Score, LIDA, and DISCERN), and reading scores. Two raters independently assessed the top 30 websites appearing on Google.com. Portals, duplicates, and news articles were excluded., Results: Twenty websites were included. The mean website accuracy score was 26 of 44 (range, 9-41). Websites with the highest scores were www.cancer.org, www.bowelcanceraustralia.org, and www.uptodate.com. The median polyp score was 3 of 10. The median global quality score was 3 of 5 (range, 2-5). The median overall LIDA score was 74% and the median DISCERN score was 45, both indicating moderate quality. The mean Flesch-Kincaid grade level was 11th grade, rating the websites as difficult to read, 30% had a reading level acceptable for the general public (Flesch Reading Ease > 60). There was no correlation between the Google rank and the website accuracy score (r s  = -0.31; P = .18)., Conclusions: There is marked variation in quality and readability of websites on CRC screening. Most websites do not address polyp surveillance. The poor correlation between quality and Google ranking suggests that screenees will miss out on high-quality websites using standard search strategies., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Adherence to surveillance colonoscopy guidelines is important to prevent colorectal cancer (CRC) and unnecessary workload., Objective: To evaluate how well Canadian gastroenterologists adhere to colonoscopy surveillance guidelines after adenoma removal or treatment for CRC., Methods: Patients with a history of adenomas or CRC who had surveillance performed between October 2008 and October 2010 were retrospectively included. Time intervals between index colonoscopy and surveillance were compared with the 2008 guideline recommendations of the American Gastroenterological Association and regarded as appropriate when the surveillance interval was within six months of the recommended time interval., Results: A total of 265 patients were included (52% men; mean age 58 years). Among patients with a normal index colonoscopy (n=110), 42% received surveillance on time, 38% too early (median difference = 1.2 years too early) and 20% too late (median difference = 1.0 year too late). Among patients with nonadvanced adenomas at index (n=96), 25% underwent surveillance on time, 61% too early (median difference = 1.85) and 14% too late (median difference = 1.1). Among patients with advanced neoplasia at index (n=59), 29% underwent surveillance on time, 34% too early (median difference = 1.86) and 37% later than recommended (median difference = 1.61). No significant difference in adenoma detection rates was observed when too early surveillance versus appropriate surveillance (34% versus 33%; P=0.92) and too late surveillance versus appropriate surveillance (21% versus 33%; P=0.11) were compared., Conclusion: Only a minority of surveillance colonoscopies were performed according to guideline recommendations. Deviation from the guidelines did not improve the adenoma detection rate. Interventions aimed at improving adherence to surveillance guidelines are needed.

Introduction: Due to the increasing demand for colonoscopy, adherence to postpolypectomy surveillance guidelines is important. Suboptimal compliance can lead to unnecessary risks and ineffective use of resources., Objective: To determine the awareness of and adherence to postpolypectomy surveillance guidelines among members of the Canadian Association of Gastroenterology (CAG)., Methods: A survey describing 14 clinical cases was mailed to all physician members (n=411) of the CAG. Respondents were required to recommend a surveillance interval and a reason for his or her choice., Results: A total of 150 colonoscopists (37%) completed the survey. Adherence to the guidelines varied from 23% to 96% per clinical scenario (median 63%). Recommended surveillance intervals were too short in 0% to 60% of the different cases (median 8%). The recommended interval was most often (60%) too short for a patient with one tubular adenoma with high-grade dysplasia. Surveillance intervals were too long in 4% to 75% of the cases (median 9%). The recommended interval was most often too long in a patient with a villous adenoma 15 mm in size and removed piecemeal (75%). Most often, recommendations were reported to be based on guidelines (median 74%; range 31% to 94%). However, in nine of 14 cases, more than 10% (median 18%; range 12% to 38%) of the respondents stated that their recommendation was based on guidelines, but did not provide the appropriate surveillance interval., Conclusions: Compliance to colonoscopy surveillance guidelines is suboptimal and reflects both overuse and underuse. The results show that awareness about the content of guidelines needs to be raised and strategies implemented to increase adherence.

Background: The Global Rating Scale (GRS) comprehensively evaluates the quality of an endoscopy department, providing a patient-centred framework for service improvement., Objective: To assess patient experiences during colonoscopy and identify areas that need service improvement using the GRS., Methods: Consecutive outpatients undergoing colonoscopy were asked to complete a pre- and postprocedure questionnaire. Questions were based on GRS items and a literature review. The preprocedure questionnaire addressed items such as patient characteristics and information provision. The postprocedure questionnaire contained questions regarding comfort, sedation, the attitude of endoscopy staff and aftercare., Results: The preprocedure questionnaire was completed by 1,187 patients, whereas the postprocedure part of the questionnaire was completed by 851 patients (71.9%). Fifty-four per cent of patients were first seen in the outpatient clinic. The indication for colonoscopy was explained to 85% of the patients. Sixty-five per cent of the patients stated that information about the risks of colonoscopy was provided. Sedation was used in 94% of the patients; however, 23% judged the colonoscopy to be more uncomfortable than expected. Ten per cent of patients rated the colonoscopy as (very) uncomfortable. Preliminary results of the colonoscopy were discussed with 87% of patients after the procedure. Twenty-one per cent of the patients left the hospital without knowing how to obtain their final results. Being comfortable while waiting for the procedure (OR 9.93) and a less uncomfortable procedure than expected (OR 2.99) were important determinants of the willingness to return for colonoscopy., Conclusions: The present study provided evidence supporting the GRS in identifying service gaps in the quality of patient experiences for colonoscopy in a North American setting. Assessing experiences is useful in identifying areas that need improvement such as the provision of pre- and postprocedure information.

Objective: The relationship between acid and dyspeptic symptoms has not been fully understood., Aim: To investigate the type and severity of dyspeptic symptoms induced by direct acid infusion into the stomach of Japanese healthy subjects., Methods: This was a multi-centre, cross-over, randomized, double-blind study in 27 healthy subjects (mean age 27). Each fasted subject received two tests with 150 mL of 0.1 mol/L hydrochloric acid infusion (15 mL/min for 10 min) and the same volume of pure water infusion. The type and severity of symptoms were assessed by a 10 cm visual analogue scale administered every 2 min up to 30 min., Results: Various symptoms were reported after both acid and water infusions. Most of the symptoms were more severe after acid infusion compared with water infusion (acid vs. water: discomfort 1.8 +/- 0.4 vs. 0.5 +/- 0.1, pain 0.6 +/- 0.3 vs. 0.1 +/- 0.1, reflux 1.0 +/- 0.3 vs. 0.3 +/- 0.1 and satiety 1.1 +/- 0.4 vs. 0.2 +/- 0.1). The area under curve for dysmotility like symptoms (heavy feeling in the stomach, bloating, nausea or feeling sick, and belching) was significantly higher in acid infusion, and symptoms continued after infusion of the acid., Conclusion: Acid induced into stomach induced dysmotility-like predominant dyspeptic symptoms in Japanese healthy control subjects, demonstrating the possible importance of acid in symptom generation.

A leading hypothesis for the role of bacteria in inflammatory bowel diseases is that an imbalance in normal gut flora is a prerequisite for inflammation. Testing this hypothesis requires comparisons between the microbiota compositions of ulcerative colitis and Crohn's disease patients and those of healthy individuals. In this study, we obtained biopsy samples from patients with Crohn's disease and ulcerative colitis and from healthy controls. Bacterial DNA was extracted from the tissue samples, amplified using universal bacterial 16S rRNA gene primers, and cloned into a plasmid vector. Insert-containing colonies were picked for high-throughput sequencing, and sequence data were analyzed, yielding species-level phylogenetic data. The clone libraries yielded 3,305 sequenced clones, representing 151 operational taxonomical units. There was no significant difference between floras from inflamed and healthy tissues from within the same individual. Proteobacteria were significantly (P = 0.0007) increased in Crohn's disease patients, as were Bacteroidetes (P < 0.0001), while Clostridia were decreased in that group (P < 0.0001) in comparison with the healthy and ulcerative colitis groups, which displayed no significant differences. Thus, the bacterial flora composition of Crohn's patients appears to be significantly altered from that of healthy controls, unlike that of ulcerative colitis patients. Imbalance in flora in Crohn's disease is probably not sufficient to cause inflammation, since microbiotas from inflamed and noninflamed tissues were of similar compositions within the same individual.

Background: Delays in access to health care in Canada have been reported, but standardized systems to manage and monitor wait lists and wait times, and benchmarks for appropriate wait times, are lacking. The objective of the present consensus was to develop evidence- and expertise-based recommendations for medically appropriate maximal wait times for consultation and procedures by a digestive disease specialist., Methods: A steering committee drafted statements defining maximal wait times for specialist consultation and procedures based on the most common reasons for referral of adult patients to a digestive disease specialist. Statements were circulated in advance to a multidisciplinary group of 25 participants for comments and voting. At the consensus meeting, relevant data and the results of voting were presented and discussed; these formed the basis of the final wording and voting of statements., Results: Twenty-four statements were produced regarding maximal medically appropriate wait times for specialist consultation and procedures based on presenting signs and symptoms of referred patients. Statements covered the areas of gastrointestinal bleeding; cancer confirmation and screening and surveillance of colon cancer and colonic polyps; liver, biliary and pancreatic disorders; dysphagia and dyspepsia; abdominal pain and bowel dysfunction; and suspected inflammatory bowel disease. Maximal wait times could be stratified into four possible acuity categories of 24 h, two weeks, two months and six months., Future Directions: Comparison of these benchmarks with actual wait times will identify limitations in access to digestive heath care in Canada. These recommendations should be considered targets for future health care improvements and are not clinical practice guidelines.

This document addresses the design of trials to assess the efficacy of new treatments for functional gastrointestinal disorders (FGID), emphasizing trials in irritable bowel syndrome and dyspepsia, because most research has been undertaken in these conditions. The double-blind, randomized, placebo-controlled, parallel group trial remains the preferred design. Randomized withdrawal designs, although encouraged by the European Agency for the Evaluation of Medicinal Products, have the same potential disadvantages as a crossover design, including carryover effects, unmasking (unblinding), and overestimation of the potential benefit for clinical practice. Innovative trial designs that evaluate intermittent (on demand) treatment are likely to become more common in the future. Investigators should include as broad a spectrum of patients as possible and should report recruitment strategies, inclusion/exclusion criteria, and attrition data. The primary analysis should be based on the proportion of patients in each treatment arm who satisfy an a priori treatment responder definition, or a prespecified clinically meaningful change in a patient-reported symptom improvement measure. Such measures of improvement are psychometrically validated subjective global assessments or a change from baseline in a validated symptom severity questionnaire. It is unethical to change the responder definition after a trial begins. Data analysis should address all patients enrolled, using an intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include an analysis of harms data and secondary outcome measures to support or explain the primary outcome. Trials should be registered in a public location, prior to initiation, and should be published even if the results are negative or inconclusive.

Background: The prevalence of Barrett's oesophagus in patients undergoing gastroscopy may be influenced by possible referral bias., Aim: To present the prevalence of Barrett's oesophagus from the the Canadian Adult Dyspepsia Empirical Therapy Prompt Endoscopy study and to explore potential risk factors for its presence., Methods: Patients had not been on treatment for dyspepsia for 2-4 weeks prior to endoscopy, which was performed within 10 working days of presentation., Results: Barrett's oesophagus was endoscopically suspected in 53 of 1040 cases (5%) and histologically confirmed by the presence of intestinal metaplasia in 25 (2.4%). The prevalence of biopsy-proven Barrett's oesophagus was 4% in patients with dominant reflux-like symptoms. Sixty-four percent with confirmed Barrett's oesophagus had dominant reflux-like symptoms compared with 37% without Barrett's oesophagus. Barrett's oesophagus was more common in patients >50 years of age; 68% of cases were males. The mean duration of symptoms was 10 years, yet 16% had symptoms of <1-year duration. Endoscopic reflux oesophagitis was present in 68% of confirmed Barrett's oesophagus patients., Conclusions: Barrett's oesophagus is confirmed on biopsy in about half of endoscopically suspected Barrett's oesophagus patients. Barrett's oesophagus is more common in males, in those with dominant reflux-like symptoms, and in patients with a longer symptom history.

Background: Currently there is no consensus on the optimal method to measure the severity of dyspepsia symptoms in clinical trials., Aim: To validate the 7-point Global Overall Symptom scale., Methods: The Global Overall Symptom scale uses a 7-point Likert scale ranging from 1 = no problem to 7 = a very severe problem. Validation was performed in two randomized-controlled trials (n = 1121 and 512). Construct validity: Global Overall Symptom was compared with the Quality of Life in Reflux And Dyspepsia, Gastrointestinal Symptom Rating Scale, Reflux Disease Questionnaire and 10 specific symptoms using Spearman correlation coefficients. Test-retest reliability: The Intraclass Correlation Coefficient was calculated for patients with stable dyspepsia defined by no change in Overall Treatment Effect score over two visits. Responsiveness: effect size and standardized response mean were also calculated., Results: Construct validity: Change in Global Overall Symptom score correlated significantly with Quality of Life for Reflux And Dyspepsia, Gastrointestinal Symptom Rating Scale, Reflux Disease Questionnaire and specific symptoms (all P < 0.0002). Reliability: The Intraclass Correlation Coefficient was 0.62 (n = 205) and 0.42 (n = 270). Responsiveness: There was a positive correlation between change in Global Overall Symptom and change in symptom severity. The effect size and standardized response mean were 1.1 and 2.1, respectively., Conclusion: The Global Overall Symptom scale is a simple, valid outcome measure for dyspepsia treatment trials.

Background: Symptom diaries are potentially attractive but, because of concerns about patient compliance, they have had limited use in clinical trials. We assessed the validity and responsiveness of a symptom diary for patients with gastro-oesophageal reflux disease., Methods: We included 215 patients with gastro-oesophageal reflux disease after starting treatment for 4 weeks with 40 mg esomeprazole once daily. Patients recorded whether they experienced night-time heartburn (yes/no), the severity of daytime heartburn on a scale from 1 (no heartburn) to 4 (severe heartburn) and their antacid use. Patients also completed a number of disease-specific and preference-based Health-related Quality of Life questionnaires at baseline and follow-up., Results: Consistent with a priori predictions, daytime heartburn showed moderate to strong correlations with the Quality of Life in Reflux and Dyspepsia questionnaire (0.36-0.67) and four scales of symptom severity (0.36-0.70) for baseline, follow-up and change scores, but low correlations with the Standard Gamble. Responsiveness of the daytime heartburn item was excellent with a mean change from baseline to follow-up of -1.3 (95% CI -1.4 to -1.1) and a standardized response mean of 1.33 while responsiveness of the daily antacid use item was moderate (mean change scores -1.8 tablets taken, 95% CI -2.3 to -1.3 and standardized response mean of 0.64)., Conclusions: The excellent psychometric properties of this simple gastro-oesophageal reflux disease diary make it an attractive measure for future trials.

Background: There are few data on empiric, stepped therapy for heartburn relief or subsequent relapse in primary care., Aims: To compare heartburn relief produced by a proton pump inhibitor-start or an H(2)-receptor antagonist-start with step-up therapy, as needed, followed by a treatment-free period to assess relapse., Methods: Heartburn-dominant uninvestigated dyspepsia patients from 46 primary care centres were randomized to one of two active treatment strategies: omeprazole 20 mg daily (proton pump inhibitor-start) or ranitidine 150 mg bid (H2-receptor antagonist-start) for the first 4-8 weeks, stepping up to omeprazole 40 or 20 mg daily, respectively, for 4-8 weeks for persistent symptoms. Daily diaries documented heartburn relief (score < or = 3/7 on < or = of 7 prior days) and relapse (score > or = 4 on > or = 2 of 7 prior days)., Results: For 'proton pump inhibitor-start' (n = 196) vs. 'H2-receptor antagonist-start' (n = 194), respectively, heartburn relief occurred in 55.1% vs. 27.3% (P < 0.001) at 4 weeks and in 88.3% vs. 87.1% at 16 weeks. After therapy, 308 patients were heartburn-free (159 vs. 149); median times to relapse were 8 vs. 9 days and cumulative relapse rates were 78.6% vs. 75.8%, respectively., Conclusions: An empiric 'proton pump inhibitor-start' strategy relieves heartburn more effectively than an 'H2-receptor antagonist-start' strategy up to 12 weeks but has no effect on subsequent relapse, which is rapid in most patients.

The present paper is an update to and extension of the previous systematic review on the primary care management of patients with uninvestigated dyspepsia (UD). The original publication of the clinical management tool focused on the initial four- to eight-week assessment of UD. This update is based on new data from systematic reviews and clinical trials relevant to UD. There is now direct clinical evidence supporting a test-and-treat approach in patients with nondominant heartburn dyspepsia symptoms, and head-to-head comparisons show that use of a proton pump inhibitor is superior to the use of H2-receptor antagonists (H2RAs) in the initial treatment of Helicobacter pylori-negative dyspepsia patients. Cisapride is no longer available as a treatment option and evidence for other prokinetic agents is lacking. In patients with long-standing heartburn-dominant (ie, gastroesophageal reflux disease) and nonheartburn-dominant dyspepsia, a once-in-a-lifetime endoscopy is recommended. Endoscopy should also be considered in patients with new-onset dyspepsia that develops after the age of 50 years. Conventional nonsteroidal anti-inflammatory drugs, acetylsalicylic acid and cyclooxygenase-2-selective inhibitors can all cause dyspepsia. If their use cannot be discontinued, cotherapy with either a proton pump inhibitor, misoprostol or high-dose H2RAs is recommended, although the evidence is based on ulcer data and not dyspepsia data. In patients with nonheartburn-dominant dyspepsia, noninvasive testing for H pylori should be performed and treatment given if positive. When starting nonsteroidal anti-inflammatory drugs for a prolonged course, testing and treatment with H2RAs are advised if patients have a history of previous ulcers or ulcer bleeding.

Bismuth subsalicylate (BSS), the active ingredient of Pepto-Bismol, has been used for many years to treat various disorders of the gastrointestinal tract. Using mass spectrometry and the agar dilution method, we determined that insoluble BSS interacts with certain dietary components and organic substrates to produce water-soluble products with activity against Clostridium difficile.

Aim: To evaluate treatment efficacy using objective quality criteria., Methods: A systematic review was performed of randomized controlled trials of endoscopically investigated dyspepsia (1979-2003) using the Jadad score and Rome II guidelines. The Jadad score differentiated studies as 'high quality' (score 4-5/5) vs. 'poor quality' (score 1-3/5). Three key Rome II guidelines on study design (cut-off of 0/3 or > 0/3) were also compared with the Jadad score., Results: Poor quality trials suggested a benefit of prokinetic therapy [relative risk (RR) of remaining dyspeptic, 0.47; 95% confidence interval (CI), 0.39-0.56), which was not confirmed in high quality trials (RR, 1.0; 95% CI, 0.84-1.19). There was a marked benefit of H2-receptor antagonist therapy in poor quality trials (RR, 0.68; 95% CI, 0.61-0.76), but a marginal benefit in good quality trials (RR, 0.87; 95% CI, 0.79-0.97). Trial quality did not affect the small statistically significant benefit seen with Helicobacter pylori eradication. Two high quality trials suggested a limited benefit with the use of proton pump inhibitors, with no poor quality trials to provide a comparison. Separation of the studies by the Rome II criteria had a similar impact on the calculated treatment estimates., Conclusions: The magnitude of benefit of prokinetic and H2-receptor antagonist therapies reported in previous meta-analyses has been over-estimated. The quality of trials has an impact on the efficacy estimates of treatment. The Rome II criteria for study methodology may be appropriate for judging study quality.

Background: Adult Helicobacter pylori-positive patients by 13C-urea breath test with uninvestigated dyspepsia symptoms were randomized to 1-week eradication treatment with omeprazole, metronidazole and clarithromycin (OMC) vs. omeprazole and placebo antimicrobials (OPP) in the Canadian Adult Dyspepsia Empiric Treatment-H. pylori-positive (CADET-Hp) study., Aim: To perform an economic evaluation of this 1-year study., Methods: Following blind eradication treatment, family practitioners managed patients according to their usual practices. Health resource utilization information was collected prospectively. From the mean costs of the health resources consumed and the treatment outcomes, the incremental cost-effectiveness ratios and incremental net benefits of eradication treatment vs. OPP were determined., Results: Eradication therapy significantly improved dyspepsia symptoms (treatment success: OMC, 50%; OPP, 36%; P = 0.02). The incremental cost-effectiveness ratio of OMC vs. OPP was - 387 Canadian dollars (CAD$) per treatment success (90% CI, - CAD$1707, CAD$607), indicating a lower cost with treatment success. The incremental net benefit analysis showed that H. pylori eradication was cost-effective if the willingness-to-pay value exceeded a nominal figure of CAD$100 from a health service perspective or CAD$607 from the societal perspective., Conclusion: In uninvestigated patients presenting with dyspepsia at the primary care level, eradication of H. pylori in those who are H. pylori positive leads to a cost-effective improvement in dyspepsia symptoms compared with a strategy of not eradicating H. pylori in these patients.

Susceptibility testing was performed at seven Canadian microbiology laboratories and the Helicobacter Reference Laboratory, Halifax, Nova Scotia, Canada, to assess susceptibility testing proficiency and the reproducibility of the results for clarithromycin and metronidazole and to compare the Epsilometer test (E test) method to the agar dilution reference method. Control strain Helicobacter pylori ATCC 43504 (American Type Culture Collection) and 13 clinical isolates (plus duplicates of four of these strains including ATCC 43504) were tested blindly. The National Committee for Clinical Laboratory Standards (NCCLS) guidelines for agar dilution testing were followed, and the same suspension of organisms was used for agar dilution and E test. Antimicrobials and E test strips were provided to the investigators. Methods were provided on a website (www.Helicobactercanada.org). Each center reported MICs within the stated range for strain ATCC 43504. Compared to the average MICs, interlaboratory agreements within 2 log(2) dilutions were 90% (range, 69 to 100%) for clarithromycin by agar dilution, with seven very major errors [VMEs], and 85% (range, 65 to 100%) by E test, with three VMEs. Interlaboratory agreements within 2 log(2) dilutions were 83% (range, 50 to 100%) for metronidazole by agar dilution, with six VMEs and eight major errors (MEs), and 75% (range, 50 to 94%) by E test, with four VMEs and four MEs. At lower and higher concentrations of antibiotic, E test MICs were slightly different from agar dilution MICs, but these differences did not result in errors. When a standardized protocol based on NCCLS guidelines was used, most participants in this study correctly identified clarithromycin- and metronidazole-susceptible and -resistant strains of H. pylori 93% of the time by either the agar dilution or E test method, and the numbers of errors were relatively equivalent by both methods.

The identification of genes associated with colonization and persistence of Helicobacter pylori in the gastric mucosa has been limited by the lack of robust animal models that support infection by strains whose genomes have been completely sequenced. Here we report that an interleukin-12 (IL-12)-deficient mouse (IL-12(-/-) p40 subunit knockout in C57BL/6 mouse) is permissive for infection by a motile variant (KE88-3887) of The Institute For Genomic Research-sequenced strain (KE26695) of H. pylori. The IL-12-deficient mouse was also more permissive for colonization by the mouse-colonizing Sydney 1 strain of H. pylori than were wild-type C57BL/6 mice. Differences in colonization efficiency were demonstrated by mouse challenge with SS1 strains containing loss-of-function mutations in two genes (hspR and hrcA), whose products negatively regulate several heat shock genes. At 5 weeks postinfection, double-knockout mutants (SS1 hspR hrcA) efficiently colonized IL-12-deficient mice (5 of 5 animals compared to 4 of 10 for C57BL6 mice) and bacterial counts were higher in stomachs of IL-12-deficient mice (10(6) versus 10(5) CFU/g of stomach, respectively). IL-12-deficient mice were efficiently colonized by KE88-3887 (29 of 30), but not by nonmotile KE26695, and bacterial numbers (10(4) to 10(5) CFU/g of stomach) were unchanged over an 8-week period postinfection. In contrast, C57BL/6 mice were inefficiently colonized by KE88-3887 (8 of 20 animals with bacterial loads at the limit of detection, approximately 10(3) CFU/g), and infection did not persist much beyond 5 weeks. Cytokine responses (tumor necrosis factor alpha and gamma interferon), pathology, and antral-predominant infection were indistinguishable between IL-12-deficient and C57BL/6 mice. The increased permissiveness of the IL-12-deficient mouse for infection with H. pylori should facilitate whole-genome-based strategies to study genes associated with virulence and immune modulation.

Background: Helicobacter pylori infection has been proposed as a protective factor against the development of gastro-oesophageal reflux disease., Aim: To study heartburn and endoscopic findings before and after H. pylori eradication therapy in patients with peptic ulcer disease., Methods: In a multicentre trial programme, patients (n = 1497) were randomized to the omeprazole triple therapy group or to the control group, and were followed for 1-6 months after treatment. Patients in whom the infection was eradicated were compared with those in whom infection persisted. The severity of heartburn was measured at baseline and at each return visit. Endoscopy was performed 6 months after therapy in two of the five studies., Results: In patients with duodenal ulcer, there was a significantly lower prevalence of heartburn after successful eradication of H. pylori relative to that after failed eradication (estimated odds ratio, 0.48). The reduction in the prevalence of heartburn in patients with gastric ulcer was independent of the post-treatment H. pylori status. In studies in which ulcer relapse was included in the model, this factor emerged as a significant factor for heartburn. The observed incidence of oesophagitis at the last visit was not influenced by H. pylori status., Conclusions: Eradication of H. pylori in patients with peptic ulcer disease was associated with a reduced prevalence of heartburn. Prevention of ulcer relapse could be the true cause of this reduction.

Currently, one of the most important unresolved questions concerning Helicobacter pylori is whether eradication of the organism leads to a sustained improvement in symptoms in patients diagnosed with functional (non-ulcer) dyspepsia. Recently, two very similar studies, the ORCHID and OCAY studies, have been completed and the combined results of these two multicentre, multinational, randomised, double blind, controlled clinical trials are reviewed.

There is a lack of consensus among researchers on how to best measure outcome in functional dyspepsia trials and more importantly a lack of validated outcome measures. If symptoms resolve completely, treatment has been successful but with partial improvement interpretation is less straightforward. It is most likely that these issues will only be resolved if unequivocally efficacious treatments emerge to which the different outcome measures can be compared. Recently, a few validated outcome measures have been developed which look promising.

Aim: To perform a meta-analysis evaluating the efficacy of H2-receptor antagonists in functional (nonulcer) dyspepsia., Selection of Studies: A Medline search was used to identify placebo controlled randomized clinical trials, using the subject headings dyspepsia and H2-receptor antagonist., Outcome Measures: Global assessment by the patient of dyspepsia symptoms, improvement of epigastric pain and complete relief of epigastric pain., Results: Twenty-two studies met the inclusion criteria, 15 of which reported the active drug to be superior to placebo. Many studies suffered from suboptimal study design. The odds ratio in favour of active drug was 1.48 (95% confidence interval: 0.9-2.3) for global assessment of dyspepsia symptoms, 2.3 (95% CI: 1.6-3.3) for improvement of epigastric pain, and 1.8 (95% CI: 1.2-2.8) for complete relief of epigastric pain., Conclusion: There is some evidence that H2-receptor antagonists are superior to placebo in functional dyspepsia, but larger studies evaluating higher doses of H2-receptor antagonists and of longer duration are necessary to determine the exact effect size.

Objective: To identify the frequency of use and appropriate monitoring guidelines for the adverse effects of azathioprine and 6-mercaptopurine (6-MP) in the therapy of patients with inflammatory bowel disease (IBD)., Methods: Surveys were sent to all physician members of the Canadian Association of Gastroenterology. Physicians were asked to describe their monitoring practices for IBD patients receiving azathioprine or 6-MP. A systematic literature search was also performed using MEDLINE for articles published in English between 1966 and 1999 using the MeSH terms 'azathioprine', '6-mercaptopurine', 'inflammatory bowel disease' and 'drug monitoring'., Results: Azathioprine and 6-MP were used to treat an average of 7% of patients - a surprisingly low number given the proven efficacy of these agents. All respondents reported monitoring complete blood counts (CBC), while liver enzyme and pancreatic enzyme levels were monitored by 62% and 29% of respondents, respectively. The most commonly reported initial CBC testing frequencies were weekly (42%), monthly (26%) and biweekly (23%). From the literature, it was determined that severe leukopenia (less than 2.10 g/L) occurs in less than 2% of cases and is sometimes associated with serious outcomes, including death. Most cases of severe leukopenia occurred abruptly, early in treatment. Other reported adverse effects and incidences were pancreatitis (3% to 5%), hepatotoxicity (less than 1%) and hypersensitivity (2% to 3%). Data concerning an increased risk of non-Hodgkin's lymphoma were equivocal., Conclusions: Use of azathioprine or 6-MP is low in patients with IBD. A CBC should be performed at weeks 1, 2, 4, 6, 8 and 12, with subsequent testing every eight weeks for the duration of azathioprine or 6-MP treatment. The evidence in support of pancreatic and hepatic monitoring is weak. The risk of non-Hodgkin's lymphoma is likely low.

Eradication of Helicobacter pylori from the gastric and duodenal mucosa is an important clinical goal in the treatment of infected patients with peptic ulcer disease and other H pylori-associated conditions. Although several oral drug combination regimens are associated with eradication rates of approximately 85% in controlled trials, the success rate in patients infected with a resistant strain of H pylori is closer to 75%. Resistance to metronidazole and clarithromycin, which are common components of combination treatment regimens, is of greatest concern. Reported rates of H pylori resistance to various antibiotics vary considerably. In Canada, the data documenting H pylori susceptibility are limited but suggest that resistance to these antibiotics varies geographically and within specific treatment groups. Although susceptibility testing is not a prerequisite for initial treatment of individual patients infected with H pylori, formal efforts to identify and monitor both the causes and prevalence of antibiotic resistance across Canada are a much needed step in the ongoing management of this important infection. Recommended treatment regimens may be useful, even for treating apparently resistant H pylori strains. However, it is important to understand the mechanisms of the development of resistant strains to manage patients with treatment failure better.

Objectives: To provide Canadian primary care physicians with an evidence-based clinical management tool, including diagnostic and treatment recommendations, for patients who present with uninvestigated dyspepsia., Recommendations: The management tool has 5 key decision steps addressing the following: (1) evidence that symptoms originate in the upper gastrointestinal tract, (2) presence of alarm features, (3) use of nonsteroidal anti-inflammatory drugs (NSAIDs), (4) dominant reflux symptoms and (5) evidence of Helicobacter pylori infection. All patients over 50 years of age who present with new-onset dyspepsia and patients who present with alarm features should receive prompt investigation, preferably by endoscopy. The management options for patients with uninvestigated dyspepsia who use NSAIDs regularly are: (1) to stop NSAID therapy and assess symptomatic response, (2) to treat with NSAID prophylaxis if NSAID therapy cannot be stopped or (3) to refer for investigation. Gastroesophageal reflux disease can be diagnosed clinically if the patient's dominant symptoms are heartburn or acid regurgitation, or both; these patients should be treated with acid suppressive therapy. The remaining patients should be tested for H. pylori infection, and those with a positive result should be treated with H. pylori-eradication therapy. Those with a negative result should have their symptoms treated with optimal antisecretory therapy or a prokinetic agent. VALIDATION AND EVIDENCE: Evidence for resolution of the dyspepsia symptoms was the main outcome measure. Supporting evidence for the 5 steps in the management tool and the recommendations for treatment were graded according to the strength of the evidence and were endorsed by consensus of committee members. If no randomized controlled clinical trials were available, the recommendations were based on the best available evidence., Literature Review: Evidence was obtained from MEDLINE searches for pertinent articles published from 1966 to October 1999. The searches focused on dyspepsia, diagnosis and treatment. Additional articles were retrieved through a manual search of bibliographies and abstracts from international gastroenterology conferences.

Until recently many clinical trials of functional gastrointestinal disorders (FGIDs) suffered from important weaknesses in trial design, study execution, and data analysis. This makes it difficult to determine whether truly efficacious therapies exist for these disorders. One of the important methodologic problems is the absence of validated outcome measures and lack of consensus among stakeholders on how to measure outcome. Currently much of the effort is being put into the development of validated outcome measures for several of the FGIDs. The randomized, controlled trial with parallel groups is the design of choice. In this report, guidelines are given for the basic architecture of intervention studies of FGIDs. Further studies on design issues are required to ensure the recommendations will become evidence based in the future.

Objective: To review current evidence for primary care physicians who manage Helicobacter pylori in peptic ulcer disease., Quality of Evidence: MEDLINE was searched to August 1997 for randomized controlled trials, systematic overviews, and consensus reports. High-quality recent reviews were often found. Randomized controlled trials presented as abstracts at recent meetings were reviewed., Main Findings: Helicobacter pylori is found in most case of duodental and gastric ulcer, and eradication of H pylori leads to "cure" of ulcer disease and prevention of ulcer complications. Eradication of H pylori is not indicated for gastroesophageal reflux disease. No evidence indicates that screening asymptomatic individuals for H pylori infection reduces the risk of subsequent development of gastric cancer. Controversial areas are the role of H pylori in functional dyspepsia and screening for H pylori before initiating nonsteroidal anti-inflammatory drugs. In primary care, H pylori can be detected using serologic tests or urea breath tests (UBT), but only UBTs can be used to confirm eradication. Whether patients suspected of having ulcers can be managed with an H pylori test-and-treat strategy without initial investigation is controversial. The first-line recommended treatment is 1 week of twice daily triple therapy with a proton pump inhibitor, clarithromycin (Biaxin), and amoxicillin (e.g., Amoxil), or metronidazole (Flagyl)., Conclusions: Helicobacter pylori eradication should be first-line therapy in primary care for infected patients with peptic ulcers. Effective H pylori testing methods and treatments are now available.

Metronidazole (Mtz) is a critical component of combination therapies that are used against Helicobacter pylori, the major cause of peptic ulcer disease. Many H. pylori strains are Mtz resistant (MtzR), however, and here we show that MtzR results from loss of oxygen-insensitive NADPH nitroreductase activity. The underlying gene (called 'rdxA') was identified in several steps: transformation of Mtz-susceptible (MtzS) H. pylori with cosmids from a MtzR strain, subcloning, polymerase chain reaction (PCR) and DNA sequencing. We also found that (i) E. coli (normally MtzR) was rendered MtzS by a functional H. pylori rdxA gene; (ii) introduction of rdxA on a shuttle vector plasmid into formerly MtzR H. pylori rendered it MtzS; and (iii) replacement of rdxA in MtzS H. pylori with an rdxA::camR null insertion allele resulted in a MtzR phenotype. The 630 bp rdxA genes of five pairs of H. pylori isolates from infections that were mixed (MtzR/MtzS), but uniform in overall genotype, were sequenced. In each case, the paired rdxA genes differed from one another by one to three base substitutions. Typical rdxA genes from unrelated isolates differ by 5% in DNA sequence. Therefore, the near identity of rdxA genes from paired MtzR and MtzS isolates implicates de novo mutation, rather than horizontal gene transfer in the development of MtzR. Horizontal gene transfer could readily be demonstrated under laboratory conditions with mutant rdxA alleles. RdxA is a homologue of the classical nitroreductases (CNRs) of the enteric bacteria, but differs in cysteine content (6 vs. 1 or 2 in CNRs) and isoelectric point (pI=7.99 vs. 5.4-5.6), which might account for its reduction of low redox drugs such as Mtz. We suggest that many rdxA (MtzR) mutations may have been selected by prior use of Mtz against other infections. H. pylori itself is an early risk factor for gastric cancer; the possibility that its carcinogenic effects are exacerbated by Mtz use, which is frequent in many societies, or the reduction of nitroaromatic compounds to toxic, mutagenic and carcinogenic products, may be of significant concern in public health.

The authors highlight new developments in research on Helicobacter pylori. There is now consensus that all patients with newly diagnosed or recurrent duodenal or gastric ulcers who have a positive test result for H. pylori should be treated for the infection. Patients presenting with complications of ulcers, such as bleeding, should also be treated. H. pylori has recently been classified as a definite human carcinogen by the International Agency for Research on Cancer. In treatment, new combination regimens, consisting of 3 or 4 different drugs, cure the infection in more than 80% of patients. Currently, the best combinations are: (1) omeprazole (or another proton-pump inhibitor), clarithromycin and metronidazole, (2) omeprazole (or another proton-pump inhibitor), clarithromycin and amoxicillin, (3) bismuth subsalicylate, tetracycline and metronidazole, and (4) omeprazole, bismuth subsalicylate, tetracycline and metronidazole.

Resistance to antimicrobial agents is a major determinant of the efficacy of regimens to eradicate Helicobacter pylori. Clarithromycin (CLA) has become one of the most commonly used antibiotics for treatment of H pylori infection. In this study, the rate of primary resistance to CLA in H pylori isolated from patients was determined. One hundred sixty-two strains were recovered from patients before treatment. Strains were grown and inoculated onto Mueller-Hinton agar with 7% sheep blood. CLA epsilometer gradient agar diffusion test (E test) strips were used to test for susceptibility. Appropriate control organisms were tested to validate the assay. Plates were incubated at 37 degrees C in a microaerophilic atmosphere for up to five days. E test results were easy to interpret. Strains were considered resistant if the minimum inhibitory concentration (MIC) was 2 micrograms/mL or greater. Three strains were resistant (two strains with MIC 8 micrograms/mL and one strain with MIC 12 micrograms/mL) and 159 strains were sensitive (MICs ranged from less than 0.016 to 0.38 micrograms/mL). Ninety per cent of the strains had MICs of 0.023 micrograms/mL. Primary resistance was 1.8%. These susceptibility data support the use of CLA for the treatment of H pylori in the Nova Scotia population.

It is currently unclear whether Helicobacter pylori (H. pylori) infection plays a role in patients who fulfil the criteria for non-ulcer dyspepsia. This paper reviews evidence for H. pylori-induced changes in gastric emptying, gastrointestinal motility, gastric acid secretion, and gastric perception in patients with non-ulcer dyspepsia. Problems in study design and execution of non-ulcer dyspepsia treatment trials are discussed. The results of non-ulcer dyspepsia treatment trials which have been performed in H. pylori-positive patients are reviewed. To date none of them has convincingly shown that cure of the H. pylori infection leads to a sustained improvement in symptoms.

In this study, we compared metronidazole (Mtz)-sensitive and -resistant strains of Helicobacter pylori for metabolic differences that might correlate with drug resistance. Included in this study was an isogenic Mtz(r) strain, HP1107, that was constructed by transforming genomic DNA from Mtz(r) strain HP439 into Mtz(s) strain HP500. Enzyme activities were also measured for Mtz(r) strains grown in the presence or absence of 18 micrograms of metronidazole per ml (ca. one-half of the MIC). These studies confirmed the presence of the Embden-Meyerhof-Parnas, Entner-Doudoroff, and pentose pathways. H. pylori strains expressed enzymatic activities indicative of a complete and active Krebs cycle. All strains expressed pyruvate oxidoreductase (POR) and alpha-ketoglutarate oxidoreductase (KOR) as measured with the redox-active dye benzyl viologen (30 to 96 nmol/min/mg of protein for POR and 30 nmol/min/mg of protein for KOR). When grown in the presence of Mtz at > or = 3.5 micrograms/ml, Mtz(r) strains expressed no detectable POR or KOR activity. The apparent repression of POR and KOR activities by Mtz affected bacterial growth as manifest by extended lag periods and growth yield reductions of > 30%. A dose-dependent relationship was demonstrated between the metronidazole concentration in the growth medium and the specific activity of POR measured in bacterial cell extracts. The observed repression was not due to inactivation of POR by Mtz. In addition to repression of POR and KOR activities, growth in the presence of Mtz also led to decreases in the activities of various Krebs cycle enzymes, including aconitase, isocitrate dehydrogenase and succinate dehydrogenase. All of the Mtz(r) strains examined expressed isocitrate lyase and malate synthase activities indicative of the glyoxylate bypass. No isocitrate lyase activity was detected in Mtz(s) strain HP500. Isocitrate lyase activity was expressed by HP500 following transformation to Mtz resistance (Mtz(r) strain HP1107) with DNA from an Mtz(r) strain. The results of this study suggest that Mtz resistance may be a recessive trait, possibly involving inactivation of a regulatory gene, that results in constitutive expression of isocitrate lyase. Repression of POR and KOR activities in response to low levels of Mtz may be a general response of H. pylori strains to Mtz, but only resistant strains manage to survive via activation of compensatory metabolic pathways.

Aims: To review the influence of three factors on the prevalence of Helicobacter pylori infection: socio-economic status, marital status and occupation., Methods: MEDLINE searches were performed using the Medical Subject Headings: Helicobacter pylori and socio-economic status, couples, children, transmission and occupation. All relevant articles were reviewed and scrutinized for further references., Conclusions: Lower socio-economic status and/or a low level of education are associated with an increase in the prevalence of H. pylori infection. There is no evidence that H. pylori is sexually transmitted and cohabitation among adult individuals is not a risk factor for transmission. A few studies suggest that the presence of (young) children may be required for spread within families. Data on occupational risk of H. pylori infection are sparse. Gastroenterologists and other health care workers may be at increased risk but the data are not conclusive.

The antibody response to Helicobacter pylori was examined in 56 children (ages 5 to 18) to determine whether serological tests can be used for diagnosis. Twenty-four children (43%) were H. pylori positive and 32 children (57%) were H. pylori negative by culture and histological examination of endoscopic biopsy specimens. The immune response was also examined in 39 nonendoscoped parents of the children. H. pylori-specific immunoglobulin G (IgG) and IgA antibodies were detected by the flow microsphere immunofluorescent assay (FMIA). IgG was also detected by using the Pyloristat enzyme-linked immunosorbent assay (ELISA). The sensitivity, specificity, and positive and negative predictive values for the FMIA for IgG were 100, 97, 96, and 100%, respectively. The respective values for the Pyloristat ELISA for IgG were 96, 94, 92, and 97%. The respective values for the FMIA for IgA were 50, 100, 100, and 73%. Both assays identified the same 19 parents as IgG positive, while FMIA identified 17 of the 19 parents as IgA positive.

It remains unclear whether acquisition of Helicobacter pylori is due to a continuous risk of acquiring the infection or a cohort effect. In this prospective 3-year cohort study, the seroprevalence, conversion, and reversion of H. pylori infection as determined by IgG antibodies was examined. The cohort consisted of 316 randomly selected, nonpatient subjects aged 18-72 years who each provided at least 2 suitable samples. Seroprevalence of H. pylori increased from 21% in the third decade to 50% in the eighth decade. Crude annual seroconversion rate was 1% and the "spontaneous" seroreversion rate was 1.6%. Age was the only identified risk factor for H. pylori infection. A continuous risk of acquisition of 1%/year rather than a cohort effect best explains the pattern of H. pylori infection in this Canadian population. Seroconversion continues in adult life, and spontaneous reversions do occur, especially in the later decades.

Objective: To determine (a) the advantages and disadvantages of treatment options for the eradication of Helicobacter pylori and (b) whether eradication of H. pylori is indicated in patients with duodenal ulcer, nonucler dyspepsia and gastric cancer., Data Sources: A MEDLINE search for articles published in English between January 1983 and December 1992 with the use of MeSH terms Helicobacter pylori (called Campylobacter pylori before 1990) and duodenal ulcer, gastric cancer, dyspepsia and clinical trial. Six journals and Current Contents were searched manually for pertinent articles published in that time frame., Study Selection: For duodenal ulcer the search was limited to studies involving adults, studies of H. pylori eradication and randomized clinical trials comparing anti-H. pylori therapy with conventional ulcer treatment. For nonulcer dyspepsia with H. pylori infection the search was limited to placebo-controlled randomized clinical trials., Data Extraction: The quality of each study was rated independently on a four-point scale by each author. For the studies of duodenal ulcer the outcome measures assessed were acute ulcer healing and time required for healing, H. pylori eradication and ulcer relapse. For the studies of nonulcer dyspepsia with H. pylori infection the authors assessed H. pylori eradication, the symptoms used as outcome measures and whether validated outcome measures had been used., Data Synthesis: Eight trials involving duodenal ulcer met our inclusion criteria: five were considered high quality, two were of reasonable quality, and one was weak. Six trials involving nonulcer dyspepsia met the criteria, but all were rated as weak. Among treatment options triple therapy with a bismuth compound, metronidazole and either amoxicillin or tetracycline achieved the highest eradication rates (73% to 94%). Results concerning treatment indications for duodenal ulcer were consistent among all of the studies: when anti-H. pylori therapy was added to conventional ulcer treatment acute ulcers healed more rapidly. Ulcer relapse rates were dramatically reduced after H. pylori eradication. All of the studies involving nonulcer dyspepsia assessed clearance rather than eradication of H. pylori. No study used validated outcome measures. A consistent decrease in symptom severity was no more prevalent in patients in whom the organism had been cleared than in those taking a placebo. Of the studies concerning gastric cancer none investigated the effect of eradication of H. pylori on subsequent risk of gastric cancer., Conclusions: There is sufficient evidence to support the use of anti-H. pylori therapy in patients with duodenal ulcers who have H. pylori infection, triple therapy achieving the best results. There is no current evidence to support such therapy for nonulcer dyspepsia in patients with H. pylori infection. Much more attention must be paid to the design of nonulcer dyspepsia studies. Also, studies are needed to determine whether H. pylori eradication in patients with gastritis will prevent gastric cancer.

Objective: To evaluate current evidence for a causal relation between Helicobacter pylori infection and gastritis, duodenal ulcer, gastric cancer and nonulcer dyspepsia., Data Sources: A MEDLINE search for articles published in English between January 1983 and December 1992 with the use of MeSH terms Helicobacter pylori, gastritis, duodenal ulcer, gastric cancer, dyspepsia and clinical trial; abstracts were excluded. Six journals and Current Contents were searched manually for pertinent articles published in that time frame., Study Selection: Original studies with at least 25 patients, case reports and reviews that examined the relation between H. pylori and the four gastrointestinal disorders; 350 articles were on gastritis, 122 on duodenal ulcer, 44 on gastric cancer and 96 on nonulcer dyspepsia., Data Extraction: The quality of the studies was rated independently on a four-point scale. The strength of the evidence was assessed using a six-point scale for each of the eight established guidelines for determining a causal relation., Data Synthesis: There was conclusive evidence of a causal relation between H. pylori infection and histologic gastritis. Koch's postulates for the identification of a microorganism as the causative agent of a disease were fulfilled for H. pylori as a causative agent of gastritis. There was strong evidence that H. pylori is the main cause of duodenal ulcers not induced by nonsteroidal anti-inflammatory drugs, but all of Koch's postulates were not fulfilled. There was moderate epidemiologic evidence of an association between chronic H. pylori infection and gastric cancer. There was a lack of convincing evidence of a causal association between H. pylori and nonulcer dyspepsia., Conclusions: The evidence supports a strong causal relation between H. pylori infection and gastritis and duodenal ulcer and a moderate relation between such infection and gastric cancer. Further studies are needed to clarify the role of H. pylori in these disorders. Thus far, there is no evidence of a causal relation between H. pylori and nonulcer dyspepsia.