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Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

PURPOSE To investigate the effect of topical tafluprost on optic disc blood flow in patients with myopic disc. MATERIALS AND METHODS Forty-eight eyes in 24 patients with a myopic disc type (oval shaped) optic disc tilted to the temporal, with a crescent peripapillary atrophy were included in this study. Twenty-eight eyes were diagnosed as normal tension glaucoma and 20 eyes were in normal subjects. None had any treatment for glaucoma. Average age was 45.3±11.9 years. One eye was treated with topical tafluprost and the fellow eye served as the control. Ocular blood flow was measured by laser speckle flowgraphy (LSFG-NAVI) at 30, 60, 90, and 120 minutes after tafluprost administration, and the mean blur rate (MBR) on the optic disc was analyzed. Blood pressure and intraocular pressure (IOP) were recorded. RESULTS In all subjects, topical tafluprost (a) significantly reduced IOP versus baseline from 60 minutes after treatment (baseline: 15.2±3.4 mm Hg, 60 min: 13.3±3.2 mm Hg, P=0.001, 90 min: 13.3±3.6 mm Hg, P=0.002, 120 min: 13.7±3.4 mm Hg, P=0.007); and (b) significantly increased the MBR versus baseline (60 min: +4.3±6.6%, P=0.008, 90 min: +5.0±4.9%, P

*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

BACKGROUND: The cost-effectiveness of initial strategies in managing Canadian patients with uninvestigated upper gastrointestinal symptoms remains controversial.OBJECTIVE: To assess the cost-effectiveness of six management approaches to uninvestigated upper gastrointestinal symptoms in the Canadian setting.METHODS: The present study analyzed data from four randomized trials assessing homogeneous and complementary populations of Canadian patients with uninvestigated upper gastrointestinal symptoms with comparable outcomes. Symptom-free months, quality-adjusted life-years (QALYs) and direct costs in Canadian dollars of two management approaches based on the Canadian Dyspepsia Working Group (CanDys) Clinical Management Tool, and four additional strategies (two empirical antisecretory agents, and two prompt endoscopy) were examined and compared. Prevalence data, probabilities, utilities and costs were included in a Markov model, while sensitivity analysis used Monte Carlo simulations. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were determined.RESULTS: Empirical omeprazole cost $226 per QALY ($49 per symptom-free month) per patient. CanDys omeprazole and endoscopy approaches were more effective than empirical omeprazole, but more costly. Alternatives using H2-receptor antagonists were less effective than those using a proton pump inhibitor. No significant differences were found for most incremental cost-effectiveness ratios. As willingness to pay (WTP) thresholds rose from $226 to $24,000 per QALY, empirical antisecretory approaches were less likely to be the most cost-effective choice, with CanDys omeprazole progressively becoming a more likely option. For WTP values ranging from $24,000 to $70,000 per QALY, the most clinically relevant range, CanDys omeprazole was the most cost-effective strategy (32% to 46% of the time), with prompt endoscopy-proton pump inhibitor favoured at higher WTP values.CONCLUSIONS: Although no strategy was the indisputable cost-effective option, CanDys omeprazole may be the strategy of choice over a clinically relevant range of WTP assumptions in the initial management of Canadian patients with uninvestigated dyspepsia.

Objective To determine relative responsiveness of disease-specific and generic preference-based health-related quality of life instruments in gastroesophageal reflux disease (GERD). Study Design and Setting We compared standardized response means (SRM) of disease-specific and preference-based instruments in 217 outpatients with GERD. Results Quality of Life in Reflux and Dyspepsia and symptom scores were responsive across all domains, whereas global rating of change and Work Productivity and Activity Impairment-GERD only in single domains. The most responsive were Quality of Life in Reflux and Dyspepsia food/drink problems (SRM: 1.90, 95% confidence interval [CI]: 1.76–2.03) and vitality (SRM: 1.68, 95% CI 1.55–1.82) domains, Work Productivity and Activity Impairment-GERD workdays with reflux symptoms (SRM: 2.02, 95% CI 1.84–2.19), symptoms of heartburn (SRM: 1.83, 95% CI 1.69–1.96) and acid reflux (SRM: 1.48, 95% CI 1.35–1.62), and global rating of change in stomach problems (SRM: 2.19, 95% CI 2.05–2.32). The least responsive were Work Productivity and Activity Impairment-GERD domains related to hours absent at work (SRM: 0.22, 95% CI 0.05–0.38), reduced productivity at work (SRM: 0.66, 95% CI 0.48–0.83) and during other activities (SRM: 0.78, 95% CI 0.65–0.92), as well as emotional global rating of change (SRM: 0.72, 95% CI 0.58–0.85), and the standard gamble (SRM: 0.35, 95% CI 0.21–0.48), which was less responsive than the feeling thermometer (SRM: 0.92, 95% CI 0.78–1.05). Conclusions In patients with GERD, disease-specific health-related quality of life instruments and symptom scores showed greater responsiveness than preference-based generic instruments. The feeling thermometer proved more responsive than the standard gamble.

SUMMARY Aims: To determine the influences of prostaglandin inhibition by indomethacin on 24-h intragastric acidity and plasma gastrin concentration, related to gastric mucosal injury. Methods: A pre- and post-treatment study design was employed in 10 Helicobacter pylori negative healthy male subjects. All subjects underwent upper gastrointestinal endoscopy at least 3 days before and after 7 days dosing with indomethacin 50 mg t.d.s. Mucosal damage was scored according to the Lanza method, and biopsies were taken for H. pylori status and assay of mucosal concentrations of prostaglandin (PG)E2 and leukotriene (LT)B4. Before and on the last day of dosing, intragastric acidity was measured by continuous 24-h pH monitoring, and plasma gastrin levels determined by radioimmunoassay in blood samples collected over the same period. Results: All subjects completed the study and no serious adverse events were reported. The mucosal injury score increased significantly from 0 (0–2) to 3.4 (0–8) (mean and range of values, P < 0.05) after dosing with indomethacin. No differences were observed in 24-h mean pH or meal stimulated plasma gastrin concentrations. Mucosal PGE2 and LTB4 were unchanged 8–10 h after the last indomethacin dose. Conclusions: Endogenous prostaglandins do not appear to alter intragastric acidity or gastrin secretion, in contrast to the PGE analogues, whose effects must be more pharmacological than physiological.

Summary Background Several meta-analyses assessing the efficacy of anti-Helicobacter pylori treatment in adults have been published but a comparable meta-analysis in children is lacking. Aims To summarize the efficacy of treatments aimed at eradicating H. pylori in children and to identify sources of variation in treatment efficacy across studies. Methods We searched Medline, reference lists from published study reports, and conference proceedings for anti-H. pylori treatment trials in children. Weighted meta-regression models were used to find sources of variation in efficacy. Results Eighty studies (127 treatment arms) with 4436 children were included. Overall, methodological quality of these studies was poor with small sample sizes and few randomized-controlled trials. The efficacy of therapies varied across treatment arms, treatment duration, method of post-treatment assessment and geographic location. Among the regimens tested, 2–6 weeks of nitroimidazole and amoxicillin, 1–2 weeks of clarithromycin, amoxicillin and a proton pump inhibitor, and 2 weeks of a macrolide, a nitroimidazole and a proton pump inhibitor or bismuth, amoxicillin and metronidazole were the most efficacious in developed countries. Conclusions Before worldwide treatment recommendations are given for eradication of H. pylori, additional well-designed randomized placebo-controlled paediatric trials are needed, especially in developing countries where both drug resistance and disease burden is high.

A validated productivity questionnaire, the Work Productivity and Activity Impairment questionnaire for Gastroesophageal Reflux Disease (WPAI-GERD), exists for Swedish patients with GERD.To assess responsiveness to change of the WPAI-GERD and construct validity of the English language version.We used the WPAI-GERD in a before-after treatment clinical study of Canadian GERD patients with moderate or severe symptoms treated with esomeprazole 40 mg once daily for 4 weeks. We measured productivity variables including GERD-specific absence from work, reduced productivity while at work and reduced productivity while carrying out regular daily activities other than work during the preceding week.The analysis included 217 patients, of whom 71% (n = 153) were employed. Before treatment, employed patients reported an average 0.9 hours of absence from work due to GERD and 14.0% reduced work productivity (5.8 hours equivalent) in the previous week, as well as 21.0% reduced productivity in daily activities (all patients). After treatment, the corresponding figures decreased to 0.3 hours, 3.0% (1.1 hours equivalent) and 4.9%, respectively. Thus, the improvement (difference from start of treatment) in productivity was 0.6 hours (p = 0.011) for absence from work and 11.0% units (p0.001) for reduced work productivity (4.7 hours equivalent, p0.001). This translated into an avoided loss of work productivity of 5.3 hours in total on a weekly basis per employed patient. In addition, a 16.1% unit (p0.001) improvement for reduced productivity in activities was observed. Cross-sectional correlation coefficients of WPAI variables with symptoms (range 0.04-0.63) and health-related quality of life (HR-QOL; range 0.02-0.65) supported cross-sectional construct validity. Corresponding change score correlations between WPAI variables and HR-QOL (range 0.05-0.56) supported longitudinal construct validity of the WPAI-GERD while low change score correlations between productivity variables and relevant symptoms (range 0.06-0.34) did not.The English version of the WPAI-GERD showed good cross-sectional construct validity, and results indicated that the WPAI-GERD is responsive to change. Although the results also indicated that longitudinal construct validity may be poor, the overall findings suggest that further study of the instrument remains warranted.

BACKGROUND & AIMS: Probiotic formulations of single species of bacteria have not been effective in preventing the recurrence of Crohn's disease after surgery. We investigated the ability of VSL#3, a mixture of 8 different bacterial probiotic species, to prevent Crohn's disease recurrence after surgery in a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Within 30 days of ileocolonic resection and re-anastomosis, patients with Crohn's disease were randomly assigned to groups given 1 sachet of VSL#3 (900 billion viable bacteria, comprising 4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus) (n = 59) or matching placebo (n = 60). Colonoscopy was performed at days 90 and 365 to evaluate the neoterminal ileum for disease recurrence and obtain mucosal biopsies for cytokine analysis. Patients from both groups with either no or mild endoscopic recurrence at day 90 received VSL#3 until day 365. The primary outcome was the proportion of patients with severe endoscopic recurrence at day 90. RESULTS: At day 90, the proportion of patients with severe endoscopic lesions did not differ significantly between VSL#3 (9.3%) and placebo (15.7%, P = .19). The proportions of patients with non-severe lesions at day 90 who had severe endoscopic recurrence at day 365 were 10.0% in the early VSL#3 group (given VSL#3 for the entire 365 days) and 26.7% in the late VSL#3 group (given VSL#3 from days 90 through 365) (P = .09). Aggregate rates of severe recurrence (on days 90 and 365) were not statistically different, 20.5% of subjects in the early VSL#3 group and 42.1% in the late VSL#3 group. Patients receiving VSL#3 had reduced mucosal inflammatory cytokine levels compared with placebo at day 90 (P < .05). Crohn's disease activity index and inflammatory bowel disease quality of life scores were similar in the 2 groups. CONCLUSIONS: There were no statistical differences in endoscopic recurrence rates at day 90 between patients who received VSL#3 and patients who received placebo. Lower mucosal levels of inflammatory cytokines and a lower rate of recurrence among patients who received early VSL#3 (for the entire 365 days) indicate that this probiotic should be further investigated for prevention of Crohn's disease recurrence

The etiologies of functional dyspepsia (FD) are unclear, but in some studies, treatment with a proton pump inhibitor has been beneficial. The objective of this study was to evaluate the efficacy of esomeprazole 40 mg once a day compared to placebo in achieving symptom relief in primary care patients with FD.This was a randomized, placebo-controlled trial in adult FD patients, who had at least moderate severity of symptoms, defined as a score ofor =4 on a 7-point Global Overall Symptom (GOS) scale. Patients were excluded if they had predominant symptoms of heartburn or regurgitation; after a normal baseline endoscopy, patients were randomized to esomeprazole 40 mg once daily or placebo for 8 wk. The primary outcome measure was symptom relief (GOSor =2) at 8 wk.Of the 502 enrolled patients, 224 were randomized. The main reasons for exclusion were abnormal endoscopic findings, especially esophagitis. A significantly greater proportion of patients in the esomeprazole group achieved symptom relief at 4 but not at 8 wk compared to placebo: 4 wk esomeprazole 50.5% versus placebo 32.2%, p= 0.009; 8 wk esomeprazole 55.1% versus placebo 46.1%, p= 0.16. A similar relationship at 4 and 8 wk was seen for symptom resolution (GOS = 1) and improvement (DeltaGOSor =2).For the primary outcome measure of symptom relief at 8 wk, there was no statistically significant difference between esomeprazole 40 mg once a day and placebo. However, at 4 wk, esomeprazole was significantly more effective than placebo for symptom relief. The difference in therapeutic gain between 4 and 8 wk was largely due to a higher placebo response rate at 8 wk.

INTRODUCTION: The increased demand for colonoscopy, coupled with the introduction of new bowel cleansing preparations and recent caution advisories in Canada, has prompted a review of bowel preparations by the Canadian Association of Gastroenterology.METHODS: The present review was conducted by the Clinical Affairs group of committees including the endoscopy, hepatobiliary/transplant, liaison, pediatrics, practice affairs and regional representation committees, along with the assistance of Canadian experts in the field. An effort was made to systematically assess randomized prospective trials evaluating commonly used bowel cleansing preparations in Canada.RESULTS: Polyethylene glycol (PEG)-; sodium phosphate (NaP)-; magnesium citrate (Mg-citrate)-; and sodium picosulphate, citric acid and magnesium oxide (PSMC)-containing preparations were reviewed. Regimens of PEG 2 L with bisacodyl (10 mg to 20 mg) or Mg-citrate (296 mL) are as effective as standard PEG 4 L regimens, but are better tolerated. NaP preparations appear more effective and better tolerated than standard PEG solutions. PSMC has good efficacy and tolerability but head-to-head trials with NaP solutions remain few, and conclusions equivocal. Adequate hydration during preparation and up to the time of colonoscopy is critical in minimizing side effects and improving bowel cleansing in patients receiving NaP and PSMC preparations. All preparations may cause adverse events, including rare, serious outcomes. NaP should not be used in patients with cardiac or renal dysfunction (PEG solution is preferable in these patients), bowel obstruction or ascites, and caution should be exercised when used in patients with pre-existing electrolyte disturbances, those taking medications that may affect electrolyte levels and elderly or debilitated patients. Health Canada’s recommended NaP dosing for most patients is two 45 mL doses 24 h apart. However, both safety and efficacy data on this dosing schedule are lacking. Many members of the Canadian Association of Gastroenterology expert panel administer both doses within 24 h, as studied in clinical trials, after careful one-on-one discussion of risks and benefits in carefully selected patients. Safety data on PSMC and combination preparations in North America are limited and clinicians are encouraged to keep abreast of developments in this area.CONCLUSIONS: All four preparations reviewed provided effective bowel cleansing for colonoscopy in the majority of patients, with varying tolerability. Adequate hydration is essential in patients receiving the preparations.

The management of Helicobacter pylori negative patients with dyspepsia in primary care has not been studied in placebo-controlled studies.H. pylori negative patients with dyspepsia symptoms of at least moderate severity (or =4 on a seven-point Likert scale) were recruited from 35 centers. Patients were randomized to a 4-wk treatment of omeprazole 20 mg od, ranitidine 150 mg bid, cisapride 20 mg bid, or placebo, followed by on-demand therapy for an additional 5 months. Treatment success was defined as no or minimal symptoms (scoreor = 2 out of 7), and was assessed after 4 wk and at 6 months.Five hundred and twelve patients were randomized and included in the intention-to-treat (ITT) analysis. At 4 wk, success rates (95% CI) were: omeprazole 51% (69/135; 43-60%), ranitidine 36% (50/139, 28-44%), cisapride 31% (32/105, 22-39%), and placebo 23% (31/133, 16-31%). Omeprazole was significantly better than all other treatments (p0.05). The proportion of patients who were responders at 4 wk and at 6 months was significantly greater for those receiving omeprazole 31% (42/135, 23-39%) compared with cisapride 13% (14/105, 7-20%), and placebo 14% (18/133, 8-20%) (p= 0.001), but not ranitidine 21% (29/139, 14-27%) (p= 0.053). The mean number of on-demand study tablets consumed and rescue antacid used was comparable across groups. Economic analysis showed a trade-off between superior efficacy and increased cost between omeprazole and ranitidine.Treatment with omeprazole provides superior symptom relief compared to ranitidine, cisapride, and placebo in the treatment of H. pylori negative primary care dyspepsia patients.

Previous consensus statements have recommended one- to two-week proton pump inhibitor (PPI)-based triple therapies with clarithromycin and either amoxicillin or metronidazole as first-line treatments for children with Helicobacter pylori infection. The objective of the present review was to summarize data from pediatric studies that have examined treatment efficacy, safety, drug resistance and reinfection rates related to anti-H pylori therapies. Data from a recent meta-analysis of pediatric studies were used along with the authors' existing databases and searches of individual studies. Regimens that were identified as greater than 80% efficacious in children included a two-week therapy with a nitroimidazole and amoxicillin in Europe; a two-week regimen of bismuth, amoxicillin and metronidazole in developed countries (except Spain); a one- to two-week regimen of a PPI, clarithromycin and amoxicillin in Northern Europe, Asia and the Middle East; and a two-week regimen of a PPI, clarithromycin and metronidazole in Canada. Although recommended as a first-line treatment in adults, two-week treatment with a PPI, clarithromycin and amoxicillin eradicated only 68% of H pylori infections in North American children. Treatment efficacy was reduced in the presence of metronidazole and/or clarithromycin resistance. Further studies of anti-H pylori treatments in children in North America and developing countries are warranted.

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.

Background: Despite recommendations that patients rating their own health using utility and preference measures such as the feeling thermometer (FT) and standard gamble (SG) should also rate hypothetical marker states, little evidence supports marker state use. We evaluated whether the administration of marker states improves measurement properties of the FT and SG. Methods: We randomized 217 patients with gastroesophageal reflux disease to complete the FT (self-administered) and SG with marker states (FT +/SG+, n = 112) or without marker states (FT-/SG-, n = 105) before and after 4 weeks of treatment with a proton pump inhibitor, esomeprazole. Patients also completed other health-related quality of life instruments. Results: The use of marker states did not influence baseline utility scores (FT+ 0.66, FT- 0.68; SG+ 0.77, SG- 0.78, on a scale from 0 [dead] to 1.0 [full health]). Improvement after therapy was 0.21 in FT+ and 0.15 in FT- (both P < 0.001; difference between FT+ and FT- = 0.06, P = 0.02). Improvement in SG+ was 0.07 (P < 0.001) and 0.06 in SG- (P = 0.003) (difference between SG+ and SG- = 0.01, P = 0.63). Correlations with other health-related quality of life scores were generally stronger, with some statistically significant differences in correlations, for FT+ compared with FT-, but tended to be weaker for SG+ compared with SG-. Conclusion: The administration of marker states improved the responsiveness and validity of the FT but not of the SG. Decisions about administering marker states should depend on whether the FT and SG is of primary interest and the importance of optimal validity and responsiveness relative to competing objectives such as efficiency.

Summary Background : The accuracy of physicians’ assessment of the severity of gastro-oesophageal reflux disease is unclear. Aim : To correlate physician and patient assessment of gastro-oesophageal reflux disease severity and its response to treatment. Methods : Adult uninvestigated gastro-oesophageal reflux disease patients (n = 217) completed symptom and health-related quality of life questionnaires at baseline and after treatment with esomeprazole 40 mg p.o. daily. Pearson coefficients quantified correlations between physician assessments and patient responses. Results : At baseline, the strongest correlations were heartburn severity (0.31), overall symptom severity (0.44) and a domain of the quality of life in reflux and dyspepsia questionnaire (0.31) (P

This pragmatic, primary care study by Meineche-Schmidt in patients with presumed acid-related uninvestigated dyspepsia showed that a standard dose of omeprazole 20 mg daily was significantly more effective than a placebo in treating their self-worded main dyspepsia complaint. As a higher dose of omeprazole 40 mg daily was not more effective, the standard dose should be used. In this study, 9% of the patients had sole reflux-like symptoms while the rest had other accompanying symptoms and would be considered to have dyspepsia. In fact, patients had on average more than five symptoms. Patients do not know that there is a controversy about whether to call their symptoms GERD or dyspepsia; they just know that they want to feel better. As no initial investigations were made, patients could have a variety of possible diagnoses such as gastroesophageal reflux disease, ulcer disease, or functional dyspepsia. The recent CADET-PE study showed that if patients had endoscopic abnormalities, these were findings such as esophagitis that would be appropriately treated with acid suppression. That study also reconfirmed that symptoms do not predict endoscopic findings and do not make a diagnosis. Thus, the approach suggested in this study to treat patients based on their main symptom complaint is practical and effective.

Summary 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.

AIM:To use current evidence-based recommendations to provide a user-friendly clinical algorithm for the management of upper gastrointestinal bleeding, adapted to the Canadian environment.METHODS:A multidisciplinary consensus group of 25 participants representing 11 national societies used a seven-step approach to develop recommendations according to accepted standards. Sources of data included narrative and systematic reviews as well as published and new meta-analyses. A small writing subgroup subsequently created the algorithm.RESULTS:Recommendations emphasize appropriate initial resuscitation of the patient and a multidisciplinary approach to clinical risk stratification that determines the need for early endoscopy. Early endoscopy allows safe and prompt discharge of selected patients classified as low risk. Endoscopic hemostasis is reserved for patients with high-risk endoscopic lesions. Although monotherapy with injection or thermal coagulation is effective, the combination is superior to either treatment alone. High-dose intravenous proton-pump inhibition is recommended in patients who have undergone successful endoscopic therapy. Routine second-look endoscopy is not recommended. Patients with upper gastrointestinal bleeding secondary to ulcer disease should be tested and treated forHelicobacter pyloriinfection.CONCLUSIONS:This algorithm should facilitate appropriate risk stratification, use of endoscopic therapy and the appropriate utilization of proton-pump inhibition to optimize the care of patients with upper gastrointestinal bleeding. The algorithm should be customized to the resources of individual medical centres. Its application should be studied with appropriate outcomes recorded and validation performed.

Summary Background: Uninvestigated dyspepsia is common in family practice. The prevalence of clinically significant upper gastrointestinal findings (CSFs) in adult uninvestigated dyspepsia patients, and their predictability based on history, is unknown. Methods: Prompt endoscopy was performed within 10 days of referral, in 1040 adult patients presenting with uninvestigated dyspepsia at 49 Canadian family practitioner centres. Subsequent management strategies during a 6-month follow-up period were determined by the individual family practitioners. Results: CSFs were identified in 58% (603/1040) of patients. Erosive oesophagitis was most common (43%; N = 451); peptic ulcer was uncommon (5.3%; N = 55). Alarm symptoms were uncommon (2.8%; N = 29). Most patients had at least three dyspepsia symptoms, more than 80% had at least six, and approximately half had eight or more. Based on the dominant symptom, 463 (45%) patients had ulcer-like, 393 (38%) had reflux-like and 184 (18%) had dysmotility-like dyspepsia. The patients' dominant symptom was not predictive of endoscopic findings. Oesophagitis was more common in those with dominant reflux-like symptoms and was the most common finding in all subgroups. The prevalence of gastroduodenal findings was similar in all symptom subgroups. Helicobacter pylori (H. pylori) infection (30%; 301/1013) was associated with gastroduodenal findings. Conclusions: Dyspepsia subclassifications, based on dominant symptom, are of limited value in predicting the presence and nature of CSFs. Oesophagitis was by far the most common diagnosis (43% of patients). CSFs were common in uninvestigated dyspepsia patients and their nature suggests patients could be initially treated effectively, without endoscopy, using empirical acid suppressive therapy.

OBJECTIVE: To assessHelicobacter pylorieradication after one week dual ranitidine bismuth citrate-clarithromycin (RBC-C) or triple omeprazole, clarithromycin and amoxicillin (OCA) therapy.METHODS: In this multicentre Canadian trial,H pylori-positive patients with functional dyspepsia or inactive peptic ulcer disease were randomized to open-label treatment with RBC-C (ranitidine bismuth citrate 400 mg plus clarithromycin 500 mg) or OCA (omezaprole 20 mg, clarithromycin 500 mg and amoxicillin 1000 mg), given twice a day for seven days. Treatment allocation was randomly assigned.H pyloriinfection was confirmed by positive13C-urea breath test (13C-UBT).H pyloristatus was reassessed by UBT at least four and 12 weeks after treatment (negative: δ13CO2below 3.5 per mil). Intention-to-treat (ITT) eradication rates were determined for all patients with confirmedH pyloriinfection. Per protocol (PP) rate was determined for all patients treated with at least two evaluable follow-up visits.RESULTS: Three hundred five patients were included in the ITT and 222 in the PP analysis. The ITT eradication rates were 66% for RBC-C and 78% for OCA. The PP success rates were 84% for RBC-C and 96% for OCA. The difference for both ITT 12% (95% CI 2 to 22) and PP 12% (95% CI 4 to 19) were statistically significant, P=0.030 and P=0.007, respectively. Treatment was generally well tolerated.CONCLUSION: The eradication rate for the seven-day dual RBC-C regimen was lower than that for OCA.

From March 3 to 6, 2002,Helicobacterenthusiasts gathered in Perth, Australia for the Fourth Western PacificHelicobacterCongress to celebrate the 20th anniversary of the modern discovery of this organism by Barry Marshall and Robin Warren. The meeting included state-of-the-art lectures highlighting the breakthroughs that have occurred since the discovery of this bacterium. As well, advances from the forefront of currentHelicobacter pyloriresearch were presented, particularly in the realm of genomics and molecular biology. A symposium about vaccines and trends for futureH pyloriresearch completed this congress. The purpose of the present review is to summarize the highlights from this conference, emphasizing new advances.

BACKGROUND: Patients with duodenal ulcer (DU) have an increased parietal cell mass and sensitivity to secretagogues, with increased acid output.AIM: To determine the effect ofHelicobacter pylorieradication on parietal cell sensitivity and gastric acid secretion.SUBJECTS AND METHODS: Twenty-fiveH pylori-positive DU patients and 18H pylori-negative healthy volunteers were studied. SerumH pyloriimmunoglobulin G, basal acid output and acid secretory response to graded doses of pentagastrin were determined before and after treatment, at six months and at one year. Subjects were randomly assigned to ranitidine or sucralfate treatment for six weeks, and all DU patients received bismuth subsalicylate, metronidazole and tetracycline for the first two weeks.RESULTS:H pyloriwas eradicated in 66% of patients receiving sucralfate and 92% receiving ranitidine. Compared with healthy volunteers, DU patients demonstrated a 2.7-fold greater basal acid output, a 1.3-fold greater peak acid output, significantly higher acid output for each dose of pentagastrin and a 1.38-fold increase in the area under the pentagastrin dose acid response curve. Cure ofH pylori, irrespective of ulcer healing regimen, resulted in a gradual decrease in acid secretory capacity with basal acid output, peak acid output and area under the pentagastrin dose acid response curve returning to healthy volunteer levels by one year. No demonstrable differences were observed in parietal cell sensitivity in all subjects before or after treatment. These data suggest that disturbances in acid secretion inH pylori-positive DU patients are not due to an increased parietal cell sensitivity to pentagastrin but rather due to an increased parietal cell mass with increased capacity to secrete acid, which gradually resolves following cure.

Recognition of the relationship betweenHelicobacter pyloriinfection and the development of gastroduodenal disease has increased greatly in recent years. To avoid complications ofH pyloriinfection, such as the development of recurrent duodenal and gastric ulcers, effective therapies are required for eradication of the infection. This article reviews ranitidine bismuth citrate (RBC), a novel complex of ranitidine, bismuth and citrate, which was developed specifically for the purpose of eradicatingH pylori. Dual therapy with RBC in combination with clarithromycin for 14 days yields eradication rates of 76%. Triple therapy bid for one week with a proton pump inhibitor, clarithromycin and either amoxicillin or a nitroimidazole (tinidazole or metronidazole) is advocated as the treatment of choice forH pylorieradication. Analogous regimens with RBC in place of proton pump inhibitors show effective eradication rates in comparative studies and with pooled data. RBC, used alone or in combination with other antibiotics, appears to be a safe and effective drug for the treatment ofH pyloriinfection. Bismuth levels do not appear to rise to toxic levels.

The meetingHelicobacter pylori: Basic Mechanisms to Clinical Cure 2000, held in Bermuda from March 26 to 29, 2000, gathered physicians and scientists from all corners of the world. State-of-the-art reviews and the most recent developments in the field were presented. This article summarizes the highlights of this meeting, including important scientific and clinical developments.

We evaluated the factors that determine the heart rate response to exercise in 60 patients with atrial fibrillation (25 men and 35 women, with a mean age of 61+/-10 years) who underwent symptom limited cardiopulmonary exercise testing with blood sampling of atrial natriuretic peptide (ANP), 2-dimensional echocardiography and cardiac catheterization. Atrial muscles resected during the Maze operation were examined histologically in 12 patients. The heart rate response to exercise depended on the severity of the atrial organic injury, which was expressed as left atrial diameter, ANP secretion during the maximal exercise testing and the histological findings of atrial tissue. Conversely, we believe that the severity of the atrial injury can be predicted from the heart rate response to exercise in patients with atrial fibrillation.

In-depth meetings of the XIth International Workshop on Gastroduodenal Pathology andHelicobacter pyloriled to the presentation and discussion of extensive new data onH pyloriand its diseases. The mode of transmission ofH pyloriremains unclear, and it remains unknown why only a small proportion of infected individuals develop duodenal or gastric ulcer disease and even fewer develop gastric cancer. The role ofH pylorieradication in persons with uninvestigated dyspepsia remains controversial. New clinical trials ofH pyloritreatment show symptom relief and improvement in the quality of life of persons with functional dyspepsia, especially in those with ulcer-like or reflux-like dyspepsia. Clearly the move is toward symptom-based management of persons with dyspepsia, with fewer endoscopies being needed in the otherwise healthy young dyspeptic patients. It remains controversial whether eradicatingH pyloriin duodenal ulcer or functional dyspepsia increases the risk of subsequent development of gastroesophageal reflux disease. The one-week proton pump inhibitor-based triple regimens remain the gold standard ofH pyloritherapy, but some of the ranitidine bismuth citrate plus two antibiotic regimens also achieve an 80%H pylorieradication rate on an intention-to-treat basis. While the urea breath test remains the noninvasive test of choice, interesting new data are available on the use of stool antigen testing to diagnoseH pyloriinfection. The number ofH pylori-associated gastroduodenal diseases grows to include possible liver, vascular, immune and skin conditions.

Over the past decade, multiple clinical reports have demonstrated that the use of propofol sedation for gastrointestinal endoscopy by gastroenterologists and trained endoscopy nurses is safe and effective in appropriately selected patients. Proposed benefits of propofol sedation include rapid onset of action, improved patient comfort and rapid clearance, as well as prompt recovery and discharge from the endoscopy unit. As a result of medical evidence, a number of international professional societies have endorsed the use of propofol in gastrointestinal endoscopy. In Canada, no formal guidelines currently exist. In the present article, the Clinical Affairs Committee of the Canadian Association of Gastroenterology presents a position statement, incorporating updated information on the use of propofol sedation for endoscopy in adult patients.

While many definitions exist, dyspepsia is best considered a symptom complex (not a diagnosis) thought to arise in the upper gastrointestinal tract, unrelated to defecation. The symptom complex includes: upper abdominal/epigastric pain or discomfort, postprandial fullness, bloating, belching, early satiety, anorexia, nausea, retching, vomiting, heartburn and regurgitation. Patients with typical gastroesophageal reflux, biliary colic and irritable bowel syndrome should not be considered to have dyspepsia. After investigations, if a cause of dyspepsia is found, this is 'organic or structural' dyspepsia. If no structural cause is found, this is best called 'functional dyspepsia', subclassified into a) ulcer-like b) dysmotility-like c) reflux-like and d) unspecified dyspepsia. This symptom guided classification should be shifted to the first presentation with uninvestigated dyspepsia, prior to any investigations, to define a clinically useful guide to patient care. As there is considerable symptom overlap, it may be useful to combine together the ulcer and reflux-like groups into an acid-related dyspepsia group. In 1998, another approach would be to screen dyspeptic patients with an H. pylori test and classify them as H. pylori positive and negative dyspepsia.

OBJECTIVE To develop a disease-specific QOL instrument (QOLRAD) addressing patient concerns in gastroesophageal reflux disease (GERD) and dyspepsia. Patients. 759 male (45%) and female (55%) patients with a mean age of 48.4 years (sd 15.2) were used in the psychometric evaluation. MAIN OUTCOME MEASURES A pilot version of QOLRAD, the Gastrointestinal Symptoms Rating Scale (GSRS) and the SF-36 were completed prior to endoscopy. Items with a high ceiling effect, items measuring a different construct, i.e. with a low squared multiple correlation (R 0.80) with another item were removed. A confirmatory factor analysis was also performed. RESULTS The final questionnaire included 25 items depicting problems with emotions, vitality, sleep, eating/drinking, and physical/social functioning. The internal consistency reliability was high (alpha value overall 0.97, dimensions 0.89-94). Construct validity, i.e. the associations between similar constructs in the QOLRAD, the SF-36 and the GSRS scores was confirmed. Pain and symptom severity were markers of impaired QOL. The impact on health-related QOL was similar across the functional gastrointestinal disorders with the exception of patients with a normal endoscopy, who did slightly worse. CONCLUSION The QOLRAD is a short and user-friendly instrument with excellent psychometric properties. Its responsiveness to change in (AVMC1) clinical trials is currently being explored.

OBJECTIVE: To determine the management of patients with new onset dyspepsia by Canadian family physicians.METHODS: A survey was mailed to 195 family physicians in August 1995 to identify how they manage dyspepsia in patients according to four scenarios: based on presenting symptoms alone; assumingHelicobacter pylori-positive; known to beH pylori-negative; and endoscopically confirmed nonulcer dyspepsia.RESULTS: A total of 170 of 195 physicians (87.2%) completed the survey. Physicians reported that 7.3% of their practice is devoted to dyspepsia and 23% of these dyspeptic patients present for the first time. Ninety-three per cent of family physicians find a symptom classification of ulcer-, reflux- and dysmotility-like dyspepsia helpful. The majority of patients are advised to make lifestyle changes and are treated with antacids or empiric drug therapy. A H2receptor antagonist was the drug of choice for ulcer and reflux-like dyspepsia, while prokinetics were often used for reflux and dysmotility-like dyspepsia. After failure of initial treatment, patients were given another course of empiric treatment, commonly with cisapride or omeprazole. Family physicians estimated that the mean time to obtain a gastrointestinal consult was five weeks, and 70% indicated that this time to consult adversely influenced their decision to refer. If this time was reduced to less than two weeks, responding physicians would consider referring all eligible patients. On average, two to 2.5 courses of empiric therapy were given before referral. IfH pyloristatus was known, fewer empiric treatments (mean 1.8) were given before gastroenterological referral compared with the other scenarios. If the patient had nonulcer dyspepsia, 30% of family physicians provided reassurance only and did not prescribe empiric drug treatment.CONCLUSIONS: Most newly dyspeptic patients in Canada are treated with empiric therapy according to symptom classification and referred for endoscopy after an average two to 2.5 treatment courses.

The Xth International Workshop on Gastroduodenal Pathology andHelicobacter pyloriwas held in Lisbon, Portugal, from September 12 to 14, 1997. State-of-the-art reviews and research findings were presented to over 2000 participants. This review focuses on important new developments and serves as a rapid communication of clinically relevant material.

Gastroesophageal reflux disease (GERD) is a disease with serious consequences that may result in significant impairment in quality of life and disease morbidity. Across all grades of severity of symptoms and severity of underlying esophageal disease, proton pump inhibitors (PPIs) provide therapeutic gains over prokinetics (PKs) or H2receptor antagonists (H2RAs). The potential cost effectiveness of using medications with higher acquisition costs that may lower health care costs overall is often disregarded when conducting cost comparisons with medications having lower 'up-front' costs. Limiting therapy to less effective agents condemns many patients to protracted suffering, repeated physician visits and needless reinvestigation of symptoms that could have been resolved by appropriate initial therapy. Based on current data, use of any classification of symptom severity as a basis for selecting one class of therapeutic agents over another for first line therapy (ie PKs, H2RAs for 'mild' GERD, versus a PPI for 'severe' disease) is unwarranted.

Esophagitis healing proportions are often incorrectly called the healing rate. The aim of this study was to compare different drug classes by expressing the speed of healing and symptom relief through a new approach.A fully recursive literature search to July 1996 identified 43 articles on gastroesophageal reflux disease (GERD) (7635 patients) meeting strict inclusion criteria: single- or double-blind randomized studies in adults with endoscopically proven erosive or ulcerative esophagitis. For each drug class, linear regression analysis estimated the average percentage of patients who were healed and heartburn free per week.Mean overall healing proportion irrespective of drug dose or treatment duration (or =12 weeks) was highest with proton pump inhibitors (PPIs; 83.6% +/- 11.4%) vs. H2-receptor antagonists (H2RAs; 51.9% +/- 17.1%), sucralfate (39.2% +/- 22.4%), or placebo (28.2% +/- 15.6%). Correcting for patients without baseline heartburn, the mean heartburn-free proportion was highest with PPIs (77.4% +/- 10.4%) vs. H2RAs (47.6% +/- 15.5%). PPIs showed a significantly faster healing rate (11.7%/wk) vs. H2RAs (5.9%/wk) and placebo (2.9%/wk). PPIs provided faster, more complete heartburn relief (11.5%/wk) vs. H2RAs (6.4%/wk).More complete esophagitis healing and heartburn relief is observed with PPIs vs. H2RAs and occurs nearly twice as fast. This semiquantitative expression of speed of healing and symptom relief permits comparisons for future economic evaluation and quality-of-life assessments.

Background: The pathogenesis of the occurrence of late potentials (LP) has not been fully elucidated. Deletion polymorphism in the Angiotensin I-converting enzyme (ACE) gene may relate the myocarclial remodeling after the myocardial infarction (Ml). The purpose of this study was to evaluate the significance of ACE gene polymorphism for the occurrence of LPs after Ml. Methods: A 287 base pair (bp) insertion/deletion polymorphism in intron 16 of the ACE gene was determined by polymerase chain reaction and LPs were also examined by signal-averaged EGC in 136 patients with Ml. Polymorphism of the ACE gene was characterized by three genotypes: II, ID, and DD. Signal-averaged ECG were recorded using X, Y, Z leads and LP were defined by time-domain analysis as low amplitude potentials exceeding 20 ms after the QRS-end and filtered QRS >115 ms. Results: Positive LPs were noted in 40 of 136 patients with Ml. No differences could be detected between patients with LP-positive and LP-negative for the location of Ml, the success rate of reperfusion therapy, and left ventricular end-diastolic volume (126 ± 40 vs 113 ± 43 mL/m2). In patients with LP-positive compared with those in LP-negative, filtered QRS was significantly higher (135 ± 8 vs 107 ± 8 ms), left ventricular ejection fraction was lower (47 ± 12 vs 54%± 11 %), and peak was higher (3602 ± 2928 vs 2614 ± 2360 IU/L). The frequency of ACE/DD genotype was associated with patients with LP-positive (18 of DD, 18 of ID, and 4 of II for patients with LP-positive, while 25 of DD, 42 of ID, and 29 of II for patients with LP-negative). In the study population, the ACE / DD genotype was associated with patients with LP-positive when compared with the ACE ID & II genotype (x2= 4.7, P = 0.03). Conclusion: ACE/DD genotype of the ACE gene may be associated with the occurrence of LP after Ml.

The discovery of Helicobacter pylori (H. pylori) opened the doors to new insight and therapy for peptic ulcer disease. Earlier eradication treatment modalities based on bismuth compounds, with or without additional antimicrobials, were not well accepted mainly because of the, at least hypothetical, risks for neurological and/or renal side effects. The first proton pump inhibitor, omeprazole, had been proven as a very effective short-term anti-ulcer therapy, but after withdrawal of the drug, the recurrence rate was high. theoretically, acid suppression was believed to increase the H. pylori infestation as the environment became more neutral. On the other hand, acid suppression could increase the effect of acid labile antimicrobials. This was not investigated before the studies presented in this thesis were performed.A small pilot study (Paper I) in 24 patients showed that 7 out of 8 patients treated for fourteen days with omeprazole 40 mg o.m. + amoxicillin 750 mg b.i.d. were cleared of H. pylori, while it remained in 7/8 patients on omeprazole as monotherapy and in 2/7 patients on amoxicillin as monotherapy. However, the eradication rates 4 weeks after treatment were 5/8, 0/8 and 1/7 in the three groups, respectively. These results were confirmed in a large study (Paper II) comprising 248 consecutive patients with active duodenal ulcer disease. All had an initial treatment period for two weeks with omeprazole 40 mg o.m., followed by continued omeprazole in combination with amoxicillin 750 mg b.i.d. or amoxicillin placebo for a further two weeks. In the dual therapy group, 54% of patients were H. pylori eradicated compared to 4% in the omeprazole mono therapy group. Furthermore, the duodenal ulcer relapse rate was significantly lower in the combination group compared to the monotherapy group (p

Costs/charges Measuring the cost of a health care intervention in monetary terms is the cornerstone of all health economic analyses. The cost of a service can be defined in local currencies as the resources consumed or depleted to provide a service. These are in contrast to charges, which may be regulated or set by the market place and may not reflect the true cost of providing a service. Indeed, as charges may reflect profit or loss, the value may be falsely inflated or deflated. The measurement of costs can be divided into costs to the health service, costs to other sectors (e.g. government social service payments), and costs to the patient and family (e.g. loss of earnings by the patient or time spent caring for a relative). Costs are often classified as direct, indirect, intangible and ‘other’. While these terms are commonplace, different authors may use them differently and hence careful reading is required. Definitions of the types of cost are as follows.

Huang et al have performed a meta-analysis to determine the relationship betweencagA seropositivity (by serology and polymerase chain reaction) and the risk of gastric cancer. An extensive review of the literature identified no previous systematic overviews. The authors identified 16 studies involving 2284 cases and 2770 controls. The overall prevalence of Helicobacter pylori was 77.7% in cases and 63.1% in controls. Tests forcagA were positive in 62.8% of cases and 37.5% of controls. Thus,H pyloriandcagA seropositivity significantly increased the risk for gastric cancer, by 2.28 (95% CI 1.71 to 3.05) and 2.87 (95% CI 1.95 to 4.22), respectively. In patients withH pylori, those who were infected by acagA-positive strain had a slightly higher risk of gastric cancer, with an odds ratio of 1.64 (95% CI 1.21 to 2.24). The authors also found that patients infected withH pyloriwith or withoutcagA seropositivity had an increased risk of noncardia gastric cancer, but not of cancer of the gastric cardia. They concluded thatcagA-positive strains confer a greater risk of gastric cancer than does H pylori infection alone.

Background & Aims Helicobacter pylori infection is increasingly difficult to treat. The purpose of these consensus statements is to provide a review of the literature and specific, updated recommendations for eradication therapy in adults. Methods A systematic literature search identified studies on H pylori treatment. 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 online platform, finalized, and voted on by an international working group of specialists chosen by the Canadian Association of Gastroenterology. Results Because of increasing failure of therapy, the consensus group strongly recommends that all H pylori eradication regimens now be given for 14 days. Recommended first-line strategies include concomitant nonbismuth quadruple therapy (proton pump inhibitor [PPI] + amoxicillin + metronidazole + clarithromycin [PAMC]) and traditional bismuth quadruple therapy (PPI + bismuth + metronidazole + tetracycline [PBMT]). PPI triple therapy (PPI + clarithromycin + either amoxicillin or metronidazole) is restricted to areas with known low clarithromycin resistance or high eradication success with these regimens. Recommended rescue therapies include PBMT and levofloxacin-containing therapy (PPI + amoxicillin + levofloxacin). Rifabutin regimens should be restricted to patients who have failed to respond to at least 3 prior options. Conclusions Optimal treatment of H pylori infection requires careful attention to local antibiotic resistance and eradication patterns. The quadruple therapies PAMC or PBMT should play a more prominent role in eradication of H pylori infection, and all treatments should be given for 14 days.

Polyketides, an important class of natural products with complex chemical structures, are widely used as antibiotics and other pharmaceutical agents. A clear barrier to heterologous polyketide biosynthesis in Escherichia coli is the lack of (2S)-methylmalonyl-CoA, a common substrate of multimodular polyketide synthases. Here we report a route for synthesizing (2S)-methylmalonyl-CoA from malonyl-CoA with a 3-hydroxypropionate cycle in thermoacidophilic crenarchaeon. The engineered E. coli strain produced both propionyl-CoA and methylmalonyl-CoA at intracellular levels similar to those of acetyl-CoA and succinyl-CoA, respectively. This approach may open a way to produce a variety of polyketide drugs in E. coli from renewable carbon sources.

The diminishing prevalence ofHelicobacter pyloriinfection among most segments of the Canadian population has led to changes in the etiologies and patterns of associated upper gastrointestinal diseases, including fewer peptic ulcers and their complications. Canadian Aboriginals and recent immigrants are among populations in which the prevalence ofH pyloriinfection remains high and, therefore, the health risks imposed byH pyloriremain a significant concern. Population-based strategies forH pylorieradication in groups with a low prevalence of infection are unlikely to be cost effective, but such measures are attractive in groups in which the prevalence rates of infection remain substantial. In addition to a lower prevalence of peptic ulcers and dyspepsia, the public health value of eradication may be particularly important if this leads to a reduction in the prevalence of gastric cancer in high prevalence groups. Therefore The Canadian Helicobacter Study Group held a conference that brought together experts in the field to address these issues, the results of which are reviewed in the present article. Canadians with the highest prevalence ofH pyloriinfection are an appropriate focus for considering the health advantages of eradicating persistent infection. In Canadian communities with a high prevalence of bothH pyloriand gastric cancer, there remains an opportunity to test the hypothesis thatH pyloriinfection is a treatable risk factor for malignancy.

Setting priorities is critical to ensure guidelines are relevant and acceptable to users, and that time, resources and expertise are used cost-effectively in their development. Stakeholder engagement and the use of an explicit procedure for developing recommendations are critical components in this process.We used a modified Delphi consensus process to select 20 high-priority conditions for guideline development. Canadian primary care practitioners who care for immigrants and refugees used criteria that emphasize inequities in health to identify clinical care gaps.Nine infectious diseases were selected, as well as four mental health conditions, three maternal and child health issues, caries and periodontal disease, iron-deficiency anemia, diabetes and vision screening.Immigrant and refugee medicine covers the full spectrum of primary care, and although infectious disease continues to be an important area of concern, we are now seeing mental health and chronic diseases as key considerations for recently arriving immigrants and refugees.

Yu Yokoyama, Naoko Aizawa, Naoki Chiba, Kazuko Omodaka, Masahiko Nakamura, Takaaki Otomo, Shunji Yokokura, Nobuo Fuse, Toru NakazawaDepartment of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, JapanBackground: Eyes with glaucoma are characterized by optic neuropathy with visual field defects in the areas corresponding to the optic disk damage. The exact cause for the glaucomatous optic neuropathy has not been determined. Myopia has been shown to be a risk factor for glaucoma. The purpose of this study was to determine whether a significant correlation existed between the microcirculation of the optic disk and the visual field defects and the retinal nerve fiber layer thickness (RNFLT) in glaucoma patients with myopic optic disks.Methods: Sixty eyes of 60 patients with myopic disks were studied; 36 eyes with glaucoma (men:women = 19:17) and 24 eyes with no ocular diseases (men:women = 14:10). The mean deviation (MD) determined by the Humphrey field analyzer, and the peripapillary RNFLT determined by the Stratus-OCT were compared between the two groups. The ocular circulation was determined by laser speckle flowgraphy (LSFG), and the mean blur rate (MBR) was compared between the two groups. The correlations between the RNFLT and MBR of the corresponding areas of the optic disk and between MD and MBR of the optic disk in the glaucoma group were determined by simple regression analyses.Results: The average MBR for the entire optic disk was significantly lower in the glaucoma group than that in the control group. The differences of the MBR for the tissue in the superior, inferior, and temporal quadrants of the optic disk between the two groups were significant. The MBR for the entire optic disk was significantly correlated with the MD (r = 0.58, P = 0.0002) and the average RNFLT (r = 0.53, P = 0.0008). The tissue MBR of the optic disk was significantly correlated with the RNFLT in the superior, inferior, and temporal quadrants.Conclusions: Our study suggests that there is a causal relationship between the thinner RNFLT that led to the MD and reduction in the microcirculation in the optic nerve head.Keywords: glaucoma, visual field defects, optic disk, optic neuropathy, myopia, microcirculation, optic nerve head, retinal nerve fiber layer

Naoko Aizawa, Yu Yokoyama, Naoki Chiba, Kazuko Omodaka, Masayuki Yasuda, Takaaki Otomo, Masahiko Nakamura, Nobuo Fuse, Toru NakazawaDepartment of Ophthalmology, Tohoku University Graduate School of Medicine Sendai, Miyagi, JapanBackground: Laser speckle flowgraphy (LSFG) enables noninvasive quantification of the retinal circulation in glaucoma patients. In this study, we tested the intrasession reproducibility of LSFG-NAVI, a modified LSFG technique.Methods: Sixty-five eyes from 33 subjects (male (M):female (F) = 17:16) with a mean age of 49.4 ± 11.2 years were examined in this study. Two parameters indicating reproducibility – the coefficient of variation (COV) and the intraclass correlation coefficient (ICC) – were analyzed three times on the same day that mean blur rate (MBR) was measured using LSFG-NAVI. The sites analyzed were the retinal artery and vein, the optic disk, and the choroid. Following classification according to the Glaucoma Hemifield Test (GHT; SITA-Standard 30-2 program), the COV and ICC were examined in patients with (GHT+; 38 eyes, M:F = 20:18, average age 48.9 ± 12.8 years) and without (GHT-; 27 eyes, M:F = 13:14, average age 50.1 ± 8.7 years) abnormal glaucomatous visual fields.Results: For all subjects, the intrasession reproducibility of MBR in the optic disk (COV: 3.4 ± 2.0; ICC: 0.95) and choroid (COV: 4.7 ± 3.4; ICC: 0.98) was excellent. The reproducibility for the retinal vein (COV: 8.4 ± 5.6, ICC: 0.90) and retinal artery (COV: 10.9 ± 9.9, ICC: 0.9) was moderate. MBRs in the optic disk had good reproducibility in both the GHT+ group (COV: 3.8 ± 2.0; ICC: 0.97) and the GHT− group (COV: 2.9 ± 2.1; ICC: 0.95). Local assessment of the optic disk in normal or glaucoma patients showed that the COVs of the quadrant optic disk areas were best in the temporal area of MBR (3.4%, 4.2%, respectively).Conclusion: LSFG-NAVI showed favorable reproducibility in evaluation of retinal circulation of glaucoma patients, particularly in the optic disk and choroid.Keywords: ocular circulation, reproducibility, optic nerve, retina