The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults.

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.

The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn's disease.

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. Clinical trials.gov number: NCT00175292.

Effect of topical tafluprost on optic nerve head blood flow in patients with myopic disc type.

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<0.001, 120 min: +6.7±7.0%, P<0.001). CONCLUSIONS: Topical tafluprost increased MBR in the optic nerve head and significantly reduced IOP, effects that may represent beneficial treatment for glaucoma patients with a myopic disc type.

Construction of a part of a 3-hydroxypropionate cycle for heterologous polyketide biosynthesis in Escherichia coli.

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.

Helicobacter pylori in First Nations and recent immigrant populations in Canada.

The diminishing prevalence of Helicobacter pylori infection 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 of H pylori infection remains high and, therefore, the health risks imposed by H pylori remain a significant concern. Population-based strategies for H pylori eradication 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 of H pylori infection are an appropriate focus for considering the health advantages of eradicating persistent infection. In Canadian communities with a high prevalence of both H pylori and gastric cancer, there remains an opportunity to test the hypothesis that H pylori infection is a treatable risk factor for malignancy.

Fractures around the lateral cortical hinge after a medial opening-wedge high tibial osteotomy: a new classification of lateral hinge fracture.

PURPOSE: The purpose of this study was to determine the frequency of lateral hinge fractures after opening-wedge high tibial osteotomy and investigate the patterns of fracture and their clinical outcome. METHODS: We analyzed 104 knees in 93 patients with a mean age of 68 ± 7 years. Of the knees, 74 were diagnosed as having primary osteoarthritis and 30 with osteonecrosis. The mean follow-up period was 41 months. Lateral hinge fractures were classified as follows: type I, the fracture reaches just proximal to or within the tibiofibular joint; type II, the fracture reaches the distal portion of the proximal tibiofibular joint; and type III, a lateral plateau fracture. A standard postoperative rehabilitation protocol was used for type I fractures, 3 of 5 patients with type II fractures were treated with non-weight bearing, and type III fractures were treated with non-weight bearing until visible callus formation. RESULTS: The Knee Society scores for the knee and for function showed improvement from 49 ± 11 to 91 ± 7.7 points and from 62 ± 13 to 95 ± 8.2 points, respectively. Lateral cortex fractures were observed in 26 knees (25%): 19 type I, 5 type II, and 2 type III. In the type II fracture group, 2 of 5 patients were judged to have a delayed bone union. There were 2 cases of infection (2%) and 1 case of traumatic neuroma (1%) but no instances of implant failure, nonunion, or deep vein thrombosis among our patient cohort. CONCLUSIONS: High tibial osteotomy patients treated with a combination of TomoFix (Synthes, Bettlach, Switzerland) and bone substitute were able to walk with full weight bearing 2 weeks after surgery. No complications were seen in 19 patients with type I fractures. Of 5 patients with type II fractures, 2 had delayed unions with a correction loss of 3° and 7°, respectively. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Significant correlations between optic nerve head microcirculation and visual field defects and nerve fiber layer loss in glaucoma patients with myopic glaucomatous disk.

BACKGROUND: 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.

Association between optic nerve blood flow and objective examinations in glaucoma patients with generalized enlargement disc type.

BACKGROUND: The purpose of this study was to investigate the correlations between microcirculation in the optic disc, average peripapillary retinal nerve fiber layer thickness cupping parameters, and visual field defects in glaucoma patients with the generalized enlargement disc type. METHODS: A total of 38 eyes from 38 glaucoma patients with the generalized enlargement disc type were included. The microcirculation of the optic nerve head was examined with laser speckle flow graphy, and the mean blur rate in all areas, in vessel area, and in tissue area were calculated using the laser speckle flow graphy analyzer software. Average peripapillary retinal nerve fiber layer thickness was measured using Stratus optical coherence tomography, and cupping parameters were accessed using the Heidelberg retina tomograph. The mean deviation in the Humphrey field analyzer (30-2 SITA standard) was analyzed. The correlation between these parameters was evaluated using the Spearman rank correlation coefficient. RESULTS: The correlation coefficient of mean blur rate in all optic disc area to the average peripapillary retinal nerve fiber layer thickness, vertical C/D, and mean deviation were r = 0.7546 (P < 0.0001), r = -0.6208 (P < 0.0001), and r = 0.6010 (P = 0.0001), respectively. The mean blur rate in tissue area of the optic disc showed r = 0.7305 (P < 0.0001), r = -0.6438 (P < 0.0001), and r = 0.6338 (P < 0.0001). CONCLUSION: We found that the mean blur rate in the optic disc was significantly correlated with the average peripapillary retinal nerve fiber layer thickness, vertical C/D, and mean deviation in patients with the generalized enlargement disc type of glaucoma. In particular, the mean blur rate in tissue area was more highly correlated than the vessel area with other results of examination in glaucoma patients with the generalized enlargement disc type.

Reproducibility of retinal circulation measurements obtained using laser speckle flowgraphy-NAVI in patients with glaucoma.

BACKGROUND: 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.

Difficulty in inserting 25- and 23-gauge trocar cannula during vitrectomy.

PURPOSE: To determine the incidence of difficulty in inserting a 25- and 23-gauge trocar cannula (DITC) during 25- or 23-gauge micro-incision vitrectomy surgery (MIVS). METHODS: Retrospective, consecutive, interventional case series performed by a single surgeon at a single centre. We defined a DITC as the condition where at least 1 trocar cannula could not be inserted into the vitreous at the beginning of MIVS. The incidence of DITC was calculated from 1,525 eyes, and the pre-operative demographics of the DITC cases were compared to those of the non-DITC cases. RESULTS: The incidence of DITC for all cases was 0.6% (9 of 1,525 eyes). Overall, there were 242 eyes with a retinal detachment (RD), and 8 of the 9 eyes with DITC had an RD with an incidence of 3.3% (8 of 242 RD eyes). Seven of these 8 eyes had a total RD, 4 also had a choroidal detachment, 4 eyes were also myopic (>-8.0 dpt, high myopia), and 6 of the 8 eyes were hypotonic (<8 mm Hg). The DITC cases had larger RDs (p<0.0001), a higher incidence of choroidal detachment (p<0.0001), higher myopia (p=0.0204) and hypotony (p=0.0003) than the non-DITC eyes with an RD. CONCLUSIONS: A large RD, a choroidal detachment, high myopia and hypotony are significant risk factors for DITC. We recommend that MIVS should be performed cautiously for eyes with these risk factors.

A one-year economic evaluation of six alternative strategies in the management of uninvestigated upper gastrointestinal symptoms in Canadian primary care.

BACKGROUND: The cost-effectiveness of initial strategies in managing Canadian patients with uninvestigated upper gastrointestinalsymptoms 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, qualityadjusted 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 costeffective 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 choiceover a clinically relevant range of WTP assumptions in the initial management of Canadian patients with uninvestigated dyspepsia.

Specific HRQL instruments and symptom scores were more responsive than preference-based generic instruments in patients with GERD.

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.

Propofol use for sedation during endoscopy in adults: a Canadian Association of Gastroenterology position statement.

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.

The Work Productivity and Activity Impairment Questionnaire for Patients with Gastroesophageal Reflux Disease (WPAI-GERD): responsiveness to change and English language validation.

BACKGROUND: A validated productivity questionnaire, the Work Productivity and Activity Impairment questionnaire for Gastroesophageal Reflux Disease (WPAI-GERD), exists for Swedish patients with GERD. OBJECTIVE: To assess responsiveness to change of the WPAI-GERD and construct validity of the English language version. METHODS: 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. RESULTS: 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 (p < 0.001) for reduced work productivity (4.7 hours equivalent, p < 0.001). 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 (p < 0.001) 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. CONCLUSION: 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.