Charles N Bernstein

University of Manitoba, Winnipeg, Manitoba, Canada

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Publications (412)3037.46 Total impact

  • Harminder Singh, Zoann Nugent, Marni Brownell, Laura E Targownik, Leslie L Roos, Charles N Bernstein
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    ABSTRACT: To determine grade 12 academic performance for children with inflammatory bowel disease (IBD). Children diagnosed with IBD at age <17 years identified from the population-based University of Manitoba IBD Epidemiology Database were matched by age-, sex-, and area of residence to 10 randomly selected controls. Grade 12 educational outcomes (scores on the provincial grade 12 language arts and mathematics standards tests, and enrollment-in-grade-12-by- age-17) were determined by linkage to the province wide Manitoba Education Database. Linear and logistic regression analysis were used to compare the educational outcomes, adjusting for socioeconomic status and comorbidities and evaluate predictors of educational outcomes among children with IBD. Grade 12 educational outcomes among 337 children with IBD were compared with 3093 without IBD. There were no significant differences among the 2 groups in the standardized scores (language arts: P = .31; mathematics: P = .48) or enrollment-in-grade-12-by- age-17 (P = .25). Lower socioeconomic status and diagnosis with mental health problems 6 months prior to and 6 months post-IBD diagnosis were independent predictors of worse educational outcomes. There was no significant effect of age of diagnosis of IBD, type of IBD (ulcerative colitis vs Crohn's disease), use of corticosteroids or immunomodulator agents, hospitalizations, or surgery for IBD. Children with IBD on average achieve similar levels of academic achievement in grade 12 as those without IBD. This study underscores the educational impact of mental health conditions at IBD diagnosis among children. Copyright © 2015 Elsevier Inc. All rights reserved.
    The Journal of pediatrics. 01/2015;
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    Mandana Amir Shaghaghi, Charles Bernstein, Peter Eck
    Advances and Controversies in Clinical Nutrition 2014. December 4-6, 2014, Gaylord National Resort & Convention Center, 201 Waterfront Street, National Harbor, MD 20745.; 12/2014
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    ABSTRACT: 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 following surgery in a multi-center, randomized, double-blind, placebo-controlled trial. Within 30 days of ileo-colonic 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 Thermophiles) (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. 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 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 to 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. 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: NCT00175292. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Clinical Gastroenterology and Hepatology 11/2014; · 6.53 Impact Factor
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    ABSTRACT: OBJECTIVES:The objective of this study was to perform a meta-analysis investigating antibiotic exposure as a risk factor for developing inflammatory bowel disease (IBD).METHODS:A literature search using Medline, Embase, and Cochrane databases was performed to identify studies providing data on the association between antibiotic use and newly diagnosed IBD. Included studies reported Crohn's disease (CD), ulcerative colitis (UC), or a composite of both (IBD) as the primary outcome and evaluated antibiotic exposure before being diagnosed with IBD. A random-effects meta-analysis was conducted to determine overall pooled estimates and 95% confidence intervals (CIs).RESULTS:A total of 11 observational studies (8 case-control and 3 cohort) including 7,208 patients diagnosed with IBD were analyzed. The pooled odds ratio (OR) for IBD among patients exposed to any antibiotic was 1.57 (95% CI 1.27-1.94). Antibiotic exposure was significantly associated with CD (OR 1.74, 95% CI 1.35-2.23) but was not significant for UC (OR 1.08, 95% CI 0.91-1.27). Exposure to antibiotics most markedly increased the risk of CD in children (OR 2.75, 95% CI 1.72-4.38). All antibiotics were associated with IBD, with the exception of penicillin. Exposure to metronidazole (OR 5.01, 95% CI 1.65-15.25) or fluoroquinolones (OR 1.79, 95% CI 1.03-3.12) was most strongly associated with new-onset IBD.CONCLUSIONS:Exposure to antibiotics appears to increase the odds of being newly diagnosed with CD but not UC. This risk is most marked in children diagnosed with CD.Am J Gastroenterol advance online publication, 16 September 2014; doi:10.1038/ajg.2014.246.
    The American Journal of Gastroenterology 09/2014; · 9.21 Impact Factor
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    ABSTRACT: We aimed to determine the predictors and risk for death among persons with either Crohn's disease (CD) or UC compared with the general population.
    Gut 09/2014; · 13.32 Impact Factor
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    ABSTRACT: Background: A comprehensive study of what individuals with inflammatory bowel disease (IBD) are eating that encompasses food avoidance, dietary sugar consumption, and a comparison with the non-IBD Canadian population has not been documented. The aim was to analyze these interrelated dietary components. Methods: Food avoidance and sugar intake data were collected from 319 patients with IBD enrolled in the University of Manitoba IBD Cohort Study. Diets of those with IBD (n = 256) were compared with a matched, non-IBD Canadian cohort using the nutrition questions obtained from the Canadian Health Measures Survey (CHMS). Results: Food avoidance among IBD is prevalent for alcohol, popcorn, legumes, nuts, seeds, deep-fried food, and processed deli meat, with a higher prevalence among those with active IBD. Patients with active IBD also consumed significantly more portions of sports drinks and sweetened beverages compared with those with inactive disease. Compared with the non-IBD Canadian population, patients with IBD consume significantly less iron-rich food but more milk. Conclusions: Food avoidance is common among those with IBD but may be due more to personal preferences, while sugar-laden beverages may be displacing other foods higher in nutrients. The overall diet of patients with IBD differed from that of the non-IBD Canadian population, but deficiencies were observed in both groups. Considering malnutrition among persons living with IBD, nutrition education by trained dietitians as part of the IBD team is imperative to address food avoidance and overall balance nutrition as part of treating and preventing nutrition deficiencies.
    Journal of Parenteral and Enteral Nutrition 09/2014; · 3.14 Impact Factor
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    ABSTRACT: OBJECTIVES:Opioids are commonly used in the treatment of pain and associated symptoms of inflammatory bowel disease (IBD). The continuous use of opioids has been associated with adverse outcomes, including death. The prevalence and the risk factors for opioid use in IBD are poorly characterized.METHODS:We used the population-based Manitoba IBD Epidemiology Database to identify all individuals in Manitoba with IBD who were prescribed opioids both before and following diagnosis. We determined the point prevalence of any opioid use, as well as the risk of becoming a heavy opioid user (defined as continuous use for 30 days at a dose exceeding 50 mg morphine/day or equivalent). Logistic regression and Cox proportional hazards models were generated to assess whether IBD was an independent risk factor for opioid use, the risk factors for opioid use in individuals with IBD, and to determine whether opioid use was associated with excess mortality in IBD.RESULTS:Within 10 years of diagnosis, 5% of individuals with IBD had become heavy opioid users. Moderate use of opioids before diagnosis was strongly predictive of future heavy use. Individuals with IBD were significantly more likely to become heavy opioid users than their matched controls (odds ratio (OR) 2.91, 95% confidence interval (CI) 2.19-3.85). Heavy opioid use was strongly associated with mortality (OR 2.82, 95% CI 1.58-5.02).CONCLUSIONS:IBD is an independent risk factor for becoming a heavy opioid user, and heavy opioid use is associated with excess mortality in IBD patients. Clinicians should recognize risk factors for future heavy opioid use among their patients with IBD.Am J Gastroenterol advance online publication, 2 September 2014; doi:10.1038/ajg.2014.230.
    The American Journal of Gastroenterology 09/2014; · 9.21 Impact Factor
  • Canadian journal of gastroenterology & hepatology. 09/2014; 28(8):454-453.
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    ABSTRACT: Background and aims Few studies have specifically examined models of care in IBD. This survey was designed to help gather information from health professionals working in IBD services on current care models, and their views on how to best reshape existing models for IBD care worldwide. Methods An online mixed-methods survey was conducted with health professionals caring for IBD patients. Recruitment was conducted using the snowballing technique, where members of professional networks of the investigators were invited to participate. Results of the survey were summarised using descriptive statistics. Results Of the 135 included respondents, 76 (56%) were female, with a median age of 44 (range: 23–69) years, 50% were GI physicians, 34% nurses, 8% psychologists, 4% dieticians, 2% surgeons, 1% psychiatrists, and 1% physiotherapists. Overall, 73 (54%) respondents considered their IBD service to apply the integrated model of care, and only 5% reported that they worked exclusively using the biomedical care (no recognition of psychosocial factors). The majority of respondents reported including mental health assessment in their standard IBD care (65%), 51% believed that an ideal IBD service should be managed in specialist led clinics, and 64% wanted the service to be publicly funded. Respondents pictured an ideal IBD service as easy-access fully multi-disciplinary, with a significant role for IBD nurses and routine psychological and nutritional assessment and care. Conclusions Health care professionals believe that an ideal IBD service should: be fully integrated, involve significant roles of nurses, psychologists and dieticians, run in specialist clinics, be easily accessible to patients and publicly funded.
    Journal of Crohn s and Colitis 08/2014; · 3.56 Impact Factor
  • Canadian journal of gastroenterology & hepatology. 07/2014; 28(7):371-372.
  • Mayur Brahmania, Charles N Bernstein
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    ABSTRACT: Mucosal healing has been proposed as the therapeutic end point in the treatment of patients with ulcerative colitis (UC).
    Canadian journal of gastroenterology & hepatology. 06/2014; 28(6):325-329.
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    ABSTRACT: To compare the incidence of, and mortality after, intensive care unit (ICU) admission as well as the characteristics of critical illness in the multiple sclerosis (MS) population vs the general population. We used population-based administrative data from the Canadian province of Manitoba for the period 1984 to 2010 and clinical data from 93% of admissions to provincial high-intensity adult ICUs. We identified 5,035 prevalent cases of MS and a cohort from the general population matched 5:1 on age, sex, and region of residence. We compared these populations using incidence rates and multivariable regression models adjusting for age, sex, comorbidity, and socioeconomic status. From January 2000 to October 2009, the age- and sex-standardized annual incidence of ICU admission among prevalent cohorts was 0.51% to 1.07% in the MS population and 0.34% to 0.51% in matched controls. The adjusted risk of ICU admission was higher for the MS population (hazard ratio 1.45; 95% confidence interval [CI] 1.19-1.75) than for matched controls. The MS population was more likely to be admitted for infection than the matched controls (odds ratio 1.82; 95% CI 1.10-1.32). Compared with the matched controls admitted to ICUs, 1-year mortality was higher in the MS population (relative risk 2.06; 95% CI 1.32-3.07) and was particularly elevated in patients with MS who were younger than 40 years (relative risk 3.77; 95% CI 1.45-8.11). Causes of death were MS (9.3%), infections (37.0%), and other causes (52.9%). Compared with the general population, the risk of ICU admission is higher in MS, and 1-year mortality after admission is higher. Greater attention to preventing infection and managing comorbidity is needed in the MS population.
    Neurology 05/2014; · 8.30 Impact Factor
  • Charles N. Bernstein
    Clinical Gastroenterology and Hepatology 05/2014; 12(5):828–830. · 6.53 Impact Factor
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    ABSTRACT: SLC22A23 is an orphan gene in the SLC22 family of organic membrane transporters, and its single-nucleotide polymorphism rs17309827-T was recently nominally associated with intestinal inflammation in a genome-wide association study. Other polymorphisms in the SLC22A23 gene have been associated with diseases with an inflammatory component, and polymorphisms in related genes in the SLC22 family have been repeatedly associated with inflammatory bowel disease (IBD). In a candidate-gene study using a well-phenotyped, highly monitored, Manitoban white cohort, we investigated whether variations in SLC22A23 were associated with intestinal inflammation. Selected genetic variations were genotyped by using fluorescent-based assays or a polymerase chain reaction-restriction fragment length polymorphism analysis in 160 individuals with Crohn disease, 149 individuals with ulcerative colitis, and 142 healthy control subjects to determine genetic associations. Homozygocity for single-nucleotide polymorphisms rs4959235-TT and rs950318-GG was associated with IBD, whereby 6% of patients (18 of 311 cases) carried these genotypes, but they were not seen in healthy controls. Associations reported in this article add to the emerging evidence that SLC22A23 variants could modify IBD risk. However, the biology of the gene and impact of variations on the gene's functions need to be tested to validate a causative role.
    American Journal of Clinical Nutrition 04/2014; · 6.50 Impact Factor
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    ABSTRACT: Little is known about how often, and for what reasons, patients with inflammatory bowel diseases (IBD) are admitted to the intensive care unit (ICU). We compared incidences of ICU admission, characteristics of critical illness, and mortality after ICU admission between patients with IBD and the general population. We identified all persons with IBD in the province of Manitoba using a validated administrative definition of IBD for the period 1984 to 2010. Cases were considered incident for IBD if their first health system contact for IBD was in 1989 or later. We identified a population-based control group, matched by age, sex, and geography (based on postal code). Case and control cohorts were linked to the Manitoba ICU database. We compared outcomes between groups using age- and sex-standardized rates, Cox proportional hazards models, and logistic regression models, adjusting for age, sex, comorbidity, and socioeconomic status. There were 8224 prevalent and 4580 incident cases of IBD. After adjustment, the risk for ICU admission was higher for patients with IBD than controls (hazard ratio [HR], 1.79; 1.58-2.02). The risk of ICU admission was higher for patients with Crohn's disease (HR, 2.31; 1.95-2.75) than ulcerative colitis (HR, 1.37; 1.13-1.65). From 2000 through 2010, age- and sex-standardized annual incidence rates for ICU admission in the prevalent IBD cohort ranged from 0.55% to 1.12%. Compared to controls admitted to ICUs, 1 year after ICU admission, mortality was 32% among patients with IBD. Patients with IBD have a higher risk for admission to the ICU than the general population, and increased mortality 1 year after admission. These findings underscore the potential severity of IBD.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 04/2014; · 5.64 Impact Factor
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    ABSTRACT: To evaluate the reporting and performance of colonoscopy in a large urban centre. Colonoscopies performed between January and April 2008 in community hospitals and academic centres in the Winnipeg Regional Health Authority (Manitoba) were identified from hospital discharge databases and retrospective review of a random sample of identified charts. Information regarding reporting of colonoscopies (including bowel preparation, photodocumentation of cecum⁄ileum, size, site, characteristics and method of polyp removal), colonoscopy completion rates and follow-up recommendations was extracted. Colonoscopy completion rates were compared among different groups of physicians. A total of 797 colonoscopies were evaluated. Several deficiencies in reporting were identified. For example, bowel preparation quality was reported in only 20%, the agent used for bowel preparation was recorded in 50%, photodocumentation of colonoscopy completion in 6% and polyp appearance (ie, pedunculated or not) in 34%, and polyp size in 66%. Although the overall colonoscopy completion rate was 92%, there was a significant difference among physicians with varying medical specialty training and volume of procedures performed. Recommendations for follow-up procedures (barium enema, computed tomography colonography or repeat colonoscopy) were recorded for a minority of individuals with reported poor bowel preparation or incomplete colonoscopy. The present study found many deficiencies in reporting of colonoscopy in typical, city-wide clinical practices. Colonoscopy completion rates varied among different physician specialties. There is an urgent need to adopt standardized colonoscopy reporting systems in everyday practice and to provide feedback to physicians regarding deficiencies so they can be rectified.
    Canadian journal of gastroenterology & hepatology. 04/2014; 28(4):185-90.
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    ABSTRACT: Mucosal inflammation in patients with inflammatory bowel disease (IBD) is characterized by an alteration of prohormone Chromogranin A (CgA) production. The recent demonstration of an implication of CgA in collagenous colitis and immune regulation provides a potential link between CgA-derived peptides (catestatin, CTS) and gut inflammation. Colitis was induced by administration of dextran sulfate sodium or 2, 4 dinitrobenzenesulfonic acid to C57BL/6 mice. Treatment with human (h)CTS or its proximal or distal part was started one day before colitis induction and colonic inflammatory markers were determined. Pro-inflammatory cytokines were evaluated in peritoneal isolated and bone marrow derived macrophages (BMDMs); p-STAT3 level was studied. Serum levels of CgA and CTS were assessed in experimental colitis and in a separate study in IBD patients and healthy controls. We show that sera from IBD patients and that in experimental colitis conditions the colonic level of mouse (m)CgA and mCTS are significantly increased. Moreover, in vivo treatment with human (h)CTS reduces the disease onset and suppresses exacerbated inflammatory responses in preclinical settings of colitis associated with an increase of p-STAT3. In vitro, hCTS treatment decreases proinflammatory cytokine release by peritoneal macrophages and BMDMs and increases p-STAT3 levels. These results support the hypothesis that CTS is increased during colitis and that hCTS modulates intestinal inflammation via the macrophage population and through a STAT-3 dependent pathway in a murine model of colitis. Identification of the molecular mechanism underlying the protective role of this peptide may lead to a novel therapeutic option in IBD.
    Biochemical pharmacology 03/2014; · 4.25 Impact Factor
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    ABSTRACT: Corticosteroids are widely used in the management of inflammatory bowel disease (IBD) and are associated with significant side effects. The real world effectiveness of newer drug therapies at reducing corticosteroid use is yet to be reported. The overall burden of corticosteroid use is poorly characterized. We used a population-based IBD database to evaluate the overall prevalence of corticosteroid exposure, corticosteroid-free survival, and heavy corticosteroid use (≥3000 mg of prednisone or equivalent in a 365-day period). Regression models were used to assess predictors of heavy corticosteroid use and the relationship between corticosteroid dose in the first year after diagnosis and the need for continued corticosteroid use and surgery. The proportion of persons with IBD prescribed corticosteroids within 1, 5, and 10 years of diagnosis was 35.2%, 52.0%, and 62.8%, respectively. Persons with ulcerative colitis, males, and diagnosis before age 25 were more likely to use corticosteroids and have higher cumulative exposure. Heavy corticosteroid use in the first year after IBD diagnosis was associated with a 3 times increased hazard of resective surgery. Cumulative corticosteroid exposure did not decrease among those diagnosed with IBD in more recent years, despite increasing use of immunomodulators. A plurality of IBD patients will be exposed to corticosteroids over the course of disease, mostly in the first year. Heavy corticosteroid use in the first year of IBD is a strong predictor of subsequent surgery. Cumulative exposure to corticosteroids use is not decreasing despite increasing uptake of immunomodulators.
    Inflammatory Bowel Diseases 02/2014; · 5.12 Impact Factor
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    ABSTRACT: & Aims: Guidelines for the management of venous thromboembolism (VTE) from the American College of Chest Physicians do not address patients with inflammatory bowel disease (IBD), a group with a high risk of both VTE and gastrointestinal bleeding. We present recommendations for the prevention and treatment of VTE in patients with IBD. A systematic literature search was performed to identify studies on VTE in IBD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Statements were developed through an iterative online platform, then finalized and voted on by a working group of adult and pediatric gastroenterologists and thrombosis specialists. IBD patients have an approximately 3-fold higher risk of VTE compared with individuals without IBD, and disease flares further increase this risk. Anticoagulant thromboprophylaxis is recommended for IBD patients who are hospitalized with IBD flares without active bleeding and is suggested when bleeding is nonsevere. Anticoagulant thromboprophylaxis is suggested during moderate-severe IBD flares in outpatients with a history of VTE provoked by an IBD flare or an unprovoked VTE, but not otherwise. The recommended duration of anticoagulation after a first VTE is based on the presence of provoking factors. Specific suggestions are made for the prevention and treatment of VTE in pediatric and pregnant IBD patients. Using the American College of Chest Physicians' guidelines as a foundation, we have integrated evidence from IBD studies to develop specific recommendations for the management of VTE in this high-risk population.
    Gastroenterology 01/2014; · 12.82 Impact Factor
  • Laura E Targownik, Charles N Bernstein, William D Leslie
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    ABSTRACT: To provide a synopsis on established and new research evaluating bone disease in patients with inflammatory bowel disease (IBD) RECENT FINDINGS: Persons with IBD, including Crohn's disease and ulcerative colitis are believed to be at high risk for osteoporosis and fracture. As osteoporosis is clinically silent and persons with IBD are not universally screened, the burden of bone disease in IBD has been difficult to accurately assess. It is also unclear whether bone disease is due to inflammatory activity, medication use, poor nutrient intake/absorption, or body habitus characteristics. Recent studies using population-wide databases of bone mineral density (BMD) analyses suggest that Crohn's disease is responsible for a small effect on BMD after adjusting for other risk factors for low BMD, whereas ulcerative colitis does not appear to confer an independent risk. Furthermore, IBD does not appear to be a risk for overall fracture once controlling for factors which are associated with both IBD and fracture risk. The ability to assess BMD on incidentally performed computed tomography scans may allow detection of low BMD in IBD patients. Although reduced BMD and fracture are more common in persons with IBD, the precise burden is not well characterized. Also, the relative impact of IBD-associated factors and IBD-specific inflammation on bone health is still uncertain.
    Current opinion in gastroenterology 01/2014; · 4.33 Impact Factor

Publication Stats

14k Citations
3,037.46 Total Impact Points

Institutions

  • 1994–2014
    • University of Manitoba
      • • Department of Internal Medicine
      • • Department of Surgery
      Winnipeg, Manitoba, Canada
  • 2013
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
  • 2007–2013
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, MD, United States
  • 2012
    • Centre Hospitalier Universitaire de Grenoble
      Grenoble, Rhône-Alpes, France
  • 2011–2012
    • University of Toronto
      Toronto, Ontario, Canada
    • University of Saskatchewan
      • School of Public Health
      Saskatoon, Saskatchewan, Canada
    • Hôpital St-Boniface Hospital
      Winnipeg, Manitoba, Canada
    • Mount Sinai Hospital, Toronto
      • Zane Cohen Centre for Digestive Diseases
      Toronto, Ontario, Canada
    • University of Newcastle
      • Faculty of Health and Medicine
      Newcastle, New South Wales, Australia
  • 2004–2012
    • University College Cork
      • • School of Medicine
      • • Alimentary Pharmabiotic Centre
      Cork, M, Ireland
  • 2007–2011
    • Health Sciences Centre Winnipeg
      Winnipeg, Manitoba, Canada
  • 2003–2011
    • The University of Winnipeg
      Winnipeg, Manitoba, Canada
  • 2006
    • Government of Manitoba, Canada
      Winnipeg, Manitoba, Canada
  • 2001–2002
    • National Research Council Canada
      • Institute for Biodiagnostics (IBD)
      Ottawa, Ontario, Canada
    • Mayo Clinic - Rochester
      • Department of Gastroenterology and Hepatology
      Rochester, Minnesota, United States
  • 1993–1995
    • University of California, Los Angeles
      • Department of Medicine
      Los Angeles, CA, United States
  • 1991–1992
    • Harbor-UCLA Medical Center
      Torrance, California, United States