Gilles Jobin

Gene-centric Association Mapping of Chromosome 3p implicates MST1 in IBD pathogenesis

Association mapping and candidate gene studies within inflammatory bowel diseases (IBD) linkage regions, as well as genome-wide association studies in Crohns disease (CD) have led to the discovery of multiple risk genes, but these explain only a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21–22 showing linkage to CD and ulcerative colitis (UC) using a gene-centric association mapping approach. We identified 12 functional candidate genes by searching for literature cocitations with relevant keywords and for gene expression patterns consistent with immune/intestinal function. We then performed an association study composed of a screening phase, where tagging single nucleotide polymorphisms (SNPs) were evaluated in 1,020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association with IBD for four SNPs within a 1.2 Mb linkage disequilibrium region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage-stimulating 1 (MST1) gene (P-value 3.62 × 10–6) that accounts for the association signal, and shows association with both CD and UC. MST1 encodes macrophage-stimulating protein (MSP), a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.

Phenotypic and Genotypic Characteristics of Inflammatory Bowel Disease in French Canadians: Comparison With a Large North American Repository

OBJECTIVES:Phenotype characteristics of inflammatory bowel disease (IBD) may differ significantly among ethnic subpopulations. The aim of this study was to characterize the IBD phenotype in French Canadians, the most prominent founder population in North America.METHODS:Using well-characterized phenotype data in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-IBD Genetics Consortium repository on patients with IBD, we compared phenotypic characteristics of 202 French Canadians with those of 1,287 other Caucasian patients. These included diagnosis, anatomical location, disease behavior, extraintestinal manifestations, surgical history, and family history of IBD.RESULTS:French-Canadian patients with Crohns disease (CD) were less likely to have stricturing disease (11 vs. 21%, P=0.005; odds ratio (OR): 0.45, 95% confidence interval (95% CI): 0.24–0.85). Using a stringent definition of ethnicity (three out of four grandparents being French Canadians, as opposed to self-report, n=148), French Canadians had a tendency toward developing fistulizing CD (37 vs. 28%, P=0.07), and there was an increased prevalence of sacroiliitis among those with IBD (4 vs. 2%, P=0.045). Among French Canadians, the numbers of current smokers in CD (40 vs. 25%, P=0.006) and former smokers in ulcerative colitis (UC) (35 vs. 20%, P=0.03) were significantly higher. The prevalence of one of the three main variants of nucleotide-binding oligomerization domain containing 2 (NOD2) single-nucleotide polymorphisms (SNPs) among French-Canadian CD patients was 43.2%. The 3020insC SNP correlated with small bowel disease in French Canadians (75 vs. 0%, P=0.006).CONCLUSIONS:French Canadians show an IBD phenotype profile distinct from other Caucasian IBD populations, with an accentuated association between smoking status and IBD. This unique profile may have implications regarding the need for a different approach to the management of IBD in this population.

Randomized controlled trial comparing outcomes of video capsule endoscopy with push enteroscopy in obscure gastrointestinal bleeding

BACKGROUND Optimal management of obscure gastrointestinal bleeding (OGIB) remains unclear. OBJECTIVE To evaluate diagnostic yields and downstream clinical outcomes comparing video capsule endoscopy (VCE) with push enteroscopy (PE). METHODS Patients with OGIB and negative esophagogastroduodenoscopies and colonoscopies were randomly assigned to VCE or PE and followed for 12 months. End points included diagnostic yield, acute or chronic bleeding, health resource utilization and crossovers. RESULTS Data from 79 patients were analyzed (VCE n=40; PE n=39; 82.3% overt OGIB). VCE had greater diagnostic yield (72.5% versus 48.7%; P<0.05), especially in the distal small bowel (58% versus 13%; P<0.01). More VCE-identified lesions were rated possible or certain causes of bleeding (79.3% versus 35.0%; P<0.05). During follow-up, there were no differences in the rates of ongoing bleeding (acute [40.0% versus 38.5%; P not significant], chronic [32.5% versus 45.6%; P not significant]), nor in health resource utilization. Fewer VCE-first patients crossed over due to ongoing bleeding (22.5% versus 48.7%; P<0.05). CONCLUSIONS A VCE-first approach had a significant diagnostic advantage over PE-first in patients with OGIB, especially with regard to detecting small bowel lesions, affecting clinical certainty and subsequent further small bowel investigations, with no subsequent differences in bleeding or resource utilization outcomes in follow-up. These findings question the clinical relevance of many of the discovered endoscopic lesions or the ability to treat most of these effectively over time. Improved prognostication of both patient characteristics and endoscopic lesion appearance with regard to bleeding behaviour, coupled with the impact of therapeutic deep enteroscopy, is now required using adapted, high-quality study methodologies.

Barriers and facilitators to implementing continuous quality improvement programs in colonoscopy services: a mixed methods systematic review

Background and aim: Continuous quality improvement (CQI) programs may result in quality of care and outcome improvement. However, the implementation of such programs has proven to be very challenging. This mixed methods systematic review identifies barriers and facilitators pertaining to the implementation of CQI programs in colonoscopy services and how they relate to endoscopists, nurses, managers, and patients. Methods: We developed a search strategy adapted to 15 databases. Studies had to report on the implementation of a CQI intervention and identified barriers or facilitators relating to any of the four groups of actors directly concerned by the provision of colonoscopies. The quality of the selected studies was assessed and findings were extracted, categorized, and synthesized using a generic extraction grid customized through an iterative process. Results: We extracted 99 findings from the 15 selected publications. Although involving all actors is the most cited factor, the literature mainly focuses on the facilitators and barriers associated with the endoscopists’ perspective. The most reported facilitators to CQI implementation are perception of feasibility, adoption of a formative approach, training and education, confidentiality, and assessing a limited number of quality indicators. Receptive attitudes, a sense of ownership and perceptions of positive impacts also facilitate the implementation. Finally, an organizational environment conducive to quality improvement has to be inclusive of all user groups, explicitly supportive, and provide appropriate resources. Conclusion: Our findings corroborate the current models of adoption of innovations. However, a significant knowledge gap remains with respect to barriers and facilitators pertaining to nurses, patients, and managers.

Tu1074 Videocapsule Versus Enteroscopy in Patients With Obscure GI Bleeding: Results of a Randomized Controlled Trial

Background: Videocapsule endoscopy (VCE), when compared to enteroscopy (E), is associated with increased detection of mucosal lesions in obscure gastrointestinal bleeding (OGB). However, few randomized trials have compared these two modalities, and data on clinical relevance are lacking. The aim of this study was to compare VCE with E in terms of diagnostic yield and subsequent clinical outcome. Methods: We randomly allocated adult patients with occult bleeding (iron deficiency anemia >6 months needing blood transfusion or iron supplementation with repeated positive stool occult blood testing) or overt bleeding (≥1episode of melena/hematochezia within 7 days of presentation and a hemoglobin drop ≥15 g/dL) to VCE or E after a negative initial work-up (single or repeated gastroscopy and colonoscopy examinations with or without small bowel radiology). The main outcomes were recurrence and persistence of bleeding using standardized criteria defined a priori over 1year. Crossovers were permitted after the main outcome was reached. Results: 79 patients (68.5±14.5yrs, 36.7% female) were included over a 5-year period. 40 subjects were allocated to VCE and 39 to E (of push type). Overall, 76.0% presented with overt bleeding. At baseline, 24.1% were taking ASA, 11.4% an anticoagulant, and 2.5% an NSAID; 76.7% of patients had a nuclear scan, and 37.0% an angiography. No significant differences were noted in baseline characteristics between the two groups. At least one lesion was detected in 72.5% of the VCE group compared to 48.7% in the E group (p=0.03); they were believed to be the source of bleeding in 79.3% and 35.0% (p=0.002), respectively. Although detection rates were similar for gastric and duodenal findings, VCE performed better in the first and second parts of the jejunum (50% vs. 10.3% P=0.0001, and 40% vs. 2.6% P<0.0001). No disparities were observed in terms of the nature of the lesions found between the two modalities. Mean duration of follow-up was 289.0±118.8 days, with 50.0% requiring a blood transfusion (42.5% VCE vs. 57.9% E, with a mean of 2.9 ± 5.0 units (VCE: 2.8±4.3 units vs. E: 3.0±5.6 units, P=NS)). Hospitalization for bleeding or continued bleeding occurred in 40.0% of VCE and in 53.9% of E patients (P=NS) (mean stay: 11.0±11.9 and 18.5±28.2 days respectively, P=NS). Crossovers occurred more frequently from E to VCE than from VCE to E (48.7% vs. 22.5%, P=0.015). Conclusions: VCE increases diagnostic yield in OGB when compared to E, especially when the bleeding source is in the jejunum. However, subsequent impact on clinical care was not significantly better in this trial although trends favored the VCE group. More crossovers were noted from E to VCE than conversely. Overall, our data support the use of VCE over E following an initial work-up in patients with OGB.

User's perspectives of barriers and facilitators to implementing quality colonoscopy services in Canada: a study protocol

BackgroundColorectal cancer (CRC) represents a serious and growing health problem in Canada. Colonoscopy is used for screening and diagnosis of symptomatic or high CRC risk individuals. Although a number of countries are now implementing quality colonoscopy services, knowledge synthesis of barriers and facilitators perceived by healthcare professionals and patients during implementation has not been carried out. In addition, the perspectives of various stakeholders towards the implementation of quality colonoscopy services and the need of an efficient organisation of such services have been reported in the literature but have not been synthesised yet. The present study aims to produce a comprehensive synthesis of actual knowledge on the barriers and facilitators perceived by all stakeholders to the implementation of quality colonoscopy services in Canada.MethodsFirst, we will conduct a comprehensive review of the scientific literature and other published documentation on the barriers and facilitators to implementing quality colonoscopy services. Standardised literature searches and data extraction methods will be used. The quality of the studies and their relevance to informing decisions on colonoscopy services implementation will be assessed. For each group of users identified, barriers and facilitators will be categorised and compiled using narrative synthesis and meta-analytical techniques. The principle factors identified for each group of users will then be validated for its applicability to various Canadian contexts using the Delphi study method. Following this study, a set of strategies will be identified to inform decision makers involved in the implementation of quality colonoscopy services across Canadian jurisdictions.DiscussionThis study will be the first to systematically summarise the barriers and facilitators to implementation of quality colonoscopy services perceived by different groups and to consider the local contexts in order to ensure the applicability of this knowledge to the particular realities of various Canadian jurisdictions. Linkages with strategic partners and decision makers in the realisation of this project will favour the utilisation of its results to support strategies for implementing quality colonoscopy services and CRC screening programs in the Canadian health system.

Erratum: Phenotypic and genotypic characteristics of inflammatory bowel disease in french canadians: Comparison with a large North American repository (Am J Gastroenterol (2009) 104 (2233-2240) (DOI: 10.1038/ajg.2009.267)

Mamatha Bhat, Geoff rey C. Nguyen, Pierre Pare, Raymond Lahaie, Colette Deslandres, Edmond-Jean Bernard, Guy Aumais, Gilles Jobin, Gary Wild, Albert Cohen, Diane Langelier, Steven Brant, Th emistocles Dassopoulos, Dermot McGovern, Esther Torres, Richard Duerr, Miguel Regueiro, Mark S. Silverberg, Hillary Steinhart, Anne M. Griffi ths, Abdul Elkadri, Judy Cho, Deborah Proctor, Philippe Goyette, John Rioux and Alain Bitton Am J Gastroenterol 2009;104:2233 – 2240; doi:10.1038/ajg.2009.267

Risk for Osteoporosis and Antiresorptive Therapies in Patients with Crohn's Disease

Background: The risk of osteoporosis is greater in patients with inflammatory bowel disease (IBD) because of several related risk factors such as the prolonged use of corticosteroids, the malabsorption of calcium and vitamin D following small-bowel disease or small-bowel resections, and the inflammatory process resulting from the illness. A reduction in bone mineral density (BMD) has been reported in 30–75% of patients with IBD (Crohns disease or ulcerative colitis). An evaluation of the risk factors of osteoporosis should be performed to identify those in need of antiresorptive drug therapies (ART) and/or calcium and vitamin D supplements. Objective: To determine whether patients with Crohns disease at risk for osteoporosis or already having decreased BMD were identified as such and treated with appropriate therapy. Methods: A cross-sectional study was performed among 54 white patients with Crohns disease who attended a gastroenterology specialized clinic between January and March 2002. All patients with Crohns disease having an outpatient medical visit were asked to participate in the study. Patients who agreed to the study were questioned for Crohns disease activity index (CDAI) and osteoporosis risk factors such as nutrition, lifestyle, and corticosteroid therapy. Serum bone-specific markers and nutritional status were assessed. BMD test of the lumbar vertebrae (L2–L4) and the nondominant hip were assessed with dual-energy X-ray absorptiometry if the participants did not have a BMD test in the year prior to the study. ART and calcium/vitamin D use were assessed through a questionnaire and on community pharmaceutical drug services in the 2 year period prior to the evaluation. Results: Mean age and CDAI severity score were 41.5 years and 145, respectively. None of the patients was evaluated for BMD in the year prior to the study. Osteopenia at the nondominant hip and/or lumbar vertebrae was seen in 29 patients. Eighty-two percent of patients with a T score under −2 SD had not been exposed to ART; 84% of patients with more than 4 risk factors for osteoporosis and a T score less than −1.5 SD had not received ART. Moreover, 88% of patients with a T score less than −1.5 SD and receiving corticosteroid therapy had not been treated with ART. Conclusions: The presence of osteoporosis risk factors and osteopenia had not been recognized and treated in our population. Adequate osteoporosis management should be implemented in patients with Crohns disease to reduce the occurrence of osteoporotic fractures.