Publications // 2019-2020

Shaffer SR, Nugent Z, Yu BN, Lix LM, Bernstein CN, Walkty A, Singh H. Time trends and predictors of laboratory-confirmed recurrent and severe Clostridioides difficile infections in Manitoba: a population-based study. CMAJ Open 2020 Nov 16;8(4):E737-E746.

Many previous studies of Clostridioides difficile infection epidemiology have used hospital discharge data codes, which can have limited accuracy. We used a data set of laboratory-confirmed cases of Clostridioides difficile in the province of Manitoba, Canada, to describe the epidemiology of Clostridioides difficile over a decade. We conducted a population-based historical cohort study using Manitoba Health's population-wide laboratory-based Clostridioides difficile data set linked to administrative health databases. All individuals living in Manitoba and experiencing a Clostridioides difficile episode between 2005 and 2015 were included (n = 8471) and followed up from Clostridioides difficile diagnosis. We assessed time trends of Clostridioides difficile, incidence and predictors of recurrence and severe outcomes, and health care encounters after Clostridioides difficile diagnosis. Clostridioides difficile episodes were stratified by community versus hospital site of acquiring Clostridioides difficile. Results: Between 2005 and 2009, overall Clostridioides difficile diagnoses decreased by an average of 12.6% per year (95% confidence interval [CI] -4.4 to -20.0), with no statistically significant change from 2010 to 2015. In stratified analysis, incident and recurrent Clostridioides difficile had a similar decrease in the initial study time period and then stabilized. The proportion of community-associated Clostridioides difficile cases increased by an average of 4.8% per year (95% CI 2.8 to 6.8) during the study period. Clostridioides difficile acquired in a health care facility had a higher recurrence rate and more severe outcomes. Recurrence of Clostridioides difficile increased the likelihood of admission to hospital. Conclusion: Between 2005 and 2015, the rates of overall laboratory-confirmed Clostridioides difficile, incident Clostridioides difficile, recurrent Clostridioides difficile and severe outcomes following Clostridioides difficile initially decreased before stabilizing, and an increasing proportion of Clostridioides difficile cases were community-associated. There is an increasing need to test for Clostridioides difficile among outpatients with diarrhea and to increase efforts to prevent recurrent Clostridioides difficile.

Rubin DT, Abreu MT, Rai V, Siegel CA; International Organization for the Study of Inflammatory Bowel Disease (Dr Bernstein is a member of group authorship). Management of Patients With Crohn's Disease and Ulcerative Colitis During the Coronavirus Disease-2019 Pandemic: Results of an International Meeting. Gastroenterology 2020;159(1):6-13.

International Organization for the Study of IBD (IOIBD) used the established RAND/UCLA method, which uses a Delphi panel approach to address the appropriateness of specific medical interventions or medical decisions. We used a modified RAND panel to allow for a rapid cycle of 2 rounds of voting by the expert panel. The panel was presented a web-based questionnaire that included clinical scenarios specific to patients with IBD during the COVID-19 pandemic. The questionnaire was created and iteratively improved by 3 of the authors and then distributed electronically to the respondents. The panelists included the membership of IOIBD in addition to other invited specialists in IBD. Respondents rated each of the patient scenarios on a scale of 1–9, such that statements rated 1–3 are considered inappropriate, 4–6 are uncertain, and 7–9 are appropriate. After the first round of anonymous voting, the first webinar occurred and related content was reviewed as summarized and the results of the first round of voting were reviewed. The subsequent discussion focused on scenarios that had a median in the uncertainty range and those with a high standard deviation. The goal of the discussion was to understand views of the panel in preparation for a second round of voting, not necessarily to achieve consensus. The second round questionnaire was nearly identical to the first, except for clarifying a few of the original scenarios and adding 2 additional sections that were not covered in round 1 (how to manage patients in IBD clinical trials and when to restart medications if they were being held for active COVID-19 infection).

Of the 76 statements in the second-round survey, 26 were rated as appropriate, 19 as uncertain, and 31 as inappropriate. Although agreement is not required, there was agreement (DI of <1) in 64 of 76 scenarios (84%). Below are some of the key statements:

The panel agreed that having IBD (either Crohn’s disease or ulcerative colitis) did not increase the risk of becoming infected with SARS-CoV-2 or developing COVID-19 and having an ostomy or J-pouch did not increase the risk for COVID-19.
The panel agreed that it is safe to continue to receive infusions in an infusion center, assuming that the infusion center has a SARS-CoV-2 screening protocol in place.
The group was in agreement that it is appropriate to reduce the dose or discontinue prednisone to prevent infection from SARS-CoV-2, but voted that it was inappropriate to reduce the dose or stop other IBD therapies to prevent infection from SARS-CoV-2.
There were mixed responses related to the other clinical scenarios and therapies. The key findings regarding the management of medical therapy for IBD in the setting of the COVID-19 pandemic are summarized in Figure 1 .
In regards to the scenario of a patient receiving combination therapy of an anti-tumor necrosis factor (TNF) and immune modulator, the group was uncertain if the immune modulator should be dose reduced to potentially modify the risk of infection with SARS-CoV-2, but was in agreement and did vote that it is appropriate to discontinue the immune modulator in a patient who is known to be infected with SARS-CoV-2 or when a patient develops COVID-19.
In the scenario of a patient who stopped IBD medications because either they tested positive for SARS-CoV-2 infection or had COVID-19, the group voted that it is appropriate to restart their medications if they do not develop symptoms after 2 weeks, or when symptoms have completely resolved.
The group was in agreement and voted it was appropriate to postpone nonessential endoscopic procedures.
Furthermore, the panel voted that patients in clinical trials should continue those therapies unless they become infected by SARS-CoV-2 or develop COVID-19.
The group voted that it was appropriate to discontinue the clinical trial drug if a patient tests positive for SARS-CoV-2 or develops COVID-19, but there was some disagreement in the responses.

Restall GA, Michaud V, Walker JR, Waldman C, Bernstein CN, Park J, Wittmeier K, Singh H. Patient experiences with colonoscopy: A qualitative study. Journal of Canadian Association of Gastroenterology 2020 Dec; 3(6): 249-256.

Patient perspectives have important roles in improving the quality of colonoscopy services. The purpose of this qualitative study was to obtain the perspectives of patients who recently had undergone colonoscopy procedures, about their experiences with bowel preparation, the procedure itself, and communication of follow-up results and recommendations. We recruited adults who had undergone a colonoscopy, to participate in semi-structured interviews. Interviews were audiotaped, transcribed and analyzed using inductive qualitative methods. Twenty-four adults (58% female) with an average age of 53.8 years participated. Results were categorized within the themes of bowel preparation, the colonoscopy procedure and communication of the results. Participants appreciated having clear consistent plain language messages about bowel preparation. Some participants experienced additional challenges to understanding, and navigating, colonoscopy procedures. At the time of the procedure, positive and reassuring interactions with, and between, members of the health care team, in addition to management of physical pain and discomfort, were important. Participants wanted clear and timely information about the results of their test. In summary, understanding patients’ needs for information and support can promote higher quality colonoscopy services. Our findings suggest that quality indicators should include: patients’ perspectives of the clarity of bowel instructions; the need for supports that are not routinely provided; the extent to which concerns about the procedure are addressed; interactions with the endoscopy team; the endoscopy team’s interactions with each other; comfort during the procedure, and the timeliness and clarity of results and follow-up instructions. These indicators should be included in annual patient surveys.

Bernstein CN. New biomarkers for Crohn’s disease. Gastroenterology 2020; 159(1):30-32.

Case control studies of patients with IBD may facilitate the identification of factors present to a greater extent in those with the disease compared with those without the disease. If these factors are present before disease expression, they might be considered as risk factors. This can lead to further exploration of the biology of the factor in relation to IBD pathogenesis, or alternatively, as a biomarker identifying that the disease may be diagnosed at some future time. It is more difficult to prove that an antedating factor is a true risk factor. One reason is that it is very difficult to determine exactly when IBD starts in an individual patient. The first clinical presentation of disease might in fact be long after the biology of the disease has been set in motion. Prediagnosis factors have not necessarily emerged before disease onset, but rather before clinical manifestation of disease. They may in fact be sequelae of the disease pathogenesis unfolding. Postoperative Crohn’s disease is a good model of preclinical disease. Asymptomatic endoscopic recurrences are quite common. Finding environmental risk factors that might unravel disease etiology in IBD has been the holy grail of IBD researchers for decades. Measurable factors strongly associated with a disease can serve as biomarkers which can aid in diagnosis regardless of the timing at which they are found in relation to disease presentation. Anti-Sacccharomyces cerivisiae (ASCA) is one such marker. ASCA is also underexplored; the antibody and its fungal antigen present interesting opportunities for etiologic hypotheses. Newly identified biomarkers may be valuable diagnostic aids, but can also represent an entrance to an important pathogenetic pathway; or alternatively, an off-ramp to a misleading coincidence. It is on this complex background that 2 studies published in Gastroenterology this month point us in different directions along the etiologic and diagnostic hunt. In the article by Nair et al (Nair N, Austin C, Curtin P. et al. Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth. Gastroenterology. 2020; 159: 383-385), the authors relate the presence of heavy metals in baby teeth to the later development of Crohn’s disease. They lead off their discussion by suggesting that this finding is a key link to urbanization associated with Crohn’s disease. Theirs is a fascinating finding, but recent data have suggested that the disease does not necessarily favor urban areas.

Wherever the metals are coming from, this study strengthens the connection of IBD risk with the mothers of affected individuals. The finding of metals that can be tracked to the in utero state suggests that the offspring who will ultimately present with IBD and have high values of these metals are likely acquiring these metals from their mothers. Mothers may have accessed these metals in their cookware, in their cosmetics, in the packaged food they have eaten, or in the homegrown food they have consumed that has been affected by the metal-laden soil in which it was grown. The authors propose that the metals found in increased amounts may be important for the development of IBD. However, having not reported any metals that were not in excess in the affected individuals’ baby teeth argues against the 4 specific metals having unique roles in IBD pathogenesis. Nonetheless, the authors have identified that persons with IBD have associated markers that can be traced to early in life. Whatever ultimately leads to IBD may be experienced in the developing child. Our mothers are even more important to our health than we even previously considered! What and when they feed us during early childhood, and even what mothers ingest themselves may impact our future health. Recently, our study from Manitoba, published in Gastroenterology, reported that the strongest risk factor for a child ultimately developing IBD was the presence of IBD in their mothers.

This factor may be genetic—the mother passing on genes that modulate how metals are handled, genes that modulate the developing gut microbiome, or both. Alternatively, this factor may be environmental—the mother passing on to the child what she is ingesting. In the Manitoba study, the second most significant risk factor for developing IBD was having an infection in the first year of life—an infection in the child independent of his or her mother. Hence, an infection that may alter a developing gut microbiome, an infection that may be treated with antibiotics which may alter the developing gut microbiome or an infection the response to which may be impacted by the presence of excess heavy metals may be a critical inciting event in the pathogenesis of IBD. In the study by Torres et al (Torres J. Petralia F. Sato T. et al. Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis. Gastroenterology. 2020; 159: 96-104), a serum bank of Department of Defense recruits was accessed to study for microbial antibodies and immune-inflammatory markers for ≤5 years antedating diagnoses of either Crohn’s disease or ulcerative colitis. Anti-Flagellin X and ASCA-IgA were predictive of Crohn’s disease. A Somologic panel of 1100 potential proteins led to a handful that collectively formed a moderately good predictive model of later diagnosis of Crohn’s disease. These included C-reactive protein, complement C5, PRSS2 (trypsin 2), serum amyloid-P, osteomodulin, and aggrecan core protein. Four additional factors, complement factor I, IL-11 receptor subunit alpha, macrophage mannose receptor 1, and protein SET II were commonly selected at timepoints 1–4 years before diagnosis. It is not surprising that anti-Flagellin X and ASCA-IgA were predictive of Crohn’s disease since they have been associated with it previously. In fact, ASCA IgA has also been a strong predictor of aggressive disease behavior in Crohn’s disease. The significantly associated proteins are all involved in immune response, cytokine-mediated signaling pathway and apoptosis. Again, not surprising. Flagellin X is a bacterial product and ASCA is a response to a yeast. ASCA has been popping up as a disease marker for 30 years.

Is this the Helicobacter pylori-equivalent that has been staring at researchers? Of note Saccharomyces cerivisae may have an important role to play in heavy metal biosorption. The authors have convincingly showed that these microbial antibodies and immune-inflammatory mediators are present years before the first clinical manifestation of Crohn’s disease. These phenomena very likely are early biological manifestations of Crohn’s disease. They may not be risk factors that Crohn’s disease is coming, but rather that it is already present. If the value in identifying these markers in asymptomatic persons is so that they can be acted upon to prevent Crohn’s disease, it may be an unfulfilled hope, analogous to identifying NOD2 mutations. There are more people in the general population who have NOD2 mutations who will never get Crohn’s disease, but without question, persons who have NOD2 mutations are more likely to get Crohn’s disease.

Will the predictive package reported by Torres et al be stronger than ASCA alone or NOD-2 mutations?

Regardless, there remains little to offer to avoid the full expression of Crohn’s disease, even when it is believed to be in the offing. Some might say knowledge of a biomarker antedating Crohn’s disease presentation could lead to advice, for example, against smoking, for example, because smoking is associated, with Crohn’s disease in Western populations. There are surely better reasons not to smoke. Regardless, smoking does not even seem to be associated with Crohn’s disease in China or India where IBD is on the rise, likely in the absence of NOD2 mutations.

Torres et al present the premise that “biomarkers are needed to identify persons at risk for developing inflammatory bowel diseases.” Until the tools are available to truly prevent Crohn’s disease evolution, at best we can say that biomarkers are needed to help expand our diagnostic armamentarium.

These 2 groups of investigators should be congratulated for harnessing extraordinary resources (long-held baby teeth and a long-held serum bank) and for challenging the research community to make sense of their findings. From many years (in utero) to a few years before being diagnosed with Crohn’s disease, affected individuals are harboring increased levels of heavy metals and subclinical inflammation and antibody responses to microbial proteins. These 2 studies may be linked through the gut microbiome (including the fungome); being altered early in its development by exposure to heavy metals and ultimately establishing a proinflammatory microbiome that stimulates inflammatory proteins and antibodies to its constituents. To understand the biology of Crohn’s disease rather than studying those newly diagnosed in search of clues, a concerted effort should be undertaken to study a large cohort of pregnant women and their children. An expanded version of the Canadian Healthy Infant Longitudinal Development (CHILD) study could facilitate an understanding of early life changes that lead to chronic immune diseases some time later

Torabi M, Bernstein CN, Yu BN, Wickramasinghe L, Blanchard JF, Singh H. Geographical variation and factors associated with inflammatory bowel disease in a central Canadian province. Inflammatory Bowel Diseases 2020; 26(4):581-590.

We investigated temporal trends, geographical variation, and geographical risk factors for incidence of inflammatory bowel disease (IBD). We used the University of Manitoba IBD Epidemiology Database to identify incident IBD cases diagnosed between 1990 and 2012, which were then geocoded to 296 small geographic areas. Sociodemographic characteristics of the SGAs (proportions of immigrants, visible minorities, Indigenous people, and average household income) were obtained from the 2006 Canadian Census. The geographical variation of IBD incidence was modeled using a Bayesian spatial Poisson model. Time trends of IBD incidence were plotted using Joinpoint regression. We found that the incidence of IBD decreased over the study years from 23.6 (per 100,000 population) in 1990 to 16.3 (per 100,000 population) in 2012. For both Crohn's disease and ulcerative colitis, the highest incidence was in Winnipeg and the southern and central regions of Manitoba, whereas most of northern Manitoba had lower incidence. There was no effect of sociodemographic characteristics of small geographic areas, other than the proportion of Indigenous people, which was associated with lower IBD incidence.

We concluded that the incidence of IBD in Manitoba is decreasing over time. We have identified geographic areas with persistently higher IBD incidence that warrant further study for etiologic clues.

El Matary W, Nugent Z, Bernstein CN, Singh H. Long-term Cancer Risk in Pediatric-onset Inflammatory Bowel Disease: A Canadian Population-based Study. Gastroenterology 2020; 159:386-387.

Persons diagnosed with IBD as children and their controls were followed for 14,938 and 132,202 person-years, respectively. The median age of participants at IBD diagnosis was 14 years (inter-quartile range 12–16 years). The overall cancer rates during the study period in the IBD and control groups were 114 and 57 per 100,000 person-years, respectively. A total of 17 post-IBD diagnosis cancer cases occurred in 947 [61%] with Crohn’s disease) persons with IBD as compared with 75 of 9272 controls (HR 2.00; 95% confidence interval [CI] 1.16–3.43). The median age at cancer diagnosis in persons with IBD was 37 years (interquartile range 24–45 years). Compared with controls, persons with Crohn’s disease had an increased risk of developing cancers (HR 2.47; 95% CI 1.31–4.66). On the other hand, the risk of developing cancers among those with ulcerative colitis was numerically but not statistically significantly higher than controls (HR 1.24; 95% CI 0.43–3.59). Cancers reported in the IBD group included colorectal cancer, nonmelanoma skin cancer, lymphoma, leukemia, and urinary bladder cancer (fewer than 6 of each type). Within the IBD group, there was no difference in exposure to 2 or more dispensations of thiopurines (odds ratio 0.43; 95% CI 0.10–1.77) or anti-TNF agents (odds ratio 0.56; 95% CI 0.10–3.26) between those who developed cancer versus those who did not. We previously demonstrated that the incidence of pediatric-onset IBD is rising in Manitoba, and we are now reporting increased cancer incidence in adulthood in pediatric-onset IBD, especially in those with Crohn’s disease, as compared with controls without IBD. Although cancer events in our cohort were rare, they were not associated with anti-TNF agents or thiopurines. Younger age of diagnosing IBD has been recognized as a risk factor for developing colorectal cancer but it is not clear if the risk is the same for extraintestinal malignancy in children with IBD. On the adult side, and similar to our findings in pediatric-onset Crohn’s disease, our group previously showed a higher incidence of cancers among adults with Crohn’s disease (incidence rate ratio 1.29; 95% CI 1.07–1.54). Our study is limited by the small number of cancers. We could not report the details of cancers (<6 events) to protect patient confidentiality, as per Manitoba Health agreement. Misclassification bias remains a possibility. In summary, children and young adults with IBD may have a 2-fold increase for developing future cancers.

Sareen J, Olafson K, Kredentser MS, Bienvenu OJ, Blouw M, Bolton JM, Logsetty S, Chateau D, Nie Y, Bernstein CN, Afifi TO, Stein MB, Leslie WD, Katz LY, Mota N, El Gabalwy R, Sweatman S, Marrie RA. The Five-Year Incidence of Mental Disorders in a Population Based ICU Survivor Cohort. Critical Care Medicine 2020; Aug; 48(8): e675-e683.

In this study we aimed to estimate incidence of newly diagnosed mental disorders among patients that had been admitted to an intensive care unit (ICU) We used the population-based administrative data of Manitoba Health for this study. A total of 49,439 ICU patients admitted between 2000 and 2012 were compared with two control groups (hospitalized persons: n = 146,968 and general population: n = 141,937), matched on age (± 2 yr), sex, region of residence, and hospitalization year. Outcomes included incident mental disorders (mood, anxiety, substance use, personality, posttraumatic stress disorder, schizophrenia, and psychotic disorders) not diagnosed during the 5-year period before the index ICU or hospital admission date (including matched general population group), but diagnosed during the subsequent 5-year period. Multivariable survival models adjusted for sociodemographic variables, Charlson comorbidity index, admission diagnostic category, and number of ICU and non-ICU exposures.

The ICU cohort had a 14.5% (95% CI, 14.0-15.0) and 42.7% (95% CI, 42.0-43.5) age- and sex-standardized incidence of any diagnosed mental disorder at 1 and 5 years post-ICU exposure, respectively. In multivariable analysis, the ICU cohort had increased risk of any diagnosed mental disorder at all time points versus the hospitalized cohort (year 5: adjusted hazard ratio, 2.00; 95% CI, 1.80-2.23) and the general population cohort (year 5: adjusted hazard ratio, 3.52; 95% CI, 3.23-3.83). A newly diagnosed mental disorder was associated with younger age, female sex, more recent admitting years, presence of preexisting comorbidities, and repeat ICU admission.

We concluded that ICU admission is associated with an increased incidence of mood, anxiety, substance use, and personality disorders over a 5-year period

Tennenhouse L, Marrie RA, Bernstein CN, Lix L. Machine-learning models for depression and anxiety in individuals with immune-mediated inflammatory disease. Journal of Psychosomatic Research 2020; Jul; 134:110126.

Individuals with immune-mediated inflammatory disease (IMID, diseases such as IBD, multiple sclerosis, rheumatoid arthritis) have a higher prevalence of psychiatric disorders than the general population. We utilized machine-learning to identify patient-reported outcome measures (PROMs) that accurately predict major depressive disorder (MDD) and anxiety disorder in an IMID population. Participants with IMID were enrolled in a cohort study and completed a Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID), and multiple PROMs. PROM items were ranked separately for MDD and anxiety disorder by the standardized mean difference between individuals with and without psychiatric disorders. Items were added sequentially to logistic regression (LR), neural network (NN), and random forest (RF) models. Discriminative performance was assessed with area under the receiver operator curve and calibration was assessed with Brier scores. Ten-fold cross-validation was used. Of 637 participants, 75% were female and average age was 51 years. Area Under the Curve and Brier scores respectively ranged from 0.87-0.91 and 0.07 (i.e., no variation) for MDD models, and from 0.79-0.83 and 0.09-0.11 for anxiety disorder models. In LR and NN, few PROM items were required to obtain optimal discriminatory performance. RF did not perform as well as LR and NN when few PROM items were included.

We concluded that predictive model performance was respectable and revealed insight into PROM items that are predictive of MDD and anxiety disorder. Models that included only the items 'I felt depressed' and 'I felt like I needed help for my anxiety' performed similarly to models that included all items from multiple PROMs.

Chen Y, Hu S, Wu H, Farraye FA, Bernstein CN, Zheng JJ, Kiran RP, Shen B. Patterns of care for inflammatory bowel disease in China during the COVID-19 pandemic. Lancet Gastroenterology and Hepatology 2020; 5: 632-634.

We did a survey involving patients with IBD to analyse their feedback on their care during the early and late phases of the COVID-19 outbreak in China. 2277 participants completed the survey. 880 (39%) were women and 1397 (61%) men; 1639 (72%) had Crohn’s disease and 555 (24%) had ulcerative colitis. 111 (5%) respondents were from Hubei province. Of the 2277 respondents, 1134 (50%) were employed full or part time. Most (934 [82%] of 1134) had to work at home during the pandemic and 443 (39%) reported reduced income (appendix). More than 50% of the respondents reported some degree of mood changes, with the peak of the frequency of moderate-to-severe psychological change in the middle of the outbreak in China—ie, mid-February, 2020. Many (1331 [58%] of 2277) respondents were worried about the risk for SARS-CoV-2 infection for themselves and their family and more than half (1184 [52%]) were concerned about the difficulty in seeing physicians Almost three-quarters of patients (1691 [74%]) reported that their disease state was stable during the initial outbreak (from January to March, 2020) and 1842 (81%) reported that their disease remained stable in the later phase (ie, mid-April, 2020). 137 (6%) patients were admitted for IBD flares and 23 (1%) had surgery. 639 (28%) patients used telemedicine—of whom 487 (76%) sought help from IBD health-care providers online—and 847 (37%) of 2277 patients had face-to-face visits. Most patients (1744 [77%]) did not change IBD medications during the outbreak. Of the 533 patients with a change in medications, the main reasons for the change were recommendations from treating physicians (157 [30%]), being unable to receive intravenous infusions (151 [28%]), and the availability of physicians or facilities (148 [28%]). Most respondents (1606 [71%] of 2277) were still able to obtain oral medications online (1125 [49%]) or from hospital pharmacies as before (481 [21%]). By mid-April, 2020, most (1628 [71%]) were able to obtain oral medicines from their hospital pharmacies as before The results from this large survey suggest that the COVID-19 pandemic affects patients with IBD medically, psychosocially, and financially. Most respondents’ disease remained stable. Respondents using maintenance therapy and those requiring medication adjustments because of disease flares often met logistical challenges. The availability of telemedicine and online drug delivery services might have eased some of the burden. Psychosocial and economic effects of the pandemic on IBD care are common. The long-lasting effects will need to be studied over time.

Shaffer S, Nugent Z, Walkty A, Yu BN, Lix LM Targownik LE, Kao D, Bernstein CN, Singh H. Time trends and predictors of laboratory confirmed recurrent and severe C.difficile infections in Manitoba: a population-based study. CMAJ Open 2020; Nov 16;8(4):E737-E746.

Many previous studies of Clostridioides difficile infection epidemiology have used hospital discharge data codes, which can have limited accuracy. We used a data set of laboratory-confirmed cases of Clostridioides difficile infection in the province of Manitoba, Canada, to describe the epidemiology of Clostridioides difficile infection over a decade. We conducted a population-based historical cohort study using Manitoba Health's population-wide laboratory-based Clostridioides difficile infection data set linked to administrative health databases. All individuals living in Manitoba and experiencing a Clostridioides difficile infection episode between 2005 and 2015 were included (n = 8471) and followed up from Clostridioides difficile infection diagnosis. We assessed time trends of Clostridioides difficile infection, incidence and predictors of recurrence and severe outcomes, and health care encounters after Clostridioides difficile infection diagnosis. Clostridioides difficile infection episodes were stratified by community versus hospital site of acquiring Clostridioides difficile infection. Between 2005 and 2009, overall Clostridioides difficile infection diagnoses decreased by an average of 12.6% per year (95% confidence interval [CI] -4.4 to -20.0), with no statistically significant change from 2010 to 2015. In stratified analysis, incident and recurrent Clostridioides difficile infection had a similar decrease in the initial study time period and then stabilized. The proportion of community-associated Clostridioides difficile infection cases increased by an average of 4.8% per year (95% CI 2.8 to 6.8) during the study period. Clostridioides difficile infection acquired in a health care facility had a higher recurrence rate and more severe outcomes. Recurrence of CDI increased the likelihood of admission to hospital.

Between 2005 and 2015, the rates of overall laboratory-confirmed Clostridioides difficile infection, incident Clostridioides difficile infection, recurrent Clostridioides difficile infection and severe outcomes following Clostridioides difficile infection initially decreased before stabilizing, and an increasing proportion of Clostridioides difficile infection cases were community-associated. There is an increasing need to test for Clostridioides difficile infection among outpatients with diarrhea and to increase efforts to prevent recurrent Clostridioides difficile infection.

Khafipour A, Eissa N, Munyaka PM, Rabbi M, Kapoor K, Kermarrec, L Khafipour E, Bernstein CN, Ghia JE. Denosumab regulates gut microbiota composition and cytokines in dinitrobenzene sulfonic acid (DNBS)-experimental colitis. Frontiers in Microbiology 2020 Jun 25;11:1405.

The pro-inflammatory mediator receptor activator of nuclear factor-kappa B ligand (RANKL) plays a significant role in the development of rheumatoid arthritis; however, its role in IBD is unknown. Genome-wide association meta-analysis for Crohn's disease identified a variant near the TNFSF11 gene that encodes RANKL and Crohn's disease risk allele increased expression of RANKL in specific cell lines. This study aims to elucidate if the RANKL inhibitor denosumab can reduce the severity of experimental colitis and modify the gut microbiota composition using murine dinitrobenzenesulfonic acid (DNBS)-experimental model of colitis mimicking Crohn's disease. In colitic conditions, denosumab treatment significantly decreased the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α within the colonic mucosa. Moreover, colitis was accompanied by disruption of gut microbiota, and preventative treatment with denosumab modulated this disruption. Denosumab treatment also modified the alpha- and beta diversity of colonic mucosa and fecal microbiota. These results provide a rationale for considering denosumab as a future potential therapy in Crohn's disease; however, more detailed experimental and clinical studies are warranted.

Atsawarungruangkit A, Silvester JA, Weiten D, Green KL, Wilkey KE, Rigaux LN, Bernstein CN, Graff LA, Walker JR, Duerksen DR. Development of the Dietitian Integrated Evaluation Tool for Gluten-free Diets (DIET-GFD). Nutrition 2020; 78: 110819.

Celiac disease treatment involves a gluten-free diet (GFD). There is no standardized tool for dietitians to objectively grade GFD adherence. This study aimed to develop a standardized tool for dietitians to evaluate and communicate GFD adherence. Participants were recruited from the Manitoba Celiac Disease Cohort. Using a consensus process, an expert panel of gastroenterologists, dietitians, clinical health psychologists, and persons with celiac disease developed the Dietitian Integrated Evaluation Tool for Gluten-free Diets (DIET-GFD). Two dietitians performed duplicate assessments of 27 newly diagnosed participants who had been advised to follow a GFD. The global adherence scale was further revised after panel discussions of the cases where there was uncertainty or discordance on dietitian ratings. Subsequently, the scoring system was evaluated using duplicate assessments of an additional 37 participants with celiac disease. The DIET-GFD includes features related to frequency and quantity of gluten ingestion based on self-reporting and food frequency evaluation, shopping and dining habits, how and where food is prepared and consumed, eating behaviors, and label reading skills. The DIET-GFD global assessment is reported using a 10-point ordinal descriptive scale, ranging from 1 (takes few precautions and regularly eats gluten) to 10 (no gluten in kitchen and rarely eats food prepared outside the home). The kappa of DIET-GFD global assessment was 0.845, which indicates excellent agreement.

We concluded that the DIET-GFD is a useful tool for dietitians to evaluate GFD adherence. Further studies are needed to confirm that the score from the DIET-GFD is reliable across various settings.

Paulides E, Daker C, Frampton C, Gearry RB, Eglinton T, de Boer NKH, Bernstein CN, McCombie AM. Overcoming Workplace Disability in IBD Patients: An Observational Study. Inflammatory Intestinal Diseases 2020 Jun;5(2):84-92.

We aimed to investigate the impact of IBD in the workplace and to better understand the need for accommodations and adaptations. Between November 2017 and March 2018, IBD patients were recruited from outpatient clinics in Christchurch Hospital, New Zealand. The survey assessed employment, the need for workplace accommodations and the difficulty arranging it, insurance, and disability using the item-reduced Inflammatory Bowel Disease Disability Index for self-report (IBD-DI-SR). Data were analyzed using descriptive statistics and multivariate logistic regression modeling. 123 patients were included (response rate 64%), 112 of whom reported that they experienced symptoms while working (60% female, 71% Crohn's disease, mean age 41.9 years). 91% needed at least 1 workplace accommodation when symptoms were most severe. Almost half of the patients who needed an accommodation had difficulty arranging it. The most needed accommodations were time to go to medical appointments (71%) and easy access to a suitable toilet (71%). Being female, having less effective medication, and being distressed were associated with the need for 2 or more accommodations, difficulty in arranging accommodations, and not asking for needed accommodation.

We concluded that many IBD patients need accommodations at work while symptomatic in order to overcome workplace disability, which can be difficult to arrange. Improved resources are needed to inform employees and employers about the disease, the possibilities for workplace accommodations, and practical strategies to request them.

Bernstein CN, Walld R, Marrie RA. Social Determinants of Outcomes in IBD. American Journal of Gastroenterology 2020; 43(12):1255-1266.

In a population-based inflammatory bowel disease (IBD) cohort, we aimed to determine whether having lower socioeconomic status (LSS) impacted on outcomes. We identified all 9,298 Manitoba residents with IBD from April 1, 1995, to March 31, 2018 by applying a validated case definition to the Manitoba Health administrative database. We could identify all outpatient physician visits, hospitalizations, surgeries, intensive care unit admissions, and prescription medications. Their data were linked with 2 Manitoba databases, one identifying all persons who received Employment and Income Assistance and another identifying all persons with Child and Family Services contact. Area-level socioeconomic status was defined by a factor score incorporating average household income, single parent households, unemployment rate, and high school education rate. LSS was identified by any of ever being registered for Employment and Income Assistance or with Child and Family Services or being in the lowest area-level socioeconomic status quintile. Comparing persons with LSS vs those without any markers of LSS, there were increased rates of annual outpatient physician visits (relative risk [RR] = 1.10, 95% confidence interval [CI] = 1.06-1.13), hospitalizations (RR = 1.38, 95% CI = 1.31-1.44), intensive care unit admission (RR = 1.94, 95% CI = 1.65-2.27), use of corticosteroids >2,000 mg/yr (RR = 1.12, 95% CI = 1.03-1.21), and death (hazard ratio 1.53, 95% CI = 1.36-1.73). Narcotics (RR = 2.17, 95% CI = 2.01-2.34) and psychotropic medication use (RR = 1.98, 95% CI = 1.84-2.13) were increased. The impact of LSS was greater for those with Crohn's disease than for those with ulcerative colitis.

We concluded that lower socioeconomic status was associated with worse outcomes in persons with IBD. In fact they were as strong predictors of outcomes as other studies have shgown with any serological or genetic marker. Social determinants of health at time of diagnosis should be highly considered and addressed.

Witges K, Shafer LA, Zarychanski R, Abou-Setta AM, Rabbani R, Dingwall O, Bernstein CN. Ipilimumab induced enterocolitis: A systematic review and meta-analysis. Drug Safety 2020; 43, 1255–1266.

Checkpoint inhibitor drugs including ipilimumab have been reported to induce intestinal injury. There are several aspects of checkpoint inhibitor induced colitis that are unknown. We aimed to evaluate the risk of chronic (> 6 weeks) enterocolitis following ipilimumab administration, and the likelihood that an enteritis vs colitis or enterocolitis is seen. We searched MEDLINE, EMBASE, CENTRAL, the World Health Organization International Clinical Trials Registry, and conference proceedings. We included: (1) randomized controlled trials comparing ipilimumab administration with placebo/standard care/other active chemotherapy regimens and (2) prospective observational studies. Separate meta-analyses were performed for randomized controlled trials and observational studies. Of 4760 records, we included 10 unique randomized controlled trials (n = 5814 subjects) and 34 unique prospective observational studies (n = 3699 subjects). In randomized controlled trials, the pooled relative risk of ≥ grade 3 enterocolitis or ≥ grade 3 diarrhea associated with ipilimumab was 13.31 (95% confidence interval 6.01-29.48, I2 = 0%, ten trials) and 6.72 (95% confidence interval 3.30-13.65, I2 = 63%, ten trials), respectively. In observational studies, the 3-monthly risk of developing grade 3 or higher enteritis, colitis, or enterocolitis was 4% (95% confidence interval 3-7, I2 = 77.40%, 25 studies). Randomized controlled trials and observational studies did not distinguish between acute and chronic enterocolitis. Of the included observational studies, the pooled risk of incurring small bowel involvement associated with ipilimumab was 1% (95% CI 0-4, I2 = 0%, four studies) per every 3-month time period.

Insufficient data exist to quantify or distinguish the risk of acute vs chronic enterocolitis following ipilmumab use. Because of the serious impact of chronic enterocolitis on quality of life and further cancer treatment, future trials evaluating the safety of immunotherapy should report gastrointestinal events in greater detail.

Szamosi JC, Forbes JD, Copeland JK, Knox, NC, Shekarriz S, Rossi, L, Graham M, Bonner C, Guttman, DS, Van Domselaar, G, Surette MG, Bernstein CN. Assessment of inter-laboratory variation in the characterization and analysis of the mucosal microbiota in Crohn’s disease and ulcerative colitis. Frontiers in Microbiology 2020; 11: e2072.

In studies evaluating the microbiome, numerous factors can contribute to technical variability. These factors include DNA extraction methodology, sequencing protocols, and data analysis strategies. We sought to evaluate the impact these factors have on the results obtained when the sequence data are independently generated and analyzed by different laboratories. To evaluate the effect of technical variability, we used human intestinal biopsy samples resected from individuals diagnosed with IBD, including Crohn's disease ( = 12) and ulcerative colitis ( = 10), and those without IBD ( = 10). Matched samples from each participant were sent to three laboratories and studied using independent protocols for DNA extraction, library preparation, targeted-amplicon sequencing of a 16S rRNA gene hypervariable region, and processing of sequence data. We looked at two measures of interest - Bray-Curtis PERMANOVA 2 values and log2 fold-change estimates of the 25 most-abundant taxa - to assess variation in the results produced by each laboratory, as well the relative contribution to variation from the different extraction, sequencing, and analysis steps used to generate these measures. The 2 values and estimated differential abundance associated with diagnosis were consistent across datasets that used different DNA extraction and sequencing protocols, and within datasets that pooled samples from multiple protocols; however, variability in bioinformatic processing of sequence data led to changes in 2 values and inconsistencies in taxonomic assignment and abundance estimates.

We concluded that although the contribution of DNA extraction and sequencing methods to variability were observable, we find that results can be robust to the various extraction and sequencing approaches used in our study. Differences in data processing methods have a larger impact on results, making comparison among studies less reliable and the combined analysis of bioinformatically processed samples nearly impossible. Our results highlight the importance of making raw sequence data available to facilitate combined and comparative analyses of published studies using common data processing protocols. Study methodologies should provide detailed data processing methods for validation, interpretability, reproducibility, and comparability.

Turpin W, Lee SH, Raygoza Garay JA, Madsen KL, Meddings JB, Bedrani L, Power N, Espin-Garcia O, Xu W, Smith MI, Griffiths AM, Moayyedi P, Turner D, Seidman EG, Steinhart HA, Marshall JK, Jacobson K, Mack D, Huynh H, Bernstein CN, Paterson AD, Croitoru K; CCC GEM Project Research Consortium. Increased Intestinal Permeability is Associated with Later Development of Crohn's Disease. Gastroenterology 2020; 159;2092-2100.

This study was from the Crohns and Colitis Canada sponsored GEM studyIncreased intestinal permeability has been associated with Crohn's disease, but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of Crohn's disease. We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio at recruitment in 1420 asymptomatic first-degree relatives (6-35 years old) of patients with Crohn's disease (collected from 2008 through 2015). Participants were then followed up for a diagnosis of Crohn's disease from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed Crohn's disease after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of Crohn's disease based on the baseline lactulose-to-mannitol ratio. An abnormal lactulose-to-mannitol ratio (>0.03) was associated with a diagnosis of Crohn's disease during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64-5.63; P = 3.97 × 10-4). This association remained significant even when the test was performed more than 3 years before the diagnosis of Crohn's disease (hazard ratio, 1.62; 95% CI, 1.051-2.50; P = .029).

We concluded that increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.

Silvester JA, Comino I, Rigaux LN, Segura V, Green KH, Cebolla A, Weiten D, Dominguez R, Leffler DA, Leon F, Bernstein CN, Graff LA, Kelly CP, Sousa C, Duerksen DR. Exposure sources, amounts and time course of gluten ingestion and excretion in patients with celiac disease on a gluten-free diet. Alimentary, Pharmacology and Therapeutics 2020; 52(9):1469-1479.

A major deficit in understanding and improving treatment in celiac disease is the lack of empiric data on real world gluten exposure. To estimate gluten exposure on a gluten-free diet (GFD) using immunoassays for gluten immunogenic peptides (GIP) and to examine relationships among GIP detection, symptoms and suspected gluten exposures Adults with biopsy-confirmed celiac disease on a GFD for 24 months were recruited from a population-based inception cohort. Participants kept a diary and collected urine samples for 10 days and stools on days 4-10. 'Doggie bags' containing ¼ portions of foods consumed were saved during the first 7 days. Gluten in food, stool and urine was quantified using A1/G12 ELISA. 18 participants with celiac disease (12 female; age 21-70 years) and 3 participants on a gluten-containing diet enrolled and completed the study. 12 of 18 celiac disease participants had a median 2.1 mg gluten per exposure (range 0.2 to >80 mg). Most exposures were asymptomatic and unsuspected. There was high intra-individual variability in the interval between gluten ingestion and excretion. Participants were generally unable to identify the food.

We concluded gluten exposure on a GFD is common, intermittent, and usually silent. Excretion kinetics are highly variable among individuals. The amount of gluten varied widely, but was typically in the milligram range, which was 10-100 times less than consumed by those on an unrestricted diet. These findings suggest that a strict GFD is difficult to attain, and specific exposures are difficult to detect due to variable time course of excretion.

Shaffer SR, Witt J, Targownik LE, Kao D, Lee C, Smielauskas F, Rubin DT, Singh H, Bernstein CN. Cost-effectiveness Analysis of a Fecal Microbiota Transplant Center for Treating Recurrent C.difficile Infection. Journal of Infection 2020; 81:758-65.

We assessed the cost-effectiveness of establishing a fecal microbial transplant (FMT) unit in Canada for the treatment of recurrent C.difficile infection. We performed a cost-effectiveness analysis to determine the number of patients with recurrent C.difficile infection needed to treat (NNT) annually to make establishing a FMT unit cost-effective. We compared treating patients for their second recurrence of C.difficile infection with FMT in a jurisdiction with a FMT unit, compared to being treated with antibiotics; then sent to a medical center with FMT available for the third recurrence. We used a willingness to pay threshold of $50,000 per quality-adjusted-life-year gained. The minimum annual NNT was 15 for FMT via colonoscopy, 17 for FMT via capsule, and 44 for FMT via enema compared with vancomycin, and 16, 18, and 47 compared with fidaxomicin, respectively. A medical center's minimum catchment area when establishing a FMT unit would have to be 56,849 if using FMT via colonoscopy, or 64,429 if using capsules.

We report the minimum number of patients requiring treatment annually with FMT to achieve cost-effectiveness, when including start-up and ongoing costs. FMT is cost-effective in Canada in populations with a sufficient number of eligible patients, ranging from 15 to 47 depending on the FMT modality used. This is crucial for medical jurisdictions making decisions about establishing a FMT unit for the treatment of recurrent C.difficile infection. The cost-effectiveness can be generalized in other countries.

Eissa N, Hussein H, Tshikudi D, Hendy GN, Bernstein CN, Ghia JE. Interdependence between chromogranin-A, alternatively activated macrophages, tight junction proteins and the epithelial functions. A human and in-vivo/in-vitro descriptive study. International Journal of Molecular Sciences 2020; Oct 27;21(21):7976.

Ulcerative colitis is characterized by altered chromogranin-A, alternatively activated macrophages (M2) and intestinal epithelial cells (IECs). We previously demonstrated that chromogranin-A is implicated in colitis progression by regulating the macrophages. Here, we investigated the interplay between chromogranin-A, M2, tight junctions (TJ) and IECs in an inflammatory environment. Correlations between mRNA expression of and TJ proteins mRNA expressions of (Occludin [], zonula occludens-1 [], Claudin-1 []), epithelial associated cytokines (interleukin , ), and collagen () were determined in human colonic mucosal biopsies isolated from active UC and healthy patients. Acute ulcerative colitis-like colitis (5% dextran sulphate sodium [DSS], five days) was induced in -C57BL/6-deficient () and wild type ( ) mice. TJ proteins, mRNA expression and collagen deposition were determined in whole colonic sections. Naïve and peritoneal macrophages were isolated and exposed six hours to IL-4/IL-13 (20 ng/mL) to promote M2 and generate M2-conditioned supernatant. Caco-2 epithelial cells were cultured in the presence of and non- or M2-conditioned supernatant for 24 h then exposed to 5% DSS for 24 h, and their functional properties were assessed. In humans, mRNA correlated positively with , and , and negatively with TJ proteins mRNA markers. In the experimental model, the deletion of reduced IL-18 mRNA and its release, mRNA and colonic collagen deposition, and maintained colonic TJ proteins. M2-conditioned supernatant protected caco-2 cells from DSS and oxidative stress injuries by improving caco-2 cells functions (proliferation, viability, wound healing) and by decreasing the release of IL-8 and IL-18 and by maintaining the levels of TJ proteins, and when compared with M2-conditioned supernatant.

We concluded that chromogranin-A contributes to the development of intestinal inflammation through the regulation of M2 and epithelial cells. Targeting chromogranin-A may lead to novel biomarkers and therapeutic strategies in ulcerative colitis.

Moayyedi P, MacQueen G, Bernstein CN, Vanner S, Bercik P, Madsen KL, Surette M, Rioux JD, Dieleman LA, Verdú E, de Souza RJ, Otley A, Targownik L, Lavis J, Cunningham J, Marshall DA, Zelinsky S, Fernandes A. IMAGINE NETWORK’s Mind And Gut Interactions Cohort (MAGIC) Study: a protocol for a prospective observational multicentre cohort study in inflammatory bowel disease and irritable bowel syndrome. BMJ Open. 2020 Oct 21;10(10):e041733.

Gut microbiome and diet may be important in irritable bowel syndrome (IBS), IBD and comorbid psychiatric conditions, but the mechanisms are unclear. We will create a large cohort of patients with IBS, IBD and healthy controls, and follow them over time, collecting dietary and mental health information and biological samples, to assess their gastrointestinal and psychological symptoms in association with their diet, gut microbiome and metabolome.

This 5-year observational prospective cohort study is recruiting 8000 participants from 15 Canadian centres. Persons with IBS who are 13 years of age and older or IBD who are at least 5 years will be recruited. Healthy controls will be recruited from the general public and from friends or relatives of those with IBD or IBS who do not have GI symptoms. Participants answer surveys and provide blood, urine and stool samples annually. Surveys assess disease activity, quality of life, physical pain, lifestyle factors, psychological status and diet. The main outcomes evaluated will be the association between the diet, inflammatory, genetic, microbiome and metabolomic profiles in those with IBD and IBS compared with healthy controls using multivariate logistic regression. We will also compare these profiles in those with active versus quiescent disease and those with and without psychological comorbidity. Approval has been obtained from the institutional review boards of all centres taking part in the study. We will develop evidence-based knowledge translation initiatives for patients, clinicians and policymakers to disseminate results to relevant stakeholders. Trial registration number: NCT03131414.

Thomann A, Mak WY, Wang ZJ, Wuestenber T, Ebert M, Sung JJY, Bernstein CN, Reindl W, Ng S. Review article: Bugs, inflammation and mood – a microbiota-based approach to psychiatric symptoms in IBD. Alimentary Pharmacology and Therapuetics 2020;52(2):247-266.

Endoscopy is an essential component in the management of IBD. There is a risk of SARS-CoV-2 transmission during endoscopic procedures. The International Organization for the study of IBD [IOIBD] has developed 11 position statements, based on an online survey, that focus on how to prioritize endoscopies in IBD patients during the COVID-19 pandemic, alternative modes for disease monitoring, and ways to triage the high number of postponed endoscopies after the pandemic. We propose to pre-screen patients for suspected or confirmed COVID-19 and test for SARS-CoV-2 before endoscopy if available. High priority endoscopies during pandemic include acute gastrointestinal bleed, acute severe ulcerative colitis, new IBD diagnosis, cholangitis in primary sclerosing cholangitis, and partial bowel obstruction. Alternative modes of monitoring using clinical symptoms, serum inflammatory markers, and fecal calprotectin should be considered during the pandemic. Prioritizing access to endoscopy in the post-pandemic period should be guided by control of COVID-19 in the local community and availability of manpower and personal protective equipment. Endoscopy should be considered within 3 months after the pandemic for patients with a past history of dysplasia and endoscopic resection for dysplastic lesion. Endoscopy should be considered 3-6 months after the pandemic for assessment of postoperative recurrence or new biologic initiation. Endoscopy can be postponed until after 6 months of pandemic for routine IBD surveillance and assessment of mucosal healing.

El Matary W, Bernstein CN. Cancer Risk in Pediatric-onset Inflammatory Bowel Disease. Frontiers in Pediatrics 2020; 8:400.

The incidence of IBD appears to have risen over the last few decades especially in the pediatric age group. IBD usually presents with gastrointestinal symptoms, including abdominal pain, diarrhea, and bleeding per rectum but can also be associated with systemic symptoms such as weight loss, fatigue, joint and skin problems, and psychological comorbidities. One major complication is gastrointestinal and extra-intestinal malignancy. This review discusses literature that focuses on cancer risk of pediatric-onset IBD.

Kobayashi T, Siegmund B, Le Berre C, Wei S, Ferrante M, Shen B, Bernstein CN, Danese S, Peyrin-Biroulet L, Hibi T. Ulcerative colitis. Nature Reviews Disease Primers 2020; 6:174-190.

This is a comprehensive review of ulcerative colitis. Ulcerative colitis is a chronic inflammatory bowel disease of unknown etiology affecting the colon and rectum. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been suggested to contribute to ulcerative colitis pathogenesis. Ulcerative colitis has evolved into a global burden given its high incidence in developed countries and the substantial increase in incidence in developing countries. An improved understanding of the mechanisms underlying ulcerative colitis has led to the emergence of new treatments. Since the early 2000s, anti-tumor necrosis factor (TNF) treatment has significantly improved treatment outcomes. Advances in medical treatments have enabled a paradigm shift in treatment goals from symptomatic relief to endoscopic and histological healing to achieve better long-term outcomes and, consequently, diagnostic modalities have also been improved to monitor disease activity more tightly. Despite these improvements in patient care, a substantial proportion of patients, for example, those who are refractory to medical treatment or those who develop colitis-associated colorectal dysplasia or cancer, still require restorative proctocolectomy. The development of novel drugs and improvement of the treatment strategy by implementing personalized medicine are warranted to achieve optimal disease control. However, delineating the etiology of ulcerative colitis is necessary to ultimately achieve disease cure.

Ng SC, Mak JWY, Hitz L, Chowers Y, Bernstein CN, Silverberg MS. COVID-19 Pandemic: Which IBD Patients Need to Be Scoped-Who Gets Scoped Now, Who Can Wait, and how to Resume to Normal. Journal of Crohns Colitis. 2020; 21; (Supplement-3): S791-S797.

Endoscopy is an essential component in the management of IBD. There is a risk of SARS-CoV-2 transmission during endoscopic procedures. The International Organization for the study of IBD [IOIBD] has developed 11 position statements, based on an online survey, that focus on how to prioritise endoscopies in IBD patients during the COVID-19 pandemic, alternative modes for disease monitoring, and ways to triage the high number of postponed endoscopies after the pandemic. We propose to pre-screen patients for suspected or confirmed COVID-19 and test for SARS-CoV-2 before endoscopy if available. High priority endoscopies during pandemic include acute gastrointestinal bleed, acute severe ulcerative colitis, new IBD diagnosis, cholangitis in primary sclerosing cholangitis, and partial bowel obstruction. Alternative modes of monitoring using clinical symptoms, serum inflammatory markers, and faecal calprotectin should be considered during the pandemic. Prioritising access to endoscopy in the post-pandemic period should be guided by control of COVID-19 in the local community and availability of manpower and personal protective equipment. Endoscopy should be considered within 3 months after the pandemic for patients with a past history of dysplasia and endoscopic resection for dysplastic lesion. Endoscopy should be considered 3-6 months after the pandemic for assessment of postoperative recurrence or new biologic initiation. Endoscopy can be postponed until after 6 months of pandemic for routine IBD surveillance and assessment of mucosal healing.

Banerjee R, Pal P, Nugent Z, Ganesh G, Adigopula B, Pendyala S, Bernstein CN. IBD in India: Similar phenotype but different demographics than the West. Journal of Clinical Gastroenterology 2020; 54:725-732.

Inflammatory bowel disease (IBD) is emerging in the developing world but phenotypic data are limited. In this study we aimed to describe the phenotype, clinical presentation, disease behavior and treatments of IBD in a large cohort in India. All persons presenting to the Asian Institute of Gastroenterology in Hyderabad, India since 2004 with a confirmed diagnosis of IBD were enrolled. The demographic profile at the first visit, family history of IBD, smoking history, time from first symptom onset to diagnosis, use of anti-tuberculous treatment before IBD-specific treatment, disease phenotype, and medication history were collected by interview and chart review. Disease and family history and treatments used were updated at each follow-up visit. Of 4006 persons enrolled, 59.9% had ulcerative colitis and the majority were male (60.3%). The median diagnostic delay in both ulcerative colitis and Crohn’s disease was at least two years. At the time of diagnosis only 4.5% of Crohn’s disease were smokers and only 3.8% of ulcerative colitis were ex-smokers. Positive family history was uncommon (2.1%). The phenotype of persons with Crohn’s disease included 22.9% with stricturing disease and 9.4% with fistulizing disease. The most common site of disease was ileo-colonic (40.9%) and only 2.5% had perineal fistulas. Among those with ulcerative colitis 18.7% had proctitis and 30.3% had pan-colitis.

This is the largest cohort of persons with IBD reported from Asia. While there are several demographic differences between persons with IBD from India compared with the West, the phenotypes of the disease are not highly different. We hope to ultimately undertake a study comparing Indians with IBD from India and Indians with IBD from Canada to contrast the differences in diet, gut microbiome and clinical presentation. This might lead us to understand causes of IBD.

Targownik LE, Kaplan GG, Witt J, Bernstein CN, Singh H, Tennakoon A, Aviña Zubieta A, Coward S, Jones J, Kuenzig ME, Murthy SK, Nguyen GC, Peña-Sánchez JN, Benchimol EI. Longitudinal trends in the direct costs and health care utilization ascribable to inflammatory bowel disease in the biologic era: Results from a Canadian population based analysis. American Journal of Gastroenterology 2020; 115(1):128-137.

We aimed to assess the total direct costs of IBD on a population-wide level in the era of biologic therapy. We identified all persons with IBD in Manitoba between 2005 and 2015, with each matched to 10 controls on age, sex, and area of residence. We enumerated all hospitalizations, outpatient visits and prescription medications including biologics, and their associated direct costs. Total and per capita annual IBD-attributable costs and health care utilization were determined by taking the difference between the costs/ health care utilization accrued by an IBD case and their controls. Generalized linear modeling was used to evaluate trends in direct costs and Poisson regression for trends in health care utilization. The number of people with IBD in Manitoba increased from 6,323 to 7,603 between 2005 and 2015. The total per capita annual costs attributable to IBD rose from $3,354 in 2005 to $7,801 in 2015, primarily driven by an increase in per capita annual anti-tumor necrosis factor costs, which rose from $181 in 2005 to $5,270 in 2015. There was a significant decline in inpatient costs for Crohn’s disease ($99 ± 25/yr. P < 0.0001), but not for ulcerative colitis ($8 increase ±$18/yr, P = 0.63).

We concluded that the direct health care costs attributable to IBD have more than doubled over the 10 years between 2005 and 2015, driven mostly by increasing expenditures on biological medications. IBD-attributable hospitalization costs have declined modestly over time for persons with Crohn’s disease, although no change was seen for patients with ulcerative colitis.

El-Matary W, Leung S, Tennakoon A, Benchimol EI, Bernstein CN, Targownik LE. Trends of utilization of tumor necrosis factor antagonists in children with inflammatory bowel disease: A Canadian population-based study. Inflammatory Bowel Diseases 2020; 26:134-8.

Population-based studies examining the prevalence of anti-tumor necrosis factor (anti-TNF) antagonist utilization in children and young adults with IBD are lacking. We aimed to describe the trend of anti-TNF utilization in pediatric IBD over time. Survival analyses were performed for all patients diagnosed with IBD before age 18 years in the province of Manitoba to determine the time from diagnosis to first anti-TNF prescription in different time eras (2005-2008, 2008-2012, 2012-2016). There were 291 persons diagnosed with IBD (157 with Crohn's disease and 134 with UC over the study period. The likelihood of being initiated on an anti-TNF by 1, 2, and 5 years postdiagnosis was 18.4%, 30.5%, and 42.6%, respectively. The proportion of persons aged <18 years utilizing anti-TNFs rose over time; in 2010, 13.0% of Crohn's disease and 4.9% of UC; by 2016, 60.0% of Crohn's disease and 25.5% of UC. For those diagnosed after 2012, 42.5% of Crohn's disease and 28.4% of UC patients had been prescribed an anti-TNF antagonist within 12 months of IBD diagnosis. Initiating an anti-TNF without prior exposure to an immunosuppressive agent increased over time (before 2008: 0%; 2008-2012: 18.2%; 2012-2016: 42.8%; P < 0.001). There was a significant reduction in median cumulative dose of corticosteroids in the year before anti-TNF initiation (2005-2008: 4360 mg; 2008-2012: 2010 mg; 2012-2016: 1395 mg prednisone equivalents; P < 0.001).

Over a period of 11 years, anti-TNFs are being used earlier in the course of pediatric IBD, with a parallel reduction in the cumulative corticosteroid dose.

Siegel C, Bernstein CN. Risk Stratifying Patients with IBD – Identifying Patients at High- vs. Low-risk of Complications. Clinical Gastroenterology and Hepatology 2020, 18(6):1261-1267.

This editorial reviewed the available evidence to classify patients with IBD at either high risk or low risk for progressing to more aggressive disease or complicated outcomes.

Bernstein CN. Is antibiotic use a cause of IBD worldwide? Inflammatory Bowel Diseases 2020; 26: 448-449.

This editorial reviewed the evidence for antibiotics as a possible culprit in triggering IBD onset.

Stone J, Grover K, Bernstein CN. The use of capsule endoscopy for diagnosis of iron deficiency anemia: A retrospective analysis. Journal of Clinical Gastroenterology 2020; 54(5):452-458.

There was some ambiguity in the recent guidelines on the use of capsule endoscopy in cases of iron deficiency anemia (IDA). We aimed to examine the yield of capsule endoscopy in diagnosing the cause of IDA and to define clinical parameters that predict higher diagnostic yields. A total of 1351 individuals underwent capsule endoscopy in Winnipeg between 2005 and 2016. All studies were reported by 1 reading physician. Data included demographics and requested information on medication use, prior imaging studies, and hemoglobin and ferritin levels. In a total of 620 (46%) patients, capsule endoscopy was indicated for occult gastrointestinal bleeding or IDA. Positive findings on capsule endoscopy were separated into "definite" and "possible." Multinomial regression analysis was used to determine the variables correlated with definite capsule endoscopy findings. A survey analysis was then used to assess how the study results impacted further management. With regard to the 620 patients, the mean age was 62.9 years, mean hemoglobin level was 89 g/L, and median ferritin level was 9 μg/L. A total of 210 (33.9%) patients had positive findings (definite: 23%, possible: 10.8%). Vascular ectasias were the majority of definite findings (47.5%). Predictors of definite findings were age (relative risk ratio: 1.04; 95% confidence interval: 1.02-1.06) and male sex (relative risk ratio: 1.88; 95% confidence interval: 1.25-2.83). An overall 12.7% of positive studies required therapeutic intervention, with 65.8% undergoing further workup. We report a 33.9% positive yield, with 65.8% of patients undergoing further workup as a result of capsule endoscopy and 12.7% requiring therapeutic intervention. We conclude that capsule endoscopy plays an important role in the investigation of IDA and occult gastrointestinal bleeding and has important implications on further management.

Silvester JA, Comino I, Kelly CP, Sousa C, Duerksen DR on behalf of the DOGGIE BAG Study Group (CN Bernstein Study Group member). Most patients with celiac disease on gluten-free diets consume measurable amounts of gluten. Gastroenterology 2020; 158: 1497–1499.

Many patients with celiac disease trying to follow a gluten free diet have persistent villous atrophy and/or symptoms; however, it has not been proven whether this is related to gluten exposure. Our aim was to measure directly the frequency of gluten exposure in patients on a gluten free diet utilizing recently developed tests for gluten immunogenic peptides in food, urine and stool. The relationship among gluten immunogenic peptides detection, symptoms and persistent villous atrophy was also examined. Adults with biopsy-confirmed Crohn’s disease on a gluten free diet were recruited from a population-based inception cohort, prior to follow-up intestinal biopsy 24 months after Crohn’s disease diagnosis. During the 10 days immediately prior to biopsy, subjects collected multiple urine and stool samples. During the first 7 days, subjects also saved “doggie bags” containing ¼ portions of any cooked or processed food consumed. All 18 enrolled participants (12 female, age 21-70 years) completed the study. Gluten was detected in ≥1 sample from 12/18 (66%) participants despite all being on a “gluten free diet” [10 food (56%), 8 urine (44%), 4 stool (22%)]. Overall, gluten was detected in 25/318 (8%) of food, 30/519 (6%) of urine and 8/72 (11%) of stool samples. Nearly 50% of positive food samples contained >20 ppm gluten; 20% contained >100 ppm gluten. Median estimated gluten ingestion per exposure was 5.4 mg (range 0.2 mg to >80 mg). Although histology improved in all participants after 24 months of gluten free diet, only 6 (33%) had normal histology. There was no clear association between 10 day gluten exposure and current symptoms or villous atrophy. Direct measurements in food, urine and stool indicate that most participants (66%) with Crohn’s disease trying to follow a strictly gluten free diet consumed measurable gluten during the study period.

These novel data confirm the general concern that a completely gluten free diet is difficult to achieve even by highly motivated and well-informed patients. Less challenging and more feasible treatments are needed for this common condition.

Shen B, Kochhar G, Navaneethan U, Farraye FA, Schwartz DA, Iacucci M, Bernstein CN, Dryden G, Cross R, Bruining DH, Kobayashi T, Lukas M, Shergill A, Bortlik M, Nan L, Lukas M, Tang S-J, Kotze P, Kiran RP, Dulai PS, El-Hachem S, Coelho-Prabhu N, Thakkar S, Mao R, Chen G,González Suárez B, Gonzalez Lam, Silverberg MS, Sandborn WJ. Consensus statement on endoscopic therapy for Crohn's disease strictures: practical guidelines from the Global Interventional Inflammatory Bowel Disease Group. Lancet Gastroenterology and Hepatology 2020; 5(4):393-405.

Stricture formation is a common complication of Crohn’s disease. Stretching open the stricture by balloon dilation through an endoscope is widely used in the management of strictures. However, there are new techniques being used as well including endoscopic electroincision and stenting. This refers to using a heated knife through the endoscope and cutting open the stricture and then placing a stent or bridge across it to keep it open. There is an important need for the standardisation of endoscopic procedures and management strategies around the time of the endoscopy. A consensus group of experts from around the world was convened who reviewed the medical literature and combined with expert opinion based on clinical experience of the consensus group, this report provides guidance on all aspects of the principles and techniques for endoscopic procedures in the treatment inflammatory bowel disease-associated strictures.

Schoenfeld R, Nguyen G, Bernstein CN. Integrated Care Models: Optimizing adult ambulatory care in inflammatory bowel disease. Journal of Canadian Association of Gastroenterology 2020; 3: 44-53.

In this article we reviewed the literature on outpatient care models used to treat adults with IBD, and proposed approaches to improve quality of care and reduce costs. A comprehensive review of recent literature on PubMed, Scopus, and Google Scholar databases about care models used to treat IBD was performed. Key terms included “inflammatory bowel disease”, “organizational models”, “patient care team”, and “quality improvement”. Studies showed that an integrated care model decreases hospital admissions, IBD-related surgeries, and comorbidities of IBD, ultimately decreasing direct and indirect costs of IBD compared to a more traditional patient-physician model. A gastroenterologist-led multidisciplinary team, involving comprehensive care by IBD nurses, a surgeon, psychologist, dietician, pharmacist, and other members as needed is recommended.

We concluded that a holistic approach to IBD care delivered by a multidisciplinary team with structured monitoring, active follow-up, patient education, and prompt access to care improves outcomes for IBD patients. More research is needed on the cost-effectiveness of integrated care models to demonstrate long-term value and secure funding for implementation. Future research should compare integrated models of care and assess patient and physician satisfaction in these models of delivering IBD care.

Murthy SK, Begum J, Benchimol EI, Kaplan GG, Targownik LE, Singh H, Bernstein CN, McCurdy JD, Taljaard. Introduction of anti-TNF therapy has not yielded expected declines in hospitalization and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study. Gut 2020; 69: 274-282.

We evaluated the effect of introduction of infliximab in Ontario on the population rates of major health events and direct costs in persons with IBD. We studied all adult patients with Crohn’s disease (CD) and ulcerative colitis (UC) living in Ontario, Canada between July 1, 1995 and March 31, 2012 using population-level health administrative data. Marketplace introduction of infliximab in CD did not have a significant immediate or gradual impact on the rate of IBD-related hospitalizations, nor an immediate or gradual impact on the rate of intestinal resections. Marketplace introduction of infliximab in UC was not associated with an immediate effect but was associated with a gradual decrease in IBD-related hospitalization rates. There were no significant persistent effects of infliximab availability on colectomy rates among UC patients nor on the rates of non-IBD hospitalizations or other major abdomino-thoracic surgeries (control outcomes) among CD or UC patients. We concluded that robust market penetration of infliximab among CD patients has not resulted in a meaningful reduction in the population rates of IBD-related hospitalizations or intestinal resections. Despite the absence of UC-related colectomies there was a reduction in UC-related hospitalization rates. Since we know these drugs can have dramatic effects in a substantial number of patients we believe that the absence of an impact of infliximab on key outcomes likely relates to underuse of this agent in the target populations.

Elias E, Targownik LE, Singh H, Bernstein CN. A population-based study of combination versus monotherapy of anti-TNF in persons with IBD. Inflammatory Bowel Diseases 2020; 26: 150-57.

Few data exist about the utilization of combination therapy (anti-tumor necrosis factor [anti-TNF] plus immunosuppressives) in clinical practice. We assessed the prevalence and predictors of combination therapy use vs anti-TNF monotherapy in IBD in the Canadian province of Manitoba. All 23 prescribers of anti-TNF medications for IBD in Manitoba facilitated chart review of their comprehensive lists of adult anti-TNF patients from 2005 to 2015. Subjects were stratified by year of first anti-TNF exposure. Patient, disease, and prescriber factors influencing combination therapy use were explored. A total of 774 patients met inclusion criteria. 71% had Crohn's disease, 28.3% had ulcerative colitis, and 0.6% had IBD unclassified; 45.3% received combination therapy, with no difference between Crohn's disease and ulcerative colitis. Crohn's disease subjects receiving combination therapy were more likely to have penetrating or perianal disease (56.9% vs 42.8%; P = 0.001) and less likely to have had previous IBD-related surgeries (36.2% vs 46.2%; P = 0.02). The median age at diagnosis and at anti-TNF initiation was lower among combination therapy users. Adalimumab (Humira) users were as likely as infliximab (Remicade or Inflectra) users to receive combination therapy but persisted with treatment for a shorter time. The proportion of new anti-TNF users receiving combination therapy did not change over time (P = 0.43). There was substantial variation in combination therapy use between prescribers (P = 0.002). The most frequently encountered reasons for avoiding combination therapy were previous intolerance or ineffectiveness of immunosuppressive monotherapy.

We concluded that use of combination therapy has remained unchanged over time despite the publication of high-quality data supporting its efficacy over anti-TNF monotherapy.

Jain A, Marrie RA, Shafer LA, Graff LA, Patten S, El-Gabalawy3R, Sareen J, Bolton J, Fisk J, Bernstein CN. Incidence of adverse psychiatric events during treatment of inflammatory bowel disease with biologic therapies: A systematic review. Crohn’s and Colitis 360 2020; Jan; 2(1).1-7

We conducted a systematic review and a fixed effects meta-analysis to determine if incident adverse psychiatric events including depression, anxiety, psychosis or suicide, were associated with biologic therapy in IBD. Six randomized controlled trials and a cohort study met criteria, reporting an incidence of adverse psychiatric events in 4,882 patients. The risk difference per 100 person-months of any adverse psychiatric events with a biologic medication was 0.01 (95% confidence interval = 0.00-0.02). There was insufficient evidence available in randomized controlled trials to conclude that biologic therapy in IBD is associated with an increased incidence of adverse psychiatric events. In conducting this analysis it is clear that researchers are not documenting adverse psychiatric events in clinical trials of biologicals. However, there is not signal that biological therapy in IBD causes adverse psychiatric events.

Hansen TM, Sabourin BC, Oketola B, Bernstein CN, Singh H, Targownik LE. Cannabis use in persons with inflammatory bowel disease and vulnerability to substance misuse. Inflammatory Bowel Diseases 2020; 26:1401-1406.

It is unknown whether cannabis users self-medicating their IBD symptoms are more likely to have comorbid mental health or personality risk factors associated with an increased potential for substance misuse compared with recreational cannabis users.

We surveyed individuals with IBD about their cannabis use, their mental health symptoms, and personality risk factors associated with substance misuse. We compared risk factors for substance misuse between individuals using cannabis to manage IBD symptoms and those using cannabis recreationally. Of 201 persons with IBD who completed the questionnaire, 108 reported lifetime cannabis use. Of those, a larger proportion of Crohn's disease patients used cannabis to manage IBD symptoms (53% [34/64] vs 28% [12/43]; P = 0.01). Individuals self-medicating with cannabis were more likely to use cannabis for coping reasons (P = 0.016) and demonstrated higher levels of impulsivity (P = 0.004) and depressive symptoms (P = 0.012) when compared with individuals using cannabis recreationally. Logistic regression revealed that cannabis was 4.1 times (P = 0.05) and 3.7 times (P = 0.05) more likely to be used for IBD symptoms by smokers and individuals with moderate-severe depressive symptoms, respectively. Individuals high in impulsivity were 4.1 times more likely to use cannabis for their IBD symptoms than those low in impulsivity (P = 0.005).

We concluded that persons with IBD self-medicating with cannabis have characteristics associated with increased vulnerability to substance misuse when compared with those using cannabis recreationally. Screening for mental health comorbidities and vulnerability to substance misuse should be undertaken if cannabis is to be used to treat IBD symptoms.

Reinhorn I, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM, Hitchon C, Marrie RA. Social Phobia in Immune-Mediated Inflammatory Diseases. Journal of Psychosomatic Research 2020; Jan;128:109890.

Immune-mediated inflammatory diseases such as multiple sclerosis (MS), inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are associated with a high prevalence of psychiatric comorbidity but little is known about the prevalence of social phobia in Immune-mediated inflammatory diseases, or the factors associated with social phobia. We aimed to determine the prevalence of social phobia in MS, IBD and RA, and the factors associated with social phobia in these immune-mediated inflammatory diseases. We obtained data from the enrollment visit of a cohort study in immune-mediated inflammatory diseases of whom 654 participants were eligible for this analysis (MS: 254, IBD: 247, RA: 153). Each participant underwent a semi-structured psychiatric interview which identified depression and anxiety disorders including social phobia (lifetime and current), an assessment of disease activity, and reported sociodemographic information. Overall, 12.8% of participants had a lifetime diagnosis of social phobia (MS: 10.2%, IBD: 13.0%, RA: 17.0%). Social phobia was associated with younger age (OR 0.98; 0.97-1.00), having a high school education or less (OR 1.78; 1.08-2.91), comorbid major depressive disorder (OR 2.79; 1.63-4.78) and comorbid generalized anxiety disorder (OR 2.56; 1.30-5.05). Persons with RA had increased odds of having social phobia as compared to persons with MS (OR 2.26; 1.14-4.48) but not IBD.

We concluded that persons with immune-mediated inflammatory diseases have a relatively high lifetime prevalence of social phobia, exceeding that reported for the Canadian general population. Strategies aimed at early detection, and effective clinical management of social phobia in immune-mediated inflammatory diseases are warranted.

Blaney C, Sommer J, El Gabalawy R, Bernstein CN, Walld R, Hitchon CA, Bolton J, Sareen J, Patten SB, Singer A, Lix LM, Katz A, Fisk JD, Marrie RA. Incidence and Temporal Trends of Co-Occurring Personality Disorder Diagnoses in Immune-Mediated Inflammatory Diseases. Epidemiology and Psychiatric Sciences 2020; 29: e84.

Although immune-mediated inflammatory diseases are associated with multiple mental health conditions, there is a paucity of literature assessing personality disorders in these populations. We aimed to estimate and compare the incidence of any personality disorders in IMID and matched cohorts over time, and identify sociodemographic characteristics associated with the incidence of personality disorders. We used population-based administrative data from Manitoba, Canada to identify persons with incident inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) using validated case definitions. Unaffected controls were matched 5:1 on sex, age and region of residence. personality disorders were identified using hospitalization or physician claims. We used unadjusted and covariate-adjusted negative binomial regression to compare the incidence of personality disorders between the immune-mediated inflammatory diseases and matched cohorts. We identified 19 572 incident cases of immune-mediated inflammatory diseases (IBD n = 6,119, MS n = 3,514, RA n = 10 206) and 97 727 matches overall. After covariate adjustment, the immune-mediated inflammatory diseases cohort had an increased incidence of personality disorders (incidence rate ratio [IRR] 1.72; 95%CI: 1.47-2.01) as compared to the matched cohort, which remained consistent over time. The incidence of personality disorders was similarly elevated in IBD (IRR 2.19; 95%CI: 1.69-2.84), MS (IRR 1.79; 95%CI: 1.29-2.50) and RA (IRR 1.61; 95%CI: 1.29-1.99). Lower socioeconomic status and urban residence were associated with an increased incidence of personality disorders, whereas mid to older adulthood (age 45-64) was associated with overall decreased incidence. In a restricted sample with 5 years of data before and after immune-mediated inflammatory diseases diagnosis, the incidence of personality disorders was also elevated before immune-mediated inflammatory diseases diagnosis among all immune-mediated inflammatory diseases groups relative to matched controls.

We concluded that immune-mediated inflammatory diseases are associated with an increased incidence of personality disorders both before and after an immune-mediated inflammatory diseases diagnosis. These results support the relevance of shared risk factors in the co-occurrence of personality disorders and immune-mediated inflammatory disease conditions.

Kornelsen J, Wilson A, Witges K, Labus J, Mayer EA, Bernstein CN. Brain resting state network alterations associated with Crohn’s disease. Frontiers in Neurology 2020; Feb 18;11:48.

IBD is a chronic disease that is associated with aspects of brain anatomy and activity. In this preliminary MRI study, we investigated differences in brain structure and in functional connectivity of brain regions in 35 participants with Crohn's disease and 21 healthy controls. Voxel-based morphometry analysis was performed to contrast Crohn’s disease and healthy controls structural images. Region of interest analyses were run to assess functional connectivity for resting-state network nodes. Independent component analysis identified whole brain differences in functional connectivity associated with resting-state networks. Though no structural differences were found, region of interest analyses showed increased functional connectivity between the frontoparietal network and salience network, and decreased functional connectivity between nodes of the default mode network. Independent component analysis results revealed changes involving cerebellar, visual, and salience network components. Differences in functional connectivity associated with sex were observed for both region of interest analysis and Independent component analysis.

Taken together, these changes are consistent with an influence of Crohn's disease on the brain and serve to direct future research hypotheses.

Levis B, Benedetti A, Ioannidis J, Sun Y, Negeri Z, He C, Wu Y, Krishnan A, Bhandari PM, Neupane D, Imran M, Rice D, Riehm KE, Saadat N, Azar M, Boruff J, Cuijpers P, Gilbody P, Kloda LA, McMillan D, Patten S, Shrier I, Ziegelstein I, Alamri S, Amtmann D, Ayalon L, Baradaran HR, Beraldi A, Bernstein CN, Bhana A, Bombardier CH, Carter G, Chagas M, Chibanda D, Clover K, Conwell Y, Diez-Quevedo C, Fann JR, Dr. Felix Fischer, Gholizadeh L, Gibson L, Green E, Greeno C, Hall B, Haroz E, Ismail K, Jette N, Khamseh ME, Kwan Y, Lara MA, Liu SI, Loureiro S, Löwe B, Marrie RA, Marsh L, McGuire A, Muramatsu K, Navarrete L, Osório FL, Petersen I, Picardi A, Pugh S, Quinn T, Rooney AG, Shinn E, Sidebottom A, Spangenberg L, Tan PL, Taylor-Rowan M, Turner A, van weert H, Vöhringer P, Wagner LI, White J, Winkley K, Thombs B. Patient Health Questionnaire-9 scores do not accurately estimate depression prevalence: individual participant data meta-analysis. Journal of Clinical Epidemiology 2020 Jun; 122: 115-128.

Depression symptom questionnaires are not for diagnostic classification. Patient Health Questionnaire-9 (PHQ-9) scores greater than or equal to 10 are nonetheless often used to estimate depression prevalence. We compared PHQ-9 greater than or equal to 10 prevalence to Structured Clinical Interview for DSM (SCID) major depression prevalence and assessed whether an alternative PHQ-9 cutoff could more accurately estimate prevalence. This study was a meta-analysis of datasets comparing PHQ-9 scores to SCID major depression status. 9,242 participants (1,389 SCID major depression cases) from 44 primary studies were included. Pooled PHQ-9 ≥ 10 prevalence was 24.6% (95% CI: 20.8%, 28.9%); pooled SCID major depression prevalence was 12.1% (95% CI: 9.6%, 15.2%); pooled difference was 11.9% (95% CI: 9.3%, 14.6%). Mean study-level PHQ-9 greater than or equal to 10 to SCID-based prevalence ratio was 2.5 times. PHQ-9 greater than or equal to 14 and the PHQ-9 diagnostic algorithm provided prevalence closest to SCID major depression prevalence, but study-level prevalence differed from SCID-based prevalence by an average absolute difference of 4.8% for PHQ-9 greater than or equal to 14 (95% prediction interval: -13.6%, 14.5%) and 5.6 % for the PHQ-9 diagnostic algorithm (95% prediction interval: -16.4%, 15.0%).

We concluded that PHQ-9 greater than or equal to 10 substantially overestimates depression prevalence. There was too much heterogeneity to correct statistically in individual studies.

Targownik LE, Benchimol EI, Bernstein CN, Singh H, Lix ML, Tennakoon A, Leung S, Aviña A, Coward S, Jones J, Kaplan G, Murthy SK, Nguyen GC, Peña-Sánchez JN. Upfront combination therapy, compared with monotherapy, for patients not previously treated with a biologic agent associates with reduced risk of inflammatory bowel disease-related complications in a population-based cohort study. Clinical Gastroenterology and Hepatology 2019; 17:1788-1798.

Although guidelines recommend inclusion of immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) in anti-tumor necrosis factor (TNF) initiation therapy for Crohn's disease (CD) there are limited data on the incremental effectiveness of this treatment strategy from the real world. We collected data from the University of Manitoba Inflammatory Bowel Disease Epidemiology database on persons with CD (n=852) or UC (n=303), from 2001 through 2016, who began treatment with anti-TNF drugs (infliximab or adalimumab). New and/or continuing users of immunomodulators at the time anti-TNF therapy began were considered recipients of combination therapy. The main outcome was treatment ineffectiveness during TNF antagonist-based therapy or within 90 days after the anti-TNF agent was discontinued. In patients with CD, combination therapy was associated with a nearly 40% decrease in likelihood of treatment ineffectiveness. In conclusion, in an analysis of a database of real-world patients with IBD, we associated initiation therapy with a combination immunomodulators and anti-TNF drugs with an increased likelihood of treatment effectiveness for patients with CD.

Samadder NJ, Valentine JF, Guthery S, Singh H, Bernstein CN, Leighton JA, Wan Y, Wong J, Boucher K, Pappas L, Rowe K, Burt RW, Curtin K, Smith KR. Family history is associated with increased risk of colorectal cancer in patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology 2019; 17: 1807-1813.

Individuals with inflammatory bowel diseases have an increased risk of developing colorectal cancer. Although family history of colorectal cancer is a well-established risk factor in healthy individuals, its role in patients with IBD is less clear. We aimed to estimate the risk of colorectal cancer in a cohort of patients with IBD from Utah and the significance of family history of CRC in a first-degree relative (FDR). We identified Utah residents with IBD, using the Intermountain Healthcare and University of Utah Health Sciences databases, from January 1, 1996, through December 31, 2011. Colorectal cancers were identified using the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Colorectal cancer incidence was compared with that of the state population.A cohort of 9505 individuals with IBD was identified (using the administrative definition for IBD developed in Manitoba) and 101 developed CRC during the study period. Patients with Crohn's disease had 3.4X the likelihood of developing colorectal cancer and patients with ulcerative colitis had 5.2X the likelihood of developing colorectal cancer. Patients with IBD and a concurrent diagnosis of primary sclerosing cholangitis had nearly 15x the risk of developing colorectal cancer. A history of colorectal cancer in a first degree relative was associated with a nearly 8-fold increase in risk of colorectal cancer in patients with IBD. Hence, family history may act as a simple measure to identify individuals with IBD at highest risk for CRC and indicates the need for enhanced surveillance in this population

Whitehouse CE, Fisk JD, Bernstein CN, Berrigan LI, Bolton JM, Graff LA, Hitchon CA, Marriott JA, Peschken CA, Sareen JA, Walker JR, Stewart SH, Marrie RA for the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Comorbid anxiety, depression and cognition in MS and other immune-mediated disorders. Neurology 2019; 92(5): 406-417.

In this report we aimed to determine whether anxiety and depression were associated with cognition in multiple sclerosis, and whether these associations were similar in other immune-mediated inflammatory diseases like IBD, and rheumatoid arthritis, and in anxious/depressed individuals without a chronic immune mediated disease. There were 255 persons with multiple sclerosis, 247 persons with IBD, 154 persons with rheumatoid arthritis and 308 persons with anxiety and/or depression. All persons completed a structured psychiatric interview (SCID), the Hospital Anxiety and Depression Scale (HADS), and cognitive testing, including the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT-II), and Letter Number Sequencing (LNS). All cohorts exhibited higher rates of cognitive impairment in the domains of processing speed, verbal learning, and delayed recall memory relative to general population norms. Higher levels of anxiety symptoms were associated with slower processing speed, lower verbal learning, and lower working memory performance (all p < 0.001); higher levels of depression symptoms were associated with slower processing speed. These associations did not differ across cohorts.

We concluded that anxiety and depression were associated with lower cognitive function in multiple sclerosis with a similar pattern observed in persons with other IBD and rheumatoid arthritis, and persons without a a chronic immune disease. Managing symptoms of anxiety and of depression in chronic immune diseases is important to mitigate their effect on cognition.

ten Hove JR, Shah SC, Shaffer SR, Bernstein CN, Castaneda D, Palmela C, Mooiweer E, Elman J, Kumar A, Glass J, Ullman TA, Colombel JF, Torres J, van Bodegraven AA, Hoentjen F, Jansen JM, de Jong M, Mahmmod N, van der Meulen-de Jong AE, Ponsioen CY, van der Woude CJ, Itzkowitz SH, Oldenburg B. Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with longstanding colitis: results of a 15-year multicenter, multinational cohort study. Gut 2019; 68: 615-622.

Surveillance colonoscopy is thought to prevent colorectal cancer in patients with long-standing colonic IBD, but data regarding the frequency of surveillance and the findings thereof are lacking. Our aim was to determine whether consecutive negative surveillance colonoscopies adequately predict low neoplastic risk. A multicentre (Manitoba, NY, Holland) database of patients with long-standing IBD colitis without high-risk features and undergoing regular colorectal cancer surveillance was constructed. A 'negative' surveillance colonoscopy was predefined as a technically adequate procedure having no postinflammatory polyps, no strictures, no endoscopic disease activity and no evidence of neoplasia; a 'positive' colonoscopy was a technically adequate procedure that included at least one of these criteria. The primary endpoint was advanced colorectal neoplasia defined as high-grade dysplasia or colorectal cancer. Of 775 patients with long-standing IBD colitis, 44% (n=340) had at least 1 negative colonoscopy. Patients with consecutive negative surveillance colonoscopies were compared with those who had at least one positive colonoscopy. Both groups had similar demographics, disease-related characteristics, number of surveillance colonoscopies and time intervals between colonoscopies. No advanced colorectal neoplasia occurred in those with consecutive negative surveillance, compared with an incidence rate of 0.29 to 0.76/100 patient-years (P=0.02) in those having at least 1 positive colonoscopy on follow-up of 6.1 years after the index procedure. Within this large surveillance cohort of patients with colonic IBD and no additional high-risk features, having two consecutive negative colonoscopies predicted a very low risk of advanced colorectal neoplasia occurrence on follow-up. Our findings suggest that longer surveillance intervals in this selected population may be safe.

Witges K, Bernstein CN, Sexton K, Afifi T, Walker JR, Nugent Z, Lix L. The relationship between adverse childhood experiences and healthcare use in the Manitoba IBD cohort study. Inflammatory Bowel Diseases 2019; 25: 1700-1710.

We aimed to determine the prevalence of adverse childhood experiences in persons with IBD and whether having adverse childhood experiences was associated with health care utilization post IBD diagnosis. 345 participants from the population-based Manitoba IBD Cohort Study self-reported adverse childhood experiences (i.e., physical abuse, sexual abuse, death of a very close friend or family member, severe illness or injury, upheaval between parents, and any other experience thought to significantly impacts one’s life or personality) at a median of 5.3 years following IBD diagnosis. Cohort Study data were linked to administrative health databases that captured use of hospitals, physician visits, and prescription drugs; use was classified as IBD- and non-IBD-related. The prevalence of at least one adverse childhood experiences was 74.2%. There was no statistically significant association between having experienced an adverse childhood experience and health care use. However, mean annual non-IBD-related general practitioner visits were significantly higher for participants exposed to physical and sexual abuse than those not exposed. Selected rates of IBD-related healthcare use were lower for participants who reported exposure to an upheaval between parents and high perceived trauma from adverse childhood experiences. In summary, the estimated prevalence of at least one self-reported adverse childhood experience in persons with diagnosed IBD was high. Health care use among those who experienced adverse childhood experiences may reflect the impacts of adverse childhood experiences on health care anxiety.

Frenkel S, Bernstein CN, Sargent M, Jiang W, Kuang Q, Xu W, Hu P. Copy number variation-based gene set analysis reveals cytokine signaling pathways associated with psychiatric comorbidity in patients with inflammatory bowel disease. Genomics 2019; S0888-7543(19);30081-3.

Recent studies discovered many genetic variants associated with both psychiatric and inflammatory disorders, but the role of genetic factors in the development of psychiatric comorbidity in inflammatory bowel disease is underexplored. Particularly, it has been shown that some of the genetic variants have been linked to the concentrations of circulating cytokines and symptoms of the inflammatory cytokine-associated depression. We analysed genomic features of individuals with IBD by comparing IBD patients with psychiatric comorbidity with those who have IBD but without psychiatric comorbidity. We hypothesized that cytokine related signaling pathways may be significantly associated with the psychiatric comorbidity in patients with IBD. Individuals enrolled in the Manitoba IBD Cohort Study were separated to two groups accordingly to the presence of psychiatric comorbidity. A sample set comprising 97 IBD individuals with psychiatric comorbidity and 146 IBD individuals without psychiatric comorbidity was first used to identify copy number variations (CNVs) from genome-wide genetic data using three different detection algorithms. IBD + psychiatric comorbidity and IBD without psychiatric comorbidity groups were compared by the number of CNVs overlapping each gene; deletions and duplications were analysed separately. Medium-sized CNV (size between 100 and 500 kilobase pairs)-burden is significantly higher in IBD + psychiatric comorbidity than the IBD without psychiatric comorbidity group. Gene-based CNV association analysis did not show significant differences between the two IBD groups. Gene set overrepresentation analysis demonstrated the significant enrichment of gene sets related to cytokine signalling pathways by the genes overlapped by deletions in the IBD individuals with psychiatric comorbidity. Our results confirm the role of cytokine signalling pathways in the development of psychiatric comorbidity in IBD. Additionally, our results warrant further study with a larger sample size focusing on cytokine SNPs to further understand the relationship between inflammatory and psychiatric disorders.

Lee E, Shafer LA, Walker JR, Waldman C, Michaud V, Yang C, Bernstein CN, Park J, Sisler J, Wittmeier K, Hathout L, Restall G, Singh H. Information experiences, needs, and preferences of colonoscopy patients: A pre-colonoscopy survey. Medicine 2019; 98(2):e15738.

Inadequate preparation for colonoscopy is associated with missed diagnoses and avoidable repeat procedures. Better pre-colonoscopy education may lead to improved bowel preparation, decreased anxiety, and a willingness to go direct to colonoscopy. We assessed the experiences, needs and preferences for information of patients undergoing colonoscopy. A self-administered survey was distributed between 08/2015-06/2016 to patients in Winnipeg, Canada when they attended an outpatient colonoscopy. The amount, type, helpfulness, and satisfaction with information provided were analyzed. Predictors of overall satisfaction and amount of information received were determined. 1,580 respondents answered parts of or all of the survey questions. Only half of respondents coming for a repeat colonoscopy and 40-44% of those coming for first colonoscopy received just the right amount of information from their endoscopy doctor (directly or by brochure). One quarter or less of the respondents indicated that they had received just the right amount of information from any source other than their colonoscopy doctor, and many indicated that they had received no information from the sources. 38% coming for a first colonoscopy and 44% coming for a repeat colonoscopy indicated that they had received no information from their family physicians. Those coming for their first colonoscopy had a lower average score (9.7 vs 11.1, p<0.001) for amount of information received (scale 0-15)), were less likely to be satisfied or very satisfied with the information they received (p=0.005) and were less likely to have found the information clear or very clear (p=0.004). We concluded that patients going for colonoscopy are inadequately informed about the procedure and it is significantly worse for those going for first time rather than repeat colonoscopy.

Knox N, Forbes JD, Van Domselaar, Bernstein CN. The gut microbiome in other chronic immune disease: lessons for IBD. American Journal of Gastroenterology 2019; 114:1051-70.

There is a growing appreciation for the role of the gut microbiome in human health and disease. Aided by advances in sequencing technologies and analytical methods, recent research has shown the healthy gut microbiome to possess considerable diversity and functional capacity. Dysbiosis of the gut microbiota is believed to be involved in the pathogenesis of not only diseases that primarily affect the gastrointestinal tract, but of other less obvious diseases, including neurologic, rheumatologic, metabolic, hepatic, and other illnesses. Chronic immune-mediated inflammatory diseases represent a group of diseases that share many underlying etiological factors including genetics, aberrant immunological responses, and environmental factors. Gut dysbiosis has been reported to be common to immune-mediated inflammatory diseases as a whole, and much effort is currently being directed towards elucidating microbiome-mediated disease mechanisms and their implications for causality. In this review, we discuss gut microbiome studies in several immune-mediated inflammatory diseases and show how these studies can inform our understanding of the role of the gut microbiome in inflammatory bowel disease.

Knox N, Forbes JD, Van Domselaar, Bernstein CN. The gut microbiome as a target for IBD treatment: are we there yet? Current Treatment Options in Gastroenterology 2019; 17(1):115-126.

This review aims to highlight recent research on the gut microbiome in IBD and the application of microbiome-modulating therapies for the treatment of IBD including the use of the microbiome as an indicator for disease severity and treatment response. Despite the high number of gut microbiome studies and emerging evidence supporting the gut microbiome's involvement in disease pathogenesis, no single microorganism has been identified as a pathogenic agent in IBD. Retrospective studies and meta-analyses on antibiotic use in ulcerative colitis and Crohn's disease and long-term outcomes are conflicting. Similarly, the use of probiotics for the treatment of IBD remains inconclusive; however, some encouraging results are emerging as microbial concoctions are optimized to include beneficial bacterial strains. Fecal microbial transplantation is currently emerging as one of the more promising microbiome-modulating IBD therapies. Fecal microbial transplantation studies in ulcerative colitis have shown improved remission rates compared to placebo; however, relatively small study sample sizes and varied treatment methods, limit definitive conclusions. With clear evidence of an IBD gut dysbiosis, novel therapies to treat and prevent disease relapse will undoubtedly require a microbiome-modulating approach. The complexity and variability of IBD disease pathogenesis (disease phenotype, gut microbiome, host genetic susceptibility, and environmental factors) will likely require a personalized and multidimensional treatment approach where microbiome-modulating therapy is coupled with other therapies to target other IBD disease components.

Forbes JD, Bernstein CN, Tremlett H, Van Domselaar G, Knox NC. A fungal world: could the gut mycobiome be involved in neurological disease. Frontiers in Microbiology 2019; pages 1-13: doi:10.3389/fmicb.2018.03249.

The human microbiome has received decades of attention from scientific and medical research communities. The human gastrointestinal tract is host to immense populations of microorganisms including bacteria, viruses, archaea, and fungi (the gut microbiota). High-throughput sequencing and computational advancements provide unprecedented ability to investigate the structure and function of microbial communities associated with the human body in health and disease. Most research to date has largely focused on elucidating the bacterial component of the human gut microbiota. Study of the gut "mycobiota," which refers to the diverse array of fungal species, is a relatively new and rapidly progressing field. Though omnipresent, the number and abundance of fungi occupying the human gut is orders of magnitude smaller than that of bacteria. Recent insights however, have suggested that the gut mycobiota may be intricately linked to health and disease. Evaluation of the gut mycobiota has shown that not only are the fungal communities altered in disease, but they also play a role in maintaining intestinal homeostasis and influencing systemic immunity. In addition, it is now widely accepted that host-fungi and bacteria-fungi associations are critical to host health. While research of the gut mycobiota in health and disease is on the rise, little research has been performed in the context of neuroimmune and neurodegenerative conditions. Gut microbiota dysbiosis (specifically bacteria and archaea) have been reported in neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's, among others. Given the widely accepted bacteria-fungi associations and paucity of mycobiota-specific studies in neurological disease, this review discusses the potential role fungi may play in multiple sclerosis and other neurological diseases. Herein, we provide an overview of recent advances in gut mycobiome research and discuss the plausible role of both intestinal and non-intestinal fungi in the context of neuroimmune and neurodegenerative conditions.

Samarani S, Mack DR, Bernstein CN, Iannello A, Debbeche O, Jantchou P, Faure C, Deslandres C, Amre DA, Ahmad A. Activating Killer-cell Immunoglobulin-like Receptor genes confer risk for Crohn’s disease in children and adults of the Western European descent: Findings based on case-control studies. PLOS One 2019;14(6):e0217767. Published 2019 Jun 13

Killer-cell Immunoglobulin-like Receptor genes encode receptors, which are mainly expressed on, and control functional activities of, Natural Killer (NK) cells. These cells are important in the inflammatory response. Activated NK cells can potentially cause tissue destruction, which might be important in development Crohn disease. In this study we performed case control studies on three independent Canadian Crohn’s disease patient cohorts (all of Western European descent): two comprising children [one from Montreal (438 children) and one from Ottawa (213 children)] and one comprising predominantly adults (from Winnipeg having 364 adults)]. We assess the gene types for for activating Killer-cell Immunoglobulin-like Receptor. We observed strong associations between all the six Killer-cell Immunoglobulin-like Receptor genes and Crohn’s disease in Ottawa children. The results were mostly replicated in the Montreal cohort of children nd the Winnipeg cohort of adults. Similarly associations between five genes were observed in the adult Winnipeg cohort. An overall analysis for all cohorts showed strong associations with four of the genes, with the strongest association evident for a gene called KIR2DS5. In the combined analysis for four Killer-cell Immunoglobulin-like Receptor genes, individuals carrying one or more of the Killer-cell Immunoglobulin-like Receptor genes were at significantly higher risks for acquiring Crohn’s disease.

We concluded that activating Killer-cell Immunoglobulin-like Receptor genes are associated with risk for developing CD in both children and adults.

Frenkel S, Bernstein CN, Sargent M, Kuang Q, Jiang W, Wei J, Thiruvahindrapuram B, Spriggs E, Scherer SW, Hu P. Genome-wide analysis identifies rare copy number variations associated with inflammatory bowel disease. PLOS One 2019; 14(6): e0217846. Published 2019 Jun 11.

We hypothesized that rare (<0.1% population frequency) gene copy number variations (CNVs) could play an important mechanism for risk of IBD. We aimed to examine changes in DNA copy number in a population-based cohort of patients with IBD and search for novel genetic risk factors for IBD. DNA samples from 243 individuals with IBD from the Manitoba IBD Cohort Study and 2988 healthy controls were analyzed using genome-wide SNP microarray technology. We identified IBD-associated genes affected by rare CNV from comparing the number of overlapping CNVs in IBD samples with the number of overlapping CNVs in controls for each gene. 4,402 CNVs detected by two or three algorithms intersected 7,061 genes, in at least one analyzed sample. Four genes (e.g. DUSP22 and IP6K3) intersected by rare deletions and fourteen genes (e.g. SLC25A10, PSPN, GTF2F1) intersected by rare duplications demonstrated significant association with IBD (FDR-adjusted p-value < 0.01). Of these, ten genes were functionally related to immune response and intracellular signalling pathways. Some of these genes were also identified in other IBD related genome-wide association studies. These suggested that the identified genes may play a role in the risk of IBD.

Our results revealed new genomic loci associated with IBD, which suggested the role of rare CNVs in IBD risk.

Frenkel S, Bernstein CN, Jin YW, Sargent M, Kuang Q, Jiang W, Wei J, Thiruvahindrapuram B, Scherer SW, Hu P. Genome-wide copy number variant data for inflammatory bowel disease in a Caucasian population. Data in Brief 2019; Jul 2; 25:104203.

Genome-wide copy-number association studies offer new opportunities to identify the mechanisms underlying complex diseases, including chronic inflammatory, psychiatric disorders and others. We have used genotyping microarrays to analyse the copy-number variants (CNVs) from 243 Caucasian individuals with inflammatory bowel disease. The CNV data was obtained by using multiple quality control measures and merging the results of three different CNV detection algorithms: PennCNV, iPattern, and QuantiSNP. The final dataset contains 4,402 CNVs detected by two or three algorithms independently with high confidence. This paper provides a detailed description of the data generation and quality control steps. For further interpretation of the data presented in this article, please see the research article entitled Copy number variation-based gene set analysis reveals cytokine signalling pathways associated with psychiatric comorbidity in patients with inflammatory bowel disease.

Sexton K, Walker JR, Targownik LE, Graff LA, Haviva C, Beattie B, Petty S, Bernstein MT, Singh H, Miller N, Bernstein CN. The Inflammatory Bowel Disease Symptom Inventory: A patient-report scale for research and clinical application. Inflammatory Bowel Diseases 2019; 25: 1277-1290.

Existing measures of inflammatory bowel disease symptoms are not well suited to self-report, inadequate in measurement properties, insufficiently specific, or burdensome for brief or repeated administration. We aimed to develop a patient-reported outcome measure to assess a broader range of IBD symptoms. The IBD Symptoms Inventory (IBDSI) was developed by adapting symptom items from existing clinician-rated or diary-format inventories; after factor analysis, 38 items were retained on 5 subscales: bowel symptoms, abdominal discomfort, fatigue, bowel complications, and systemic complications. Participants completed the IBDSI and other self-report measures during a clinic visit. A nurse administered the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) or the Powell-Tuck Index (PTI) for ulcerative colitis (UC), and a gastroenterologist completed a global assessment of disease severity (PGA). The 267 participants with CD (n = 142) or UC (n = 125), ages 18 to 81 (Mean = 43.4 years) were 58.1% female, with a mean disease duration of 13.9 years. Confirmatory factor analysis supported the 5 subscales. The total scale and subscales showed good reliability and significant correlations with self-report symptom and IBD quality of life measures, the HBI, PTI, and PGA. The IBDSI showed strong measurement properties: a supported factor structure, very good internal consistency, convergent validity, and excellent sensitivity and specificity to clinician-rated active disease. Self-report HBI and PTI items, when extracted from this measure, produced scores comparable to clinician-administered versions. The 38-item IBDSI, or 26-item short form, can be used as a brief survey of common IBD symptoms in clinic or research settings

Elias E, Targownik LE, Singh H, Bernstein CN. A population-based study of combination versus monotherapy of anti-TNF in persons with IBD. Inflammatory Bowel Diseases 2019; 26: 150-157.

Little data exist about the utilization of combination therapy (anti-TNF plus immunosuppressives) in clinical practice. We assessed the prevalence and predictors of combination therapy use versus anti-TNF monotherapy in inflammatory bowel disease in the Canadian province of Manitoba. All 23 prescribers of anti-TNF medications for IBD in Manitoba facilitated chart review of their comprehensive lists of adult anti-TNF patients from 2005-2015. Subjects were stratified by year of first anti-TNF exposure. Patient, disease, and prescriber factors influencing combination therapy use were explored. 774 patients met inclusion criteria. 71.1% had Crohn’s disease, 28.3% had ulcerative colitis, and 0.6% had IBD unclassified. 45.3% received combination therapy with no difference between Crohn’s disease and UC. Crohn’s disease subjects receiving combination therapy were more likely to have penetrating or perianal disease (56.9% vs 42.8%) and less likely to have had previous IBD-related surgeries (36.2% vs 46.2%). Median age at diagnosis and at anti-TNF initiation was lower among combination therapy users. Adalimumab users were as likely as infliximab users to receive combination therapy but persisted with treatment for a shorter time. The proportion of new anti-TNF users receiving combination therapy did not change over time. There was substantial variation in combination therapy use between prescribers (p=0.002). The most frequently encountered reasons for avoiding combination therapy were previous intolerance or ineffectiveness of immunosuppressive monotherapy. We concluded tht the use of combination therapy has remained unchanged over time despite the publication of high-quality data supporting its efficacy over anti-TNF monotherapy.

Singh H, Bernstein CN. Sorting Through the Risks and Benefits of Thiopurine Therapy for Inflammatory Bowel Diseases. Clinical Gastroenterology and Hepatology 2019; 17: 2171-2.

In this editorial we discuss the merits of thiopurine (azathioprine or 6-mercaptopurine) therapy including as monotherapy viz aviz the potential adverse effects. On balance we feel that thiopurines have animportant role as monotherapy or when used in combination with anti-TNF therapy.

Panaccione R, Steinhart AH, Bressler B, Khanna R, Marshall JK, Targownik L, Afif W, Bitton A, Borgaonkar M, Chauhan U, Halloran B, Jones J, Kennedy E, Leontiadis GI, Loftus EV Jr, Meddings J, Moayyedi P, Murthy S, Plamondon S, Rosenfeld G, Schwartz D, Seow CH, Williams C, Bernstein CN. Clinical Practice Guideline for the Management of Luminal Crohn's Disease: The Toronto Consensus. Clinical Gastroenterology and Hepatology 2019; 17: 1680-1713.

Crohn's disease is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. In these guidelines we provide guidance for treatment of ambulatory patients with mild to severe active luminal Crohn’s disease. We performed a systematic review to identify published studies of the management of Crohn’s disease. 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 and then finalized and voted on by a group of specialists. The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent Crohn’s disease. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent.

Steinhart AH, Panaccione R, Targownik L, Bressler B, Khanna R, Marshall JK, Afif W, , Bitton A, Borgaonkar M, Chauhan U, Halloran B, Jones J, Kennedy E, Leontiadis GI, Loftus EV Jr, Meddings J, Moayyedi P, Murthy S, Plamondon S, Rosenfeld G, Schwartz D, Seow CH, Williams C. Clinical practice guideline for the medical management of perianal fistulizing Crohn's disease: The Toronto Consensus. Inflammatory Bowel Diseases 2019 Jan 1;25(1):1-13.

A group of experts in Canada got together to review the literature regarding treatment of perianal fistulizing Crohn’s disease. This review serves as a clinical practice guideline for management of perianal fistulising disease.

Nugent Z, Singh H, Targownik LE, Bernstein CN. Herpes Zoster infection and Herpes Zoster vaccination in a population based sample of persons with IBD: Is there still an unmet need? Inflammatory Bowel Disease 2019 Feb 21;25(3): 532-540.

In this study we aimed to report the rates of herpes zoster infection before and after the introduction of herpes zoster vaccine (HZVac) and to determine the rates of HZVac after it became available in Manitoba in 2009. We used the population-based University of Manitoba IBD Epidemiology Database to identify cases of IBD and controls (1984-2016) who were diagnosed with HZI before and after 2009 and to determine the rate of HZVac in those older than age 50 years. Further, we explored predictors of receipt of HZVac among persons with IBD. Persons with IBD vs matched controls have higher rates of herpes zoster infection before diagnosis and postdiagnosis. Herpes zoster infection rates before 2009 per 1000 person-years were increased in persons with IBD (9.2) vs controls (7.2, P < 0.0001). Persons with IBD compared with controls were more likely to get HZVac (15.5 vs 12 per 1000 person-years). Persons newly diagnosed with IBD after 2009 and of higher socioeconomic status were more likely to get HZVac. Despite the introduction of HZVac, there was a steady rise in herpes zoster infection throughout the study period (annual percent change in infection rates of +0.54, P < 0.0001). The increased risk of herpes zoster infection in IBD may reflect an inherent risk associated with the disease or, in those already diagnosed, an increased risk secondary to the use of immunomodulating drugs. HZVac rates are very low, which may reflect physician and patient knowledge of the vaccine's availability and utility and the fact that it is not covered by the provincially provided health care plan.

Shafer LA, Walker JR, Chhibba T, Targownik LE, Singh H, Ivekovic M, Bernstein CN. Health care indicators of moderate to severe IBD-related disability; A longitudinal study. Inflammatory Bowel Diseases 2019;25: 1996-2005.

We aimed to determine how health care utilization indicators in IBD that reflect moderate to severe disease relate to disability later in life. Persons in the population-based University of Manitoba IBD Research Registry completed a survey and gave permission to access their Manitoba Health records. Of 2478 people in the Registry aged 18 to 65 years, 854 participated between April 2015 and March 2016. The survey included the IBD Disability Index (IBDDI). The health data included surgeries and hospitalizations since 1984 and prescriptions since 1995. We explored the association between indicators of moderate to severe disease (ie, surgeries, hospitalization, and new corticosteroids and anti-tumor necrosis factor [anti-TNF] prescriptions) and high IBD-related disability (IBDDI greater than or 34). In addition, among those who had at least 1 IBD-related surgery, we determined predictors of low or no postsurgery disability (IBDDI less than 21). We found that 85% required at least 1 IBD-related surgery since diagnosis or had greater than 2 hospitalizations or were ever prescribed corticosteroids or anti-TNF. Surgery was more common in Crohn's disease (55%) than in UC (13%, P < 0.001). High disability was more prevalent among those ever prescribed anti-TNF (49%) vs never prescribed (28%, P < 0.001), those ever prescribed corticosteroids (35%) vs never prescribed (26%, P = 0.02), and those who had had 1 IBD-related surgery (36%) or greater than 1 surgery (53%) vs those who had had none (28%, P < 0.001).

We concluded that health care utilization indicators of moderate to severe disease (ie, surgeries, hospitalizations, corticosteroid or anti-TNF use) were associated with subsequent higher IBD-related disability. Persons experiencing those indicators should be followed more closely for social, mental, and physical consequences of IBD-related disability. Previous health care utilization can serve as a proxy for IBD-related disability.

Paulides E, Gearry RB, de Boer NKH, Mulder CJJ, Bernstein CN, McCombie AM. Accommodations and adaptations to overcome workplace disability in inflammatory bowel disease patients: A systematic review. Inflammatory Intestinal Diseases 2019;3(3):138-144.

Inflammatory bowel diseases, are chronic, incurable diseases which are often characterized by unpredictable flares and troubling symptoms which can interfere with a patient’s ability to work. Accommodations in the workplace can help persons with IBD to cope with their illness and work effectively. We systematically reviewed all studies regarding workplace disability in IBD patients. Systematic searches were undertaken on February to March 2018, for the following databases: Pubmed, Medline (Ovid), Cochrane Central Register of Controlled Trials and CINAHL for studies that addressed workplace needs, accommodations and adaptations using survey tools. Of 430 studies screened, 54 met initial eligibility criteria and then six studies were ultimately included, with a total of 7700 participants. Five studies were quantitative, 1 study was qualitative. Common themes were the importance of reasonable adjustments and accommodations in the workplace, mixed with the finding that a significant proportion reported that they had some difficulty arranging accommodations. Adaptations most required were access to a toilet or toilet breaks and time to go to medical appointments. People with IBD often need accommodations, but many do not ask or have difficulty arranging it. Better resources are needed to inform people with IBD about the possibilities for workplace accommodations and practical strategies to request them.

Shafer LA, Walker JR, Restall G, Chhibba T, Ivekovic M, Singh H, Targownik LE, Bernstein CN. Association between IBD Disability and Reduced Work Productivity (Presenteeism): a population-based study in Manitoba, Canada. Inflammatory Bowel Disease 2019 Jan 10;25(2): 352-359.

One effect of IBD disability is reduced productivity when at work (presenteeism). We explored potential predictors of work presenteeism and compared the predictive ability of the recently developed IBD Disability Index (IBDDI) with 4 other scales in predicting presenteeism. Participants (aged 18-65 years) were recruited from the University of Manitoba IBD Research Registry. We calculated a presenteeism score (range, 0-24) from the Stanford Presenteeism Scale, with higher scores representing greater degrees of presenteeism. We explored associations between presenteeism and the IBDDI, the World Health Organization Disability Assessment Schedule (WHODAS 2.0), the Work and Social Adjustment Scale (WSAS), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the Kessler-6 (K6) distress scale. Out of 744 respondents working at least half-time (20+ hours/wk), 472 (63%) reported no reduced productivity in the previous 14 days. Reduced productivity was reported for 1-2 days by 131 (18%), for 3-9 days by 119 (16%), and on most days by 22 (3%). When predicting the Stanford Presenteeism Scale, similar model fits were found for the IBDDI, WHODAS, WSAS, IBDQ, and K6. Each increase of 10 on the IBDDI score was associated with an increase of 2.19 (95% confidence interval, 2.00-2.37) on the Stanford Presenteeism Scale. Each additional year of disease duration was associated with a reduction in Stanford Presenteeism Scale score of 0.08 (P < 0.01). We concluded that more than one-third of persons with IBD report presenteeism. We found strong associations between presenteeism and disability, lower quality of life, and emotional distress. The IBDDI performs equally as well as the more established scales in predicting presenteeism.

Lewis K, Marrie RA, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM; CIHR Team in Defining the Burden and Managing the Effects of Immune-Mediated Inflammatory Disease. The prevalence and risk factors of undiagnosed depression and anxiety disorders among patients with inflammatory bowel disease. Inflammatory Bowel Diseases 2019; 25 (10), 1674-1680.

Inflammatory bowel disease is associated with a high prevalence of comorbid depressive and anxiety disorders. A significant proportion of IBD patients with comorbid psychiatric disorders remain undiagnosed and untreated, but factors associated with diagnosis are unknown. We evaluated the prevalence of undiagnosed depression and anxiety in an IBD cohort, along with the associated demographic and clinical characteristics. We obtained data from the enrollment visit of a cohort study of psychiatric comorbidity in immune-mediated diseases including IBD. Each participant underwent a Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) to identify participants who met lifetime criteria for a diagnosis of depression or anxiety. Those with a SCID-based diagnosis were classified as diagnosed or undiagnosed based on participant report of a physician diagnosis. Of 242 eligible participants, 97 (40.1%) met SCID criteria for depression, and 74 (30.6%) met criteria for anxiety. One-third of participants with depression and two-thirds with anxiety were undiagnosed. Males were nearly 3.5x more likely to have an undiagnosed depressive disorder. Nonwhite participants were 80% less likely to have an undiagnosed anxiety disorder. Our findings highlight the importance of screening for depression and anxiety in patients with IBD, with particular attention to those of male sex and with a lower education level.

Bernstein CN, Hitchon CA, Walld R, Bolton JM, Sareen J, Walker JR, Graff LA, Pattem SB, Singer A, Lix LM, El-Gabalawy R, Katz A Fisk JD, Marrie RA. Increased burden of psychiatric disorders in inflammatory bowel disease. Inflammatory Bowel Disease 2019 Jan 10;25(2): 352-359.

Psychiatric comorbidity in inflammatory bowel disease (IBD) is well known; however, data from a truly representative sample are sparse. We aimed to estimate the incidence and prevalence of psychiatric disorders in an IBD cohort compared with a matched cohort without IBD. Using the population-based University of Manitoba IBD Epidemiology Database, we identified all persons with incident IBD from 1989 to 2012 and a general population matched cohort (5:1). We applied validated algorithms for IBD, depression, anxiety disorders, bipolar disorder, and schizophrenia to determine the annual incidence of these conditions post-IBD diagnosis and their lifetime and current prevalence. There were 6119 incident cases of IBD and 30,573 matched individuals. After adjustment for age, sex, socioeconomic status, region of residence, and year, there was a 60% higher incidence in the IBD cohort compared with controls for depression (incidence rate ratio [IRR], 1.58; 95% confidence interval [CI], 1.41-1.76), 40% for anxiety disorder (IRR, 1.39; 95% CI, 1.26-1.53), 80% for bipolar disorder (IRR, 1.82; 95% CI, 1.44-2.30), and 65% for schizophrenia (IRR, 1.64; 95% CI, 0.95-2.84). Incidence rate ratios were similar for Crohn's disease and ulcerative colitis and between males and females and were stable over time. However, within the IBD cohort, the incidence rates of depression, anxiety, and bipolar disorders were higher among females, those aged 18-24 years vs those older than 44 years, urbanites, and those of lower socioeconomic status. The lifetime and current prevalence rates of psychiatric disorders were also higher in the IBD than the matched cohort. We concluded that the incidence and prevalence of psychiatric disorders are elevated in the IBD population.

Marrie RA, Walker JR, Graff LA, Patten SB, Bolton JM, Marriott JJ, Fisk JD, Hitchon C, Bernstein CN for the CIHR Team in Defining the Burden and Managing the Effects of Immune-mediated Inflammatory Disease. Gender differences in information needs and preferences regarding depression among individuals with multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis. Patient and Education Counseling 2019; Apr 6. pii: S0738-3991(19)30132-6.

We assessed the information needs of persons with any of three immune-mediated inflammatory diseases (multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis) regarding depression, as a first step toward developing patient-relevant information resources, ultimately to facilitate self-management and appropriate care. We also compared information needs across genders. We surveyed participants with multiple sclerosis, IBD and rheumatoid arthritis regarding depression-related information needs including types of treatments, effectiveness, risks, benefits, and perceived helpfulness of treatments. We compared responses between groups using multivariate regression. 328 participants provided complete responses (Multiple sclerosis: 141, IBD: 114, rheumatoid arthritis: 73). Most of the topics queried were perceived as very important, and similarly important for all groups. Women placed higher importance than men on most topics. The most popular formats for receiving information were discussion with a counselor (very preferred: 67.4%) and written information (very preferred: 65.5%); this did not differ between groups. We concluded that persons affected by multiple sclerosis, IBD and rheumatoid arthritis are interested in receiving information about multiple topics related to depression treatment, from multiple sources. Women desire more information than men. PRACTICE IMPLICATIONS: These findings can be used to design information resources to meet information needs regarding depression in multiple sclerosis, IBD and rheumatoid arthritis.

Coward S, Clement F, Benchimol EI, Bernstein CN, Avina-Zubieta JA, Bitton A, Carroll MW, Hazlewood G, Jacobson K, Jelinski S, Deardon R, Jones JL, Kuenzig ME, Leddin D, McBrien KA, Murthy SK, Nguyen GC, Otley AR, Panaccione R, Rezaie A, Rosenfeld G, Peña-Sánchez JN, Singh H, Targownik LE, Kaplan GG. Past and future burden of inflammatory bowel diseases based on modeling of population-based data. Gastroenterology 2019; 156:1345-1353.

Inflammatory bowel diseases exist worldwide, with high prevalence in North America. IBD is complex and costly, and its increasing prevalence places a greater stress on health care systems. In this study we aimed to determine the past current, and future prevalences of IBD in Canada. We used administrative health data from Alberta (2002-2015), British Columbia (1997-2014), Manitoba (1990-2013), Nova Scotia (1996-2009), Ontario (1999-2014), Quebec (2001-2008), and Saskatchewan (1998-2016). In 2018, the prevalence of IBD in Canada was estimated at 725 per 100,000 (95% PI 716-735) and the annual average percent change increase was nearly 3% per year. The prevalence in 2030 was forecasted to be 981 per 100,000 159 per 100,000 in children, 1118 per 100,000 in adults, and 1370 per 100,000 in the elderly. In 2018, 267,983 Canadians were estimated to be living with IBD, which was forecasted to increase to 402,853 by 2030.

Targownik LE, Benchimol E, Witt J, Bernstein CN, Singh H, Lix L, Tennakoon A, Zubieta AA, Coward S, Jones J, Kuenzig E, Murthy S, Nguyen G, Peña Sánchez JN, Kaplan GG. The effect of initiation of anti-TNF therapy on the subsequent direct healthcare costs of inflammatory bowel disease. Inflammatory Bowel Diseases 2019; 25: 1718-1728.

Background: The prevalence of inflammatory bowel disease (IBD) is known to be increasing. The total direct costs of IBD have not been assessed on a population wide level in the era of biologic therapy. We identified all persons with IBD in Manitoba in the University of Manitoba Inflammatory Bowel Disease Epidemiology Database between January 2005 and December 2015, with each matched to 10 controls on age, sex, and geographic area of residence. Costs of all hospitalizations, outpatient physician-patient contacts and prescription medication use were enumerated for cases and controls. Total and per-capital annual costs attributable to IBD were determined by taking the difference between the costs accrued by an IBD case and their control. The number of people with IBD in Manitoba increased from 6,323 to 7,603 between 2005 and 2015. The total per capita annual costs attributable to IBD rose from $3,354 in 2005 to $7,801 in 2015, primarily driven by an increase in pre capital annual anti-TNF drug (i.e. infliximab and adalimumab) costs, which rose from $181 in 2005 to $5,270 in 2015. There was a significant decline in inpatient costs for CD ($180±35/year. p=0.0006), but not for UC ($56±35/year, p=0.23), In summary, the direct health care costs attributable to IBD have more than doubled over the 10 years between 2005 and 2015, driven mostly by increasing expenditures on biological medications (i.e. anti-TNF drugs). IBD-attributable hospitalization costs have declined modestly over time for persons with CD, though no change was seen for patients with UC.

Bernstein CN, Burchill C, Targownik LE, Singh H, Roos LL. Events within the first year of life, but not the neonatal period, affect risk for later development of inflammatory bowel diseases. Gastroenterology 2019; 156(8): 2190-2197.

We performed a population-based study to determine whether there was an increased risk of inflammatory bowel diseases (IBD) in persons with critical events at birth and within 1 year of age. We collected data from the University of Manitoba IBD Epidemiology Database, which contains records on all Manitobans diagnosed with IBD from 1984 through 2010 and matched controls. From 1970 individuals' records can be linked with those of their mothers, so we were able to identify siblings. All health care visits or hospitalizations during the neonatal and postnatal periods were available from 1970 through 2010. In previous studies using this data source we showed that development of IBD was not associated with being born by caesarean section (versus vaginal delivery) and was not associated with mothers’ having antenatal or perinatal infections. In this study we collected data on infections, gastrointestinal illnesses, failure to thrive, and hospital readmission in the first year of life and sociodemographic factors at birth. From 1979, data were available on gestational age, Apgar score, neonatal admission to the intensive care unit, and birth weight. We compared incident rate of infections, gastrointestinal illnesses, and failure to thrive between IBD cases and matched controls as well as between IBD cases and siblings. Data on 825 IBD cases and 5999 matched controls were available from 1979. Maternal diagnosis of IBD was the greatest risk factor for IBD in offspring (increased the risk for IBD development in offspring 4.5x). When we assessed neonatal events, only being in the highest vs lowest socioeconomic quintile increased risk for later development of IBD. For events within the first year of life, being in the highest socioeconomic quintile at birth and infections increased risk for developing IBD at any age. Infection in the first year of life was associated with diagnosis of IBD before age 10 years (by 3x) and before age 20 years (by 1.5x) Risk for IBD was not affected by gastrointestinal infections, gastrointestinal disease, or abdominal pain in the first year of life. In a population-based study, we concluded that infection within the first year of life was associated with a diagnosis of IBD. This might be due to use of antibiotics or a physiologic defect at a critical age for gut microbiome development.

El Matary W, Nugent Z, Yu BN, Lix LM, Targwonik LE, Bernstein CN, Singh H. Trends and predictors of Clostridium difficile infection among children: A Canadian population-based study. Journal of Pediatrics 2019 Mar; 206:20-25.

In this paper we report on the incidence rates over time of children with IBD presenting with Clostridium difficile infection. We explored our provincial database on all persons with Clostridium difficile infection between 2005-2014 so that we could identify the rates of this infection in children and what diseases increased the risk for Clostridium difficile infection. In children. The overall Clostridium difficile infection rate over the study period was 7.77 per 100,000. There was no significant increase in Clostridium difficile infection rates over the observation period. Co-morbid conditions that were more prevalent among children with Clostridium difficile infection than matched controls included Hirschsprung’s disease (p<0.001) and IBD (p<0.0001). Recurrent Clostridium difficile infections were responsible for 10.4% of CDI episodes (range 2-6 infections). Children with cancer were 3 times as likely to have recurrent Clostridium difficile infection (Hazard ratio (HR) = 3.0, 95% confidence interval (CI) 1.1, 8.8), children with diabetes were nearly 5 times as likely to have recurrent Clostridium difficile infection (HR=4.8, 95% CI 1.1, 21.4) and children with neurodegenerative diseases were over 8 times as likely to have recurrent Clostridium difficile infection (HR=8.4, 95% CI 1.9, 37.5). We concluded that the incidence of Clostridium difficile infection was not increasing among children in Manitoba. Children with malignancy, diabetes and neurodegenerative disorders are more likely to have recurrent Clostridium difficile infection.

El-Matary W, Leung S, TennakoonA, Benchimol EI, Bernstein CN, Targownik LE. Trends of utilization of tumor necrosis factor antagonists in children with inflammatory bowel disease: A Canadian population-based study. Inflammatory Bowel Diseases 2019; 206: 20-25.

We aimed to describe the trend of utilization of anti-TNF drugs (infliximab and adalimumab) in children with IBD over time. We assessed all persons diagnosed with IBD prior to age 18y identified in the University of Manitoba IBD Epidemiology Database to determine the time from diagnosis to first anti-TNF in different eras (2005-2008, 2008-2012, 2012-2016). There were 291 persons diagnosed with IBD (157 CD, 134 UC) prior to age 18y. The likelihood of being initiated on anti-TNFs by 1, 2 and 5 years post-diagnosis was 18.4%, 30.5% and 42.6% respectively. The proportion of persons <18 using anti-TNFs increased over time; in 2010, 13.0% of Crohn’s disease (CD) and 4.9% of ulcerative colitis (UC); by 2016 60.0% of CD and 25.5% of UC were actively using an anti-TNF agent. For those diagnosed after 2012, 42.5% of CD and 28.4% of UC had been started on an anti-TNF agent within 1 year of IBD diagnosis. The median cumulative dose of corticosteroids in the year prior to anti-TNF initiation significantly decreased over time (prior to 2008: 4360mg; 2008-2012: 2010mg, 2012-present 1395mg prednisone equivalents) meaning the use of anti-TNF drugs has likely translated into a reduced use of corticosteroids.

Eissa N, Hussein H, Diarra A, Kapoor K, Gounni AS, Bernstein CN, Ghia JE. Semaphorin 3E regulates apoptosis in the intestinal epithelium during the development of colitis. Biochemical Pharmacology 2019; 166:264-273.

Semaphorin 3E is a protein that regulates various biological processes including immune responses and apoptosis. However, its role in the pathophysiology of colitis is not fully known. We investigated the role of Semaphorin 3E in intestinal epithelial cells activation, using biopsies from patients with active ulcerative colitis (UC), a mouse model of UC, and an in-vitro model of intestinal mucosal healing. In this study, we confirmed that the mRNA level of Semaphorin 3E is reduced significantly in patients with UC and demonstrated a negative linear association between Semaphorin 3E mRNA and p53-associated genes. In mice, genetic deletion of Sema3e (gene for Semaphorin 3E) resulted in an increase in onset and severity of colitis, p53-associated genes, apoptosis, and IL-1beta production. Recombinant Semaphorin 3E treatment protected against colitis and decreased these effects. Furthermore, in stimulated epithelial cells, recombinant Semaphorin 3E treatment enhanced wound healing, resistance to oxidative stress and decreased apoptosis and p53-associated genes.

Together, these findings identify Semaphorin 3E as a novel regulator in intestinal inflammation that regulates intestinal epithelial cells apoptosis and suggest a potential novel approach to treat UC.

Benchimol E, Bernstein CN, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Siddq S, Windsor JW, Carroll M, Coward S, El-Matary W, Griffiths AM, Jones J, Kuenzig E, Lee L, Mack DR, Mawani M, Otley A, Singh H, Targownik LE, Weizman AV, Kaplan GG. The Impact of Inflammatory Bowel Disease in Canada 2018: A Scientific Report from the Canadian Gastro-Intestinal Epidemiology Consortium to Crohn's and Colitis Canada. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S1-S5.

Kaplan GG, Bernstein CN, Coward S, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Benchimol E. The Impact of Inflammatory Bowel Disease in Canada 2018: Epidemiology. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S6-S16.

Carroll M, Kuenzig E, Mack DR, Otley A, Griffiths AM, Kaplan GG, Bernstein CN, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Benchimol E. The Impact of Inflammatory Bowel Disease in Canada 2018: Children and Adolescents with IBD. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S49-S67.

Nguyen GC, Targownik LE, Singh H, Benchimol E, Bitton A, Murthy SK, Bernstein CN, Lee K, Cooke-Lauder J, Kaplan GG. The Impact of Inflammatory Bowel Disease in Canada 2018: IBD in Seniors. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S68-S72.

Bernstein CN, Benchimol E, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Kaplan GG. The Impact of Inflammatory Bowel Disease in Canada 2018: Extra-intestinal Diseases in IBD. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S73-S80.

Rose K, Sherman PM, Cooke-Lauder J, Mawani M, Benchimol E, Kaplan GG, Bernstein CN, Bitton A, Murthy SK, Nguyen GC, Lee K. The Impact of Inflammatory Bowel Disease in Canada 2018: IBD Research Landscape in Canada. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S81-S91.

Jones J, Nguyen GC, Benchimol E, Bernstein CN, Bitton A, Kaplan GG, Murthy SK, Lee K, Cooke-Lauder J, Otley A. The Impact of Inflammatory Bowel Disease in Canada 2018: Quality of Life. Journal of the Canadian Association of Gastroenterology. 2019; 2 Supplement 1: S42-S48.

Keunzig ME, Lee L, El-Matary W, Weizman AV, Benchimol EI, Targownik LE, Singh H, Kaplan GG, Bernstein CN, Bitton A, Nguyen GC, Lee K, Cooke-Lauder J, Murthy S. The Impact of Inflammatory Bowel Disease in Canada 2018: Direct Costs and Health Services Utilization. Journal of the Canadian Association of Gastroenterology. 2019; 2 Supplement 1: S17-S33.

Keunzig ME, Benchimol E, Lee L, Targownik LE, Singh H, Kaplan GG, Nguyen GC, Bernstein CN, Bitton A, Lee K, Cooke-Lauder J, Murthy S. The Impact of Inflammatory Bowel Disease in Canada 2018: Indirect costs of IBD care. Journal of the Canadian Association of Gastroenterology. 2019; 2 Supplement 1: S34-S41.

Publications // from the Manitoba IBD Epidemiology Database

Publications // 2019-2020

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Publications // from the Manitoba IBD Epidemiology Database