Propofol sedation in routine endoscopy: A case series comparing target controlled infusion vs manually controlled bolus concept.

BACKGROUND: Many studies have addressed safety and effectiveness of non-anaesthesiologist propofol sedation (NAPS) for gastrointestinal (GI) endoscopy Target controlled infusion (TCI) is claimed to provide an optimal sedation regimen by avoiding under- or oversedation. AIM: To assess safety and performance of propofol TCI sedation in comparison with nurse-administered bolus-sedation. METHODS: Fouty-five patients undergoing endoscopy under TCI propofol sedation were prospectively included from November 2016 to May 2017 and compared to 87 patients retrospectively included that underwent endoscopy with NAPS. Patients were matched for age and endoscopic procedure. We recorded time of sedation and endoscopy, dosage of medication and adverse events. RESULTS: There was a significant reduction in dose per time of propofol administered in the TCI group, compared to the NAPS group (8.2 ± 2.7 mg/min vs 9.3 ± 3.4 mg/min; P = 0.046). The time needed to provide adequate sedation levels was slightly but significantly lower in the control group (5.3 ± 2.7 min vs 7.7 ± 3.3 min; P < 0.001), nonetheless the total endoscopy time was similar in both groups. No differences between TCI and bolus-sedation was observed for mean total-dosage of propofol rate as well as adverse events. CONCLUSION: This study indicates that sedation using TCI for GI endoscopy reduces the dose of propofol necessary per minute of endoscopy. This may translate into less adverse events. However, further and randomized trials need to confirm this trend.

Development of non-alcoholic steatohepatitis is associated with gut microbiota but not with oxysterol enzymes CH25H, EBI2, or CYP7B1 in mice.

Liver steatosis is the most frequent liver disorder and its advanced stage, non-alcoholic steatohepatitis (NASH), will soon become the main reason for liver fibrosis and cirrhosis. The "multiple hits hypothesis" suggests that progression from simple steatosis to NASH is triggered by multiple factors including the gut microbiota composition. The Epstein Barr virus induced gene 2 (EBI2) is a receptor for the oxysterol 7a, 25-dihydroxycholesterol synthesized by the enzymes CH25H and CYP7B1. EBI2 and its ligand control activation of immune cells in secondary lymphoid organs and the gut. Here we show a concurrent study of the microbial dysregulation and perturbation of the EBI2 axis in a mice model of NASH.We used mice with wildtype, or littermates with CH25H-/-, EBI2-/-, or CYP7B1-/- genotypes fed with a high-fat diet (HFD) containing high amounts of fat, cholesterol, and fructose for 20 weeks to induce liver steatosis and NASH. Fecal and small intestinal microbiota samples were collected, and microbiota signatures were compared according to genotype and NASH disease state.We found pronounced differences in microbiota composition of mice with HFD developing NASH compared to mice did not developing NASH. In mice with NASH, we identified significantly increased 33 taxa mainly belonging to the Clostridiales order and/ or the family, and significantly decreased 17 taxa. Using an Elastic Net algorithm, we suggest a microbiota signature that predicts NASH in animals with a HFD from the microbiota composition with moderate accuracy (area under the receiver operator characteristics curve = 0.64). In contrast, no microbiota differences regarding the studied genotypes (wildtype vs knock-out CH25H-/-, EBI2-/-, or CYP7B1-/-) were observed.In conclusion, our data confirm previous studies identifying the intestinal microbiota composition as a relevant marker for NASH pathogenesis. Further, no link of the EBI2 - oxysterol axis to the intestinal microbiota was detectable in the current study.

Because I'm happy - positive affect and its predictive value for future disease activity in patients with inflammatory bowel diseases: a retrospective cohort study.

Background: While the detrimental impact of negative emotions on the clinical course of inflammatory bowel disease (IBD) and quality of life has been extensively investigated, evidence for a potential impact of positive emotions is scarce. Objectives: We aim to analyse contributing factors of positive affect and their predictive value for disease course in IBD patients. Design: In this retrospective cohort study, epidemiological, psychosocial and IBD disease characteristics of Swiss IBD cohort study patients were analysed longitudinally. Methods: Epidemiological, psychosocial and disease characteristics were extracted from the database of the Swiss IBD cohort study. Participants' positive emotions were assessed cross-sectionally with the seven-item Marburg questionnaire (range 1-6) addressing positive affect in different aspects of daily life. Predictors of positive emotions were identified by linear regression. The quantitative longitudinal impact of positive emotions on the further disease course was analysed using a multivariable Cox proportional hazards model. Results: Among 702 IBD patients, those reporting more positive emotions were found to have significantly less intense medical treatment, less pain and fewer depressive symptoms (p < 0.05). A higher percentage of variability in positive emotions was explained by pain (36%) and depressive symptoms (13%) than by epidemiological characteristics (0.3%), or characteristics of IBD and its treatment (2.4%). Patients with higher levels of positive emotions (score > 3.5) experienced longer flare-free survival, also after adjusting for confounders (adjusted hazard ratio: 0.39, p < 0.05). Conclusions: The absence of pain and depressive symptoms were the strongest drivers for high positive affect. Higher scores of positive affect were associated with longer disease-free survival in IBD patients.

STAR SIGN study: Evaluation of COVID-19 vaccine efficacy against the SARS-CoV-2 variants BQ.1.1 and XBB.1.5 in patients with inflammatory bowel disease.

BACKGROUND: Vaccine-elicited immune responses are impaired in patients with inflammatory bowel disease (IBD) treated with anti-TNF biologics. AIMS: To assess vaccination efficacy against the novel omicron sublineages BQ.1.1 and XBB.1.5 in immunosuppressed patients with IBD. METHODS: This prospective multicentre case-control study included 98 biologic-treated patients with IBD and 48 healthy controls. Anti-spike IgG concentrations and surrogate neutralisation against SARS-CoV-2 wild-type, BA.1, BA.5, BQ.1.1, and XBB.1.5 were measured at two different time points (2-16 weeks and 22-40 weeks) following third dose vaccination. Surrogate neutralisation was based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Primary outcome was surrogate neutralisation against tested SARS-CoV-2 sublineages. Secondary outcomes were proportions of participants with insufficient surrogate neutralisation, impact of breakthrough infection, and correlation of surrogate neutralisation with anti-spike IgG concentration. RESULTS: Surrogate neutralisation against all tested sublineages was reduced in patients with IBD who were treated with anti-TNF biologics compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.001) at visit 1. Anti-TNF therapy (odds ratio 0.29 [95% CI 0.19-0.46]) and time since vaccination (0.85 [0.72-1.00]) were associated with low, and mRNA-1273 vaccination (1.86 [1.12-3.08]) with high wild-type surrogate neutralisation in a ß-regression model. Accordingly, higher proportions of patients treated with anti-TNF biologics had insufficient surrogate neutralisation against omicron sublineages at visit 1 compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.015). Surrogate neutralisation against all tested sublineages decreased over time but was increased by breakthrough infection. Anti-spike IgG concentrations correlated with surrogate neutralisation. CONCLUSIONS: Patients with IBD who are treated with anti-TNF biologics show impaired neutralisation against novel omicron sublineages BQ.1.1 and XBB.1.5 and may benefit from prioritisation for future variant-adapted vaccines.

Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.

Systemic and T cell-associated responses to SARS-CoV-2 immunisation in gut inflammation (STAR SIGN study): effects of biologics on vaccination efficacy of the third dose of mRNA vaccines against SARS-CoV-2.

BACKGROUND: Immunosuppressed patients with inflammatory bowel disease (IBD) experience increased risk of vaccine-preventable diseases such as COVID-19. AIMS: To assess humoral and cellular immune responses following SARS-CoV-2 booster vaccination in immunosuppressed IBD patients and healthy controls. METHODS: In this prospective, multicentre, case-control study, 139 IBD patients treated with biologics and 110 healthy controls were recruited. Serum anti-SARS-CoV-2 spike IgG concentrations were measured 2-16 weeks after receiving a third mRNA vaccine dose. The primary outcome was to determine if humoral immune responses towards booster vaccines differ in IBD patients under anti-TNF versus non-anti-TNF therapy and healthy controls. Secondary outcomes were antibody decline, impact of previous infection and SARS-CoV-2-targeted T cell responses. RESULTS: Anti-TNF-treated IBD patients showed reduced anti-spike IgG concentrations (geometric mean 2357.4 BAU/ml [geometric SD 3.3]) when compared to non-anti-TNF-treated patients (5935.7 BAU/ml [3.9]; p < 0.0001) and healthy controls (5481.7 BAU/ml [2.4]; p < 0.0001), respectively. In multivariable modelling, prior infection (geometric mean ratio 2.00 [95% CI 1.34-2.90]) and vaccination with mRNA-1273 (1.53 [1.01-2.27]) increased antibody concentrations, while anti-TNF treatment (0.39 [0.28-0.54]) and prolonged time between vaccination and antibody measurement (0.72 [0.58-0.90]) decreased anti-SARS-CoV-2 spike antibodies. Antibody decline was comparable in IBD patients independent of anti-TNF treatment and antibody concentrations could not predict breakthrough infections. Cellular and humoral immune responses were uncoupled, and more anti-TNF-treated patients than healthy controls developed inadequate T cell responses (15/73 [20.5%] vs 2/100 [2.0%]; p = 0.00031). CONCLUSIONS: Anti-TNF-treated IBD patients have impaired humoral and cellular immunogenicity following SARS-CoV-2 booster vaccination. Fourth dose administration may be beneficial for these patients.

Intelectin-1 binds and alters the localization of the mucus barrier-modifying bacterium Akkermansia muciniphila.

Intelectin-1 (ITLN1) is a lectin secreted by intestinal epithelial cells (IECs) and upregulated in human ulcerative colitis (UC). We investigated how ITLN1 production is regulated in IECs and the biological effects of ITLN1 at the host-microbiota interface using mouse models. Our data show that ITLN1 upregulation in IECs from UC patients is a consequence of activating the unfolded protein response. Analysis of microbes coated by ITLN1 in vivo revealed a restricted subset of microorganisms, including the mucolytic bacterium Akkermansia muciniphila. Mice overexpressing intestinal ITLN1 exhibited decreased inner colonic mucus layer thickness and closer apposition of A. muciniphila to the epithelial cell surface, similar to alterations reported in UC. The changes in the inner mucus layer were microbiota and A. muciniphila dependent and associated with enhanced sensitivity to chemically induced and T cell-mediated colitis. We conclude that by determining the localization of a select group of bacteria to the mucus layer, ITLN1 modifies this critical barrier. Together, these findings may explain the impact of ITLN1 dysregulation on UC pathogenesis.

Plasticity of the adult human small intestinal stoma microbiota.

The human distal small intestine (ileum) has a distinct microbiota, but human studies investigating its composition and function have been limited by the inaccessibility of the ileum without purging and/or deep intubation. We investigated inherent instability, temporal dynamics, and the contribution of fed and fasted states using stoma samples from cured colorectal cancer patients as a non-invasive access route to the otherwise inaccessible small and large intestines. Sequential sampling of the ileum before and after stoma formation indicated that ileostoma microbiotas represented that of the intact small intestine. Ileal and colonic stoma microbiotas were confirmed as distinct, and two types of instability in ileal host-microbial relationships were observed: inter-digestive purging followed by the rapid postprandial blooming of bacterial biomass and sub-strain appearance and disappearance within individual taxa after feeding. In contrast to the relative stability of colonic microbiota, the human small intestinal microbiota biomass and its sub-strain composition can be highly dynamic.

The personality traits activity, self-reproach, and negative affect jointly predict clinical recurrence, depressive symptoms, and low quality of life in inflammatory bowel disease patients.

BACKGROUND: The bidirectional "gut-brain axis" has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). While the influence of stress and depressive symptoms on IBD is well-characterized, the role of personality remains insufficiently investigated. METHODS: Personality was assessed in 1154 Swiss IBD cohort study (SIBDCS) patients via the NEO-Five-Factor Inventory (NEO-FFI) as well as in 2600 participants of the population-based CoLaus¦PsyCoLaus cohort study (NEO-FFI-revised). The NEO-FFI subcomponents activity, self-reproach and negative affect were associated with higher IBD disease activity and were combined to a NEO-FFI risk score. This risk score was validated and its effect on clinical IBD course and psychological endpoints was analysed in time-to-event and cumulative incidence analyses. RESULTS: In time-to-event analyses, a high NEO-FFI risk score was predictive for the clinical endpoints of new extraintestinal manifestation [EIM, adjusted hazard ratio (aHR) = 1.64, corrected p value (q) = 0.036] and two established composite flare endpoints (aHR = 1.53-1.63, q = 0.003-0.006) as well as for the psychological endpoints depressive symptoms (aHR = 7.06, q < 0.001) and low quality of life (aHR = 3.06, q < 0.001). Furthermore, cumulative incidence analyses showed that patients at high NEO-FFI risk experienced significantly more episodes of active disease, new EIMs, one of the flare endpoints, depressive episodes and low disease-related quality of life. Personalities of IBD patients showed only minor differences from the general population sample (Pearson's r = 0.03-0.14). CONCLUSIONS: Personality assessed by the NEO-FFI contained considerable predictive power for disease recurrence, depressive symptoms and low quality of life in IBD patients. Nevertheless, the personalities of IBD patients did not substantially differ from the general population.

Effectiveness of golimumab in patients with ulcerative colitis: results of a real-life study in Switzerland.

BACKGROUND: Tumor necrosis factor (TNF) inhibitors have improved treatment of ulcerative colitis (UC), but loss of response remains a frequent problem. The anti-TNF agent, golimumab, was approved in Switzerland for the treatment of UC in 2014. This study aims to summarize the experience of golimumab in a real-world setting in Switzerland. METHODS: We analyzed real-world data from 1769 UC patients from the Swiss Inflammatory Bowel Disease Cohort (SIBDC) study and performed a chart review of golimumab-treated patients. We extracted the partial Mayo score at t0 (baseline), t1 (2-16 weeks), t2 (17-35 weeks), and t3 (36-89 weeks). The primary endpoint was clinical response at t1, defined as marked improvement in partial Mayo score and objective parameters. Clinical remission was defined as resolution of symptoms and normalization of objective parameters. RESULTS: Our chart review included 103 UC patients with golimumab treatment (5.8% of all SIBDC UC patients); only 16 (15.5%) were anti-TNF naïve. Sixty-three patients remained on golimumab (61.2%) after 180 days, 51 (44.7%) after 365 days, and 34 (33%) after 630 days after the start of treatment. Upon golimumab treatment, the partial Mayo score decreased from 4 [interquartile range (IQR): 2-6] at t0 to 2 (IQR: 0-4) at t1, 1 (IQR: 0-3.5) at t2, and 1 (IQR: 0-3) at t3 (p < 0.001 for all comparisons with t0). The primary endpoint, clinical response at t1, could be evaluated in 52 patients and was met in 15 individuals (28.8%). Clinical remission at t1 was observed in 8 out of 52 patients (15.4%). Golimumab was generally well tolerated, one patient developed meningitis. The most frequent reasons to stop treatment were primary and secondary non-response. CONCLUSION: Golimumab was used in 5.8% of Swiss UC patients, mainly in biologic-experienced individuals. Golimumab treatment was associated with a sustained reduction of symptoms and clinical response in approximately 30% of patients.[ClinicalTrials.gov identifier: NCT00488631].

Depressive Symptoms Predict Clinical Recurrence of Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) patients are at high risk for depression, and depression has been shown to affect disease course. We examined interrelations between depression, genetic risk factors for depression, and IBD flares. METHOD: In 1973 patients (1137 Crohn's disease, 836 ulcerative colitis) of the Swiss IBD Cohort Study (SIBDCS), depressive status (hospital anxiety and depression subscale for depression, HADS-D ≥11) was assessed on a yearly basis. We investigated the impact of depression on IBD-relevant clinical outcomes in Cox proportional hazards models. We used active disease (CDAI ≥150 or MTWAI ≥10) and 2 published composite flare definitions-FNCE (physician-reported flare, nonresponse to therapy, new complication, or extraintestinal manifestation) and AFFSST (active disease, physician-reported flare, fistula, stenosis, and new systemic therapy)-as clinical end points. Additionally, 62 preselected single nucleotide polymorphisms (SNPs) were screened for cross-sectional associations with depression, and if present, their predictive value for future depression and clinical deterioration was assessed. RESULTS: Depression was a strong risk factor for disease-related end points, including active disease (adjusted hazard ratio [aHR], 3.55; P < 0.001), AFFSST (aHR, 1.62; P < 0.001), and FNCE (aHR, 1.35; P = 0.019). The SNP rs2522833 was significantly associated with depression at enrollment (q = 0.059). The TC allele of rs588765 was negatively associated with the presence of depression at enrollment (q = 0.050) and after enrollment (aHR, 0.67; P = 0.035) and with fewer active disease states (aHR, 0.72; P = 0.045) during follow-up. CONCLUSION: In IBD, depressive symptoms and inflammatory activity are intimately related. Depressive symptoms were a strong predictor of clinical deterioration, and genetic markers may play a role in this relationship.

Association between proton-pump inhibitors and the risk of gastric cancer: a systematic review with meta-analysis.

INTRODUCTION: The use of proton-pump inhibitors (PPI) may be associated with an increased risk of gastric cancer (GC). OBJECTIVE: To review and meta-analyse available literature investigating the association between PPI use and GC risk. METHODS: Two independent reviewers systematically searched Ovid MEDLINE, EMBASE, and Cochrane Library (inception to July 2020) for case-control and cohort studies assessing the association between PPI use and GC according to a predefined protocol in PROSPERO (CRD42018102536). Reviewers independently assessed study quality, extracted data, and meta-analysed available and newly calculated odds ratios (ORs) using a random-effects model, and stratified for GC site (cardia versus non-cardia) and PPI duration (<1 year, 1-3 years, >3 years). RESULTS: We screened 2,396 records and included five retrospective cohort and eight case-control studies comprising 1,662,881 individuals in our meta-analysis. In random-effect models, we found an increased GC risk in PPI users [OR: 1.94, 95% confidence interval (95% CI): 1.47-2.56] with high statistical heterogeneity (I 2 = 82%) and overall moderate risk of bias. Stratified analyses indicated a significant risk increase in non-cardia (OR: 2.20, 95% CI: 1.44-3.36, I 2 = 77%) with a similar non-significant trend in cardia regions (OR: 1.77, 95% CI: 0.72-4.36, I 2 = 66%). There was no GC increase with longer durations of PPI exposure (<1 year: OR: 2.29, 95% CI: 2.13-2.47, I 2 = 0%; 1-3 years: OR: 1.46, 95% CI: 0.53-4.01, I 2 = 35%; >3 years: OR: 2.08, 95% CI: 0.56-7.77, I 2 = 61%). CONCLUSION: We found a twofold increased GC risk among PPI users, but this association does not confirm causation and studies are highly heterogeneous. PPI should only be prescribed when strictly indicated.

Effects of anti-TNF therapy and immunomodulators on anxiety and depressive symptoms in patients with inflammatory bowel disease: a 5-year analysis.

BACKGROUND AND AIMS: Anxiety and depression are prevalent in patients with inflammatory bowel diseases (IBD), especially during IBD flares. IBD therapies can profoundly affect the mood of patients with IBD. We aimed to determine the long-term impact of anti-tumor necrosis factor (anti-TNF) and immunomodulators (IM) on anxiety and depressive symptoms in IBD patients. METHODS: We compared three treatment groups with IM only (group A), anti-TNF ± IM (group B) and no such therapy (group C). Patients completed the hospital anxiety and depression scale (HADS) at 1 year, 3 years, and 5 years after start of treatment. RESULTS: In total, 581 patients with IBD (42.9% Crohn's disease, 57.1% ulcerative colitis/IBD unclassified) participated in this study. Effects of treatment were analyzed in a mixed effects model, with and without correction for confounders. Compared with group C, group B showed a significant treatment-related improvement in both anxiety and depressive symptoms within the first 2.5 years and also thereafter. Group A showed a significant long-term improvement of anxiety and both short-term and long-term improvement in depressive symptoms. The significance of these results was maintained after correction for confounders, including corticosteroid treatment. Additionally, both groups A and B showed a significant decrease in disease activity in the first 2.5 years after start of treatment and also thereafter. Anti-TNF and IM treatment were associated with a similarly significant decrease in anxiety and depressive symptoms over an observation period of up to 5 years. CONCLUSION: Besides a clear benefit for disease activity, anti-TNF and IM apparently improve the mood of patients with IBD.

Type D personality is associated with depressive symptoms and clinical activity in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) can be exacerbated by stress and depression. Type D personality, characterised by high negative affectivity and social inhibition, represents a vulnerability towards stressors and is associated with adverse outcomes in coronary heart disease. AIMS: To assess the prevalence of Type D personality in IBD patients and investigate potential associations with disease course. METHODS: We tested for associations between Type D (Type D Scale-14), depressive symptoms (Hospital Anxiety and Depression Scale's depression subscore ≥11) and recurrent IBD amongst Swiss IBD cohort patients. We built regression models for cross-sectional and Cox proportional hazards models for time-to-event analyses. IBD disease course was assessed by the future occurrence of active disease (Crohn's Disease Activity Index ≥150/Modified Truelove & Witts activity index ≥10) and several IBD-relevant endpoints. RESULTS: Amongst 2275 patients (1005 ulcerative colitis, 1270 Crohn's disease), 672 (29.5%) had Type D. Type D was a significant risk factor for future active disease (adjusted hazard ratio, aHR: 1.60, corrected P value, q = 0.007) and predicted the future presence of depressive symptoms (aHR: 3.30, P < 0.001). The combination of Type D and depressive symptoms further increased the risk for active disease (aHR: 3.98, q < 0.001). However, Type D associated depressive symptoms seemed to be the main contributor to this effect as Type D's predictive power decreased considerably in models corrected for depressive symptoms (aHR: 1.32, CI: 0.97-1.79, q = 0.292). CONCLUSIONS: Type D personality's prevalence amongst IBD patients was comparable with its prevalence in the general population. Type D was strongly associated with depressive symptoms and showed modest independent associations with IBD prognosis.

Evaluating key characteristics of ideal colorectal cancer screening modalities: the microsimulation approach.

BACKGROUND AND AIMS: Screening for colorectal cancer (CRC) can effectively reduce CRC incidence and mortality. Besides colonoscopy, tests for the detection of biomarkers in stool, blood, or serum, including the fecal immunochemical test (FIT), ColoGuard, Epi proColon, and PolypDx, have recently been advanced. We aimed to identify the characteristics of theoretic, highly efficient screening tests and calculated the effectiveness and cost effectiveness of available screening tests. METHODS: Using the microsimulation-based colon modeling open-source tool (CMOST), we simulated 142,501 theoretic screening tests with variable assumptions for adenoma and carcinoma sensitivity, specificity, test frequency, and adherence, and we identified highly efficient tests outperforming colonoscopy. For available screening tests, we simulated 10 replicates of a virtual population of 2 million individuals, using epidemiologic characteristics and costs assumptions of the United States. RESULTS: Highly efficient theoretic screening tests were characterized by high sensitivity for advanced adenoma and carcinoma and high patient adherence. All simulated available screening tests were effective at 100% adherence to screening and at expected real-world adherence rates. All tests were cost effective below the threshold of 100,000 U.S. dollars per life year gained. With perfect adherence, FIT was the most effective and cost-efficient intervention, whereas Epi proColon was the most effective at expected real-world adherence rates. In our sensitivity analysis, assumptions for patient adherence had the strongest impact on effectiveness of screening. CONCLUSIONS: Our microsimulation study identified characteristics of highly efficient theoretic screening tests and confirmed the effectiveness and cost-effectiveness of colonoscopy and available urine-, blood-, and stool-based tests. Better patient adherence results in superior effectiveness for CRC prevention in the whole population.

Abdominal pain in patients with inflammatory bowel disease: association with single-nucleotide polymorphisms prevalent in irritable bowel syndrome and clinical management.

BACKGROUND: Abdominal pain is a frequent symptom in patients with inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC). Pain can result from ongoing inflammation or functional disorders imitating irritable bowel syndrome (IBS). Several single-nucleotide polymorphisms (SNPs) have been associated with IBS. However, the impact of IBS genetics on the clinical course of IBD, especially pain levels of patients remains unclear. METHODS: Data of 857 UC and 1206 CD patients from the Swiss IBD Cohort Study were analysed. We tested the association of the maximum of the abdominal pain item of disease activity indices in UC and CD over the study period with 16 IBS-associated SNPs, using multivariate ANOVA models. RESULTS: In UC patients, the SNPs rs1042713 (located on the ADRB2 gene) and rs4663866 (close to the HES6 gene) were associated with higher abdominal pain levels (P = 0.044; P = 0.037, respectively). Abdominal pain was not associated with any markers of patient management in a model adjusted for confounders. In CD patients, higher levels of abdominal pain correlated with the number of physician contacts (P < 10-15), examinations (P < 10-12), medical therapies (P = 0.023) and weeks of hospitalisation (P = 0.0013) in a multivariate model. CONCLUSIONS: We detected an association between maximal abdominal pain in UC patients and two IBS-associated SNPs. Abdominal pain levels had a pronounced impact on diagnostic and therapeutic procedures in CD but not in UC patients.

The oxysterol receptor GPR183 in inflammatory bowel diseases.

Immune cell trafficking is an important mechanism for the pathogenesis of inflammatory bowel disease (IBD). The oxysterol receptor GPR183 and its ligands, dihydroxylated oxysterols, can mediate positioning of immune cells including innate lymphoid cells. GPR183 has been mapped to an IBD risk locus, however another gene, Ubac2 is encoded on the reverse strand and associated with Behçet's disease, therefore the role of GPR183 as a genetic risk factor requires validation. GPR183 and production of its oxysterol ligands are up-regulated in human IBD and murine colitis. Gpr183 inactivation reduced severity of colitis in group 3 innate lymphoid cells-dependent colitis and in IL-10 colitis but not in dextran sodium sulphate colitis. Irrespectively, Gpr183 knockout strongly reduced accumulation of intestinal lymphoid tissue in health and all colitis models. In conclusion, genetic, translational and experimental studies implicate GPR183 in IBD pathogenesis and GPR183-dependent cell migration might be a therapeutic drug target for IBD. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Epithelial endoplasmic reticulum stress orchestrates a protective IgA response.

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.