bluuebunny/crossref_metadata_2025 huggingface dataset:
13 ASTROVIRUS ALTERS THE GUT MUCUS BARRIER AND REDUCES COLONIZATION TO ENTEROPATHOGENIC E. COLI
Authors: Cortez Valerie , Sharp Bridgett , Livingston Brandi , Rowe Hannah , Alsallaq Ramzi , Rosch Jason , Margolis Elisa , Schultz-Cherry Stacey
Published: January 2020

Goblet cells, specialized epithelial cells that produce mucus, are essential for gut health. Dysfunctional goblet cell secretion can weaken the mucus barrier, bringing commensal microbes and other lumenal contents in contact with the epithelial barrier, triggering inflammation. We recently discovered that murine astroviruses infect goblet cells in the small intestine, making it the first enteric virus in which this tropism has been recognized in vivo. To first determine whether astrovirus infection alters mucus production in goblet cells, we used periodic acid-Schiff staining of small intestinal tissues and found a thicker mucus layer in infected compared to mock-infected animals (1.85 to 2.51-fold, p<0.001). Because changes to the mucus barrier can alter the microbial environment in the gut, we used 16S metagenomic to characterize the microbiome after infection. We found that the relative frequency of well-characterized mucus-degrading bacteria significantly increased after infection (p<0.001). Using phylogenetic edge principal components analysis, we also identified distinct microbiome shifts between 0 and 14 days post-infection, corresponding to peak infection. Finally, to determine the extent to which these changes in the mucus barrier could have a functional consequence to host disease susceptibility, we developed a neonatal model for astrovirus and tested whether animals inoculated with enteropathogenic E. coli (EPEC), an adherent bacterial pathogen, would be protected from colonization. In comparison to animals inoculated with EPEC alone, co-infected animals had significantly reduced EPEC colonization (p<0.01). Together, these studies reveal a new avenue of enteric virus regulation of gut homeostasis and immunity via goblet cells and highlight astroviruses as a novel model to study the mucus barrier. Future studies are needed to determine whether astrovirus-induced increases in the mucus barrier protect from other gastrointestinal diseases and how these data translate to human astroviruses, which predominately infect children <1-year-old and coincides with the development of gut immunity.
P142 TARGETED COLON DELIVERY OF NIPEP-IM-0127 PEPTIDE FOR INFLAMMATORY BOWEL DISEASE (IBD) TREATMENT
Authors: Kim Deogil , Lee Dong Woo , Jo Beom Soo , Park Yoon Shin , Lee Jue Yeon , Park Yoon Jeong , Chung Chong Pyung
Published: January 2020

Under Inflammatory bowel disease (IBD), autoantibody-type VII collagen complex can induce autoimmune reaction and continue with the inflammation. Here, we introduced synthetic 19 amino acid sequenced peptide termed as NIPEP-IM-0127 that inhibits autoantibody-type VII collagen complex formation. The NIPEP-IM-0127 was further formulated for oral administration. Primary function of NIPEP-IM-0127 selectively localizes to wound gut barrier and masks exposed type VII collagen, which is the starting of autoimmune reaction. Disrupted type VII collagen by the disease was bound to the applied peptide, which interfere autoimmune complex formation by competitive binding inhibition between antibody and peptide. NIPEP-IM-0127 thus recovered inflammatory cytokine level by the inhibition of immune complex creation. The orally applied NIPEP-IM-0127 peptide was primarily detected at the surface of colon tissue after 9 hours of administration, while no distributions were shown in other organs. Most importantly, significant mucosal regeneration and healing has been achieved by NIPEP-IM-0127. The following GLP toxicity studies, including safety pharmacology, genotoxicity, single and repeated dose toxicity, demonstrated that NIPEP-IM-0127 showed no significant toxic effect in in mouse and monkey. Taken together, the NIPEP-IM-0127 is suggested to be a novel therapeutic candidate for IBD treatment by the dual effects combining immune modulation and intestine barrier healing.
P078 DONOR SELECTION INFLUENCES THERAPEUTIC EFFECTS OF FECAL MICROBIOTA TRANSPLANTATION FOR ULCERATIVE COLITIS
Authors: Haga Keiichi , Ishikawa Dai , Okahara Koki , Nomura Kei , Ito Shoko , Takahashi Masahito , Shibuya Tomoyoshi , Nagahara Akihito
Published: January 2020

Background

We have recently reported the efficacy of combination of triple-antibiotic therapy and fecal microbiota transplantation (A-FMT) for patients with ulcerative colitis (UC). It has been reported that FMT with frozen donor faeces (frozen-FMT) is as effective as fresh-FMT for Clostridium difficile infection. However, it is still unclear which donor and condition is suitable for FMT on UC. The aim of this study was to evaluate the effectiveness of frozen-FMT compared to fresh-FMT, and verify effective conditions. Moreover, we explore the concept of best donor for A-FMT success.

Methods

This prospective and randomized controlled study was conducted from July 2017 to September 2019 at Juntendo University Hospital. Eligible patients were at least 20 years of age, with a diagnosis of active UC which were required a Lichtiger’s clinical activity index (CAI) of 5 or more, or with an endoscopic Mayo score of 1 or more. Patients were randomly allocated fresh or frozen faecesfrom 2 healthy donors. Triple-antibiotic therapy (Amoxicillin, Fosfomycin, Metronidazole; AFM) was administered to patients with UC for 2 weeks, and up to 2 days before FMT. Clinical outcomes were assessed at8 weeks and 1 year after treatment. Clinical response was defined as a decrease of CAI of 3 points or more, and remission was defined as 3 points or less. Maintenance of efficacy was defined as no exacerbation of CAI and no intensification of treatments.

Results

29 patients completed protocol (fresh-FMT; n = 15, frozen-FMT; n = 14). At 8 weeks after treatment, clinical response and remission were observed in fresh-FMT (46.7%, 33.3%), and in frozen-AFM (64.3%, 42.9%) respectively.There were no significant differencesin therapeutic effectsbetween frozen-FMT and fresh-FMT.On the other hand, in cases which age difference between donor and patient was more than 16 years, maintenance rate was significantly lower than 0–15 age difference (0–15 vs ≧16, n = 14, 15 p<0.05). Interestingly,in cases that age difference between patient and donor was 0–15 years, high therapeutic effect was observed in patients treated withfresh- FMT.

Conclusion

This study showed that A-FMT with frozen faeces is as effective as cases treated with fresh faeces. In addition, findings from this study indicate that donor selection influences treatment effects, and age difference between patient and donor might be an important factor for A-FMT success.
P075 SER-287, AN INVESTIGATIONAL MICROBIOME THERAPEUTIC, INDUCES WIDESPREAD METABOLOMIC AND HOST TRANSCRIPTIONAL CHANGES RELATED TO CLINICAL REMISSION IN PATIENTS WITH ACTIVE MILD-TO-MODERATE ULCERATIVE COLITIS
Authors: Diao Liyang , O’Brien Edward , Ford Christopher , Wortman Jennifer , Aunins John , Henn Matthew
Published: January 2020

Background

Firmicute bacteria and the metabolites they produce are perturbed in ulcerative colitis (UC) patients. SER-287, an oral formulation of live Firmicute spores, was found to be safe and effective in achieving clinical remission in a Phase 1b clinical trial in mild-to-moderate UC. We assessed changes in the stool metabolome and host transcriptome among remitters and non-remitters as a measure of SER-287 pharmacodynamics.

Methods

58 UC subjects (modified Mayo score 4–10) were randomly assigned to one of four 8-week induction treatment arms preceded by a 6-day antibiotic preconditioning phase as follows: a) placebo/placebo b) placebo/SER-287 weekly c) vancomycin/SER-287 weekly or d) vancomycin/SER-287 daily. Clinical remission was defined as a Total Modified Mayo Score ≤2 plus an endoscopic subscore ≤1. Stool samples were evaluated for microbiome composition (whole metagenomic sequencing), targeted and global metabolomics (liquid chromatography-mass spectrometry) and transcriptomics (RNA-Seq with mucosal biopsy) at baseline and at week 8.

Results

Vancomycin/SER-287 daily was associated with higher rates of clinical remission compared to placebo/SER-287 weekly, vancomycin/SER-287 weekly or placebo/placebo (40%, 13.3% 17.6% and 0%, respectively; p=0.024 for the comparison of daily SER-287 versus placebo/placebo). Significant changes in microbial-associated metabolites (bile acids, indole, taurine, and arachidonate) were associated with clinical outcome across all arms (p<0.05, Mann-Whitney; Figure A). Similar associations with treatment were also observed (p<0.05, Mann-Whitney). Host transcriptomic changes associated with clinical outcome across arms included decreased expression of genes associated with signaling of TNF, NF-kappaB and IL-17, as well as increased expression of genes associated with the metabolism of the short chain fatty acid propanoate (adjusted p-value<0.05, gene set enrichment analysis, GSEA; Figure B). Similar associations with treatment were also observed (adjusted p-value<0.05, GSEA).

Conclusions

In this Phase 1b study of SER-287 the highest rates of remission were associated with daily dosing of SER-287, preceded by vancomycin preconditioning. Across treatment arms, clinical remission was associated with a wide range of metabolomic and transcriptomic changes relevant to UC pathogenesis. Changes in metabolomics and transcriptomics are associated with immune cell recruitment and activation, epithelial integrity and mucosal barrier function, giving insights into the mechanism of action of this microbiome therapeutic.
P165 INFLUENCE OF THE GUT MICROBIOTA ON COLONIC HISTONE MODIFICATIONS THROUGH BUTYRATE METABOLISM UNDER HEALTHY AND INFLAMMATORY CONDITIONS
Authors: Lund Peder , Smith Sarah , Simithy Johayra , Chau Lillian , Friedman Elliot , Saiman Yedidya , Gates Leah , Leboeuf Marylene , Trefely Sophie , Lopes Mariana , Yuan Zuo-Fei , Janssen Kevin , Kim Min-Soo , Petucci Christopher , Snyder Nathaniel , Bewtra Meena , Allis C David , Wu Gary , Garcia Benjamin
Published: January 2020

Inflammatory bowel disease (IBD) is often associated with a disruption in the composition and activity of the gut microbiota, referred to as dysbiosis. Since the microbiota has the potential to interact with host epithelial cells through small molecules generated from microbial metabolism, knowledge of how inflammation alters the microbial metabolome and how epithelial cells react is important for a better understanding of how IBD develops and persists. Butyrate, a short chain fatty acid produced through fermentation of dietary polysaccharides, has long been known to inhibit histone deacetylases (HDACs), which represent one of the many types of enzymes responsible for the epigenetic control of gene expression through the post-translational modification of histone proteins. We and others have observed that colonic epithelial cells from germ-free mice have reduced levels of acetylation on histone H4, which appears to be distributed throughout the genome based on sequencing analysis. The decreased levels of H4 acetylation may stem from a lack of butyrate, and therefore uninhibited HDAC activity, in germ-free mice. However, since colonic epithelial cells utilize short chain fatty acids as an energy source, an alternative explanation is that the germ-free condition results in less oxidation of butyrate to acetyl-CoA, which is the donor substrate for histone acetylation reactions. Isotope tracing experiments, in which cultured cells were incubated with labeled butyrate, demonstrated that the acetyl groups of histones contained carbon derived from butyrate. We have also performed isotope tracing experiments in mice using labeled inulin, a plant polysaccharide that presumably undergoes fermentation into short chain fatty acids. In this more physiologically relevant model, we detected isotope incorporation into the acetylated histones of colonic epithelial cells at rates of 5–20%, which appears dependent on the microbiota since labeling is sensitive to antibiotic treatment. To identify the metabolic pathways that link inulin to histone acetylation, we are investigating which metabolites become isotopically labeled using untargeted metabolomics. We will apply the same approach to the DSS-induced model of colitis to investigate how inflammation modulates the gut metabolome as well as the metabolic connections between the microbiota and the host. Our studies may uncover metabolic pathways that become dysregulated during inflammation, which may contribute to the pathogenesis of diseases such as IBD.
P012 HOSPITAL RE-ADMISSION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE – WHAT ARE THE RISK FACTORS?
Authors: Patel Rajan , Fromson Renate , Routledge Emma , Johnson Emma , Jameie-Oskooei Sina , Blad William , Moledina Saadiq , Wong Voishim
Published: January 2020

Introduction

Early re-admission after hospitalisation for an inflammatory bowel disease (IBD) flare is a negative quality indicator and causes unnecessary healthcare expense. Scoring systems to predict IBD readmissions have been shown to be ineffective. We aimed to describe the IBD re-admission rate at our hospital and investigate the risk factors.

Methods

Retrospective study of patients admitted to a London-based district general hospital under the gastroenterology team with a flare of inflammatory bowel disease between 2015 and 2018. Characteristic including but not limited to demographics, disease type, length of stay during index admission, biochemistry and biologic use were recorded. Hospital software (Sunquest Integrated Clinical Environment, Medway) was used to identify patients re-admitted at 30 and 90 days after discharge. Multivariate logistic regression was performed.

Results

138 patients were admitted with an IBD flare during the study period (74 (53.6%) Crohn’s disease (CD), 56 (40.6%) ulcerative colitis (UC), 8 (5.8%) IBD-U). Median age 33.5 (IQR 26 – 52), 71 (51.4%) female. Median length of stay was 4.5 days (IQR 1.8 – 8). 36 (26%) patients were taking a biologic.

Re-admissions occurred within 30 days in 19 patients (13.7%) and within 90 days in 30 patients (21.7%).

Multivariate logistic regression showed that a raised CRP on discharge was associated with re-admission. For every increased unit of CRP by one there was an increased risk of readmission by 1.1 times (p=0.05). Patients aged 22–39 were significantly less likely to be readmitted (OR: 0.38, p=0.015). Male patients were significantly more likely to be readmitted (OR: 2.52, p=0.05).

Conclusion

The 30 day and 90 day re-admission rate for our IBD population is just over 10% and 20%, respectively. CRP at discharge is significantly associated with both 30 and 90 day re-admission. After adjusting for confounders; CRP, age older than 40 and male gender were associated with re-admission to hospital. We advise caution in discharging IBD patients with raised inflammatory markers. Close follow up within a few days of discharge would be appropriate in this high risk sub-group.
P003 INFLAMMATORY BOWEL DISEASE PATIENTS’ PERSPECTIVES OF CLINICAL TRIALS
Authors: Rubin David , Peyrin-Biroulet Laurent , Reinisch Walter , Tole Swati , Sullivan Laura , Park K T , Regueiro Miguel
Published: January 2020

Background

Despite recent progress in treatment for inflammatory bowel diseases (IBD), there is a need for therapies with long-term efficacy and improved safety. Clinical trials in IBD face challenges with patient recruitment because of study designs, competitive or overlapping trials, and a limited number of eligible patients. We sought to better understand patients’ motivations, awareness of, and experience with IBD clinical trials.

Methods

We conducted an international survey of adult patients with IBD consisting of 2 components. The quantitative component, a 15-minute online survey, was completed by all patients. A qualitative component, a 30-minute telephone interview, was completed by a subset of patients from the United States (US). All percentages indicate results from the online survey.

Results

226 patients (mean age, 41.9 y) completed the online survey. Survey respondents included patients with ulcerative colitis (52%) and Crohn’s disease (48%) from the US (n=100, 21 of whom underwent a phone interview), Brazil (n=26), Canada (n=25), France (n=25), Germany (n=25), and Spain (n=25). Ninety-six percent of respondents reported at least a basic understanding of clinical trials, and 34 (15%) were current or past clinical trial participants.

Patients reported learning about trials through 1 or more sources (could select as many as applied): health care providers (42%), pharmaceutical manufacturer websites (31%), social media (30%), online support groups (28%), and foundations (18%-23%). In the survey, patients rated conversations with health care providers most helpful, but patients who were interviewed revealed that most physicians often do not initiate conversations about clinical trials, and patients typically do not ask.

Primary motivators for trial participation (rated from “does not encourage me at all” to “encourages me very much”) included altruistic goals of advancing medicine (67%), potentially mitigating risks of uncontrolled IBD such as colon cancer (59%), and access to treatment options that could improve quality of life (59%) or would otherwise be unaffordable (52%). Major barriers to participation (rated from “does not discourage me at all” to “discourages me very much”) included invasive screening and monitoring (35%), concern over receiving placebo (35%), or suboptimal treatment (33%), and concerns about posttrial access to study medication (27%). The majority (68%) reported that being in a clinical trial means being a “guinea pig” for an experimental treatment.

Conclusion

Opportunities to improve patients’ clinical trial experience in IBD include better communication with health care providers and improved patient education about clinical trial design and ethics. Ultimately, a better understanding of the patient perspective will be important for more informed patients and potentially higher recruitment and enrollment.
P021 READABILITY AND QUALITY OF ONLINE RESOURCES ON NUTRITION AS IT RELATES TO IBD
Authors: Khan Ali , Baumgartner Scott , Rao Vinay , Borum Marie
Published: January 2020

Background

Nutrition plays an essential role in inflammatory bowel disease (IBD). Optimizing nutritional status can help prevent malnutrition, osteoporosis, and may be an effective primary therapy for many patients. Patients with IBD are increasingly turning to the Internet for information. This study evaluated the readability and quality of online resources discussing nutrition for IBD.

Methods

Google search engine was used to query “nutrition and inflammatory bowel disease” to access the first 100 websites. Websites that were non-accessible, duplicates, videos without transcripts or evaluated animal models were excluded. Websites were categorized as informational or academic/professional. Readability was determined using the validated Flesch-Kincaid Grade Level Calculation. The quality of the information was determined using the validated DISCERN score. Websites were reviewed for inclusion of a discussion of shared decision making between patients and physicians. Statistical analysis was performed using a two-tailed Fisher’s Exact Test and a two-sample T-test with a significance value set at p <0.05.

Results

89 of 100 websites met the inclusion criteria. 50 (56.2%) websites were informational and 39 (43.8%) were academic. The average Flesch-Kincaid Grade level was 13.2, with no significant difference between informational and academic websites (13.1 and 13.4 grade levels, respectively; p=0.760). The average DISCERN score was “good” without significant difference between informational and academic websites (45.75 and 45.74, respectively; p=0.994).

Academic websites had significantly more “excellent” DISCERN scores than informational websites (76% and 24%, respectively; p = 0.0054). There were no significant difference in “good” or “poor” DISCERN scores between academic and informational websites (p=0.527 and p=0.095, respectively) (Figure 1). Shared decision making between patient and physician was discussed among 33.7% of all sources, significantly more often among informational than academic sources (60% and 0%, respectively; p=0.0001).

Discussion

Patients often self-manage their symptoms using easily accessible online resources. While our study demonstrated near identical DISCERN scores between academic and informational websites, the average Flesch-Kincaid Grade Level exceeded the NIH recommended 6th grade reading level. Informational websites, however, were more likely to encourage shared decision making between physician and patient. It may be important for academic online resources to specifically emphasize communication that encourages shared decision making between IBD patients and physicians. As the use of online resources continues to increase, further efforts should focus on developing informational resources written at a grade level which is applicable to the general public.
P022 SHIFTING COST-DRIVERS OF HEALTH CARE EXPENDITURES IN INFLAMMATORY BOWEL DISEASE
Authors: Click Benjamin , Lopez Rocio , Arrigain Susana , Schold Jesse , Regueiro Miguel , Rizk Maged
Published: January 2020

Background

Inflammatory bowel diseases (IBD) are costly, chronic illnesses. Key cost-drivers of IBD healthcare expenditures include pharmaceuticals and unplanned care, but evolving treatment approaches have shifted these factors. We aimed to assess changes in cost of care, determine shifts in IBD cost-drivers, and examine differences by socioeconomic and insurance status over time.

Methods

The Medical Expenditure Panel Survey (MEPS), a nationally representative database that collects data on healthcare utilization and expenditures from a nationally representative sample since 1998 was utilized. Adult subjects with IBD were identified by ICD-9 codes. In order to determine changes in per-patient costs or cost-drivers unique to IBD, a control population of rheumatoid arthritis (RA) subjects was generated and matched in 1:1 case to control. Total annual healthcare expenditures were obtained and categorized as outpatient, inpatient, emergency, or pharmacy related. Temporal cohorts from 1998 to 2015 were created to assess change over time. Per-patient expenditures were compared by disease state and temporal cohort using weighted generalized linear models.

Results

Total of 641 IBD subjects were identified and matched to 641 RA individuals. From 1998 to 2015, median total annual healthcare expenditures nearly doubled (adjusted estimate 2.20; 95% CI 1.6–3.0) and were 36% higher in IBD compared to RA. In IBD, pharmacy expenses increased 7% to become the largest cost driver (44% total expenditures). Concurrently, inpatient spending in IBD decreased by 40%. There were no significant differences in the rate of change of cost-drivers in IBD compared to RA.

Conclusions

Per-patient healthcare costs for chronic inflammatory conditions have nearly doubled over the last 20 years. Increases in pharmaceutical spending in IBD may be accompanied by reduction in inpatient care. Additional studies are need to explore patient, disease, system, and industry level cost mitigation strategies.
P030 WHAT ABOUT DEPRESSION? INCREASED DISCUSSION BY GASTROENTEROLOGISTS MAY BE NEEDED.
Authors: Negreira Katherine , Gibilisco Jessica , Rao Vinay , Dave Jenny , Borum Marie
Published: January 2020

Introduction

Studies have reported an increased prevalence of depression in patients with inflammatory bowel disease (IBD). Depression rates have been reported as high as 21.2% in IBD patients compared to 13.4% in healthy controls (1). Addressing depression and improvement in psychological health has been associated with decrease in IBD-related morbidity, reduction in health-care utilization and improvement in quality of life (2). This study evaluated the rate at which gastroenterology providers discussed or documented depression and /or anxiety in IBD patients.

Methods

A 5-year chart review of all IBD patients seen in a university GI clinic was conducted. A confidential database using Microsoft Excel included patient age, gender, race, disease type, depression or anxiety (in GI notes or remainder of electronic medical record) was created. Statistical analysis using Fisher’s Exact Test was performed with significance set at p<0.05. The study was approved by the institutional IRB.

Results

381 records of IBD patients were reviewed. There were 209 females and 172 males (mean age 44 years; range 20–82). 96 had Crohn’s disease, 279 had Ulcerative Colitis, and 6 had indeterminate colitis. Self-reported race/ethnicity included 195 White, 97 African American (AA), 11 Asian, 1 Hawaiian, 34 other and 43 did not document an ethnicity. 66 (17.32%) patients had depression and/or anxiety, 298 (78.22%) did not have depression and/or anxiety and 17 (4.46%) patients did not have documentation of mental health discussion during appointments. In patients with depression and/or anxiety, 46.97% had it documented by a gastroenterology provider. There was no statistically significant difference of depression and / or anxiety based upon gender (p=1.000), ethnicity (White vs AA p=1.000; White vs Asian p=0.2129; Asian vs AA p=0.208) or disease type (p=0.091).

Conclusion

Depression is reported to occur more frequently in patients with IBD compared to the general population. However, this study revealed that university gastroenterology providers did not consistently document the presence of or a discussion about depression and/or anxiety. While this study is limited based upon size and single institution design, it suggests that increased attention to psychological health is needed in IBD patients to optimize health and clinical outcomes.

References
P038 ASSESSING THE ASSOCIATION BETWEEN ACTIVE IBD AND DEPRESSION/ANXIETY USING ADAPTIVE TESTING TECHNOLOGY
Authors: Karpin Jordan , Rodriguez Tina , Traboulsi Cindy , Rai Victoria , Rubin David
Published: January 2020

Introduction

Both depression and anxiety are comorbidities of inflammatory bowel disease (IBD). Though previous studies have proposed a relationship between depression, anxiety and IBD, causality and directionality are unknown. We used a novel computerized adaptive testing technology to screen IBD patients for depression and anxiety and compared the screening results to disease activity.

Methods

Consecutive patients at our tertiary IBD clinic were asked to complete the validated CAT-MH™ survey (Adaptive Testing Technologies, Chicago, IL); we then reviewed disease and patient characteristics. Clinical remission status was determined by the senior author, blinded to the CAT-MH results. Simple statistics were performed.

Results

100 patients (57 women, 81 Caucasian, 63 Crohn’s disease) participated in the study, 58 of whom had no previous history of psychiatric disorders. We identified 42 patients with depression (40 mild, 2 moderate). Of those with mild depression, 25/40 (62.5%) were previously undiagnosed; of those with moderate depression, 1/2 (50%) were previously undiagnosed. 27 subjects tested positive for anxiety (21 mild, 6 moderate). 11/21 (52.38%) of mild anxiety cases and 3/6 (50%) of moderate anxiety cases were previously undiagnosed. 1 of the 100 patients was positive for suicidal ideation in the past month. Sex, race, type of IBD, smoking status, IBD-related surgical history, and number of discontinued medications were not statistically significant factors in depression or anxiety by proportion of patients or severity score. Clinically active disease status was found to be positively associated with depression severity score (p=0.002, 95% CI 4.3–19.5) and anxiety severity score (p=0.019, 95% CI 1.4–16.0) (Table 1). Of the 30 patients who had clinically active disease, 18 (60%) were positive for depression and 12 (40%) were positive for anxiety. Of the 70 patients in clinical remission, 24 (34%) were positive for depression and 15 (21%) were positive for anxiety (Figure 1). Patients with active disease have a significantly greater relative risk for having depression (RR 1.8, 95% CI 1.1–2.7) and an almost significantly greater relative risk of having anxiety (RR 1.9, 95% CI 0.99–3.5).

Conclusions

Using a novel screening tool for depression and anxiety in IBD patients, we identified a positive correlation between clinically active disease status and the presence of depression and anxiety. Our results show that regardless of past surgical and therapeutic IBD history, patients in clinical remission are less likely to have these mental health conditions than those with active disease. Gastroenterologists should consider patients with clinically active disease at higher risk for psychological co-morbidities, and include such screening in their routine care. Further research will explore directionality between disease activity and psychological outcomes.
P040 DEPRESSION SCREENING IN A PEDIATRIC IBD CENTER
Authors: Talmadge Clair , Lewis Glen , Gold Benjamin , Gomez Samantha , Reed Bonney , Dykes Dana
Published: January 2020

Introduction

Depression is a common pediatric problem affecting approximately 25% of U.S. adolescents and up to 35% of patients with Inflammatory Bowel Disease (IBD). Suicide is associated with mood disorders and is a leading cause of death for youth ages 10–25. Despite known risks of depression, up to 75% of depressed youth go unrecognized. Recently published guidelines recommend annual screening for youth 12 and older diagnosed with IBD (Mackner et al., 2019). We sought to implement these guidelines in a large outpatient pediatric gastroenterology practice.

Methods

We used quality improvement (QI) methodology and Plan-Do-Study-Act (PDSA) cycles to design and implement a pilot screening process for depression. We aimed to prospectively screen at least 80% of patients diagnosed with IBD who were at least 13 years old from March 3, 2019 to October 11, 2019. Screening was done using the PHQ-9, a brief and validated screening tool widely used in the medical setting. Initial steps of the PDSA cycle focused on training in tool administration, as well as scoring of the PHQ-9 simulated interviews, management of suicidal ideation, and office staff training. Next steps included eligible patient identification and distribution of screeners. As screening processes were improved, we focused on streamlining process of screener distribution and scoring during the visit, as well as disposition of patients based on screening results. The ImproveCareNow Depression Screening Toolkit was used as a resource for implementation.

Results

During the study period, screening of all eligible patients with IBD was implemented across three pediatric gastroenterologists within the larger practice of 15 physicians. Weekly screenings improved from 0% per week to over 80% per week at the culmination of this 32-week pilot. Across the pilot, a total of 141 patients were screened, and of these, 32% had actionable scores indicating mild, moderate, or severe depressive symptoms, with 7 of these endorsing suicidal thoughts.

Conclusions

Development and implementation of a depression screening protocol in an IBD outpatient clinic is feasible and sustainable. A large number of patients were affected by depression and many were previously unrecognized. Next steps include expansion to a larger number of providers and automation of screening tools.
P044 HIGH STRESS REACTIVITY AND SYMPTOM FLARES IN ULCERATIVE COLITIS PATIENTS
Authors: Sauk Jenny , Ryu Hyo Jin , Labus Jennifer , Liu Cathy , Stains Jean , Dvorsky Miriam , Lagishetty Venu , Naliboff Bruce , Jacobs Jonathan , Mayer Emeran
Published: January 2020

Psychological stress has long been implicated as a cause of symptom relapse in IBD. Whether psychological stress is associated with alterations in the brain-gut-microbiome (BGM) axis and intestinal inflammation requires further investigation.

Aims: We hypothesize that stress-induced changes in BGM interactions play a role in the development of symptomatic flares in patients with ulcerative colitis (UC). We aimed to test this hypothesis in a prospective study of 100 UC patients in clinical remission to identify gut microbiome, brain network connectivity, and stress-associated biomarkers of UC patients at baseline that can predict the risk of future symptomatic flares.

Methods: Ninety-four subjects in clinical remission (Mayo score ≤ 1 AND Simple Colitis Clinical Activity Index (SCCAI) score < 5) underwent comprehensive phenotyping, including clinical and behavioral assessments, brain imaging, and autonomic testing for heart rate variability (HRV) and electrodermal activity (EDA) before, during, and after a 3 minute arithmetic stress test at baseline, with longitudinal follow-up every 3 months and at time of flare. Clinical flares (SCCAI >5) and subjective flares (“Do you think you are in a flare?”) were assessed. Fecal calprotectin has been collected at baseline and every 3 months and at time of flare.

Results: To date, there have been 18 clinical flares (19%) and 8 symptomatic flares (8.5%) in 94 patients over a mean follow-up time of 8.1 months. Baseline measurements have identified two clusters of patients (low stress reactivity in cluster 1, high stress reactivity in cluster 2), based on trait anxiety (International Personality Item Pool [IPIP]-Neuroticism), and perceived stress (Cohen’s Perceived Stress Scale) measured at baseline. These groups differed in the frequency of clinical flares (9.3% vs. 27.4%, p=0.03) and subjective flares (3.6% vs. 11.8%, p=0.28), respectively. There were no cluster differences in heart rate variability, but there was overall greater EDA noted in the high stress reactivity group (EDA: 3.99 (SE: 0.27) vs. 5.02 (SE: 0.25); p=0.007).

Conclusions: Based on our current results, the frequency of symptomatic flares in UC patients in clinical remission is predicted by measures of perceived stress and trait anxiety and by heightened sympathetic arousal as measured by electrodermal activity. We expect that gut microbiome profiles and brain imaging networks will further delineate the stress-responsive subset of UC patients with heightened flare risk and that fecal calprotectin levels collected will confirm whether the stress-responsive subset of UC patients experiences biochemical flare with increase in symptoms.
P093 IDENTIFICATION OF PATIENTS AT RISK OF SUBTHERAPEUTIC DRUG EXPOSURE PRIOR TO INITIATION OF CERTOLIZUMAB PEGOL THERAPY FOR THE TREATMENT OF CROHN’S DISEASE
Authors: Lefevre Pavine , Guizzetti Leonardo , Feagan Brian , Pop Anca , Yassine Mohamed , Sandborn William , Casteele Niels Vande
Published: January 2020

Background

Certolizumab pegol (CZP) is effective treatment for moderately-to-severely active Crohn’s disease (CD)1, 2 at approved subcutaneous doses of 400 mg on weeks 0, 2 and 4 (induction) and every 4 weeks thereafter (maintenance). Prior research has demonstrated a relationship between CZP drug exposure and outcomes, with higher plasma CZP concentrations during induction and maintenance therapy associated with more favorable clinical, endoscopic and biologic (C-reactive protein [CRP], fecal calprotectin [FC]) disease outcomes.3 Increased drug clearance is the driver of subtherapeutic CZP concentrations, although the identification of patients at risk for accelerated clearance prior to therapy initiation has not previously been possible.

Methods

A population pharmacokinetic model4 was used to estimate baseline CZP clearance (i.e., at the time of therapy initiation) using baseline clinical variables (i.e., gender, body weight, albumin and CRP concentration) available from patients with CD previously included in nine randomized, controlled, phase 2 and 3 trials (N=2157). Baseline CZP clearance was compared between patients who achieved observed Week 6 CZP plasma concentrations previously associated with meaningful clinical (>36 μg/mL for Crohn’s Disease Activity Index [CDAI] ≤ 150), biologic (>44 μg/mL for FC ≤ 250 μg/g) and composite clinical and biologic (>48 μg/mL for CDAI ≤ 150 and FC ≤ 250 μg/g) outcomes at Week 6. Receiver operating characteristic curve analysis identified baseline CZP clearance thresholds associated with effective CZP concentrations at Week 6.

Results

Baseline CZP clearance was significantly higher in patients not achieving effective Week 6 CZP plasma concentration thresholds of 36 μg/mL, 44 μg/mL and 48 μg/mL compared to patients who achieved these thresholds (Figure 1; p<0.0001 for all comparisons). Baseline CZP CL of ≥ 0.5 L/day was associated with subtherapeutic observed Week 6 CZP plasma concentrations. The sensitivity, specificity, likelihood ratios and area under the concentration curves for the association between baseline CZP clearance and observed Week 6 CZP concentration thresholds are shown in Table 1.

Conclusion

Patients with CD who have accelerated baseline CZP clearance are at risk of subtherapeutic CZP concentrations. Clearance can be calculated using baseline clinical variables and would allow for identification of patients for whom therapeutic CZP concentrations may be achieved with current approved dosing. Implementing therapeutic drug monitoring may increase the likelihood of achieving therapeutic drug exposure during induction as well as treatment success.

References
P088 REAL-WORLD EXPERIENCE WITH TOFACITINIB FOR THE MANAGEMENT OF CROHN’S COLITIS
Authors: Kumar Anand , Gordon Benjamin , Yang Stevie , Longman Randy , Scherl Ellen , Battat Robert , Lukin Dana
Published: January 2020

Background

Treatment options in Crohn’s disease (CD) are limited. Tofacitinib, a Janus Kinase 1–3 inhibitor, is not currently approved for use in CD, however, its effect on biochemical markers suggests that tofacitinib does impact disease activity in CD.

Aim

To evaluate the real-world experience with off-label tofacitinib in the treatment of Crohn’s colitis at a large inflammatory bowel disease center.

Methods

We evaluated 5 adult patients with moderate-to-severely active Crohn’s colitis who were started on tofacitinib therapy after failing ≥2 biologic agents. Pre- and post-tofacitinib treatment characteristics including clinical, endoscopic and biochemical disease activity, presence of extra-intestinal manifestations, and potential adverse effects were recorded (figure 1). Endpoints evaluated were clinical remission [defined as Harvey Bradshaw index (HBI) <4) and response (>50% reduction in HBI); endoscopic remission (simple endoscopic score (SES)-CD<3) and response (>50% reduction in SES-CD); and biochemical remission [fecal calprotectin (FC)<50 μg/g)].

Results

Post-tofacitinib, patients were followed for a median period of 18 weeks (range 8–34 weeks). Four of the 5 (80%) patients achieved clinical remission, 4/5 (80%) achieved clinical response. All patients that underwent a follow-up endoscopy (n=3) achieved endoscopic response and 2/3 (67%) achieved endoscopic remission (figure 2). Three of the 4 patients with a follow-up FC (75%) achieved biochemical remission. Of the 4 patients on baseline corticosteroids, 3 (75%) were corticosteroid-free by week 18. Four of the 5 (80%) patients exhibited improvement in CD-related arthropathy. No significant treatment-emergent adverse events were observed.

Conclusions

In this case series, use of tofacitinib was safe and effective in the treatment of refractory Crohn’s colitis and CD-related arthropathy. Further investigation of tofacitinib in CD, particularly involving the colon, is warranted.
P169 DEFINITION OF REMISSION IN INFLAMMATORY BOWEL DISEASE: ASSESSMENT OF PATIENT AND PHYSICIAN PERSPECTIVES
Authors: Rubin David , Sninsky Charles , Siegmund Britta , Sans Miquel , Hart Ailsa , Bressler Brian , Bouhnik Yoram , Armuzzi Alessandro , Afzali Anita
Published: January 2020

Background

A primary goal in IBD management is achieving disease remission; however, patient (pt)-physician alignment on this goal is unclear. International online surveys were conducted to gain insights into pts’ and physicians’ perspectives on real-world management of IBD. Herein, we report survey findings pertaining to their understanding and perceptions of disease remission in IBD.

Methods

Surveys were completed online by pts and physicians in Canada, France, Germany, Italy, Spain, UK, and US. Using a mixed-recruitment method, pts were identified by physicians, pt advocacy groups, and panels, while physicians were identified by recruitment agencies and panels. Eligible pts were aged ≥18 y who were diagnosed with and received treatment for Crohn’s disease (CD) or ulcerative colitis (UC) and had not undergone surgery for UC. Eligible physicians were gastroenterologists who had treated pts with CD or UC (≥12 each) in the last month, were responsible for treatment decisions of their IBD pts, and for whom ≥30% of their IBD pts had moderate or severe disease per prespecified clinical criteria. A 1:1 CD:UC ratio was targeted for the pt survey. Alignment between pts and physicians on remission definitions and pt-physician communication about remission was assessed. Physicians’ estimates of remission rates in their moderate/severe IBD pts receiving biologic therapy and their satisfaction (1=very dissatisfied to 7=very satisfied) with remission rates with current IBD treatments also were reported.

Results

A total of 2398 IBD pts (1368 CD [40% male], 1030 UC [45% male]) and 654 physicians completed the surveys. Mean pt age was 42 y (CD) and 44 y (UC). Physicians had mean monthly caseloads of 42.9 (CD) and 43.3 (UC). The most common primary care settings were university/teaching hospitals (41%), private practices (31%), and regional/community hospitals (20%). Nearly one quarter of pts reported never having discussed remission with their physician; only 7% of physicians reported that they typically did not discuss remission with their pts. Pts most commonly defined remission as symptom resolution (45%), whereas most physicians defined remission through test results (64% CD, 70% UC), including colonoscopies (56% CD, 58% UC), biopsies (36%, 37%), and biochemical tests (8%, 6%). Most pts (62% CD, 64% UC) had never heard of the term “mucosal healing.” Despite low physician-reported remission rates (CD: 37%–54%; UC: 37%–55%), 25% and 36% of physicians reported high satisfaction (score ≥6) with CD and UC remission rates, respectively.

Conclusions

This international survey demonstrated differences in pts’ and physicians’ definitions of IBD remission and in their understanding of the role of histologic remission in IBD. The findings highlight the need for improved pt-physician communication and education regarding remission, which may improve adherence and outcomes.
Correlation without a cause: an epidemiological odyssey
Authors: Davey Smith George , Phillips Andrew N
Published: January 2020

Background

In the 1980s debate intensified over whether there was a protective effect of high-density lipoprotein cholesterol (HDL-C) or an adverse effect of triglycerides on coronary heart disease (CHD) risk. In a 1991 paper reprinted in the IJE we suggested that the high degree of correlation between the two, together with plausible levels of measurement error, made it unlikely that conventional epidemiological approaches could contribute to causal understanding. The consensus that HDL-C was protective, popularly reified in the notion of ‘good cholesterol’, strengthened over subsequent years. Reviewing the biostatistical and epidemiological literature from before and after 1991 we suggest that within the observational epidemiology pantheon only Mendelian randomization studies—that began to appear at the same time as the initial negative randomized controlled trials—made a meaningful contribution. It is sobering to realize that many issues that appear suitable targets for epidemiological investigation are simply refractory to conventional approaches. The discipline should surely revisit this and other high-profile cases of consequential epidemiological failure—such as that with respect to vitamin E supplementation and CHD risk—rather than pass them over in silence.
OccIDEAS: web-based assessment of occupational agent exposure
Authors: Fritschi Lin , Sadkowsky Troy , Glass Deborah C
Published: January 2020

Most epidemiological studies of disease aetiology do not consider potential risk factors at work. This may be because work is a complex exposure: people usually have a series of different jobs over their working lifetime; within each job there may be a range of different tasks; and there may be a variety of exposures in each job. Because of this complexity, many epidemiologists do not have the expertise or training to assess occupational exposures accurately. Our web-based application, OccIDEAS, manages the process of occupational agent assessment in epidemiological studies. The epidemiologist chooses the agents of interest for the study and OccIDEAS provides an online set of questionnaires that are tailored to those agents. The participant is asked specific questions about their job and evidence-based algorithms provide an assessment of exposure to each agent. OccIDEAS puts the world’s best occupational epidemiological expertise within reach of any researcher.
Energy-preserving methods for nonlinear Schrödinger equations
Authors: Besse Christophe , Descombes Stéphane , Dujardin Guillaume , Lacroix-Violet Ingrid
Published: January 2020

This paper is concerned with the numerical integration in time of nonlinear Schrödinger equations using different methods preserving the energy or a discrete analogue of it. The Crank–Nicolson method is a well-known method of order $2$ but is fully implicit and one may prefer a linearly implicit method like the relaxation method introduced in Besse (1998, Analyse numérique des systèmes de Davey-Stewartson. Ph.D. Thesis, Université Bordeaux) for the cubic nonlinear Schrödinger equation. This method is also an energy-preserving method and numerical simulations have shown that its order is $2$. In this paper we give a rigorous proof of the order of this relaxation method and propose a generalized version that allows one to deal with general power law nonlinearites. Numerical simulations for different physical models show the efficiency of these methods.
Rilpivirine plus cobicistat-boosted darunavir as a two-drug switch regimen in HIV-infected, virologically suppressed subjects on steady standard three-drug therapy: a randomized, controlled, non-inferiority trial (PROBE 2)
Authors: Maggiolo F , Gianotti N , Comi L , Di Filippo E , Fumagalli L , Nozza S , Galli L , Valenti D , Rizzi M , Castagna A
Published: January 2020

Background

We explored the combination of rilpivirine plus cobicistat-boosted darunavir [a two-drug regimen (2DR)] when switching from standard triple combined ART.

Methods

In this randomized, open-label, non-inferiority trial, participants had an HIV-RNA <50 copies/mL on a stable (>6 months) three-drug regimen. The primary endpoint was proportion with HIV-RNA <50 copies/mL at Week 24 (snapshot algorithm), with a –12% non-inferiority margin. ClinicalTrials.gov: NCT04064632.

Results

One hundred and sixty patients were allocated (1:1) to 2DR or to continue current ART (CAR). At Week 24, 72 (90.0%) of participants with 2DR and 75 (93.8%) with CAR maintained HIV-RNA <50 copies/mL [difference −3.75% (95% CI = −11.63 to 5.63)], confirming non-inferiority. Non-inferiority was confirmed considering an HIV-RNA >50 copies/mL (0% for 2DR; 3.7% for CAR; 95% CI = −0.4 to 7.9). Four patients reported adverse events not leading to treatment discontinuation (one patient in the 2DR group and three patients in the CAR group); eight subjects discontinued therapy in the 2DR group and three in the CAR group. With 2DR, lipid serum concentrations increased, but differences were statistically significant only for tenofovir disoproxil fumarate-containing CAR and in 2DR patients receiving a pre-switch regimen including tenofovir disoproxil fumarate. Median bone stiffness decreased in the CAR group from 86.1 g/cm2 (IQR = 74–98) to 83.2 g/cm2 (IQR = 74–97) and increased in the 2DR group from 84.9 g/cm2 (IQR = 74–103) to 85.5 g/cm2 (IQR = 74–101). The reduction within the CAR group was significant (P = 0.043).

Conclusions

Once-daily rilpivirine plus cobicistat-boosted darunavir is an effective 2DR that combines a high virological efficacy with a potential to avoid major NRTI toxicities.