bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prevalence and Burden of Non-AIDS Comorbidities Among Women Living With or at Risk for Human Immunodeficiency Virus Infection in the United States
Authors: Collins Lauren F , Sheth Anandi N , Mehta C Christina , Naggie Susanna , Golub Elizabeth T , Anastos Kathryn , French Audrey L , Kassaye Seble , Taylor Tonya , Fischl Margaret A , Adimora Adaora A , Kempf Mirjam-Colette , Palella Frank J , Tien Phyllis C , Ofotokun Ighovwerha
Published: February 2020

Background

The prevalence and burden of age-related non-AIDS comorbidities (NACMs) are poorly characterized among women living with HIV (WLWH).

Methods

Virologically suppressed WLWH and HIV-seronegative participants followed in the Women’s Interagency HIV Study (WIHS) through at least 2009 (when >80% of WLWH used antiretroviral therapy) were included, with outcomes measured through 31 March 2018. Covariates, NACM number, and prevalence were summarized at most recent WIHS visit. We used linear regression models to determine NACM burden by HIV serostatus and age.

Results

Among 3232 women (2309 WLWH, 923 HIV-seronegative) with median observation of 15.3 years, median age and body mass index (BMI) were 50 years and 30 kg/m2, respectively; 65% were black; 70% ever used cigarettes. WLWH had a higher mean NACM number than HIV-seronegative women (3.6 vs 3.0, P < .0001) and higher prevalence of psychiatric illness, dyslipidemia, non-AIDS cancer, kidney, liver, and bone disease (all P < .01). Prevalent hypertension, diabetes, and cardiovascular and lung disease did not differ by HIV serostatus. Estimated NACM burden was higher among WLWH versus HIV-seronegative women in those aged 40–49 (P < .0001) and ≥60 years (P = .0009) (HIV × age interaction, P = .0978). In adjusted analyses, NACM burden was associated with HIV, age, race, income, BMI, alcohol abstinence, cigarette, and crack/cocaine use; in WLWH, additional HIV-specific indices were not associated, aside from recent abacavir use.

Conclusions

Overall, NACM burden was high in the cohort, but higher in WLWH and in certain age groups. Non-HIV traditional risk factors were significantly associated with NACM burden in WLWH and should be prioritized in clinical guidelines for screening and intervention to mitigate comorbidity burden in this high-risk population.
Systematic analysis of the human tumor cell binding to human vs. murine E- and P-selectin under static vs. dynamic conditions
Authors: Starzonek Sarah , Maar Hanna , Labitzky Vera , Wicklein Daniel , Rossdam Charlotte , Buettner Falk F R , Wolters-Eisfeld Gerrit , Guengoer Cenap , Wagener Christoph , Schumacher Udo , Lange Tobias
Published: February 2020

Endothelial E- and P-selectins promote metastasis formation by interacting with sialyl-Lewis X and A (sLeX/sLeA) on circulating tumor cells. This interaction precedes extravasation and can take place under dynamic and static conditions. Metastasis formation is often studied in xenograft models. However, it is unclear whether species differences exist in the ligand specificity of human (h) vs. murine (m) selectins and whether different ligands are functional under dynamic vs. static conditions. We systematically compared the h vs. m E- and P-selectin (ESel/PSel) binding of a range of human tumor cells under dynamic vs. static conditions. The tumor cells were categorized by their sLeA/X status (sLeA+/sLeX+, sLeA−/sLeX+ and sLeA−/sLeX−). The general biological nature of the tumor–selectin interaction was analyzed by applying several tumor cell treatments (anti-sLeA/X blockade, neuraminidase, pronase and inhibition of O/N-glycosylation). We observed remarkable differences in the static vs. dynamic interaction of tumor cells with h vs. m ESel/PSel depending on their sLeA/X status. The tumor cell treatments mostly affected either static or dynamic as well as either h- or m-selectin interaction. mESel showed a higher diversity of potential ligands than hESel. Inhibition of O-GalNAc-glycosylation also affected glycosphingolipid synthesis. Summarized, different ligands on human tumor cells are functional under static vs. dynamic conditions and for the interaction with human vs. murine ESel/PSel. Non-canonical selectin ligands lacking the sLeA/X glycan epitopes exist on human tumor cells. These findings have important implications for the current development of glycomimetic, antimetastatic drugs and encourage the development of immunodeficient mice with humanized selectins.
Maternal pre-pregnancy overweight/obesity and the risk of attention-deficit/hyperactivity disorder in offspring: a systematic review, meta-analysis and quasi-experimental family-based study
Authors: Li Lin , Lagerberg Tyra , Chang Zheng , Cortese Samuele , Rosenqvist Mina A , Almqvist Catarina , D’Onofrio Brian M , Hegvik Tor-Arne , Hartman Catharina , Chen Qi , Larsson Henrik
Published: February 2020

Background

Previous studies are inconclusive concerning the association between maternal pre-pregnancy overweight/obesity and risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. We therefore conducted a systematic review and meta-analysis to clarify this association. To address the variation in confounding adjustment between studies, especially inadequate adjustment of unmeasured familial confounding in most studies, we further performed cousin and sibling comparisons in a nationwide population-based cohort in Sweden.

Methods

We searched PubMed, Embase and PsycINFO during 1975–2018. We used random-effects models to calculate pooled risk ratios (RRs) with 95% confidence interval. In the population-based study, Cox proportional hazard models were used to calculate the unadjusted hazard ratios (HRs) and HRs adjusted for all confounders identified in previous studies. Stratified Cox models were applied to data on full cousins and full siblings to further control for unmeasured familial confounding.

Results

Eight cohorts with a total of 784 804 mother–child pairs were included in the meta-analysis. Maternal overweight [RRoverweight = 1.31 (1.25–1.38), I2 = 6.80%] and obesity [RRobesity = 1.92 (1.84–2.00), I2 = 0.00%] were both associated with an increased risk of ADHD in offspring. In the population-based cohort of 971 501 individuals born between 1992 and 2004, unadjusted Cox models revealed similar associations [HRoverweight = 1.30 (1.28–1.34), HRobesity = 1.92 (1.87–1.98)]. These associations gradually attenuated towards the null when adjusted for measured confounders [HRoverweight = 1.21 (1.19–1.25), HRobesity = 1.60 (1.55–1.65)], unmeasured factors shared by cousins [HRoverweight = 1.10 (0.98–1.23), HRobesity = 1.44 (1.22–1.70)] and unmeasured factors shared by siblings [HRoverweight = 1.01 (0.92–1.11), HRobesity = 1.10 (0.94–1.27)].

Conclusion

Pre-pregnancy overweight/obesity is associated with an increased risk of ADHD in offspring. The observed association is largely due to unmeasured familial confounding.
Parametric analysis of a combined ejector-vapor compression refrigeration cycle
Authors: Ouelhazi I , Ezzaalouni Y , Kairouani L
Published: February 2020

From the last few years, the use of efficient ejector in refrigeration systems has been paid a lot of attention. In this article a description of a refrigeration system that combines a basic vapor compression refrigeration cycle with an ejector cooling cycle is presented. A one-dimensional mathematical model is developed using the flow governing thermodynamic equations based on a constant area ejector flow model. The model includes effects of friction at the constant-area mixing chamber. The current model is based on the NIST-REFPROP database for refrigerant property calculations. The model has basically been used to determine the effect of the ejector geometry and operating conditions on the performance of the whole refrigeration system. The results show that the proposed model predicts ejector performance, entrainment ratio and the coefficient of performance of the system and their sensitivity to evaporating and generating temperature of the cascade refrigeration cycle. The simulated performance has been then compared with the available experimental data from the literature for validation.
Association of Picornavirus Infections With Acute Otitis Media in a Prospective Birth Cohort Study
Authors: Seppälä Elina M , Oikarinen Sami , Lehtonen Jussi P , Neupane Subas , Honkanen Hanna , Tyni Iiris , Siljander Heli , Ilonen Jorma , Sillanpää Saara , Laranne Jussi , Knip Mikael , Hyöty Heikki
Published: February 2020

Background

Human rhinoviruses (HRVs), human enteroviruses (HEVs) and human parechoviruses (HPeVs) have been linked to acute otitis media (AOM). We evaluated this association in a prospective birth cohort setting.

Methods

A total of 324 healthy infants were followed up from birth to age 3 years. Nasal swab samples were collected at age 3, 6, 12, 18, 24, and 36 months and screened for HRV and HEV using real-time reverse-transcription quantitative polymerase chain reaction. Stool samples were collected monthly and analyzed for HRV, HEV, and HPeV. AOM episodes diagnosed by physicians were reported by parents in a diary. The association of viruses with AOM was analyzed using generalized estimation equations, and their relative contributions using population-attributable risk percentages.

Results

A clear association was found between AOM episodes and simultaneous detection of HEV (adjusted odds ratio for the detection of virus in stools, 2.04; 95% confidence interval, 1.06–3.91) and HRV (1.54; 1.04–2.30). HPeV showed a similar, yet nonsignificant trend (adjusted odds ratio, 1.44; 95% confidence interval, .81–2.56). HRV and HEV showed higher population-attributable risk percentages (25% and 20%) than HPeV (11%).

Conclusions

HEVs and HRVs may contribute to the development of AOM in a relatively large proportion of cases.
Evaluation and characterization of multimorbidity profiles, resource consumption and healthcare needs in extremely elderly people
Authors: Briongos-Figuero Laisa Socorro , Cobos-Siles Marta , Gabella-Martín Miriam , Abadía-Otero Jesica , Lobo-Valentin Rosa , Aguado-De-La-Fuente Ana , Vargas-Ruiz Beatriz , Martín-Escudero Juan Carlos
Published: February 2020

Objectives

Spanish population lifespan is one of the longest in the world. Moreover, it is known that elderly people have less chronic illnesses associated with aging. Our aims were to determine how Clinical Risk Group (CRG) predicts future use of healthcare resources in extremely elderly people without diabetes (T2DM) and to explore CRG correlation with health conditions.

Design

Prospective cross-sectional study.

Setting

Rio Hortega University Hospital.

Participants

Hospitalized patients >80 years old without T2DM, during 2017.

Main outcome measures

Mental status was evaluated using Pfeiffer test (SPMQS), Basic Activities of Daily Living (BADLs) and Instrumental Activities of Daily Living (IADLs) were estimated using the Older Americans Resources and Services questionnaire. Comorbidity was evaluated using Charlson index (CI) and health-related quality of life (HRQoL) with EuroQoL (EQ5D3L). CRG classification system was obtained from electronic clinical records. Data were analyzed using SPSS v.15.0.

Results

In total, 305 patients were identified (59% women), mean age 88 ± 5 and 38% were aged >90. Estimated HRQoL was 0.43 ± 0.33 for EQ5D3L-index-value. Mean dependence level was 6.2 ± 5 for BADLs and 9.2 ± 5 for IADLs. In total, 31.6% of patients had severe cognitive impairment with a mean score of 5.4 ± 3.6 in SPMQS. In total, 30.2% of patients were categorized as G3, and presented high comorbidity more frequently than the rest. Corrected CI mean score was 6.2 ± 1.7. Significant relationship was founded in survival time, number of admissions and CI score.

Conclusions

Using predictive risk models like CRG is supposed to assess the complexity of morbidity but in our extremely elderly population partially fail in stratify and predict health resource consumption.
Capitalization
Authors: Gregoline Brenda
Published: February 2020

The Capitalization chapter of the 11th edition of the AMA Manual of Style provides guidance on capitalization in a wide variety of situations: first word of sentences, quotations, titles, and subtitles; titles and headings in articles, tables, figures, and boxes; hyphenated compounds; proper nouns (geographic names; sociocultural designations; events, awards, and legislation; eponyms and words derived from proper nouns; proprietary names; organisms; seasons, deities, and holidays; tests; official names; and titles and degrees of persons); designators; types and sections of articles; acronyms; computer terms; and “intercapped” compounds. New to this edition is a subsection on capitalization of URLs.
Correct and Preferred Usage
Authors: Frey Tracy , Young Roxanne K.
Published: February 2020

The Correct and Preferred Usage chapter of the 11th edition of the AMA Manual of Style includes a large glossary of frequently misused or confused terms. In addition to this updated and cross-referenced glossary, additional examples illustrate other usage problems, such as redundant, expendable, and incomparable words and phrases; jargon; and back-formations. Specific advice is provided on describing the administration of drugs, age and sex referents, anatomy, clock referents, laboratory values, and articles before abbreviations and acronyms and before the aspirate h and nonvocalicy. Guidance is also provided on inclusive language (eg, sex/gender, presenting data in tables, personal pronouns, sexual orientation, race and ethnicity, age, socioeconomic status, and terminology for persons with diseases, disorders, or disabilities). New to this edition is a discussion of spelling and spacing variations, with preferences of the JAMA Network journals indicated.
A5 ADMISSION AND RE-ADMISSION FOR UPPER GASTROINTESTINAL BLEEDING ARE MORE COMMON IN REGIONS UNDERREPRESENTED BY GASTROENTEROLOGISTS: A POPULATION BASED COHORT STUDY
Authors: Charette J H , Stach J , Tanyingoh D , Coward S , Jelinski S , Lang E , van Zanten S , Morrin L , Reeb L , Grigat D , Hair H , Novak K L , Kaplan G G
Published: February 2020

Background

Lack of access to gastroenterologists may influence outcomes for upper gastrointestinal bleeding (UGIB).

Aims

To evaluate admission and re-admissions for patients with UGIB across the five health zones in Alberta that vary by access to local gastroenterologists.

Methods

Administrative databases identified all patients presenting to an emergency department with an UGIB who were admitted to hospital in Alberta from 2010 to 2015 (n = 17143). Admissions were stratified based the patients’ residence: Calgary, Edmonton, South, Central and North. Log-linear regression assessed an Average Annual Percentage Change (AAPC) in the incidence of UGIB hospitalizations with associated 95% confidence intervals (CI). Endoscopy and readmission to hospital within 30 days of discharge was evaluated.

Results

The per capita number of gastroenterologists was highest in Calgary (3.9 per 100,000) and Edmonton (3.8) as compared to Central (0.84), South (0.66), and North (0.41). Incidence of hospital admission for UGIB decreased in Alberta (AAPC=-6.9%; 95%CI: -8.4,-5.4); though rates for UGIB in Calgary and Edmonton was less common than non-metropolitan zones (Figure 1). Patients living in Calgary and Edmonton had lower 30-day hospital readmission rate (4.30% and 4.84%) as compared to North (11.95%), Central (10.74%), and South (8.24%) (Table 1). Patients in Calgary and Edmonton underwent endoscopic evaluation more frequently (79.6% and 76.1%) than the North, Central, and South (68.41%, 66.3%, and 71.36%).

Conclusions

Patients presenting to emergency departments with UGIB were more likely to be admitted to hospital and subsequently be re-admitted within 30-days of discharge in regions underrepresented by gastroenterologists. Improving access to local gastroenterologists in may reduce the burden of hospitalizations for an UGIB.

Funding Agencies

Partnership for Research and Innovation in the Health System (PRIHS) funded by Alberta Health Services and Alberta Innovates
A6 EFFECTS OF ELUXADOLINE TREATMENT ON ABDOMINAL AND BOWEL SYMPTOMS IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH DIARRHEA REPORTING INADEQUATE SYMPTOM CONTROL WITH LOPERAMIDE: AGGREGATED RESULTS FROM PHASE 3 AND 4 CLINICAL TRIALS
Authors: Brenner D M , Sayuk G , Saeed M , Janiszewski P , Liu L W
Published: February 2020

Background

The heterogeneous nature of irritable bowel syndrome with diarrhea (IBS-D) presents a complex challenge in the management of a wide range of symptoms. Despite the need for more effective treatments that provide global IBS-D symptom relief, many therapies currently available in Canada only treat individual IBS-D symptoms. Eluxadoline (ELX) is a mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved by Health Canada for the treatment of IBS-D in adults.

Aims

To analyze the efficacy of ELX for managing a constellation of IBS-D symptoms among patients (pts) self-reporting inadequate responses to loperamide (LOP) from Phase 3 and 4 trials of ELX.

Methods

Adults with IBS-D were randomized to placebo (PBO) or ELX (75 or 100 mg) twice daily (BID) for 26 or 52 weeks in two Phase 3 trials (NCT01553591 and NCT01553747); the data from a subset reporting inadequate IBS-D symptom control with prior LOP use were pooled and prospectively analyzed. In the Phase 4 trial (RELIEF: NCT02959983), IBS-D pts with self-reported inadequate symptom control with LOP over the previous 12 months were randomized to PBO or ELX 100 mg BID for 12 weeks. In all trials, pts recorded their daily IBS-D symptoms including worst abdominal pain (0–10 scale), stool consistency (Bristol Stool Form Scale score 1–7), and daily urgency episodes. Results for ELX 100 mg vs. PBO were evaluated after 12 weeks of treatment, which included the generation of radar plots to visualize multiple efficacy endpoints.

Results

Of pts enrolled in the Phase 3 trials with prior LOP use, inadequate control of IBS-D symptoms was reported in 58.9% (n=166) and 58.8% (n=174) of pts in the PBO and ELX groups, respectively; in the Phase 4 trial, 174 and 172 pts were treated with PBO and ELX, respectively. ELX-treated pts had a greater proportion of responders compared to PBO-treated pts for all outcomes, including a significant increase in the proportion of pts achieving both ≥50% and ≥75% urgency-free days in the Phase 3 trials (Figure). Analysis of the global symptoms of pts enrolled in the Phase 4 trial further supported these results. Across Phase 3 and 4 trials, adverse events occurred in similar proportions regardless of treatment, with the most common being nausea.

Conclusions

In pts with inadequate responses to LOP, a greater proportion of ELX-treated pts were responders compared to PBO-treated pts in all Phase 3 and 4 trials for the respective primary composite endpoints, abdominal pain, stool consistency, and urgency after 12 weeks of treatment. These results validate the effectiveness of ELX in alleviating IBS-D symptoms in this population.

Funding Agencies

Writing assistance by Complete HealthVizion, funded by Allergan plc
A9 BACTERIAL BILE SALT HYDROLASE GENE ABUNDANCE IS ASSOCIATED WITH RORC GENE EXPRESSION IN INTESTINAL MUCOSA OF INFLAMMATORY DISEASE PATIENTS
Authors: Hernandez-Rocha C , Borowski K , Turpin W , Smith M , Stempak J , Silverberg M S
Published: February 2020

Background

The role of gut microbes involved in bile acid metabolism and their impact on mucosal immune regulation is beginning to be appreciated. For instance, changes in microbial bile salt hydrolase (BSH) activity which deconjugates bile acids in the gastrointestinal tract of gnotobiotic mice, significantly alters gene expression patterns of immune-related genes in ileum. Moreover, bile acid dysmetabolism may participate in the chronic inflammation loop of Inflammatory bowel disease (IBD).

Aims

We carried out an integrated mucosal microbiome-transcriptome analysis to elucidate associations between microbial bile-acid metabolizing function and host gene expression.

Methods

Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) patients were recruited prior to scheduled colonoscopy performed as part of clinical care. Only patients with non-inflamed mucosa defined as a segmental simple endoscopic score 0–2 in CD and a segmental Mayo endoscopic score of 0 in UC/IBDU were included in this analysis to minimize the effect of inflammation on gene expression. Biopsy samples were obtained from terminal ileum, ascending colon and sigmoid colon, and microbial DNA and human RNA was extracted. V4 region of 16S rRNA gene was sequenced and the relative abundance of bile acid-metabolizing genes was inferred using PICRUSt. RNA-seq was used to sequence total human RNA and a supervised transcript reduction analysis focus upon 65 genes previously associated with bile acid metabolism and IBD was utilized. Associations between microbiome clusters of orthologous groups (COGs), transcriptome, diagnosis (CD vs UC/IBDU), and biopsy site were analyzed using linear mixed-effects model with lmer4 function in R. An adjusted-p value after false discovery rate correction < 0.05 was considered significant.

Results

A total of 126 samples from 86 subjects were analyzed corresponding to 35 CD and 51 UC/IBDU. Mean age for the total cohort was 34.7 ± 11 years and 35 (40.6%) were females. There was a significant negative correlation between relative abundance of bacterial bsh genes (COG3049) and human RORC gene (p < 0.03). This association was independent of type of diagnosis and biopsy site. There was no association among other analyzed bacterial COGs and host genes.

Conclusions

Using an integrative microbiome-host transcriptome approach, our data provide new evidence linking microbial bile acid deconjugation (bsh genes) and host gene expression in the mucosal-luminal interface in quiescent IBD-affected tissue. Nuclear receptor RORC is pivotal in the differentiation and function of innate lymphoid cells and T-helper 17 cells. Modulation of this pathway by bile acids or gut bacteria involved in their metabolism could shed light on the immune role of bile acids in IBD patients.

Funding Agencies

CAG, CIHRNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
A11 MICROBIAL AND METABOLOMIC PROFILES IDENTIFY SUBSETS OF DIARRHEA PREDOMINANT IRRITABLE BOWEL SYNDROME
Authors: Bennet S M , De Palma G , Bercik P , Lomax A E , Vanner S , Reed D E
Published: February 2020

Background

Irritable bowel syndrome (IBS) patients are subtyped by predominant bowel habit rather than pathophysiological mechanisms and this may underlie challenges in identifying more effective targets for designing new treatments. Metabolomics and microbial analysis can distinguish IBS patients from healthy controls but it is unknown if they can identify pathophysiological IBS subgroups.

Aims

To phenotype subgroups of IBS patients using metabolomics and microbial analysis and determine if these subgroups have different underlying pain signalling mechanisms.

Methods

Symptom history, stool and urine were collected from 30 diarrhea predominant (IBS-D) and 30 constipation predominant (IBS-C) IBS patients (Rome IV). Liquid Chromatography-Mass Spectrometry quantified 130 metabolites in stool and urine. The GA-map™ Dysbiosis Test targeting ≥300 bacteria on different taxonomic levels was used to identify stool microbial composition. Multivariate OPLS discriminatory analysis assessed metabolomics and microbial profiles. To assess potential effects on pain signalling, the effect of stool supernatant on dissociated dorsal root ganglia (DRG) neuron responses to capsaicin (10nM) was assessed using Ca2+ imaging.

Results

Within both IBS-D and IBS-C, combined stool/urine metabolomic profiles of patients with a dysbiosis-like (DL) IBS (onset following antibiotics, enteric infection, or travel) were distinct from patients with a non-DL IBS onset (IBS-D R2=0.7, Q2=0.5; IBS-C R2=0.5, Q2=0.4); fecal glutamic acid and urinary pyruvic acid were the main metabolites driving separation. However, microbial profiles of DL vs non-DL onset could only be discriminated in IBS-D (R2=0.8, Q2=0.4). In the patients with a DL IBS onset, stool metabolomic profiles of the 7 IBS-C discriminated from the 8 IBS-D patients (R2=0.9, Q2=0.8). Profile differences were not seen between IBS-C and IBS-D with a non-DL onset of IBS. In preliminary studies, incubation of DRG neurons with stool supernatant from 1 DL IBS-D and 1 non-DL IBS-D increased peak [Ca2+]i responses to capsaicin compared to incubation with media (DL: 5.5±0.9 vs 2.3±0.7; non-DL: 6.9±0.7 vs 3.9±0.4% ΔF/F). Similarly, the number of responsive neurons to capsaicin was increased after incubation with IBS stool supernatant vs media (DL: 27% vs 8%; non-DL 19% vs 12%).

Conclusions

Different metabolomic and bacterial profiles between DL and non-DL onset of IBS-D suggests a novel means to better phenotype clinically defined IBS subgroups. While initial results with stool supernatants from both a DL and non-DL IBS-D patient suggest increased pain signalling in DRG neurons, more studies are needed to determine if there are differences between these two subgroups as well as healthy controls.

Funding Agencies

CIHRSoutheastern Ontario Academic Medical Organization (SEAMO)
A22 ADVERSE EARLY LIFE EVENTS ARE COMMON IN PATIENTS WITH FUNCTIONAL AND ORGANIC GASTROINTESTINAL DISORDERS
Authors: Noejovich C V , Miranda P M , Collins S M , Verdu E , Pinto-Sanchez M I , Bercik P
Published: February 2020

Background

Stressful events in childhood have been associated with the development of functional gastrointestinal (GI) disorders in adulthood, especially irritable bowel syndrome. The influence of early life adverse events in patients with common organic disorders, such as celiac disease and inflammatory bowel disease (IBD), has been poorly investigated.

Aims

To evaluate the frequency of early life adverse events in patients with organic and functional gastrointestinal disorders compared to healthy controls.

Methods

Adult patients with an established diagnosis of IBS (Rome IV criteria), celiac disease and inflammatory bowel disease (IBD) attending a tertiary medical center, as well as healthy volunteers were interviewed by a psychologist. Early life adverse events were assessed during the semi-structured interview using a modified version of the Adverse Childhood Experience (ACE) questionnaire. Number of early life events and the presence of GI and extraintestinal symptoms based on a 10-point Likert scale were quantified. Data are presented as Median (IQR) and n (%). Statistical analysis was performed using Mann-Whitney and Fisher’s exact tests as appropriate.

Results

Sixty-eight patients (18 IBS, 28 celiac, 22 IBD) and 23 healthy controls were enrolled in the study. Patients with IBS, celiac disease and IBD had increased number of early life events compared with healthy controls (6.5 (4.8–8.3), 5.0 (3.0–9.0), 6.0 (4–8.3) vs 2.0 (1.0–4.0) respectively, p<0.0001). Patients reported a higher number of mental disorders in their mothers (IBS p=0.01; celiac disease p=0.01; IBD p=0.001) and increased number of close family member abusing alcohol or drugs during their childhood (IBS p=0.01; celiac p=0.02; IBD p=0.02) compared to healthy controls. History of sexual abuse was higher in patients with IBS (p=0.01), while history of verbal abuse was higher in patients celiac disease and IBD (p=0.003 and p=0.001, respectively) compared to healthy controls. The number of early life adverse events was strongly correlated with number of GI (r= 0.91; p=0.01) and extra-intestinal (r=0.87; p=0.02) symptoms, but not with symptoms severity. Most patients with IBS (83.3%), celiac disease (89.3%) and IBD (85.7%) reported stressful events before the onset of their disease.

Conclusions

Adverse events in childhood are frequent in patients with chronic GI disorders, both of functional and organic origin. Furthermore, stressful events often precede their diagnosis. These data strongly suggest that better psychosocial assessment in patients with chronic GI disorders is needed to improve their overall management.

Funding Agencies

None
A23 NUTRITIONAL DEFICIENCIES ARE FREQUENT IN CELIAC PATIENTS ON A GLUTEN-FREE DIET, REGARDLESS OF THE DURATION AND COMPLIANCE OF THE DIET
Authors: Jivraj A , Connan V , Balart T , Ching E , Marwaha A , Verdu E , Armstrong D , Pinto-Sanchez M I
Published: February 2020

Background

The only available treatment for celiac disease (CD) is adherence to a strict gluten-free diet (GFD). CD is associated with several nutritional deficiencies, which could be explained by malabsorption when the disease is active. However, the magnitude of nutritional deficiencies in treated CD and how this is influenced by the duration and compliance of GFD is less clear.

Aims

We aim to evaluate the presence of nutritional deficiencies in celiac patients on short term (≤2yrs) vs long-term (>2yrs) GFD, and in those with persistent symptoms or asymptomatic in the follow up.

Methods

We included consecutive biopsy-proven CD patients attending the McMaster Adult Celiac Clinic. GFD adherence was assessed by validated Celiac Dietary Adherence Test (CDAT) and by anti-tissue transglutaminase antibody IgA(tTG IgA) levels. Serology, vitamins and minerals were measured in blood samples collected at enrolment. Continuous data was expressed as Median (IQR) and categorical data as proportion%. Mann-U-Whitney and Chi2 were used to compare difference between groups.

Results

We enrolled 171 CD patients (80% female; Median age 43 years). 76/171 (44%) of CD patients were following a GFD for over 2 years. Eighty-two percent of the patients (141/171) had persistent symptoms in the follow up and 80.7% had normal tTG IgA levels. The most common nutritional abnormalities were deficiencies in zinc (56%), iron (23%), copper (20%). Chromium was increased in 74% of patients. There were no differences in nutritional deficiencies between group of patients with short and long-term duration of GFD, nor between those strictly compliant with GFD compared to those fairly compliant (p>0.05).

Conclusions

Nutritional deficiencies are frequent in celiac patients on a GFD regardless of the presence of symptoms, dietary compliance or duration. The previous suggest that nutrients deficiencies may be more related to GFD nutritional inadequacy rather than malabsorption.

Funding Agencies

None
A28 RELATIVE RATES OF ULCERATIVE COLITIS TO CROHN’S DISEASE: PARALLEL EPIDEMIOLOGIES IN NEWLY VS. HIGHLY INDUSTRIALIZED COUNTRIES
Authors: Windsor J W , Buie M , Coward S , Gearry R , Hansen T , King J A , Kotze P , Ma C , Ng S , Panaccione N , Panaccione R , Quan J , Seow C , Underwood F , Kaplan G G
Published: February 2020

Background

Inflammatory bowel disease (IBD) first presents in a population as cases of ulcerative colitis (UC) followed by cases of Crohn’s disease (CD). Newly industrialized countries (NIC) show a prallel epidemiology of IBD to highly industrialized countries (HIC) in the previous century; one marker of this is the relative incidence/prevalence rates of UC to CD, which approximates 1 over time.

Aims

Provide evidence for the UC:CD ratio as a proxy for disease penatrance in a population.

Methods

Systematic review of MedLine and Embase for studies reporting incidence or prevalence of UC and CD. Log-linear regression (by region and NIC/HIC [2019 United Nations definitions]) was used to calculate average annual percent change (AAPC) and associated 95% confidence intervals (CI). Data were plotted on an online, interactive map to show trends (link provided).

Results

We extracted data from 218 studies compising population-level data from 69 countries. We found negative AAPCs as the prevalence ratio of UC:CD significantly decreased over time in East Asia, West Asia, North Europe, and South Europe; 6/12 global regions displayed significantly decreasing incidence ratios. No AAPC was found to be significantly increasing (Table 1). When examing HIC/NIC, we found a significant effect of NIC on the UC:CD prevalence ratio after 2000 (AAPC:−3.83;95%CI:−6.28,−1.31) while HIC regions remained stable (AAPC:2.14;95%CI:−1.40,5.82). Looking at all available data, both HICs and NICs show significantly decreasing UC:CD prevalence ratios (HIC:AAPC:−3.72;95% CI:−4.46,−2.97; NIC:AAPC:−2.62;95%CI:−4.13,−1.08).

Conclusions

In some HICs (eg. Canada), the UC:CD incidence ratio was <1 in the earliest available data (1966), explaining the stable AAPC in North America (AAPC:−0.24;95%CI:−1.12,0.65). However, in NICs (eg. Southern Asia), the AAPC is rapidly decreasing (AAPC:−24.68;95%CI:−37.85,−8.71) as areas like Sri Lanka rapidly fall from an incidence ratio of 7.5 (2007) to 2.8 (2012), mimicking trends in IBD epidimeology of HICs in the previous century.

Funding Agencies

None
A31 ALTERED SMALL INTESTINAL EPITHELIAL HOMEOSTASIS AND CELL FATE DECISION UPON LOSS OF TRP53 IN KRT15+ INTESTINAL STEM CELLS
Authors: Dubey A , Giroux V
Published: February 2020

Background

Intestinal homeostasis is mainly maintained by two groups of stem cells: Lgr5+ stem cells and reserve stem cells. Recently, we reported that Krt15+ cells are present in small intestinal and colon epithelia, and harbor self-renewal, multipotent and regenerative capacities. Initiation of sporadic colorectal cancer has been described in Krt15+ stem cells, Lgr5+ stem cells and reserve stem cells following the loss of Apc. While these intestinal stem cell (ISC) populations can act as tumor-initiating cells in sporadic colon cancer, little is known about the cell-of-origin of colitis-associated colon cancer. TP53 alteration is reported as an early event in colitis-associated colon cancer cases. Therefore, we hypothesize that Trp53 loss specifically in Krt15+ stem cells will perturb the epithelial homeostasis and lead to tumor formation

Aims

Identify if Krt15+ cells may act as the cell-of-origin in colitis-associated colorectal cancer.

Methods

To induce Trp53 loss specifically in Krt15+ cells, we generated Krt15-CrePR1;Trp53fl/fl (Krt15△Trp53) mice, induced Cre recombination by injecting RU486 (PR agonist) and euthanized the mice after 12 months following recombination. Histological analysis was performed on small intestinal tissues.

Results

Results: Trp53 loss in Krt15+ cells severely perturbed small intestinal morphology. Increased crypt (proliferative compartment) length correlated with no proliferation changes surprisingly but higher number of Paneth cells and abnormal presence of goblet cells. Interestingly, we also observed the presence of cells expressing both Paneth and goblet cells markers suggesting a deregulation of secretory cell fate decision. Decreased expression of Hes1 and increased β-catenin nuclear expression in the small intestinal crypt of Krt15△Trp53 mice suggest altered Notch and Wnt signaling. Furthermore, villi (differentiated compartment) were significantly wider and shorter, and showed accumulation of activated fibroblasts. Finally, we observed inflammatory lesions as well as adenomas in the small intestine of Krt15△Trp53 mice which remain to be further characterized

Conclusions

Conclusion: In summary, Trp53 loss specifically in Krt15+ cells impaired cell fate decision, induced inflammation and initiated tumor formation. Overall, these results suggest that Krt15+ cells could act as the cell-of-origin of colitis-associated colon cancer.

Funding Agencies

Cancer Research Society, CRC Tier 2
A39 NOVEL GAIN OF FUNCTION NON-RECEPTOR TYROSINE KINASE MUTATIONS ARE LINKED TO THE PATHOGENESIS OF VEOIBD
Authors: Mehta M , Wang L , Guo C , Warner N , Li Q , Pan J , Boztug K , Uhlig H , Muise A
Published: February 2020

Background

Very early-onset inflammatory bowel disease (VEOIBD) is an emerging global disease, that results in inflammation of the digestive tract. Severe forms of VEOIBD can be caused by mutations in a single gene (monogenic variants) and, can result in death. A candidate gene which codes for a non-receptor tyrosine kinase (nRTK) has recently been implicated as a monogenic cause of IBD (unpublished). Whole exome sequencing was performed in two unrelated children who presented with symptoms of IBD identifying two distinct de novo gain of function mutations (S550Y and P342T). Both mutations are located in the highly conserved region of the nRTK, and were predicted to have similar downstream effects. Furthermore, four other patients with a variety of adult-onset immune disorders have recently been identified with rare variants in the same gene (M450I, R42P, A353T, V433M, S550F) but, their potential gain of function status remains to be determined. Studies show that this nRTK is an essential mediator in inflammation. It is expressed in both intestinal epithelial and immune cells however, its role in infantile IBD is unclear. This protein is first activated by phosphorylation and is linked to activating downstream transcription factors such as ERK and JNK. All these target proteins play a meaningful role in intestinal inflammation in patients with IBD.

Aims

Since we identified P342T and S550Y to be gain of function, we wanted to determine if the new variants exhibit a similar downstream impact on target protein expression levels when compared with S550Y and P342T. We also wanted to identify if all variants can be rescued with a known nRTK inhibitor. It is hypothesized that the new variants are gain of function and that all variants can be rescued with the inhibitor.

Methods

Using western blot analysis, the activation of ERK, JNK and nRTK was compared between wildtype (WT) and mutants. This in vitro method helped identify the degree of activation. For the second part of the study, HEK293T cells were treated with inhibitor to test for a rescue of phenotypes via western blot analysis.

Results

Results show an increased activation of nRTK, ERK and JNK in all variants with S550Y and S550F having the highest activation. Furthermore, pharmacological inhibition using small molecular kinase inhibitors resulted in decreased activation of nRTK, ERK and JNK suggesting a rescue of phenotypes.

Conclusions

Characterizing the downstream functional impact of these nRTK variants is an important first step to determine if gain of function nRTK mutations drive IBD. With a rising prevalence of IBD worldwide, these findings may lead to the development of pharmacological nRTK inhibitors as a novel personalized therapeutic approach for these patients and possibly for the broader IBD population.

Funding Agencies

CIHR
A40 INTESTINAL EPITHELIAL NCOR1 TARGETS TRYPTOPHAN METABOLISM AND PROTECTS AGAINST EXPERIMENTAL COLITIS
Authors: Lecours M , Di Castro A , Reyes-Nicolas V , St-Jean S , Loiselle A , Jones C , Perreault N , Boudreau F
Published: February 2020

Background

The nuclear co-repressor NCOR1 is a central protein that orchestrates the assembly of a large transcriptional repression complex. NCOR1 controls activation of macrophages by repressing a large variety of pro-inflammatory genes.

Aims

We aimed to investigate the role of intestinal epithelial NCOR1 during experimental colitis.

Methods

Conditional deletion of Ncor1 in the whole intestinal epithelium was achieved by crossing Villin-Cre and Ncor1loxP/loxP C57BL/6 mouse models. A gene profiling analysis in the colon of non-diseased NCOR1ΔIEC and control mice was performed. NCOR1ΔIEC and control littermate mice were treated with dextran sulfate sodium (DSS) in drinking water.

Results

DSS-induced colitis in NCOR1ΔIEC mice was more severe than control mice according to survival as well as clinical observations. A statistical analysis predicted 85 unique and mapped transcripts being significantly modulated between NCOR1ΔIEC and control mice. An Ingenuity Pathway Analysis from these predicted target genes identified gastrointestinal disease (79 transcripts) as top disease and biofunction. Analysis of enriched targets in specific canonical pathways predicted an increase in the tryptophan degradation pathway (P = 3.2E-02), a pathway recently demonstrated to be strongly relevant to inflammatory bowel disease severity. Indoleamine-pyrrole 2,3-dioxygenase (IDO1), that catalyzes the first and rate-limiting step of tryptophan oxidation, was induced more than 7 times in the colon of NCOR1ΔIEC mice. Induction of Ido1 was also confirmed in cultured ex vivo colon organoids deleted for Ncor1.

Conclusions

Our results highlight the critical role of NCOR1 to maintain intestinal inflammatory homeostasis during experimental colitis and uncover a novel function for NCOR1 in the regulation of Ido1 expression and potentially tryptophan metabolism.

Funding Agencies

CIHR
A61 FOCUSING ON THE FUTURE: REDUCING BARRIERS AND IMPROVING ACCESS TO IBD SPECIALTY CARE ACROSS CANADA
Authors: Heisler C , Mirza R , Kits O , Zelinsky S , Veldhuyzen van Zanten S , Nguyen G C , MacMillan M A , Lakatos P L , Targownik L , Fowler S , Rioux K P , Jones J
Published: February 2020

Background

Canada has the highest global age-adjusted incidence and prevalence rates of Inflammatory Bowel Disease (IBD). Resulting from compounding prevalence and limited resources, timely access to specialty care is a challenge faced by patients and healthcare providers. Despite this issue, there has been no published research elucidating the patient perspective using qualitative approaches to compare and contrast the patient experience across Canada.

Aims

To elicit a qualitative data stream to better understand phenomena related to access to healthcare for Canadians living with IBD from a patient-centered perspective.

Methods

Patients diagnosed with IBD (≥18 years of age) were recruited from gastroenterology clinics and communities through IBD specialists and Crohn’s & Colitis Canada. To ensure geographic diversity and representation, patients were recruited from urban and rural regions. In order to acquire multiple access perspectives, patients were invited to bring a family member who was involved in their care to the focus groups. Co-facilitated by a researcher and a patient research partner, the focus groups were held in Nova Scotia, New Brunswick, Quebec, Ontario, Manitoba, Saskatchewan, and British Columbia. All focus groups were audio recorded, transcribed, and coded for themes. Themes were distilled through qualitative thematic analysis using Atlas.ti software to ascertain congruence or discordance of IBD specialty care access experiences.

Results

A total of 63 participants were recruited in fourteen focus groups across seven provinces. The majority of participants were female (41/63, 65%) and from urban/suburban regions (34/63, 54%). The mean age of participants was 48 years (SD=16 years, range=16 to 77 years). Preliminary analyses illustrated three patient-identified access barrier themes: 1) Lack of multidisciplinary care (psycho-social and nutrition support), 2) Diagnostic delay, and 3) Inability to effectively receive and provide communication with healthcare providers. In response, four solutions were proposed: 1) Integration of holistic care into the clinical practice, 2) Readily accessible psycho-social and nutritional support, 3) Increased patient advocacy, and 4) Continuity and liaison through provision of a healthcare navigator resource.

Conclusions

The complexity of specialty care access for IBD patients in Canada cannot be underestimated. It is vital to possess a robust understanding of healthcare system structures, processes, and the significant impact these factors have on patients and the care received. Through the use of patient-centered exploration of barriers and facilitators, access to IBD specialty care in Canada can be better understood and improved on both a provincial and national scale.

Funding Agencies

CIHRNova Scotia Health Authority Research Fund
A63 HOSPITALIZATION RATES FOR INFLAMMATORY BOWEL DISEASE VARY GEOGRAPHICALLY IN SOUTHERN ALBERTA: A POPULATION-BASED COHORT STUDY
Authors: Stach J , Coward S , Charette J H , Jelinski S , van Zanten S , Morrin L , Kroeker K , Baumgart D , Seow C , Panaccione R , Novak K L , Kaplan G G
Published: February 2020

Background

Hospitalization rates for patients with inflammatory bowel disease (IBD) are decreasing throughout Canada; however, this may vary across Canadian jurisdictions. Access to gastroenterologists is limited in many parts of Canada, resulting in care by non-gastroenterologists, and variation in outcomes.

Aims

To assess trends of hospitalization rates in three regions in Southern Alberta: Calgary zone, a metropolitan city; Chinook region: local gastroenterologists; and Palliser region: no local gastroenterologists.

Methods

The Alberta IBD Surveillance Cohort is a population-based database consisting of an algorithmically defined prevalent IBD population for Alberta. IBD patients in Southern Alberta were identified by 3-digit postal code and their hospitalizations from the Discharge Administrative Database were extracted (2002 to 2015). IBD patients were stratified by the number of IBD prevalent patients: Calgary Zone (n=9625 in 2015), Palliser region (n=1419), and Chinook region (n=727). Age- and sex- standardized hospitalization rates, per 100 prevalent IBD patients, were calculated for each year. Average Annual Percentage Change (AAPC with associated 95% confidence intervals (CI)) were calculated using the log-linear regression. Rate ratios of standardized hospitalization rates between Calgary, Chinook, and Palliser were calculated.

Results

From 2002 to 2015 the average hospitalization rate (per 100 prevalent population) was: 27.6 in Calgary, 30.2 in Chinook, and 37.4 in Palliser (Table 1). The AAPCs across these regions were significantly decreasing (Figure 1). By 2011–2015 hospitalization rates fell to 23, 26.3, and 30.2 in Calgary, Chinook, and Palliser, respectively (Table 1). Calgary and Chinook had significantly lower hospitalization rates compared to Palliser (Calgary: 0.72, 95% CI: 0.70, 0.75; Chinook: 0.80, 95% CI: 0.76, 0.84) (Table 1).

Conclusions

Hospitalization rates for patients with IBD are decreasing, which may be explained by advances in therapeutic modalities and increased expertise of gastroenterologists. The lack of access to a local gastroenterologist in Palliser may account for higher hospitalization rates for patients with IBD. Future studies are needed.

Funding Agencies

CIHRDHSCN (Digestive Health Strategic Clinical Network), AHS (Alberta Health Services)
A68 CLOSTRIDIOIDES DIFFICILE INFECTION IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE
Authors: Zohni H , Chandrakumar A , El-Matary W
Published: February 2020

Background

Toxigenic Clostridioides difficile (C. difficile), previously known as Clostridium difficile, is an anaerobic gram-positive spore-forming opportunistic pathogen associated with profuse diarrhea and gastroenteritis associated mortality and morbidity especially in patients with inflammatory bowel disease (IBD).

Aims

To investigate the incidence and risk factors associated with clostridioides difficile infection (CDI) in children with IBD in the province of Manitoba.

Methods

Our longitudinal population-based cohort comprised of all children and young adults < 17y diagnosed with IBD in the Canadian province of Manitoba between 2011 and 2019. The diagnosis of CDI was confirmed based on the Triage C. difficile immunoassay and polymerase chain reaction assay to detect the presence of toxigenic C. difficile. Fisher’s exact test was used to examine the relationship between categorical variables. Cox-regression model was used to estimate the risk of CDI development in IBD patients.

Results

Among the 261 children with IBD, 20 (7.7%) developed CDI with an incidence rate of 5.04 cases per 1000 person-years and the median age at diagnosis of 12.96 years (IQR: 9.33–15.81). The incidence rate of CDI among UC and CD patients were 4.16 cases per 1000 person-years and 5.88 cases per 1000 person-years, respectively (p=0.46). Compared to children without CDI, those who had CDI were at increased risk of future exposure to systemic corticosteroids (hazard ratio (HR)=4.30; 95% CI: 1.44–12.87) and anti-tumor necrosis factor (TNF) biologics (HR=3.37; 95% CI: 1.13–10.09). Recurrence rate of CDI in our pediatric IBD population was 25%.

Conclusions

Our findings confirm that children with IBD are at a high risk of developing CDI, which may predict future escalation of IBD therapy.

Funding Agencies

The Children’s Hospital Research Institute of Manitoba