bluuebunny/crossref_metadata_2025_split huggingface dataset:
P004 Critical paralog proteins has a cell-type specific rewiring role in Ulcerative Colitis associated signalling processes
Authors: Kornilova P , Potari-Gul L , Modos D , Madgwick M , Haerty W , Korcsmaros T 
Published: May 2021

Abstract

Background
Cell functions are regulated by signalling pathways that often cross-talk with each other. These cross-talks are usually cell-type specific and, as we showed earlier, often mediated by so called critical paralog proteins (proteins resulted due to gene duplication but then diverged both in terms of their regulation and their functions). As dysregulation of cell functions is a hallmark of chronic inflammatory diseases, including Ulcerative Colitis (UC), here we investigated the role of such critical paralog proteins in the regulation of some key functions, in UC-associated cell types.

Methods
In this study, we compared healthy and diseased (non-inflamed UC) conditions. Using network biology approaches combined with single-cell RNAseq data, we identified critical paralog groups in myofibroblasts, regulatory T cells and goblet cells that show cell and/or condition specificity in the process of autophagy, Notch and T-cell receptor signalling.

Results
We focused our analysis on the Notch pathway-related processes, in particular the EGLN paralogs (EGLN1-3). The EGLN enzymes are prolyl hydroxylases and EGLN1, EGLN3 can directly inhibit the HIF1A transcription factor, while HIF1A induces the expression of all the three EGLN gene upon hypoxia. This negative feedback loop tends to control the amount of EGLNs and the activation status of the HIF1A proteins, therefore maintaining an adequate hypoxia response. In the intestine, EGLN2 and EGLN3 are described as potential regulators of inflammation, and both are downregulated in UC patients. Importantly, we found that the expression of EGLN paralogs shows cell-type and condition specificity. While goblet cells express all three paralogs in both healthy and UC conditions, myofibroblasts express EGLN3 only in the healthy condition. As EGLN3 is responsible for tight junction integrity, and it can regulate hypoxia response, the lack of EGLN3 in UC could contribute to the disrupted epithelial barrier function and dysregulation of myofibroblasts. Accordingly, in mice, depletion of Egln3 causes an increased susceptibility to colitis.

Conclusion
We have developed a bioinformatic pipeline to reconstruct cell-type specific signalling networks to identify the key differences among critical regulators of the signalling flow (ie., critical paralog proteins) in UC-associated cell types and in comparison of healthy and non-inflamed UC conditions. We analysed the altered expression of paralog genes in signalling pathways in UC-associated cell-types, and demonstrated their role with the condition and cell-type specific expression of EGLN3.
P005 Cytokine mediated intercellular communication in inflammatory bowel disease
Authors: Thomas J P , Olbei M , Hautefort I , Modos D , Korcsmaros T 
Published: May 2021

Abstract

Background
During inflammatory bowel disease the mucosal immune system is altered. The mucosal immune cells are communicating through the various cytokines. Single cell and small volume RNA-seq and proteomics approaches make the investigation of cytokine networks plausible However the lack of specific resources make such efforts hard.

Methods
To address this need in this project, we built a cell-cell communication map, CytokineLink, which collates cytokine mediated intercellular interactions. CytokineLink collects the cytokine-cytokine receptor interactions from the OmniPath, immuneXpresso and immunoGlobe databases. We demonstrate the applicability of CytokineLink by presenting how cytokine feedback loops are built and altered during Ulcerative Colitis. We mapped single-cell RNA-seq expression data from inflamed and uninflamed Ulcerative Colitis biopsies to the interactions between cytokines and cytokine receptors, and then we compared the specific cytokine-mediated cell-cell interactions.

Results
Using our approach, we were able to point out major differences in cell-cell communication between inflamed and uninflamed conditions, and identify key cytokine changes. For example, the generally anti-inflammatory cytokine IL-10 is produced by regulatory T-cells in both conditions. However the IL-10 receptor positive cells are altered between the inflamed and uninflamed condition: dendritic cells and innate lymphocytes did not express the receptor in the sufficient amount. It suggests that not the cytokine level directly but the receptor level alterations are involved in ulcerative colitis. Also the chemokine CXCL12 was expressed by the inflammatory fibroblasts. This cytokine promotes the T-cell recruitment and through that inflammation.

Conclusion
With CytokineLink, researchers are capable to pinpoint the most important interactions in the changing mucosal immune system and propose novel therapeutic approaches. We are currently developing a website and easy to follow workflows to make CytokineLink available.
P062 Effects of exposure to steroids on the PredictSURE whole blood prognostic assay in Inflammatory Bowel Disease
Authors: Alsoud D , Verstockt S , Sabino J , Ferrante M , Noor N , Verstockt B , Vermeire S 
Published: May 2021

Abstract

Background
Accurately predicting disease course at diagnosis is critical to facilitate personalized therapy in inflammatory bowel disease (IBD). PredictSURE IBDTM is a whole blood qPCR assay that was developed to predict prognosis in newly diagnosed, treatment-naïve IBD patients – classifying them into IBDhi (high-risk) or IBDlo (low-risk). The current recommendation is that PredictSURE IBDTM should not be used in those who have commenced steroids. In this study, we aimed to determine the impact of steroid therapy on the performance of PredictSURE IBDTM.

Methods
Whole blood was serially taken from patients admitted with severe IBD requiring intravenous (IV) steroids (pre-steroid, day 3, day 5; n=10, cohort 1) and from patients receiving oral steroids as outpatients (pre-steroid, week 1, week 6; n=10, cohort 2). An independent cohort of 43 IBD patients, all within 3 months of diagnosis and on corticosteroid treatment (41 systemic and 2 topical, cohort 3) was recruited. RNA was extracted and analyzed with PredictSURE IBDTM (PredictImmune, UK). Patients were prospectively followed and treated according to routine clinical management by physicians blinded to the test results, and clinically stratified according to one of the original definitions used to construct and validate the test (need for step up to immunosuppressive or biological therapy or surgery).

Results
In cohorts 1 and 2, both oral and intravenous steroids affected the PredictSURE IBDTM result: misclassification as IBDlo occurred in 5/8 IBDhi patients receiving oral, and 5/7 IBDhi patients receiving IV, steroids. In 60% this change was detectable early (within 1 week of oral steroids and 3 days of IV steroids). Steroids did not affect the classification of IBDlo patients. Consistently, the prognostic accuracy was limited in patients already receiving steroids (cohort 3). After a median follow-up of 31.8 [IQR 18.7 - 42.1] months, 35 (81%) patients required step-up therapy. PredictSure IBDTM correctly classified only 23 (54%) patients with accuracy of 0.53 (sensitivity: 0.51, specificity: 0.63, positive likelihood ratio: 1.38, negative likelihood ratio: 0.77). Seventeen (80%) of the misclassifications were clinically high-risk patients who were predicted as IBDlo. Time to treatment escalation was similar between patients classified as IBDhi or IBDlo after starting steroid therapy (p= 0.47) (Figure 1).

Conclusion
The prognostic accuracy of PredictSURE IBDTM is limited if performed after steroid therapy has begun, most likely because of the misclassification of high-risk patients as low risk. Therefore, the test should only be performed in patients with active disease who are not receiving steroid therapy, as currently recommended.
P086 Sphk2 deletion is involved in structural abnormalities and Th17 response but does not aggravate colon immune dysregulation and intestinal permeability in a stress-induced colonic inflammation
Authors: Martin-Hernández D , Robledo Montaña J , López-Gutiérrez I , González-Prieto M , González Bris Á , Ulecia-Morón C , MacDowell K , Tendilla-Beltrán H , Moreno B , Calleja-Rodríguez N , Rodríguez-Mascarenhas S , Caso J R , García-Bueno B , Marín-Jiménez I , Leza J C , Menchen Viso L A 
Published: May 2021

Abstract

Background
Colon immune dysregulation results in a chronic inflammatory response typical of IBD and mainly driven by T-cell response to microbial antigens. Interestingly, stress can trigger or modulate inflammation and even modify the clinical course of IBD. Sphingosine 1-phosphate (S1P) increase in tissues is involved in T-cell recruitment and different compounds acting on S1P signaling are currently under clinical trials to test their ability to impact IBD progression, including sphingosine kinase 2 (Sphk2) inhibitors.

Methods
Male C57BL/6NJ and Sphk2-/- mice were randomly assigned to 4 experimental groups: Control WT (n=5), Control Sphk2-/- (n=5), Stress WT (n=8), and Stress Sphk2-/- (n=8). A sub-chronic stress mixed model based on immobilization and ultrasound exposure for 2h during 4 days was used. A set of tissue and biochemical assays was performed to evaluate stress and immune responses, S1P pathways, and epithelial barrier integrity.

Results
Stress caused weight loss and corticosterone upregulation regardless of the genotype. S1P was increased in the colon of stressed mice due to a decrease in its degradation enzymes and Sphk2, leading to an immune dysregulation reflected by an upregulation of TLR4 pathway, an inhibition of anti-inflammatory mechanisms – 15-lipoxygenase, N-formyl-peptide receptor 2 and Liver X Receptor – a decrease in IgA+ and a decrease in IgM+ B-cells and plasmablasts, and a Th17 polarization. Sphk2 deletion did not affect inflammatory processes but could interfere with Th17 response. Moreover, Sphk2-/- mice showed lower expression levels of claudins 3, 4, 5, 7, and 8 that could be related to structural abnormalities relevant to IBD. Stress exposure also decreased some of these claudins and increased intestinal permeability, but a synergistic effect between stress and genotype for permeability was not detected.

Conclusion
Sub-chronic stress induced colon S1P increase, immune dysregulation and increased intestinal permeability. Sphk2 deletion is involved in structural abnormalities and Th17 response but did not aggravate the inflammatory processes exerted by stress.
P102 Outcomes of coronavirus disease 2019 among patients with inflammatory bowel diseases and the influence of IBD-related medications– A Danish prospective population-based cohort study
Authors: Attauabi M , Poulsen A , Kajbæk Verner-Andersen M , Rosager Hansen M , Pedersen N , Pilegaard Prahm A , Berg Lødrup A , Haderselv K , Larsen L , Jess T , Glerup H , Molazahi A , Mathiassen Oppfeldt A , Dahlerup J F , Lodberg Hvas C , Neumann A , Wase A , Dam Jensen M , Nathan T , Jensen S , Theede K , Kiszka-Kanowitz M , Benedict Seidelin J , Burisch J 
Published: May 2021

Abstract

Background
Population-based data regarding outcomes of coronavirus disease 2019 (COVID-19) among patients with ulcerative colitis (UC) and Crohn’s disease (CD) are limited. Studies on the association of COVID-19 outcomes and immunomodulating therapies, are scarce. Therefore, we aimed to conduct a population-based study investigating the outcomes of COVID-19 among patients with UC and CD in Denmark.

Methods
The Danish COVID-19 IBD Database is an extensive population-based database that prospectively monitors the disease course of laboratory-confirmed COVID-19 among patients with UC and CD in Denmark. Severe COVID-19 was defined as COVID-19 necessitating intensive care unit admission, ventilator use, or death. Regression analysis was adjusted for age, sex, disease type, disease activity, cardiovascular disease, and corticosteroids.

Results
The study recruited 363 patients (UC: 223; CD: 140) from January 28th, 2020, to February 7th, 2021. A total of 36 (16.1%) and 18 (12.9%) patients with UC and CD, respectively, required a COVID-19 related hospitalization, while eight (3.6%) and three (2.1%) patients required intensive care treatment. Death due to COVID-19 was observed among eight (3.6%) and two (1.4%) patients, respectively. The association between these outcomes and IBD-related treatment is presented in Table 1. As shown, none of the IBD-related medications were associated with severe COVID-19 in univariate and adjusted analysis. However, systemic steroids were found to be associated with the risk of COVID-19 related hospital admission among patients with UC (adjusted odds ratio (aOR)=6.54 (95% CI 1.09-36.39)) and CD (aOR=5.45 (95% CI 2.07-12.24)).

Conclusion
This ongoing Danish population-based study on COVID-19 outcomes among patients with UC and CD demonstrated severe COVID-19 among only a minority of patients, which was not associated with IBD-related medications. However, use of systemic steroids were associated with COVID-19 necessitating hospital admission among patients with UC and CD.
P103 Minimal Clinically Important Difference (MCID) for the Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) Tool
Authors: Pulley J , Galloway D , Oh Y , Devine J , Petrek H , Khavarian A , Matsui A 
Published: May 2021

Abstract

Background
The UC-PRO/SS tool developed by the IBD PRO Consortium is undergoing FDA Drug Development Tool qualification (COA DDT# 000040). Derivation of minimal clinically important difference (MCID) thresholds for improvement in bowel and functional signs and symptoms domain scores are presented here.

Methods
MCID estimates for bowel and functional domains were derived using anchor- and distribution-based approaches applied to data from three studies of Etrolizumab. Initial MCIDs were developed using Mayo Clinic Score (MCS) and Inflammatory Bowel Disease Questionnaire (IBDQ) response thresholds as anchors; Cronbach’s alpha SEM and Cohen’s moderate effect size statistics were calculated. MCIDs were then cross-validated internally and externally, i.e. within and across target populations, using clinical (modified and partial MCS) and patient-centered (IBDQ “general wellness” item 10 and EQ5D VAS) measures, to support generalizability. CDF plots with pooled data provide further empirical support.

Results
Study populations had mean ages of 39.2–40.5 years; were 54.5–58% male; 77.5–93.9% white; and had mean disease duration of 8.75–8.98 years. Six points was selected as the bowel domain threshold as change of this magnitude aligns with the anchor settings (5.89, 6.93, and 7.15 for IBDQ and 5.63, 6.12, and 7.63 for MCS) and exceeds measurement error as shown by distributional methods (Cronbach’s alpha SEM 2.071, 2.160, and 2.167, Cohen’s moderate effect size range 2.086, 2.135, and 2.191). A two-point threshold was similarly selected for the functional domain based on anchor settings (1.77, 1.98, and 2.53 for IBDQ and 1.56, 1.68, and 2.01 for MCS) and distributional methods (Cronbach’s alpha SEM 1.336,1.140, and 1.417, Cohen’s moderate effect size range 1.204, 1.270, and 1.309). External, cross-validation showed numerically robust differences (no overlapping CI’s) between the group achieving the MCID versus not across clinical and PRO variables for both domains. Magnitudes of change on IBDQ item 10 and EQ5D VAS variables scores exceeded the ½ SD for interpreting moderate levels of PRO score change. For the bowel domain, separation of CDF curves between responder groups showed cumulative percentages of approximately 60% and 70% based on IBDQ and MCS anchors, respectively, at the thresholds indicating change of a six-point magnitude. For the functional domain, separation between CDF curves at the 2-point threshold occurred at points indicating cumulative proportions of response greater than 50% using both anchors.

Conclusion
MCIDs of 6 and 2 points for the bowel and functional domains of the UC-PRO/SS are robustly defined and cross-validated, allowing interpretation of clinical improvement in symptoms among moderate to severe adult UC patients.
P114 Frequent work productivity and activity impairment in caregivers of children with inflammatory bowel disease: a project of the prospective PIBD-SETQuality inception cohort study
Authors: Klomberg R , Kemos P , Aardoom M , Rizopoulos D , Croft N , de Ridder L , Neyt M 
Published: May 2021

Abstract

Background
Paediatric inflammatory bowel disease (IBD) can disrupt daily lives of patients and their caregivers, who may be impaired in performing work or daily activities due to increased caretaking responsibilities, accompanying to frequent hospital visits and increased school absence of their children. However, literature on these impairments is sparse. The aims of this study were to longitudinally quantify this work and activity impairment and evaluate associated factors. Second, to assess the impact of these impairments on caregiver’s health-related quality of life (HRQoL).

Methods
Since January 2017, children with newly diagnosed IBD are included for the international prospective PIBD-SETQuality inception cohort study1. Patient and disease characteristics are collected at time of diagnosis, at three and twelve months. The impact of the child’s IBD on caregiver’s socioeconomic functioning and HRQoL (rate 1–10) is longitudinally evaluated by the Work Productivity and Activity Impairment (WPAI) and EQ-5D-5L questionnaire. Primary outcomes, including absenteeism (percentage work time missed), presenteeism (percentage impairment while working), work productivity loss (percentage overall work impairment) and activity impairment (percentage affected daily activities, such as householding or exercise), were evaluated using generalized estimating equations models.

Results
Up to February 2021, 436 children (247 Crohn’s disease (CD); 169 ulcerative colitis (UC)/IBD-unclassified (IBDU)) were eligible for analysis of the WPAI questionnaire. Mean employment rate at diagnosis was 81.0% (74.8% CD, 86.0% UC/IBD-U, p=0.050). At diagnosis, mean absenteeism, presenteeism, work productivity loss and activity impairment were 28.0%, 31.4%, 46.4% and 36.5% respectively (Figure 1A-D). Work productivity loss and activity impairment significantly decreased over time and were associated with disease activity, but not with IBD diagnosis or age at diagnosis (Figure 2A-B). Work productivity loss, but not activity impairment was negatively associated with HRQoL (β -0.067, p&lt;0.01; β -0.027, p=0.387 respectively). Estimated costs related to absenteeism associated with the child’s disease were €8711 per patient during the first year after diagnosis.

Conclusion
Parents of children with IBD experience significant impairments in their work and daily activities. The impact is biggest at diagnosis, plateaus thereafter and is associated with disease activity. Work productivity impairment results in indirect costs and reduced HRQoL.

Reference

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P117 Patient perceptions about causes of flare in IBD: results from the baseline dataset of the PREdiCCt study
Authors: Siakavellas S , Derikx L , Derr L , Williams L , Plevris N , Jenkinson P , Laura L , Constantine-Cooke N , Covil K , Murdoch L , Jones G R , Lees C 
Published: May 2021

Abstract

Background
Patient reported outcomes are important endpoints in IBD management, but patient perceptions of the causes of disease flare are unknown and thus may reveal novel areas for future study.

Methods
The PREdiCCt study (https://www.predicct.co.uk) is the largest prospective study of the causes of IBD flare. 2629 patients in clinical remission were recruited from 48 UK sites and followed for 2 years with detailed assessment of environmental and dietary factors via monthly questionnaires. 1946 (74%) patients completed the baseline questionnaires. We present here the results of the baseline questionnaire analysis of patient perceptions of disease flare, derived from a list of 17 putative causes from the literature and their own experience via free text input.

Results
In total 1,946 IBD patients [male=852, CD=1000; UC/IBDU=946, age 45.8±15.5 (mean±SD in years)] gave their opinion about factors initiating a flare. The commonest causes reported were stress (n=1359, 69.8%), dietary changes (n=911, 46.8%), alcohol use (n=385, 19.8%), sleep disturbances (n=331, 17%) and that their medication stopped working (n=308, 15.8%) (Figure 1). CD participants were more likely to identify dietary changes (50% vs 43%, p&lt;0.001) and menstruation (16% vs 10% of female patients, p&lt;0.001) as flare triggers than UC/IBDU participants, while UC/IBDU participants more frequently reported loss of response to medication as a trigger for flare (9% vs 5% for CD participants, p&lt;0.001). CD patients with small bowel involvement were more likely to name dietary changes (61% vs 42%, p&lt;0.001), travel (14% vs 9%, p=0.016) and smoking (4% vs 1%, p=0.04) as flare triggers. When compared by gender, the ranking of causes was identical but female participants were more likely to identify stress (77% vs 65%, p&lt;0.001) and antibiotic use (12% vs 6%, p&lt;0.001) as reasons for disease relapse compared to male participants.

Conclusion
Stress, dietary changes and alcohol use were identified as the main causes of flare by patients with dietary changes more frequently reported in CD (especially those with small bowel involvement). The impact of environmental and dietary factors in the development of flare is being further investigated with ongoing longitudinal data collection in the PREdiCCt Study.
P128 Depression, anxiety and stress among Inflammatory Bowel Disease patients during COVID-19: A UK cohort study
Authors: Luber R , Duff A , Pavlidis P , Honap S , Meade S , Ray S , Anderson S , Mawdsley J , Samaan M , Irving P 
Published: May 2021

Abstract

Background
Patients with chronic diseases, particularly those requiring immunosuppression, are thought to be at increased risk of poor mental health during the COVID-19 pandemic. However, few studies have assessed the mental health of such patients during the current or past pandemics.
We aimed to assess the incidence of depression, anxiety & stress in a cohort of inflammatory bowel disease (IBD) patients early during the COVID-19 pandemic, & explore for association with risk of severe COVID-19 based on British Society of Gastroenterology guidelines, & other factors.

Methods
A survey including the Patient Health Questionnaire-9, General Anxiety Disorder-7, & Perceived Stress Scale tools for depression, anxiety & stress, respectively, was administered to a cohort of IBD patients from a tertiary centre in London, United Kingdom, in June 2020.

Results
274 patients responded to the survey (57% response rate), including 54 low risk, 152 moderate risk, & 68 high risk for severe COVID-19. Moderate-severe depression was observed in 61 (22.5%), moderate-severe anxiety in 49 (18%), while 39 (14%) had both diagnoses (Table). Mean (SD) stress score was 16.2 (7.4). There was no association between degree of severe COVID-19 risk & psychological morbidity. Flare symptoms & fatigue were associated with worse psychological morbidity across all measures, while accessibility of information regarding COVID-19 risk & reducing that risk was protective for depression (OR 0.56 [0.33–0.94], p=0.03), anxiety (OR 0.62 [0.4–0.96], p=0.03), & stress (standardized β-coefficient -0.15 [-0.28--0.03], p=0.02) (Figure). 79 (30%) respondents were interested in receiving psychological support during the pandemic, while 200 (76%) expressed interest beyond the pandemic.

Conclusion
Depression, anxiety & stress among IBD patients during the pandemic are common, however their frequency is similar to pre-pandemic rates & general population levels reported during the same period. Ensuring easy access to personalized risk information with targeted psychological support may mitigate psychological burden as patients reintegrate into society & deal with future COVID-19 waves or variants.