bluuebunny/crossref_metadata_2025_split huggingface dataset:
The healing myocardium mobilizes a distinct B-cell subset through a CXCL13-CXCR5-dependent mechanism
Authors: Heinrichs Margarete , Ashour DiyaaElDin , Siegel Johanna , Büchner Lotte , Wedekind Georg , Heinze Katrin G , Arampatzi Panagiota , Saliba Antoine-Emmanuel , Cochain Clement , Hofmann Ulrich , Frantz Stefan , Campos Ramos Gustavo 
Published: May 2021

Abstract

Aims
Recent studies have revealed that B cells and antibodies can influence inflammation and remodelling following a myocardial infarction (MI) and culminating in heart failure—but the mechanisms underlying these observations remain elusive. We therefore conducted in mice a deep phenotyping of the post-MI B-cell responses in infarcted hearts and mediastinal lymph nodes, which drain the myocardium. Thereby, we sought to dissect the mechanisms controlling B-cell mobilization and activity in situ.

Methods and results
Histological, flow cytometry, and single-cell RNA-sequencing (scRNA-seq) analyses revealed a rapid accumulation of diverse B-cell subsets in infarcted murine hearts, paralleled by mild clonal expansion of germinal centre B cells in the mediastinal lymph nodes. The repertoire of cardiac B cells was largely polyclonal and showed no sign of antigen-driven clonal expansion. Instead, it included a distinct subset exclusively found in the heart, herein termed ‘heart-associated B cells’ (hB) that expressed high levels of Cd69 as an activation marker, C-C-chemokine receptor type 7 (Ccr7), CXC-chemokine receptor type 5 (Cxcr5), and transforming growth factor beta 1 (Tgfb1). This distinct signature was not shared with any other cell population in the healing myocardium. Moreover, we detected a myocardial gradient of CXC-motif chemokine ligand 13 (CXCL13, the ligand of CXCR5) on Days 1 and 5 post-MI. When compared with wild-type controls, mice treated with a neutralizing CXCL13-specific antibody as well as CXCR5-deficient mice showed reduced post-MI infiltration of B cells and reduced local Tgfb1 expression but no differences in contractile function nor myocardial morphology were observed between groups.

Conclusion
Our study reveals that polyclonal B cells showing no sign of antigen-specificity readily infiltrate the heart after MI via the CXCL13-CXCR5 axis and contribute to local TGF-ß1 production. The local B-cell responses are paralleled by mild antigen-driven germinal centre reactions in the mediastinal lymph nodes that might ultimately lead to the production of specific antibodies.
DOP26 The relationship between vedolizumab therapeutic drug monitoring, biomarkers of inflammation, and clinical outcomes in Inflammatory Bowel Disease in the real-world setting
Authors: Afif W , Marshall J K , Kaidanovich-Beilin O , Ward R , Seow C 
Published: May 2021

Abstract

Background
Despite widespread use of therapeutic drug monitoring to guide anti-TNF biologic prescribing in IBD, its role for other biologic classes remains unclear. The present study aimed to assess the relationship between early vedolizumab trough concentrations (VTC) and real-world outcomes in inflammatory bowel disease (IBD).

Methods
Individuals with IBD enrolled in the Takeda Canada Patient Support Program were assessed at regular intervals from 2018–2020. VTC, albumin, faecal calprotectin (FC), C-reactive protein (CRP), and disease scores were collected from Crohn’s disease (CD; Harvey-Bradshaw Index, HBI) and ulcerative colitis (UC; Partial Mayo scores, PMS) patients. The relationship between post-induction (Week 6) VTC, baseline albumin, and Week 30 remission as defined by CRP (&lt;5mg/L), FC (&lt;250µg/g), or disease scores (HBI &lt;5; PMS &lt;3) was assessed.

Results
Week 6 VTC levels were higher in IBD patients who achieved Week 30 CRP remission compared with those who did not (n=248, p=0.0004). The Week 6 VTC cut-off that best predicted CRP remission for all IBD patients was 39.65µg/mL (AUROC: 0.61, 95% CI: 0.54–0.69, p&lt;0.001), with significance in both univariate (n=248; p&lt;0.001) and multivariate (p=0.002) analyses. In disease-specific subgroups, optimal VTC cut-offs in CD and UC patients displayed this same relationship. UC patients with Week 6 VTC levels &gt;39.65µg/mL had significantly longer treatment duration (n=115; HR: 0.29, 95% CI: 0.10–0.86); CD patients did not. Week 6 VTC levels were higher in IBD patients who achieved Week 30 FC remission compared with those who did not (n=170, p=0.003). The Week 6 VTC cut-off that best predicted Week 30 FC remission for all IBD patients was 41.9µg/mL (AUROC: 0.62, 95% CI: 0.54–0.7, p&lt;0.0001), with significance in univariate (n=170; p=0.002) but not multivariate analyses. Baseline albumin levels in all IBD patients were independently associated with Week 30 FC remission by multivariate analyses (n=170, p=0.006). In disease-specific subgroups, optimal Week 6 VTC cut-offs and baseline albumin levels were associated with Week 30 FC remission in CD patients only. All IBD patients with Week 6 VTC levels &gt;41.9µg/mL had longer treatment duration (n=170; HR: 0.31, 95% CI: 0.12–0.83). No relationships were found between Week 6 VTC and HBI or PMS disease scores.

Conclusion
Post-induction VTC predicts remission by CRP in individuals with CD and UC but not remission by FC or clinical disease indices. Baseline albumin is independently associated with FC remission. Further research is warranted to better understand these relationships, and to develop multivariable predictive tools that combine baseline biomarkers with early vedolizumab pharmacokinetics.
DOP48 Use of biologic therapies with different mechanisms of action (MOA) in the first-line (1L) treatment of Crohn’s Disease (CD) in the U.S
Authors: Huang Z , Ba Y , Kamble P , Wang S 
Published: May 2021

Abstract

Background
Anti-cytokine biologics (anti-TNF agents, anti-IL-12/23 agent) and gut-selective anti-lymphocyte trafficking agent (MAdCAM α4β7 blocker) are available treatment options for patients (pts) with moderate-to-severe CD. There are limited data on treatment persistence of these different MOA as 1L biologic treatment of CD in real-world setting.

Methods
This retrospective study used the Truven Health MarketScan administrative claims database to assess treatment patterns in a large U.S. insured population. Biologic naïve adult CD pts (CD diagnosed by using ICD 9 and 10 codes) who initiated (date of initiation defined as index date) 1L biologic treatment (adalimumab [ADA], infliximab [IFX], vedolizumab [VDZ] or ustekinumab [UST] between 09/2016 and 09/2019) with ≥6 months of continuous health benefits enrolment post biologics initiation were included. Treatment persistence was defined as time to index drug discontinuation with a pre-defined gap or switch to other biologic drugs.

Results
Overall, 2648 ADA, 1446 IFX, 474 VDZ, and 415 UST treated CD pts were identified. The mean age was highest for VDZ pts (45.5 y), followed by UST (42.2 y), ADA (40.1 y) and IFX (38.8 y). The use of corticosteroid in 12 months prior to 1L biologics was highest for ADA pts (74.3%), then UST (68.2%), VDZ (65.2%), and IFX (64.9%). Disease duration (time from the first observed CD diagnosis to 1L biologics initiation date) ≤ 2 yrs was found lowest in VDZ pts (48.1%), then UST (54.7%), ADA (59.6%), and IFX (67.6%). Fistulising condition in 12 months before 1L biologics was highest in IFX pts (11.9%), then UST (9.4%), ADA (7.7%), and VDZ (5.3%). Continuation on 1L biologics was highest in VDZ pts (59.1%), followed by IFX (58.0%), UST (57.6%), and ADA (50.8%). Treatment discontinuation was highest in UST pts (35.7%), then ADA (35.4%), VDZ (30.2%), and IFX (28.2%). Switch to 2L biologics was highest in IFX pts (13.9%), then ADA (13.8%), VDZ (10.8%) and UST (6.8%). Median treatment persistence was highest for VDZ pts (842 days), followed by IFX (770 days), UST (566 days) and ADA (507 days). VDZ pts showed higher treatment persistence than ADA pts (log-rank p-value=0.005) or UST pts (p=0.14). IFX pts had higher persistence than ADA pts (p&lt;0.0001) or UST pts (p=0.07). The adjusted hazard ratio of treatment discontinuation, with VDZ as the reference group, was highest for ADA (1.36, p&lt;0.0001), then UST (1.27, p=0.023) and IFX (1.07, p=0.45).

Conclusion
In biologic naïve CD pts, real-world evidence shows that VDZ is associated with longer treatment persistence when compared with any of the currently approved anti-cytokine biologics. With &gt;2 years of treatment persistence, VDZ and IFX were significantly superior to both ADA and UST.
DOP76 No durable impact of COVID-19 on disease activity and microbiome composition in patients with IBD
Authors: Funez-dePagnier G , Lima S , Duenas-Bianchi L , Lai D , Ahmed W , Battat R , Scherl E , Lukin D , Longman R 
Published: May 2021

Abstract

Background
Although patients with inflammatory bowel disease (IBD) reported an increased frequency of gastrointestinal (GI) symptoms following infection, the durable impact of COVID-19 on underlying IBD is not well defined.

Methods
In 118 IBD patients with COVID-19, clinical and endoscopic IBD activity, laboratory markers (ESR, CRP, hemoglobin (Hb), fecal calprotectin(FCP)), and medication utilization was assessed up to 6 months post-infection and compared to during infection or up to 6 months prior to infection. Active disease was defined by a Harvey Bradshaw Index &gt; 4, Mayo Score ≥2, SES-CD ≥2, Mayo endoscopic score ≥1. 16S rRNA analysis was used to evaluate microbiome composition in a subset of 12 patients before and after COVID-19.

Results
Although upper respiratory (86.6%) and new GI symptoms (39.1%) were common in patients with IBD, there was no significant change in IBD clinical disease activity (Pre vs. Post-COVID-19 HBI: 4.7 vs. 4.9; partial Mayo: 3.0 vs. 2.1), endoscopic evaluation (Pre vs. Post-COVID-19 SES-CD: 7.2 vs. 8.9, Mayo endoscopic score: 1.5 vs. 1.7), or laboratory markers (Pre vs. Post-COVID-19 CRP: 1.2 vs. 1.3; ESR: 25 vs. 26; Hb 12.8 vs. 13.2; FCP: 388 vs. 250) up to 7 months post-COVID-19 compared to the 6 months prior to infection (Table 1). Overall active disease was present in 60% of the cohort prior to COVID-19 and 55% and 59% during and post-COVID-19, respectively. More subjects (8.5%) reported a delay in medical therapy during COVID-19, but there were no differences in the need for corticosteroids, a change in medical therapy, or IBD-related surgery or hospitalization during or post-COVID-19 compared to the prior 6 months. Microbiome composition stratified by underlying IBD disease activity, but did not show significant change post-COVID-19 (Figure 1).

Conclusion
COVID-19 showed no durable impact on clinical IBD disease activity or microbiome composition supporting guidelines for continued maintenance care.
N01 Does physical activity positively impact fatigue in individuals with Inflammatory Bowel Disease?
Authors: Farrell D , Bager P , Bredin F , Cairnes V , Forry M , Gilham E , Godwin N , Herdmangrant R , Ni Dhalaigh D , O’ Shea T , Sugrue K 
Published: May 2021

Abstract

Background
Patients with Inflammatory Bowel Disease (IBD) often experience the problematic and burdensome symptom of fatigue, both during periods of relapse and remission. The optimal management of fatigue in IBD is uncertain, however there is evidence suggesting that physical activity is likely to be a beneficial way of managing the symptom. The aim of this study is to explore the relationship between fatigue and objective measurements of both physical activity metrics and varying intensities of physical activity for individuals with IBD.

Methods
A multi-centred, European, cross-sectional, correlational study was employed. A consecutive sample of 187 patients with Crohn’s disease (59%) or ulcerative colitis (41%) were recruited from six IBD centres in the Republic of Ireland (42%), United Kingdom (40%) and Denmark (18%). Fatigue was measured using the IBD-Fatigue (IBD-F) scale, including both the level of fatigue (IBD-F, Section 1) and impact of fatigue (IBD-F, Section 2). Physical activity was objectively measured using scientifically validated triaxial accelerometers (ActiGraph wGT3X-BT) during seven consecutive days.

Results
A moderate level of fatigue (IBD-F Section 1 Md (IQR) = 10 (6 – 13)), predominantly intermittent in nature (72%) was reported by participants (57.4% female; 59% Crohn’s disease; 43% active disease). Participants self-reported sleeping an average of 8.7 hours over the seven nights. During the week, the intensity of activity was predominantly sedentary (Md 5 days, 22 hours, 20 minutes) or light (Md 19 hours, 35 minutes). The median moderate-to-vigorous intensity of physical activity per day was 32.2 minutes and step count over the week was 47052 steps. There was no evidence of a unique linear or non-linear relationship between each of the objective measurements of physical activity with IBD-related fatigue. This lack of evidence extended separately to patients in remission and to patients with active disease. These findings are in the context of a statistically significant moderately-strong relationship between disease activity (measured using both HBI and SCCAI) and level of fatigue for both patients of Crohn’s disease (rs = .327, p = .001, n = 96) and ulcerative colitis (rs = .353, p = .003, n = 71).

Conclusion
This large multi-centred study shows no association between objective measurements of physical activity and IBD-fatigue. These findings suggest that engaging or not engaging in physical activity has no differential impact on self-assessment of fatigue.
N12 A decade of waiting to know is not good enough! Experiences of women with vulval Crohn’s disease
Authors: Fourie S , Czuber-Dochan W , Jackson D , Norton C 
Published: May 2021

Abstract

Background
Vulval Crohn’s disease is a rare extra manifestation of inflammatory bowel disease, and there is no treatment consensus for it. Current evidence is mainly from case studies and includes only about 250 participants globally. We explored how vulval Crohn’s disease affects women’s sexual well-being, and aimed to understand what might be the specific experiences of sexuality in this group

Methods
Three participants from a phenomenological study exploring sexuality in inflammatory bowel disease have self-reported as diagnosed with vulval Crohn’s disease. Data collected from telephone interviews were analysed using thematic analysis.

Results
Women with vulval Crohn’s disease reported a severe disease course with devastating consequences on their sexuality, and suffered years of delay in their diagnosis. Their experiences were summarised in four main themes: Scarred by Crohn’s, Striving for normality, Waiting too long, and Who’s going to help? Sex posed extreme challenges imposed by the condition, and participants waited almost a decade to get a diagnosis, which negatively affected their trust in clinicians. In their effort to continue to enjoy a sexual life as normal as possible, they had feared for the future, as they felt healthcare professionals were unsure of who should help those living with vulval Crohn’s disease.

Conclusion
In spite of specialists having knowledge of vulval Crohn’s disease, participants experienced lengthy periods to get a diagnosis, with damaging consequences for their lives. Discussing sexual well-being in clinical settings may increase chances of early detection and avoid worsening symptoms.
N16 ‘Sex? Don’t even remember what that is …’ exploring IBD patient engagement with online forums regarding the topics of relationships and intimacy
Authors: Barnes H , Fourie S 
Published: May 2021

Abstract

Background
Online forums available to those living with Inflammatory Bowel Disease (IBD) are a platform enabling peer support. Some use online forums to discuss sensitive issues, such as the effect of chronic conditions on their intimate and sexual lives. This study explored the common topics regarding relationships and intimacy with IBD that are discussed on online forums.

Methods
This study collected anonymous data available from a public domain (online forum) and analysed it using Braun and Clarke’s thematic analysis. Data were collected from 15 threads discussing topics relating to IBD and relationships from 2008 to 2016. In total, it involved around 144 people engaged in group conversations on the topics. No subscription was needed to access the data, and all participants used pseudonyms.

Results
Two themes were developed from analysing online forum engagement on sensitive topics: Relationships and IBD and ‘ Sex? What’s that?’ . The most prevalent discussions were around broken-down relationships: ‘The guy I was dating when I was diagnosed broke up with me 6–8 months later, in large part because of how the disease was changing my life’. There were many concerns about the right time for disclosure of illness whilst dating: ‘I feel like 5 dates/one months was definitely the right time. It’s not first date material.’ Participants actively sought others’ intimate experiences for advice and found consolation in sharing common experiences, particularly regarding symptoms affecting sex:’ Intimacy and Crohn’s can be an awful combination’, or relationships: ‘I am dating two! My iPad and my UC! Neither snore, but both are very needy!’ Participants also expressed their findings of comfort from hearing others experiences online: ‘This thread gives us hope though that it is possible to be with someone with this disease’. Additionally, sexual minority groups can also feel that they have a platform where they can discuss sexuality without prejudice and easily access others of the same sexual orientation when asking for advice.

Conclusion
IBD patients use online forums to discuss their intimate lives when looking for help from others experiencing a similar situation or looking for acceptance. This suggests patients may feel embarrassed talking about sex and may not see their health care professionals as the first port of call for questions about intimacy, highlighting the importance of online forums in seeking peer support for such topics. Further research is recommended to understand how patients might prefer to express their worries in an anonymous, safe environment.
OP07 Artificial intelligence surpasses gastrointestinal experts in the classification of endoscopic severity among Ulcerative Colitis
Authors: Lo B Z S , Liu Z , Bendtsen F , Igel C , Vind I , Burisch J 
Published: May 2021

Abstract

Background
Evaluation of endoscopic disease severity is a key component in the management of ulcerative colitis (UC) patients. However, endoscopic assessment suffers from substantial intra- and interobserver variation, up to 75 %, thereby limiting the reliability of individual assessments. Our aim was to develop an artificial intelligence (AI) model capable of distinguishing active from healed mucosa as well as to differentiate different levels of endoscopic disease activity.

Methods
1484 unique endoscopic images from 467 patients were extracted for classification. Two experts classified all images independent of each other according to the Mayo endoscopic subscore (MES). In case of disagreement, a third expert classified the images.
Different convolutional neural network architectures were implied in the development of the AI model. Five-fold cross-validation was employed to select the best model. Unseen test data were used for evaluation.
The final model was evaluated on its performance for distinguishing MES 0 from 1–3, MES 0–1 (i.e. mucosal healing) from 2–3, and distinguish between all MES.
The accuracy, sensitivity, specificity, positive and negative predictive value, and Cohen’s Kappa were used to evaluate the final models.

Results
Our final model achieved at the most difficult task (distinguishing between all 4 categories of MES) a mean accuracy of 0.82, mean AUC of 0.99, test accuracy of 0.84, a sensitivity of 0.88, and a specificity of 0.81 and a weighted Cohens Kappa of 0.83 (p&lt;0.001 compared to the experts).
The results from the other tasks are shown in table 1.

Conclusion
We propose a new standardised way of evaluating endoscopic images from UC patients for both clinical and academic purposes. The proposed AI model demonstrated a very good capability of distinguishing between all 4 MES levels of activity. This will optimize and unify the evaluation of the disease severity measured by the Mayo endoscopic subscore across all centres and hospitals no matter the level of medical expertise.
OP10 Response to biologics in IBD patients assessed by Computerized image analysis of Probe Based Confocal Laser Endomicroscopy with molecular labeling and gene expression profiling
Authors: Iacucci M , Jeffery L , Acharjee A , Nardone O M , Smith S C , Labarile N , Zardo D , Cannatelli R , Shivaji U N , Ungar B , Buda A , Grisan E , Gkoutos G , Subrata G 
Published: May 2021

Abstract

Background
Biologics are being used increasingly in the treatment of Inflammatory Bowel Disease. However, up to 40% of patients do not respond to biologics. Therefore, methods to predict response are imperative. We aimed to identify novel genes and pathways predictive of anti-TNF response in patients with Ulcerative Colitis (UC) undergoing electronic chromoendoscopy and probe confocal laser endomicroscopy (pCLE). We further evaluated the ex-vivo binding of fluorescent labelled biologics as markers of response

Methods
26 UC patients starting anti-TNF therapy as standard of care were recruited. Pre-treatment colonoscopy, with electronic chromoendoscopy and pCLE (Cellvizio, Mauna Kea) by injecting intravenous fluorescein (2.5-5mls), was performed to assess disease activity. Targeted biopsies were taken for fluorescein isothiocyanate (FITC)-labelled infliximab staining and RNA extraction and gene expression analysis. Ex vivo labelling was evaluated by an automated analysis: after a first pre-processing step to remove biases, the labelled regions were identified using statistical multi-level thresholding, and evaluated as area and intensity. To assess response, the same endoscopic procedure was repeated at week 12–14 after anti-TNF. cDNA libraries were prepared using QIAseq UPX 3’Transcriptome reagents and sequenced. Normalised gene expressions were obtained through the CLC Genomics Workbench. Differentially expressed genes (DEGs) (FDR-corrected P-value&lt;0.05) were determined using the Limma package and PLS-DA modelling performed to calculate their importance (VIP score). Functionally related genes were identified and classified using DAVID tools. Strongest indicators of response were predicted by Random Forest area under the curve (AUC) analysis in this cohort and a similar validation cohort

Results
At baseline increased binding of the labelled biologic was associated with a higher likelihood of response to treatment (AUROC81%, accuracy77%, PPV100%, NPV63%). 342 DEGs (75 up-regulated, 267 down-regulated) distinguished responders from non-responders, 76 fell within enriched pathways. Pathways related to inflammation, chemotaxis, TGF-beta signalling, extracellular matrix and carbohydrate metabolism were reduced and cell-cell adhesion increased in responders pre-treatment. Among the 37 genes with VIP&gt;1, CRIP2, CXCL6,EMILIN1,GADD45B, LAMA4 and MAPKAPK2 were upregulated in non-responders pre-treatment and were good predictors of response (AUROC&gt;0.7) in this cohort and validation cohort

Conclusion
A higher mucosal binding of the biologics before treatment was observed in anti-TNF responders. Responsive UC patients have a less inflamed and fibrotic state pre-treatment. Chemotactic pathways, involving CXCL6 may be novel targets to treat non-responders