bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-time frequency transfer system over ground-to-satellite link based on carrier-phase compensation at 10−16 level*
Authors: Liang Hui-Jian , Wang Shi-Guang , Bai Yu , Sun Si-Chen , Wang Li-Jun
Published: May 2021

We demonstrate a novel and stable frequency transfer scheme over ground-to-satellite link based on real-time carrier-phase detection and compensation. We performed a zero-baseline measurement with the designed system, an uninterrupted frequency standard signal is recovered in the reception station without additional post-correction of delay error caused in the route, which is because the phase error of the entire route is tracked and compensated continuously in real-time. To achieve this goal, we employed two carriers in the system and the differential signal is transferred in order to eliminate the instability results from the local oscillator at the satellite transponder as well as the common-mode noise induced in the transfer route and microwave components. The stability of 3 × 10−16 with an integration time of 1 day was achieved and the time fluctuation during one day was measured to be about ±20 ps. Error sources and possible solutions are discussed. Our zero-baseline method shows a promising result for real-time satellite-based time and frequency transfer and deserves further research to find whether it works between long-baseline stations.
Effects of initial states on the quantum correlations in the generalized Grover search algorithm*
Authors: Chen Zhen-Yu , Qiu Tian-Hui , Zhang Wen-Bin , Ma Hong-Yang
Published: May 2021

We investigate the correlations between two qubits in the Grover search algorithm with arbitrary initial states by numerical simulation. Using a set of suitable bases, we construct the reduced density matrix and give the numerical expression of correlations relating to the iterations. For different initial states, we obtain the concurrence and quantum discord compared with the success probability in the algorithm. The results show that the initial states affect the correlations and the limit point of the correlations in the searching process. However, the initial states do not influence the whole cyclical trend.
Stability analysis of multiple-lattice self-anticipative density integration effect based on lattice hydrodynamic model in V2V environment*
Authors: Zhang Geng , Tian Da-Dong
Published: May 2021

Under the environment of vehicle-to-vehicle (V2V) communication, the traffic information on a large scale can be obtained and used to coordinate the operation of road traffic system. In this paper, a new traffic lattice hydrodynamic model is proposed which considers the influence of multiple-lattice self-anticipative density integration on traffic flow in the V2V environment. Through theoretical analysis, the linear stability condition ofthe new model is derived and the stable condition can be enhanced when more-preceding-lattice self-anticipative density integration effect is taken into account. The property of the unstable traffic density wave in the unstable region is also studied according to thenonlinear analysis. It is shown that the unstable traffic density wave can be described by solving the modified Korteweg–de-Vries (mKdV) equation. Finally, the simulation results demonstrate the validity of the theoretical results. Both theoretical analysis and numerical simulations demonstrate that multiple-lattice self-anticipative density integrationeffect can enhance the stability of traffic flow system in the V2V environment.
A condensed-matter analogue of the false vacuum
Authors: Gibbons Mark
Published: May 2021

Through experimental investigation into the behaviour of a polar dielectric working fluid, an ideal ‘quasi-thermodynamic’ cycle has been established. Particular stages of this cycle are described in terms of a condensed-matter analogue of the false vacuum, when operating under negative pressure. The cycle is established between 37 °C and 15 °C under isochoric conditions. Phase-change work is created in two-directions, positive expansion-work and negative contraction-work. A large proportion of the expansion-work derives from a cooling process where the fluid exhibits negative heat capacity. When heat flux ceases, the fluid becomes unstable and heat capacity switches from negative to positive, displaying a ‘non-equivalence of ensembles’ phase-change. Whilst elements of the fluid behaviour can only be described by the statistical mechanics of non-equilibrium systems, the calculated equations of state for classical thermodynamics are confirmed to be accurate from the experimental investigation. However, the classical thermodynamic calculations for cycle-efficiency do not produce a symmetry of energy conservation. This suggests that an additional form of energy, having long-range interaction and distinct from heat and work input, is involved in the performance of the quasi-thermodynamic cycle. The expansion of a negative pressure fluid that contains inclusion compounds appears responsible for this potential energy interaction as an analogue of the false vacuum potential that can be explained by application of the virial theorem.
Stochasticity helps to navigate rough landscapes: comparing gradient-descent-based algorithms in the phase retrieval problem
Authors: Mignacco Francesca , Urbani Pierfrancesco , Zdeborová Lenka
Published: May 2021

In this paper we investigate how gradient-based algorithms such as gradient descent (GD), (multi-pass) stochastic GD, its persistent variant, and the Langevin algorithm navigate non-convex loss-landscapes and which of them is able to reach the best generalization error at limited sample complexity. We consider the loss landscape of the high-dimensional phase retrieval problem as a prototypical highly non-convex example. We observe that for phase retrieval the stochastic variants of GD are able to reach perfect generalization for regions of control parameters where the GD algorithm is not. We apply dynamical mean-field theory from statistical physics to characterize analytically the full trajectories of these algorithms in their continuous-time limit, with a warm start, and for large system sizes. We further unveil several intriguing properties of the landscape and the algorithms such as that the GD can obtain better generalization properties from less informed initializations.
Development of an antimicrobial stewardship module in an electronic health record: Options to enhance daily antimicrobial stewardship activities
Authors: Dzintars Kathryn , Fabre Valeria M , Avdic Edina , Smith Janessa , Adams-Sommer Victoria , Townsend Jennifer , Jenh Hsu Alice , Cosgrove Sara E
Published: May 2021

Purpose

The purpose of this manuscript is to describe our experience developing an antimicrobial stewardship (AS) module as a clinical decision support tool in the Epic electronic health record (EHR).

Clinical decision support systems within the EHR can be used to decrease use of broad-spectrum antibiotics, improve antibiotic selection and dosing, decrease adverse effects, reduce antibiotic costs, and reduce the development of antibiotic resistance. The Johns Hopkins Hospital constructed an AS module within Epic. Customized stewardship alerts and scoring systems were developed to triage patients requiring stewardship intervention. This required a multidisciplinary approach with a team comprising AS physicians and pharmacists and Epic information technology personnel, with assistance from clinical microbiology and infection control when necessary. In addition, an intervention database was enhanced with stewardship-specific interventions, and workbench reports were developed specific to AS needs. We herein review the process, advantages, and challenges associated with the development of the Epic AS module.

Conclusion

Customizing an AS module in an EHR requires significant time and expertise in antimicrobials; however, AS modules have the potential to improve the efficiency of AS personnel in performing daily stewardship activities and reporting through a single system.
Aiming off the target: recycling target capture sequencing reads for investigating repetitive DNA
Authors: Costa Lucas , Marques André , Buddenhagen Chris , Thomas William Wayt , Huettel Bruno , Schubert Veit , Dodsworth Steven , Houben Andreas , Souza Gustavo , Pedrosa-Harand Andrea
Published: May 2021

Background and Aims

With the advance of high-throughput sequencing, reduced-representation methods such as target capture sequencing (TCS) emerged as cost-efficient ways of gathering genomic information, particularly from coding regions. As the off-target reads from such sequencing are expected to be similar to genome skimming (GS), we assessed the quality of repeat characterization in plant genomes using these data.

Methods

Repeat composition obtained from TCS datasets of five Rhynchospora (Cyperaceae) species were compared with GS data from the same taxa. In addition, a FISH probe was designed based on the most abundant satellite found in the TCS dataset of Rhynchospora cephalotes. Finally, repeat-based phylogenies of the five Rhynchospora species were constructed based on the GS and TCS datasets and the topologies were compared with a gene-alignment-based phylogenetic tree.

Key Results

All the major repetitive DNA families were identified in TCS, including repeats that showed abundances as low as 0.01 % in the GS data. Rank correlations between GS and TCS repeat abundances were moderately high (r = 0.58–0.85), increasing after filtering out the targeted loci from the raw TCS reads (r = 0.66–0.92). Repeat data obtained by TCS were also reliable in developing a cytogenetic probe of a new variant of the holocentromeric satellite Tyba. Repeat-based phylogenies from TCS data were congruent with those obtained from GS data and the gene-alignment tree.

Conclusions

Our results show that off-target TCS reads can be recycled to identify repeats for cyto- and phylogenomic investigations. Given the growing availability of TCS reads, driven by global phylogenomic projects, our strategy represents a way to recycle genomic data and contribute to a better characterization of plant biodiversity.
From the Strait of Gibraltar to northern Europe: Pleistocene refugia and biogeographic history of heather (Calluna vulgaris, Ericaceae)
Authors: Gil-López Manuel Jesús , Segarra-Moragues José Gabriel , Casimiro-Soriguer Ramón , Ojeda Fernando
Published: May 2021

Calluna vulgaris (Ericaceae) is the most widespread and prevalent woody species of the European dry heathland, from the African side of the Strait of Gibraltar to northern Europe. However, previous biogeographic analyses of this species have ignored the western Mediterranean region, despite its preponderant role as a major glacial refugium for European biota. Here, we explore the existence of further Pleistocene glacial refugia for C. vulgaris in the Iberian Peninsula and the Strait of Gibraltar area and provide new insights into the post-glacial colonization of Europe by this emblematic heathland species. We carried out phylogeographical analyses of C. vulgaris samples from 44 locations using four plastid markers (matK, trnH-psbA, trnL-F and rpl16). We built palaeodistribution models using MAXENT to identify possible refugia for C. vulgaris during the mid-Pliocene, Last Interglacial (LIG), Last Glacial Maximum (LGM) and mid-Holocene. Our results identified a genetic lineage exclusive to the Strait of Gibraltar area s.l. (south-western Iberian Peninsula and north-western tip of Africa) as the most probable close to the clade of origin of the species. This lineage also had more private haplotypes than more recent, Eurosiberian clades. The obtained data highlighted two main refugia for C. vulgaris during the LGM, one around the Strait of Gibraltar and another in the north-western Iberian Peninsula. The Strait of Gibraltar area is a major centre of origin or glacial refugium for the heather C. vulgaris. However, the north-western Iberian Peninsula seems to have acted as a secondary glacial refugium for the more recent, Eurosiberian lineage of this species. This study stresses the importance of the Strait of Gibraltar area in the biogeographic history and conservation of the heather and, by extension, the European heathland habitat.
N15 Transition of care programme and treatment adherence in adolescents with Inflammatory Bowel Disease
Authors: Garzia Stafrace N
Published: May 2021

Background

The purpose of this study was to address the grey areas influencing the transition of care (TOC) aspect in adolescents suffering from IBD. In the context of healthcare, the term ‘transition’ refers to a phase of development from one stage to another. ‘TOC’ is defined as the “purposeful planned movement of adolescents and young adults with chronic conditions from child-centred to adult-oriented health care systems” (Blum et al., 1993). The point where the adolescent becomes an adult represents a milestone not only in health care delivery but also in the wider context of knowledge of medication, education, and employment, as well as sexual and psychosocial development amongst others (Greveson et al., 2011). Although this concept of care is still in its early stages, it has found its application in various specialities of medicine, including but not limited to diabetes, juvenile rheumatology, congenital heart diseases (Afzali & Wahbeh, 2017) and gastroenterology conditions, namely inflammatory bowel disease (IBD).

Methods

From this systematic review of literature that discussed TOC, it became evident that this essential process is undervalued and understudied. Transition standards vary between healthcare services and goals. The selected 3 cross-sectional, 1 cohort and 1 multi-site comparison studies published between 2013 and 2018 analysed how IBD treatment compliance in adolescents is affected when going through an established TOC compared to no TOC. While TOC has successfully created clinical targets, identified deficiencies in knowledge, adherence, and transition readiness assessments, there are still few evidence-based tools to assist in the transition process and a relative absence of transition models that have been critically appraised (Bollegala & Nguyen, 2015).

Results

Findings determined that the establishment and attendance of IBD adolescent patients in structured TOC programmes or clinics ensure cohesive treatment adherence. Nevertheless, it was established that further studies must be carried out on the matter at hand.

Conclusion

Recommendations for clinical practice, management, education, and further studies were endorsed. Such suggestions concluded that transition should be delayed until the patient has been assessed for readiness, along with the importance of involving a multidisciplinary team and the development of practical guidelines and skills aimed for optimal, lifelong IBD management.
OP38 Developing a Cost-Effective Genomic Biomarker of Cancer Risk in Patients with Ulcerative Colitis using Low-Pass Whole Genome Sequencing of Unselected Endoscopic Biopsies: A Case-Control Study
Authors: Al Bakir I , Curtius K , Smith K , Kopczynska M , Moorghen M , Hart A , Graham T
Published: May 2021

Background

Patients with ulcerative colitis (UC) are enrolled into surveillance programs for the early detection of colorectal cancer (CRC). However, most patients under surveillance are low-risk and never progress to CRC, while a significant proportion of CRCs in UC form without a preceding confirmed diagnosis of dysplasia. High resolution chromosomal copy-number alteration (CNA) analysis of unselected formalin-fixed paraffin embedded biopsies taken at surveillance colonoscopies using low pass whole genome sequencing (lpWGS) offers an appealing approach to CRC stratification.

Methods

We conducted a retrospective case-control study to compare the CNA burden in four unselected non-neoplastic left-sided colorectal biopsies from patients with E2/E3 UC derived 1–5 years prior to HGD/CRC detection (cases), with that of biopsies from patients who subsequently remained HGD/CRC-free for at least 5 years (controls). The two patient groups were matched by age, gender, duration of IBD and PSC status. lpWGS was performed using a standardised pipeline for epithelial enrichment, DNA extraction, library preparation, next generation sequencing and bioinformatic analysis.

Results

476 biopsies, derived from 42 cases and 77 controls, were analysed. Nearly 80% of patients had a detectable CNA in at least one of their biopsies, with the maximal CNA burden in a typical biopsy involving a median 1.1% of that biopsy’s genome. The CNA burden was significantly greater in the rectum compared to the sigmoid colon and descending colon. The most common CNA events were losses of between 1–30 megabases involving the sub-telomeric regions of chromosomes 5–9 and 22, which were found in similar proportion in both case and control biopsies. However, losses extending beyond sub-telomeric regions, as well as copy number gains, were found more frequently in cases biopsies (p<0.0001). The most discriminating CNA event was the presence of such a loss extending beyond subtelomeric regions in any of the patient’s four biopsies, with a high specificity exceeding 0.95 (see Kaplan-Meier plot). ROC analysis demonstrates that lpWGS output has a fair level of accuracy at predicting future HGD/CRC risk (AUC 0.73).

Conclusion

We identified multiple biopsies, predominantly in cases, with a surprisingly marked CNA burden involving over 10% of the genome, highlighting the fluid phenotype-genotype relationship. Non-dysplastic colitic epithelium can bear a significant burden of CNAs and maintain phenotypic stability for years without neoplastic transformation. Remarkably, by analysing the CNA burden of only four random biopsies, derived from less than 0.05% of the colonic surface area, we can significantly discriminate between case and control cohorts.
P015 Differential expression in colitis-associated cancer compared to Crohn′s disease and ulcerative colitis
Authors: Manna S , Sehn M , Cardoso da Silva D , Elezkurtaj S , Cineus R , Hegazy A , Siegmund B , Weixler B , Hummel M , Gröne J , Schumann M
Published: May 2021

Background

Crohn’s disease (CD) and ulcerative colitis (UC) are autoimmune-mediated conditions of chronic inflammation affecting the intestinal mucosa, that pose a lifelong risk to patients to develop a colitis-associated carcinoma (CAC). Much of current knowledge on mechanisms in CAC development result from murine CAC models, while studies on human CAC carcinogenesis are scarce. Thus, in our present study, we aimed to contribute to the understanding of colitis-associated carcinogenesis by comparative analysis of gene expression in human samples and further validation of these findings in colon organoids.

Methods

RNA isolation was done from microdissected surgical colon specimen from 60 patients that suffered from either UC, CD, UC-CAC, CD-CAC or inflammation-free healthy controls (10 patients per group). Nanostring nCounterTM technology with a gene panel comprising >630 genes was performed to examine genes focusing on mucosal immunology, epithelial barrier/polarity. nSolverTM data analysis software was used for primary data analysis and statistics. Patients were grouped using expression patterns (by heat maps), differential expression and pathway analysis. For organoid cultures, crypts were isolated from mouse colon and cultured using the R-Spondin method. Organoids were subjected to osteopontin treatment. Consecutively, RNA was isolated. This was followed by gene expression analysis of core EMT (epithelial to mesenchymal transition) transcription factors (TFs) focusing on Twist1, Snai1, Snai2 by RT-PCR.

Results

Heat maps generated from the expression data revealed close-to-optimal grouping recapitulating the clinical subgroups. Differential expression comparing CD with CD-CAC and UC with UC-CAC identified 203 and 271 differentially expressed genes, respectively. Genes most significantly upregulated included SPP1/Osteopontin (OPN), GRHL2 and EMT signature gene as fibronectin1 and ZEB1, generating the hypothesis of OPN driving EMT and thereby inducing inflammation-associated carcinogenesis. Furthermore, mouse colon organoids treated with OPN (50ng/µl) revealed an increased expression by 3fold of core the EMT TFs Twist1, Snai1, Snai2.

Conclusion

We provide a comprehensive quantitative gene expression analysis for CAC with comparison of gene expression in CAC to the respective underlying IBD, CD and UC. Identified upregulated or downregulated genes allow to allocate signal transduction pathways important for CAC carcinogenesis. OPN as the most upregulated gene in CAC in our gene panel might be crucial for regulating EMT in CAC carcinogenesis. Thus, our findings uncover the role of OPN in CAC carcinogenesis.
P025 Identification and validation of predictors for tofacitinib through supervised and unbiased approaches in Inflammatory Bowel Disease
Authors: Liu B , Spalinger M , Perez L G , Machicote A , Gagliani N , Scharl M , Huber S
Published: May 2021

Background

Inflammatory Bowel Disease (IBD) is characterized by an overwhelming gut inflammation, where CD4+ effector T cells are main mediators of the inflammatory response. Tofacitinib, a small molecular drug recently used in IBD patients, blocks the JAK/STAT signaling pathway necessary for CD4+ effector T-cell activation. However, clinical data show that a percentage of patients do not respond to the treatment. Our main goal is to identify biomarkers predicting the response of patients to tofacitinib.

Methods

Tofacitinib efficacy was studied in vivo in wild type (WT) and T-cell-specific PTPN2 deficient mice (CD4-Cre;Ptpn2 floxed) in which the JAK/STAT signaling pathway is over activated. WT and PTPN2 deficient mice were gavaged with tofacitinib (50mg/kg, twice daily) or vehicle. Acute DSS-colitis was induced. Colitis development was evaluated by weight loss, colonoscopy and histology. CD4+ T cells were isolated from the colon and analyzed by flow cytometry. To study the effect of tofacitinib on T-cell differentiation, we isolated naïve T cells from mouse spleen and polarized them in vitro to different T-cell subsets with or without tofacitinib. CD4+ T cells differentiation and cytokine production were analyzed by flow cytometry. To evaluate the influence of tofacitinib on human CD4+ T cells, human peripheral blood mononuclear cells (PBMCs) from healthy donors and IBD patients were stimulated in presence of tofacitinib, and analyzed by flow cytometry.

Results

While no protective effect was found after tofacitinib treatment in WT mice, PTPN2 deficient mice were protected from colitis based on less weight loss, lower endoscopic and histological scores. The expression of pro-inflammatory cytokines such as IL-17 and IFN-γ by colonic CD4+ T cells was also decreased by tofacitinib. Consistent with the in vivo observations, in vitro experiments revealed a strong impact of tofacitinib on CD4+ T-cells cytokine production. In PBMCs from IBD patients, IFN-γ and TNF-α expression was strongly impacted. In contrast, in healthy donors, IL-10 was the most impacted cytokine. Finally, tofacitinib decreased the in vitro differentiation of Th1, Th2, Th17, Th22, Treg and Tr1.

Conclusion

In the T-cell-specific PTPN2 deficient mice, tofacitinib exerts a protective effect after DSS-induced colitis. In line with the in vivo findings, in vitro experiments show that tofacitinib has a strong impact on pro-inflammatory cytokine production, especially in the IBD patients. Taken together, these data suggest that tofacitinib might be suitable primarily for IBD patients where the JAK/STAT signaling pathway is over activated.
P040 USP16 regulates p65 activation in macrophages and promotes the inflammatory-carcinoma transformation process in IBD patients
Authors: Zhang Y , Wang C , Yao L , Li M , Jin J , Cao Q
Published: May 2021

Background

Long duration colonic inflammation increases the risk in developing intestinal dysplasia and further tumorigenesis, which is known as colitis-associated cancer (CAC). USP16, a deubiquitinase, is reported to regulate the T cell and macrophage function in acute colitis. But its function in CAC is never been studied.

Methods

We analyzed USP16 expression in tumor tissues and para-tumor tissues from patients with CAC by immunofluorescent staining. Then we established a CAC model in USP16MKO (conditional knock out in macrophage cells) and wild type mice by azoxymethane (AOM) and dextran sodium sulfate (DSS). Associated inflammatory cytokines were examined in normal colon and CAC by real-time polymerase chain reaction. And the signaling pathways and molecular mechanisms were studied.

Results

Expression of USP16 was found to be increased in tumor tissues from CAC patients than that in para-tumor controls. USP16MKO mice had fewer and smaller colon tumors than their WT littermates. Various inflammatory cytokines, including Tnf, Il12a, IL12b, Il23a and Il1b, were decreased in the colon tissues of USP16MKO mice. USP16 deficiency leads to the decrease of p65 activation and nucleation in macrophage. Through co-IP and immunofluorescent staining, USP16 was found to have an interaction with p65. And p65 deubiquitination was decreased in USP16 deficient macrophages.

Conclusion

USP16 is increased in colitis-associated cancer and regulates intestinal epithelial carcinogenesis by modulating pro-inflammatory responses in macrophages. USP16 serves as a deubiquitinase of P65 and thus promoting the activation and nucleation. Therefore, USP16 may serve as a novel therapeutic target to block inflammatory-cancer transformation
P045 Oncostatin M induces strong fibrotic and chemokine responses from primary colonic subepithelial myofibroblasts
Authors: Kokkotis G , Tarapatzi G , Drygiannakis I , Filidou E , Kandilogiannakis L , Arvanitidis K , Valatas V , Koutroubakis I , Vradelis S , Kolios G , Bamias G
Published: May 2021

Background

Oncostatin M (OSM) may play an important role in Inflammatory Bowel Disease (IBD) pathogenesis. Specifically, both OSM and its receptor are upregulated in inflamed colonic regions of IBD patients, and high OSM expression has been associated with failure to respond to anti-TNF therapy. Our aim was to investigate the effect of OSM in fibrotic factors and chemokine expression on primary colonic subepithelial myofibroblasts (SEMFs) from healthy individuals (HI).

Methods

Primary SEMFs were isolated from endoscopically-obtained colonic biopsies from HI. SEMFs were stimulated with 1, 10, or 100ng/ml OSM for 6 hours, with or without pre-stimulation with 5ng/ml IL-1α plus 50ng/ml TNF-α for 24h. Total RNA was collected and mRNA transcripts for collagen type I, type III, fibronectin, and the chemokines CCL2, CXCL9, CXCL10 and CXCL11 were measured by reverse transcription quantitative PCR.

Results

Unstimulated SEMFs had a basal expression of collagen type I, III, fibronectin, CCL2, CXCL9, CXCL10 and CXCL11. OSM stimulation augmented chemokine mRNA expression in a dose-dependent manner (Table 1) but had no effect on fibrotic factors expression. Pre-stimulation of myofibroblasts with TNF-α and IL-1α resulted in augmented expression of collagens I and III and fibronectin, in addition to further increases in chemokine expression in response to subsequent stimulation by OSM (Table 2).

Conclusion

Our results show that stimulation with OSM induces fibrotic and chemokine responses by SEMFs. Our findings further support the hypothesis that SEMFs may play a key role in regulating chronic intestinal inflammation and response to biological therapy.
P054 Modulation of the Gut Microbiota-Farnesoid X Receptor Axis Improves Deoxycholic Acid-induced Intestinal Inflammation in Mice
Authors: Xu M , Shen Y , Cen M
Published: May 2021

Background

Inflammatory bowel disease (IBD) is associated with gut dysbiosis and dysregulation of bile acid metabolism. A high luminal content of deoxycholic acid (DCA) with consumption of a Westernized diet is implicated in the pathogenesis of IBD. The aim of the study is to explore the role of intestinal microbiota and bile acid metabolism in mice with DCA-induced intestinal inflammation.

Methods

4-week-old wild-type C57BL mice were fed with AIN-93G (control diet), AIN-93G+0.2% DCA, AIN-93G+0.2% DCA+6 weeks of fexaramine (FXR agonist), or AIN-93G+0.2% DCA+antibiotic cocktail for 24 weeks. Histopathology, Western blotting, and qPCR were performed on the intestinal tissue. Fecal microbiota was analyzed by 16S rDNA sequencing. Fecal bile acid and short-chain fatty acid (SCFA) levels were analyzed by chromatography.

Results

Gut dysbiosis and enlarged bile acid pool were observed in DCA-treated mice, accompanied by a lower farnesoid X receptor (FXR) activity in the intestine. Administration of fexaramine mitigated DCA-induced intestinal injury, restored intestinal FXR activity, activated ﬁbroblast growth factor 15, and normalized bile acid metabolism. Furthermore, fexaramine administration increased the abundance of SCFA-producing bacteria. Depletion of the commensal microbiota with antibiotics decreased the diversity of the intestinal microbiota, attenuated bile acid synthesis, and reduced intestinal inflammation induced by DCA.

Conclusion

DCA induced-intestinal inflammation is associated with alterations of gut microbiota and bile acid proﬁles. Interventions targeting the gut microbiota-FXR signaling pathway may reduce DCA-induced intestinal disease.
P063 The immunological landscape of intestinal fibrosis in Crohn’s Disease
Authors: Jacobs I , Creyns B , Dragoni G , Cremer J , Bislenghi G , D’Hoore A , Ke B J , Matteoli G , De Hertogh G , Ferrante M , Joao G S , Breynaert C , Vermeire S , Verstockt B , Vanuytsel T
Published: May 2021

Background

Patients with Crohn’s disease (CD) often develop strictures, necessitating surgical intervention. The immune pathways expressed in the fibrotic regions, especially in the deeper intestinal layers, are poorly characterized hence hampering therapeutic development for anti-fibrotic agents. We performed a detailed analysis of the immune cell populations in both inflammation and fibrosis in the mucosa and deeper intestinal layers in CD patients.

Methods

Patients with stricturing CD (n=25) or colorectal cancer (CRC, n=10), undergoing ileocolonic resection were included. The resection specimen of CD patients was macroscopically subdivided into fibrotic, inflammatory but not fibrotic, and unaffected regions by an IBD-experienced histopathologist. The mucosal layer was furthermore separated from the deeper intestinal layers. Immune cells were isolated, followed by flow cytometry. Quantitative real time PCR (qRT-PCR) was performed for the eosinophil chemoattractant CCL11 coding for eotaxin-1 and normalized against the housekeeping genes RPL13a and PPIA. Wilcoxon matched-pairs sign rank test was performed on paired samples while Dunn’s multiple testing was performed for unpaired comparisons.

Results

Flow cytometric analysis in CD patients showed mainly B cell enrichment in fibrotic tissue compared to the unaffected tissue, both in the mucosa (30.2% vs 20.9% of CD45+ cells, p=0.001) as in deeper layers (34.4% vs 24.1% of CD45+ cells, p=0.01) (figure 1). Mature dendritic cells (mDC), alternatively-activated macrophages and eosinophils were also enriched but in the deeper layers of the fibrotic segment compared to the mucosa (4.3% vs 3.4%, 1.07% vs 0.04% and 2.3% vs 1.5% of CD45+ cells; p = 0.02, 0.008 and 0.02) (figure 2). Moreover, increased eosinophilic presence was also shown in the unaffected CD region compared to the fibrotic area, both in deeper layers (4.0% vs 2.3% of CD45+ cells; p=0.03) as the mucosa (2.4% vs 1.5% of CD45+ cells; p=0.01) as well as in the inflamed deeper layers compared to the superficial layers (3.3% vs 2.1% of CD45+ cells, p=0.04). These data were corroborated by increased CCL11 mRNA expression, in the deeper layers of fibrotic tissue compared to the mucosa (52.3% vs 31.0%, p=0.03).

Conclusion

Our results suggest a role for innate immune cells in CD complicated with fibrosis. Especially in the deeper layers, eosinophils, mature dendritic cells and alternatively-activated macrophages are implicated. The eosinophilic enrichment in the deeper layers may partly be attributed to an increased eosinophil recruitment by CCL11. Our results offer opportunities for anti-fibrotic drug development in CD.
P074 Crohn’s disease clinical data standards: Adoption and implementation to promote data sharing and reuse
Authors: Owen J
Published: May 2021

Background

Creation and adoption of clinical data standards will transform incompatible and disparate data into universal and illuminating information, facilitating discoveries that could have invaluable impact on Crohn’s Disease clinical research. Implementation of CDISC standards deliver on the promise of FAIR data through consistent organization and analysis that allow all researchers to leverage information from studies globally.

Methods

With support from The Leona M. and Harry B. Helmsley Charitable Trust and following the CDISC consensus-based standards development process, a team of Crohn’s disease and standards development experts was created to develop clinical data standards for Crohn’s disease.The CDISC standards development process consists of five stages:

Results

Free and publicly available data standards are anticipated to be available in May 2021 in the following areas:

- Questionnaires, Ratings and Scales (including standard symptom measures, patient/investigator reported outcomes, and socio-economic measures)

- Prior and Baseline, and On-Study Treatments (including response to prior treatment)

- Disease Classification (location and phenotypic descriptions of the disease)- Endoscopy Assessments

- Cross Section Imaging Assessments (including CT, MRI and Ultrasound)

- Histopathology of Biopsy Samples

- Biomarkers of Interest for Crohn’s Disease

Conclusion

Widespread promotion of the standards for researchers to adopt and implement is of highest importance. CDISC provides complementary education courses and implementation information to assist in adoption for academic teams new to CDISC standards. Widespread adoption of the standards will bring clarity to Crohn’s Disease data and will enable the accessibility, interoperability, and reusability of data (FAIR).
P080 Burden of Disease and Cost of Illness of Inflammatory Bowel Diseases in Portugal
Authors: Magro F , Portela F , Lago P , Chagas C , Moreira F , Pereira F , Rodrigues B , Pedrosa H , Correia L
Published: May 2021

Background

Estimate the burden of the disease (BoD) of IBD in Portugal and quantify society’s cost of illness (CoI) associated, including direct and indirect costs. Raise awareness to IBD in Portugal and thus bringing empowerment to the patient community.

Methods

Burden of disease was assessed considering the impact in terms of DALY, estimated considering a prevalence-based model. Costs were estimated considering the societal perspective, using a prevalence-based model. Direct costs comprise hospitalizations, surgeries, medical appointments, emergency visits, pharmacological treatment, exams and transportation. Indirect costs were calculated from patient and caretaker absence, presenteeism, early retirement and premature death.

An expert panel composed by 5 Portuguese gastroenterologists and a patient reported study were conducted to support the cost analysis and fill in information gaps. The expert panel followed a two-round modified Delphi methodology. The patient reported study was conducted with 370 Portuguese IBD patients by the Portuguese Association of Inflammatory Bowel Disease (APDI).

Results

Considering a prevalence of 24,070 patients, 6,067 DALYs were estimated to be lost in Portugal due to IBD. This result reflects a total of 507 YLLs (8%) and a total of 5,560 YLDs (92%)

The total annual cost associated with IBD patients in Portugal was estimated to be €146,293,082, with an average annual cost of €6,075 per patient. This value is divided into €86,834,011 direct costs (59%) and €59,459,070 (41%) indirect costs.

Indirect costs account for 41% of IBD’s total cost. Interestingly, costs of patient work absences showed very similar values to those associated with presenteeism. This demonstrates that IBD does not manifest its impact only in isolated timepoints, but rather that it is present in the everyday lives of patients.

Conclusion

It is essential to discuss the relationship between the burden of disease and its cost, especially when discussing a clinical condition with an increasing incidence rate in an ageing population as it is in Portugal. Due to the need to generate further data and evidence regarding IBD, this study provides the first comprehensive insight at a national level considering all the dimensions of disease burden. The results presented will raise social-economic awareness of IBD, allow for the definition of disease management strategies and support prioritization on resource allocation, especially considering the availability of new treatment approaches. Moreover, this study will set the basis for the thorough assessment of the real burden of IBD in the Portuguese healthcare system and society overall.
P122 Machine learning for prediction of intra-abdominal abscesses in patients with Crohn’s disease visiting the emergency department
Authors: Levartovsky A , Barash Y , Ben-Horin S , Ungar B , Klang E , Soffer S , Amitai M M , Kopylov U
Published: May 2021

Background

Intra-abdominal abscess is an important clinical complication of Crohn’s disease (CD), which can be diagnosed using computed tomography (CT) or magnetic resonance imaging (MRI). However, a high index of clinical suspicion is needed to diagnose an abscess as abdominal imaging is not routinely used during hospital admission. This study aimed to identify clinical predictors of an intra-abdominal abscess among hospitalized patients with CD.

Methods

We created an electronic data repository of all patients with CD who visited the emergency department (ED) of our tertiary medical center between 2012 and 2018. Data included tabular demographic and clinical variables, as well as CT and MRI imaging outcomes. We searched the data repository for the presence of an abscess on abdominal imaging within seven days from the ED visit. Machine learning models were trained to predict the presence of an abscess. A logistic regression model was compared to a random forest model. The area under the receiver operator curve (AUC) was used as a metric. To establish statistical significance, bootstrapping of 100 experiments with random 80/20 training/testing splits was performed. We included only patients who were hospitalized due to complaints that can be attributed to CD exacerbation. Patients presenting within 30 days from an abdominal surgery were excluded.

Results

Overall, 1556 patients with CD visited the ED, of those 555 patients with a CD exacerbation. Of them, 339 patients were hospitalized and underwent abdominal imaging within 7 days from the ED visit. Forty-two patients (12.1%) were diagnosed with an abscess on abdominal imaging. The average length of the abscess was 32 mm (IQR 21.5, 43.5), mainly in the mesentery adjacent to the small bowel (38.1%). On multivariate analysis, high CRP values (64.97 mg/L, aOR 14.42 [95% CI 4.93–42.13]), high platelet count (322.5 K/microL, aOR 4.01 [95% CI 1.97–8.15]), leukocytosis (10.55 K/microL, aOR 3.83 [95% CI 1.71–8.56]) and higher heart rate (over 87.5 beats per minute, aOR 2.58 [95% CI 1.22–5.46]) were independently associated with an intra-abdominal abscess. Overall, random forest and logistic regression showed similar performance. The random forest model showed an AUC of 0.824±0.065 with eight features (CRP, Hemoglobin, WBC, age, current biologic medical treatment, BUN, current immunomodulatory medical treatment, gender).

Conclusion

In our large tertiary center cohort, the machine-learning model identified features associated with the presentation of an intra-abdominal abscess. Such a decision support tool may assist in triaging CD patients for imaging to exclude this potentially life-threatening complication.
P135 Proximal Extension of lower rectal Ulcerative Proctitis
Authors: Yokoo T , Yoshikawa S , Masuda T , Terauchi S , Uchida H , Nakao T , Yamaoka K , Inagaki M , Okamoto K , Shibata Y , Higashio T , Inatsugi N
Published: May 2021

Background

Previous studies have shown proximal extension (PE) rate of ulcerative proctitis (UP) is approximately 50%. This rate teach us the importance of treating UP adequately. Basically, we have to treat them with topical 5-ASA. But in clinical practice, we sometimes experience the case whose inflammation remain endoscopically, even though the symptoms have been relieved. Should we strengthen our treatment at this situation, especially inflammation at lower rectum? We aimed to know PE rate of lower rectal UP and optimize the treatment.

Methods

We retrospectively investigated the medical charts of patients with UP from 2010 to 2020 at Kenseikai Nara Coloproctology Center. We excluded the patients with UP shrinking from left-sided or pancolitis as a result of the treatment. The cases with missing value were excluded too. Variables of interest included gender, onset age, disease location, initial mayo endoscopic subscore (MES) and treatment, and the time to PE. To compare the cohorts we used Fisher’s exact test and Mann-Whitney test. Proximal extension free survival (PEFS) was calculated using the Kaplan-Meier method.

Results

Sixty-five patients were recruited. Mean age was 42 years old, the ratio of males to females was 1.17. The number of lower rectal UP patients at first examination was 24. We observed MES 1 inflammation for 30 patients, and MES 2 for 35. Median follow-up duration was 73.5 months. PE occurred in 34 patients: 28 patients had left-sided colitis and 6 had pancolitis. Fifty-four patients were medicated and other 11 patients were just observed. Among the patients medicated, 23 patients were took only topical drugs, 18 were took only oral drugs and other 13 were took both. We couldn’t find any relationships between initial medication and PE rate. The multivariate analysis revealed that having peri-appendiceal red patch and lower rectal UP were reduce the risk of PE. MES was not related to PE (table 1).

PEFS at 1 year, 2 year are 81%, 81% for lower rectal UP (Rb group), and 66%, 61% for the patients having the disease beyond middle Houston’s valve (Not-Rb group), though we couldn’t find significant difference (Fig.1). Among 34 patients having PE, we used biologics for only five patients and got their inflammation under control.

Conclusion

Patients with lower rectal UP is less likely to extent their disease location. There’s no difference between the route of treatment and PE rate, but it’s important to carefully check PE within first one year.
P151 Validation of the MaRIA Score in pediatric patients
Authors: Palomino Pérez L M , Velasco Rodríguez-Belvis M , Sirvent Cerdá S I , Vazquez Gómez J A , Muñoz Codoceo R A
Published: May 2021

Background

To validate the Magnetic Resonance Index of Activity (MaRIA Score) in the pediatric population and determine if it would be possible to monitor inflammatory bowel disease (IBD) without invasive tests in some cases.

Methods

A cross-sectional and descriptive study of paediatric patients with previously diagnosed or suspected IBD who underwent upper endoscopy (EGD) and colonoscopy, blood tests, stool analysis and MR Enterography (MRE) in a 15 days range, from October 2018 to February 2020. The clinical and endoscopic situation were assessed with the activity indices PUCAI/PCDAI/shPCDAI and the activity scores UCEIS/Mayo/SES-CD respectively, according to the underlying pathologies. We considered analytical remission as FC< 250 mcg/g, ERS< 20 mm and CRP< 1 mg/dl. The MRE results were assessed with the MaRIA Score, that is validated for adults.

Results

Amongst 21 patients, 12 (57%) were males. 12 patients had Crohn ́s disease (CD) (57%), 3 had ulcerative colitis (UC) (14%), 6 had IBD unclassified (IBDu) (28%). The mean age at diagnosis was 14.2 ± 0.7 and the progression time of the disease was 3.9 ± 0.6 years. A total of 16 patients showed clinical remission (76%), 6 of them (28%) also had endoscopic and histological remission. Eight patients were receiving biological treatment (38%). The measured acute phase reactants (APR) were: CRP 0.9 ± 0.5 mg/dl, ESR 13.7 ± 2.6 mm, α1 acid glycoprotein 95.5 ± 1.1 mg/dl and fecal calprotectin (FC) of 1154.3 ± 254.8 mcg/g. Rotavirus, adenovirus, Clostridium difficile toxin analysis and stool culture were performed in 14 patients, all of them negative.

The MaRIA Score values were 54.3 ± 53.3, being 0 in 11 cases. We found no differences between the MaRIA Score and the analytical remission. We found a significant correlation between the MaRIA Score and the PUCAI value (p < 0.05), but not with other clinical scores. Patients in clinical remission showed a tendency to have a lower MaRIA Scores, but these differences were not statistically significant (p = 0.09). The MaRIA Score showed lower values for those with endoscopic and histological remission (p < 0.05), All the patients with MaRIA Score> 0 were CD except one, diagnosed with UC. Out of the 15 patients with endoscopic/histological involvement, 10 presented a MaRIA Score> 0. Five of the 11 patients (45%) in whom the MaRIA Score was 0 did not have endoscopic and histological remission, only one of them had a diagnosis of CD.

Conclusion

The MaRIA Score was significantly correlated with endoscopic scores in pediatric IBD patients, especially in CD. However, based on the results of this study, the MRE should not replace the EGD and colonoscopy in order to thoroughly evaluate the disease activity.