bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk factors associated with adenoma recurrence following cold snare endoscopic mucosal resection of polyps ≥ 20 mm: a retrospective chart review
Authors: Suresh Suraj , Zhang Jinyu , Ahmed Abdelwahab , Abu Ghanimeh Mouhanna , Elbanna Ahmed , Kaur Randeep , Isseh Mahmoud , Watson Andrew , Dang Duyen T. , Chathadi Krishnavel V. , Pompa Robert , Singla Sumit , Piraka Cyrus , Zuchelli Tobias
Published: May 2021

Background and study aims Cold snare endoscopic mucosal resection (EMR) is being increasingly utilized for non-pedunculated polyps ≥ 20 mm due to adverse events associated with use of cautery. Larger studies evaluating adenoma recurrence rate (ARR) and risk factors for recurrence following cold snare EMR of large polyps are lacking. The aim of this study was to define ARR for polyps ≥ 20 mm removed by cold snare EMR and to identify risk factors for recurrence.

Patients and methods A retrospective chart review of colon cold snare EMR procedures performed between January 2015 and July 2019 at a tertiary care medical center was performed. During this period, 310 non-pedunculated polyps ≥ 20 mm were excised using cold snare EMR with follow-up surveillance colonoscopy. Patient demographic data as well as polyp characteristics at the time of index and surveillance colonoscopy were collected and analyzed.

Results A total of 108 of 310 polyps (34.8 %) demonstrated adenoma recurrence at follow-up colonoscopy. Patients with a higher ARR were older (P = 0.008), had endoscopic clips placed at index procedure (P = 0.017), and were more likely to be Asian and African American (P = 0.02). ARR was higher in larger polyps (P < 0.001), tubulovillous adenomas (P < 0.001), and polyps with high-grade dysplasia (P = 0.003).

Conclusions Although cold snare EMR remains a feasible alternative to hot snare polypectomy for resection of non-pedunculated polyps ≥ 20 mm, endoscopists must also carefully consider factors associated with increased ARR when utilizing this technique.
Selbsthilfeverein Psychokardiologie – niedrigschwellige Ansätze für Betroffene
Authors: Bundschuh Helmut , Wilde Anja
Published: May 2021

Jeder 3. Herzpatient ist psychisch belastet und hat damit eine schlechtere gesundheitliche Prognose. Während dieser Zusammenhang unter dem Begriff „Psychokardiologie“ im akademischen Bereich gut erforscht wird, gibt es kaum praktische Ansätze für die Prävention im Öffentlichen Raum. Es fehlen v. a. niedrigschwellige Angebote und nachhaltige Begleitung im Alltag. Als Teil eines Gesamtkonzeptes kann Selbsthilfe hier unterstützend wirken.
Synthesis and Applications of Cyclopropanones and Their Equivalents as Three-Carbon Building Blocks in Organic Synthesis
Authors: Jang Yujin , Machín-Rivera Roger , Lindsay Vincent N. G.
Published: May 2021

Cyclopropanone derivatives constitute highly strained cycloalkanones with promising applications as three-carbon building blocks in organic synthesis. Due to the presence of a ketone in such a small ring system, all C–C bonds and the carbonyl group are considered to be labile in suitable conditions, leading to a wide variety of synthetic disconnections, including nucleophilic addition, ring expansion, ring-opening, and (formal) cycloaddition. Despite their synthetic potential, the widespread adoption of cyclopropanones as substrates has been considerably hampered by the difficulties associated with the preparation and storage of such unstable compounds, prompting the development of cyclopropanone surrogates that can equilibrate to the parent ketone in situ via elimination. This review summarizes the syntheses and applications of cyclopropanone derivatives and their equivalents, and offers a perspective of the state of the field as well as its expected future directions.

1 Introduction

2 Preparation of Cyclopropanones and Their Equivalents

2.1 Carbenoid Chemistry

2.2 Allene Oxide Rearrangement

2.3 Ring Closure by Dehydrohalogenation or Dehalogenation

2.4 Photolytic Processes

2.5 Miscellaneous Formation of Cyclopropanones

2.6 Cyclopropanone Equivalents

3 Synthetic Applications of Cyclopropanones and Their Equivalents

3.1 Nucleophilic Addition to the Carbonyl Group

3.2 Ring Expansion

3.3 Ring-Opening

3.4 Cycloaddition and Formal Cycloaddition

4 Conclusion and Outlook
Wir brauchen einen „Change of Mindset“
Authors: Herrschelmann Anna
Published: May 2021

Um die Digitalisierung in den Krankenhäusern ist es nicht gut bestellt. Das gilt nicht nur für Einrichtungen in Deutschland. Auch der Blick zu unseren deutschsprachigen Nachbarn zeichnet ein sehr heterogenes Bild vom digitalen Reifegrad der Kliniken und Spitäler. Während sich manche Klinik noch mit der Bereitstellung von Netzwerk- und IT-Strukturen schwertut, beschäftigen sich andere schon mit dem Einsatz von „Künstlicher Intelligenz“ (KI) im Versorgungsprozess. Ein Paradebeispiel für den Einsatz von KI im Klinikalltag ist das Universitätsspital Zürich, das gemeinsam mit dem Start-Up Prognosix kürzlich den „Leipziger Innovationspreis für Krankenhauslogistik“ verliehen bekommen hat. Die Geschichte dazu lesen Sie in diesem Heft ab Seite 46.
Tunable elastic waveguide based on a soft phononic crystal
Authors: Kim Meeri
Published: May 2021

A soft, porous phononic crystal with hard inclusions serves as the basis for a unique type of waveguide that can be tuned by applying an external force.
Coherent and dissipative cavity magnonics
Authors: Harder M. , Yao B. M. , Gui Y. S. , Hu C.-M.
Published: May 2021

Strong interactions between magnetic materials and electrodynamic cavities mix together spin and photon properties, producing unique hybridized behavior. The study of such coupled spin-photon systems, known as cavity magnonics, is motivated by the flexibility and controllability of these hybridized states for spintronic and quantum information technologies. In this Tutorial, we examine and compare both coherent and dissipative interactions in cavity magnonics. We begin with a familiar case study, the coupled harmonic oscillator, which provides insight into the unique characteristics of coherent and dissipative coupling. We then examine several canonical cavity-magnonic systems, highlighting the requirements for different coupling mechanisms, and conclude with recent applications of spin-photon hybridization, for example, the development of quantum transducers, memory architectures, isolators, and enhanced sensing.
Density functional theory study of chemical pressure in multicaloric MTX compounds
Authors: Hartnett Timothy Q. , Sharma Vaibhav , Barua Radhika , Balachandran Prasanna V.
Published: May 2021

The MTX-based compounds are promising rare-earth-free candidates for multicaloric applications due to the proximity of their structural and magnetic phase transitions. In this paper, we use first principles calculations to study how chemical pressure affects the energetics, saturation magnetization, and volume change. Our calculations reveal the presence of a complex interplay between the M-, T-, and X-site elements in tuning the properties. The choice of elements for rational alloy design should be informed by the site-specific response. Our work motivates future synthesis and characterization efforts to focus on uncovering site-specific data to tailor strategies for maximizing the caloric response and bridge the knowledge-gap.
Neuron-like spiking and bursting in Josephson junctions: A review
Authors: Mishra Arindam , Ghosh Subrata , Kumar Dana Syamal , Kapitaniak Tomasz , Hens Chittaranjan
Published: May 2021

The superconducting Josephson junction shows spiking and bursting behaviors, which have similarities with neuronal spiking and bursting. This phenomenon had been observed long ago by some researchers; however, they overlooked the biological similarity of this particular dynamical feature and never attempted to interpret it from the perspective of neuronal dynamics. In recent times, the origin of such a strange property of the superconducting junction has been explained and such neuronal functional behavior has also been observed in superconducting nanowires. The history of this research is briefly reviewed here with illustrations from studies of two junction models and their dynamical interpretation in the sense of biological bursting.
Concurrent overexpression of amino acid permease
Authors: Grant Jan E. , Ninan Annu , Cripps-Guazzone Natalia , Shaw Martin , Song Jiancheng , Petřík Ivan , Novák Ondřej , Tegeder Mechthild , Jameson Paula E.
Published: May 2021

Using pea as our model crop, we sought to understand the regulatory control over the import of sugars and amino acids into the developing seeds and its importance for seed yield and quality. Transgenic peas simultaneously overexpressing a sucrose transporter and an amino acid transporter were developed. Pod walls, seed coats, and cotyledons were analysed separately, as well as leaves subtending developing pods. Sucrose, starch, protein, free amino acids, and endogenous cytokinins were measured during development. Temporal gene expression analyses (RT-qPCR) of amino acid (AAP), sucrose (SUT), and SWEET transporter family members, and those from cell wall invertase, cytokinin biosynthetic (IPT) and degradation (CKX) gene families indicated a strong effect of the transgenes on gene expression. In seed coats of the double transgenics, increased content and prolonged presence of cytokinin was particularly noticeable. The transgenes effectively promoted transition of young sink leaves into source leaves. We suggest the increased flux of sucrose and amino acids from source to sink, along with increased interaction between cytokinin and cell wall invertase in developing seed coats led to enhanced sink activity, resulting in higher cotyledon sucrose at process pea harvest, and increased seed number and protein content at maturity.
Helicobacteriology update
Authors: Tay Alfred , Wise Michael J , Marshall Barry J
Published: May 2021

Helicobacter pylori colonises the gastric mucosa and is associated with various gastric diseases, including stomach cancer. At least 1 million new cases of stomach cancer cases are reported annually, and it is the fifth top cancer-killer in the world. Although H. pylori can be eradicated by a combination of antibiotics, the treatment success rate is declining due to the rise of antibiotic resistance. The same antibiotic combination must not be prescribed repeatedly. Susceptibility guided precision medicine is the most effective strategy to combat antibiotic resistant H. pylori cases. In addition, maintaining a stomach pH ≥6 during the antibiotic treatment is an important factor to increase cure rates. The new type of acid blocker, P-CABs, have shown promising results in H. pylori treatment. Natural products may suppress the H. pylori growth or relieve the symptoms but have not been successful in solving the root of the problem. New combination therapies show promise and the dream of 100% cure of the infection with minimal side effects from treatment seems achievable. The next decade will see combination therapies with newer acid blockers in widespread use at reasonable cost.
Flow to nowhere: the disconnect between environmental watering and the conservation of threatened species in the Murray–Darling Basin, Australia
Authors: Ryan Albie , Colloff Matthew J. , Pittock Jamie
Published: May 2021

The Murray–Darling Basin Plan was established with the objective of restoring water from irrigation to the environment, thereby conserving wetlands and biodiversity. We examined whether the Plan is achieving this objective by assessing whether environmental watering has helped conserve threatened flow-dependent fauna. Two frog species, two waterbirds and four fishes, were assessed for their conservation status in relation to (1) whether they were targeted in environmental watering plans, (2) whether population monitoring had occurred and (3) evidence of population recovery. We determined indicators of abundance and occurrence of species between 2012–13 and 2018–19 and found widespread inconsistencies in the targeting of environmental watering for these species, including their being overlooked in watering plans and actions in several catchments. Environmental watering had some positive outcomes for some threatened species in some locations on some occasions, but benefits, and their monitoring and reporting, are patchy and inconsistent. Monitoring of temporal trends in distribution, occurrence and abundance of species is inadequate to evaluate success. If the Plan is to achieve its objective and uphold Australia’s international environmental treaty obligations, more needs to be done to target and deliver environmental water for threatened species and improve the monitoring and reporting of outcomes.
A topological approach to a class of one-dimensional Kirchhoff equations
Authors: Goodrich Christopher
Published: May 2021

We consider, for

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and demonstrate the existence of at least one positive solution to this problem. The main contribution is to show that by using a nonstandard order cone together with topological fixed point theory much weaker conditions than usual can be imposed on the coefficient function

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Outpatient Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 Infection to Prevent Coronavirus Disease 2019 Progression
Authors: Cohen Myron S , Wohl David A , Fischer William A , Smith Davey M , Eron Joseph J
Published: May 2021

As of March 2021, coronavirus disease 2019 (COVID-19) had caused more than 123 million infections and almost 3 million deaths worldwide. Dramatic advances have been made in vaccine development and nonpharmaceutical interventions to stop the spread of infection. However, treatments to stop disease progression are limited. A wide variety of “repurposed” drugs evaluated for treatment of COVID-19 have had little or no benefit. More recently, intravenous monoclonal antibody (mAb) combinations have been authorized by the US Food and Drug Administration for emergency use for outpatients with mild to moderate COVID-19 including some active against emerging severe acute respiratory syndrome coronavirus 2 variants of concern. Easier to administer therapeutics including intramuscular and subcutaneous mAbs and oral antivirals are in clinical trials. Reliable, safe, effective COVID-19 treatment for early infection in the outpatient setting is of urgent and critical importance. Availability of such treatment should lead to reduced progression of COVID-19.
DOP03 Early change in epithelial neutrophilic infiltrate predicts long-term response to biologics in Ulcerative Colitis
Authors: Narula N , Wong E , Colombel J F , Riddell R , Marshall J , Reinisch W , Dulai P
Published: May 2021

Background

The prognostic value of histologic scores, grades, and individual histologic sub-components, alone or in combination with endoscopy, for predicting endoscopic improvement (EI) and histo-endoscopic mucosal improvement (HEMI) during maintenance therapy in ulcerative colitis (UC) remains uncertain.

Methods

Post-hoc analysis of participants from the VARSITY trial (n=734 with histology). Receiver operating characteristic and multi-variate logistic regression analyses were performed to assess whether baseline and/or week 14 assessments for the Robarts Histopathology Index (RHI), Geboes score, or individual histologic sub-components, could predict the achievement of EI and HEMI at week 52.

Results

RHI and Geboes scores at baseline, and changes in scores at week 14, had fair to poor accuracy for predicting week 52 EI or HEMI (Area Under the Curve [AUC] 0.58–0.67). Among individual sub-components, changes in epithelial neutrophil involvement from baseline to week 14 had the best performance for predicting week 52 EI (AUC 0.83, 95% confidence interval (CI) 0.74–0.91) and HEMI (AUC 0.85, 95% CI 0.76–0.94). On multivariate analyses, improvement of neutrophils in the epithelium was associated with increased odds of week 52 EI (Odds Ratio [OR] 3.63, 95% CI 1.45–9.08, p=0.0059) and HEMI (OR 6.88, 95% CI 3.29–14.36, p<0.0001), and lack of improvement of neutrophils in the epithelium was associated with lack of week 52 EI (OR 0.24, 95% CI 0.12–0.48, p<0.0001) and lack of HEMI (OR 0.03, 95% CI 0.01–0.014, p<0.0001). No other parameters significant on univariate analysis were significant within the multivariate model. Among patients with endoscopic Mayo scores of 2 or 3 at week 14, those who had >50% crypts involved with neutrophils at week 14 were significantly less likely to achieve week 52 EI (18.0%; 31/172 vs. 34.3%; 72/210, p<0.001), HEMI (9.9%; 17/172 vs. 22.4%; 47/210, p=0.001) (Figure 1) and clinical remission (11.0%; 19/172 vs. 23.3%; 49/210, p=0.002). Among patients with endoscopic Mayo scores of 0 or 1 at week 14, those who had >50% crypts involved with neutrophils were significantly less likely to achieve HEMI at week 52 (33%; 4/12 vs. 62.4%; 141/226, p=0.044) (Figure 1).

Conclusion

Our results on epithelial neutrophilic infiltrate following induction therapy as the only independent predictor for achievement of maintenance EI or HEMI helps clarify the clinical relevance of measuring histologic disease activity in UC. Epithelial neutrophilic infiltrate poses a means to stratify patients according to their likelihood of response to biologic treatment.
DOP16 The ratio of submucosa thickness to the total bowel wall thickness can be a sonographic parameter to estimate endoscopic remission in Ulcerative Colitis
Authors: Miyoshi J , Ozaki R , Yonezawa H , Mori H , Kawamura N , Matsuura M , Hisamatsu T
Published: May 2021

Background

A less invasive examination that can estimate endoscopic remission is needed. Intestinal ultrasound (IUS) is a promising option. The bowel wall thickness (BWT) is a widely-accepted objective parameter in IUS to assess colonic inflammation, but BWT is influenced by intestinal peristalsis and the volume of luminal content. A feasible, objective index that is not affected by these factors could improve the diagnostic potential of IUS. The submucosa, which is observed as the third layer of the intestinal wall on IUS, becomes swollen and standing out in the active UC. Given BWT and submucosa thickness (SMT) can be influenced by the peristalsis and luminal content simultaneously, we hypothesized that the ratio of SMT to BWT can be an index for submucosal swelling regardless of those factors and this index can be a new parameter to estimate endoscopic remission.

Methods

Inclusion criteria were (1) both IUS and endoscopy (sigmoidoscopy or colonoscopy) for UC were performed in Kyorin University Hospital between April 2019 and December 2020 and (2) time-interval between IUS and endoscopy was within 2 weeks. BWT and SMT were measured based on IUS images for ascending (A/C), transverse (T/C), descending (D/C), and sigmoid colon (S/C), respectively. We defined the submucosa index (SMI) as a percentage of SMT to BWT (Figure 1). When SMT was too thin to be measured, we scored 0 for SMI. The loss of stratification (LOS) was defined as the condition where the submucosa cannot be identified even with BWT > 3 mm (Figure 2). The parts with LOS were considered as inflamed mucosa. Mayo endoscopic subscore (MES) was scored for each part of the colon based on the endoscopic images. MES of 0/1 was defined as the endoscopic remission. Informed consent was obtained in the opt-out method. This study was approved by the Institutional Review Board of Kyorin University School of Medicine (IRB No. 1668).

Results

In total 68 parts of the colon (A/C: 11, T/C: 12, D/C: 14, and S/C: 31) were analyzed. With ROC analysis with the Youden index, the cutoff value of BWT for endoscopic remission was 3.7 mm (AUC: 0.84). Among the parts without LOS, the cutoff value of SMI for endoscopic remission was 47.9 (AUC: 0.75). The positive predictive value for endoscopic remission of the diagnostic criteria (1) BWT ≤ 3.7 mm, (2) BWT ≤ 3.7 mm and no LOS, (3) SMI ≤ 48 (no LOS), and (4) BWT ≤ 3.7 mm, SMI ≤ 48 (no LOS) was 83.3%, 88.2%, 60.7%, and 93.3%, respectively. The negative predictive value was 88.0%, 88.2%, 90.0%, and 86.8%, respectively.

Conclusion

Given the feasibility and objectiveness of assessing bowel wall structure, our findings provide “proof of concept” that SMI can be an additional sonographic parameter for endoscopic remission.
DOP18 UCEIS is associated with PRO2, partial Mayo and SCCAI remission in UC: Final results from a prospective study
Authors: Golovics P , Gonczi L , Reinglas J , Verdon C , Pundir S , Afif W , Wild G , Bitton A , Bessissow T , Lakatos P L
Published: May 2021

Background

Optimal management of patients with ulcerative colitis (UC) requires the accurate assessment of disease activity. Endoscopic evaluation is considered the gold standard approach, but it is invasive. We aimed to determine the operating characteristics of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), to quantify the cut off most closely correlated with clinical remission or activity and determine agreement with the Mayo endoscopic subscore (MES), Baron score, clinical scores and biomarkers.

Methods

171 patients were included prospectively and consecutively (age: 49 (IQR: 38–61) years, duration 12 (4–19)years, 79 females (46.2%), 57.3% extensive disease, 42.7% on biologicals) at the time of the colonoscopy. Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Mayo endoscopic subscore (MES), Baron scores were calculated, as well as the 2 item patient reported outcome (PRO), partial MAYO, Simple Clinical Colitis Activity Index (SCCAI). C reactive Protein (CRP) and fecal calprotectin (FCAL) was available in 83 and 45.6% of patients. 17.0% had clinical flare, treatment was escalated in 14.6% of patients. Sensitivity, specificity, PPV and NPV values were calculated, ROC analysis and K-statistics were performed.

Results

UCEIS was strongly associated to PRO2 SF (AUC:0.863), RBS (AUC:0.924), PRO2 combined (AUC:0.898), partial MAYO (AUC:0.945) and SCCAI (AUC:0.901) remission in a ROC analysis. A UCEIS of ≤3 was identified as the best cut-off to identify RBS subscore of 0, or total PRO2 remission (RBS 0 and SF ≤1), partial MAYO (≤2) and SCCAI (≤2.5) remission, while a UCEIS≥4 identified active disease frequently needing change in medical therapy.

A moderate agreement was found between UCEIS <4 and MES 0 (K=0.471) or Baron 0 (K=0.414)/Baron 0–1 (K=0.353). Correlation between FCAL and UCEIS (coeff:0.701, p<0.0001) was strong, while modest only with CRP (coeff:0.248, p=0.01).

Conclusion

UCEIS was strongly associated with clinical remission defined as PRO2, SF, RBS, partial Mayo or SCCAI with best agreement with RBS and partial Mayo remission. A UCEIS of ≤3 was identified as a cut-off for quiescent disease, while a UCEIS≥4 identified active disease, which can support clinical decision-making based on endoscopic findings. Agreement between UCEIS and FCAL was strong, while agreement with UCEIS and MES/Baron scores was moderate.
DOP27 The fibre fermentative capacity of the gut microbiota is diminished in children with Crohn’s Disease and it is independent of disease activity or treatment with exclusive enteral nutrition
Authors: Gkikas K , Logan M , Milling S , Ijaz U Z , Hansen R , Russell R K , Gerasimidis K
Published: May 2021

Background

Induction of clinical remission with exclusive enteral nutrition (EEN), has been associated with accompanying changes in the concentration of short chain fatty acids (SCFA) (a biomarker of fibre fermentation) in faeces of children with Crohn’s disease (CD) 1. Here, we assessed the fibre fermentative capacity of the gut microbiota of children with active CD in vitro, before, during and after EEN and compared with healthy children.

Methods

44 faecal samples from 14 children (female, n=7, age, median [Q1, Q3]: 14.1 [11.1, 15.1] years) with active CD were collected before, during (4 weeks) and at the end of EEN (8 weeks) and after food reintroduction (median [Q1, Q3]: 21 [16, 31] days post-EEN). All children had achieved clinical remission at the end of EEN (weighted Paediatric Crohn’s Disease Activity Index <12.5). A single faecal sample was collected from 11 healthy children (female, n=4, age, median [Q1, Q3]: 12.4 [9.6, 13.0] years). 24-hour in vitro batch fermentations were performed using 4 fibre substrates (pectin, high-resistant maize starch, wheat bran and a mixture of the three). Net production of SCFA was measured with gas chromatography.

Results

Compared to healthy children, the total production of SCFA was significantly lower in children with CD, for all 4 fibre substrates, and regardless of the study timepoint (Figure 1). Net production of SCFA remained unchanged during EEN and at food reintroduction, and for all fibre substrates (Figure 1). No significant association with levels of faecal calprotectin was observed at any of the timepoints. Acetate production was significantly lower in children with CD compared to healthy children for all fibre substrates except for resistant maize starch (Figure 1). Likewise, except for pectin, production of butyrate was significantly lower in children with CD than healthy controls (Figure 1). Production of propionate did not significantly differ between any of the groups.

Legend: Production of SCFA after 24-hour in vitro fermentation of faecal samples from CD and healthy children. Asterisks indicate significant differences. A: before EEN, B: 4-week EEN, C: End of EEN, D: Food reintroduction, HC: Healthy children

Conclusion

Fibre fermentative capacity is independent of disease activity in patients with CD and remains lower compared to healthy controls. It might be unlikely that the mechanism of action of EEN is mediated by modulation of fibre fermenting bacteria.

Reference

1. Gerasimidis K, Bertz M, Hanske L, Junick J, Biskou O, Aguilera M, et al. Decline in presumptively protective gut bacterial species and metabolites are paradoxically associated with disease improvement in pediatric Crohn’s disease during enteral nutrition. Inflamm Bowel Dis. 2014;20(5):861–71.
DOP36 Non-invasive assessment of postoperative disease recurrence in Crohn’s Disease: A multicenter, prospective cohort study
Authors: Furfaro F , Zilli A , Craviotto V , Aratari A , Bezzio C , Gilardi D , D’Amico F , Saibeni S , Papi C , Peyrin-Biroulet L , Fiorino G , Danese S , Allocca M
Published: May 2021

Background

Prevention of postoperative recurrence is a critical goal in Crohn’s disease (CD) management.

Currently, postsurgical CD management and treatment are based on endoscopic monitoring performed within the first year after surgery. However, colonoscopy (CS) is an invasive and expensive procedure, unpleasant to patients. A non-invasive and patient friendly approach is required.

Methods

Consecutive CD patients who underwent ileo-cecal resection from July 2017 to January 2020 were prospectively enrolled in three Italian Centers and performed CS and bowel ultrasound (US) after six months from the surgery, in a blinded fashion. The patients also underwent complete clinical assessment and blood and stool samples were obtained for C-reactive protein (CRP), and fecal calprotectin (FC) measurements. The disease was considered clinically active if the Harvey–Bradshaw Index (HBI) was higher than 4. Uni- and multivariable analyses were used to assess the correlation between non-invasive parameters, including bowel US findings and FC values and endoscopic recurrence, defined by a Rutgeerts’s score (RS) > 2. Sensitivity, specificity, accuracy, PPV and NPV of bowel US parameters alone and in combination with FC in assessing endoscopic recurrence were calculated.

Results

Seventy patients were enrolled, 45 patients (64%) had an endoscopic recurrence (RS > 2) at 6 months. Thirteen out of 45 (29%) were symptomatic (HBI > 4). Bowel wall thickness (BWT), bowel wall flow (BWF, presence of vascular signals at color Doppler), the presence of mesenteric hypertrophy, the presence of limph-nodes and FC values significantly correlated with the endoscopic recurrence (p < 0.005). Independent predictors for endoscopic recurrence were BWT (for 1-mm increase: OR 2.63; 95% CI 1.136.12; p= 0.024), presence of lymph-nodes (OR 23.24; 95% CI 1.85291.15; p= 0.014) and FC > 50 µg/g (OR 11.86; 95% CI 2.60–54.09; p= 0.001). Sensitivity, specificity, accuracy, PPV and NPV of bowel US and/or FC are showed in Table 1.

Table 1: Diagnostic accuracy of Bowel US and/or FC compared to CS in assessing endoscopic activity (CI 95%): per-patient analysis

Conclusion

Combined use of bowel US and FC is accurate in assessing endoscopic recurrence at 6 months in CD patients and represent a valid alternative to endoscopic assessment after surgery
DOP59 Evaluation of the efficacy of tofacitinib as maintenance therapy in patients with Ulcerative Colitis stratified by OCTAVE Sustain baseline endoscopic subscore
Authors: Lee S D , Allegretti J R , Steinwurz F , Connelly S B , Lawendy N , Paulissen J , Gecse K B
Published: May 2021

Background

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib in patients (pts) with UC were evaluated in two 8-week, Phase 3 induction studies (OCTAVE Induction 1&2), a 52-week, Phase 3 maintenance study (OCTAVE Sustain), and an open-label, long-term extension study. Here, we evaluate tofacitinib efficacy in OCTAVE Sustain (NCT01458574) by baseline Mayo endoscopic subscore (ES).

Methods

Pts with an OCTAVE Sustain baseline ES of 0 or 1 were included. Proportion of pts achieving efficacy endpoints at Week 52 of OCTAVE Sustain (responders from OCTAVE Induction 1&2; tofacitinib 5 or 10 mg twice daily [BID] or placebo [PBO]) was evaluated in relation to OCTAVE Sustain baseline ES. Using logistic regression, the difference in treatment effect (tofacitinib vs PBO) between baseline ES (0 vs 1) for each efficacy endpoint was assessed. Cox proportional hazards regression was used to model the difference in treatment effect between baseline ES (0 vs 1) for time to treatment failure and loss of response.

Results

At Week 52 of OCTAVE Sustain, a numerically higher proportion of pts with a baseline ES of 0 achieved remission and endoscopic improvement vs pts with a baseline ES of 1, regardless of tofacitinib dose (Table). Logistic regression analyses showed a larger treatment effect of tofacitinib 5 mg BID at Week 52 in pts with a baseline ES of 0 vs 1 (p=0.0306) for clinical response (Table). Treatment effect of tofacitinib 10 mg BID was not significantly different between baseline ES 0 vs 1 for any endpoint (Table).

In tofacitinib 5 mg BID-treated pts, Cox proportional hazards regression showed difference in risk vs PBO to be larger in pts with a baseline ES of 0 vs 1 for treatment failure (p=0.0231) and loss of response (p=0.0209); corresponding differences for 10 mg BID-treated pts were not significant (p=0.9239 and p=0.9613, respectively).

Conclusion

In general, at Week 52 of OCTAVE Sustain, a higher proportion of tofacitinib-treated pts achieved endpoints with a baseline ES of 0 vs 1. Based on proportions, the treatment effect of tofacitinib 5 mg BID was more evident in pts with a baseline ES of 0 vs 1. This difference in treatment effect related to baseline ES was not observed with tofacitinib 10 mg BID. Baseline ES may be an important factor in predicting outcomes, and suggests that aiming for a deeper remission after induction may allow successful maintenance with tofacitinib 5 mg BID. These analyses were post hoc and limited by the small sample sizes.
OP12 Blood proteins related to immunoregulation or cellular junctions reveal distinct biological profiles associated with the risk of short-term versus mid/long-term relapse in Crohn’s Disease patients stopping infliximab
Authors: Pierre N , Huynh-Thu V A , Allez M , Bouhnik Y , Laharie D , Bourreille A , Colombel J F , Meuwis M A , Louis E
Published: May 2021

Background

In Crohn’s disease (CD), biologics can induce mucosal healing and stable remission. After reaching this target, treatment de-escalation could be considered but the risk of relapse needs to be estimated. Current biomarkers used to predict relapse (C-reactive protein: CRP, faecal calprotectin) offer a limited prognostic capacity. Furthermore, they only monitor inflammation while we recently highlighted various and distinct pathological processes associated with the risk of short-term (<6 months) and mid/long-term (>6 months) relapse in CD patients stopping infliximab. Herein, the aim of our study was to further characterise this distinction.

Methods

Serum abundance of 92 proteins were measured by proximity extension assay (immune response panel, Olink) at baseline of the STORI cohort (infliximab diScon-Tinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors, n=102). Association of markers with the risk of relapse was determined by univariable Cox model in stratified (relapse <6 months or >6 months) and non-stratified datasets. Study of protein characteristics and enrichment analyses were performed to find biological patterns differentiating short-term from mid/long-term relapsers. To evaluate the predictive capacity of markers, we combined them systematically by pairs (‘AND’ or ‘OR’ logical operators) and used log-rank statistics with false discovery rate (FDR) correction (Benjamini-Hochberg).

Results

The risk of mid/long-term relapse was associated with a decreased circulating level of anti-inflammatory effectors while the risk of short-term relapse was associated with an increased circulating level of pro-inflammatory effectors (Fig. 1A, 1B).

The risk associated with the downstream signalling of cytokine and pattern recognition receptors showed an opposite pattern in the short-term versus mid/long-term relapsers (Fig. 1D, 1E).

The risk of short-term relapse was characterised by a perturbed circulating level of proteins inducing tolerance and immunity in antigen presenting cells (Fig. 2A, 2B).

The risk of mid/long-term relapse was characterised by an increased circulating level of proteins promoting lymphocyte tolerance (Fig. 2D, 2E) and a decreased circulating level of cellular junction proteins (Fig. 3).

We found 1223 (short-term relapse dataset), 233 (mid/long-term relapse dataset) and 101 (non-stratified dataset) novel marker combinations with FDR<0.05 and higher Z-scores than CRP and faecal calprotectin. The best combinations are showed in Fig. 4.

Conclusion

In CD patients stopping infliximab, blood proteins linked to immunoregulation or cellular junctions support the distinct profiles of short-term and mid/long-term relapsers. These proteins showed a capacity to predict the relapse.
P003 HDAC7 Controls Differentiation and Regeneration in the Intestinal Epithelium
Authors: Gerbeth L , Glauben R , Siegmund B
Published: May 2021

Background

The precise causes and drivers of inflammatory bowel disease (IBD) are still incompletely understood. In recent years, intensive research has shown that not only chronic activation of the immune compartment, but also the integrity of the epithelial barrier plays a central role in disease progression. Inhibitors of histone deacetylases (HDACs) are known for their anti-inflammatory effects and increasing evidence suggests them as promising therapeutics for chronic inflammatory conditions such as IBD. However, the roles of single HDACs in the intestinal epithelium, especially class II HDACs, are still scarcely investigated. In genome wide association studies, HDAC7 has been identified as a risk locus for the development of IBD. Here, we investigated the role of HDAC7 in the intestinal epithelium to evaluate its potential as a therapeutic target.

Methods

Intestinal epithelial organoids were derived from the ileum and colon of tamoxifen-inducible HDAC7 knockout mice. Hdac7 deletion of organoids was achieved in vitro by tamoxifen treatment over five consecutive days of culture. Morphological changes were monitored via microscopy and gene expression was analysed using qPCR. To examine barrier function, colon organoids were seeded as monolayers into filter inserts and transepithelial electrical resistance (TEER) was measured. Monolayer structure was verified using immunofluorescence.

Results

Hdac7 silencing in organoids of the small intestine caused a significant morphological shift to a spheroidal shape typical for an undifferentiated phenotype. Gene expression analysis revealed a dramatic downregulation of differentiation markers for all epithelial subtypes and an upregulation of stem cell markers. In colon organoids, undifferentiated HDAC7 knockout spheroids showed a significantly increased expression of goblet cell markers but displayed reduced enterocyte marker expression when subjected to differentiation medium. TEER build-up was consistently slower in colon organoid-derived monolayers after Hdac7 deletion but was higher after differentiation compared to wild type monolayers.

Conclusion

In the ileal epithelium, HDAC7 seems to play an important role in the differentiation process of all specialized epithelial subtypes while it appears to suppress mainly secretory lineages and promote differentiation into absorptive cells in the colon epithelium. These results suggest HDAC7 as an important regulator of intestinal differentiation and regeneration making it an interesting therapeutic target to treat inflammation-induced injuries in the gut.
P031 Class A1 scavenger receptor mediates macrophage polarization and apoptotic progression in a murine dextran sulfate sodium-induced colitis
Authors: Su J , Xie C , Hu Y , Huang Q , Shi H , Wang L , Ren J
Published: May 2021

Background

This study aimed to investigate the role of class A1 scavenger receptor (SR-A1) for regulating macrophage function and apoptotic pathway during intestinal inflammation of inflammatory bowel disease (IBD) in a DSS-induced murine colitis model.

Methods

A murine colitis model was established by feeding with 5% dextran sulfate sodium (DSS). Treatment groups were injected intravenously with SR-A1 antibody (100ug/kg), and control groups were injected with the vehicle only. Inflammatory activity and histological changes were evaluated on Day 8, and the percentage of macrophage markers in lamina propria mononuclear cells (LPMC) was measured by flow cytometer. The apoptosis and proliferation of intestinal epithelial cells were detected by TUNEL and Ki67 staining, and the expressions of related signaling pathway protein were determined with western blot.

Results

Treatment group showed a preventive effect on colitis symptoms and fewer inflammatory cell infiltrates compared with control group. After SR-A1 antibody treatment, flow cytometry of LPMC indicated that the percentage of F4/80+CD206+ Macrophages was elevated, while the percentage of F4/80+CD11c+ Macrophages was not obviously changed. Immunohistochemistry revealed that TUNEL-positive cells were significantly downregulated and Ki67- positive cells were upregulated in colonic mucosa of treatment group. In addition, the expressions of TLR4, MyD88 and NF-kB proteins in colonic mucosa were decreased after SR-A1 antibody injection.

Conclusion

Treatment with SR-A1 antibody could ameliorate macrophage-associated inflammatory response and epithelial cell apoptosis in a murine colitis model, which suggested that SR-A1 was a negative regulator of M2 polarization in IBD. SR-A1 mediated its effect by synergizing with TLR4/ MyD88 / NF-kB signaling pathway. Our research identified SR-A1 as a potential therapeutic target in IBD.
P043 Succinate receptor (SUCNR1) mediates leukocyte-endothelial cell interactions induced by TNFa
Authors: Coll S , Bauset C , Cosín-Roger J , Ortiz-Masià D , Gisbert-Ferrándiz L , Barrachina D , Calatayud S
Published: May 2021

Background

The Krebs cycle metabolite succinate contributes to inflammatory conditions like arthritis and colitis by activating its receptor SUCNR1. We aimed to analyze whether the succinate-SUCNR1 pathway contributes to the leukocyte-endothelial cell interactions that initiate the inflammatory response.

Methods

We evaluated leukocyte rolling and adhesion by intravital microscopy in cremaster venules of wild-type (WT) and Sucrn1−/− mice treated, 4h before, with succinate (1 Mm, intraescrotally), combined or not with the common pro-inflammatory cytokine TNFα (500 ng/mice, i.p.), or with their vehicles. We analyzed the activity of the NF-κB signaling pathway in endothelial cells (HUVEC) treated (4h) with succinate (0.5–1 mM) ± TNFα (20ng/ml), by detecting this transcription factor, its inhibitor iκBα, and their phosphorylated forms, by western blot. Results are expressed as mean±SEM (N≥6) and analyzed by ANOVA + Newman-Keuls test.

Results

In WT mice, succinate tended to induce leukocyte rolling and adhesion, and amplified the effects of TNFα on rolling. SUCNR1-deficient mice failed to increase leukocyte rolling in response to these treatments while showed an attenuated response to the effect of TNFα on leukocyte adhesion (Figure 1). Succinate treatment intensified the activation of the NF-κB pathway in HUVEC treated with TNFα, as shown by the increased IκBα phosphorylation, which allows its degradation, the reduced total IκBα, and the increased NF-κB/IκBα ratio (Figure 2).

Conclusion

Our results suggest that the endogenous release of succinate and the consequent stimulation of the SUCNR1 mediates the leukocyte-endothelial cell interactions induced by TNFα, and this pro-inflammatory activity may be related with an increased activation of the NF-κB signaling pathway in endothelial cells. Thus, the accumulation of succinate observed in various inflammatory diseases probably contributes to the initiation of the inflammatory focus by promoting the accumulation of leukocytes.

Bibliography
P059 GB004 drives protective effects on immune cells and epithelial cells using human ex vivo monolayer and co-culture systems
Authors: Taylor Meadows K , Murphy S , Levesque B G , Carter L L , Salter-Cid L
Published: May 2021

Background

GB004 is a small molecule that stabilizes hypoxia inducible factor (HIF-1α), a key transcription factor involved in the cellular responses at the intersection of hypoxia and inflammation. GB004 induction of HIF-1a target genes improves barrier integrity and reduces barrier permeability in rodent models of colitis. Here we investigated gene expression and secretion of soluble factors elicited by GB004 treatment on immune cells and epithelial cells, human monolayer assays and immune co-culture studies to further explore its protective mechanism.

Methods

In the BioMAP human co-culture assay, cells were treated with GB004 one hour prior to stimulation and incubated for 24–168 hours. Biomarkers, cell viability and proliferation were assessed. Repligut human stem-cell-derived monolayer platforms were used to assess GB004 effects under unstimulated or TNFa stimulation conditions. Barrier integrity was assessed by Transepithelial Endothelial Electric Resistance (TEER), HIF-1a target genes were assessed in cell lysates, and tight junction formation and epithelial monolayer viability were investigated by immunofluorescence staining.

Results

GB004 demonstrated activity in 11 of 12 systems in the BioMAP human co-culture assay, which covers a range of disease-relevant immune and non-immune mechanisms under stimulation conditions. Collectively, GB004 treatment led to changes in biomarkers associated with inflammation (sTNFa, IL-8, MCP-1, CXCL11), immunomodulation (sIL-17F, sIL-17A), and tissue remodeling (collagen I, collagen IV). GB004 treatment also reduced the proliferative activity in the in vitro lymphocyte assay systems. In the human Repligut intestinal epithelium assay, GB004 significantly reduced cell death and improved barrier integrity in response to pro-inflammatory cytokines. The protective role of GB004 on barrier integrity was further supported by immunostaining experiments demonstrating that GB004 treatment protected epithelial cells from TNFa-induced cell apoptosis, improving both epithelial cell number and tight junction protein ZO-1 staining.

Conclusion

GB004 modulates key anti-inflammatory and immunomodulatory activities in human co-culture systems. Furthermore, GB004 demonstrates protective effects on human derived monolayer cultures by reducing cell death, promoting tight junction formation, and improving barrier integrity. Targeting both barrier function and local colonic inflammation represents a multi-faceted approach to treatment of inflammatory bowel disease. A phase 2 clinical study of GB004 is ongoing in patients with ulcerative colitis (NCT04556383). Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.
P081 Resolvin D2 attenuates colonic inflammation of Crohn’s disease patients
Authors: Pascoal L B , Palma B B , Chaim F H , Nogueira G , Rodrigues B L , Ayrizono M L S , Velloso L A , Leal R F
Published: May 2021

Background

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract. Usually, the clinical management are based on sulphasalazine, corticosteroid, immunomodulators, biologics therapy and bioactive small molecules. However, new therapeutic strategies involving the inflammatory process are being proposed as the use of pro-resolution lipid mediators. This study aimed to investigate the potential therapeutical role of Resolvin D2 (RvD2) in the intestinal mucosa of CD patients and its therapeutic potential.

Methods

The study included 16 CD patients, 8 patients in remission (CDR) and 8 with active disease (CDA) and 6 healthy subjects in the control group (CTR); all were followed up in tertiary referral hospital. Blood sample and colonic biopsies were collected during colonoscopy. Disease activity was determined by the Crohn’s Disease Endoscopic Index of Severity (CDEIS). The serum blood level of RvD2 was determined by enzymatic immunosorption assay (ELISA). Intestinal biopsies were submitted to cell culture and treated with Infliximab (IFX) or RvD2. The expression of inflammatory cytokines was evaluated by real-time PCR and RvD2 levels through the ELISA. A nonparametric test was used for statistical analysis, with adopted p<0.05. The study was approved by the University of Campinas research ethics committee.

Results

The intestinal mucosa of the CDA group showed higher levels of pro-inflammatory markers, such as, IL1β (p=0.008 and p=0.01), IL6 (p=0.002), IL23 (p=0.03) and S100A8 (p=0.004 and p=0.01), compared to CTR and CDR groups, respectively. Although serum RvD2 levels of CDA (p=0.002) and CDR (p=0.004) groups were increased when compared to the CTR group, there is no differences between CDA and CDR groups (p>0.05). However, intestinal explants of the CDA group treated with RvD2 showed a significantly decrease of IL1β expression (p<0.05) when compared to the non-treated biopsies in the ex vivo culture experiments, similar to what was as verified by IFX treatment (p<0.05).

Conclusion

The results suggest the participation of RvD2 in the modulation of colonic inflammation associated with CD. RvD2 showed to be as effective as IFX in attenuating the pro-inflammatory response present in the intestinal mucosa of patients with CD and provide insights into pro-resolution lipid mediators approaches to modulate chronic inflammation.