bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparation and characterization of coal gangue modified road asphalt
Authors: Yao Shuang , Zhao Liang , Yang Jiayi , Jiang Hong , Nan Yunxi
Published: May 2021

Coal gangue is one of the largest industrial wastes in China, a large number of coal gangue accumulation not only occupies too much land area, but also causes surrounding land and air pollution. In this paper, the coal gangue samples were activated at first, and then the coal gangue powder was modified by adding coal gangue powder to road asphalt with the ratio of 0.5 and 1.2, and the penetration, softening point and ductility of the modified asphalt were tested. The results show that the viscosity, strength and softening temperature of modified asphalt can be improved by adding coal gangue powder into asphalt. With the increase of the amount of coal gangue powder in asphalt, the change of penetration and softening point of asphalt will be greater, and the strength of asphalt will also increase, but it will also make the toughness of asphalt worse. By adjusting the powder-binder ratio, the modified asphalt can adapt to different environments and use conditions, so that it can be widely used.
Finite element analysis of stress and distortion for welding reinforced structure of angular steel
Authors: Zhang Hui , Huang Zhenning
Published: May 2021

A 3-D finite element model of residual stress and distortion in welded structure with square section for angle steel is developed based on thermal-elastic-plastic theory. The residual stress and deformation for welded structure under different conditions are calculated and their distribution characteristics are comparatively analyzed. Results show that, relatively larger stress is generated in and near the weld zone for the welded joint. With an increase in weld length, both equivalent stress and residual distortion increase accordingly, but the effect of weld length on welding residual stress is limited. Under the conditions of 20 mm, 50 mm and 100 mm long welds, the deformations of the three reinforced structures caused by 15000 Pa external load are 4.80mm, 4.79mm and 4.78mm respectively, indicating they have the similar bearing capacity.
Lithium sulfur battery cathode materials based on COFs ordering
Authors: Lin Hong , Zhang Junli
Published: May 2021

In recent years, lithium-sulfur batteries and fuel cells, as a kind of new energy which is expected to replace traditional fossil fuels, have attracted people’s attention. At present, the “shuttle effect” of lithium-sulfur batteries is one of the key factors limiting the performance and application of lithium-sulfur batteries. It is urgent to find a suitable positive electrode composite material to suppress the “shuttle effect”. Covalent organic compounds (COFs) have been considered as ideal potential cathode composites for the anchors of sulfur and lithium compounds because of their regularized structure and polar functional groups. This paper mainly discusses the structure order of COF material, and gives the synthesis method of this kind of porous polymer material. The method of COFs synthesis is to design and assemble 2-D and 3-D COFs materials with different topological structures by choosing different geometrically constructed monomers and linking methods. Lithium-sulfur battery is a kind of battery with high energy density and theoretical capacity. The key to solve the shuttle effect is to find a suitable cathode composite material. Based on the order of COFs material structure, the feasibility and advantages of COFs as cathode material for lithium sulfur batteries were proposed.
Application of microbial remediation in the treatment of offshore oil pollution
Authors: Zhu Xinru
Published: May 2021

With the development of offshore oil industry, the pollution caused by frequent oil spill accidents has brought great pressure to marine ecology. How to repair the oil polluted sea area economically, efficiently and safely has become an urgent problem to be solved in marine ecological environment protection. In this paper, the main factors affecting the bioremediation of marine oil pollution are the polluted sea environment, the physical and chemical properties of oil and the types of microorganisms. The research progress of marine ecological restoration at home and abroad and the main research direction of marine oil pollution ecological restoration technology are summarized. The possible problems in the repair application are analyzed, and the further research direction is proposed.
Mechanical Properties of Vitrified Micro Bubbles Recycled Concrete Mixed with Calcined Diatomite
Authors: Bing Song
Published: May 2021

In order to prepare vitrified micro bubbles recycled concrete that meets the requirements of strength, the basic mechanical properties of recycled concrete with different vitrified micro bubbles were tested by adding calcined diatomite. The results show that: Calcined diatomite can fill the macroscopic cracks existing in the recycled coarse aggregate and effectively improve the performance of concrete and enhance the compressive strength of recycled concrete; With the increase of the amount of vitrified micro bubbles, the apparent density, compressive strength, splitting tensile strength and elastic modulus of recycled concrete all show a downward trend. When the amount of vitrified micro bubbles is 100% and the amount of calcined diatomite is 3%, the cubic compressive strength of recycled concrete can reach 32.36Mpa and the apparent density is only 1945kg/m3. Based on the experimental analysis, a linear relationship between cubic compressive strength fcu
and axial compressive strength fc
of vitrified micro bubbles recycled concrete is presented.
Study on the explanation rate of Fungi based on Ecological Model
Authors: Wang Shaoyilin , Zhou Yifei , Shen Zhujun
Published: May 2021

This article analyzes the relationship between fungal decomposition rate and its two important characteristics: extension rate and moisture resistance by establishing a fungal lignocellulose decomposition model when multiple types of fungi decompose wood fibers in the same area, and further predicts the role of the diversity of fungal communities in an ecosystem. we first divide fungi into two categories based on temperature: fast-growing but highly affected by the environment, called RABBIT; and slow-growing but relatively stable fungi (less affected by the environment), called TORTOISE. Humidity is an independent variable, using regression analysis method to establish a fungal growth decomposition model, we can find that the fungal decomposition rate and the logarithm of the expansion rate and the logarithm of moisture resistance are roughly linear. According to the fungal decomposition model obtained in question1, we use cellular automata and Lotka-Volterra model to establish interaction models between different types offungi, and find two types of bacteria with different competitiveness, RABBIT and TORTOISE, when competition coefficient of the mare different, we can find that the two groups of fungi will produce different competition results (may coexist, or one group of fungi may be eliminated).
Study on Layered Double Hydroxide and Its Electrochemical Performance
Authors: Chen Siwei , Peng Jing , Liu Tianyu , Song Ming
Published: May 2021

The layered double metal hydroxide can be used as a battery cathode material with the advantages of good stability, easy synthesis and low price. This article mainly studies the electrochemical performance of Ruthenium-containing Fe-Ni layered double metal hydroxide as the cathode material of the battery. The experiment mainly adopts the hydrothermal method to prepare FeNiRu-LDHs, and further calcines them in an argon atmosphere at different temperatures to obtain FeNiRu-LDOs with different Ru concentrations at different temperatures. Through cyclic voltammetry curve and impedance analysis, temperature is used as a variable to determine the electrochemical performance of the material has been tested in groups, and it is found that the 20FeNi-LDO calcined at 450°C showes excellent electrochemical performance. XRD, RAMAN and SEM are further used to study the characterization properties of the sample, and it is found that the shape of Ru20FeNi-LDHs at 450°C is better. Meanwhile, the comprehensive electrochemical performance of Ru20FeNi-LDHs material is best.
Design of solar power plants with hybrid systems
Authors: Koko J , Riza A , Mohamad Khadik U K
Published: May 2021

The design of hybrid power plants aims to provide alternative solutions to the community in the event of a power outage. This solar power generation system utilizes solar panels that have the function of converting sunlight energy into direct electrical energy which is used as the main source in battery charging. In a hybrid solar power plant system that is made equipped with a logger system that stores data about temperature, current, voltage on the solar panel, battery percentage, output power at the load, charging source and the power used at the load. From the results of the design and testing of the hybrid charging system, the main power source of the solar panel, if the battery power is less than 40%, the charging system moves to PLN (the state electricity company) and when the battery power is above 50%, the charging from the PLN will be turned off, at Auto Transfer Switch (ATS) system will be active if the power from the PLN goes out, the relay will move the PLN power to battery power for 3 seconds due to the start of the inverter, if the PLN power is on, the power from the inverter will move to PLN directly with no pause.
Catalysts for change: the cellular neurobiology of psychedelics
Authors: Banks Matthew I. , Zahid Zarmeen , Jones Nathan T. , Sultan Ziyad W. , Wenthur Cody J.
Published: May 2021

The resurgence of interest in the therapeutic potential of psychedelics for treating psychiatric disorders has rekindled efforts to elucidate their mechanism of action. In this Perspective, we focus on the ability of psychedelics to promote neural plasticity, postulated to be central to their therapeutic activity. We begin with a brief overview of the history and behavioral effects of the classical psychedelics. We then summarize our current understanding of the cellular and subcellular mechanisms underlying these drugs’ behavioral effects, their effects on neural plasticity, and the roles of stress and inflammation in the acute and long-term effects of psychedelics. The signaling pathways activated by psychedelics couple to numerous potential mechanisms for producing long-term structural changes in the brain, a complexity that has barely begun to be disentangled. This complexity is mirrored by that of the neural mechanisms underlying psychiatric disorders and the transformations of consciousness, mood, and behavior that psychedelics promote in health and disease. Thus, beyond changes in the brain, psychedelics catalyze changes in our understanding of the neural basis of psychiatric disorders, as well as consciousness and human behavior.
OCTID: a one-class learning-based Python package for tumor image detection
Authors: Wang Yanan , Yang Litao , Webb Geoffrey I , Ge Zongyuan , Song Jiangning
Published: May 2021

Motivation

Tumor tile selection is a necessary prerequisite in patch-based cancer whole slide image analysis, which is labor-intensive and requires expertise. Whole slides are annotated as tumor or tumor free, but tiles within a tumor slide are not. As all tiles within a tumor free slide are tumor free, these can be used to capture tumor-free patterns using the one-class learning strategy.

Results

We present a Python package, termed OCTID, which combines a pretrained convolutional neural network (CNN) model, Uniform Manifold Approximation and Projection (UMAP) and one-class support vector machine to achieve accurate tumor tile classification using a training set of tumor free tiles. Benchmarking experiments on four H&E image datasets achieved remarkable performance in terms of F1-score (0.90 ± 0.06), Matthews correlation coefficient (0.93 ± 0.05) and accuracy (0.94 ± 0.03).

Availability and implementation

Detailed information can be found in the Supplementary File.

Supplementary information

Supplementary data are available at Bioinformatics online.
Dynamic Network Analysis Demonstrates the Formation of Stable Functional Networks During Rule Learning
Authors: Morin Thomas M , Chang Allen E , Ma Weida , McGuire Joseph T , Stern Chantal E
Published: May 2021

Variations in the functional connectivity of large-scale cortical brain networks may explain individual differences in learning ability. We used a dynamic network analysis of fMRI data to identify changes in functional brain networks that are associated with context-dependent rule learning. During fMRI scanning, naïve subjects performed a cognitive task designed to test their ability to learn context-dependent rules. Notably, subjects were given minimal instructions about the task prior to scanning. We identified several key network characteristics associated with fast and accurate rule learning. First, consistent with the formation of stable functional networks, a dynamic community detection analysis revealed regionally specific reductions in flexible switching between different functional communities in successful learners. Second, successful rule learners showed decreased centrality of ventral attention regions and increased assortative mixing of cognitive control regions as the rules were learned. Finally, successful subjects showed greater decoupling of default and attention communities throughout the entire task, whereas ventral attention and cognitive control regions became more connected during learning. Overall, the results support a framework by which a stable ventral attention community and more flexible cognitive control community support sustained attention and the formation of rule representations in successful learners.
The Incubation Period Distribution of Coronavirus Disease 2019: A Systematic Review and Meta-analysis
Authors: Xin Hualei , Wong Jessica Y , Murphy Caitriona , Yeung Amy , Taslim Ali Sheikh , Wu Peng , Cowling Benjamin J
Published: May 2021

Incubation period is an important parameter to inform quarantine period and to study transmission dynamics of infectious diseases. We conducted a systematic review and meta-analysis on published estimates of the incubation period distribution of coronavirus disease 2019, and showed that the pooled median of the point estimates of the mean, median and 95th percentile for incubation period are 6.3 days (range, 1.8–11.9 days), 5.4 days (range, 2.0–17.9 days), and 13.1 days (range, 3.2–17.8 days), respectively. Estimates of the mean and 95th percentile of the incubation period distribution were considerably shorter before the epidemic peak in China compared to after the peak, and variation was also noticed for different choices of methodological approach in estimation. Our findings implied that corrections may be needed before directly applying estimates of incubation period into control of or further studies on emerging infectious diseases.
NIAID ClinRegs—a Public Database of Country Clinical Research Regulatory and Ethics Requirements: Design and Utilization Analysis
Authors: Kagan Jonathan , Goodman Geoffrey N , Oh Rachel , Whitworth Diane , Gladden Darcie , Graves Gail , Nguyen Antonia , Shrestha Orish , Burge Gerald , Smolskis Mary , Andrews Janet , Cramer Brian , Lane H Clifford
Published: May 2021

Regulatory compliance is challenging for multinational clinical trials. Conflicts between country requirements impedes research and slows the approval of medicines, leading the pharmaceutical industry to devote significant resources to this area. Many academic centers and nonprofits cannot support industry-level investment and are vulnerable to noncompliance. To address an insufficiency in public access to this information, the National Institute of Allergy and Infectious Diseases developed ClinRegs—a public access database of clinical research regulations. This report describes ClinRegs’ features, maintenance, and usage. From September 2019 through August 2020, ClinRegs had 68 504 users, 60% from outside the United States, demonstrating the demand for accessible, reliable, country-specific regulatory information. Tools such as ClinRegs can help increase regulatory compliance and free up resources for research. We encourage our partner agencies and biomedical research industries to promote greater regulatory knowledge sharing and harmonization for the betterment of clinical research and improved public health.
KMDATA: a curated database of reconstructed individual patient-level data from 153 oncology clinical trials
Authors: Fell Geoffrey , Redd Robert A , Vanderbeek Alyssa M , Rahman Rifaquat , Louv Bill , McDunn Jon , Arfè Andrea , Alexander Brian M , Ventz Steffen , Trippa Lorenzo
Published: May 2021

We created a database of reconstructed patient-level data from published clinical trials that includes multiple time-to-event outcomes such as overall survival and progression-free survival. Outcomes were extracted from Kaplan–Meier (KM) curves reported in 153 oncology Phase III clinical trial publications identified through a PubMed search of clinical trials in breast, lung, prostate and colorectal cancer, published between 2014 and 2016. For each trial that met our search criteria, we curated study-level information and digitized all reported KM curves with the software Digitizelt. We then used the digitized KM survival curves to estimate (possibly censored) patient-level time-to-event outcomes. Collections of time-to-event datasets from completed trials can be used to support the choice of appropriate trial designs for future clinical studies. Patient-level data allow investigators to tailor clinical trial designs to diseases and classes of treatments. Patient-level data also allow investigators to estimate the operating characteristics (e.g. power and type I error rate) of candidate statistical designs and methods.

Database URL: https://10.6084/m9.figshare.14642247.v1
DOP53 Pregnancy outcomes in the ozanimod clinical development program in relapsing multiple sclerosis, Ulcerative Colitis, and Crohn’s Disease
Authors: Dubinsky M C , Mahadevan U , Charles L , Afsari S , Henry A , Comi G , Selmaj K , van der Woude C J
Published: May 2021

Background

Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, has demonstrated efficacy in patients with relapsing multiple sclerosis (rMS) and ulcerative colitis (UC), and is being studied in Crohn’s disease (CD). S1P1-3 receptors are involved in vascular formation during embryogenesis. Within studies in the ozanimod clinical development program, female participants of childbearing potential were required to use effective contraception while receiving and up to 3 months after discontinuing ozanimod; treatment discontinuation was required if pregnancy was confirmed. Here we review pregnancy outcomes data with ozanimod use in rMS, UC, and CD.

Methods

All pregnancies, including participant and partner pregnancies, in the ozanimod clinical development program with an initial diagnosis prior to a cut-off date of September 30, 2020 were assessed for pregnancy outcomes.

Results

At cut-off, safety data on 4131 participants were available. A total of 83 pregnancies were reported in the safety database of participants treated with ozanimod or their partners (Table). All pregnancy exposures occurred during the first trimester. Of the 60 pregnancies in ozanimod clinical trials, 9 were reported in patients with UC, and 3 in patients with CD. Participants discontinued study medication promptly except for those who elected pregnancy termination and did not discontinue study medication. Among all pregnancies in the ozanimod clinical development program, the incidence of spontaneous abortion in clinical trial participants was 15%; the rate in the general population is between 12% and 22%. The rate of preterm birth was 10.7% of live births; as reference, the global population estimate is 10.6% and the European estimate is 8.7%. No teratogenicity was observed. Outcomes in patients with UC included 2 live births that resulted in 2 full-term healthy newborns, 2 ongoing pregnancies, 2 spontaneous early losses, and 3 elective terminations.

Conclusion

While pregnancy should be avoided in patients on and 3 months after stopping ozanimod and clinical experience with ozanimod during pregnancy is limited, there has been no increased event of foetal abnormalities or adverse pregnancy outcomes seen with ozanimod exposure in early pregnancy.
DOP55 Histopathological features at diagnosis to predict long-term disease course of Crohn’s Disease
Authors: Rezazadeh Ardabili A , Goudkade D , Wintjens D S J , Romberg-Camps M J L , Winkens B , Pierik M J , Grabsch H I , Jonkers D M A E
Published: May 2021

Background

Crohn’s disease (CD) is characterized by a heterogeneous disease course and treatment response. There is a clinical need to identify CD patients at diagnosis who are at risk for developing a severe disease course. Patient stratification using state-of-the-art clinical, serological or genetic markers does not predict disease course sufficiently to facilitate clinical decision making. The current study aimed to investigate the additive predictive value of histopathological features at diagnosis to discriminate between patients with a long-term mild and severe disease course.

Methods

Diagnostic biopsies from treatment-naïve CD patients with mild or severe disease courses in the first 10 years after diagnosis (i.e. based on the number of quarterly flares) were reviewed by two senior gastrointestinal pathologists after developing a standardized form comprising 15 histopathological features related to acute and chronic inflammation. Multivariable logistic regression models were built to identify predictive features and compute receiver operating characteristics (ROC) curves. Model 1 included clinically relevant baseline characteristics (Montreal classification, smoking status and gender). Next, histopathological were added by applying two different model-building strategies (forward selection and purposeful selection algorithm)(Model 2). Prediction models were internally validated using bootstrapping to obtain optimism-corrected performance estimates.

Results

In total, 817 biopsies from 137 CD patients (64 mild disease course, 73 severe disease course) were included. Based on clinical baseline characteristics alone, disease course could only be moderately predicted (Model 1 Area under ROC (AUROC): 0.738 (optimism 0.018), 95%CI 0.65–0.83, sensitivity 83.6%, specificity 53.1%). When adding histopathological features, in colonic, but not ileal, biopsies a combination of (1) basal plasmacytosis, (2) severe lymphocyte and plasma cell infiltration in the lamina propria, (3) Paneth cell metaplasia and (4) absence of ulcers were identified and resulted in significantly better prediction of a severe disease course (Model 2 AUROC: 0.883 (optimism 0.033), 95%CI 0.82–0.94, sensitivity 80.4%, specificity 84.2%, model 2 vs. model 1 AUROC p = 0.001)[Figure 1].

Conclusion

In this first study investigating the additive predictive value of multiple histopathological features in biopsies at CD diagnosis, we found that certain features of chronic inflammation in colonic biopsies contributed to prediction of a severe disease course, thereby presenting a novel approach to improve stratification and facilitate clinical decision making.
DOP64 Endoscopically injected allogeneic mesenchymal stromal cells alter the mucosal immune cell compartment in patients with ulcerative proctitis
Authors: Ouboter L , Barnhoorn M , Plug L , van Pel M , Zwaginga J J , Roelen D , Pascutti F , Koning F , Hawinkels L , Verspaget H , van der Meulen - de Jong A
Published: May 2021

Background

Local mesenchymal stromal cell (MSC)-therapy is approved for the treatment of Crohn’s disease-associated perianal fistulas. However, little is known about the working mechanism of local MSC-therapy. For the first time we evaluated engraftment and immunoregulatory effects of local MSC-therapy in patients with refractory proctitis. To do so, we analyzed biopsies and serum from patients with ulcerative proctitis before and after treatment with endoscopically injected MSCs in a phase IIa clinical trial (EudraCT number 2017-003524-75).

Methods

Thirteen therapy-refractory ulcerative proctitis patients were endoscopically injected bone marrow-derived allogeneic MSCs from healthy donors. Clinical efficacy was evaluated by the endoscopic and full Mayo score. Engraftment of the MSCs was investigated using fluorescence in-situ hybridization (FISH) of sex chromosomes on post-treatment biopsies. The presence of anti-HLA-antibodies against the MSC-donor was determined in the serum. Changes in immune cell subsets were evaluated using cytometry-by-time-of-flight (CyTOF) analysis.

Results

Thirteen patients with an endoscopic Mayo score of 2 (n=3) or 3 (n=10) of the rectum were treated with local MSC-therapy. Although complete remission was not achieved, full Mayo score was improved at week 6 (median 8 [IQR 6–10]) compared to baseline (median 11 [IQR 9.5–12]) (p=0.001). Preliminary data using FISH on the Y-chromosome, indicated the presence of MSCs in the rectum biopsies of female patients treated with male donor derived-MSCs at week 6. At baseline, HLA-antibodies were present in four patients. Six weeks after local injection of the MSCs, two out of thirteen patients developed new class I and II HLA-antibodies against the MSCs. Interestingly, in two patients pre-existing HLA-antibodies showed increased/boosted levels after local MSC-therapy, while one additionally developed new HLA-antibodies. CyTOF analysis of inflamed rectal biopsies 6 weeks after MSC treatment revealed significantly increased frequencies of several myeloid subsets (i.e. CD11b+CD14+CCR7+/-CD127+CD25+HLADR+ and CD14+HLA-DR-CD123-CCR7+) and a subset of CD4+ memory T cells with a more exhausted/regulated phenotype (PD-1+TIGIT+CD69+CD38+CD69).

Conclusion

Local MSC-therapy in patients with refractory proctitis changed the rectal immune profile characterised by a significant increase in a subset of effector memory CD4+ cells and several myeloid subsets, which might be associated with immune modulation. These results provide the basis for future studies on the mechanism of action of MSCs on rectal mucosa. New anti-HLA class antibodies developed in 2/13 patients after local administration. Whether these latter results have consequences for MSC-donor selection deserves further study.
OP01 Comparison of fecal transplantation, fecal transplantation with the novel UC diet or the UC diet alone for Refractory Mild to Moderate Active Ulcerative Colitis: The CRAFT UC randomized controlled trial
Authors: Levine A , Scaldaferri F , Sarbagili Shabat C , Zittan E , Hirsch A , Mentella M C , Musca T , Cohen N A , Ron Y , Fliss Isakov N , Pfeffer J , Yaakov M , Fanali C , Turchini L , Masucci L , Quaranta G , Anastasia G , Weinberger A , Kopylov U , Maharshak N
Published: May 2021

Background

We evaluated if integration of novel diets for donors and patients in addition to fecal transplantation (FT) could increase FT remission in refractory ulcerative colitis (UC) or have an independent effect on remission. We developed a novel diet specifically designed for the dysbiosis of UC and to decrease factors that impair goblet cells or mucous production.

Methods

This was a blinded randomized controlled pilot trial in adults with UC, defined by a simple clinical colitis activity index (SCCAI) of ≥5 and < 11 and endoscopic Mayo score 2–3, refractory to medication. Group 1 received free diet and standard FT by colonoscopy on day 1and rectal enemas from a single donor on days 2 and 14 without dietary conditioning of the donor. Group 2: FT as above but with dietary pre-conditioning of the donor for 14 days and a diet (UC Diet- UCD) for the patients after FT. Group 3 received the UC Diet alone without FT. Patients underwent a repeat endoscopy at week 8. The primary endpoint was clinical steroid free remission, defined as SCCAI <3, at week 8.

Results

Fifty-one of the 96 planned patients were enrolled. The mean age was 40.4 ±12.5 years, 28/51(54.9%) had failed a biologic, 15/40 (29.4%) were on steroids at enrolment. Remission week 8 in Group 1 was 2/17(11.8%), Group 2 was 4/19 (21.1%), and 6/15 (40%) Group 3 (NS). Endoscopic remission was present in Group 1: 2/17(12%), Group 2: 3/19(16%) and 4/15 (27%) Group 3. Mucosal healing (Mayo 0) was achieved only in Group 3 (3/15, 20%) vs. 0/36 patients receiving FT (P=0.022). Exacerbation of disease occurred in 3/17 (17.6%) Group1, 4/19 (21.1%) Group 2, and 1/15 (6.7%) Group 3 (NS). The study was stopped for futility by a safety monitoring board.

Conclusion

Fecal transplantation was not effective in this UC cohort. A UC Diet alone appeared to achieve higher clinical remission (40%) and mucosal healing than single donor FT with or without diet in mild to moderate UC failing medical therapy. This diet should be investigated further in a RCT specifically designed for the UCD. This study was supported by an ECCO Pioneer grant
OP09 Patient reported outcomes reflect histologic disease activity in patients with Ulcerative Colitis: Interim analysis of the APOLLO study
Authors: Verstockt B , Jorissen C , Hoefkens E , Lembrechts N , Pouillon L , Bossuyt P
Published: May 2021

Background

Treating beyond endoscopic remission, aiming for histological remission, has shown to reduce relapse and hospitalization rates in patients with ulcerative colitis (UC). However, very little is known on how histological remission associates with patient reported outcomes (PROMs).

Methods

PROMs (Simple clinical colitis activity index [SCCAI], IBD disk and Visual Analogue Scales [VAS]) were prospectively collected through a digital questionnaire in all patients with UC undergoing colonoscopy between July 21st 2020-Jan 21st 2021. Mayo endoscopic sub score and UCEIS were determined, as well as the Nancy histologic index (NHI) of the most affected area. Endoscopic remission was defined as Mayo endoscopic sub score 0 and UCEIS 0; histologic remission as NHI 0, absence of active inflammation as NHI ≤ 1. PRO2 remission was defined as stool frequency ≤ 1 (absolute stool frequency ≤ 3 OR 1–2 stools more than usual) and rectal bleeding score of 0.

Results

Fifty-six paired assessments were collected in 48 unique patients (Table 1), with a histologic, endoscopic and PRO-2 remission rate of 23.2%, 28.6% and 38.2% respectively. Patients with histologic remission or absence of histologic inflammation had a significantly lower overall IBD disability (p=0.007, p=0.003) and disease activity score (p=0.003, p<0.001), as compared to patients without. In line, NHI correlated with the overall IBD disk (r=0.40, p=0.002) and SCCAI score (r=0.50, p<0.001). Many individual components of both scores (abdominal pain, arthralgia, impact on education and work/interpersonal interactions/sexual function, regulation of defecation, blood loss, general wellbeing, joint pain, numbers of stools during night/day, urgency) differed significantly between patients with and without histologic remission. VAS scores assessing general wellbeing (r=0.33, p=0.01), impact on daily activities (r=0.41, p=0.002), UC-related symptoms (r=0.42, p=0.001) and worries (r=0.40, p=0.002) correlated with histology. Quartile analysis of the overall IBD disk and SCCAI scores confirmed the highest likelihood for histologic remission in patients with the lowest scores (Q1-Q2 vs Q3-Q4 39.3% vs 7.1%, p=0.01; 40.0% vs 9.7%, p=0.01) (Figure 1). Nevertheless, the overall accuracy of the IBD disk (0.75) or SCCAI score (0.76) for histologic remission is lower (p<0.05) than the accuracy of the Mayo endoscopic (0.90) or UCEIS (0.90) score.

Table 1: Baseline features

Abstract OP09 – Figure 1: Quartile analysis

Conclusion

In patients with UC, PROMs for disability and clinical disease activity reflect histologic disease activity and should therefore be further explored in (trial) endpoint discussions. However, they cannot fully replace endoscopic and histologic findings, and should be considered complementary.
OP17 Impact of phenotypic and genetic factors on Crohn’s Disease evolution in a cohort of 13,926 patients
Authors: Zhang Q , Fachal L , Shawky R , Parkes M , Anderson C , Raine T
Published: May 2021

Background

Patients with Crohn’s disease (CD) can develop complications including stricturing and penetrating disease [1, 2]. Although reliable baseline predictors of disease progression are urgently needed to inform management strategies, few studies have comprehensively explored the phenotypic and genetic determinants of disease progression in a sufficiently powered cohort.

Methods

We used data from 13,926 patients with CD in the UK IBD BioResource to investigate the effects of clinical phenotypes and genetics on CD progression. Median follow-up was 10.6 years and total follow-up was 193,033 patient-years. We applied the Montreal classification system to define disease as B1 (inflammatory), B2 (stricturing) and B3 (penetrating). Patients with B2 or B3 disease (N = 5,185) were compared to patients with B1 disease (N = 8,471) in a multivariate model fitted with both phenotype data and a polygenic score that we developed. Associations with q-values (false discovery rate adjusted p-values) less than 0.05 were defined as statistically significant.

Results

CD progression occurred over time from diagnosis (Figure 1). Consistent with previous findings, we confirmed factors including smoking, disease location and perianal disease were associated with disease progression [3] (Table 1). The impact of a genetic influence on disease progression was confirmed and shown to be independent of genetic effects on disease location [4]. Early prescription of medications showed a protective effect on disease progression: Infliximab, adalimumab and thiopurines significantly reduced the chance of B2/B3 progression when prescribed within two years of diagnosis. Additionally, we observed a decreased progression to B2/B3 disease in patients diagnosed recently (between 2012–2020) compared to those diagnosed before 2012. This finding persisted after conditioning on exposure to biologics and correcting for follow-up time and interval to first thiopurine prescription, and thus may be indicative of other improvements in standards of care in recent years.

Conclusion

Using a large, well-characterised cohort we confirm the importance of disease location, smoking status and genetics on disease progression. We highlight the positive impact of early medication prescription on disease progression and discover an independent signal relating to potential improvements in the standard of care in CD over time. These results create the framework for reliable predictors of CD progression that may better guide future CD management strategies.

References
OP31 RESTORE: Interim analysis of a Phase 2 study of QBECO SSI for the induction and maintenance of clinical and endoscopic remission in subjects with Moderate to Severe Crohn’s Disease
Authors: Bressler B , Marshall J K , Atkinson K , Sutcliffe S , Pankovich J , Jones M , Kalyan S , Gunn H
Published: May 2021

Background

Innate immune defects play a role in the pathogenesis of CD. Enhancing innate immune competency and restoring mucosal barrier function provide a novel approach to treat CD. QBECO SSI is a first-in-class immunotherapy designed to correct innate immune dysfunction underlying CD. This analysis is from subjects in the open label portion of a planned controlled trial. Objectives were to assess endoscopic response at Wks 16 and 26, and select the optimal induction timepoint for the RCT. Safety and treatment compliance were also evaluated.

Methods

20 pts with moderate-to-severe CD were enrolled and received QBECO SSI by sc injection every other day for up to 52 wks. Minimum eligibility: Simple Endoscopic Score for CD (SES-CD) ≥7 (ileitis ≥4), abdominal pain (AP) score >21 (11-point scale) or liquid/very soft stools (SF) (BFS Type 6 or 7) >10 for 7 consecutive days during screening. Pts were evaluated for clinical symptoms and endoscopy at Wks 16, 26, and 52. After evaluation at the induction period (Wk 26) pts could continue in maintenance up to Wk 52. Endoscopies were evaluated by central blinded read and pts reported daily symptoms. Endoscopic response defined as ≥50% reduction in SES-CD from baseline. Clinical remission defined as AP and SF ≤21.

Results

Mean age was 43.6 (SD 13.6) yrs; 60% men and 60% previously treated with biologics. Mean yrs since CD diagnosis was 14.4 (10.1), AP score 30.4 (15.8), SF score 36.2 (19.1) and mean SES-CD at baseline was 12.5 (6.7) indicating a more difficult to treat population. Endoscopic response rate by central read during the induction period was 30% (6/20) overall, 38% (3/8) for biologic naïve and 25% (3/12) biologic experienced pts (ITT analysis). Similar number of pts achieved endoscopic response at Wk 16 (4 pts) as 26 (3 pts). Mean SES-CD improved through Wk 26 with a 0.6 point greater reduction at Wk 26 compared to 16. Change in SES-CD from baseline in biologic naïve pts was -2.9 (5.8) at Wk 16 and -4.1 (6.7) at 26. Clinical remission was achieved by 45% (9/20) of pts at Wk 16 and 40% (8/20) at Wk 26; 16 pts continued into the maintenance phase of the study. By central evaluation, 13% (2/16) were in endoscopic response at Wk 52. QBECO SSI was very well tolerated. 8/20 (40%) pts reported AEs related to treatment. Most frequency reported related AE was injection site erythema (2/20, 10% pts). Majority of AEs were mild and no other related AE was reported by more than 1 patient.

Conclusion

Week 26 was the optimal endoscopic evaluation timepoint for QBECO SSI treatment and will be utilized in the larger RCT. Both biologics naïve and experienced patients showed response to QBECO SSI treatment by Weeks 26 and 52, with higher response rates in biologics naïve patients. QBECO SSI was well tolerated.
OP32 Stool microbiome communities predict remission in treatment-naïve Pediatric Crohn’s Disease patients
Authors: Verburgt C , Dunn K , Bielawski J , Otley A , Heyman M , Sunseri W , Shouval D , Levine A , de Meij T , Hyams J , Denson L , Kugathasan S , Benninga M , de Jonge W , Van Limbergen J
Published: May 2021

Background

Early relapse in paediatric Crohn’s Disease (CD) is associated with severe disease course that heavily impairs quality of life. Changes in gut microbiome composition have been linked to active CD and disease course. This has led to development of microbiome-based prediction models for diagnosis and response to treatment. Our aim was to identify community-level microbiome signatures of treatment-naïve children with mild-to-moderate CD who did not require anti-TNF or surgery at diagnosis, with the goal of predicting need for re-induction or treatment escalation within the first year after diagnosis.

Methods

We selected de novo, treatment-naïve paediatric CD patients from the RISK cohort(Gevers 2014). Taxonomic labels were assigned to the 16s rRNA amplicon data using QIIME and closed OTU-picking. A hierarchical Bayesian model for microbial community structure was used to learn how baseline gut microbiomes differed according to treatment outcome. Model predictions were assessed using a leave-one-out analysis. We compared 16S rRNA sequences of CD patients with non-IBD controls(Gevers 2014) and healthy siblings of CD patients(Turpin 2016).

Results

Metadata and 16S rRNA amplicon data were available from 197 stool samples of de novo paediatric CD patients from the RISK cohort. We selected 44 out of 197 samples of patients that were treatment-naïve. Prior to treatment, PCDAI scores were similar between patients reaching remission and those that did not at 6 months. Bayesian analysis characterized 4 assemblages that accounted for 93% of the posterior probability distribution. The Bayesian model on pre-treatment stool microbiomes was able to predict 6-month outcome of patients that maintained remission and those that did not from the pre-treatment microbiome in 81% and 75% of samples (AUC=0.79). When comparing CD samples to 28 non-IBD controls (many with GI symptoms but negative for IBD during endoscopy, e.g. Irritable Bowel Syndrome), 6 assemblages were characterized with 44% of distributions shared between groups (AUC=0.61). In contrast, in CD samples compared to 728 healthy sibling samples (with increased genetic susceptibility), shared distribution within 4 characterized assemblages was less than 1% (AUC=1).

Conclusion

A Bayesian approach predicted clinical course in treatment-naïve children with CD in the first year after diagnosis with high accuracy, when ensuring only treatment-naïve faecal samples in the analysis. This classification level is comparable to previous findings using mucosal samples. Further study is needed to validate these pre-treatment microbiome signatures of newly diagnosed paediatric CD patients to allow identification of patients with mild-to-moderate disease who are most likely to require treatment escalation.
OP34 AJM300, an Oral Antagonist of α4-Integrin, as induction therapy for patients with Moderately Active Ulcerative Colitis: A Phase 3, randomized, double-blind, placebo-controlled induction study
Authors: Watanabe M , Matsuoka K , Ohmori T , Nakajima K , Ishida T , Ishiguro Y , Kanke K , Kobayashi K , Hirai F , Watanabe K , Hibi T
Published: May 2021

Background

AJM300 (INN; carotegrast methyl), an orally active small molecule antagonist of the α4 subunit of α4β1/α4β7 integrins, demonstrated the efficacy and safety in patients with moderately active ulcerative colitis (UC) in a phase 2 study. The phase 3 study (NCT 03531892) of AJM300 as induction therapy was conducted in patients with moderately active UC.

Methods

Eligible patients were moderately active Japanese UC, defined as total Mayo Clinic scores (MCS) of 6–10, endoscopic subscores (ES) ≥2, and rectal bleeding subscores (RBS) ≥1, who had inadequate response or intolerance to oral 5-ASA. Followed by a 2-week single-blind placebo (PBO) run-in phase, patients were randomized 1:1 to receive AJM300 960 mg or PBO 3 times daily for 8 weeks. Responders or remitters were allowed to receive AJM300 960 mg again at the subsequent relapse (open-label). The primary endpoint was clinical response at week 8, defined as reduction of the MCS of ≥3-pts and ≥30%, reduction in RBS of ≥1-pt or RBS of ≤1, and ES ≤1.

Results

The randomized 203 patients had moderately active endoscopic evidence at baseline with median UC duration of 6.1 years and MCS of 7.8. For the primary endpoint, 45.1% (46/102) and 20.8% (21/101) of patients in the AJM300 and PBO groups, respectively, achieved clinical response at week 8 (OR=3.30 [95% CI, 1.73–6.29]; p=0.0003). Symptomatic remission, endoscopic improvement and endoscopic remission were also statistically significant for AJM300 vs PBO (Table). In case of episodic AJM300 treatment, AJM300 exhibited similar response to initial treatment. Overall, the incidence of AEs and serious AEs were similar between AJM300 and PBO. There were no deaths or cases of progressive multifocal leukoencephalopathy.

Conclusion

AJM300 induced clinical response as well as endoscopic remission with good tolerability. AJM300 may become a novel therapeutic option for patients who had inadequate response or intolerance to oral 5-ASA.
OP39 The effect of phenotype and genotype on the plasma proteome in patients with Inflammatory Bowel Disease
Authors: Bourgonje A R , Hu S , Spekhorst L M , Zhernakova D V , Vich Vila A , Li Y , Voskuil M D , van Berkel L A , Bley Folly B , Charrout M , Mahfouz A , Reinders M J T , van Heck J I P , Joosten L A B , Visschedijk M C , van Dullemen H M , Faber K N , Samsom J N , Festen E A M , Dijkstra G , Weersma R K
Published: May 2021

Background

Protein profiling in patients with inflammatory bowel diseases (IBD) for diagnostic and therapeutic purposes is underexplored. Assessment of interactions between genetics and the plasma proteome could lead to identification of novel disease-associated molecular pathways. In this study, we performed the largest gene-protein association analysis thus far in patients with IBD, taking into account relevant phenotypic covariates and integrating information from multiple biological data layers.

Methods

Ninety-two (92) inflammation-related proteins were quantified in plasma of 1,028 patients with IBD (567 Crohn’s disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess proteome-phenotype associations. Both whole-exome sequencing (WES) and global screening array (GSA) data of 919 patients with IBD were included to study associations between over 8 million genetic variants and protein levels (protein quantitative trait loci [pQTL]). Cis-pQTLs were defined within ± 1 Mb of the region of each protein-coding gene center, whereas trans-pQTLs were outside of that region. After adjusting for phenotypic covariates, a step-wise conditional analysis was used to identify all independent pQTLs in CD and UC separately, followed by a meta-analysis. Intestinal mucosal RNA sequencing and fecal metagenomic data were used for complementary analyses.

Results

Thirty-four (34) proteins were differentially abundant between IBD and healthy individuals, of which 24 proteins independent of active inflammation. (Figure 1) Seventy-two (72) proteins were significantly associated to 14 phenotypic factors, including age, sex, medication use, and surgical history. (Figure 2) Fibroblast growth factor-19 (FGF-19) levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen (13) novel cis-pQTL variants were identified and 10 replicated from previous studies, together affecting 21 different plasma proteins. One trans-pQTL variant of the FUT2 gene (rs602662) and two independent cis-pQTL variants of the CCL25 gene significantly affected plasma C-C motif chemokine ligand 25 (CCL25) levels. (Figure 3) Intestinal gene expression data revealed an overlapping cis-expression (e)QTL-variant (rs3745387) of the CCL25 gene. The FUT2 rs602662 trans-pQTL variant associated significantly with reduced abundances of multiple fecal butyrate-producing bacteria, including the genus Blautia and the species Faecalibacterium prausnitzii.

Conclusion

This study shows that both genotype and multiple disease phenotypes strongly associate with the plasma proteome in patients with IBD and identifies disease-associated pathways that may help to improve disease management in the future.