bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and Optimization of the Collector of Electric Sugarcane Leaves Returning Field Machine
Authors: Lin Yisen , Yu Meng , Wen Fujun , Zhang Zengxue , Tang Yanqin , Wang Yuxing
Published: January 2020

In this paper, the collector is designed for electric sugarcane leaves returning field machine. According to the working principles of the collector and the moving trace rules of collecting components, we confirm the important structural parameters of the collector by using the ADAMS software for motion simulation optimization, including the rotor radius, crank length, the locus curve in the center of cam disc slide and et al. The ADAMS software is used for simulating the movement of the collector with different combinations of two factors (the forward speed of machine and rotate speed of roller plate), and we can obtain the results about the angular acceleration at the end of collecting components and the leakage area per meter. The data obtained from the simulation test is analyzed by Central Composite Design (CCD) with the aim of assessing the best working parameter combination on low leakage rate. The best parameter combination of two variables are determine, i.e., the forward speed is v=0.4 m/s, and the rotate speed is ω=49.41 rpm. The sum area of leakage area is 26.95cm2/m, and the largest angular acceleration at the end of collecting components is 200 rad/s2. The collector based on the theoretical design results is produced, and it would be tested in the forward speed of v=0.4 m/s, and rotate speed of ω=50 rpm for analyzing its performance. The test results show that the collecting effect of the collector is well, and the leakage rate is 2.93 %, which can be up to the requirement of agricultural technical index. The collector can complete the collecting work of the sugarcane leaves returning field machine.
Quenching Process Simulation of Spur Gear Based on ANSYS
Authors: Zhang JingDong , Yang Kuan , Zhao Shenglian , Zheng Bin
Published: January 2020

Gear transmission is one of the most common mechanical transmissions in contemporary machinery. It is the main form of transmission of mechanical power and movement, and it is an important part of all kinds of machinery. For gear transmission, better hardness and wear resistance are required, which can be achieved by quenching process. But the spur gear in quenching process, its size and shape will appear different degree of deformation, this paper uses the Pro/Engineering software to establish solid parameterized model of the spur gears. Then, the simplified single tooth solid model of the spur gear imported to ANSYS software to obtain the finite element model. The temperature field of the single tooth spur gear during quenching were carried out. Thus, it is concluded that the relationship between the factors influencing the quenching. The results provide a certain reference basis for the establishment of the hot working processes of the spur gear.
The effect of impingement angle on erosion wear characteristics of HVOF sprayed WC-Ni and WC-Cr3C2-Ni cermet composite coatings
Authors: Chen Yirui , Wu Yuping , Hong Sheng , Long Weiyang , Ji Xiulin
Published: January 2020

The present study investigated the erosion wear behavior of WC-Ni and WC-Cr3C2-Ni cermet coatings deposited by high velocity oxy-fuel (HVOF) spray process on the substrate of 1Cr18Ni9Ti stainless steel. Microstructures and morphologies of the coatings were examined using SEM images, and x-ray diffractometer was used to analyze the phase composition of the powder and the coatings. The erosion test was carried out using home-made jet rig. In order to better fit the research background of this study, the erodent used for erosion was taken from the Yellow River, China. The coating is well combined with the substrate; and WC-Cr3C2-Ni coating consists of WC, Cr3C2 and Ni phases, WC-Ni coating consists of WC, W2C and Ni phases. Some mechanical properties of the two coatings were compared, WC-Cr3C2-Ni coatings have higher hardness to be compared with WC-Ni ones due to a lower binder content; and the elasticity modulus and nano-hardness values of the WC-Cr3C2-Ni coating are higher than that of the WC-Ni coating. The relationship between the wear performance of the coatings and impingement angle was obtained; and the erosion resistance of the coatings was analyzed. It was observed that WC-Cr3C2-Ni cermet coating exhibits higher erosion resistance under all testing conditions as compared with the WC-Ni cermet coating and 1Cr18Ni9Ti stainless steel. The results show that the erosion mechanism at low angle is mainly cutting, while erosion pits dominate at high angle for the coatings, moreover, plastic deformation could be observed in the case of the binder depletion and cracking found place. and the erosion mechanisms of the 1Cr18Ni9Ti stainless steel are mainly cutting and plastic deformation at low angle and high angle, respectively.
The politics of frailty
Authors: Vernon Martin J
Published: January 2020

The world population is ageing because of falling fertility and improved life expectancy. Knowing this has not helped governments develop sustainable health and care policies because the underlying causes and impacts of population ageing remain poorly understood. Planning using only population age structure does not account for uneven geographical distribution of older people, their health characteristics, functional needs or lived experiences. English National Health Service (NHS) policy has previously focused on arbitrary age segmentation, failing to capture the origins of cumulative disease and functional burden and missing the opportunity to incorporate wider determinants of health into prevention of poor-quality ageing. This is despite growing international evidence that adults living in places with low per capita income and educational attainment experience a higher burden of age-related disease. Lack of a credible ageing narrative and good quality population health data have contributed to a focus on single disease prevention, rather than life course disease aggregation and its personal impacts. However, a fully explicated health and care narrative incorporating frailty does now give some cause for optimism. In 2017, England became the first country to characterise and systematically identify frailty as a long-term treatable health condition. This was coincident with a UK Government’s Industrial Strategy targeting societal ageing. In 2019, the English NHS published a funded long-term plan including a major programme focused on ageing well. Policy makers, health leaders and clinicians must not squander these opportunities but instead pursue frailty prevention and intervention to improve the quality of population ageing.
Design powerful predictor for mRNA subcellular location prediction inHomo sapiens
Authors: Zhang Zhao-Yue , Yang Yu-He , Ding Hui , Wang Dong , Chen Wei , Lin Hao
Published: January 2020

Messenger RNAs (mRNAs) shoulder special responsibilities that transmit genetic code from DNA to discrete locations in the cytoplasm. The locating process of mRNA might provide spatial and temporal regulation of mRNA and protein functions. The situ hybridization and quantitative transcriptomics analysis could provide detail information about mRNA subcellular localization; however, they are time consuming and expensive. It is highly desired to develop computational tools for timely and effectively predicting mRNA subcellular location. In this work, by using binomial distribution and one-way analysis of variance, the optimal nonamer composition was obtained to represent mRNA sequences. Subsequently, a predictor based on support vector machine was developed to identify the mRNA subcellular localization. In 5-fold cross-validation, results showed that the accuracy is 90.12% for Homo sapiens (H. sapiens). The predictor may provide a reference for the study of mRNA localization mechanisms and mRNA translocation strategies. An online web server was established based on our models, which is available at http://lin-group.cn/server/iLoc-mRNA/.
sismonr: simulation of in silico multi-omic networks with adjustable ploidy and post-transcriptional regulation in R
Authors: Angelin-Bonnet Olivia , Biggs Patrick J , Baldwin Samantha , Thomson Susan , Vignes Matthieu
Published: January 2020

We present sismonr, an R package for an integral generation and simulation of in silico biological systems. The package generates gene regulatory networks, which include protein-coding and non-coding genes along with different transcriptional and post-transcriptional regulations. The effect of genetic mutations on the system behaviour is accounted for via the simulation of genetically different in silico individuals. The ploidy of the system is not restricted to the usual haploid or diploid situations but can be defined by the user to higher ploidies. A choice of stochastic simulation algorithms allows us to simulate the expression profiles of the genes in the in silico system. We illustrate the use of sismonr by simulating the anthocyanin biosynthesis regulation pathway for three genetically distinct in silico plants.

Availability and implementation

The sismonr package is implemented in R and Julia and is publicly available on the CRAN repository (https://CRAN.R-project.org/package=sismonr). A detailed tutorial is available from GitHub at https://oliviaab.github.io/sismonr/.

Supplementary information

Supplementary data are available at Bioinformatics online.
Network-based prediction of drug–target interactions using an arbitrary-order proximity embedded deep forest
Authors: Zeng Xiangxiang , Zhu Siyi , Hou Yuan , Zhang Pengyue , Li Lang , Li Jing , Huang L Frank , Lewis Stephen J , Nussinov Ruth , Cheng Feixiong
Published: January 2020

Motivation

Systematic identification of molecular targets among known drugs plays an essential role in drug repurposing and understanding of their unexpected side effects. Computational approaches for prediction of drug–target interactions (DTIs) are highly desired in comparison to traditional experimental assays. Furthermore, recent advances of multiomics technologies and systems biology approaches have generated large-scale heterogeneous, biological networks, which offer unexpected opportunities for network-based identification of new molecular targets among known drugs.

Results

In this study, we present a network-based computational framework, termed AOPEDF, an arbitrary-order proximity embedded deep forest approach, for prediction of DTIs. AOPEDF learns a low-dimensional vector representation of features that preserve arbitrary-order proximity from a highly integrated, heterogeneous biological network connecting drugs, targets (proteins) and diseases. In total, we construct a heterogeneous network by uniquely integrating 15 networks covering chemical, genomic, phenotypic and network profiles among drugs, proteins/targets and diseases. Then, we build a cascade deep forest classifier to infer new DTIs. Via systematic performance evaluation, AOPEDF achieves high accuracy in identifying molecular targets among known drugs on two external validation sets collected from DrugCentral [area under the receiver operating characteristic curve (AUROC) = 0.868] and ChEMBL (AUROC = 0.768) databases, outperforming several state-of-the-art methods. In a case study, we showcase that multiple molecular targets predicted by AOPEDF are associated with mechanism-of-action of substance abuse disorder for several marketed drugs (such as aripiprazole, risperidone and haloperidol).

Availability and implementation

Source code and data can be downloaded from https://github.com/ChengF-Lab/AOPEDF.

Supplementary information

Supplementary data are available at Bioinformatics online.
Antioxidant supplementation partially rescues accelerated ovarian follicle loss, but not oocyte quality, of glutathione-deficient mice†
Authors: Lim Jinhwan , Ali Samiha , Liao Lisa S , Nguyen Emily S , Ortiz Laura , Reshel Samantha , Luderer Ulrike
Published: January 2020

The tripeptide thiol antioxidant glutathione (GSH) has multiple physiological functions. Female mice lacking the modifier subunit of glutamate cysteine ligase (GCLM), the rate-limiting enzyme in GSH synthesis, have decreased GSH concentrations, ovarian oxidative stress, preimplantation embryonic mortality, and accelerated age-related decline in ovarian follicles. We hypothesized that supplementation with thiol antioxidants, N-acetyl cysteine (NAC), or α-lipoic acid (ALA) will rescue this phenotype. Gclm−/− and Gclm+/+ females received 0 or 80 mM NAC in drinking water from postnatal day (PND) 21–30; follicle growth was induced with equine chorionic gonadotropin (eCG) on PND 27, followed by an ovulatory dose of human CG and mating with a wild type male on PND 29 and zygote harvest 20 h after hCG. N-acetyl cysteine supplementation failed to rescue the low rate of second pronucleus formation in zygotes from Gclm−/− versus Gclm+/+ females. In the second study, Gclm−/− and Gclm+/+ females received diet containing 0, 150, or 600 mg/kg ALA beginning at weaning and were mated with wild type males from 8 to 20 weeks of age. α-Lipoic acid failed to rescue the decreased offspring production of Gclm−/− females. However, 150 mg/kg diet ALA partially rescued the accelerated decline in primordial follicles, as well as the increased recruitment of follicles into the growing pool and the increased percentages of follicles with γH2AX positive oocytes or granulosa cells of Gclm−/− females. We conclude that ovarian oxidative stress is the cause of accelerated primordial follicle decline, while GSH deficiency per se may be responsible for preimplantation embryonic mortality in Gclm−/− females.
Niclosamide suppresses macrophage-induced inflammation in endometriosis†
Authors: Sekulovski Nikola , Whorton Allison E , Tanaka Tomoki , Hirota Yasushi , Shi Mingxin , MacLean James A , de Mola Julio Ricardo Loret , Groesch Kathleen , Diaz-Sylvester Paula , Wilson Teresa , Hayashi Kanako
Published: January 2020

Endometriosis is a common gynecological disease, which causes chronic pelvic pain and infertility in women of reproductive age. Due to limited efficacy of current treatment options, a critical need exists to develop new and effective treatments for endometriosis. Niclosamide is an efficacious and FDA-approved drug for the treatment of helminthosis in humans that has been used for decades. We have reported that niclosamide reduces growth and progression of endometriosis-like lesions via targeting STAT3 and NFĸB signaling in a mouse model of endometriosis. To examine the effects of niclosamide on macrophage-induced inflammation in endometriosis, a total of 29 stage III–IV endometrioma samples were used to isolate human endometriotic stromal cells (hESCs). M1 or M2 macrophages were isolated and differentiated from fresh human peripheral blood samples. Then, hESCs were cultured in conditioned media (CM) from macrophages with/without niclosamide. Niclosamide dose dependently reduced cell viability and the activity of STAT3 and NFκB signaling in hESCs. While macrophage CM stimulated cell viability in hESCs, niclosamide inhibited this stimulation. Macrophage CM stimulated the secretion of proinflammatory cytokines and chemokines from hESCs. Most of these secreted factors were inhibited by niclosamide. These results indicate that niclosamide is able to reduce macrophage-induced cell viability and cytokine/chemokine secretion in hESCs by inhibiting inflammatory mechanisms via STAT3 and/or NFκB signaling.
Consensus on the reporting and experimental design of clinical and cognitive-behavioural neurofeedback studies (CRED-nf checklist)
Authors: Ros Tomas , Enriquez-Geppert Stefanie , Zotev Vadim , Young Kymberly D , Wood Guilherme , Whitfield-Gabrieli Susan , Wan Feng , Vuilleumier Patrik , Vialatte François , Van De Ville Dimitri , Todder Doron , Surmeli Tanju , Sulzer James S , Strehl Ute , Sterman Maurice Barry , Steiner Naomi J , Sorger Bettina , Soekadar Surjo R , Sitaram Ranganatha , Sherlin Leslie H , Schönenberg Michael , Scharnowski Frank , Schabus Manuel , Rubia Katya , Rosa Agostinho , Reiner Miriam , Pineda Jaime A , Paret Christian , Ossadtchi Alexei , Nicholson Andrew A , Nan Wenya , Minguez Javier , Micoulaud-Franchi Jean-Arthur , Mehler David M A , Lührs Michael , Lubar Joel , Lotte Fabien , Linden David E J , Lewis-Peacock Jarrod A , Lebedev Mikhail A , Lanius Ruth A , Kübler Andrea , Kranczioch Cornelia , Koush Yury , Konicar Lilian , Kohl Simon H , Kober Silivia E , Klados Manousos A , Jeunet Camille , Janssen T W P , Huster Rene J , Hoedlmoser Kerstin , Hirshberg Laurence M , Heunis Stephan , Hendler Talma , Hampson Michelle , Guggisberg Adrian G , Guggenberger Robert , Gruzelier John H , Göbel Rainer W , Gninenko Nicolas , Gharabaghi Alireza , Frewen Paul , Fovet Thomas , Fernández Thalía , Escolano Carlos , Ehlis Ann-Christine , Drechsler Renate , Christopher deCharms R , Debener Stefan , De Ridder Dirk , Davelaar Eddy J , Congedo Marco , Cavazza Marc , Breteler Marinus H M , Brandeis Daniel , Bodurka Jerzy , Birbaumer Niels , Bazanova Olga M , Barth Beatrix , Bamidis Panagiotis D , Auer Tibor , Arns Martijn , Thibault Robert T
Published: January 2020

Neurofeedback has begun to attract the attention and scrutiny of the scientific and medical mainstream. Here, neurofeedback researchers present a consensus-derived checklist that aims to improve the reporting and experimental design standards in the field.
Pharmacoepidemiology of Ceftazidime-Avibactam Use: A Retrospective Cohort Analysis of 210 US Hospitals
Authors: Strich Jeffrey R , Ricotta Emily , Warner Sarah , Lai Yi Ling , Demirkale Cumhur Y , Hohmann Samuel F , Rhee Chanu , Klompas Michael , Palmore Tara , Powers John H , Dekker John P , Adjemian Jennifer , Matsouaka Roland , Woods Christopher W , Danner Robert L , Kadri Sameer S
Published: January 2020

Background

Ceftazidime-avibactam has in vitro activity against some carbapenem-resistant gram-negative infections (GNIs), and therefore may be a useful alternative to more toxic antibiotics such as colistin. Understanding ceftazidime-avibactam uptake and usage patterns would inform hospital formularies, stewardship, and antibiotic development.

Methods

A retrospective cohort study assessed inpatient encounters in the Vizient database. Ceftazidime-avibactam and colistin administrations were categorized into presumed empiric (3 consecutive days of therapy or less with qualifying exclusions) versus targeted therapy (≥4 consecutive days of therapy) for presumed carbapenem-resistant GNIs. Quarterly percentage change (QPC) using modified Poisson regression and relative change in frequency of targeted ceftazidime-avibactam to colistin encounters was calculated. Factors associated with preferentially receiving targeted ceftazidime-avibactam versus colistin were identified using generalized estimating equations.

Results

Between 2015 quarter (q) 1 and 2017q4, ceftazidime-avibactam was administered 21 215 times across 1901 encounters. Inpatient prescriptions for ceftazidime-avibactam increased from 0.44/10 000 hospitalizations in 2015q1 to 7.7/10 000 in 2017q4 (QPC, +11%; 95% CI, 10–13%; P < .01), while conversely colistin prescriptions decreased quarterly by 5% (95% CI, 4–6%; P < .01). Ceftazidime-avibactam therapy was categorized as empiric 25% of the time, targeted 65% of the time, and indeterminate 10% of the time. Patients with chronic kidney disease were twice as likely to receive targeted ceftazidime-avibactam versus colistin (RR, 2.02; 95% CI, 1.82–2.25), whereas those on dialysis were less likely to receive ceftazidime-avibactam than colistin (RR, 0.71; 95% CI, .61–.83).

Conclusions

Since approval in 2015, ceftazidime-avibactam use has grown for presumed carbapenem-resistant GNIs, while colistin has correspondingly declined. Renal function drove the choice between ceftazidime-avibactam and colistin as targeted therapy.
Appraisal of Two Arabic Opinion Summarization Methods: Statistical Versus Machine Learning
Authors: Touati Imen , Ellouze Mariem , Graja Marwa , Hadrich Belguith Lamia
Published: January 2020

In this paper, we propose to overcome the challenge of digesting opinions in a news article. Our objective is to provide a summary of opinions delivered by many sources about a main topic in an Arabic news article. In literature, several studies addressed issues related to opinion summarization. However, we noticed a lack of studies that address this problem in Arabic language. So, we have proposed two different methods: multi-criteria and machine learning-based methods. We proceed by comparing the results provided by the proposed methods for opinionated sentence extraction. The proposed methods were evaluated using two feature types: text-based features and opinion-specific features. Experimental results show the robustness of machine learning method to extract opinionated sentences with consideration of two sets of features.
Effects of ultraviolet-B radiation on physiology, immune function and survival is dependent on temperature: implications for amphibian declines
Authors: Lundsgaard Niclas U , Cramp Rebecca L , Franklin Craig E
Published: January 2020

Multiple environmental changes are thought to be contributing to the widespread decline of amphibians in montane regions, but interactions between drivers of decline are not well understood. It has been proposed previously that elevated ultraviolet-B radiation (UBVR) and low temperatures may interact in their negative effects on health, immune function and disease susceptibility in exposed amphibians. In the present study, we chronically exposed larvae of the striped-marsh frog (Limnodynastes peronii) to a factorial combination of high and low UVBR and high and low temperature to assess interactive effects on growth, survival and indices of immune function. The high UVBR treatment reduced growth and survival of larvae compared to the low UVBR treatment at both temperatures, but the effects were significantly enhanced at low temperature. High UVBR exposure also induced a chronic inflammatory response as evidenced by an increase in the leucocyte proportion of total cells and altered the ratio of neutrophils to lymphocytes in the blood, highlighting a potential mechanistic basis for increased disease susceptibility in amphibians living at high altitudes. Our findings stress the importance of investigating environmental factors in combination when assessing their effects and highlight the mechanistic basis for how key environmental drivers in montane regions affect amphibian health. Continuation of this work is necessary for the development of targeted conservation strategies that tackle the root causes of montane amphibian declines.
Perioperative immunonutrition in esophageal cancer patients undergoing esophagectomy: the first meta-analysis of randomized clinical trials
Authors: Mingliang Wang , Zhangyan Ke , Fangfang Fan , Huizhen Wang , Yongxiang Li
Published: January 2020

Although several randomized controlled trials have been published in recent years, the effect of perioperative immunonutrition in esophageal cancer (EC) patients remains unclear. This initial meta-analysis was conducted to assess whether perioperative enteral immunonutrition reduces postoperative complications in patients undergoing esophagectomy for EC. Relevant randomized controlled trials published before 1st September 2019 were retrieved from the Cochrane Library, PubMed, and EMBASE databases. After the literature was screened, two researchers extracted the information and data from eligible studies according to predefined selection criteria. Obtained data were pooled and analyzed by RevMan 5.3 software. The results were presented as risk ratios (RRs) with 95% confidence intervals (CIs). The heterogeneity among studies was tested by I2 test. Seven high-quality randomized controlled trials were included, with a total of 606 patients, 311 of whom received immunonutrition before and after surgery, while 295 received perioperative standard nutrition. No significant difference was observed between the two groups in the incidence of postoperative infection complications, including total infection complications (RR = 0.97, CI: 0.78–1.20, P = 0.76), pneumonia (RR = 0.97, CI: 0.71–1.33, P = 0.84), wound infection (RR = 0.80, CI: 0.46–1.40, P = 0.44), sepsis (RR = 1.35, CI: 0.67–2.71, P = 0.40), and urinary tract infection (RR = 0.87, CI: 0.54–1.40, P = 0.56). The prevalence of anastomotic leakage in the two groups was 9.4 and 5.4%, but the difference was not statistically significant (RR = 0.59, CI: 0.33–1.04, P = 0.07). Perioperative enteral immunonutrition provided no benefit in terms of the incidence of infection complications and anastomotic leakage in EC patients undergoing esophagectomy. Further large-scale randomized controlled trials are needed to confirm this conclusion.
Long-term oncological outcomes following completely minimally invasive esophagectomy versus open esophagectomy
Authors: Patel K , Askari A , Moorthy K
Published: January 2020

Open esophagectomy (OE) for esophageal and gastroesophageal junctional cancers is associated with high morbidity. Completely minimally invasive esophagectomy (CMIE) techniques have evolved over the last two decades and significantly reduce surgical trauma compared to open surgery. Despite this, long-term oncological outcomes following CMIE compared to OE remain unclear. This systematic review and meta-analysis aimed to compare overall 5-year survival (OFS) and disease-free 5-year survival (DFFS) between CMIE and OE. It was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive electronic literature search from MEDLINE, EMBASE, Web of Science, Scopus and the Cochrane Central Register of Controlled Trials was conducted. The PROSPERO database was also searched for studies comparing OFS and DFFS between CMIE and OE. The Newcastle Ottawa Scale was used to assess study quality for included studies. Overall, seven studies (containing 949 patients: 527 OE and 422 CMIE) were identified from screening. On pooled meta-analysis, there was no significant difference in OFS or DFFS between CMIE and OE cohorts ([odds ratio 1.12; 95% CI: 0.85 to 1.48; P = 0.41] and [odds ratio 1.34; 95% CI: 0.81–2.22; P = 0.25] respectively). Sensitivity and subgroup analysis with high-quality studies, three highest sample sized studies, and three most recent studies also revealed no difference in long-term oncological outcomes between the two operative groups. This review demonstrates long-term oncological outcomes following CMIE appear equivalent to OE based on amalgamation of existing published literature. Limited high-level evidence comparing OFS and DFFS between CMIE and OE exists. Further research with a randomized controlled trial is required to clinically validate these findings.
OP06 Comparison between Crohn and coeliac diseases small intestine transcriptomics and microbial data define similarities and divergent pathways linked to pathogenesis
Authors: Haberman Ziv Y , Loberman-Nachum N , Katya S , Di Segni A , Efroni G , Braun T , BenShoshan M , Shouval D , Denson L A , Amir A , Unger R , Weiss B
Published: January 2020

Background

Crohn disease and coeliac disease are two inflammatory conditions known to cause small intestine inflammation. Using high throughput transcriptomics, microbial, and bioinformatics approaches we aimed to capture differences and similarities linked to the pathogenesis and to future potential interventions for those chronic manifestations.

Methods

We performed high throughput transcriptomics and 16S microbial characterisation of 55 paediatric new-onset coeliac patients and controls using clinical pathology specimens, and compared those signatures to our previously reported 248 RISK Crohn’s disease newly diagnosed cohort. ToppGene/ToppCluster and ClueGO platforms were used for functional annotation enrichment analyses, and MaAsLin for microbial differential abundance.

Results

A substantial number (>90%) of genes passed the expression filtering criteria in both studies enabling the comparison. Of the 354 coeliac down-regulated genes, 59% (209/354) overlapped with the reduced Crohn signature. Shared reduced signatures and functions included a decrease in epithelial lipid metabolism, oxidoreductase activity, and brush border transport signatures. In contrast, a significantly smaller proportion [19% (97/427, Chi-squares p < 0.001] of the coeliac disease 524 up-regulated genes overlapped with the induced Crohn disease signature. We noted shared enriched signatures for adaptive immune-related pathways and interferon-γ in both coeliac and Crohn diseases. However, the Crohn disease signature exhibited more specific enrichments for signatures associated with innate immune pathways and with a strong signal for granulocytes, an extracellular matrix signature, and CXCR chemokines signalling, while the coeliac up-regulated signature showed unique enrichment for cell cycle and mitosis. As opposed to the robust dysbiosis previously characterised in Crohn disease, we were only able to identify significant enrichment for Bacteroidetes taxa in coeliac patients in comparison to controls.

Conclusion

We highlight important biologic differences between Crohn and coeliac diseases emphasising an intensified innate granulocytes activation signature in Crohn disease and a specific epithelial proliferative signal in coeliac disease. Unlike the robust dysbiosis linked to Crohn disease, the coeliac patient showed only modest enrichment for several Bacteroidetes taxa in comparison to controls. It is possible that microbial alteration in Crohn disease triggers granulocytes activation, and that this signal inhibits epithelial proliferation/renewal, eventually leading the epithelial damage seen in Crohn but not coeliac disease. Inhibiting innate immune activation or reverting Crohn dysbiosis may be a beneficial future therapy for Crohn disease.
OP10 IgA coating of intestinal microbiota is associated with inflammatory bowel disease in twin pairs discordant for inflammatory bowel disease
Authors: Brand E , Laenen Y , van Wijk F , de Zoete M , Oldenburg B
Published: January 2020

Background

The pathogenesis of inflammatory bowel disease (IBD) is thought to result from an interplay between microbiota, the immune system and the environment in genetically susceptible hosts. Immunoglobulin A (IgA) produced by the immune system can be specifically directed against bacteria. The IgA-coating pattern of intestinal bacteria thus reflects interactions between the immune system and specific bacteria. Studying IBD in twins, concordant and discordant for IBD, reduces the impact of genetic predisposition and childhood exposures and therefore offers the unique opportunity to focus on other factors such as intestinal microbiota composition and immune-interactions in IBD.

Methods

Faecal samples from twin pairs discordant for Crohn’s disease (CD) or ulcerative colitis (UC) were collected. Employing fluorescence-activated cell sorting, IgA+ and IgA− bacteria from the intestinal microbiota were sorted. Subsequently, (1) the total, (2) IgA+ and (3) IgA− microbial composition was determined by 16S rRNA sequencing (IgA-SEQ). We estimated the relative IgA coating per bacterial species by dividing the abundance of that species in the IgA+ fraction over the abundance in the IgA- fraction, representing the IgA coating index. Linear discriminant analyses were performed with LefSE.

Results

We included 31 twin pairs (62 individuals) discordant for IBD (CD: 15, UC: 16). 15/32 twin pairs were monozygotic, 43/62 of participants were female, the median age was 47 years (interquartile range: 34–58.5). Of 31 participants with IBD, 7 had signs of active inflammation based on endoscopy, Harvey–Bradshaw index or short clinical colitis activity index. Differences (log-linear discriminant analysis score >3) in the microbial composition of IgA-coated bacteria were observed between CD patients and their twin-siblings not affected by IBD: Dorea formicigenerans (increased in IgA coating), Parabacteroides sp., Christensenellaceae sp., Clostridium sp. and Mollicutes RF39 sp. (decreased in IgA coating). In ulcerative colitis patients, an increase in IgA-coating was observed for Ruminococcus gnavus and Dorea formicigenerans, while Turicibacter sp., Barnesiellaceae sp. and an unclassified Clostridiales sp. were decreased in IgA-coating compared with their twin-siblings not affected by IBD.

Conclusion

In twins affected by IBD, the pattern of IgA-coated bacteria differs between IBD and non-IBD affected individuals. These data on immune-bacteria interactions could serve as a starting point for the elucidation of the immune-responses triggered by specific bacteria in IBD.
OP13 Glyco-fingerprint as a relevant risk factor on colitis-associated cancer
Authors: Dias A , Gomes E , Silva M , Fernandes Â , Garrido M , Marcos-Pinto R , Lago P , Pinho S
Published: January 2020

Background

Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract being considered a serious risk factor for the development of colitis-associated cancer (CAC). However, the molecular mechanisms underlying CAC progression are still elusive. We previously showed that decreased expression of MGAT5 glycogene on intestinal T lymphocytes from UC patients was associated with a hyperimmune response and with disease severity (Dias, AM et al. HMG,2014; Dias, AM et al. PNAS, 2018). On the other hand, we also demonstrated that the aberrant expression of MGAT5 glycogene in gastrointestinal cancer cells was associated with tumour invasiveness and progression (Carvalho S et al., Oncogene 2015). However, whether this differential expression of glycans in colitis and cancer contexts mediated by MGAT5 glycogene constitutes a new mechanism in CAC remains completely unknown.

Methods

A well-characterised cohort of paraffin samples from CAC patients at different stages of carcinogenesis (colitis; dysplasia and colon cancer) were evaluated by immunohistochemistry, using specific lectins to evaluate the N-glycosylation profile either in stroma or in epithelial cells. Furthermore, in vivo studies (using Azoxymethane (AOM)/dextran sodium sulphate (DSS) to induce CAC) were conducted in MGAT5 wild-type and null mice. The combined glycoimmune profile of colonic cells was analysed by flow cytometry. Analysis of RNAseq data from colitis-associated cancer mice model (the AOM/DSS mouse model) was performed to decipher the glyco-fingerprint in colonic cells during colitis; low- and high-grade dysplasia and adenocarcinoma.

Results

Our cross-sectional study revealed a distinct glycoprofile in stroma, characterised by a decreased expression of branched N-glycans in colitis followed by increased expression in dysplasia and colon carcinoma stages corroborated by the RNASeq analysis on the colon of AOM/DSS mouse model. Additionally, colonic T cells isolated from both AOM/DSS MGAT5 WT and KO mice presented a distinct glycoprofile along CAC development.

Conclusion

Our preliminary results both from human and mice samples demonstrate a distinct glycoimmuno profile along the colitis-associated carcinoma cascade, which potentially represents a biomarker to early identify risk UC patients.
OP15 Multi-omic data integration with network analysis reveals underlying molecular mechanisms driving Crohn’s disease heterogeneity
Authors: Sudhakar P , Verstockt B , Cremer J , Verstockt S , Korcsmaros T , Ferrante M , Vermeire S
Published: January 2020

Background

Crohn’s disease (CD) is a heterogeneous disease characterised by clinical phenotypes including differences in disease behaviour, disease location and extraintestinal manifestations. However, the molecular mechanisms which orchestrate CD heterogeneity are relatively unexplored. We tried to infer such mechanisms by integrating two -omic datasets (genomics and blood proteomics) generated from CD patients.

Methods

576 unique proteins were measured from blood isolated from CD patients (n = 98) using seven different Olink® panels. All patients were also genotyped using Immunochip. We integrated the above two datasets using an unsupervised data integration algorithm called Multi-Omics Factor Analysis (MOFA). MOFA identifies Latent Factors (LFs) which are hidden representative variables which capture the sources of variation in the provided -omic datasets. LFs capturing less than 2% of the variance were discarded. By using a regression model, we identified explanatory LFs which associate with clinical phenotypes. Proteins and mutations were ranked according to the scores assigned by the corresponding explanatory LF. Potential effects of mutations were inferred by analysing their impacts on coding and non-coding functions. Local network motifs which capture the direct and indirect effects of mutations on protein expression were identified by using the Cytoscape tool ISMAGS. Protein–protein and transcriptional regulatory relationships retrieved from the OmniPath and DoRothEA databases, respectively, were combined to compile the interaction networks used by ISMAGS.

Results

From the MOFA analysis, we identified five LFs associated with at least one clinical phenotype. Clustering patients along the explanatory LFs achieved meaningful separation of clinical phenotypes such as perianal penetrating disease. The top-ranking proteins associated with perianal-disease included those involved in inflammatory pathways, autophagy or already known to be involved in CD such as IL-8, Rho-GTPase activators, MIF, Caspase 8, TRIM5 and SNAP29. The networks corresponding to the top ranking proteins associated with the perianal phenotype could be broken down into 102 local network motifs. These local motifs pointed out control mechanisms by which a total of 7 mutations mapped to transcription factors (SMAD3, BACH2) and post-translational regulators (such as IFNGR2, IL10, IL2RA, SLC2A4RG and ZMIZ1) could potentially regulate perianal disease‘s pathophysiology and could, therefore, be considered novel drug targets.

Conclusion

By using integrated signature profiles generated from multiple -omic datasets, we identified molecular mechanisms which could potentially describe CD phenotypes such as the occurrence of perianal disease.
OP19 Perinatal factors do not affect paediatric inflammatory bowel disease risk: A Scottish Nationwide Cohort study using administrative health data 1981–2017
Authors: Burgess C , Schnier C , Chalmers I , Russell R K , Hansen R , Henderson P , Wood R , Wilson D C
Published: January 2020

Background

The incidence of paediatric-onset inflammatory bowel disease (PIBD) continues to rise, with genetic-environmental interactions expected to play a vital role. Given gestation and infancy are sensitive periods for environmental change, we aimed to determine whether a mode of delivery, gestational age or type of infant feeding contribute to the development of PIBD in a nationwide cohort of high-risk Scottish children using administrative health data research methodology.

Methods

All children born in Scotland 1981–2017 were identified within the Scottish Morbidity Record maternity inpatient dataset (SMR02). Data linkage was applied to determine mode of delivery, gestational age and type of infant feeding, with PIBD cases defined as any inpatient International Classification of Diseases (ICD) coding for Crohn’s disease (CD; 555/K50), ulcerative colitis (UC; 556/K51) or inflammatory bowel disease unclassified (IBDU; 558.9/K52.3) until age 16. Validation was performed within an entire Scottish health board (16% of the total population) via individual case-note verification. Hazard ratios (HRs) were calculated for each exposure using Cox proportional hazards models with the following potential confounding factors included as covariates: sex, maternal age, year of birth, postcode area and deprivation quintile. Dependent interactions were also explored between the three main exposures.

Results

A study population of 2 013 851 children were identified including 1721 PIBD cases. Individual validation was performed on all 298 (17%) PIBD-coded patients within NHS Lothian; 242/261 CD and UC cases were validated as true positive (positive predictive value 93%); all 37 IBDU cases were false positive with this ICD code excluded from all further analysis. Children delivered vaginally did not have an altered risk of developing PIBD compared with Caesarean section; adjusted HR 0.95 [95% CI 0.84–1.08] (p = 0.424). Children born prematurely did not have an altered risk of developing PIBD; 24–31 weeks gestation HR 0.97 [95% CI 0.56–1.68] (p = 0.922); 32–36 weeks gestation HR 0.96 (95% CI 0.76–1.20] (p = 0.699). Children not exclusively breast feeding at 6 weeks of age did not have an altered risk of developing PIBD; formula feeding HR 0.97 [95% CI 0.81–1.15] (p = 0.705); other/unknown feeding type HR 0.90 [95% CI 0.74–1.08] (p = 0.259). No two-way interactions were significant and none of the three exposures was significantly related to CD or UC in PIBD subtype analysis.

Conclusion

This robust, validated population-based study of over 2 million Scottish births utilising administrative health data confidently demonstrates no association between mode of delivery, gestational age, type of feeding and the development of PIBD.
OP25 Biologics before surgery for IBD: Are they associated with post-operative infectious outcomes? Results from the national surgical quality improvement programme inflammatory bowel disease collaborative
Authors: Holubar S , Jai X , Hull T , Hyman N , Ramamoorthy S , Einsenstein S
Published: January 2020

Background

We aimed to utilise the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Inflammatory Bowel Disease (IBD) Collaborative, which includes disease-specific variables, to assess the association between preoperative biologic exposure and post-operative infectious complications in the largest cohort reported to date.

Methods

Were obtained from ten IBD centres from 2017 - 2018. Univariate and multivariate analyses were performed, with any biologic use within 60-days of surgery as the primary predictor, adjusting for diagnosis, chronic steroid use, immunomodulator (IMM) use, ostomy construction, anaemia, malnutrition, operative length, emergency surgery, and other variables with p < 0.05 from the univariate analysis. The primary endpoint was any (composite) infectious complication, and the secondary endpoint was any (composite) surgical site infection.

Results

A total of 1,562 patients were included, of which 832 (53%) were not exposed to biologics, and 730 (47%) were exposed to biologics before surgery. The biologics group had more preoperative weight loss, lower albumin, more systemic sepsis, more IMM and steroid use, and more had Crohn’s disease (all p < 0.001). The biologics group were also more likely to receive a new ostomy and to have a colectomy (vs. proctectomy or small bowel procedure), and fewer had elective surgery (all p < 0.001). On univariate analysis (Table 1), compared with no biologic exposure, biologic exposure was not associated with any infectious complications, any surgical site infections, anastomotic leak after colectomy, or other post-operative outcomes, but was associated with increased rate of anastomotic leak after proctectomy (n = 423), 6.7% vs. 1.9%, p = 0.02. With respect to the primary and secondary outcomes, the results of the multivariate analyses are shown in Table 2. Biologics were shown not to be associated with any infectious complication (OR 0.88, 95% CI 0.54 – 1.42) or any surgical site infection (OR 0.77, 95% CI 0.46 – 1.28), while Crohn’s disease was associated with any infectious complications (OR 2.11 95% CI 1.12 – 4, p = 0.02).

Conclusion

In the largest retrospective cohort to date, we found that biologics exposure within 60 days of surgery for IBD, using a well-validated methodology and after vigorous adjustment for disease- and surgery-specific covariates, was not associated with post-operative infectious or surgical site infectious complications.
OP35 Treatment outcomes of inflammatory bowel disease in the biological era—a nationwide retrospective cohort study in three Nordic countries: Results from the TRINordic study
Authors: Zhao M , Lördal M , Langholz E , Knudsen T , Voutilainen M , Høivik M L , Moum B , Saebo B , Haiko P , Malmgren C , Coskun M , Melberg H O , Burisch J
Published: January 2020

Background

Biological therapy has been suggested to decrease surgery and hospitalisation risk in patients diagnosed with inflammatory bowel disease (IBD). During 2010 to 2016, the use of biologics in Denmark (DEN), Sweden (SWE) and Norway (NOR) increased dramatically and the time to first biologic treatment declined.1 However, the impact of increasing use of biologics on disease outcomes remains to be shown in real-life practice. In this nationwide study in three Nordic countries, we aimed to investigate trends in surgery and hospitalisation rates in IBD patients in the biological era.1 Høivik ML et al. Time to first treatment with biologic agents for Ulcerative Colitis and Crohn’s Disease across four Nordic countries: Results from the TRINordic study, Submitted to ECCO 2020.

Methods

A total number of 67 758 IBD patients (42 894 patients with ulcerative colitis (UC) and 24 864 Crohn’s disease (CD) diagnosed during the period from 2010 to 2017 in DEN, NOR and SWE were included using the National Patient Registries. Patients were required to have 1-year follow-up; results are limited to patients diagnosed between 2010 and 2016, inclusive. Using the unique personal identification number, individual-level information on surgery, hospitalisation and drug treatment were extracted from the National Patient Registries and the National Prescription Registries. Disease outcomes within two years after diagnosis were compared across annual cohorts.

Results

During 2010 to 2016, 2-year surgery rates in CD patients showed a non-significant decline from 11.9% in 2011 to 9.5% in 2016 in SWE while remaining stable in NOR and DEN (Figure 1). No temporal pattern in surgery risk was observed for UC. The proportion of CD patients being hospitalised within two years from diagnosis declined in SWE and NOR from 52.3% and 51.0% in 2011 to 47.3% and 38.5% in 2015 (p < 0.001), respectively, while hospitalisation in UC remained stable. In contrast, 2-year hospitalisation rates in DEN increased in CD from 27.0% in 2011 to 31.5% in 2016 (p = 0.045) and similarly in UC from 20.4 to 35.0% (p < 0.001), respectively (Figure 2).

Conclusion

No clear pattern was seen in two-year surgery and hospitalisation rates in IBD patients during 2010 to 2017 despite a concurrent increase in biological use in all countries. However, differences in treatment practices across countries might influence these findings. The impact of increased biological use on long-term outcomes in IBD remains to be shown.