bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis and Experiment of Flow Field in Sugarcane Leaf Cutting and Returning Machine
Authors: Dai Haiyan , Wang Yuxing , Wen Fujun , Tang Yanqin
Published: January 2020

In order to improve the sugarcane leaves cutting effect of electric sugarcane leaves returning machine, the sugarcane cutting process is modeled and simulated by ANSYS/LS-DYNA software. It shown that in the double-support cutting mode, the cutter roller ensures the multi-layer sugarcane leaves were cut at the rotate speed of 800r/min. During the cutting process of sugarcane leaves, the stress is mainly concentrated at the incision, and the sugarcane leaves on the side of the blade are subjected to greater stress. The smaller the distance between the rotary blade and the fixed blade of the same combination, the easier the sugar cane leaves are cut off. In the cutting test of sugarcane leaves, the cutting rate was 91.47%, which echoed the simulation results, indicating that modeling and simulation have reference value.
The Study of Thermal Environment during the Movement of Air-conditioned Train
Authors: Li Hongmin
Published: January 2020

During the movement of air-conditioned train, outdoor temperature is constantly changing with the shift of time and space, and the thermal environment of compartment is affected by periodic temperature variation. In this paper, we simulated outdoors thermal environment in the period of the movement of air-conditioned train, and obtained outdoor temperature wave, sol-air temperature waves and temperature waves of interior wall for all orientations of compartment. As the effect of periodic temperature variation, it leads to the variety of quantity of heat transmitted from enclosure to compartment. By calculated the attenuation and delay for temperature wave, the fluctuation of quantity of heat transmitted from enclosure is obtained. It will establish theoretical basis for the study of thermal comfort about compartment and real time regulation about air-conditioned unit.
Drilling Fluid Leakage Model Based on the Dual-Medium Theory
Authors: Liu Jinjiang , Wu Wenlin , Qian Peng , Wang Shuo
Published: January 2020

In view of the lost circulation in carbonate formation, based on the dual-medium model, a two-dimensional transient model for fracture-porous formation is established. All the factors that influence the leakoff rate in the fracture-porous formation are analyzed. The result shows that the leakoff rate increases as the normal stiffness of the crack decreases; the leakoff rate increases as the initial fracture aperture increases; The larger the pressure difference is, the larger the drilling fluid leakage is; The larger the porosity is, the more drilling fluid flows from fracture to matrix, the slower the leakoff descent is; The larger the permeability of matrix is, the larger of leakoff rate is at the initial stage of leakage.
The Influence of Particle Sizes and Inlet-Outlet Configuration on The Hydraulic Characteristics of Horizontal Subsurface Constructed Wetlands
Authors: Zhong Hua , Li Peng , Guo Xuan , Zhang Chengjun
Published: January 2020

The objective of this study was to evaluate the influence of inlet and outlet location and matrix particle size on the hydraulic efficiency of horizontal subsurface constructed wetlands. A quasi-two-dimensional model was set up to evaluate its hydraulic efficiency by salt tracer test, and the change of flow state in the system was observed by dye tracer test. Three inlet and outlet settings: top inlet-bottom outlet, middle inlet-middle outlet and bottom inlet-top outlet; three particle size distributions are 3 mm, 5 mm and 3/5 mm (one half part 3 mm, the other 5 mm). According to the tracer test, the position of inlet and outlet and the size distribution of matrix have an effect on the hydraulic characteristics of constructed wetlands. Larger substrate size with bottom inlet–top outlet configuration could improve hydraulic behaviour, improve water treatment efficiency.
Study on the Theory of High Pressure Water Jet Coal Breaking and Its Main Controlling Factors
Authors: Zhang Yongjiang
Published: January 2020

In order to solve the problems of gas extraction and pressure relief and permeability enhancement under low permeability and high surrounding rock stress conditions in deep coal seams, the ultra-high pressure hydraulic cutting technology is proposed. The mechanical mechanism of coal breaking by high pressure water jet is analyzed. The process of coal breaking by jet is divided into stress wave effect and secondary crack propagation effect. The effects of physical and mechanical properties of coal and rock and jet parameters on jet cutting depth are analyzed theoretically. The results show that the shear strength, tensile strength, fracture and pore development degree of coal and rock correspond to different types of coal and rock failure. With the increase of jet pressure and flow rate (nozzle diameter), the jet cutting depth increases gradually. The influence of jet rotating speed on cutting depth is analyzed. It is concluded that reducing rotating speed should be adopted to improve cutting depth in field practice. The research results can effectively improve the stress state of coal body, play the role of pressure relief and permeability enhancement, and improve coal seam permeability and gas release capacity, which can well meet the control needs of coal mine gas complex dynamic disasters.
Selective bias deposition of CuO thin film on unpolished Si wafer
Authors: Su Jiangbin , Wang Zhiwei , Ma Ji , Bin Tang  , Lang Xianzhong , Jiang Meiping , He Zuming
Published: January 2020

In order to enhance the performances of CuO-based surface-sensitive materials and devices, one feasible scheme is depositing CuO thin films on textured Si wafers to enlarge the specific surface area. In this work, the bias deposition of CuO thin film on unpolished Si wafer was carried out in a RF balanced magnetron sputtering system. The as-achieved CuO thin film was further characterized with scanning electron microscope, powder x-ray diffractometer and ultraviolet-visible spectrophotometer. It was found that the CuO thin film shows a pyramid-textured film morphology consisting of composite structures: a loose and porous thinner film at the bottom of bevel, a dense and compact thicker film at the top of bevel and on the underside, and many nanosheets standing on the film surface. The tip charging effect and bevel influence were discussed to reveal the selective deposition mechanism of CuO thin film on the unpolished Si wafer. It was also demonstrated that the unpolished rough Si wafer surface seems more suitable for the crystallization of CuO along (002) orientation rather than (111) orientation. Meanwhile, the CuO thin film on unpolished Si wafer exhibits the strongest absorption at the wavelength of ∼554 nm and a band gap of 1.94 eV, both of which show redshift relative to those of CuO thin film on polished Si wafer.
Molecular dynamics simulation of lateral ultrasonic excitation in atomic-scale friction
Authors: Wang Zining , Duan Zaoqi , Dong Yun , Zhang Yan
Published: January 2020

The normal and lateral (in the sliding direction) vibration can achieve ‘dynamic superlubricity’ at the atomic scale which has been studied and proved by other researchers. In this study, we have found that the lateral excitation (perpendicular to the sliding direction) which has rarely been studied before can also reduce the average friction force greatly. By utilizing the tip path on the interaction potential energy surface and plotting the interaction potential energy as a function of support position, we elucidated the reason of dynamic superlubricity caused by lateral excitation. The details of the lateral excitation at the atomic scale friction have been demonstrated by molecular dynamics simulations and numerical computation based on the Prandtl-Tomlinson model. This study can increase the understanding of the ultrasonic vibration excitation at atomic scale friction.
Analysis of Historical Worker Exposures to Respirable Dust from Talc Mining and Milling Operations in Vermont
Authors: Rossner Alan , Williams Pamela R D , Mellas-Hulett Elayna , Rahman Mohammad Arifur
Published: January 2020

Objectives

Talc is mined and milled throughout the world for use in a variety of industrial and consumer products. Although prior studies have evaluated workplace exposures or health effects from talc operations, the primary emphasis of these investigations has been on certain mineral contaminants (e.g. crystalline silica and asbestos) rather than talc itself. The purpose of this analysis is to evaluate historical worker exposures to respirable dust (as a measure of talc exposures) in the Vermont talc mines and mills, which involved a relatively pure form of talc (i.e. no asbestos and <0.25% or <1% crystalline silica).

Methods

Respirable dust sampling data collected for workers in the Vermont mines and mills, which have not been previously published, were obtained from both mining company records and Mine Safety and Health Administration (MSHA) inspections. Because of differences in sampling design, the company and MSHA data were analyzed and reported separately. Overall, nearly 700 respirable dust samples collected for 44 job categories at 7 site locations over an approximate 30-year period were analyzed.

Results

Average respirable dust concentrations were found to exceed occupational exposure limits (OELs) in the United States and other countries for several job categories and site locations. Regardless of data source, the highest observed exposures were for mining jobs involving the operation of heavy equipment to break up, move, or load raw ore from the mines and milling or shipping jobs involving the crushing of raw ore, cleaning and drying of processed talc, and bagging and packaging of the final talc product. When analyzing the company data, the arithmetic mean respirable dust concentration was 2.73 mg m−3 for Muckerman at Hammondsville Mine, 3.18 mg m−3 for dosco operator at Ludlow mines, 1.35 mg m−3 for crusher operator at Gassetts Mill, 2.4 mg m−3 for palletizer at West Windsor Mill, and 2.68 mg m−3 for bagging operator at Columbia Shipping Center. When analyzing the MSHA data, the arithmetic mean respirable dust concentration was 3.5 mg m−3 for kiln/dryer operator at Hammondsville Mine, 1.27 mg m−3 for driller at Ludlow mines, 3.69 mg m−3 for ball mill operator at Columbia mill, 3.02 mg m−3 for flotation operator at West Windsor Mill, and 3.24 mg m−3 for bagging operator at Columbia Shipping Center. Worker exposures were found to decline over time for many, but not all, jobs.

Conclusions

Our findings highlight potential high-risk jobs that might benefit from additional exposure control strategies at current or future talc manufacturing sites. The respirable dust measurements summarized here may also be used to reconstruct historical worker exposures at the Vermont sites or aid in subsequent epidemiology studies of this cohort focused on malignant or non-malignant respiratory disease.
For things to stay the same, things must change: polyploidy and pollen tube growth rates
Authors: Williams Joseph H , Oliveira Paulo E
Published: January 2020

Background and Aims

Pollen tube growth rate (PTGR) is an important single-cell performance trait that may evolve rapidly under haploid selection. Angiosperms have experienced repeated cycles of polyploidy (whole genome duplication), and polyploidy has cell-level phenotypic consequences arising from increased bulk DNA amount and numbers of genes and their interactions. We sought to understand potential effects of polyploidy on several underlying determinants of PTGR – pollen tube dimensions and construction rates – by comparing diploid–polyploid near-relatives in Betula (Betulaceae) and Handroanthus (Bignoniaceae).

Methods

We performed intraspecific, outcrossed hand-pollinations on pairs of flowers. In one flower, PTGR was calculated from the longest pollen tube per time of tube elongation. In the other, styles were embedded in glycol methacrylate, serial-sectioned in transverse orientation, stained and viewed at 1000× to measure tube wall thicknesses (W) and circumferences (C). Volumetric growth rate (VGR) and wall production rate (WPR) were then calculated for each tube by multiplying cross-sectional tube area (πr2) or wall area (W × C), by the mean PTGR of each maternal replicate respectively.

Key Results

In Betula and Handroanthus, the hexaploid species had significantly wider pollen tubes (13 and 25 %, respectively) and significantly higher WPRs (22 and 18 %, respectively) than their diploid congeners. PTGRs were not significantly different in both pairs, even though wider polyploid tubes were predicted to decrease PTGRs by 16 and 20 %, respectively.

Conclusions

The larger tube sizes of polyploids imposed a substantial materials cost on PTGR, but polyploids also exhibited higher VGRs and WPRs, probably reflecting the evolution of increased metabolic activity. Recurrent cycles of polyploidy followed by genome reorganization may have been important for the evolution of fast PTGRs in angiosperms, involving a complex interplay between correlated changes in ploidy level, genome size, cell size and pollen tube energetics.
Spreading Pattern and Tissue Response to Hyaluronic Acid Gel Injections in the Subcutis: Ultrasound Videos, Ultrasound Measurements, and Histology
Authors: Vandeputte Joan , Leemans Gaëlle , Dhaene Karl , Forsyth Ramses , Vanslembrouck Jurgen , Hatem Frank , Micheels Patrick
Published: January 2020

Background

Despite the popularity of hyaluronic acid (HA) filler treatments, few publications focus on their effects on adipose tissue.

Objectives

The authors assessed the deposition pattern in the subcutis of injected HA, the tissue response at short and intermediate term, and the effects of remodeling the filler by strong finger pressure immediately after the treatment.

Methods

Two brands, specifically developed by the industry for deep injection, were compared. The gels were injected subcutaneously in 5 candidates for abdominoplasty or breast reduction, in the area of excision, 6 to 98 days before surgery. Ultrasound measurements and films were compared with postoperative histological findings. Tissue response was scored semi-quantitatively.

Results

Real-time ultrasound showed a slightly different deposition pattern of the 2 brands. Histologically, both were present in large pools of the same magnitude and looked the same. Linear retrograde injection sometimes resulted in a globular deposit due to elastic recoil of septae. After remodeling and over time, HA deposits became difficult to detect by ultrasound. Firm remodeling of the tissue immediately after injection or time had no significant effect on filler spread or tissue response. Except for 1 zone of granuloma formation, tolerance for both fillers was good.

Conclusions

HA deposition in adipose tissue occurs in much larger pools than in the dermis. Ultrasound examination is useful during and immediately after the injection but less reliable after filler remodeling or over time. Filler deposition can be less precise, and reshaping by finger pressure can have less effect than expected.

Level of Evidence: 4
Does Collective Efficacy Matter at the Micro Geographic Level?: Findings from a Study Of Street Segments
Authors: Weisburd David , White Clair , Wooditch Alese
Published: January 2020

Many scholars argue that collective efficacy is not relevant to understanding crime at the microgeographic level. We examine variation in collective efficacy across streets with different levels of crime in Baltimore City, MD, and, then, employ multilevel modelling to assess this relationship. We find that people who live in crime hot spots have much lower levels of collective efficacy than people who live in non-hot spot streets and that this relationship persists when controlling for a large number of potential confounders both at the street and community levels. These findings suggest the importance of collective efficacy both in understanding and controlling crime at microgeographic units.
Dynamics of recovery from anaesthesia-induced unconsciousness across primate neocortex
Authors: Patel Shaun R , Ballesteros Jesus J , Ahmed Omar J , Huang Pamela , Briscoe Jessica , Eskandar Emad N , Ishizawa Yumiko
Published: January 2020

How the brain recovers from general anaesthesia is poorly understood. Neurocognitive problems during anaesthesia recovery are associated with an increase in morbidity and mortality in patients. We studied intracortical neuronal dynamics during transitions from propofol-induced unconsciousness into consciousness by directly recording local field potentials and single neuron activity in a functionally and anatomically interconnecting somatosensory (S1, S2) and ventral premotor (PMv) network in primates. Macaque monkeys were trained for a behavioural task designed to determine trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We found that neuronal dynamics were dissociated between S1 and higher-order PMv prior to return of consciousness. The return of consciousness was distinguishable by a distinctive return of interregionally coherent beta oscillations and disruption of the slow-delta oscillations. Clustering analysis demonstrated that these state transitions between wakefulness and unconsciousness were rapid and unstable. In contrast, return of pre-anaesthetic task performance was observed with a gradual increase in the coherent beta oscillations. We also found that recovery end points significantly varied intra-individually across sessions, as compared to a rather consistent loss of consciousness time. Recovery of single neuron multisensory responses appeared to be associated with the time of full performance recovery rather than the length of recovery time. Similar to loss of consciousness, return of consciousness was identified with an abrupt shift of dynamics and the regions were dissociated temporarily during the transition. However, the actual dynamics change during return of consciousness is not simply an inverse of loss of consciousness, suggesting a unique process.
Outcomes Associated With Medications for Opioid Use Disorder Among Persons Hospitalized for Infective Endocarditis
Authors: Barocas Joshua A , Morgan Jake R , Wang Jianing , McLoone Dylan , Wurcel Alysse , Stein Michael D
Published: January 2020

Background

Endocarditis, once predominately found in older adults, is increasingly common among younger persons who inject drugs. Untreated opioid use disorder (OUD) complicates endocarditis management. We aimed to determine if rates of overdose and rehospitalization differ between persons with OUD with endocarditis who are initiated on medications for OUD (MOUDs) within 30 days of hospital discharge and those who are not.

Methods

We performed a retrospective cohort study using a large commercial health insurance claims database of persons ≥18 years between July 1, 2010, and June 30, 2016. Primary outcomes included opioid-related overdoses and 1-year all-cause rehospitalization. We calculated incidence rates for the primary outcomes and developed Cox hazards models to predict time from discharge to each primary outcome as a function of receipt of MOUDs.

Results

The cohort included 768 individuals (mean age 39 years, 51% male). Only 5.7% of people received MOUDs in the 30 days following hospitalization. The opioid-related overdose rate among those who did receive MOUDs in the 30 days following hospitalization was lower than among those who did not (5.8 per 100 person-years [95% confidence interval [CI], 5.1–6.4] vs 7.3 per 100-person years [95% CI, 7.1–7.5], respectively). The rate of 1-year rehospitalization among those who received MOUDs was also lower than those who did not (162.0 per 100 person-years [95% CI, 157.4–166.6] vs 255.4 per 100 person-years [95% CI, 254.0–256.8], respectively). In the Cox hazards models, the receipt of MOUDs was not associated with either of the outcomes.

Conclusions

MOUD receipt following endocarditis may improve important health-related outcomes in commercially insured persons with OUD.
Impaired Cytokine Responses to Live Staphylococcus epidermidis in Preterm Infants Precede Gram-positive, Late-onset Sepsis
Authors: Strunk Tobias , Hibbert Julie , Doherty Dorota , Nathan Elizabeth , Simmer Karen , Richmond Peter , Currie Andrew , Burgner David
Published: January 2020

Background

Late-onset sepsis (LOS) with Staphylococcus epidermidis is common in preterm infants, but the immunological mechanisms underlying heightened susceptibility are poorly understood. Our aim is to characterize the ontogeny of cytokine responses to live S. epidermidis in preterm infants with and without subsequent Gram-positive LOS.

Methods

We conducted a prospective, observational cohort study of preterm infants (<30 weeks gestational age [GA]) with blood sampling on Days 1, 7, 14, 21, and 28 of life. Cytokine responses in peripheral whole blood stimulated with live S. epidermidis were analyzed by 11-plex immunoassay.

Results

Of 129 infants (mean GA, 26.2 weeks; mean birth weight, 887g), 23 (17.8%) had confirmed LOS with Gram-positive organisms and 15 (11.6%) had clinical sepsis, with median onsets at 13 and 15 days, respectively. Blood cytokine responses to an in vitro S. epidermidis challenge were similar between infected and uninfected infants on Day 1, but diverged thereafter. Infants with subsequent LOS displayed broadly reduced S. epidermidis–induced responses from Day 7 onwards, compared to those who did not develop LOS. This pattern was observed with chemokines (interleukin [IL]-8, monocyte chemotactic protein–1, and macrophage inflammatory protein–1α), pro-inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor–α) and the regulatory cytokine IL-10.

Conclusions

Cytokine responses to a live S. epidermidis challenge are impaired in infants with LOS and precede the onset of clinical illness. Quantifying pathogen-specific cytokine responses at Day 7 may identify those high-risk preterm infants at the greatest risk of LOS, and prospective replication is warranted.
Classification Model on Big Data in Medical Diagnosis Based on Semi-Supervised Learning
Authors: Wang Lei , Qian Qing , Zhang Qiang , Wang Jishuai , Cheng Wenbo , Yan Wei
Published: January 2020

Big data in medical diagnosis can provide abundant value for clinical diagnosis, decision support and many other applications, but obtaining a large number of labeled medical data will take a lot of time and manpower. In this paper, a classification model based on semi-supervised learning algorithm using both labeled and unlabeled data is proposed to process big data in medical diagnosis, which includes structured, semi-structured and unstructured data. For the medical laboratory data, this paper proposes a self-training algorithm based on repeated labeling strategy to solve the problem that mislabeled samples weaken the performance of classifiers. Aiming at medical record data, this paper extracts features with high correlation of classification results based on domain expert knowledge base first, and then chooses the unlabeled medical record data with the highest confidence to expand the training set and optimizes the performance of the classifiers of tri-training algorithm, which uses supervised learning algorithm to train three basic classifiers. The experimental results show that the proposed medical diagnosis data classification model based on semi-supervised learning algorithm has good performance.
OP20 The gut microbiota during biological therapy for inflammatory bowel disease
Authors: Caenepeel C , Viera-Silva S , Verstockt B , Machiels K , Davani N A , Sabino J , Ferrante M , Raes J , Vermeire S
Published: January 2020

Background

The expansion of therapeutic options in IBD brought forward a need to personalise treatment. Gut inflammation in inflammatory bowel disease (IBD) patients has been associated with reduced microbial richness and abundance of SCFA producers. We aimed to explore the longitudinal impact of treatment on the inflammatory burden and faecal microbiota in patients with CD and UC, treated with anti-tumour necrosis factor (anti-TNF) therapy, vedolizumab (VDZ) or ustekinumab (UST).

Methods

We analysed faecal samples from 349 IBD patients (112 UC, 237 CD) initiating biological therapy (anti-TNF; VDZ; UST), regardless baseline disease activity, between 2010 and 2019 at a tertiary referral centre. Samples were collected at week 0, 14 and 24. Microbiota phylogenetic profiling was conducted by 16S rRNA gene sequencing and faecal cell counts were determined using flow cytometry. Moisture levels were measured using lyophilisation. Disease activity and response were assessed by faecal calprotectin (FCal). Statistics were performed in R, v3.5.1. Enterotyping was based on the Dirichlet multinomial mixtures approach.

Results

Faecal microbiota profiles showed high diversity, with samples classified into all four enterotypes (Fig1), although Bact2 was 6- to 10-fold more prevalent in patients compared with controls (Fig2). The variation in faecal microbiota composition was explained (multivariate dbRDA) by diagnosis (R2 = 1.2%, p = 1.00E−04), timepoint (R2 = 0.52, p = 0.006), significantly by age, gender and faecal moisture. The full model only explained 2.85% of the microbiota variation.

A slight non-significant decrease in the Bact2 enterotype prevalence was observed in the CD, but not in the UC cohort, during treatment.

A significant decrease in FCal concentrations (w0 vs. 14, UC p = 5.12E-08, CD p = 2.56E−08; week 0 vs. 24: CD p = 4.86E-08) was observed with treatment, accompanied by a significant increase in cellcounts (w0 vs. 14: UC p = 0.024, CD p = 0.0022; week 0 vs. 24: CD p = 0.0201) (Figure 3). No significant change in Bact2 prevalence was found during treatment.

Only treatment-associated variables—week of treatment (p = 2.4E−18), diagnosis (0.0005) and timepoint (p = 0.0073)—were significant predictors for response, while microbiota-associated variables (enterotype, cell counts and faecal moisture) not. Baseline samples were associated with higher FCal levels. This suggests that the response time of the microbiota to treatment may be higher than the host inflammatory response.

Conclusion

The prevalence of the inflammatory Bact2 enterotype was 5- to 10-fold higher in CD and UC patients as compared with controls. Although initiation of biological therapies leads to a decrease in inflammation levels as witnessed by faecal calprotectin and increase in microbial richness, a shift in enterotypes did not occur.
OP30 The interplay of microbiome dysbiosis and immune system deregulation in patients with Crohn’s disease
Authors: Seyed Tabib N S , Caenepeel C , Machiels K , Verstockt S , Verstockt B , Ardeshir Davani N , Sabino J , Ferrante M , Vermeire S
Published: January 2020

Background

The perturbation of composition, function, and structure of the gut microbiota known as dysbiosis is a key factor in inflammatory bowel disease (IBD) pathogenesis. There is a crosstalk between the microbiota and the gut immunological niche. To better understand this interaction, we characterised the degree of dysbiosis and dysregulation of the immune proteome in Crohn’s disease (CD) patients to see whether subtypes of patients could be identified.

Methods

We collected faecal and serum samples of 146 CD patients and 63 healthy controls (HC) (Figure 1), and studied microbiota phylogenetic (16S rRNA gene sequencing) and serum proteomic (91 inflammatory proteins OLINK). Microbial dysbiotic index (MDI), defined as the logarithm of the sum of [abundance in organisms increased in CD] over the [abundance of organisms decreased in CD] was calculated and patients were ranked from Q1 (the least dysbiotic state) to Q4 (the most dysbiotic state). For the proteomic score, 32 proteins that correlated (adj. p ≤ 0.01) with faecal calprotectin (FC) were selected. A penalised logistic regression model was trained on these proteins, to distinguish HC from super active (defined as FC ≥ 1800 μg/g). We next developed an inflammatory proteomic score (IPS) defined as the weighted sum of the serum level of inflammatory proteins, using the coefficient value of the regression model as the protein’s weight. Using the IPS score, patients were clustered from Q1 (the least inflammatory state) to Q4 (the most inflammatory state). Statistical analyses were performed in R 3.5.2.

Results

The MDI did not correlate with standard phenotypic subgroups based on the Montreal classification but did positively correlate with C-reactive protein (CRP) and FC level (p ≤ 0.001). The regression model identified 14 proteins [including CCL20, CXCL1, IL-7, IL-17A, FGF-19] distinguishing super active CD patients from HC with accuracy, sensitivity, and specificity of 95.6%, 92.3%, 100%, respectively. IPS positively correlated with CRP and FC level (p ≤ 0.001). Likewise, MDI and IPS-based clusters were significantly different in CRP and FC levels. Different components of the microbiome correlated with the proteome in a subset of samples. For example, fibroblast growth factor 19 (FGF-19) positively correlated with Faecalibacterium and negatively with Fusicatenibacterium. Of note, we observed a significant positive correlation between MDI and IPS (r = 0.33, p ≤ 0.001) (Figure 2).

Conclusion

We were able to define clusters of patients based on molecular characterisation of different players in IBD pathogenesis such as microbiota and proteome. This molecular clustering in a given patient could be considered as a novel therapeutic and personalised approach to IBD. Further validation in larger cohorts is required.
OP37 Fibrogenesis in chronic DSS colitis is driven by an innate lymphoid cell-independent innate immune response
Authors: Creyns B , Cremer J , De Hertogh G , Boon L , Ferrante M , Vermeire S , Van Assche G , Ceuppens J , Breynaert C
Published: January 2020

Background

Obtaining insights in the pathogenesis of intestinal fibrosis is a priority for improving outcomes in inflammatory bowel diseases (IBD). Studies in murine models and human organ fibrosis indicate a role for innate immunity pathways in fibrosis. The aim of this study was to dissect the role of innate lymphoid cells (ILC) in chronic intestinal inflammation and fibrosis.

Methods

A chronic 3-cycles dextran sulphate sodium (DSS) model was induced in wild-type (WT), recombinant activating gene (RAG)-deficient (lacking adaptive immunity), RAG−/− common γ-chain (ɣc)−/− (lacking ILC) and anti-CD90.2 treated (ILC depleted) C57Bl/6 RAG−/− mice. One cycle of DSS comprised 1 week of DSS administration followed by 2 weeks of recovery with normal drinking water. Colonic lamina propria cells were isolated and CD45+Lineage−CD127+CD90.2+ ILC, Ly6C+ monocytes and Ly6G+ neutrophils were identified after staining by flow cytometry. Inflammation and fibrosis were scored by macroscopic and HE and Martius Scarlet Blue staining and fibrosis was evaluated by hydroxyproline quantification. For analysis Kruskal–Wallis testing with multiple Dunn’s comparisons was performed.

Results

In RAG-1−/− mice chronic inflammation and fibrosis developed similarly as in WT mice, with elevated KLRG-1+ ILC2 (68.90 vs. 48.00% of ILC, p = 0.012) after repeated DSS exposure as compared with control mice (Figure 1). Chronic colitis could also be induced in RAG−/−ɣc−/− or ILC depleted RAG−/− mice (ILC: 0.99 vs. 25.70% of CD45+ cells, p = 0.029), with no attenuation of fibrosis (p > 0.99) as compared with chronic DSS exposed RAG-1−/− mice despite the absence of ILC (Figure 2). Colon length decrease was more pronounced in RAG−/−yc−/− as compared with RAG-1−/− mice after chronic DSS colitis (7.15 vs. 8.30 cm, p = 0.046), while hydroxyproline levels and thickness of mucosa and muscularis propria were not different in RAG−/−yc−/− as compared with RAG-1−/− mice after chronic DSS. Moreover, after the second cycle of DSS a slower recovery of weight was seen in RAG−/−yc−/− mice as compared with RAG-1−/− mice (d31: 88.64 vs. 111.0% of initial weight, p < 0.001; d35 p = 0.001; d39 p = 0.006 and d42 p = 0.002) (Figure 3). In absence of ILC, RAG−/−yc−/− mice increased lamina propria neutrophils (19.10 vs. 5.91% of CD45+ cells, p = 0.004) and monocytes (11.80 vs. 3.25% of CD45+ cells, p = 0.004) may represent an alternative source of inflammation.

Conclusion

These data argue against a pro-fibrotic role of ILC in the induction of fibrosis in chronic DSS colitis, and suggest a protective and recovery-enhancing role of ILC after repeated intestinal injury.
DOP24 Patient-reported health-related quality-of-life outcomes with vedolizumab vs. adalimumab treatment of ulcerative colitis: Results of the VARSITY trial
Authors: Loftus E V , Schreiber S W , Danese S , Peyrin-Biroulet L , Colombel J F , Sands B E , Wang S , Chen J , Lirio R A
Published: January 2020

Background

Patients with ulcerative colitis (UC) experience substantial impairment in quality of life (QOL). Patient QOL endpoints are important measures of treatment outcome. We evaluated the effects of intravenous vedolizumab vs. adalimumab on QOL in VARSITY, the first head-to-head trial comparing the efficacy and safety of biologics in patients with moderately to severely active UC.

Methods

VARSITY was a phase 3b, double-blind, double-dummy, randomised trial (NCT02497469; EudraCT 2015-000939-33). QOL was assessed using the inflammatory bowel disease questionnaire (IBDQ) at baseline, Week (Week) 30, and Week 52. Endpoints included clinically meaningful IBDQ improvement (defined as an increase in total score of ≥16 points from baseline to Week 52), IBDQ remission (defined as a total score of >170 points at Week 52) and change from baseline in IBDQ-specific domain scores (bowel symptoms, systemic symptoms, emotional function, and social function) at Week 30 and Week 52. Serum C-reactive protein (CRP) and faecal calprotectin (FCP) were also assessed as indicators of disease activity.

Results

Among randomised patients, 383 (vedolizumab) and 386 (adalimumab) patients received ≥1 dose of study drug (N=769). At Week 52, clinically meaningful IBDQ improvement was observed in 52.0% (vedolizumab) vs. 42.2% (adalimumab) of patients (treatment difference 9.7%; 95% confidence interval [CI], 2.7% to 16.7%), while IBDQ remission was achieved by 50.1% (vedolizumab) vs. 40.4% (adalimumab) of patients (treatment difference 9.6%; 95% CI, 2.8% to 16.5%). Mean (standard deviation [SD]) changes in IBDQ total score from baseline for observed cases favoured vedolizumab over adalimumab (Week 30: 61.3 [39.8] vs. 52.6 [42.8]; Week 52: 66.1 [41.8] vs. 60.4 [42.2]; Figure 1). IBDQ subscores showed similar favourable trends for vedolizumab (Figure 2). At Week 52, mean (SD) changes from baseline in CRP for patients treated with vedolizumab vs. adalimumab were –50.9 (174.8) nmol/l vs. –37.2 (169.2) nmol/l and for FCP were –2187.3 (7440.4) µg/g vs. –1846.6 (4560.6) µg/g (Figure 3). Among patients with FCP >250 µg/g at baseline, the proportion of patients achieving FCP ≤250 µg/g was 33.9% vs. 24.5% at Week 30 and 35.2% vs. 28.9% at Week 52 for patients treated with vedolizumab vs. adalimumab, respectively.

Conclusion

Based on IBDQ total score and subscores, more patients with UC treated with vedolizumab than with adalimumab achieved clinically meaningful improvement and clinical remission. Reduced inflammation, as indicated by improvements in CRP and FCP, was consistent with improvements in QOL.
DOP30 Multi-‘omics profiling in patients with quiescent inflammatory bowel disease identifies biomarkers predicting relapse
Authors: Borren N , Plichta D , joshi A , Bonilla G , Sadreyev R , Vlamakis H , Xavier R , Ananthakrishnan A
Published: January 2020

Background

Inflammatory bowel diseases (IBD) are characterised by intermittent relapses and their course is heterogeneous and often unpredictable. The ability of protein, metabolite, or microbial biomarkers to predict relapse in patients with quiescent disease is unknown.

Methods

This prospective study enrolled patients with quiescent Crohn’s disease (CD) and Ulcerative colitis (UC) defined as absence of clinical symptoms (HBI < 4, SCCAI < 2) and a colonoscopy within the 1 year prior with endoscopic remission. The primary outcome was relapse within 2 years, defined as symptomatic worsening accompanied by elevated inflammatory markers resulting in a change in therapy, or IBD-related hospitalisation or surgery. Metabolomic and proteomic profiling was performed on serum samples and stool samples underwent shotgun metagenomic sequencing on Illumina HiSeq platform. Biomarkers were tested in a derivation cohort and their performance examined in an independent validation cohort.

Results

Our prospective cohort study included 164 patients with IBD (108 CD, 56 UC). Upon follow-up for a median of 1 year, 22 patients (13.4%) experienced a relapse. Three protein biomarkers (IL-10, GDNF, and CD8A) and four metabolomic markers (propionyl-l-carnitine, carnitine, sarcosine, and sorbitol) were associated with relapse in multivariable models at p < 0.05. Proteomic and metabolomic risk scores, defined as the tertile sum of the serum levels of these biomarkers independent predicted relapse with a combined AUC of 0.83. This risk score clearly differentiated relapsers from those who remained in remission in both the derivation and validation cohort (Figure 2). A high proteomic risk score (OR 9.11, 95% CI 1.90–43.61) or metabolomic risk score (OR 5.79, 95% CI 1.24–27.11) independently predicted higher risk of relapse over 2 years. Faecal metagenomics from 85 patients demonstrated increased abundance of Proteobacteria (p = 0.0019, q = 0.019) and Fusobacteria (p = 0.0040, q=0.020) and at the species-level Lachnospiraceae_bacterium_2_1_58FAA (p = 0.000008, q = 0.0009) among relapses. Proinflammatory changes in the microbiome correlated with the metabolomic and proteomic perturbations associated with relapse.

Conclusion

Proteomic, metabolomic, and microbial biomarkers identify a pro-inflammatory state in quiescent IBD that predisposes to clinical relapse.
DOP41 Low-grade dysplasia prognosis and predictive factors for advanced neoplasia progression in the 21st century: A large multi-centre retrospective cohort study
Authors: Kabir M , Curtius K , Al-Bakir I , Hartono J , Johnson M , East J E , Lindsay J O , Vega R , Thomas-Gibson S , Hart A , Graham T , Wilson A
Published: January 2020

Background

Recent advances in ulcerative colitis (UC) endoscopic surveillance such as high-definition imaging and greater chromoendoscopy (CE) use have led to an increase in detection and resection of visible dysplasia. An updated study of prognosis of low-grade dysplasia (LGD) is needed to address uncertainty as to the accuracy of progression rates based on historical studies.

Methods

This retrospective cohort study involved four UK IBD centres. Hospital and endoscopy pathology databases were searched between 1 January 2001 and 30 December 2018 to identify adult patients with UC who had their first LGD diagnosis diagnosed within the extent of colitis. Only patients followed up with at least one colonoscopy or colectomy by 30 August 2019 were included. The study endpoint was time to high-grade dysplasia (HGD) or cancer (CRC), i.e. advanced neoplasia (AN), or end of follow-up. Survival analyses were performed using Kaplan–Meier estimation and Cox proportional hazards (PH) models.

Results

In total, 460 patients met the inclusion criteria and were followed up for a median of 4.1 years (IQR 6), equating to 2,232 patient-years. A mean of 3.7 (range 0–17) subsequent colonoscopies was performed per patient. Seventy-seven per cent of patients had CE surveillance. Complete endoscopic resection was achieved in 94% and 64% of the polypoid and non-polypoid LGD, respectively. There was progression to AN in 88 cases (19%) during follow-up. There was no significant difference in AN progression between centres. Unresectable non-polypoid or invisible LGD carried the greatest risk of AN development (Figure 1).

On univariate Cox PH analysis, CE use was protective against AN progression (HR 0.5; 95% CI 0.3–1.0; p = 0.04). However, only highly significant predictors of LGD progression to AN on univariate analysis (Bonferroni adjusted p < 0.003), were entered into the multivariate model:

Cumulative risk of AN increased with the number of risk factors (Figure 2).

Conclusion

This is the largest study examining prognosis of LGD, based on endoscopic features, in this century. Five-year cumulative incidence of AN is low after complete endoscopic resection of visible LGD without surrounding dysplasia. Lesion size of 1 cm or more, invisibility, multifocality and unresectability of LGD are significant risk factors for progression to AN. These factors should be taken into consideration when discussing management options with patients.
DOP54 Integrated network analysis using patient-specific single-nucleotide polymorphism profiles uncovers new pathways involved in ulcerative colitis pathogenesis
Authors: Modos D , Brooks J , Sudhakar P , Verstockt B , Alexander-Dann B , Zoufir A , Fazekas D , Vermeire S , Korcsmaros T , Bender A
Published: January 2020

Background

Genome-wide association studies have deciphered the single nucleotide polymorphisms (SNPs) which are responsible for ulcerative colitis (UC) susceptibility. However, to understand how these SNPs are involved in UC, additional methods are necessary. One such approach is in silico network propagation modelling, which can discover how the effects of SNPs in UC can affect the whole cell. A complementary approach is weighted gene co-expression network analysis (WGCNA), where co-regulated genes are identified using transcriptomic data. Integrating these two methods can shed light on how SNPs are affecting the transcriptome of UC patients.

Methods

We used immunochip profiles of 941 UC patients and focussed on UC-associated SNPs altering regulatory regions. Based on these regions, we identified affected genes. To understand how their corresponding proteins rewire transcriptional regulation, we predicted the path between these proteins and relevant transcription factors (TF) using the OmniPath signalling network (http://omnipathdb.org). From the TFs, we propagated the signal further to target genes using TFlink (https://tflink.net) and GTRD (http://gtrd.biouml.org). To evaluate the predicted network propagation signal, we conducted WGCNA with transcriptomics data from 46 matching patients’ (GEO ID: GSE48959). To interpret the results, we used Gene Ontology Biological Process annotations of the target genes, and we compared the function and regulation of affected genes and the determined WGCNA modules.

Results

We found 9 predominant signalling pathways, some already known from other studies to be involved in UC pathogenesis, including NFkB signalling, chemokine signalling, Notch pathway, JAK/STAT signalling. Downstream of these pathways we identified potential key TFs regulate the UC phenotype, for example NFKB1, GATA3, GTF2I. The targets of these TFs were enriched in the WGCNA modules of the patients. The WGCNA modules and the transcriptionally affected genes had enriched processes including cell migration, TGF-β signalling, exocytosis, adaptive T- and B-cell-specific immune responses and tight junctions. We also found myogenetic development specific TFs affected transcriptionally such as MyoD, MEF2A, MEF2D. We are currently validating these results through patient-specific biopsies.

Conclusion

In silico methods bring us closer to understanding UC pathogenesis. Our results suggest that in a well-defined set of patients, weakened tight junctions and insufficient immune response can lead to dysfunctional epithelial barrier, resulting in poor wound healing in UC. We hope the developed workflow will provide novel diagnostic and therapeutic options in UC.
DOP63 Efficacy and safety of iron carboxymaltose on chronic fatigue in patients with inflammatory bowel disease: a randomised controlled trial
Authors: Fiorino G , Allocca M , Gilardi D , Alfieri M , Danieli P , Furfaro F , Roda G , Loy L , Zilli A , Radice S , Peyrin-Biroulet L , Danese S
Published: January 2020

Background

Patients with inflammatory bowel diseases (IBD) have an altered quality of life, also due to chronic fatigue (CF). Iron administration is effective in iron deficiency associated with CF in patients with heart failure. Our hypothesis was that iron administration in patients with iron-deficiency could improve CF and quality of life in IBD patients.

Methods

This was a phase 2, randomised, placebo-controlled, double-blind trial. Adult patients with established IBD diagnosis in clinical remission (HB <5; Mayo clinical score ≤2) from ≥ 6 months, CF symptoms (MFI-20> 13), martial deficiency (ferritin <100 µg/l, or <300 µg/l if transferrin saturation<20%), but not anaemia, were eligible. Patients were randomised to receive 200 mg of i.v. iron carboxymaltose (ICM) or placebo (PBO) every month up to 6 months. The primary objective was to compare the rate of patients in CF remission (Multidimensional Fatigue Inventory, MFI-20 <13) between the 2 groups. Secondary objectives were CF response (MFI-20 decrease of ≥4 points, but MFI-20 total >13) at week 24 and CF remission (MFI-20 <13) at week 12. Evolution of anxiety and depression and change in the quality of life at weeks 4, 12 and 24 from baseline trough week 24 were also assessed. The calculated sample size was 36 patients (18 for each treatment arm).

Results

Forty-six patients were screened, 30 patients completed 24 weeks of treatment (21 Crohn’s disease, 9 ulcerative colitis). Baseline characteristics were not different among the two groups. Between patients treated with ICM vs. PBO, 2/15 patients vs. 0/15 respectively were in CF remission at week 24 (13% vs. 0%, p = 0.46). CF response was observed in 7/15 patients treated with ICM vs. 10/15 patients with PBO (47% vs. 67%, p = 0.46). At week 12, 1/17 vs. 0/17 patients were in CF remission (6% vs. 0%, p = 0.96), and 12/17 vs. 10/17 (71% vs. 59%, p = 0.90) showed CF response. At the study completion, ferritin restoration was found in 12/14 patients (86%) treated with ICM vs. 1/15 (7%) receiving PBO (p < 0.001). No significant differences in terms of anxiety, depression and quality of life restoration were found between the two groups at week 12 and 24. A total number of 69 adverse events (AEs) were reported in 17 patients (37 mild, 31 moderate, 1 severe), only 5 were related to the study treatment (3 nausea, 1 gastric pain, 1 arthralgia), and only 1 (nausea) led to study drug discontinuation.

Conclusion

Intravenous ICM is not effective in treating CF in IBD patients, with no significant adverse events. ICM was more effective than PBO in restoring ferritin in the majority of IBD patients.

Funding

This study was funded by the ECCO Vifor Grant 2017.