bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimization of processing parameters and its effect on the mechanical properties of recycled low density polyethylene composite reinforced with Tetracarpidium conophorum shell particulates
Authors: Okeke P E , Atuanya C U , Umembamalu J C
Published: January 2020

This work explored the effect of African Walnut Shell Particle (AWSP) (Tetracarpidium conophorum) on the properties of recycled low density polyethylene (rLDPE) composite. rLDPE/ AWSP composite were prepared via compressive moulding techniques using AWSP of sizes 300 and 600μm respectively. Composite design of experiment and analysis of variant (ANOVA) were employed for optimization. Mechanical and morphological analysis of the composite were studied. rLDPE reinforced with AWSP of particle size 300 μm exhibited better tensile strength, modulus of rupture (MOR) and modulus of elasticity (MOE) than those of 600 μm. Morphological analysis showed that uniform distribution of the Walnut shell particulates in the microstructure of the composite is the major factor responsible for the improvement in the mechanical properties. Optimality occurred at a press temperature of 206.465 °C, press time of 10 min, press pressure of 7 MPa yielding a tensile strength of 14.082 MPa, MOR of 17.019 MPa and MOE of 755.028 MPa for 300 μm particle sized composite whereas for 600 μm size, it was achieved at press temperature of 199.993 °C, press time of 6 min, press pressure of 7 MPa giving a tensile strength of 11.252 MPa, MOR of 15.401 MPa and MOE of 459.531 MPa respectively. The result from the optimization met the standard for interior and exterior mirror casing of automobiles.
Use of Antiasthmatic Drugs and the Risk of Type 1 Diabetes in Children: A Nationwide Case-Cohort Study
Authors: Metsälä Johanna , Lundqvist Annamari , Virta Lauri J , Kaila Minna , Gissler Mika , Virtanen Suvi M , Nevalainen Jaakko
Published: January 2020

Asthma has been reported to be associated with an increased risk of type 1 diabetes mellitus in childhood, but the reasons are unclear. We examined whether the use of antiasthmatic drugs was associated with the development of type 1 diabetes in childhood in a nationwide, register-based case-cohort study. We identified all children who were born January 1, 1995, through December 31, 2008, in Finland and diagnosed with type 1 diabetes by 2010 (n = 3,342). A 10% random sample from each birth-year cohort was selected as a reference cohort (n = 80,909). Information on all dispensed antiasthmatic drugs (Anatomical Therapeutic Chemical classification system code R03) during 1995–2009 was obtained, and associations between the use of antiasthmatic drugs and the development of type 1 diabetes were investigated using time-dependent and time-sequential Cox regression models. Dispensed inhaled corticosteroids and inhaled β-agonists were associated with an increased risk of type 1 diabetes after adjusting for other antiasthmatic drugs, asthma, sex, and birth decade (hazard ratio = 1.29, 95% confidence interval: 1.09, 1.52, and hazard ratio = 1.22, 95% confidence interval: 1.07, 1.41, respectively). These findings suggest that children using inhaled corticosteroids or inhaled β-agonists might be at increased risk of type 1 diabetes.
Surgical site infection rate is higher following hip and knee arthroplasty when cefazolin is underdosed
Authors: Morris Arthur J , Roberts Sally A , Grae Nikki , Frampton Chris M
Published: January 2020

Purpose

While many guidelines recommend higher doses of cefazolin for patients with higher body weights, there are scant outcome data showing the benefit of higher doses. Surgical site infection (SSI) rates by dose of cefazolin used for surgical prophylaxis after hip or knee arthroplasty were analyzed.

Methods

Analysis of patient data entered into New Zealand’s national, prospective, surveillance and quality improvement SSI Improvement Programme database for the period July 2013 through December 2017 was conducted. The US Centers for Disease Control and Prevention’s National Healthcare Safety Network SSI definitions were used, and patients were followed for 90 days after surgery. Underdosing was defined as use of 1 g of cefazolin in patients weighing 80 kg or more or a cefazolin dose of <3 g in those weighing 120 kg or more.

Results

There were 38,288 procedures where cefazolin was used for prophylaxis; patient body weight was known for all these procedures. Of the 1,840 patients who received 1 g of cefazolin, 676 (37%) weighed 80 kg or more. Of the 2,011 patients weighing 120 kg or more, 1,464 (73%) were underdosed. After multivariable analysis, male gender, higher total surgical risk scores, performance of revision and hip arthroplasties, and cefazolin underdosing were associated with higher SSI rates. For the 2,106 underdosed patients, the odds ratio for SSI was 2.19 (95% confidence interval, 1.61-2.99; P < 0.0001). The number of higher-weight patients needed to treat to prevent 1 SSI was 83, with an estimated cost of <NZ$500 to prevent 1 infection costing an estimated NZ$40,000.

Conclusion

Patients undergoing hip or knee arthroplasty and with weights of ≥80 kg and those with weights of ≥120 kg should receive cefazolin doses of 2 g and ≥3 g, respectively, for SSI prophylaxis. The question of whether a dose of ≥4 g is needed in patients weighing 120 kg or more or who are above a given body mass index threshold (eg, >35 kg/m2 or >40 kg/m2) remains unanswered.
Categorical perception in animal communication and decision-making
Authors: Green Patrick A , Brandley Nicholas C , Nowicki Stephen
Published: January 2020

The information an animal gathers from its environment, including that associated with signals, often varies continuously. Animals may respond to this continuous variation in a physical stimulus as lying in discrete categories rather than along a continuum, a phenomenon known as categorical perception. Categorical perception was first described in the context of speech and thought to be uniquely associated with human language. Subsequent work has since discovered that categorical perception functions in communication and decision-making across animal taxa, behavioral contexts, and sensory modalities. We begin with an overview of how categorical perception functions in speech perception and, then, describe subsequent work illustrating its role in nonhuman animal communication and decision-making. We synthesize this work to suggest that categorical perception may be favored where there is a benefit to 1) setting consistent behavioral response rules in the face of variation and potential overlap in the physical structure of signals, 2) especially rapid decision-making, or 3) reducing the costs associated with processing and/or comparing signals. We conclude by suggesting other systems in which categorical perception may play a role as a next step toward understanding how this phenomenon may influence our thinking about the function and evolution of animal communication and decision-making.
The antithrombin binding regions of heparin mediate fetal growth and reduced placental damage in the RUPP model of preeclampsia†
Authors: Wat Jovian M , Baczyk Dora , Kingdom John C
Published: January 2020

Preeclampsia is a serious hypertensive disorder of pregnancy, which is only cured with delivery of the placenta, thereby commonly necessitating preterm birth of the fetus. Low-molecular-weight heparin (LMWH) has demonstrated potential to reduce the incidence of preeclampsia in high-risk pregnant women, although the underlying mechanism by which LMWH protects against preeclampsia is unknown. Given the complex structure and biologic actions of heparin, we tested the hypothesis that heparin can mediate preeclampsia prevention via nonanticoagulant pathways. We compared the effects of a nonanticoagulant, glycol-split LMWH (gsHep)—rendered nonanticoagulant through disruption of the antithrombin binding regions—with the LMWH dalteparin in the rat reduced uterine perfusion pressure (RUPP) surgical model of preeclampsia. Although RUPP animals exhibit significantly elevated blood pressure and reduced plasma levels of placental growth factor (PGF) compared to sham, neither dalteparin nor gsHep treatment significantly impacted these parameters. However, the observed positive correlation between PGF levels and number of viable fetuses in RUPP-induced animals suggests that reduced PGF levels were predominately due to placental loss. Daily subcutaneous injections of low-dose dalteparin but not gsHep significantly restored fetal growth that was impaired by RUPP surgery. Placentas from RUPP animals exhibited an abnormal labyrinth structure, characterized by expanded sinusoidal blood spaces, relative to sham-operated animals. Morphometric analysis demonstrated that dalteparin but not gsHep treatment normalized development of the labyrinth in RUPP-exposed conceptuses. These data suggest that the antithrombin-binding regions of LMWH are required to confer its protective effects on fetal growth and placental development.
Generalized instrumental inequalities: testing the instrumental variable independence assumption
Authors: Kédagni Désiré , Mourifié Ismael
Published: January 2020

This paper proposes a new set of testable implications for the instrumental variable independence assumption for discrete treatment, but unrestricted outcome and instruments: generalized instrumental inequalities. When outcome and treatment are both binary, but instruments are unrestricted, we show that the generalized instrumental inequalities are necessary and sufficient to detect all observable violations of the instrumental variable independence assumption. To test the generalized instrumental inequalities, we propose an approach combining a sample splitting procedure and an inference method for intersection bounds. This idea allows one to easily implement the test using existing Stata packages. We apply our proposed strategy to assess the validity of the instrumental variable independence assumption for various instruments used in the returns to college literature.
α-Synuclein oligomers in skin biopsy of idiopathic and monozygotic twin patients with Parkinson’s disease
Authors: Mazzetti Samanta , Basellini Milo J , Ferri Valentina , Cassani Erica , Cereda Emanuele , Paolini Matilde , Calogero Alessandra M , Bolliri Carlotta , De Leonardis Mara , Sacilotto Giorgio , Cilia Roberto , Cappelletti Graziella , Pezzoli Gianni
Published: January 2020

A variety of cellular processes, including vesicle clustering in the presynaptic compartment, are impaired in Parkinson’s disease and have been closely associated with α-synuclein oligomerization. Emerging evidence proves the existence of α-synuclein-related pathology in the peripheral nervous system, even though the presence of α-synuclein oligomers in situ in living patients remains poorly investigated. In this case-control study, we show previously undetected α-synuclein oligomers within synaptic terminals of autonomic fibres in skin biopsies by means of the proximity ligation assay and propose a procedure for their quantification (proximity ligation assay score). Our study revealed a significant increase in α-synuclein oligomers in consecutive patients with Parkinson’s disease compared to consecutive healthy controls (P < 0.001). Proximity ligation assay score (threshold value > 96 using receiver operating characteristic) was found to have good sensitivity, specificity and positive predictive value (82%, 86% and 89%, respectively). Furthermore, to disclose the role of putative genetic predisposition in Parkinson’s disease aetiology, we evaluated the differential accumulation of oligomers in a unique cohort of 19 monozygotic twins discordant for Parkinson’s disease. The significant difference between patients and healthy subjects was confirmed in twins. Intriguingly, although no difference in median values was detected between consecutive healthy controls and healthy twins, the prevalence of healthy subjects positive for proximity ligation assay score was significantly greater in twins than in the consecutive cohort (47% versus 14%, P = 0.019). This suggests that genetic predisposition is important, but not sufficient, in the aetiology of the disease and strengthens the contribution of environmental factors. In conclusion, our data provide evidence that α-synuclein oligomers accumulate within synaptic terminals of autonomic fibres of the skin in Parkinson’s disease for the first time. This finding endorses the hypothesis that α-synuclein oligomers could be used as a reliable diagnostic biomarker for Parkinson’s disease. It also offers novel insights into the physiological and pathological roles of α-synuclein in the peripheral nervous system.
Basal forebrain volume reliably predicts the cortical spread of Alzheimer’s degeneration
Authors: Fernández-Cabello Sara , Kronbichler Martin , Van Dijk Koene R A , Goodman James A , Spreng R Nathan , Schmitz Taylor W ,   on behalf of the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2020

Alzheimer’s disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer’s degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer’s disease using two independent samples of the Alzheimer’s Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-β and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-β moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer’s disease pathogenesis.
The role of macrophages in the formation of hypertrophic scars and keloids
Authors: Xu Xiangwen , Gu Shuchen , Huang Xin , Ren Jieyi , Gu Yihui , Wei Chengjiang , Lian Xiang , Li Haizhou , Gao Yashan , Jin Rui , Gu Bin , Zan Tao , Wang Zhichao
Published: January 2020

Numerous studies have shown that macrophages can orchestrate the microenvironment from the early stage of wound healing to the later stages of scar formation. However, few reviews have highlighted the significance of macrophages during the formation of abnormal scars. The purpose of this review was to outline the polarization of macrophages from early to late stage of pathological scar formation, focusing on spatiotemporal diversity of M1 and M2 macrophages. In this review, the role of macrophages in the formation of hypertrophic scars and keloids is summarized in detail. First, an increased number of M2 cells observed before injuries are significantly associated with susceptibility to abnormal scar pathogenesis. Second, decreased expression of M1 at the early stage and delayed expression of M2 at the late stage results in pathological scar formation. Third, M2 cells are highly expressed at both the margin and the superficial region, which is consistent with the invasive property of keloids. Finally, this review helps to characterize strategies for the prediction and prevention of pathological scar formation.
Multispecies Outbreak of Verona Integron-Encoded Metallo-ß-Lactamase-Producing Multidrug-Resistant Bacteria Driven by a Promiscuous Incompatibility Group A/C2 Plasmid
Authors: de Man Tom J B , Yaffee Anna Q , Zhu Wenming , Batra Dhwani , Alyanak Efe , Rowe Lori A , McAllister Gillian , Moulton-Meissner Heather , Boyd Sandra , Flinchum Andrea , Slayton Rachel B , Hancock Steven , Spalding Walters Maroya , Laufer Halpin Alison , Rasheed James Kamile , Noble-Wang Judith , Kallen Alexander J , Limbago Brandi M
Published: January 2020

Background

Antibiotic resistance is often spread through bacterial populations via conjugative plasmids. However, plasmid transfer is not well recognized in clinical settings because of technical limitations, and health care–associated infections are usually caused by clonal transmission of a single pathogen. In 2015, multiple species of carbapenem-resistant Enterobacteriaceae (CRE), all producing a rare carbapenemase, were identified among patients in an intensive care unit. This observation suggested a large, previously unrecognized plasmid transmission chain and prompted our investigation.

Methods

Electronic medical record reviews, infection control observations, and environmental sampling completed the epidemiologic outbreak investigation. A laboratory analysis, conducted on patient and environmental isolates, included long-read whole-genome sequencing to fully elucidate plasmid DNA structures. Bioinformatics analyses were applied to infer plasmid transmission chains and results were subsequently confirmed using plasmid conjugation experiments.

Results

We identified 14 Verona integron-encoded metallo-ß-lactamase (VIM)-producing CRE in 12 patients, and 1 additional isolate was obtained from a patient room sink drain. Whole-genome sequencing identified the horizontal transfer of blaVIM-1, a rare carbapenem resistance mechanism in the United States, via a promiscuous incompatibility group A/C2 plasmid that spread among 5 bacterial species isolated from patients and the environment.

Conclusions

This investigation represents the largest known outbreak of VIM-producing CRE in the United States to date, which comprises numerous bacterial species and strains. We present evidence of in-hospital plasmid transmission, as well as environmental contamination. Our findings demonstrate the potential for 2 types of hospital-acquired infection outbreaks: those due to clonal expansion and those due to the spread of conjugative plasmids encoding antibiotic resistance across species.
Eva1a ameliorates atherosclerosis by promoting re-endothelialization of injured arteries via Rac1/Cdc42/Arpc1b
Authors: Li Jingxuan , Chen Yingyu , Gao Jianing , Chen Yue , Zhou Changping , Lin Xin , Liu Changjie , Zhao Mingming , Xu Yangkai , Ji Liang , Jiang Zongzhe , Pan Bing , Zheng Lemin
Published: January 2020

Aims

Eva-1 homologue 1 (Eva1a) is a novel protein involved in the regulation of cardiac remodelling and plaque stability, but little is known about its role in re-endothelialization and the development of atherosclerosis (AS). Thus, in the present study, we aimed to elucidate the function of Eva1a in re-endothelialization and AS.

Methods and results

Wire injuries of carotid and femoral arteries were established in Eva1a−/− mice. Eva1a-deficient mice were crossed with apolipoprotein E−/− (ApoE−/−) mice to evaluate AS development and re-endothelialization of carotid artery injuries. Denudation of the carotid artery at 3, 5, and 7 days was significantly aggravated in Eva1a−/− mice. The neointima of the femoral artery at 14 and 28 days was consequently exacerbated in Eva1a−/− mice. The area of atherosclerotic lesions was increased in Eva1a−/−ApoE−/− mice. To explore the underlying mechanisms, we performed transwell, scratch migration, cell counting kit-8, and bromodeoxyuridine assays using cultured human aorta endothelial cells (HAECs), which demonstrated that EVA1A promoted HAEC migration and proliferation. Proteomics revealed that the level of actin-related protein 2/3 complex subunit 1B (Arpc1b) was decreased, while Eva1a expression was absent. Arpc1b was found to be a downstream molecule of EVA1A by small interfering RNA transfection assay. Activation of Rac1 and Cdc42 GTPases was also regulated by EVA1A.

Conclusion

This study provides insights into anti-atherogenesis effects of Eva1a by promoting endothelium repair. Thus, Eva1a is a promising therapeutic target for AS.
OP05 Validation of the Lémann index in Crohn’s disease
Authors: Pariente B , Torres J , Burisch J , Arebi N , Barberio B , Duricova D , Ellul P , Goldis A , Kaimakliotis I , Katsanos K , Krznaric Z , Mc Namara D , Pedersen N , Sebastian S , Weimars P , Lung P , Lacognata C , Horak M , Domislovic V , Murphy I , Ungaro R , Colombel J F , Mary J Y
Published: January 2020

Background

The Lémann index (LI) is the first instrument developed to measure cumulative structural bowel damage in Crohn’s disease (CD).1 We here report its validation.

Methods

This was an international, multicentre, prospective cross-sectional observational study. At each centre, 10 inclusions, stratified by known or suspected CD location and duration, were planned. Clinical examination and abdominal MRI had to be performed in all patients, and upper endoscopy, colonoscopy, and pelvic MRI according to CD location. Upper tract (UT), small bowel (SB), colon/rectum (CR), and anus (AN) were divided into 3, 20, 6 and 1 segments, respectively. History of previous surgery was collected per segment. For each segment, 1 gastroenterologist and 1 radiologist per centre, identified the presence of predefined stricturing and/or penetrating lesions of maximal severity (grade 1 to 3) at each investigation. They provided a damage evaluation for each non-resected segment ranging from 0 to 10, 10 corresponding to the damage of a completely resected segment. Investigator organ damage evaluation was calculated as the sum of segmental damage evaluations. Finally, investigators provided a global damage evaluation from 0 to 10 for each patient according to the 4 organ damage scores, calculated as a function of investigator organ damage evaluations, resections and a total number of segments. The correlation between the investigator global damage evaluation and the LI was high on the construction sample, since coefficients to derive the LI were estimated by maximising this correlation, and is expected to be lower on data obtained in new patients by new investigators. Thus, the LI would be validated if the linear regression model of investigator global damage evaluation on LI shows a still high correlation. The same applies to investigator damage evaluation of each organ and each organ component of the LI.

Results

134 patients were included in 15 centres, 7 to 10 per centre. Correlation coefficients between investigator organ damage evaluation and each organ component of the LI were 0.91, 0.96, 0.95, and 0.81, for UT, SB, CR and AN, respectively. The correlation coefficient between investigator global damage evaluation and the LI was 0.98 (Figure 1). Proportions of the investigator organ damage evaluation variance explained by each organ component of the LI were 82%, 91%, 89%, 65%, for UT, SB, CR, AN, respectively. This proportion was 96% for the investigator global damage evaluation and the LI.

Conclusion

The Lémann index is now a validated index to assess cumulative bowel damage in CD that can be used in epidemiological studies and disease modification trials.

Reference
OP11 Exposure to an inflammatory mix re-induces inflammation in organoids of ulcerative colitis patients, independent of the inflammatory state of the tissue of origin
Authors: Arnauts K , Verstockt B , Sabino J , Vermeire S , Verfaillie C , Ferrante M
Published: January 2020

Background

Patient-derived intestinal organoids provide a powerful tool to unravel mechanisms underlying inflammatory bowel disease (IBD). Recently, we showed that organoids derived from inflamed regions in ulcerative colitis (UC) patients lose their inflammatory phenotype during ex vivo culture and were indistinguishable from organoids of non-inflamed regions in these patients.1 To study UC in an ex vivo model, we hypothesised that inflammation should be re-induced towards levels corresponding to the in vivo situation. In addition, we aimed to elucidate if organoids derived from inflamed regions are more sensitive towards inflammatory stimulation, compared with organoids from non-inflamed regions of UC patients and non-IBD controls.

Methods

Biopsies were obtained from 8 patients with active UC (endoscopic Mayo score of ≥2), both in inflamed and non-inflamed regions, and in 8 non-IBD controls. Crypts were isolated and cultured as organoids for at least four weeks. Organoids were subjected to a predefined inflammatory mix (MIX: 100 ng/ml TNF-α, 20 ng/ml IL-1β, 1 µg/ml Flagellin) or medium only (CTRL) for 24 h (Figure 1). RNA was extracted from organoids for RNA sequencing by Lexogen QuantSeq for Illumina. Differential gene expression and pathways were studied through DESeq2 and ingenuity pathway analysis (false discovery rate <0.05).

Results

Prior to inflammatory stimulation, principal component analysis (PCA) demonstrated separate clustering between organoids derived from non-IBD controls and UC patients. Exposure to the inflammatory mix induced transcriptional activation of inflammatory genes (CXCL1, DUOXA2, IL1β, IL8, IL23α, etc., all p < 0.001) and pathways in all conditions (Figure 2). However, organoids of non-IBD controls clustered separate from organoids of UC patients. Within organoids of UC patients (inflamed vs. non-inflamed origin), we observed no differentially expressed genes after inflammatory stimulation but organoids clustered per patient instead (Figure 3). Inflammatory markers in UC organoids reached transcriptional expression levels (CXCL1, CXCL2, IFNGR1, IL1β, DUOXA2, etc.) and activated pathways (antigen presentation, interferon signalling, granulocyte adhesion and diapedesis) similar to those observed in crypts derived from inflamed biopsies.

Conclusion

Inflammation can efficiently be (re-)induced in organoids from both UC and non-IBD origin. However, a different response was observed between organoids of non-IBD and UC origin. Of note, in UC organoids, the state of inflammation in the source tissue was irrelevant. In conclusion, we showed that it is essential to re-induce inflammation in patient-specific organoids, but there is no need to obtain biopsies from inflamed regions.

Reference
OP12 The incidence and disease course of perianal Crohn’s disease: A Danish nationwide cohort study
Authors: Wewer M D , Zhao M , Nordholm-Carstensen A , Seidelin J B , Burisch J
Published: January 2020

Background

Perianal Crohn’s disease (pCD) has a major negative impact on patients’ quality of life and is complex to treat. Despite its putative high frequency and burden for patients, only a few studies have investigated the incidence, disease course and associated cancer-risk in a population-based setting. The aim was to assess the incidence and course of pCD in adult patients with CD within a 19-year period. Specifically, describing changes in medical and surgical management as well as rates of cancer.

Methods

The cohort comprised all individuals >18 years diagnosed with CD in Denmark between 1 January 1997 and 31 December 2015. Patients were identified in the National Patient Registry. Chi-square test, Mann–Whitney–Wilcoxon test and multivariate Cox regression analysis were used.

Results

A total of 1,697/9,739 (17%) patients with CD were found to have pCD. Perianal fistulas were the most common manifestation accounting for 943 (56%) cases. The onset of pCD before CD diagnosis occurred in 32%. The overall incidence of pCD was 20/1,000 patient-years. The incidence of pCD remained stable over time. More patients with pCD were treated with immunomodulators (70%) and biologics (35%) than those without pCD (51%, p < 0.001 and 15%, p < 0.001, respectively). Defunctioning stoma was performed in 157/943 (17%) of perianal fistula patients. Stoma formation in relation to resection was performed in 112/943 (12%) of perianal fistula patients. Patients with pCD were found to have a significantly increased risk of undergoing major abdominal surgery compared with patients without pCD (hazard ratio: 1.52, 95% CI: 1.40 to 1.65, p < 0.001). The incidence rate ratios of anal and rectal cancer in pCD patients were 12.46 (95% CI: 5.07 to 30.59, p < 0.001) and 2.41 (95% CI: 1.31 to 4.42, p = 0.003) respectively, when compared with non-IBD matched controls. The incidence rate ratio of anal and rectal cancer in pCD patients was 2.36 (95% CI: 0.86 to 6.50, p = 0.09) and 1.35 (95% CI: 0.68 to 2.68, p = 0.38) respectively, when compared with CD patients without pCD.

Conclusion

In this nationwide study, 17% of the CD patients developed pCD. The continuing high incidence of pCD suggests a limited disease-modifying effect of biologics. Patients with pCD were at increased risk of undergoing major surgery compared with non-pCD patients. The risk of rectal or anal cancer was increased in patients with pCD compared with non-IBD matched controls. These findings encourage surveillance of rectal and anal cancer.
OP18 Surgical prevention of anastomotic recurrence by excluding mesentery in Crohn’s disease: The SuPREMe-CD study
Authors: Luglio G , Rispo A , Imperatore N , Amendola A , Tropeano F P , Peltrini R , Castiglione F , De Palma G D , Bucci L
Published: January 2020

Background

Recently, a new antimesenteric, functional end-to-end, hand-sewn ileocolic anastomosis (Kono-S) has shown a significant reduction in endoscopic recurrence score and surgical recurrence rate in Crohn’s disease (CD).This trial aimed to provide randomised controlled data comparing Kono-S anastomosis and stapled ileocolic side-to-side anastomosis.

Methods

Randomised controlled trial at a tertiary referral institution, enrolling and randomising to undergo either the ‘Kono group’ or the ‘Conventional group’, all CD subjects needing surgery. Primary endpoint: endoscopic recurrence (ER) (Rutgeerts score ≥i2) after 6 months. Secondary endpoints: clinical recurrence (CR) after 12 and 24 months, ER after 18 months and surgical recurrence (SR) after 24 months. Also, short-term outcomes and postoperative complications were recorded. A sample size of 70 patients (35 in each group) was considered necessary to demonstrate a reduction >30% in endoscopic recurrence at 6 months follow-up in the Kono group when assuming a 60% endoscopic recurrence expected rate in the control group.

Results

79 CD patients were enrolled and randomised in the Kono group (36) or Conventional group (43) (Table 1). After 6 months, 22.2% in the Kono group and 62.8% in the Conventional group presented an ER (p < 0.001; OR 5.91). A severe postoperative ER (Rutgeerts score ≥i3) was found in 13.8% of Kono vs. 34.8% of Conventional group (p = 0.03; OR 3.32). CR rate was 8% in the Kono group vs. 18% in the Conventional group after 12 months (p = 0.2) and 18% vs. 30.2% after 24 months (p = 0.04, OR 3.47). SR rate after 24 months was 0% in the Kono group vs. 4.6% in the Conventional group (p = 0.3). Patients with Kono-S anastomosis presented a longer time until CR than patients with side-to-side anastomosis (HR 0.36, p = 0.037). On binary logistic regression analysis, the Kono-S anastomosis was the only variable significantly associated with a reduced risk of ER (OR 0.19, p < 0.001). About postoperative outcomes, there were no differences between Kono and Conventional groups in terms of surgery duration (p = 0.8), days to gas (p = 0.4) or stool canalisation (p = 0.8) and postoperative stay (p = 0.3). Infections (included wound infection) were found in 4 subjects in the Kono group (13.7%) vs. 6 patients (16.6%) in the Conventional group (p = 0.749).

Conclusion

This is the first RCT comparing Kono-S anastomosis vs. standard anastomosis in CD, which found a significant reduction of postoperative endoscopic recurrence rate by using the novel technique, without concerns about safety. The Kono-S anastomosis could be considered the new recommended surgical technique in CD.

ClinicalTrial.gov

NCT02631967.
OP31 Meta–omics reveals microbiome-driven proteolysis as a contributing factor to the severity of ulcerative colitis disease activity
Authors: Mills R , Dulai P , Vázquez-Baeza Y , Zhu Q , Humphrey G , DeRight Goldasich L , Quinn R , Gewirtz A , Chassaing B , Chu H , Sandborn W , Dorrestein P , Knight R , Gonzalez D
Published: January 2020

Background

Ulcerative colitis (UC) is characterised by an aberrant immune response directed towards the gut microbiota. It remains poorly understood which mechanisms govern pathogenic roles of the microbiome in UC.

Methods

A prospective cohort of 40 UC patients were phenotyped with clinical (partial Mayo), biochemical (faecal calprotectin), endoscopic (Mayo endoscopic sub-score and ulcerative colitis Endoscopic Index of Severity) and histologic (Geboes) disease activity indices. Individual patient-matched faecal samples collected within 24 h prior to the lower endoscopy underwent 16S, shotgut metagenomic, metabolomic, metaproteomic, and metapeptidomic sequencing in addition to proteomic sequencing of paired serum samples. Sequencing datasets were integrated and analysed for microbial determinants of UC disease severity. Confirmatory in-vivo and in-vitro experiments were performed in Caco-2 epithelial monolayers and IL10 knockout mice.

Results

All meta-omics displayed large-scale shifts related to disease severity, with the metabolome and metaproteome best predicting disease severity and the metapeptidome demonstrating an increase of peptide fragments in UC patients with high severity. Broad-scale analyses and taxonomic inferences identified Bacteroides proteases as a distinguishing feature of disease severity, with the Bacteroides association being driven by changes in protease protein expression. Using a Caco-2 model we confirmed that epithelial disruption by Bacteroides vulgatus was prevented by protease inhibition, without influencing growth rates. Guided by the metagenome and metaproteome we transplanted a high-severity UC faecal sample with an increased abundance of proteases related to Bacteroides vulgatus into an IL10−/− gnotobiotic mouse model, and observed that colitis induced by transplant of faeces was attenuated by oral administration of protease inhibitors.

Conclusion

Through an integrated multi-omics data analysis we demonstrate that certain members of the microbiome, such as Bacteroides vulgatus, may contribute to exacerbating disease activity in UC through protease activity. In-vivo and in-vitro experiments provide evidence that bacterial protease inhibition may be a novel therapeutic approach in UC.
DOP03 The impact of elemental diet on the human gut microbial structure and intestinal metabolites
Authors: Miyoshi J , Saito D , Nakamura M , Miura M , Mitsui T , Kudo T , Murakami S , Matsuura M , Hisamatsu T
Published: January 2020

Background

The incidence and prevalence of Crohn’s disease (CD) are increasing globally. The efficacy of elemental nutrition (EN) for CD has been reported for decades. Recent studies demonstrated that elemental diet (ED), one of the types of EN, which contains individual amino acids, sugars (mono- or polysaccharides), and low fat, improves the anti-TNFa antibody therapy outcome by reducing the loss of response and has the preventive effect against the postoperative recurrence. Given its excellent safety, ED can be a promising concomitant therapeutic option for CD. However, the underlying mechanisms of ED remain unclear. Imbalance of the gut microbiota, dysbiosis, is thought to be involved in CD pathogenesis. Meanwhile, diet influences gut microbiota. We hypothesised that ED exerts clinical efficacy by shifting the gut microbiota to the anti-inflammatory environment. We also believe that investigating human samples is crucial to obtain mechanistic insights into ED therapy, considering species-specific differences in interactions between the host and microbiota. In this study, we examined the impact of ED on the intestinal bacterial compositions as well as metabolites in human subjects.

Methods

Four healthy individuals participated in the study. The subjects continued their dietary habits for 2 weeks after the registration of the study and then replaced 900 kcal/day of their regular diet with 900 kcal/day of ED (time point 1, T1). ED was continued for 2 weeks (T2). After the withdrawal of ED, subjects resumed their original dietary habits for 2 weeks until the endpoint of this study (T3). Faecal samples were collected from all subjects at all time points, T1-3. Faecal DNA and metabolites were extracted and analysed with 16S rRNA gene amplicon sequencing and metabolomic analysis, respectively. This study was approved by the Institutional Review Board of Kyorin University School of Medicine (IRB No. 720) and performed in accordance with the principles of the Declaration of Helsinki.

Results

Interindividual differences were observed in the gut bacterial compositions (Figure 1) as well as metabolites (Figure 2) at all time points. Changes over time varied among subjects. On the other hand, some bacteria (e.g. [Ruminococcus] gnavus group and Parabacteroides) and metabolites including short-chain fatty acids and bile acids changed significantly between time points among the 4 subjects. The bacterial and metabolite profiles at T3 were different from those T1 in all subjects.

Conclusion

The alterations of the gut microbiota induced by ED vary with each individual. Some microbes and metabolites change commonly across the subjects. ED may have a lasting effect on the gut environment even after the withdrawal.
DOP05 Perioperative Dietary Therapy in inflammatory bowel disease
Authors: Adamina M , Gerasimidis K , Sigall-Boneh R , Zmora O , de Buck van Overstraeten A , Campmans-Kuijpers M , Ellul P , Katsanos K , Kotze P , Noor N , Schäfli-Thurnherr J , Vavricka S , Wall C , Wierdsma N , Yassin N , Lomer M
Published: January 2020

Background

The incidence of inflammatory bowel disease [IBD] is rising worldwide and no cure is available. Many patients require surgery and they often present with nutritional deficiencies. Although randomised controlled trials of dietary therapy are lacking, expert IBD centres have long-established interdisciplinary care, including tailored nutritional therapy, to optimise clinical outcomes and resource utilisation. This topical review aims to share expertise and offers current practice recommendations to optimise outcomes of IBD patients who undergo surgery.

Methods

A consensus expert panel consisting of dietitians, surgeons, and gastroenterologists, convened by the European Crohn’s and Colitis Organisation, performed a systematic literature review. Nutritional evaluation and dietary needs, perioperative optimisation, surgical complications, long-term needs, and special situations were critically appraised. Statements were developed using a Delphi methodology incorporating three successive rounds. Current practice positions were set when ≥80% of participants agreed on a recommendation.

Results

A total of 26 current practice positions were formulated which address the needs of IBD patients perioperatively and in the long term following surgery. Routine screening, perioperative optimisation by oral, enteral, or parenteral nutrition, dietary fibre, and supplements were reviewed. IBD-specific situations, including management of patients with a restorative proctocolectomy, an ostomy, strictures, or short-bowel syndrome, were addressed.

Conclusion

Perioperative dietary therapy improves the outcomes of IBD patients who undergo a surgical procedure. This topical review shares interdisciplinary expertise and provides guidance to optimise the outcomes of patients with Crohn’s disease and ulcerative colitis. taking advantage of contemporary nutrition science.
DOP10 Intestinal ultrasound response and transmural healing after ustekinumab induction in Crohn’s disease: Week 16 interim analysis of the STARDUST trial substudy
Authors: Kucharzik T , Wilkens R , Maconi G , D’Agostino M A , Le Bars M , Nazar M , Sloan S , Lahaye M , Ni L , Ercole E , Alloca M , Machková N , Maaser C
Published: January 2020

Background

Intestinal ultrasound (IUS) is a non-invasive tool for evaluating transmural disease activity in Crohn’s disease (CD) patients. We report interim Week (W)16 results from an IUS substudy of STARDUST, a phase 3B randomised trial of CD patients treated with ustekinumab (UST), comparing a treat-to-target (T2T) maintenance treatment strategy vs. standard of care (SoC). The aim of the substudy was to assess changes in IUS parameters, including transmural response to UST induction therapy.

Methods

Patients (≥18 years) with moderate–severe active CD (CD Activity Index [CDAI] 220–450 and simple endoscopic index for CD [SES-CD] ≥3) who failed conventional therapy and/or 1 biologic, received weight-based IV UST dosing of ~6mg/kg at Week 0, then SC UST 90mg at W8. At Week 16, patients with CDAI reduction ≥70 points were randomised (1:1) to T2T or SoC treatment arms. Exclusion criteria: characteristics precluding IUS visualisation of affected bowel segments and normal bowel wall thickness (BWT) (≤2.0mm terminal ileum; ≤3.0mm colon) for all segments at baseline (BL). Key IUS endpoints assessed at W4, W8 and W16 (central reading): IUS response ≥25% BWT reduction from BL; BWT change from BL (mm); IUS remission (transmural healing) ‒ BWT normalisation, colour Doppler signal ≤1, normal echo stratification, and absence of inflammatory fat. The most affected bowel segment at BL was used for all IUS parameters. Correlations/% agreement between IUS response/remission and clinical (CDAI70, clinical response/remission), biomarker (CRP/FCal levels) and endoscopy outcomes (SES-CD scores) were assessed.

Results

The analysis included 82/94 patients enrolled in the IUS substudy; n = 76 patients had BL and ≥1 post-BL IUS assessment. BL characteristics were similar to those of the main STARDUST population. Overall IUS response and remission (transmural healing) rates at W16 were 33.8% and 11.3%, respectively (Table 1). The most affected segments were ileum in 66% and colon in 34% of patients, with better outcomes found in the colon (Table 2). BWT and Doppler’s signal started to normalise at W8, inflammatory fat and echo stratification at W16 (Table 2). Mean BWT improvement from BL was statistically significant as early as W4 (p = 0.0002; Table 3). Moderate agreement was observed between earlier IUS responses and later biomarkers/endoscopic improvements.

Conclusion

This was the first international, interventional, multicentre study using IUS in CD. IUS response to UST was detected as early as Week 4, and a clinically meaningful % of patients achieved transmural healing, primarily in the colon, at W16. IUS could be a valuable tool to detect early response to treatment in CD. Future studies need to confirm whether early IUS response is predictive of long-term outcomes for CD patients.
DOP20 Can lifestyle and psychosocial factors predict flares of IBD; an exploratory study using telemedicine
Authors: Lalisang R C A , Adriaans G , de Jong M , van der Meulen-de Jong A , Romberg-Camps M , Mahmmod N , Markus-de Kwaadsteniet T , Dijkstra G , Haans J , Stamm C , Vanwersch R , Jonkers D , Almeida R J , Pierik M J
Published: January 2020

Background

Tight control of mucosal inflammation and prevention of disease flares are emerging treatment goals to prevent disease progression in inflammatory bowel disease (IBD). The state of the art clinical classification only marginally predict flare occurrence. Mounting evidence shows that psychosocial and lifestyle factors are associated with flares. Longitudinal monitoring of these factors has been made possible by implementing a web-based telemedicine tool, called myIBDcoach. This study is an exploration on the potential additive predictive value of data captured in a telemedicine system to predict flares.

Methods

Consecutive IBD patients (n = 393) were recruited from the prospective myIBDcoach telemedicine study cohort (ClinicalTrials.gov, NCT02173002). During a one-year follow-up, every 1–3 months, participants reported information on all variables displayed in Figure 1 via myIBDcoach. Variables were subdivided into two main categories; Baseline and myIBDcoach. The myIBDcoach variables were once again subdivided (Figure 1). The outcome of interest, a flare during follow-up, was defined as having clinical symptoms of disease activity (using the Monitor IBD At Home questionnaire) combined with either a faecal calprotectin > 250g/g, disease activity on endoscopy, MRI or CT. Stepwise group-Lasso logistic regression (G-LASSO) was used to estimate associations between flares and individual variables, as well as between flares and the different variable categories (Figure 1). G-LASSO performs variable selection, resulting in models that contain only the most relevant explanatory variables.

Results

Seven G-LASSO regressions were estimated and evaluated using the Akaike information criteria (AIC), the area under the curve (AUC) and stepwise importance using 10-fold cross-validated penalty parameter. Figure 2 shows that the overall model performance increased when consecutively adding extra variable categories, the largest increase occurred for psychosocial and lifestyle factors. All telemedicine variable categories were found to be more important compared with the baseline variable category, as shown in Figure 3. Results shown in Figure 4 indicate that the information from myIBDcoach was found to be more important than the baseline variables.

Conclusion

In this exploratory study, psychosocial and lifestyle factors monitored via telemedicine are of superior value to predict flares in IBD patients compared with clinical stratification. Holistic monitoring, including psychosocial and lifestyle factors, and targeted interventions are of interest for future trials and are a promising strategy to prevent flares and improve the outcome of IBD.