bluuebunny/crossref_metadata_2025_split huggingface dataset:
Much more than a clasp: evolutionary patterns of amplexus diversity in anurans
Authors: Carvajal-Castro Juan D , López-Aguirre Yelenny , Ospina-L Ana María , Santos Juan C , Rojas Bibiana , Vargas-Salinas Fernando 
Published: January 2020

AbstractThe evolution and diversification of animal reproductive modes have been pivotal questions in behavioural ecology. Amphibians present the highest diversity of reproductive modes among vertebrates, involving various behavioural, physiological and morphological traits. One such feature is the amplexus, which is the clasp or embrace of males on females during reproduction and is found almost universally in anurans. Hypotheses about the origin of amplexus are limited and have not been tested thoroughly, nor have they taken into account evolutionary relationships in most comparative studies. However, these considerations are crucial to an understanding of the evolution of reproductive modes. Here, using an evolutionary framework, we reconstruct the ancestral state of amplexus in 685 anuran species. We investigate whether the type of amplexus has a strong phylogenetic signal and test whether sexual size dimorphism could have influenced amplexus type or male performance while clasping females. Overall, we found evidence of ≥34 evolutionary transitions in amplexus type across anurans. We found that amplexus type exhibits a high phylogenetic signal and that amplexus type does not evolve in association with sexual size dimorphism. We discuss the implications of our findings for the diversity of amplexus types across anurans.
Can the impacts of cold-water pollution on fish be mitigated by thermal plasticity?
Authors: Parisi M A , Cramp R L , Gordos M A , Franklin C E 
Published: January 2020

AbstractIncreasingly, cold-water pollution (CWP) is being recognised as a significant threat to aquatic communities downstream of large, bottom-release dams. Cold water releases typically occur during summer when storage dams release unseasonably cold and anoxic hypolimnetic waters, which can decrease the temperature of downstream waters by up to 16°C. Depending on the release duration, these hypothermic conditions can persist for many months. The capacity of ectothermic species to tolerate or rapidly adjust to acute temperature changes may determine the nature and magnitude of the impact of CWP on affected species. This study assessed the impacts of an acute reduction in water temperature on the physiological function and locomotor performance of juvenile silver perch (Bidyanus bidyanus) and examined their capacity to thermally compensate for the depressive effects of low temperatures via phenotypic plasticity. Locomotor performance (Ucrit and Usprint) and energetic costs (routine and maximum metabolic rate) were measured at multiple points over a 10-week period following an abrupt 10°C drop in water temperature. We also measured the thermal sensitivity of metabolic enzymes from muscle samples taken from fish following the exposure period. Cold exposure had significant depressive effects on physiological traits, resulting in decreases in performance between 10% and 55%. Although there was partial acclimation of Ucrit (~35% increase in performance) and complete compensation of metabolic rate, this occurred late in the exposure period, meaning silver perch were unable to rapidly compensate for the depressive effects of thermal pollution. The results of this study have substantial implications for the management of cold water releases from large-scale dams and the conservation of native freshwater fish species, as this form of thermal pollution can act as a barrier to fish movement, cause reduced recruitment, ecological community shifts and disruptions to timing and success of reproduction.
OP01 Higher vs. standard adalimumab maintenance regimens in patients with moderately to severely active ulcerative colitis: Results from the SERENE-UC maintenance study
Authors: Colombel J F , Panés J , D’Haens G , Schreiber S , Panaccione R , Peyrin-Biroulet L , Loftus E V , Danese S , Louis E , Armuzzi A , Ferrante M , Vogelsang H , Lefebvre J , Doan T , Xie W , Huang B , Petersson J , Kalabic J , Robinson A , Sandborn W J 
Published: January 2020

Abstract

Background
Adalimumab (ADA) is efficacious and well tolerated in adult patients with ulcerative colitis (UC).1,2 SERENE-UC (NCT02065622) is a study evaluating higher ADA dosing regimens from which induction study results have previously been reported3; here, we report data from the maintenance study.

Methods
This Phase 3, double-blind, randomised, multicentre study evaluated higher vs. standard ADA dosing regimens for induction and maintenance therapy in adult patients with moderately to severely active UC. Following completion of the induction study at Week 8, all patients were re-randomised 2:2:1 to ADA 40 mg every week (40 EW), ADA 40 mg every other week (40 EOW), or exploratory ADA 40 mg with therapeutic drug monitoring (TDM) regimens, stratified by induction treatment regimen, clinical response status at Week 8, and clinical remission (CRem) status at Week 8 among Week 8 responders. Efficacy endpoints were evaluated in Week 8 responders (ITT-RP) unless indicated differently. The primary efficacy endpoint was proportion of patients achieving CRem (full Mayo Score ≤2 with no subscore &gt;1) at Week 52. The endoscopic component of the Mayo Score was scored via central reading. Non-responder imputation was used for missing values. Comparisons between 40 EW and 40 EOW dosing regimens used the Cochran–Mantel–Haenszel test adjusted for stratification. Safety assessment included a collection of adverse events (AEs), vital signs, and laboratory data.

Results
Of 852 patients in the Global (ex-Japan) induction study, 757 were re-randomised at Week 8 and 371 were included in the ITT-RP. In the ITT-RP, induction baseline demographics and disease characteristics were generally balanced across the 3 treatment arms; range across arms for mean UC disease duration was 6.2–7.8 years, 6.8–11.7% had prior infliximab use, and 62.5–63.5% were receiving corticosteroids. The overall mean ADA exposure was 252.2 days. The table displays results for efficacy endpoints. The observed safety profile was similar between maintenance treatment arms, including AEs of special interest (generally &lt;1% across arms).

Conclusion
In the Global (ex-Japan) study of SERENE-UC, CRem at Week 52 was numerically higher among Week 8 responders in patients receiving ADA 40 EW compared with 40 EOW maintenance regimens (∆ = 10.5%), but not statistically significant. Higher maintenance treatment with 40 EW was generally safe and well tolerated with a similar safety profile to 40 EOW. No new long-term safety concerns were observed.

References
OP08 Inflammatory bowel disease and risk of small bowel cancer: A binational population-based cohort study from Denmark and Sweden
Authors: Axelrad J , Olen O , Sachs M , Erichsen R , Pedersen L , Halfvarson J , Askling J , Ekbom A , Sørensen H T , Ludvigsson J 
Published: January 2020

Abstract

Background
Crohn’s disease (CD) is associated with increased risk of small bowel cancer (SBC), but previous studies were limited by a small number of cases, short follow-up, lack of individually matched comparators, and over-representation of tertiary referral centres, leading to exaggerated relative risks and incidence data. Data on ulcerative colitis (UC) and SBC are scarce.

Methods
In a binational, population-based cohort study from Sweden and Denmark of patients diagnosed with inflammatory bowel disease (IBD) during 1969–2017 and matched reference individuals from the general population, we evaluated the risk of incident SBC, including SBC subtypes (small bowel adenocarcinoma, neuroendocrine tumours, and sarcoma). Cox regression was used to compute adjusted hazard ratios (aHRs) as a measure of relative risks for incident SBC and SBC subtypes.

Results
We identified 161,896 individuals with IBD (CD: 47,370; UC: 97,515; unclassified IBD:17,011). During follow-up, 237 cases of SBC were diagnosed in patients with IBD (CD: 24.4/100,000 person-years; UC: 5.88/100,000 person-years), compared with 640 cases in reference individuals (2.81/100,000 person-years and 3.32/100,000 person-years, respectively, Table). This corresponded to one extra case of for small bowel cancer in 385 CD patients, and one extra case in 500 UC patients, followed-up for 10 years. The aHR for incident SBC of 9.09 (95% CI = 7.34–11.3) in CD patients and 1.85 (95% CI = 1.43–2.39) in UC patients (Figure). When the first year after IBD diagnosis was excluded, the aHRs for incident SBC decreased to 4.96 in CD patients and 1.69 in UC patients. Among CD patients, relative risks were highest for recently diagnosed, childhood-onset, ileal, and stricturing CD; among UC patients, relative risks were highest for those with extensive colitis and primary sclerosing cholangitis (PSC). In CD patients, the risk of all SBC subtypes was increased (aHR 15.8 for adenocarcinoma, 5.51 for neuroendocrine tumours, and 4.04 for sarcoma) whereas in UC patients only the risk of adenocarcinoma (aHR 1.99) and neuroendocrine tumours (aHR 2.01) were increased.

Conclusion
SBC was more common in IBD patients, particularly among patients with CD, although absolute risks were low. Further studies should evaluate the utility of SBC surveillance in selected populations such as those with ileal CD, extensive colitis, or UC-PSC.
OP22 Crohn’s disease exclusion diet reduces bacterial dysbiosis towards healthy controls in paediatric Crohn’s disease
Authors: Van Limbergen J , Dunn K , Wine E , Sigall Boneh R , Bielawski J , Levine A 
Published: January 2020

Abstract

Background
Dietary therapy with the Crohn’s disease Exclusion Diet (CDED) or Exclusive Enteral Nutrition (EEN) induces remission, reduces inflammation and is associated with compositional changes in the microbiome. We performed metagenome analysis to elucidate whether diet induces remission via correction of dysbiosis and/or community structure.

Methods
Whole metagenome and 16S rDNA sequences were obtained in 178 samples from 70 participants at 3 time points (baseline, week 6, week 12) from the two study groups (CDED+PEN/EEN). For metagenome analysis, we divided the groups further into samples of patients achieving ITT-remission at week 6 (CDED+PEN: 31/38 and EEN: 23/32) and those who did not.

Results
Dietary therapy decreased the relative abundance of genera from Proteobacteria towards healthy controls. CDED+PEN remission is associated with a significant increase (p &lt; .05) in Clostridiales, and a significant decrease (p &lt; .05) in Proteobacteria (particularly Γproteobacteria). Microbiome comparison of all baseline CD samples with healthy controls showed significant (p &lt; .05) increases in Proteobacteria in an active CD at baseline. Healthy controls had increased Firmicutes species notably Roseburia, Oscillibacter and Anaerostipes, as well as increased Bacteroides and Ascomycota (driven by Saccharomyces). Proteobacteria decreased when diet-induced remission was achieved (with either CDED+PEN or EEN) at week 6: relative abundance of Proteobacteria (including Α- and Γproteobacteria (e.g. Escherichia, Klebsiella and Citrobacter) were significantly lower compared with baseline but were still more abundant in CD patients, whereas Bacilli and Firmicutes remained more predominant in healthy samples. Continued dietary treatment with CDED+PEN between week 6 and week 12 was associated with a further decrease in Proteobacteria: although improving with dietary treatment, only Escherichia remained more abundant in CD. Faecalibacterium became more abundant in CD by week 12, as did Blautia and Sutterella. Anaerostipes, Ruminococcus, Bacilli, Porphyromonadaceae, Bifidobacteriales, Ascomycota and Caudovirales were more abundant in healthy samples compared with week 12 of CDED+PEN. Bayesian analysis of the 16S rDNA data training on patients in remission at week 6 compared with baseline (week 0) samples identified seven assemblages. Predominate taxa identified in these assemblages (Posterior Probability &gt;.01) are shown as a connected network, with taxa (nodes) found in the same assemblage connected to each other by edges (Figures).

Conclusion
Dietary therapy corrected dysbiosis towards healthy controls. Sustained dietary therapy beyond 6 weeks with CDED+PEN avoids the ‘rebound’ in disease-associated species, notably Proteobacteria, when the oral diet is reintroduced.
OP33 Multi-omics analysis reveals specific bio-geographical and functional characteristics in inflammatory bowel disease intestinal mucosa
Authors: Maimon N , Gerassy-Vainberg S , Bar-Yosef H , Alpert A , Starosvetsky E , Abu-Arisha M , Shvedov T , Shen-Orr S , Chowers Y 
Published: January 2020

Abstract

Background
Anatomical location and extent of disease are main factors that affect inflammatory bowel disease (IBD) course and prognosis. No explanation is available for segmental intestinal involvement in either Crohn’s disease (CD) or ulcerative colitis (UC), or for selective segmental response to therapy or disease complications. Therefore, studying the cellular composition of different intestinal segments may provide pathophysiological insights into these phenomena.

Methods
We compared location-specific cell composition and function by Cytometry Time-of-Flight (CyTOF), gene expression and single-cell (sc) RNAseq data obtained from 3 independent cohorts of healthy donors and IBD patients during remission and flare-ups. Using CyTOF data (n = 38 biopsies), we built a high-resolution screening of immune cell behaviour along the intestine. We validated the findings with gene expression data of 370 samples, and expanded screening resolution by computational methodologies. We then tested a specific pathway in scRNAseq data (n = 10 paired biopsies from 5 patients) and validated its significance by cell-specific Significance Analysis of Microarrays (csSAM).

Results
We found a location along the intestine to be a dominant feature determining immune and non-immune cell composition. We observed that inflammation reduced anatomic segregation beyond cell infiltration, and decreased the ability to cope with oxidative stress. An upregulated IL-6 pathway in T regulatory cells in UC patients was recognised as sigmoid-specific compared with known inflammatory IL-6 roles in macrophages, as seen in the right colon. This observation may be linked to colonic perforations associated with anti-IL-6R treatment. Suppressor of cytokine signalling 3 (SOCS3) may control IL-6 location-specific action.

Conclusion
Our study displays a unique and comprehensive cell map of IBD in a location-specific context, providing potential explanations to unexplained clinical phenomena. These observations may allow to tailor therapies to affected areas with improved therapeutic index and efficacy.
OP34 Whole blood profiling of T-cell-derived miRNA allows the development of prognostic models in inflammatory bowel disease
Authors: Kalla R , Adams A , White R , Clarke C , Ivens A , Ventham N , Kennedy N , McTaggart S ,   I. IBD Character Consortium, Ho G T , Buck A , Satsangi J 
Published: January 2020

Abstract

Background
There is an unmet need for blood-based biomarkers that help predict disease and its course at inception to allow tailoring of treatments, achieve early mucosal healing and improve clinical outcomes. In our study, we explore the clinical utility of miRNAs in Inflammatory bowel disease (IBD).

Methods
A 2-stage prospective multi-centre case–control study was performed. Small RNA sequencing was performed on a discovery cohort of immunomagnetically separated leucocytes (90 CD4+ and CD8+ T-lymphocytes and CD14+ monocytes) from 32 patients (9 CD, 14 UC, 8 healthy controls) to identify differentially expressed cell-specific miRNAs.Top miRNAs were then validated in whole blood in 294 treatment naïve newly diagnosed IBD and non-IBD patients (97 UC, 98 CD, 98 non-IBD) using RT-qPCR, recruited across 5 centres in UK and Europe. Phenotype and outcome data were collected and Cox proportional hazards were derived to assess the contribution of each miRNA to outcomes; defined as the need for 2 or more immunosuppressants and/or surgery after initial disease remission. RT-qPCR target miRNA relative quantification was calculated using 2−ΔΔCq method.

Results
Each leucocyte subset (30 CD4+ T cells, 28 CD8+ T cells and 32 CD14+ monocytes) was analysed between disease and controls, adjusting for age, gender and batch effects. A total of three miRNAs differentiated IBD from controls in CD4+ T cells including miR-1307-3p (FDR p = 0.01), miR-3615 (p = 0.02) and miR-4792 (p = 0.01); these signals being UC specific. In CD8 T cells, miR-200b-3p was the only differentially expressed miRNA and no CD14+ signals were seen.Three miRNAs were validated in whole blood in an independent multi-centre cohort of 294 patients using RT-qPCR. miR-1307-3p predicted IBD (1.55 fold change (fc),IQR: 1.00–1.87; p = 2.77 × 10–5),in particular UC (1.69 fc, IQR: 1.01–2.00; p = 1.56 × 10–6). Similarly, miR-3615 and miR-4792 were up-regulated in UC compared with controls (1.21fc, IQR:0.91–1.48; p = 8.26 × 10−4and 1.91 fc, IQR: 0.81–2.56; p = 9.21 × 10–3, respectively).There was no correlation with conventional inflammatory markers. Follow-up data were available on 195 IBD patients of which 80 patients required treatment escalation over a median time of 371 days (IQR: 140–711). miR-1307-3p was able to predict disease course in IBD (HR 1.98, IQR: 1.20–3.27; log-rank p = 1.80 × 10−3), in particular CD (HR 2.81; IQR: 1.11–3.53, p = 6.50 × 10–4). In UC, both miR-3615 (HR 3.34, CI: 1.43–7.78, p = 0.01) and miR-4792 (HR 3.96, CI: 1.65–9.52; p = 2.11 × 10–3) predicted treatment escalation.

Conclusion
We have identified unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These blood-based miRNAs are able to predict treatment escalation at disease inception and have the potential for clinical translation.
OP40 A core transferable microbiota in responders to faecal microbiota transplant for ulcerative colitis shape mucosal T-cell immunity
Authors: Gogokhia L , Lima S , Viladomiu M , Gerardin Y , Crawford C , Jacob V , Scherl E , Rosenthal M , Brown S E , Hambor J , LONGMAN R 
Published: January 2020

Abstract

Background
Biologic therapy has significantly improved treatment for UC, but nearly two-thirds of patients attenuate the response. Additional therapeutic modalities are therefore needed to address the underlying pathophysiology of UC. Faecal microbiota transplant (FMT) is an emerging therapy for the treatment of UC, but several randomised controlled trials have shown variable efficacy of FMT, and the microbial mechanisms responsible for clinical response are not well understood. Therefore, using samples from our pilot FMT study (Jacob, V, et al. Inflamm. Bowel Dis. 2017), we aim to identify the core transferable microbiota (CTM) in UC patients responsive to FMT therapy and to define the therapeutic mechanism of these strains in pre-clinical models.

Methods
IBD disease activity scores were used to define a clinical response. Metagenomic sequencing of a donor, recipient, and 4-week post-FMT faecal samples was performed to define the CTM. Strain-level transferability was defined using the StrainFinder algorithm. To define the transferable immune-reactive microbiota (TIM), IgA-seq was performed on a donor, recipient, and 4-week post-FMT faecal samples. TIM strains were isolated from faecal samples and gnotobiotic mouse models were used to evaluate their impact on mucosal immunity and mouse models of colitis.

Results
Here, we defined a CTM associated with clinical response to FMT for UC. Strain-level tracking of the CTM confirmed that clinical response correlated with strain transferability. In addition, we defined a core TIM by IgA-seq that correlated with clinical response. In humanised mouse models, these TIM were found to induce IgA in a T-cell independent manner. Colonisation of germ-free mice with a core TIM strain of Odoribacter induced IL-10-dependent, RORgt+/Foxp3+ iTreg cells and reduced the severity of transfer T-cell colitis in mono-colonised RAG−/− mice.

Conclusion
Our data highlight an immune-reactive, core transferable microbiota in responders to FMT for UC. Using pre-clinical mouse models of colitis, we define the mechanistic impact of these TIM in shaping mucosal immunity and guiding the response to UC. This work provides a framework for the rational selection of TIM for microbial-therapy in IBD.
DOP11 Normalisation of faecal calprotectin within 12 months of diagnosis is associated with a reduced risk of disease progression in Crohn’s disease
Authors: Plevris N , Fulforth J , Jenkinson P , Lyons M , Chuah C , Siakavellas S , Pattenden R , Arnott I , Jones G , Lees C 
Published: January 2020

Abstract

Background
Faecal calprotectin (FC) demonstrates an excellent correlation with endoscopic inflammation. In addition, a treatment-decision algorithm for Crohn’s disease (CD) incorporating FC outperforms and improves 12-month mucosal healing compared with a strategy based on symptoms alone. The aim of this study was to determine whether normalisation of FC (&lt;250 μg/g) within 12-months of diagnosis is associated with a reduction in disease progression in CD.

Methods
This was a retrospective cohort study performed at a tertiary IBD centre. All incident cases of CD diagnosed between 2005 and 2017 were identified. Patients with an FC measurement of &gt;250 μg/g at diagnosis who also had at least 1 follow-up FC measured within the first 12-months of diagnosis and &gt;12 months of follow-up were included. The primary endpoint was a composite of progression in Montreal disease behaviour (B1 to B2/3 or B2 to B3 or new perianal disease), surgery or hospitalisation.

Results
A total of 375 patients were included with a median follow-up of 5.3 years (IQR 3.1–7.4). Normalisation of FC (&lt;250 μg/g) within 12 months of diagnosis was confirmed in 43.5% (n = 163/375) of the cohort. On multivariable Cox-proportional hazards regression analysis, individuals who normalised their FC within 12 months of diagnosis had a significantly lower risk of composite disease progression (HR 0.351, 95% CI 0.235–0.523, p &lt; 0.001) (Figure 1). Cumulative rates of composite disease progression were 7.8%, 21.4% and 29.9% in those that normalised their FC vs. 22.8%, 50.7% and 60.5% in those that did not at 2, 5 and 7 years after diagnosis, respectively. In addition, normalisation of FC was the only predictor that remained significant for all the separate progression end-points (progression in Montreal behaviour / new perianal disease: HR 0.250, 95% CI 0.122–0.512, p &lt; 0.001; hospitalisation: HR 0.346, 95% CI 0.217–0.553, p &lt; 0.001; surgery: HR 0.370. 95% CI 0.181–0.755, p = 0.006). The strongest predictor of whether an individual normalised their FC within 12 months was the commencement of a biologic within 3 months of diagnosis (OR 4.288, 95% CI 1.585–11.0601, p = 0.004).

Conclusion
Normalisation of FC by 12-months of diagnosis is associated with a reduced risk of disease progression in CD. Our data provide strong support for implementation of treat-to-target strategies earlier than previously tested in Crohn’s disease. The immediate implication for healthcare providers and patients is that by ensuring resolution of mucosal inflammation - measured by proxy with faecal calprotectin, and regardless of other variables - within 1 year of diagnosis has a dramatic effect on disease course.