bluuebunny/crossref_metadata_2025_split huggingface dataset:
mPPI: a database extension to visualize structural interactome in a one-to-many manner
Authors: Zhou Yekai , Chen Hongjun , Li Sida , Chen Ming 
Published: May 2021

AbstractProtein–protein interaction (PPI) databases with structural information are useful to investigate biological functions at both systematic and atomic levels. However, most existing PPI databases only curate binary interactome. From the perspective of the display and function of PPI, as well as the structural binding interface, the related database and resources are summarized. We developed a database extension, named mPPI, for PPI structural visualization. Comparing with the existing structural interactomes that curate resolved PPI conformation in pairs, mPPI can visualize target protein and its multiple interactors simultaneously, which facilitates multi-target drug discovery and structure prediction of protein macro-complexes. By employing a protein–protein docking algorithm, mPPI largely extends the coverage of structural interactome from experimentally resolved complexes. mPPI is designed to be a customizable and convenient plugin for PPI databases. It possesses wide potential applications for various PPI databases, and it has been used for a neurodegenerative disease–related PPI database as demonstration. Scripts and implementation guidelines of mPPI are documented at the database tool website.Database URL http://bis.zju.edu.cn/mppi/
DOP19 Urinary metabolome in newly diagnosed treatment-naïve Crohn’s Disease patients: Results from the IBDomics study
Authors: Aldars-García L , Gil-Redondo R , Embade N , Riestra S , Rivero M , Gutiérrez A , Rodríguez I , Fernández L , Ceballos D , Benítez J M , Aguas M , Bastón-Rey I , Algaba A , Casanova M J , Lorente R , Ber Y , Royo V , Esteve M , Millet O , Gisbert J P , Chaparro M 
Published: May 2021

Abstract

Background
The urinary metabolome of patients with Crohn’s disease (CD) differs significantly from healthy subjects and, among other features, reflects the specific gut dysbiosis affecting these patients. However, most of the studies included established and treated CD patients. Our aim was to characterize the urinary metabolome of onset and treatment-naïve CD patients and to identify the metabolic profile related to the different CD clinical classifications.

Methods
Patients newly diagnosed with CD (n=131) were prospectively included. Control healthy subjects (HC, n=338) were recruited among the general population and matched for sex, age and BMI to the IBD subjects. Fasting urine was obtained before starting any treatment. Metabolomic analysis was performed by proton nuclear magnetic resonance (1H NMR).
We performed a comparative assessment of the urinary metabolome profile using a linear regression model for each metabolite, including sex, age, BMI, and smoking habit as covariates to control for confounding. The different subgroup comparisons within CD were made as follows: (1) CD; (2) CD location (Montreal Classification): L1 (ileal) + L4 (ileal and upper-intestinal), L2 (colonic) and L3 (ileocolonic); (3) endoscopic CD activity: 0, 1, 2 and 3; and (4) CD phenotype: B1 (inflammatory), B2 (stricturing) and B3 (penetrating), versus HC. In addition, data analysis was carried out using partial least squares-discriminate analysis (PLS-DA) to determine class membership based on distinct metabolomic profile.

Results
The primary characteristics of the CD patients and HC are shown in Table 1. Several metabolites were identified to be differently abundant in each group (Table 2). These metabolites are involved in relevant processes related to energy and aminoacids metabolism, and also include gut-derived metabolites. The PLS-DA model separated patients within the different clinical subgroups (Figures 1–4). Figures 1–4(b) show the main metabolites involved in each group separation. Many of these metabolites are in accordance with the differential metabolites obtained using the univariate analysis (Table 2), showing the potential of this approach to group CD patients and to identify potential biomarkers.

Conclusion
Analysis of urinary metabolites can help to understand the etiopathological mechanisms in CD. It has the potential to provide a non-invasive means of diagnosing CD, and can differentiate between CD clinical expressions.
DOP35 Ambulatory care management of 70 patients with Acute Severe Ulcerative Colitis in comparison to 700 inpatients: Insights from a multicentre UK cohort study
Authors: Patel K V , Segal J , Sebastian S , Subramanian S , Conley T , Gonzalez H , Kent A , Saifuddin A , Hicks L , Mehta S , Bhala N , Brookes M , Lamb C , Kennedy N , Walker G 
Published: May 2021

Abstract

Background
Acute severe ulcerative colitis (ASUC) traditionally requires inpatient hospital management for intravenous therapies and/or colectomy. Patients with ASUC can deteriorate rapidly and hence require close monitoring of vital signs correlated with clinical, biochemical and radiological investigations. Traditionally, patients are admitted to hospital to facilitate endoscopic assessment, exclude concomitant infective complications, monitor response to first-line corticosteroid treatment and determine the need for and timing of rescue therapy and/or colectomy. Ambulatory care pathways, which utilise outpatient monitoring and drug delivery, have been shown to deliver safe and effective treatment for conditions which have historically mandated hospitalisation e.g. pulmonary embolus. To date there are a paucity of data regarding the use of ambulatory pathways in ASUC cohorts. We used data from PROTECT, a UK multicentre observational COVID-19 i (IBD) study, to report the extent, safety and effectiveness of ASUC ambulatory pathways.

Methods
Adults (≥ 18 years old) meeting Truelove and Witts criteria between 01/01/2019- 01/06/2019 and 01/03/2020–30/06/2020 were recruited to PROTECT (Figure 1). We utilised demographic, disease phenotype, treatment outcomes and 3-month follow-up data. Primary outcome was rate of rescue therapy and/or colectomy. Secondary outcomes included corticosteroid response, response to rescue therapy, colectomy, mortality and hospital readmission within 3-months. We compared outcomes in 3 cohorts: i) patients treated entirely in inpatient setting; ambulatory patients subdivided into ii) patients hospitalised and subsequently discharged to ambulatory care; iii) patients managed as ambulatory
from diagnosis .

Results
38%(23/60) participating hospitals used ambulatory pathways. Of 770 eligible patients, 700(91%) patients received entirely inpatient care, 55(7%) patients were discharged to ambulatory pathways and 15(2%) patients were managed as ambulatory from diagnosis. The rate of rescue therapy and/or colectomy (49%[339/696] vs 41%[22/54] vs 67%[10/15], respectively, p=0.18) (figure 2) and secondary outcomes were similar among all three cohorts. After 3-months follow up from the index ASUC diagnosis there was no significant difference in either rate of UC flare, readmission to hospital with UC flare or colectomy between the cohorts.

Conclusion
In the largest description of ambulatory ASUC care to date, we report an emerging practice which challenges treatment paradigms. Our data suggest ambulatory ASUC treatment may be safe and effective in selected patients but further studies exploring clinical and cost effectiveness as well as patient and physician acceptability are needed.
DOP39 Utilization and sustainability of biologics in UC - A nationwide study from the epi-IIRN
Authors: Atia O , Yogev D , Friss C , Focht G , Orlanski-Meyer E , Magen Rimon R , Ledderman N , Greenfeld S , Kariv R , Loewenberg Weisband Y , Gabay H , Nevo D , Matz E , Gorelik Y , Chowers Y , Dotan I , Turner D 
Published: May 2021

Abstract

Background
25% of UC patients fail to respond to induction therapy with biologics. In this nationwide study we aimed to evaluate trends in biologics utilization and sustainability in UC during the last 15 years.

Methods
This study was performed on data from four the four Israeli Health Maintenance Organizations, covering 98% of the population. Sustainability was defined as continuous treatment without IBD-related surgeries and at most one short steroid course. Sustainability was compared across different biologics utilizing a propensity score (PS) weighted analysis, estimated by generalized boosted modeling (GBM).

Results
13,231 patients were diagnosed with UC in Israel since 2005 (1,426 [11%] pediatric-onset,11,805 [89%] adult-onset), of whom 1,692 (13%) were ever treated with biologics (400 [24%] pediatric-onset, 1,292 adults [76%], OR 3.2 [95%CI 2.8–3.6]; p&lt;0.001) with a median of 6.4 years follow up (IQR 3.4–9.9). Infliximab was the most common first-line treatment in both children and adults (75% and 54%, respectively, p&lt;0.001). However, in recent years there was an increase in adalimumab and vedolizumab utilization in parallel with a decrease in infliximab (Figure). The rate of initiating biologics in the first year of diagnosis increased from from 11% during 2005–2010 to 25% during 2011–2014 and 61% since 2015 (p&lt;0.001). The use of combination therapy with immunomodulators is becoming less common and decreased with infliximab: from 36% in 2010 to 17% in 2018 (p&lt;0.001) and with adalimumab from 32% to 12%, respectively (p&lt;0.001).
The sustainability rate in those treated with infliximab was 52% at one year from initiation of biologics, and 37% and 34% at three and five years, thereafter; compared to 55%, 43% and 40% with adalimumab and 72% and 67% after one and two years with vedolizumab. The primary non-response rate was 30% with infliximab, 31% with adalimumab and 16% with vedolizumab.
Sustainability was associated with earlier initiation of biologics during the disease course (HR 0.9 [95%CI 0.85–0.95]). In the PS-adjusted model where vedolizumab served as the reference, the sustainability of both infliximab (HR 0.7 [95%CI 0.6–0.95]) and adalimumab (HR 0.8 [95%CI 0.6–0.99]) were lower. Compared with monotherapy, combination therapy increased the sustainability rate with both adalimumab (HR 0.3 [95%CI 0.2–0.6]) and infliximab (HR 0.4 [95%CI 0.-0.6]), but not with vedolizumab (HR 1.4 [95%CI 0.98–2.1]).

Conclusion
Biologics are being increasingly used in UC but only half of patients sustain treatment at one year. Treatment is commenced earlier during the disease course, and this is associated with improved sustainability. Sustainability rate is higher with vedolizumab, and in combination therapy of IMM and infliximab or adalimumab.
DOP44 Long term outcomes of patients with untreated IBD - A population-based analysis from the epi-IIRN
Authors: Magen Rimon R , Atia O , Friss C , Ledderman N , Greenfeld S , Kariv R , Loewenberg Weisband Y , Gabay C , Shaoul R , Odes S , Matz E , Dotan I , Turner D 
Published: May 2021

Abstract

Background
Therapy in IBD is recommended in order to treat or prevent complications. In this nationwide study we aimed to assess the incidence of patients with IBD who were not receiving maintenance treatment after diagnosis and the duration of non-treatment.

Methods
This study was performed on data from four Health Maintenance Organizations (HMOs), covering 98% of the Israeli population. We included all patients with IBD diagnosed from 2005 to 2019. Non-treatment was defined as lack of drug prescription of maintenance medication for at least six months from diagnosis. Sustainability was defined as lack of maintenance medications and without IBD-related surgeries. Cox regression model was used to explore estimated predictors of sustainability.

Results
A total of 30,168 patients were diagnosed with IBD in Israel since 2005 (16,936 [56%] Crohn’s disease [CD] and 13,231 [44%] ulcerative colitis [UC]). A total of 5,448 (32%) patients with CD were untreated, compared to 5,158 (39%) with UC (OR 1.35 [95%CI 1.3–1.4]; p&lt;0.001). Non-treatment was more likely in adult compared to pediatric-onset (34% vs 21%, respectively, p&lt;0.001 in CD; and 41%% vs 22%, respectively, in UC; p&lt;0.001) (Figure 1). Sustainability rate in CD was 72%, 46%, 36% and 28% after one, two, five and ten years from diagnosis, while in UC the corresponding rates were 59%, 39%, 24% and 16%. In CD, sustainability was associated with older age at diagnosis (HR 0.996 [95%CI 0.994–0.998]) and no induction therapy (HR 0.7 [95%CI 0.6–0.9] compared to steroids). In UC, sustainability was associated only with female sex (HR 0.9 [95%CI 0.88–0.98]).

Conclusion
Most patients with IBD eventually require maintenance therapy. Lack of maintenance treatment is more common in UC. Nevertheless, a third of patients with CD and one quarter with UC who had no medical treatment at six months from diagnosis remained untreated for five years, especially in older patients with CD and those who did not require induction therapy, suggesting milder disease.
DOP62 Immunogenicity to second anti-TNF therapy (IMSAT): Implications for sequencing of biologic therapy
Authors: Chanchlani N , Lin S , Thomas A , Hamilton B , Nice R , Chee D , Kennedy N , Goodhand J , Ahmad T 
Published: May 2021

Abstract

Background
Anti-TNF (aTNF) treatment failure in patients with IBD is common. International guidelines recommend switching out of class when aTNF drug levels are therapeutic and within class with an immunomodulator when aTNF drug levels are suboptimal and associated with antibody development. We sought to define the: 1) risk of immunogenicity to a second aTNF stratified by immunogenicity to the first aTNF and 2) rates of drug persistence to a second aTNF in patients with pharmacodynamic or immunogenic failure of their first aTNF drug.

Methods
We performed a retrospective cohort study across 32 UK hospitals. 870 patients (444 male, 630 (72%) Crohn’s disease) who had both infliximab and adalimumab therapeutic drug monitoring performed by our service from May 2013 to November 2020 were identified. Drug and antibody levels were measured using the IDKmonitor® drug tolerant ELISA assays. Treatment failure included primary nonresponse, secondary loss of response, adverse drug reactions and IBD-related surgeries, and was identified by case note review. Immunogenic failure was defined as treatment failure with suboptimal drug levels (infliximab level &lt;2 mg/L, adalimumab level &lt;6 mg/L) with an antibody concentration ≥10 AU/ml. Pharmacodynamic failure was defined as treatment failure despite adequate drug levels.

Results
Patients who developed immunogenicity to adalimumab (first) were more likely to develop immunogenicity to infliximab (second) (63% vs 40%, p = 0.004), and patients who developed immunogenicity to infliximab (first) were more likely to develop immunogenicity to adalimumab (second) (33% vs 19%, p = 0.002) (Fig 1). Patients who developed: antibodies and undetectable drug, low drug levels, or low drug levels with immunogenicity to infliximab (first), were more likely to develop these outcomes to adalimumab (second) (all p&lt;0.001).
There was no difference in drug persistence to second aTNF in patients with pharmacodynamic and immunogenic treatment failure (Fig 2). In patients with immunogenic (but not pharmacodynamic) failure, commencing an immunomodulator at the time of switching to second aTNF drug was associated with longer drug persistence than in patients treated with an immunomodulator throughout or not all (Fig 3).

Conclusion
Immunogenicity to the first aTNF was associated with immunogenicity to the second aTNF, irrespective of drug sequence. Commencing an immunomodulator at the time of switching to second aTNF was associated with improved drug persistence in immunogenic, but not pharmacodynamic, failure. However, 50% of patients remained on second aTNF at 5 years in both groups, suggesting switching in-class may be appropriate irrespective of the cause of treatment failure to first aTNF.
DOP82 Corticosteroid-free remission of Ulcerative Colitis with filgotinib maintenance therapy: Post hoc analysis of the phase 2b/3 SELECTION study
Authors: Loftus E , Vermeire S , Feagan B , Yun C , Hsieh J , Liu X , Zhao S , Moerch U , Sandborn W J , Hibi T 
Published: May 2021

Abstract

Background
Filgotinib (FIL) is a once-daily, oral, preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel disease. FIL for the treatment of moderately to severely active ulcerative colitis (UC) was evaluated in the phase 2b/3 randomized, double-blind, placebo (PBO)-controlled SELECTION study (NCT02914522). Long-term use of corticosteroids (CS) is associated with significant side effects. The aim of this post hoc analysis was to assess the CS-sparing effects of FIL in the SELECTION study.

Methods
Patients (18–75 years old) with moderately to severely active UC were randomized (2:2:1) to receive FIL 100 mg (n = 564), FIL 200 mg (n = 507) or PBO (n = 280) once daily orally for up to 11 weeks (induction study). At week 11, FIL induction responders were rerandomized 2:1 to continue their induction FIL dose or to receive PBO (maintenance study). CS use was kept stable up to week 14, at which point mandatory CS tapering occurred. CS could be resumed during the maintenance study; however, if the baseline CS dose was exceeded this was considered treatment failure. In this post hoc analysis, CS-free remission was defined as remission at week 58 (endoscopic subscore ≤ 1, rectal bleeding subscore = 0 and ≥ 1-point decrease in stool frequency subscore to achieve 0 or 1) without systemic or localized CS use that was indicated for UC in the previous 1, 3, 6 or 8 months.

Results
The baseline characteristics of patients in the maintenance study were similar across treatment groups (Table 1). Of the 92 patients receiving CS at maintenance baseline (week 11; maintenance week 0) who received FIL 200 mg during the maintenance study, 25 (27%) were in remission at week 58 and had been continuously CS-free for at least the previous 6 months (Table 2). The proportion of CS-free remitters in the FIL 200 mg group was consistently higher than with PBO (Table 2). In patients taking CS at maintenance baseline who had continued CS-use post baseline, lower median prednisone dosing was observed with FIL 200 mg than with PBO throughout the maintenance study (maximum difference at week 34 [maintenance week 23]: 5.0 mg vs 13.8 mg) (Figure 1). In SELECTION, a total of 199 patients received FIL 200 mg in the maintenance study, of whom 74 (37.2%) were in remission at week 58; of these 74 patients, 69 (93.2%) were continuously CS-free for at least the previous 6 months (Figure 2).

Conclusion
In this post hoc analysis of SELECTION maintenance study data, FIL 200 mg was effective in reducing and eliminating CS use through to week 58 in patients with moderately to severely active UC. The vast majority of patients taking FIL 200 mg who were in remission at week 58 had not taken CS in the previous 6 months.
DOP85 Corticosteroid-free efficacy and safety outcomes in patients receiving tofacitinib in the OCTAVE Sustain maintenance study
Authors: Vavricka S R , Greuter T , Cohen B L , Reinisch W , Steinwurz F , Fellmann M , Guo X , Lawendy N , Paulissen J , Peyrin-Biroulet L 
Published: May 2021

Abstract

Background
Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. Here, we report corticosteroid-free efficacy and safety among patients (pts) who received oral corticosteroids at baseline of the maintenance study (OCTAVE Sustain).

Methods
Pts with clinical response following OCTAVE Induction 1&2 who were re-randomised to receive placebo or tofacitinib 5 or 10 mg twice daily (BID) in OCTAVE Sustain, and who were receiving oral corticosteroids at baseline of OCTAVE Sustain, were included. Corticosteroid tapering was mandatory at the beginning of OCTAVE Sustain. Steroid-free (not requiring any treatment with corticosteroids for ≥4 weeks prior to the visit) rates of remission, endoscopic improvement and clinical response were assessed at Week 24 and/or Week 52. The association between baseline characteristics and steroid-free efficacy outcomes was evaluated using logistic regression. Safety outcomes were stratified by tofacitinib dose and steroid-free remission status.

Results
Of 593 pts entering OCTAVE Sustain, 289 had oral corticosteroid use at baseline. Of these, 101 (34.9%) received placebo and 188 received tofacitinib (101 [34.9%] 5 mg BID; 87 [30.1%] 10 mg BID) in OCTAVE Sustain. Among pts receiving oral corticosteroids on Day 1 of OCTAVE Sustain, the mean dose (mg/day [standard deviation], prednisone equivalent) received was 15.8 (6.2), 14.9 (6.2) and 14.4 (6.0) in the placebo, tofacitinib 5 mg BID and tofacitinib 10 mg BID groups, respectively. At Week 24 or Week 52 of OCTAVE Sustain, there was a significant treatment effect for tofacitinib 5 or 10 mg BID vs placebo for steroid-free efficacy endpoints (Table 1). Prior immunosuppressant failure was associated with lower odds of achieving steroid-free remission at Week 52 of OCTAVE Sustain (odds ratio [OR] 0.47 [95% confidence interval (CI) 0.23, 0.95]), while prior tumour necrosis factor inhibitor (TNFi) failure status only had a limited effect, which was not statistically significant (OR 0.53 [95% CI 0.27, 1.02]). Oral corticosteroid dose received at baseline of OCTAVE Sustain did not affect the likelihood of achieving steroid-free remission at Week 52. Adverse events of special interest were infrequent (Table 2). Discontinuations were numerically higher among pts without steroid-free remission (Table 2).

Conclusion
For pts with baseline oral corticosteroid use in OCTAVE Sustain, the odds of achieving steroid-free efficacy endpoints were significantly higher for tofacitinib 5 or 10 mg BID compared with placebo. Prior TNFi failure was not associated with lower odds of achieving steroid-free remission at Week 52. There were no apparent differences in safety by steroid-free remission status. Data interpretation is limited by small pt numbers.