bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and Validation of a Sensitive GC–MS/MS Method for the Determination of Five Potential Genotoxic Impurities in Abiraterone Acetate
Authors: Zhong ZhenHua , Chen YuPing , Xia HongYing , Chen ZhenZhen , Cheng QiZhen 
Published: May 2021

Abstract
A sensitive and selective gas chromatography–tandem mass spectrometry method was developed for the identification and quantification of five potential genotoxic impurities (PGIs), i.e., chloromethane, 2-chloropropane, 2-bromopropane, 4-chloro-1-butanol and diethyl sulfate, in abiraterone acetate. The method was validated according to the International Council for Harmonisation (ICH) guidelines. The linearity was established for the concentration range of 30–480 ng/mL (2-chloropropane, 2-bromopropane, 4-chloro-1-butanol and diethyl sulfate) and 90–1440 ng/mL (chloromethane). The correlation coefficient of each PGIs was &gt;0.995. The extraction recoveries ranged from 90.49 to 106.79% for the five PGIs. The quantitation limit, detection limit, accuracy, precision, repeatability and stability of the method demonstrated that the method was an adequate quality control tool for quantitation and identification of chloromethane, 2-chloropropane, 2-bromopropane, 4-chloro-1-butanol and diethyl sulfate at trace levels in drug substances and drug products.
DOP23 Single-cell RNA sequencing identifies an important role for class I histone-deacetylase enzymes in intestinal myofibroblasts from patients with Crohn’s Disease strictures
Authors: Lewis A , Pan-Castillo B , Berti G , Felice C , Gordon H , Gadhok R , Minicozzi A , Chinaleong J , Feakins R , Lindsay J , Silver A 
Published: May 2021

Abstract

Background
Histone-deacetylase (HDAC) enzymes are a broad class of ubiquitously expressed enzymes that modulate histone acetylation, chromatin accessibility and gene expression. In models of Inflammatory bowel disease (IBD), HDAC inhibitors, such as Valproic acid (VPA) are proven anti-inflammatory agents and evidence suggests that they also inhibit fibrosis in non-intestinal organs. However, the role of HDAC enzymes in stricturing Crohn’s disease (CD) has not been characterised; this is key to understanding the molecular mechanism and developing novel therapies.

Methods
To evaluate HDAC expression in the intestine of SCD patients, we performed unbiased single-cell RNA sequencing (sc-RNA-seq) of over 10,000 cells isolated from full-thickness surgical resection specimens of non-SCD (NSCD; n=2) and SCD intestine (n=3). Approximately, 1000 fibroblasts were identified for further analysis, including a distinct cluster of myofibroblasts. Changes in gene expression were compared between myofibroblasts and other resident intestinal fibroblasts using the sc-RNA-seq analysis pipeline in Partek. Changes in HDAC expression and markers of HDAC activity (H3K27ac) were confirmed by immunohistochemistry in FFPE tissue from patient matched NSCD and SCD intestine (n=14 pairs). The function of HDACs in intestinal fibroblasts in the CCD-18co cell line and primary CD myofibroblast cultures (n=16 cultures) was assessed using VPA, a class I HDAC inhibitor. Cells were analysed using a variety of molecular techniques including ATAC-seq, gene expression arrays, qPCR, western blot and immunofluorescent protein analysis.

Results
Class I HDAC (HDAC1, p= 2.11E-11; HDAC2, p= 4.28E-11; HDAC3, p= 1.60E-07; and HDAC8, p= 2.67E-03) expression was increased in myofibroblasts compared to other intestinal fibroblasts subtypes. IHC also showed an increase in the percentage of stromal HDAC2 positive cells, coupled with a decrease in the percentage of H3K27ac positive cells, in the mucosa overlying SCD intestine relative to matched NSCD areas. In the CCD-18co cell line and primary myofibroblast cultures, VPA reduced chromatin accessibility at Collagen-I gene promoters and suppressed their transcription. VPA also inhibited TGFB-induced up-regulation of Collagen-I, in part by inhibiting TGFB1|1/SMAD4 signalling. TGFB1|1 was identified as a mesenchymal specific target of VPA and siRNA knockdown of TGFB1|1 was sufficient suppress TGFB-induced up-regulation of Collagen-I.

Conclusion
In SCD patients, class I HDAC expression is increased in myofibroblasts. Class I HDACs inhibitors impair TGFB-signalling and inhibit Collagen-I expression. Selective targeting of TGFB1|1 offers the opportunity to increase treatment specificity by selectively targeting meschenymal cells.
DOP29 The Normalization and Transition of J-Pouch Phenotype in the Chicago Classification of Pouchitis
Authors: Akiyama S , Cohen N , Traboulsi C , Rai V , Glick L , Yi Y , Runde J , Cohen R , Skowron K , Hurst R , Umanskiy K , Shogan B , Hyman N , Rubin M , Dalal S , Sakuraba A , Pekow J , Chang E , Ollech J , Rubin D 
Published: May 2021

Abstract

Background
Pouchitis can develop in up to 70% of patients with inflammatory bowel disease (IBD) treated by proctocolectomy with ileal pouch-anal anastomosis (IPAA). In our recent work, we proposed the “Chicago classification of pouchitis” describing 7 main pouch phenotypes with differing outcomes. In this study, we assessed the transition of pouch phenotypes in our classification.

Methods
This is a retrospective study of IBD patients with IPAA who subsequently underwent pouchoscopies at the University of Chicago between June 1997 and December 2019. We reviewed all available reports of pouchoscopies after ileostomy takedown and classified the pouches into 7 main phenotypes: (a) normal, (b) afferent limb (AL) involvement, (c) inlet (IL) involvement, (d) diffuse, (e) focal inflammation of the pouch body, (f) cuffitis, and (g) pouch fistulas (Figure 1). A normal pouch was defined as a pouch without any abnormal findings including fistulas. AL, IL involvement, and cuffitis were defined as any type of endoscopic inflammation in the AL, IL, and rectal cuff, respectively. Diffuse inflammation was defined as two or more endoscopic inflammatory findings in all anatomical locations of the pouch body (the tip, proximal, and distal pouch). Focal inflammation was defined as pouchitis that did not meet the criteria for diffuse inflammation. Pouch fistulas included pouches with any type of fistulas noted ≥6 months from ileostomy takedown. Using a Kaplan-Meier curve, event-free survival (EFS) was assessed from the scope date when a primary phenotype was first identified to the date when a subsequent phenotype was described. We excluded patients if a subsequent phenotype was identified before or at the scope date when a primary phenotype was initially noted. Logistic regression analysis was performed with variables with a P-value &lt;0.05 in a Fisher’s exact test.

Results
We reviewed 1,359 pouchoscopies from 426 patients (90% preoperative diagnosis of ulcerative colitis). The most common subsequent inflammatory phenotype was focal inflammation (55%-88%), followed by IL involvement (31%-67%), cuffitis (33%-46%), diffuse inflammation (20%-38%), AL involvement (21%-32%), and pouch with fistulas (9%-20%). The rate of subsequent normal pouch was 6%-25% with pouch fistulas having the lowest normalization rate (6%, 5-year EFS 93%) (Table 1, Figure 2). On multivariable analysis, pouch fistulas were negatively associated with pouch normalization (OR 0.17, 95% CI 0.06–0.48) (Table 2).

Conclusion
We demonstrated that pouch phenotype can change over time and pouch normalization is possible. Further studies are needed to determine if pouch normalization should be a goal of treatment for IBD patients with IPAA.
DOP33 Predictors of ileo-rectal anastomosis, permanent ileostomy and recurrence of disease after total colectomy for Crohn’s Colitis: Results over 20 years
Authors: Rottoli M , Melina M , Tanzanu M , Romano A , Belvedere A , Parlanti D , Pezzuto A P , Salice M , Rizzello F , Gionchetti P , Poggioli G 
Published: May 2021

Abstract

Background
Patients with surgical Crohn’s colitis (CC) might either undergo a total colectomy (TC) and ileo-rectal anastomosis (IRA), or TC and end ileostomy. Among the latter group, a second-stage IRA is not always performed. The predictors of the different outcomes after TC (including the recurrence of disease at the level of the anastomosis) are yet to be identified.

Methods
Retrospective study including 354 patients undergoing TC for CC (2000–2019), with a minimum preoperative follow-up of 2 years in our centre. The mean postoperative follow-up was 67.5+/-49.8 months (62 patients lost). The primary end-points were to identify the predictors for the following outcomes:
a) IRA (87 cases, 24.6%) vs. end ileostomy (267 cases, 75.4%) at the primary colectomy.
b) second-stage IRA (80 cases, 39%) vs. no IRA (125 cases, 61%) at the last follow-up.
c) recurrence of the disease after IRA (167 patients).
Considering the large number of regressors and the risk of over-fitting, the least absolute shrinkage and selection operator (LASSO) method was used. A multivariate analysis was carried out using the preselected covariates. The analysis was conducted using logistic regression and cox regression for dichotomus and time-dependent outcomes. A p-value&lt;0.05 was considered significant.

Results
a) Predictors against the IRA at primary TC: preoperative biologic exposure (OR=1.96, CI 1.15–3.33, p=0.014), Crohn’s rectal location (OR=4.17, CI 2.0–8.33, p&lt;0.0001), perianal disease (OR=3.33, CI 1.75–6.25, p&lt;0.0001), and low hemoglobin concentration (OR=1.26, CI 1.01–1.58, p=0.037).
b) Predictors of the risk of still having the ileostomy at the follow-up: age (OR: 1.02, CI 1.00–1.04, p=0.045), exposure to biologics before (OR 1.85, CI 1.11–3.03, p=0.017) and after (OR 1.79, CI 1.11–2.89, p=0.018) the TC; postoperative use of azathioprine was associated with a greater chance of a second-stage IRA (OR 2.66, CI 1.21–5.83, p=0.014).
c) Risk of anastomotic recurrence was 8.7% and 30.8% at 5 and 10 years. Significant predictors were: female gender (OR 2.38, CI 1.11–5.55, p=0.046), use of more than one biologic (OR 5.65, CI 2.18–9.89, p&lt;0.0001) and worsening of symptoms needing for drug escalation (OR 5.51, CI 2.06–8.59, p=0.001) during the follow-up.

Conclusion
The location and severity of the disease at diagnosis predict the long-term behavior of the disease. The exposure to biologics, especially if multiple drugs are required, does not represent a risk for worse outcomes per se, but rather identifies a population at higher risk of permanent ileostomy due to more severe disease. These predictors might be implemented in the assessment of patients affected by CC, in order to identify the population at risk of permanent ileostomy.
DOP40 Comorbidities and epidemiological risk factor but not immunosuppressive therapies increase the risk of COVID-19 in Inflammatory Bowel Disease (IBD): An ENEIDA-based, case-control study
Authors: Zabana Abdo Y , Marín-Jiménez I , Rodríguez-Lago I , Vera I , Martín M D , Guerra I , Gisbert J P , Mesonero F , Benítez O , Taxonera C , Ponferrada-Díaz Á , Piqueras M , Lucendo A , Caballol B , Mañosa M , Martínez-Montiel P , Bosca-Watts M , Gordillo J , Bujanda L , Manceñido N , Martínez-Pérez T , López A , Rodríguez C , García-López S , Vega P , Rivero M , Melcarne L , Calvo M , Iborra M , Barreiro-de Acosta M , Arias L , Barrio J , Pérez J L , Busquets D , Pérez-Martínez I , Navarro-Llavat M , Hernández V , Argüelles-Arias F , Domènech E , Esteve M 
Published: May 2021

Abstract

Background
The information regarding IBD patients with COVID-19 suggests that the factors related to bad outcome are older age and comorbidity whereas immunosuppressants do not have a significant impact worsening the disease evolution. To date, there is no information to assess if there are differences in epidemiological, demographical, and clinical characteristics between infected and non-infected IBD patients.

Methods
Case-control study in IBD patients with COVID-19 (cases) compared to IBD without COVID-19 (controls) in the period March-July/2020 within the ENEIDA registry (promoted by GETECCU and with more than 60.000 IBD patients included). Cases were matched 1:2 by age (±5y), type of disease (CD/UC), gender, and centre. All controls were selected from only one investigator blind to other clinical characteristics of the patients to avoid selection bias.

Results
496 cases and 964 controls from 63 Spanish centres were included. No differences were found within the basal characteristics including CD location, CD behaviour, extraintestinal manifestations, family history of IBD or smoking habits. Cases had ≥ 1 comorbidities (cases:43%vs. controls:36%, p=0.01) and occupational risk (cases:27% vs. controls:10.6%, p&lt;0.0001) in a higher proportion. Strict lockdown but not sick leave nor telecommuting was the only measure demonstrating protection against COVID-19 (cases:49% vs. controls:70%, p&lt;0.0001). There were no differences in the use of systemic steroids (p=0.19), immunosuppressants (p=0.54) or biologics (p=0.25) between cases and controls. Cases were more often treated with aminosalicylates (45% vs.34%, p=0.022). Having ≥ 1 comorbidities (OR:1.4, 95%CI: 1–1.8), occupational risk (OR:2.05, 95%CI:1.5–2.9) and the use of aminosalicylates (OR:1.4, 95%CI: 1–1.8) were risk factors for COVID-19. On the other hand, the strict lockdown was a protective factor (OR:0.36, CI:0.27–0.48).

Conclusion
Comorbidities and epidemiological risk factors are the most relevant aspects for the risk of COVID-19 in IBD patients. This risk of COVID-19 seems to be increased by aminosalicylates but not by immunosuppressants or biologics. The attitude regarding treating IBD patients with aminosalicylates during the COVID-19 pandemic deserves a deeper analysis.
Funded by the Carlos III Health Institute COV20/00227.
DOP84 Early treatment responses within 14 days of intravenous vedolizumab induction therapy for Crohn’s Disease: Post hoc analysis of patient-reported outcomes from the VISIBLE 2 study
Authors: D’Haens G , Baert F , Danese S , Kobayashi T , Loftus E V , Sandborn W J , Dornic Q , Lindner D , Kisfalvi K , Marins E G , Vermeire S 
Published: May 2021

Abstract

Background
Vedolizumab (VDZ), an anti-a4β7 integrin antibody that selectively blocks lymphocyte trafficking to the gut, is approved for the treatment of adult patients with moderate-to-severe Crohn’s disease (CD). This post hoc analysis of data from the VISIBLE 2 trial evaluated early patient-reported outcomes assessed within the first 14 days of VDZ induction.

Methods
VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a phase 3, multicentre, placebo-controlled study, evaluating the efficacy and safety of subcutaneous VDZ for maintenance treatment in patients with moderately to severely active CD. Efficacy was assessed based on CD Activity Index (CDAI). Patients received induction treatment with intravenous (IV) VDZ 300 mg open-label at Weeks 0 and 2. For this analysis, responses to VDZ were assessed using CDAI sub-scores for patient-reported abdominal pain (AP) and stool frequency (SF) collected daily via electronic diary in the first 14 days of VDZ treatment (Day 1 to 15) in all patients receiving ≥1 VDZ dose at induction. Descriptive statistics were used.

Results
The analysis included 611 patients (mean [SD] age 37.6 [13.4] years; CD duration 9.0 [8.1] years); 323 (53%) were male; 228 (37%) had severe disease (CDAI &gt;330) at baseline; and 350 (57%) were anti-TNF-experienced. In the first 14 days of VDZ IV induction, the rate of patients with daily SF≤3 increased from 30% at baseline (Day 1) to 47.7% on Day 15. Increases were similar in both anti-TNF-naïve vs. anti-TNF-experienced patients and in patients with severe vs. moderate disease (Figure 1). Mean baseline SF was reduced from 6.4 to 5.0 at Day 15 in patients with severe disease and from 4.3 to 3.5 in patients with moderate disease. Overall, the proportion of patients rating AP as severe/moderate declined from baseline to Day 15 of induction (from 14.6% to 8.2% for severe AP and from 60.7% to 40.6% for moderate AP). Similar Day 1-to-15 reductions were reported in both anti-TNF-naïve (severe AP: 14.2% to 9.2%; moderate AP: 62.6% to 44.6%) and anti-TNF-experienced patients (severe AP: 14.8% to 7.4%; moderate AP: 59.3% to 37.7%), respectively. Although a minority of patients (6.3%) in the sub-group with moderate AP at baseline had worse pain at Day 15, there were early improvements in AP ratings for most patients reporting severe or moderate AP at baseline (Figure 2).

Conclusion
This post hoc analysis of daily patient-reported SF and AP in the VISIBLE 2 CD study indicates an early onset of response to VDZ IV induction within the first 14 days of treatment.
P148 ANA and Anti-dsDNA antibody enabling the prediction of inflammatory arthritis in inflammatory bowel disease
Authors: de Sousa Magalhães R , Lima Capela T , Rosa B , Moreira M J , Cotter J 
Published: May 2021

Abstract

Background
Inflammatory arthritis is frequent as an extraintestinal manifestation of IBD, as well as a paradoxical reaction to biological treatment. Anti-nuclear antibody (ANA) and Anti-dsDNA antibody have been associated with inflammatory arthritis. We aim to assess the correlation between the presence of ANA and Anti-dsDNA antibody and the diagnosis of inflammatory arthritis in patients with IBD under biological treatment.

Methods
We present a cohort study, including IBD patients under biological treatment, presenting at least a treatment session in the first 2 months of 2020. Data was gathered from medical records, laboratorial analysis, namely ANA and Anti-dsDNA, were collected in the treatment session, and every patient posteriorly answered telephonically validated questionnaires to assess the presence of inflammatory arthritis, the outcome variable. A univariate analysis followed by a multivariate logistic regression, including statistically significant variables, tested the correlation towards inflammatory arthritis. A ROC curve tested the performance of the final model.

Results
We included 122 patients, 64 (52.5%) were women, and the mean age was 39 years old. Eighty-six (70.5%) patients presented Crohn’s Disease and 36 (29.5%) Ulcerative Colitis. A hundred (82%) patients were under Infliximab, 21 under Vedolizumab (17.2%) and only 1(0.8%) under Adalimumab. Thirty-three patients (27%) met questionnaire criteria for inflammatory arthritis, either peripheric or axial. The variables age, ANA and ANA’s title, age at IBD diagnosis and number of symptomatic articulations involved were associated with the presence of inflammatory arthritis. The multivariate model including ANA (OR 4.149 [1.03–16.711] p=0.045); number of articulations involved (OR 2.683 [1.783–4.038] p&lt;0.001) and higher age at IBD diagnosis, accurately identified patients with diagnosis of inflammatory arthritis (ROC AUC 0.957 [0.926–0.987] p&lt;0.001). A sub-analysis correlating ANA and the presence of inflammatory arthritis after biological initiation showed a statistical tendency (OR 2.231 [0.908–5.478] p&lt;0.08).

Conclusion
The presence of ANA antibodies and a higher number of symptomatic articulations involved independently increased the rate of inflammatory arthritis diagnosis in up to 4 times, in a cohort of patients with IBD under biological treatment. The inclusion in a multivariate model displayed an excellent accuracy and performance towards the diagnosis of inflammatory arthritis. ANA antibodies together with validated questionaries may aid in the identification of IBD patients suffering from inflammatory arthritis.
P152 Bowel ultrasound as an early monitoring tool to assess disease activity in Crohn’s disease patients after induction therapy with infliximab
Authors: Morão B , Nascimento C , Frias Gomes C , Gonçalves T , Castro F , Moreira M J , Cotter J , Pereira F , Caldeira A , Sousa R , Coelho R , Macedo G , Macedo C , Ferreira M , Cravo M , Glória L , Torres J , Palmela C 
Published: May 2021

Abstract

Background
Bowel wall thickness (BWT) is an accurate sonographic parameter to assess disease activity in Crohn’s disease (CD). International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) was developed to allow a reproducible assessment of intestinal inflammation in CD using bowel ultrasound (IUS).

Aim
to assess BWT and IBUS-SAS variation after induction therapy with infliximab (IFX) and their correlation with clinical and laboratory parameters.

Methods
Prospective multicentre study including patients with active CD starting IFX. Harvey-Bradshaw index (HBI), C-reactive protein (CRP), faecal calprotectin (FC) and IUS were performed at week 0 (W0) and 14 (W14). IUS response and remission were defined as a reduction in BWT ≥25% and its normalization(≤3mm) in the most affected segment, respectively. IBUS-SAS was calculated using BWT, Doppler signal, bowel wall stratification (BWS) and inflammatory fat.

Results
We included 37 patients (62% males; median age 30 years, range 16–73). According to Montreal classification, most patients were A2 (70%), had ileocolonic disease (L3 57%) and an inflammatory phenotype (B1 60%); 41% had perianal disease. Most were anti-TNF therapy naive(84%), and combination therapy was used in 62%. Terminal ileum was the most affected segment identified by IUS (60%).
Table 1 shows clinical, laboratory and sonographic parameters [median (IQR)]. At W14, 81% were in clinical remission, 43% in laboratorial remission (normal CRP and FC), 24% had IUS response and 11% had IUS remission. There was a significant reduction in HBI, CRP, FC and sonographic parameters (except for BWS) between W0 and W14. We found a fair to good correlation between BWT and HBI(r=0.363, p=0.03), CRP(r=0.391, p=0.02) and FC(r=0.373, p=0.03) at W14. IBUS-SAS had also a fair to good correlation with CRP(r=0.340, p=0.04) and FC(r=0.527, p=0.001) at W14. The area under the curve of IBUS-SAS for predicting clinical and laboratorial remission was 0.60; best-cut off 64.65 (sens. 57%; specif. 63%).

Conclusion
There was a significant reduction in sonographic parameters after 14 weeks of IFX and one quarter of our patients had an IUS response, suggesting that reduction in BWT could be an early marker of response to therapy. We found a good correlation between IUS and clinical and laboratory parameters at W14. IUS evaluation after induction therapy can be a helpful tool to monitor disease activity and guide CD patient management in our daily practice.