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Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

Background The efficacy of faecal microbiota transplantation (FMT) in UC has been reported to be donor-, patient- and procedure-dependent (Rees et al., 2022). The RESTORE-UC trial [NCT03110289] aimed to improve the outcome of FMT in patients with active UC by donor preselection on microbiota level, a strict anaerobic preparation and repeated FMT administration. The trial was prematurely stopped for futility (Caenepeel et al., 2022). We investigated changes in resp. biopsy and faecal samples obtained host transcriptomics and microbiota profiles from baseline to primary endpoint (PE) at week 8 to understand reasons for the observed lack of efficacy. Methods Active UC patients (total Mayo score 4-10 with endoscopic sub-score ³2, n=72) were randomly allocated to receive 4 anaerobic-prepared superdonor (S) FMT or autologous (A) FMT. Primary endpoint was defined as steroid-free clinical remission (Total Mayo ≤ 2, with no sub-score >1). Host RNA extractions were performed from mucosal biopsies collected at week 0 (n=63) and 8 (n=54) using the Qiagen AllPrep DNA/RNA Mini kit, and sequenced using Illumina HiSeq4000. Sequencing data was further processed (read-count filtering, normalization) and further analyzed using DESeq2 package. Corresponding faecal samples (resp. n=62 and n=50) were submitted to DNA extractions using MagAttract PowerMicrobiome DNA/RNA kit on an automated extraction platform, followed by library prep and 16S rDNA-sequencing using Illumina MiSeq. The obtained sequences were subjected to the DADA2 pipeline in R and the Quantitative Microbial Composition (QMP) was quantified by flow cytometry. Results Eight responders were observed: 3 after S-FMT and 5 after A-FMT, as well as 58 non-responders considering the intention-to-treat population. Responders to FMT tended to cluster at baseline (adonis p=0.34) and PCA analysis on the top 500 mucosal genes with the highest variance (Fig.1), showed a significant host effect at week 8 between responders and non-responders (adonis p Conclusion A trend towards clustering of responders on host mRNA level and QMP was observed at baseline as well as at the primary endpoint, showing a potential role for pre-FMT patient selection by phenotype. Moreover, the dysbiotic enterotype Bacteroides-2 seems to be decreased after FMT. However, further analyses are mandatory to identify specific predictors of response and the origin of the microbiota shift.

Patients with malignant hilar biliary strictures can suffer from obstructive jaundice. Controversy remains on the optimal approach to obtain preoperative or palliative biliary drainage in these patients. A systematic review and meta-analysis was conducted to compare the two modalities most commonly used in this scenario: endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC).MEDLINE via PubMed was searched for relevant articles published from 2005 to April 2019. Following outcome measures were used to compare ERCP and PTC: therapeutic success rate, cholangitis, pancreatitis, bleeding, tube dislocation, reintervention rate, mortality such as 30d mortality and in-hospital death, median survival time, drainage patency, duration until decompression and hospital stay. Risk of bias assessment for the retrospective studies was conducted by NOS. RoB 2 was used for RCT. A meta-analysis was performed by using Review Manager 5.3. The certainty of evidence was appraised using GRADE.Eleven articles of which one RCT and ten retrospective cohort studies fulfilled the inclusion criteria for data-analysis (1417 patients; 784 ERCP, 633 PTC). The combined odds ratio (OR) for therapeutic succes was 3.5 times higher in the PTC group (95% CI 2.05-5.97; high certainty). In terms of cholangitis, ERCP carried a 1.7-fold risk as compared to PTC (95% CI 0.92-3.08; moderate certainty). Patients who underwent ERCP were 11.50 times more likely to undergo a reintervention (95% CI 3.51-37.70; moderate certainty). ERCP was comparable to PTC in terms of pancreatitis (low certainty), bleeding (high certainty) and tube dislocation rate (moderate certainty). Mortality tended to be numerically higher in the PTC group but low patient numbers, selection bias and study heterogeneity did not allow uniform comparative analysis.In patients with malignant hilar biliary strictures, PTC is associated with a better therapeutic success rate, less cholangitis and lower reintervention rate as compared to ERCP.

Background and Aims Since there are no accurate methods for fibrosis identification or quantification, the purpose is to investigate the utility of magnetization transfer (MT) MRI and texture analysis (TA) of T2-weighted MR images for intestinal fibrosis assessment in a mouse model of gut fibrosis. Methods Chronic colitis was obtained in 16 C57BL/6 mice by cyclic administration of dextran sodium sulphate (DSS) inducing early phase inflammation and progressive bowel fibrosis. Mice underwent 7.0 T MR imaging at various timepoints. MT ratio (MTR) in the bowel wall was calculated. Textural features (skewness, kurtosis, entropy) were extracted by a filtration histogram technique. Resected colonic tissue was scored for inflammation and fibrosis. Performance of MT-MRI and TA was validated in a consecutive experiment in mice using antifibrotic therapy. Finally, a retrospective study was conducted in five CD patients who underwent bowel surgery. Results MTR and texture entropy both correlated with histopathological fibrosis (r = .85 and .81, respectively). Entropy was superior to MTR for monitoring bowel fibrosis in presence of coexisting inflammation (linear regression R² = .93 versus R2 = .01). Furthermore, texture entropy was able to assess antifibrotic therapy response (placebo mice versus treated mice at endpoint scan; Δ mean = 0.128, p < .0001). An increase in entropy was indicative of fibrosis accumulation in human CD strictures (1.29 in inflammation; 1.40 and 1.48 in mixed strictures; 1.73 and 1.90 in fibrosis). Conclusion Texture analysis of T2-weighted MR images outperforms magnetization transfer imaging in detecting the fibrotic component in mixed inflammatory-fibrotic bowel tissue and can be used for monitoring antifibrotic treatment response.

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

Background and Aims Buried bumper syndrome (BBS) is a rare adverse event of percutaneous endoscopic gastrostomy (PEG) placement in which the internal bumper migrates through the stomal tract to become embedded within the gastric wall. Excessive tension between the internal and external bumpers, causing ischemic necrosis of the gastric wall, is believed to be the main etiologic factor. Several techniques for endoscopic management of BBS have been described using off-label devices. The Flamingo set is a novel, sphincterotome-like device specifically designed for BBS management. We aimed to evaluate the effectiveness of the Flamingo device in a large, homogeneous cohort of patients with BBS. Methods A guidewire was inserted through the external access of the PEG tube into the gastric lumen. The Flamingo device was then introduced into the stomach over the guidewire. This dedicated tool can be flexed by 180 degrees, exposing a sphincterotome-like cutting wire, which is used to incise the overgrown tissue until the PEG bumper is exposed. A retrospective, international, multicenter cohort study was conducted on 54 patients between December 2016 and February 2019. Results The buried bumper was successfully removed in 53 of 55 procedures (96.4%). The median time for the endoscopic removal of the buried bumper was 22 minutes (range, 5-60). Periprocedural endoscopic adverse events occurred in 7 procedures (12.7%) and were successfully managed endoscopically. A median follow-up of 150 days (range, 33-593) was performed in 29 patients (52.7%), during which no significant adverse events occurred. Conclusions Through our experience, we found this dedicated novel device to be safe, quick, and effective for minimally invasive, endoscopic management of BBS.

Endoscopic ultrasound-guided rendezvous (EUS-RV) is a recently added alternative salvage technique to percutaneous transhepatic cholangiography rendezvous (PTC-RV) for achieving biliary cannulation in failed ERCP. Comparative data on these two techniques are lacking. The aim of this study is to evaluate the efficacy and safety of EUS-RV versus PTC-RV in a tertiary referral center.A case-control study was conducted in the tertiary referral center, Ghent University Hospital. All consecutive patients that underwent a rendezvous procedure between February 2014 and March 2022 for failed biliary cannulation were included. Patients that underwent PTC-RV (between February 2014 and February 2018) were compared to those who underwent EUS-RV (between March 2018 and March 2022). A sub-analysis was performed for malignant biliary strictures (MBO), benign biliary strictures (BBO) and common bile duct stones (CBDS). The primary endpoints of interest were technical success rate and complication rate. These outcome variables were compared among techniques using Fisher's exact test. Statistical analyses were performed using STATA version 15.A total of 59 consecutive procedures in 57 patients were included for analysis; 20/59 (33.9%) were PTC-RV; the remaining 39/59 (66.1%) procedures were EUS-RV. Two patients in the PTC-RV group underwent two procedures. Of the PTC-RV procedures, 18/20 (90.0%) were technically successful, as compared to 28/39 EUS-RV procedures (71.8%) (P = 0.184; Fig. 1). Adverse events were reported in 7/20 PTC-RV procedures (35.0%) and in 13/39 EUS-RV procedures (33.3%) (P = 1.000). In 5/20 PTC-RV procedures (25.0%) and 4/39 EUS-RV procedures (10.3%), the adverse event was considered major (defined as AGREE classification of 3 or more; P = 0.249).EUS-RV has an acceptable success rate and is not associated with an increased risk of adverse events as compared to PTC-RV.

Objective To compare the outcomes of different treatments for spontaneous intra-abdominal abscesses (IAA) in active Crohn's disease (CD). Methods A retrospective analysis of patients with CD between January 2007 and December 2018 was performed in two Belgian inflammatory bowel disease centers. Successful conservative management was defined as complete resolution of abscesses without the need for bowel resection. The primary outcome was suboptimal evolution, defined as a composite outcome of recurrence of abscess, postoperative complications or the need for a non-elective resection. Results Forty CD patients presenting with 43 independent episodes of spontaneous IAA development were included. One underwent immediate bowel resection. In all other 42 cases a conservative approach was taken, which led to a complete abscess resolution rate of 28.6% (12/42). The remaining abscesses required bowel resection. Anti-tumor necrosis factor (TNF) agent use was associated with successful conservative management (odds ratio [OR] 13.36, 95% confidence interval [CI] 11.19-15.52, P = 0.006), while the opposite trend was found for corticosteroids (OR 0.14, 95% CI 0.02-1.26, P = 0.055). There was a trend towards suboptimal evolution in case of previous bowel resection (OR 4.77, 95% CI 0.77-29.66, P = 0.094) or in patients aged above 50 years (OR 5.17, 95% CI 0.86-30.91, P = 0.072). Conclusions Bowel resection appears to be inevitable in most CD patients presenting with IAA. An attempt at conservative treatment may be particularly successful with anti-TNF agents in younger patients who have not undergone previous bowel resection. Large-scale prospective studies are needed to confirm these findings.

Tom Holvoet,1,2 Triana Lobaton,2 Pieter Hindryckx2 1Department of Gastroenterology, AZ Nikolaas, Sint-Niklaas, Belgium; 2Department of Gastroenterology, University Hospital Ghent, Ghent, BelgiumCorrespondence: Tom Holvoet Email tom.holvoet@aznikolaas.beAbstract: Acute severe colitis is a severe complication of ulcerative colitis, affecting approximately 20% of patients. For physicians, it remains a challenging condition to treat. Current treatment algorithms have diminished the mortality associated with acute severe ulcerative colitis (ASUC), but colectomy rates remain high (approximately 30%) despite advances in therapy. Colectomy in ASUC is particularly associated with important postoperative complications and morbidity. In this review, reasons for the inability to improve care and avoid evolution to colectomy for ASUC are explored and solutions that might lead to a better management of the disease are investigated.Keywords: acute severe colitis, ulcerative colitis, inflammatory bowel disease

Acute severe colitis is a severe complication of ulcerative colitis, affecting approximately 20% of patients. For physicians, it remains a challenging condition to treat. Current treatment algorithms have diminished the mortality associated with acute severe ulcerative colitis (ASUC), but colectomy rates remain high (approximately 30%) despite advances in therapy. Colectomy in ASUC is particularly associated with important postoperative complications and morbidity. In this review, reasons for the inability to improve care and avoid evolution to colectomy for ASUC are explored and solutions that might lead to a better management of the disease are investigated.

A common and untreatable complication of Crohn’s disease (CD) is the development of intestinal fibrosis for which no adequate noninvasive tools for fibrosis progression monitoring exist. For this purpose, we assessed the performance of magnetization transfer (MT) magnetic resonance imaging (MRI) and texture analysis (TA) on T2-weighted images by correlating them with histology in a fibrosis mouse model. MT-MRI and TA performance was validated during antifibrotic therapy in mice and on MR enterography images of CD patients undergoing bowel surgery. The MT-MRI and TA entropy correlated with histological fibrosis (r = .85 and .81, respectively). However, TA entropy was superior to MT-MRI for quantifying fibrosis progression during coexisting inflammation (linear regression R² = .93). TA entropy could efficiently monitor anti-fibrotic therapy efficacy and correlated with the grade of intestinal fibrosis in CD. In conclusion, MT-MRI and TA entropy are highly promising surrogate markers of intestinal fibrosis, but TA entropy performed better in the presence of concomitant inflammation.

Background: A treat-to-target strategy, in which strictly defined treatment targets facilitate decision making in clinical practice, is advocated as an optimised management approach for some chronic disorders. The aim of the STARDUST trial was to assess whether a treat-to-target strategy with early endoscopy, regular biomarker and clinical symptom monitoring, and dose intensification for persistent inflammatory activity, was more successful in achieving endoscopic improvement at week 48 than a clinically driven maintenance strategy in patients with moderate-to-severe active Crohn's disease receiving ustekinumab. Methods: This open-label, multicentre, randomised phase 3b trial included adults with active, moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220–450 and Simple Endoscopic Score in Crohn's Disease [SES-CD] ≥3) for whom conventional therapy or one biologic therapy, or both, had failed. Patients received intravenous ustekinumab approximating 6 mg/kg at baseline and subcutaneous ustekinumab 90 mg at week 8. At week 16, patients with a CDAI improvement of 70 or more points from baseline were randomly assigned (1:1) to receive standard-of-care or treat-to-target maintenance treatment through week 48. Randomisation was balanced by using randomly permuted blocks and was stratified by biologic history status and baseline SES-CD score. All patients who signed informed consent, who were not screening failures, and who received at least one dose of study treatment were included in week 16 analyses. All patients included in week 16 analyses and randomly assigned to one of the maintenance treatment regimens were included in the week 48 efficacy and safety analyses (ie, on an intention-to-treat basis). Patients assigned to the treat-to-target arm received ustekinumab every 12 weeks or every 8 weeks based on SES-CD improvement from baseline and could escalate to every 4 weeks through week 48 if prespecified targets were missed. Patients assigned to the standard-of-care arm received ustekinumab every 12 weeks or every 8 weeks; those receiving treatment every 12 weeks could escalate per European labelling. The primary efficacy endpoint was endoscopic response at week 48 (SES-CD score ≥50% decrease from baseline), analysed by non-responder imputation. This trial is registered at ClinicalTrials.gov, NCT03107793, and is active but not recruiting. Findings: 498 patients received standard induction treatment, of whom 440 were randomly assigned to the treat-to-target group (n=219) or the standard-of-care group (n=221). At week 48, there was no significant difference in endoscopic response (83 [38%] of 219 patients vs 66 [30%] of 221 patients; p=0·087), endoscopic remission (25 [11%] vs 32 [15%]; p=0·334), mucosal healing (31 [14%] vs 37 [17%]; p=0·449), and clinical remission (135 [62%] vs 154 [70%]; p=0·072) between the two groups; clinical response was significantly lower in the treat-to-target group than in the standard-of-care group (149 [68%] vs 172 [78%]; p=0·020). Other endoscopic, clinical, and biomarker outcomes were generally not significantly different between groups. The most commonly reported treatment-emergent adverse events were nasopharyngitis (29 [13%] of 219 patients in the treat-to-target group vs 29 [13%] of 221 patients in the standard-of-care group), abdominal pain (23 [11%] vs 19 [9%]), arthralgia (24 [11%] vs 19 [9%]), and headache (24 [11%] vs 21 [10%]). Interpretation: Timely escalation of ustekinumab therapy for patients with Crohn's disease, based on early endoscopic response, clinical symptoms, and biomarkers, did not result in significantly better endoscopic outcomes at week 48 than symptom-driven decisions alone. Future studies need to confirm if some subgroups of patient might benefit from a treat-to-target strategy with ustekinumab. Funding: Janssen-Cilag.

Altres ajuts: The study is partially made possible by support of the 'Programme Hospitalier de Recherche Clinique and 'La Foundation de la Recherche Médicale (grant number DEQ20170336759, France). M.T. was supported by the Polish Mothers Memorial Hospital Research Institute (internal grant number 2016/IV/54-GW. LvdZ is supported by a Kolff grant from the Dutch Kidney Foundation (13OKJ36) and a ZonMW-VENI grant from the Netherlands Organisation for Scientific Research (91618036). This project has been supported by ERN ERKNet and ERN eUROGEN, which are partly co-funded by the European Union within the framework of the Third Health Programme 'ERN-2016-Framework Partnership Agreement 2017-2021'. Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted in utero with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature. Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming α = 0.05, 1-β = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature. In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment. Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV.

Lumen-apposing stents (LAMS) are approved to treat peripancreatic collections and for gallbladder and bile duct drainage. Over the last years, LAMS have also been used for off-label indications including gastrojejunostomy, gastro-gastrostomy and drainage of postsurgical collections. We aimed to analyze indications, technical/clinical success rates and complications of all LAMS placed over the last 2 years. Data from 61 consecutive LAMS (Hot Axios, Boston Scientific) in 57 patients were analyzed. Technical success was defined as successful deployment of the LAMS in the desired position. Clinical success was defined as follows: for pancreatic collections: resolution without the need for non-endoscopic interventions; for choledochoduodenostomy: ≥ 50% drop in baseline serum bilirubin within 2 weeks AND patient can receive chemotherapy if indicated; for gastrojejunostomy: resolution of gastric outlet obstruction and successful re-initiation of oral intake; for gastro-gastrostomy: successful endoscopic access to the excluded stomach; for gallbladder or postsurgical collection drainage: resolution of sepsis. Indications were drainage of peripancreatic collections in 24 cases (39.3%), choledochoduodenostomy in 13 (21.3%), gastrojejunostomy in 6 (9.8%), gastro-gastrostomy in 13 (21.3%), gallbladder drainage in 1 (1.6%) and postsurgical collection drainage in 4 (6.6%). Overall technical and clinical success rates were high (57/61; 93.4% and 54/61; 88.5%, respectively). Clinical success rate for non-approved indications was 95.6% (22/23 cases). Complications occurred in 13 patients (21.3%, 4 serious). LAMS are increasingly used in interventional endoscopy. In our cohort, more than one third of LAMS are placed for off-label indications, with a high success rate and acceptable complication rate.

Introduction: Differentiation between inflammatory and fibrotic bowel strictures remains a holy grail in Crohn’s disease (CD) management, primarily because of the therapeutic implications. Stricture characterisation in CD patients is further hampered by the co-occurrence of inflammation and fibrosis in various degrees. Currently, there are no validated imaging tools to differentiate fibrotic from inflammatory or mixed strictures, but several new techniques, such as magnetization transfer magnetic resonance imaging (MT-MRI) and magnetic resonance texture analysis (MR-TA), seem promising. Aims & Methods: To investigate these possible new imaging techniques for stricture management, we assessed the performance of magnetization transfer (MT) magnetic resonance imaging (MRI) and texture analysis (TA) of T2-weighted images. Temporal MT and T2-weighted magnetic resonance (MR) images were correlated with histology as the gold standard in a model of gut fibrosis resulting from chronic colitis induced in C57BL/6J mice by cyclic administration of dextran sulfate sodium. The performance of MT-MRI and TA was validated in the same model with an antifibrotic therapy administrated to one group of mice. To check the translatability of the results, MR enterography images of patients with CD who underwent bowel surgery were retrospectively analyzed and matched with histopathology. Results: The MT-MRI and TA entropy correlated with fibrosis on the histopathology (r=.85 and .81, respectively). However, TA entropy was superior to the MT-MRI for quantifying the progression of fibrosis (linear regressionR²=.93) because the MT-MRI signal was severely biased due to coexisting inflammation. The effect of the successful antifibrotic therapy was efficiently captured using TA entropy. Finally, TA entropy was a valid parameter to detect and grade intestinal fibrosis in axial T2-weighted MR images of patients with CD. Conclusion: Based on the applied model of relapsing-remitting colitis, which allowed the study of coexisting inflammation and progressive fibrosis, we demonstrated that although MT-MRI and TA entropy are highly promising surrogate markers of intestinal fibrosis, TA entropy performed better in monitoring and quantifying fibrotic lesions in the presence of concomitant inflammation.

Background Prediction of endoscopic postoperative recurrence (POR) and prophylactic treatment based on clinical risk profile have thus far been inconclusive. This study aimed to examine the association between clinical risk profile and the development of endoscopic POR in a Crohn’s disease population without postoperative treatment and to identify individual risk factors of endoscopic POR. Methods Medical records of 142 patients with Crohn’s disease during follow-up after ileocecal or ileocolonic resection without prophylactic treatment at 3 referral centers were reviewed. Endoscopic POR was defined as a modified Rutgeerts score ≥i2b. Clinical risk profiles were distilled from current guidelines. Both uni- and multivariate logistic regression analysis were used to assess the relationship between risk profiles and endoscopic POR. Results Endoscopic POR was observed in 68 out of 142 (47.9%) patients. Active smoking postsurgery (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.24-7.34; P = 0.02), a Montreal classification of A3 (OR, 3.05; 95% CI, 1.07-8.69; P = 0.04), and previous bowel resections (OR, 2.58; 95% CI, 1.07-6.22; P = 0.03) were significantly associated with endoscopic POR. No significant association was observed between endoscopic POR and any guideline defined as a high-/low-risk profile. However, patients with a combination of any 3 or more European Crohns & Colitis Organisation– (OR, 4.87; 95% CI, 1.30-18.29; P = 0.02) or British Society of Gastroenterology–defined (OR 3.16; 95% CI, 1.05-9.49; P = 0.04) risk factors showed increased odds of developing endoscopic POR. Conclusions Our results suggest that patients with a combination of any 3 or more European Crohns & Colitis Organisation– or British Society of Gastroenterology–defined risk factors would probably benefit from immediate prophylactic treatment.

Background and aims: Lumen-apposing metal stents (LAMSs) are increasingly used both for on- and off-label indications. We continuously adapt our step-by-step protocol to optimize the safe deployment of LAMSs for the different indications. The aim of this study was to evaluate the impact of this approach over time. Methods: We conducted a single-center study on consecutive patients who underwent LAMS placement for on- and off-label indications between June 2020 and June 2022. Endpoints included technical success, clinical success and adverse event rates. We compared the results with our previously published early experience with LAMSs (N = 61), between March 2018 and May 2020. Results: This cohort consisted of 168 LAMSs in 153 patients. Almost half of them (47.6%) were placed for off-label indications (gastro-enterostomy, temporary access to the excluded stomach in patients with previous gastric bypass, drainage of postsurgical collections, stenting of short refractory gastrointestinal strictures). While the technical and clinical success rates were similar to those in our previously published cohort (97% and 93.5% versus 93.4% and 88.5%, respectively), the adverse event rate dropped from 21.3% to 8.9%. Conclusions: Our results demonstrate the impact of a learning curve in LAMS placement, with a clinically relevant drop in LAMS-related adverse events over time.

A 59 year-old man without past medical history was referred with biochemical features of cholestasis (aspartate aminotransferase (AST) 117 U/L, alanine aminotransferase (ALT) 83 U/L, gamma-glutamyl transferase (GGT) 1307 U/L, alkaline phosphatase (AP) 1803 U/L, total bilirubin 0,7 mg/dL), a strongly positive antimitochondrial M2 antibody (AMA-M2) titer (88 U), weight loss and abdominal pain since several months. He did not take any medications, nor there was a history of alcohol abuse or sexual risk behavior. Upon presentation, clinical examination showed a rather cachectic patient (body mass index 19 kg/m²), without further abnormalities. As primary biliary cholangitis (PBC) was suspected, treatment with ursodeoxycholic acid had been initiated but did not improve the cholestasis nor the pain. Additional investigations didn’t reveal any other irregularities, except for a mildly dilated aortic sinus root of 42 mm. The histopathological findings of a liver biopsy are shown below (Figure 1). This showed granulomas with cholangitis and increased presence of neutrophils, which raised suspicion for an infectious cause.

Simple Summary Hypoxia-induced signalling represents an important contributor to inflammatory bowel disease (IBD) pathophysiology. However, available data solely focus on colonic inflammation while the primary disease location in Crohn's disease patients is the terminal ileum. Therefore, we explored the effects of environmental hypoxia and immune cell-specific deletion of oxygen sensor prolyl hydroxylase (PHD) 1 in a Crohn's like ileitis mouse model. Five-week-old TNF (increment ARE/+) mice and wildtype (WT) littermates were housed in normoxia (21% O-2) or hypoxia (8% O-2) for 10 weeks. Although environmental hypoxia increased both systemic as ileal markers of hypoxia, the body weight evolution in both WT and TNF (increment ARE/+) mice was not affected. Interestingly, hypoxia did increase circulatory monocytes, ileal mononuclear phagocytes and proinflammatory cytokine expression in WT mice. However, no histological or inflammatory gene expression differences in the ileum could be identified between TNF (increment ARE/+) mice housed in hypoxia versus normoxia nor between TNF (increment ARE/+) and WT mice with additional loss of immune cell-specific Phd1 expression. This is the first study showing that long-term environmental hypoxia or haematopoietic Phd1-deletion does not impact experimental ileitis. Therefore, it strongly questions whether targeting hypoxia-induced signalling via currently available PHD inhibitors would exert an immune suppressive effect in IBD patients with ileal inflammation. Environmental hypoxia and hypoxia-induced signalling in the gut influence inflammatory bowel disease pathogenesis, however data is limited to colitis. Hence, we investigated the effect of environmental hypoxia and immune cell-specific deletion of oxygen sensor prolyl hydroxylase (PHD) 1 in a Crohn's like ileitis mouse model. Therefore, 5-week-old C57/BL6 TNF (increment ARE/+) mice and wildtype (WT) littermates were housed in normoxia (21% O-2) or hypoxia (8% O-2) for 10 weeks. Systemic inflammation was assessed by haematology. Distal ileal hypoxia was evaluated by pimonidazole staining. The ileitis degree was scored on histology, characterized via qPCR and validated in haematopoietic Phd1-deficient TNF (increment ARE/+) mice. Our results demonstrated that hypoxia did not impact body weight evolution in WT and TNF (increment ARE/+) mice. Hypoxia increased red blood cell count, haemoglobin, haematocrit and increased pimonidazole intensity in the ileum. Interestingly, hypoxia evoked an increase in circulatory monocytes, ileal mononuclear phagocytes and proinflammatory cytokine expression in WT mice. Despite these alterations, no histological or ileal gene expression differences could be identified between TNF (increment ARE/+) mice housed in hypoxia versus normoxia nor between haematopoietic Phd1-deficient TNF (increment ARE/+) and their WT counterparts. Therefore, we demonstrated for the first time that long-term environmental hypoxia or haematopoietic Phd1-deletion does not impact experimental ileitis development.

Introduction Autosomal dominant polycystic kidney disease (ADPKD) causes kidney failure typically in adulthood, but the disease starts in utero. Copeptin, epidermal growth factor (EGF), and monocyte chemoattractant protein-1 (MCP-1) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. Methods In a cross-sectional study, plasma copeptin, urinary EGF, and urinary MCP-1 were evaluated in a pediatric ADPKD cohort and compared with age-, sex-, and body mass index (BMI)-matched healthy controls. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells, and fetal kidney tissue. Results Fifty-three genotyped ADPKD patients and 53 controls were included. The mean (SD) age was 10.4 (5.9) versus 10.5 (6.1) years (P = 0.543), and the estimated glomerular filtration rate (eGFR) was 122.7 (39.8) versus 114.5 (23.1) ml/min per 1.73 m2 (P = 0.177) in patients versus controls, respectively. Plasma copeptin and EGF secretion were comparable between groups. The median (interquartile range) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 [213.8]) compared with controls (154.7 [98.0], P = 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. Conclusion An increase in tubular MCP-1 secretion is an early event in ADPKD. MCP-1 is an early disease severity marker and a potential treatment target., Graphical abstract

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and Ulcerative Colitis (UC), are immune mediated conditions associated with progressive damage of the inflamed gut tissue, and have a considerable impact on the patient's quality of life. The pathogenesis remains uncertain, but it is clear that complex mechanisms associated with host and luminal factors are involved, generating an unbalance between pro- and anti-inflammatory signaling. It is well established that the purpose of an adequate and complete control of the intestinal inflammation measured not only by clinical symptoms, but also with more objective data such as fecal biomarkers (calprotectin) and endoscopy. The treat to target approach possibly correlates with minor risk for complications associated with IBD, specially surgery and cancer. The most studied inflammatory pathway in IBD, is described to be dependent of the pro-inflammatory cytokine tumor necrosis factor-alfa (TNF-α), and compose the first line studies for development of biological drugs, in this case, targeting specifically the action of TNF-α. Even though, the use of anti-TNFs drugs are associated with improvement of the inflammation in some patients, a great portion do not respond at first or lose response over time. These findings made clear about the possibility of other mechanisms involved in perpetuating the chronic inflammatory state. Many years of intensive research have led to the identification of different inflammatory pathways that form the basis of the intensive drug development that we are experiencing today. These novel drugs include agents that target leukocyte trafficking, Interleukin (IL) 23, Janus kinases (JAK), Sphingosine 1 phosphate (S1P) and Smad7, an inhibitor of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1). In this manuscript, we aim to review the most promising late-stage drug candidates for the treatment of IBD.

Background Four randomized controlled trials studying faecal microbiota transplantation (FMT) in active UC patients showed variable success rates. The efficacy of FMT appears to be influenced by various factors including donor- and procedure-specific characteristics. We hypothesized that the outcome of FMT in patients with active UC could be improved by donor preselection on microbiota level, by using a strict anaerobic approach, and by repeated FMT administration. Methods The RESTORE-UC trial (NCT03110289) was a national, multi-centric double-blind, sham-controlled randomized trial. Active UC patients (Total Mayo score 4–10 with endoscopic sub-score ≥2) were randomly allocated (1:1) to receive 4 anaerobic-prepared superdonor (S) FMT or autologous (A) FMT (Figure 1) by permutated blocks (2 and 4) and stratified for weight, concomitant steroid use, and therapy refractoriness. S-FMTs were selected after a rigorous screening excluding samples with Bacteroides2 enterotype, high abundances of Fusobacterium, Escherichia coli and Veillonella and the lowest microbial loads (Q1). A futility analysis after 66% (n=72) of inclusions was planned per protocol including a modified intention-to-treat (mITT) analysis using non-responder imputation (NRI) for patients receiving at least one FMT. The primary endpoint was steroid-free clinical remission (Total Mayo ≤ 2, with no sub-score >1) at week 8. Results Between March 2017–2021, 72 patients signed the ICF and 66 were randomly allocated to S-FMT (n=30) or A-FMT (n=36) and received at least one FMT. In the S-FMT and the A-FMT resp. 4 and 5 patients terminated the trial early due to worsening of colitis (4 in both arms) or FMT enema intolerance (1 A-FMT). They were included in the mITT analysis using NRI (Fig. 2). Both study arms were matched for baseline characteristics (Table 1), yet a trend (p= 0.066) towards higher concomitant biological use in the S-FMT arm was observed. After 66% of intended inclusions, the primary endpoint was reached in 3/30 (10%) S-FMT and 5/31 (13.9%) patients randomized to A-FMT (p=0.72). As the predefined minimum difference between both treatment arms was not attained, the study was stopped due to futility. The full set of endpoints are summarized in Table 2.Of note, no patients on concomitant biologicals reached the primary endpoint. There were 2 serious adverse events in the A-FMT arm: dysuria requiring hospitalization and worsening of UC requiring colectomy. Conclusion In this double-blind sham-controlled trial comparing repeated administrations of anaerobic-prepared S-FMT with A-FMT in patients with active UC, no significant difference in steroid-free remission rates at week 8 were observed. The FMT procedure was generally well tolerated, and no new safety signals were observed.

Background Buried bumper syndrome (BBS) is a complication of percutaneous endoscopic gastrostomy (PEG) in which the internal bumper is overgrown by the gastric mucosa. Apart from loss of patency of the PEG tube, the buried bumper may evoke symptoms such as abdominal pain or peritubular leakage. While the management of an incompletely buried bumper is fairly straightforward, this is not the case for a completely buried bumper. Different approaches to remove completely buried bumpers have been described, including endoscopic knife- or papillotome-based techniques. However, these devices are used off-label and the procedures can be laborious. Methods The Flamingo device has recently been introduced as the first tool specifically designed to remove a completely buried bumper. Results We describe the technique and our first experience in five patients with a completely (n = 4) or almost completely (n = 1) buried bumper. Fast and save removal of the buried bumper was obtained in all patients. Conclusion We believe that this device has the potential to become the standard first-line tool for the management of completely buried bumpers.

Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either the PKD1 or PKD2 gene. While kidney failure typically occurs in adulthood, the disease starts in utero. The best change of preserving renal function long term might be the use of agents with few side effects as early as possible. For this approach, both better early prognostic stratification and novel treatment options are needed. The pediatric phase of ADPKD, while kidney function is still normal and before significant tissue destruction has occurred could be the best stage both to identify and study prognostic biomarkers as well as to identify novel targets for early treatment. Copeptin (a surrogate for vasopressin), epidermal growth factor (EGF) ( a measure for functional tubular mass) and monocyte chemoattractant protein-1 (MCP-1) ( a chemoattractant for macrophages) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. Method A monocentric cross-sectional study in a tertiary referral center was performed. All consenting genotyped ADPKD patients attending the outpatient pediatric ADPKD clinic of the university hospital of Leuven and age, sex and BMI matched healthy controls were included between June and October 2017. Plasma copeptin, urinary EGF and urinary MCP-1 were evaluated. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells and fetal kidney tissue. Results 53 genotyped ADPKD patients and 53 controls were included. Mean (SD) age was 10.4 (5.9) vs 10.5 (6.1) years (P=0.543), and eGFR 122.7 (39.8) vs 114.5 (23.1) ml/min/1.73 m2 (P= 0.177) in patients vs controls respectively. Outcome parameters in table. Plasma copeptin and EGF secretion were comparable between both groups. Median (IQR) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 (213.8)) compared to controls (154.7 (98.0)) (P= 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion triggered by fetal bovine serum. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. Conclusion An increase in tubular MCP-1 secretion is an early event in ADPKD, long before kidney function decline and in children with few kidney cysts. MCP-1 is a promising early disease severity marker and a potential treatment target.

Fatigue is a highly prevalent but relatively ignored problem in IBD patients. It is one of the most burdensome symptoms to the patient with an important impact on the quality of life. Therefore, fatigue is a highly relevant patient-reported outcome that should be included not only in disease activity measurement but also in the endpoints of clinical trials in IBD. However, most of the currently available scoring systems to quantify fatigue are not specifically designed for patients with IBD and none of them has undergone a complete validation process for IBD-related fatigue. Fatigue is more prevalent in patients with active disease and may improve or disappear when remission is reached. Far more complex is the persistence or onset of fatigue in quiescent IBD which presents in up to 40% of the patients. In this subgroup of patients, fatigue can be related to smoldering systemic inflammation, a poor sleep quality, anemia, nutritional deficiencies, or comorbidities. In most cases, however, no direct cause can be identified. The lack of knowledge on the mechanisms that drive fatigue in IBD hamper the development of specific drugs to treat the condition and only psychological support can be offered to the patient. Rodent models are indispensable to increase our understanding of the molecular pathways that lead to fatigue in chronic intestinal inflammation, and to develop novel therapies.

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-β4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-β4 abundance was confirmed with ELISA. Knockout of thymosin-β4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin β4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable. ispartof: KIDNEY INTERNATIONAL vol:99 issue:3 pages:737-749 ispartof: location:United States status: published

En Belgique francophone, un décret sur la formation des enseignants précise un ensemble d’objectifs et d’attitudes que doit viser tout dispositif didactique conçu pour les préparer à leur futur métier. Cet ensemble est largement dicté par le modèle du « praticien réflexif » capable de « porter un regard réflexif sur sa pratique » pour adapter son enseignement aux circonstances par un « va-et-vient » permanent entre théorie et pratique. Deux analyses didactiques au niveau de l’enseignement secondaire, concernant les sciences biologiques et les mathématiques, nous permettent de pointer des connaissances liées à l’épistémologie des savoirs concernés et dont l’absence de maitrise, chez les élèves-professeurs en formation initiale, les empêche de faire preuve de réflexivité pour choisir une méthode d’enseignement et surtout l’alimenter de manière appropriée. À travers la réflexivité, nous questionnons ici le concept de compétence transversale et sa « sensibilité » aux connaissances plus proprement disciplinaires, en espérant apporter des éléments dans le débat déjà engagé à ce propos, que ce soit au sujet d’apprentissages disciplinaires ou dans la formation professionnelle. In French-speaking Belgium, a decree on the training of teachers specifies a set of objectives and of attitudes that must be aimed by any didactic device designed to prepare them for their future job. This set is largely dictated by the model of the "reflective practitioner" able to "have reflective regards to his practice" in order to adapt the way he teaches to the classroom circumstances by a "back and forth" between theory and practice. Two didactic analyzes at the upper secondary level, concerning the biological sciences and the mathematics, allow us to point out knowledge related to the epistemology of the concerned knowledge, whose lack of control, by the students-teachers in initial formation, prevents them to be reflexive in choosing a teaching method and especially feeding it appropriately. Looking at reflexivity, we examine here the concept of cross-curricular competence and its "sensitivity" to more strictly disciplinary knowledge, hoping to add elements into the current debate on this subject whether it is about disciplinary learning or teachers training.

Background and Aims The correlation between genotype and phenotype is well described in ADPKD adults. PKD2 is milder than PKD1 disease, with end stage kidney disease (ESKD) occurring on average 20 years later, and patients with PKD1 truncating mutations having a more severe outcome than PKD1 non-truncating mutations. Still, large differences in outcome occur even within families carrying the same gene variation. Only a few cases series reported the genetic profile of severely affected ADPKD children and suggest an additional effect of hypomorphic genes. We therefore aim to analyse the geno-phenotype profile in a well characterized pediatric ADPKD cohort. Method Clinical, familial, biological and imaging data were collected longitudinally in children diagnosed with ADPKD. Genotypic analysis was done using a custom Agilent SureSelect gene panel containing 136 ciliopathy-associated genes, including PKD1 and PKD2. Mutations and/or variants identified were individually evaluated for pathogenicity. Results 57 ADPKD children from 44 families were diagnosed at a mean (± SD) age of 4.1 (±4.8) years. ADPKD diagnosis was made in 32 children (56%) because of asymptomatic screening as requested by the family; 7 (12%) due to presenting symptoms (6 due to urinary tract infection and 1 due to post-traumatic macroscopic hematuria); 9 (16%) due to a coincidental finding of renal cysts on US performed for another reason and in 9 cases (16%) a prenatal diagnosis was performed. Twenty-nine children (51%) met the definition of very-early onset (VEO) disease. We identified pathogenic mutations in 100% of our patients, in which the prevalence of PKD1 truncating, PKD1 non-truncating, PKD2 and GANAB mutations was 75%, 19%, 4%, and 2%, respectively. Four cases (7%) were due to a de novo mutation. Interestingly, in 29 patients (51%) the germline mutation was the only identified mutation. However, in the rest of the subjects additional variants were identified in other ciliopathy-associated genes. In 12 cases (21%) the additional identified variants found in either the PKD, PMM2, HNF1B, DNAJC1, CEP290, NEK1, MKKS, NPHP4 or PKHD1 genes were scored to have a potential phenotypic effect, which will be evaluated by continued follow-up of this cohort. Conclusion We report the first large cohort of genotyped ADPKD children, including an extensive panel of ciliopathy genes next to the PKD genes. Interestingly, we found a high prevalence of additional and potentially modifying variants in this young population.

INTRODUCTION Que maitrisent les élèves de la Fédération Wallonie-Bruxelles (FW-B) après quatre années d’apprentissage de la lecture ? Selon les résultats de l’étude internationale PIRLS 2011, leurs performances se révèlent très faibles : parmi les pays comparables , la FW-B se positionne en queue de peloton. Comment tenter d’améliorer les performances de ces élèves ? Parmi les divers facteurs en jeu, il est plus que vraisemblable que leurs résultats et certaines pratiques de classe soient lié...

Background and aims: With the first wave of the COVID-19 pandemic declining, activities in the gastrointestinal clinic are being recommenced after a period of stringent measures. Since a second COVID-19 wave is not entirely ruled out health care professionals might remain faced with the need to perform endoscopic procedures in patients with a confirmed positive or unknown COVID-19 status. With this report we aim to provide a practical relevant overview of preparation and protective measures for gastroenterologists based on the currently available guidelines and our local experience and results of a national Belgian survey, to guarantee a fast recall of an adequate infection prevention if COVID-19 reoccurs. Methods: From the 23rd of March 2020 and the 13th of May 2020 we performed a Pubmed, Embase and Medline search, resulting in 37 papers on COVID-19 and endoscopy. Additionally, we combined these data with data acquired from the national BSGIE survey amongst Belgian gastroenterologists. Results: Based on 72 completed surveys in both university and non-university hospitals, the results show (1) a dramatic (, SCOPUS: re.j, info:eu-repo/semantics/published

Despite many publications regarding the role of faecal calprotectin (FC) in inflammatory bowel disease (IBD), clear recommendations for its use in clinical practice are currently lacking in the literature., info:eu-repo/semantics/published

Une des priorites contemporaines en education scientifique est d’envisager une utilisation des acquis de la recherche en didactique des sciences pour la formation, afin que la recherche qui parle des pratiques d’enseignants parle egalement aux enseignants. Les formateurs d’enseignants ont, dans cette perspective, un role de passeurs a jouer. Il serait utile de definir les conditions necessaires pour que les apports des chercheurs deviennent un eclairage usuel des enseignants. Ces conditions sont relatives au mode d’accompagnement et a la posture du formateur, au contenu de la recherche elle-meme, au parcours de l’enseignant, aux attentes prescrites. A partir de l’analyse de pratiques de quelques formateurs d’enseignants (enquete) ainsi que d’exemples vecus d’essais d’integration d’apports de la recherche par des enseignants en formation (recits de pratique), nous tentons ici de reperer des modes d’utilisation de formateurs et de leurs etudiants face aux ecrits issus de la recherche en didactique des sciences ainsi que des freins et moteurs a l’integration d’elements issus de la recherche dans la construction de reponses a des questions d’ordre didactique.

Background Aminosalicylates are the most frequently prescribed drugs for patients with Crohn’s disease (CD), yet evidence to support their efficacy as induction or maintenance therapy is controversial. Aims To quantify aminosalicylate use in CD clinical trials, identify factors associated with use, and estimate direct annual treatment costs of therapy. Methods MEDLINE, Embase, and CENTRAL were searched to April 2017 for placebo-controlled trials in adults with CD treated with corticosteroids, immunosuppressants, or biologics. The proportion of patients co-prescribed aminosalicylates in placebo arms was pooled using a random effects model. Meta-regression was used to identify factors associated with aminosalicylate use. Annual treatment costs were estimated using the 2016 Ontario Drug Benefit Program. Results Forty-two induction and ten maintenance trials were included. The pooled proportion of patients co-prescribed aminosalicylates was 44% [95% CI: 39%-49%] in induction trials and 49% [95% CI: 35%-64%] in maintenance trials. There was substantial to considerable heterogeneity (I2=86.0%, 91.8% for induction and maintenance trials, respectively). In multivariable meta-regression, aminosalicylate use has decreased over time in induction trials (OR 0.50 [95% CI: 0.34, 0.74] per 10-year increment). Whilst a decline has been seen over time, 35% of CD patients were still using aminosalicylates in contemporary trials from the last five years. The estimated annual cost for the lowest price mesalamine formulation is approximately $32 million for the Canadian CD population. Conclusions Over one-third of CD patients entering clinical trials are still co-prescribed aminosalicylates. A definitive trial is needed to inform the conventional practice of using aminosalicylates as CD maintenance therapy.

Background: Adalimumab (ADM) has been shown efficacious in ulcerative colitis (UC). In randomized controlled trials, dose escalation from 40 mg ADM every other week to 40 mg every week was required in 20%-25% of patients within 1 year. Real-life data suggest higher escalation rates. Attempts for dose de-escalation have not been studied yet. We assessed the need for, outcome of, and predictors of dose escalation and de-escalation in a large retrospective cohort of UC patients treated with ADM. Methods: We included 231 consecutive patients from 10 Belgian centers initiating ADM treatment for active UC before September 1, 2015 (follow-up >= 1 year in each patient). We performed detailed chart review to identify variables associated with short-term clinical benefit (based on physician global assessment and absence of rectal bleeding at week 10), success of dose escalation, and dose de-escalation. Backward Cox regression and Wald Logistic regression were used to identify predictive variables. Results: Short-term clinical benefit was achieved in 101 patients (44%) and was less frequent in infliximab failures [37% vs 50%, Odds ratio 0.57 (95% CI 0.34-0.97), P = 0.038]. After a median of 2.8 (1.7-5.1) months, 164 patients (71%) needed ADM discontinuation (n = 35, 15%) or dose escalation (n = 129, 56%). Dose escalation was successful in 77/129 (60%). Dose de-escalation was attempted in 71% (55/77) after a median of 4.3 (2.9-7.2) months and was successful in 80% (43/54). Conclusions: In this cohort, 56% of patients with UC required ADM dose escalation with a 60% success rate. Of note, most patients could be successfully de-escalated later on.

European consensus guidelines and reimbursement policies position biologic drugs for ulcerative colitis (UC) as a third-line treatment, after failure of 5-aminosalicylic acid (5-ASA) and corticosteroids/thiopurines. While 5-ASA have a very favorable safety profile, (prolonged) use of corticosteroids and thiopurines is associated with potentially serious adverse events. The therapeutic landscape of UC is rapidly evolving and selective biologic drugs with improved safety are being introduced. The first biosimilars have entered the market, leading to improved cost-effectiveness of older biologic drugs. In addition, new insights have been gained in the importance of stringent therapeutic targets such as mucosal and histological healing to improve the long-term outcome of UC patients, and in the role of therapeutic drug monitoring and treatment optimization in this regard. In this manuscript we tackle the question of whether we should move directly from 5-ASA treatment to biologic drugs to offer better and/or safer care to UC patients.

SummaryBackground Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. Aims To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. Methods A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. Results Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. Conclusions Although “almost perfect” intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

Vedolizumab is a humanized monoclonal antibody to the α4β7-integrin that blocks lymphocyte trafficking to the gut and is approved for treatment of patients with moderate-to-severe ulcerative colitis (UC). The gut-selective mechanism of action has the potential to improve vedolizumab's safety profile compared to other approved biologic drugs. Areas covered: We review the mechanism of action, efficacy and safety of vedolizumab treatment for UC. The positioning of vedolizumab in management algorithms is also discussed. Expert opinion: The highly selective mechanism of action of vedolizumab restricts immunosuppressive effects to the gut. Vedolizumab is efficacious as induction and maintenance therapy in UC patients who are naive or refractory to tumor necrosis factor antagonists. No clinically important safety signals have been identified. Infusion reactions are reported in