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ObjectivesWe aimed to determine whether changes in acute severe colitis (ASC) management have translated to improved outcomes and to develop a simple model predicting steroid non-response on admission.DesignOutcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015 and 2019 were compared with data from 1992 to 1993. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)). Steroid non-response was defined as receiving medical rescue therapy or surgery. A predictive model developed in the Oxford cohort was validated in Australia and India (Gold Coast University Hospital 2015–2020, n=110; All India Institute of Medical Sciences, New Delhi 2018–2020, n=62).ResultsIn the 2015–2019 Oxford cohort, 15% required colectomy during admission vs 29% in 1992–1993 (p=0.033), while 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-tumour necrosis factor, compared with 27% ciclosporin in 1992–1993 (p=0.0015). Admission C reactive protein (CRP) (false discovery rate, p=0.00066), albumin (0.0066) and UCEIS scores (0.015) predicted steroid non-response. A four-point model was developed involving CRP of ≥100 mg/L (one point), albumin of ≤25 g/L (one point), and UCEIS score of ≥4 (1 point) or ≥7 (2 points). Patients scoring 0, 1, 2, 3 and 4 in the validation cohorts had steroid response rates of 100, 75.0%, 54.9%, 18.2% and 0%, respectively. Scoring of ≥3 was 84% (95% CI 0.70 to 0.98) predictive of steroid failure (OR 11.9, 95% CI 10.8 to 13.0). Colectomy rates in the validation cohorts were were 8%–11%.ConclusionsEmergency colectomy rates for ASC have halved in 25 years to 8%–15% worldwide. Patients who will not respond to corticosteroids are readily identified on admission and may be prioritised for early intensification of therapy.

This case illustrates an atypical mitral valve prolapse presentation with superimposed stress of acute respiratory distress syndrome (ARDS) as well as the importance of extracorporeal membrane oxygenation therapy (ECMO) as a bridge to definitive surgical intervention. Switching from venovenous (VV) to venoarterial (VA) ECMO allowed bypass of the pulmonary circulation and provided cardiac support to assist in systemic circulation in the setting of severe mitral regurgitation with mitral valve prolapse. However, VA ECMO increases afterload, thus an Impella was used to offload the left ventricle and provide forward flow. Relying on evidence-based medicine for each modality despite its complexity also optimized this patient’s chance for recovery. Thereby, we demonstrate a complex case of ARDS, mitral valve prolapse secondary to myocardial infarction, and subsequent multiple arrhythmic arrests, where successful VV and VA ECMO resuscitation afforded bridge therapy to definitive surgical management. Our patient showed promising results, and we would like to encourage this strategy to bridge patients requiring surgical intervention.

Biomarkers to guide clinical decision making at diagnosis of inflammatory bowel disease [IBD] are urgently needed. We investigated a composite serum N-glycomic biomarker to predict future disease course in a discovery cohort of 244 newly diagnosed IBD patients. In all, 47 individual glycan peaks were analysed using ultra-high performance liquid chromatography, identifying 105 glycoforms from which 24 derived glycan traits were calculated. Multivariable logistic regression was performed to determine associations of derived glycan traits with disease. Cox proportional hazard models were used to predict treatment escalation from first-line treatment to biologics or surgery (hazard ratio [HR] 25.9, p = 1.1 × 10-12; 95% confidence interval [CI], 8.52–78.78). Application to an independent replication cohort of 54 IBD patients yielded an HR of 5.1 [p = 1.1 × 10-5; 95% CI, 2.54–10.1]. These data demonstrate the prognostic capacity of serum N-glycan biomarkers and represent a step towards personalised medicine in IBD.

Background Epigenetic alterations may provide valuable insights into gene–environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohn’s disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 × 10−15] and RPS6KA2 [6.43 × 10−13], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 × 10−15]. Age acceleration is seen in IBD [coefficient 0.94, p Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.

Background & Aims: There is great current interest in the potential application of DNA methylation alterations in peripheral blood leukocytes (PBLs) as biomarkers of susceptibility, progression, and treatment response in inflammatory bowel disease (IBD). However, the intra-individual stability of PBL methylation in IBD has not been characterized. Here, we studied the long-term stability of all probes located on the Illumina HumanMethylation EPIC BeadChip array. Methods: We followed a cohort of 46 adult patients with IBD (36 Crohn's disease [CD], 10 ulcerative colitis [UC]; median age, 44 years; interquartile range [IQR] 27–56 years; 50% female) that received standard care follow-up at the Amsterdam University Medical Centers. Paired PBL samples were collected at 2 time points with a median of 7 years (range, 2–9 years) in between. Differential methylation and intra-class correlation (ICC) analyses were used to identify time-associated differences and temporally stable CpGs, respectively. Results: Around 60% of all EPIC array loci presented poor intra-individual stability (ICC

IntroductionThere is great current interest in the potential application of DNA methylation alterations in peripheral blood leukocytes (PBL) as biomarkers of susceptibility, progression and treatment response in inflammatory bowel disease (IBD). However, the intra-individual stability of PBL methylation in IBD has not been characterised. Here, we studied the long-term stability of all probes located on the Illumina HumanMethylation EPIC BeadChip array.MethodsWe followed a cohort of 46 adult IBD patients (36 Crohn’s disease (CD), 10 ulcerative colitis (UC), median age 44 (IQR: 27-56), 50% female) that received standard care without any intervention at the Amsterdam UMC. Paired PBL samples were collected at two time points with a median 7 (range: 2-9) years in between. Differential methylation and intra-class correlation (ICC) analyses were used to identify time-associated differences and temporally stable CpGs, respectively.ResultsAround 60% of all EPIC array loci presented poor intra-individual stability (ICC HLA genes.ConclusionOur data provide insight into the long-term stability of the PBL DNA methylome within an IBD context, facilitating the selection of biologically relevant and robust IBD-associated epigenetic biomarkers with increased potential for independent validation. These data also have potential implications in understanding disease pathogenesis.

Background MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn’s disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results In stage 1, each leukocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20–3.27; logrank p = 1.80 × 10–3), in particular CD [HR 2.81; IQR: 1.11–3.53, p = 6.50 × 10–4]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.

Up to half of the approximately 10,000 people resident in a UK secure hospital are parents. There are well-established child safeguarding policies, but no model for social work support of parenting. Our study aimed to investigate social workers’ experience of secure hospital patients as parents and develop a testable model of good practice. Each social worker in one medium security hospital unit was invited to an individual semi-structured interview about his/her perspectives on patients parenting from the unit. Six social workers participated; all had experience there of patients with and without children. A core concern of ‘artificiality’ best encompassed the emergent themes covering the nature of the setting, poor mental health with sometimes delusional family life, difficult family dynamics, weakened parenting skills and patient-parent wish for communication inhibited by a sense of stigma. Resolution towards ‘naturalness’, with improved mental health, communication skills, family dynamics, and reducing confinement was partially achieved during the inpatient stay, much of the change actively facilitated by clinical interventions. While child safeguarding during a parent’s secure hospital stay is vital, longer-term psychosocial repair of relationships seems feasible. An actively restorative model envisaged by these social workers offers a testable progression towards responsible parenting.

Simen Svendsen Vatn,1,2,* Jonas Christoffer Lindstrøm,3,4,* Aina EF Moen,1,4,5 Stephan Brackmann,1,2 Tone M Tannæs,1,5 Christine Olbjørn,1,6 Daniel Bergemalm,7 Åsa V Keita,8 Fernando Gomollon,9 Trond Espen Detlie,1,2 Torben Lüders,5 Rahul Kalla,10 Alex Adams,10,11 Jack Satsangi,10,11 Jørgen Jahnsen,1,2 Morten H Vatn,1 Jonas Halfvarson,7 Petr Ricanek,2 Hilde Nilsen1,5 On behalf of IBD-CHARACTER consortium1Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 2Department of Gastroenterology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway; 3Health Services Research Unit (HØKH), Akershus University Hospital, Lørenskog, Norway; 4Department of Methods Development and Analytics, Division of Infectious Disease Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway; 5Section for Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway; 6Department of Pediatric and Adolescent Medicine, Akershus University Hospital, Lørenskog, Norway; 7Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 8Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; 9Digestive Diseases Unit, IIS Aragón, Zaragoza, Spain; 10Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, Division of Medical and Radiological Sciences, University of Edinburgh, Edinburgh, UK; 11Translational Gastroenterology Unit, Medical Sciences/ Experimental medicine Division, University of Oxford, Oxford, UK*These authors contributed equally to this workCorrespondence: Simen Svendsen Vatn, Akershus University Hospital, Postbox 1000, Lørenskog, 1478, Norway, Tel +47 94277594, Email bikkjas@hotmail.comBackground: Studies of the mucosal transcriptomic landscape have given new insight into the pathogenesis of inflammatory bowel disease (IBD). Recently, the predictive biomarker potential of gene expression signatures has been explored. To further investigate the mucosal gene expression in IBD, we recruited a cohort of treatment naïve patients and compared them to both symptomatic and healthy controls.Methods: Altogether, 323 subjects were included: Crohn’s disease (N = 75), ulcerative colitis (N = 87) and IBD unclassified (N = 3). Additionally, there were two control groups: symptomatic controls (N = 131) and healthy controls (N = 27). Mucosal biopsies were collected during ileocolonoscopy and gene expression in inflamed and non-inflamed mucosa was explored. Gene expression profiling was performed using Agilent G3 Human Gene Expression 860K v3 One-Color microarray. We recorded information about treatment escalation to anti-TNF agents or surgery, and anti-TNF response, to explore predictive opportunities of the mucosal transcriptome.Results: Gene expression profiles in symptomatic controls in whom IBD had been excluded resembled that of IBD patients and diverged from that of healthy controls. In non-inflamed Crohn’s disease and ulcerative colitis, gene set enrichment analysis revealed dysregulation of pathways involved in basic cellular biological processes. Mitochondria-associated pathways were dysregulated both in non-inflamed and inflamed Crohn’s disease and ulcerative colitis (> 2.6 normalized enrichment scores

BACKGROUND: We aimed to investigate the effects of incremental PEEP titration in patients with ARDS on regional diaphragmatic motion with bedside ultrasound. METHODS: Dorsal diaphragmatic excursion (DDE) and ventral diaphragmatic excursion (VDE) were measured using anatomic M-mode ultrasonography of the right hemidiaphragm as PEEP was randomized to −6, −3, +3, and +6 cm H2O from baseline to achieve a positive transpulmonary pressure. Inter-operator variability of DDE was assessed in 10 separate subjects. RESULTS: A total of 14 subjects ventilated for ARDS were enrolled. Subjects had a mean age of 54 ± 12 y, mean PaO2/FIO2 = 137 ± 54 mm Hg, and mean sequential organ failure assessment (SOFA) score = 14 ± 1). Transpulmonary pressure, DDE, and DDE/VDE ratio increased with incremental PEEP titration (−1.15 cm H2O vs 3.63 cm H2O, P CONCLUSIONS: DDE was affected by incremental PEEP titration toward a positive transpulmonary pressure. The ultrasound assessment using anatomic M-mode allowed for specific measurement of regional diaphragmatic excursion. This pattern of motion in the dependent regions of the diaphragm during PEEP titration in subjects with ARDS achieving a positive transpulmonary pressure may reflect a potential target for future studies in the bedside assessment for lung recruitment. (Clinical Trials.gov registration NCT02463773.)

We read with great interest the recent publication from Ungaro and colleagues,1 reporting the latest data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry. These data, while raising concerns regarding the use of thiopurine and corticosteroid therapy in the SARS-CoV-2 pandemic, also provide valuable reassurance that monotherapy with anticytokine therapies, in particular those directed against tumour necrosis factor (TNF), are not associated with adverse outcomes in patients with IBD developing COVID-19. It has been postulated that anticytokine therapies may ameliorate or abrogate the ‘cytokine storm’ associated with severe COVID-19,2 with anti-IL6 strategies now approved for use.3 We have assessed the SARS-CoV-2 antibody seroprevalence in patients with IBD, receiving either intravenous anti-TNF therapy, or anti-integrin therapy, during the first wave of the pandemic in the UK. Sera from 640 patients attending for maintenance infliximab or vedolizumab infusions between April and June 2020 at the John Radcliffe Hospital (Oxford, UK) and Royal London Hospital (London, UK) were tested using the Abbott SARS-CoV-2 IgG assay. Adults (180) and paediatric (56) patients were included from London. Demographic and clinical data are summarised (online supplemental tables 1, 2). Key differences between the Oxford and London adult cohorts included ethnicity, smoking, comorbidities, disease type, concomitant thiopurines and biologic; in our data set, patients attending Royal London Hospital had significantly greater evidence for deprivation than Oxford (deprivation score 4 (3–6.3) vs 8 (6–9.3), p

Background & aimsWe aimed to determine whether changes in ulcerative colitis management have translated to improved outcomes, in order to develop a simple model to predict steroid non-response on admission.MethodsOutcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015-19 were compared with prospectively collected data from 1992-3. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (UCEIS). Steroid non-response was defined as receiving rescue medical therapy or surgery. A predictive model created in the Oxford cohort was validated in Australia and India (110 hospitalised patients Gold Coast University Hospital 2015-20; 62 hospitalised patients AIIMS, New Delhi 2018-20).ResultsIn the 2015-19 Oxford cohort, 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-TNF), compared to 27% ciclosporin in 1992-3, p=0.0015. Only 15% required colectomy during admission vs 29% in 1992-3 (p=0.033). Admission CRP, albumin, and UCEIS scores predicted steroid non-response (FDR p=0.00066, 0.0066 and 0.015). A four-point model was developed involving CRP ≥100mg/L (1 point), albumin ≤25g/L (1 point), UCEIS ≥4 (1 point) or ≥7 (2 points). Scoring 0 or 4 was 100% predictive of steroid response and non-response, respectively, in all three cohorts. Patients scoring 3-4 had 83% risk of steroid non-response in Oxford and 84% (0.70-0.98) in the validation cohorts – OR 11.9 (10.8-13).ConclusionColectomy rates for ASC have halved in 25 years, while use of rescue medical therapy has doubled. Patients who are highly unlikely to respond to parenteral steroid treatment alone may be readily identified on admission, to be prioritised for early intensification of therapy.WHAT YOU NEED TO KNOWBackground and contextAcute severe colitis (ASC) requires hospitalisation and, frequently, colectomy. The accepted management of ASC is three-five days of intravenous steroids followed by protocolised response assessment.New findingsMedical rescue therapy has doubled and the colectomy rate halved in 25 years. A predictive index identifying steroid non-response was derived and validated in three independent centres in three countries.LimitationsA need remains to demonstrate that earlier rescue medical therapy for patients predicted to be steroid non-responders will further improve outcomes.ImpactThe outcome of ASC has substantially improved in the past 25 years, with the potential for further improvement by identifying patients on admission for early escalation of therapy.

Background and aimsThe IBD-Character consortium has recruited large internationally based inception cohorts of treatment-naïve inflammatory bowel disease (IBD) patients, providing a unique resource to derive a simple transcriptome signature in the field of prognostication.MethodsThe discovery cohort (n=160) was recruited in Norway, Sweden and Spain. The replication inception cohort from the United Kingdom (n=97) was followed-up for a mean (±SD) of 350±228 days. Treatment escalation was formally defined as the need for a biologic agent, ciclosporin and/or surgery, instituted for disease flare after initial remission, or colectomy during the index admission for ulcerative colitis. Whole blood RNA was subject to paired-end sequencing. In the discovery cohort a simple procedure was applied, which exploited differences of transcript ratios. The ten top performing ratios were tested using Cox regression models in the validation cohort.ResultsNewly diagnosed IBD patients with high CACNA1E/LRRC42 expression ratio had an increased risk of treatment intensification (validation cohort: HR=19.3, 95%CI 2.6–143.9, p=0.000005; AUC 0.76, 95%CI 0.66–0.86). In 51 patients with CRP < 3.5 mg/L, CACNA1E/LRRC42 still predicted escalation (HR=10.4; 95%CI 1.2-86.5, p=0.007). The second best performing transcript ratio was CACNA1E/CEACAM21 yielding a HR of 10.9 (95%CI 2.5-46.7, p=0.00002) and an AUC of 0.76 (95%CI 0.65-0.86) in the validation cohort.ConclusionTranscriptomic profiling of an IBD inception cohort identified gene expression ratios CACNA1E/LRRC42 and CACNA1E/CEACAM21 as prognostic biomarkers. These were validated in a replication cohort as strongly associated with short- and long-term risk of treatment intensification and may provide valuable information in clinical decision-making.

Introduction: Healthcare-associated infections (HAI) after viral illnesses are important sources of morbidity and mortality. This has not been extensively studied in hospitalized COVID-19 patients. Methods: This study included all COVID-19-positive adult patients (≥18 years) hospitalized between 01 March and 05 August 2020 at the current institution. The Centers for Disease Control and Prevention definition of HAI in the acute care setting was used. The outcomes that were studied were rates and types of infections and in-hospital mortality. Several multivariable logistic regression models were constructed to examine characteristics associated with development of HAI. Results: Fifty-nine (3.7%) of 1565 patients developed 140 separate HAIs from 73 different organisms: 23 were Gram-positive, 39 were Gram-negative and 11 were fungal. Patients who developed HAI did not have higher odds of death (OR 0.85, 95% CI 0.40–1.81, p = 0.69). HAIs were associated with the use of tocilizumab (OR 5.04, 95% CI 2.4–10.6, p

Background Complex interactions between the environment and the mucosal immune system underlie inflammatory bowel disease (IBD). The involved cytokine signaling pathways are modulated by a number of transcription factors, one of which is runt-related transcription factor 3 (RUNX3). Objective To systematically review the immune roles of RUNX3 in immune regulation, with a focus on the context of IBD. Methods Relevant articles and reviews were identified through a Scopus search in April 2020. Information was categorized by immune cell types, analyzed, and synthesized. IBD transcriptome datasets and FANTOM5 regulatory networks were processed in order to complement the literature review. Results The available evidence on the immune roles of RUNX3 allowed for its description in twelve cell types: intraepithelial lymphocyte, Th1, Th2, Th17, Treg, double-positive T, cytotoxic T, B, dendritic, innate lymphoid, natural killer, and macrophages. In the gut, the activity of RUNX3 is multifaceted and context-dependent: it may promote homeostasis or exacerbated reactions via cytokine signaling and regulation of receptor expression. RUNX3 is mostly engaged in pathways involving ThPOK, T-bet, IFN-γ, TGF-β/IL-2Rβ, GATA/CBF-β, Smad/p300, and a number of miRNAs. RUNX3 targets relevant to IBD may include RAG1, OSM, IL17B. Moreover, in IBD RUNX3 expression correlates positively with GZMM, and negatively with IFNAR1, whereas in controls it strongly associates with TGFBR3. Conclusions Dysregulation of RUNX3, mostly in the form of deficiency, likely contributes to IBD pathogenesis. More clinical research is needed to examine RUNX3 in IBD.