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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 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.

Background Return of normal gastrointestinal (GI) function is a critical determinant of recovery after colorectal surgery. The aim of this meta-analysis was to evaluate whether perioperative intravenous (IV) lidocaine benefits return of gastrointestinal function after colorectal resection. Methods A comprehensive search of Ovid Medline, PubMed, Embase, Cochrane library, and clinicaltrials.org was performed on 1st July 2018. A manual search of reference lists was also performed. Inclusion criteria were as follows: randomized controlled trials (RCTs) of intravenous (IV) lidocaine administered perioperatively compared to placebo (0.9% saline infusion) as part of a multimodal perioperative analgesic regimen, human adults (> 16 years), and open or laparoscopic colorectal resectional surgery. Exclusion criteria: non-colorectal surgery, non-placebo comparator, children, non-general anaesthetic, and pharmacokinetic studies. The primary endpoint was time to first bowel movement. Secondary endpoints were time to first passage of flatus, time to toleration of diet, nausea and vomiting, ileus, pain scores, opioid analgesia consumption, and length of stay. Results One hundred and ninety one studies were screened, with 9 RCTs meeting inclusion criteria (405 patients, four laparoscopic and five open surgery studies). IV lidocaine reduced time to first bowel movement compared to placebo [seven studies, 325 patients, mean weighted difference − 9.54 h, 95% CI 18.72–0.36, p = 0.04]. Ileus, pain scores, and length of stay were reduced with IV lidocaine compared with placebo. Conclusions Perioperative IV lidocaine may improve recovery of gastrointestinal function after colorectal surgery. Large-scale effectiveness studies to measure effect size and evaluate optimum dose/duration are warranted. Electronic supplementary material The online version of this article (10.1007/s10151-019-1927-1) contains supplementary material, which is available to authorized users.

Background Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. Methods We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. Results A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p = 4.1 × 10–23] and oncostatin-M [OSM; p = 3.7 × 10–16]. Nine of these proteins are associated with cis-germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224–756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43–6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohn’s disease respectively. Conclusion We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings.

SummaryBackgroundSuccess in personalised medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay (PEA) to identify diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD).MethodsWe conducted a prospective case-control study in an inception cohort of 552 patients (328 IBD, 224 non-IBD), profiling proteins recruited across 6 centres. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross validation was used to examine the performance of diagnostic and prognostic proteins.ResultsA total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls including Matrix Metalloproteinase-12 (Holm adjusted p=4.1×10−23) and Oncostatin-M (OSM, p=3.7×10−16). Nine of these proteins associate with cis- germline variation (59 independent SNPs). Fifteen proteins, all members of TNF independent pathways including interleukin-1 and OSM predicted escalation, over a median follow-up of 518 (IQR 224-756) days. Nested cross-validation of the entire data set allows characterisation of 5-protein-models (96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7, and IL8) which define a high-risk subgroup in IBD (HR 3.90, 95% CI: 2.43-6.26), or allows distinct 2, and 3 protein models for UC and CD respectively.ConclusionWe have characterised a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and predicts the evolution of disease over time. The technology could be suitable as a point of care testing in defining risk. Further prospective work is required to characterise the utility of the approach.

Background & Aims Gene expression patterns of CD8+ T cells have been reported to correlate with clinical outcomes of adults with inflammatory bowel diseases (IBD). We aimed at validating these findings in independent patient cohorts. Methods We obtained peripheral blood samples from 112 children with a new diagnosis of IBD (71 with Crohn’s disease and 41 with ulcerative colitis) and 19 children without IBD (controls) and recorded medical information on disease activity and outcomes. CD8+ T cells were isolated from blood samples by magnetic bead sorting at the point of diagnosis and during the course of disease. Genome-wide transcription (n=192) and DNA methylation (n=66) profiles were generated using Affymetrix and Illumina arrays, respectively. Publicly available transcriptomes and DNA methylomes of CD8+ T cells from three adult patient cohorts with and without IBD were included in data analyses. Results Previously reported CD8+ T cell prognostic expression and exhaustion signatures were only found in the original adult IBD patient cohort. These signatures could not be detected either in a pediatric, or in a second adult IBD cohort. In contrast, an association between CD8+ T cell gene expression with age and sex was detected across all three cohorts. CD8+ gene transcription was clearly associated with IBD in the two cohorts that included non-IBD controls. Lastly, DNA methylation profiles of CD8+ T cells from children with Crohn’s disease correlated with age but not with disease outcome. Conclusions We were unable to validate previously reported findings of an association between CD8+ T cell gene transcription and disease outcome in IBD. Our findings reveal the challenges of developing prognostic biomarkers for patients with IBD and the importance of their validation in large, independent cohorts before clinical application., Graphical abstract

Background Increased life expectancy and improved medical management of co-morbidities has led to an increasing number of nonagenarian patients with colorectal cancer being considered for surgical intervention. This study aims to describe the morbidity and mortality of nonagenarians who had operative and non-operative management for colorectal cancer. Materials and Methods A retrospective study of consecutive colorectal cancer patients from 2010 to 2016 in a district general hospital in Scotland who were 90 years old or above was performed. Demographic and perioperative data were obtained from case note review. Survival analysis and multivariable regression was conducted to determine factors associated with cancer-specific and all-cause mortality. Results Forty-nine patients were identified; 24 patients underwent operative management (median age: 91) while 25 received non-operative management (median age: 92). Fifteen patients (62.5%) had an elective operation, and 8 (37.5%) had an urgent or emergency procedure. None of the patients treated operatively suffered a significant complication or anastomotic leakage. Median hospital stay was 14 days. Five patients (20.8%) required a higher level of care in the community following discharge. Surgical mortality within 30 days was 4.2%. Patients undergoing an elective operation had a significantly improved survival compared to those undergoing an emergency operation or non-operative management. On multivariable analyses, non-operative management, and presence of metastases at diagnosis were associated with higher cancer-specific mortality. Conclusion Elective operative management for carefully selected nonagenarian patients with colorectal cancer is generally acceptable in terms of morbidity and mortality. The majority of operatively managed patients returned to the same functional level of care following discharge. Patients with metastases at the outset and those requiring emergency surgery have a poorer prognosis.

Background: Many genome- and epigenome-wide association studies (GWAS and EWAS) and studies of promoter methylation of candidate genes for inflammatory bowel disease (IBD) have demonstrated significant associations between genetic and epigenetic changes and IBD. Independent GWA studies have identified genetic variants in the BACH2, IL6ST, LAMB1, IKZF1, and MGAT3 loci to be associated with both IBD and immunoglobulin G (IgG) glycosylation. Methods: Using bisulfite pyrosequencing, we analyzed CpG methylation in promoter regions of these five genes from peripheral blood of several hundred IBD patients and healthy controls (HCs) from two independent cohorts, respectively. Results: We found significant differences in the methylation levels in the MGAT3 and BACH2 genes between both Crohn's disease and ulcerative colitis when compared to HC. The same pattern of methylation changes was identified for both genes in CD19 + B cells isolated from the whole blood of a subset of the IBD patients. A correlation analysis was performed between the MGAT3 and BACH2 promoter methylation and individual IgG glycans, measured in the same individuals of the two large cohorts. MGAT3 promoter methylation correlated significantly with galactosylation, sialylation, and bisecting GlcNAc on IgG of the same patients, suggesting that activity of the GnT-III enzyme, encoded by this gene, might be altered in IBD. The correlations between the BACH2 promoter methylation and IgG glycans were less obvious, since BACH2 is not a glycosyltransferase and therefore may affect IgG glycosylation only indirectly. Conclusions: Our results suggest that epigenetic deregulation of key glycosylation genes might lead to an increase in pro-inflammatory properties of IgG in IBD through a decrease in galactosylation and sialylation and an increase of bisecting GlcNAc on digalactosylated glycan structures. Finally, we showed that CpG methylation in the promoter of the MGAT3 gene is altered in CD3 + T cells isolated from inflamed mucosa of patients with ulcerative colitis from a third smaller cohort, for which biopsies were available, suggesting a functional role of this glyco-gene in IBD pathogenesis. The authors would like to thank Stephanie Scott for her organizational and administrational contribution. The study has been funded by the EU FP7 grant European Commission IBD-BIOM (contract # 305479), EU FP7 Regional Potential Grant INTEGRA-Life (contract # 315997), European Structural and Investment Funds grant for the Croatian National Centre of Research Excellence in Personalized Healthcare (contract # KK.01.1.1.01.0010), and Croatian Science Foundation grant EpiGlycoIgG (contract # 3361). Financial support from Portugal (PI: SSP): FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Inovação in the framework of the project (POCI-01/0145-FEDER-016601; PTDC/DTP-PIC/0560/2014) was received. SSP also acknowledges the European Crohn’s and Colitis Organization (ECCO) and the “Broad Medical Research program at Crohn’s and Colitis Foundation of America-CCFA” for funding. SSP acknowledges the Portuguese Group of Study on IBD (GEDII) for funding. A.M.D. [PD/BD/105982/2014] also acknowledges FCT for funding. IBD-BIOM consortium: Daniel Kolarich (Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany), Manfred Wuhrer (Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands; Division of BioAnalytical Chemistry, VU University Amsterdam, Amsterdam, the Netherlands), Dermot P. B. McGovern (F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles), Iain K. Pemberton (IP Research Consulting SAS, Paris, France), Daniel IR Spencer (Ludger Ltd., Culham Science Centre, Oxford, UK, Daryl L. Fernandes (Ludger Ltd., Culham Science Centre, Oxford, UK), Rahul Kalla, Kate O’Leary, Alex T Adams, Hazel Drummond, Elaine Nimmo, Ray Boyapati, David C Wilson (Centre for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK), Ray Doran (Ludger Ltd., Culham Science Centre, Oxford, UK), Igor Rudan (all, Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK), Paolo Lionetti (Paediatric Gastroenterology Unit, AOU Meyer, Viale Pieraccini, Florence, Italy), Natalia Manetti (Department of Medical and Surgical Sciences, Division of Gastroenterology, University Hospital Careggi, Florence, Italy), Fabrizio Bossa (Department of Medical Sciences, Division of Gastroenterology, IRCCS-CSS Hospital, Viale Cappuccini, Rotondo, Italy), Paola Cantoro, Anna Kohn (Division of Gastroenterology, S. Camillo Hospital, Rome, Italy), Giancarlo Sturniolo (Gastrointestinal Unit, University of Padua, Padua, Italy), Silvio Danese (IBD Unit, Humanitas Research Institute, Rozzano, Milan, Italy), Mariek Pierik (Maastricht University Medical Centre (MUMC), Maastricht, the Netherlands), and David C. Wilson (Centre for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK). This independent research was generously supported by the following grants: EU FP7 research grant IBD-BIOM (contract # 305479) to JS, VA, GL, and VZ; EU FP7 Regional Potential Grant INTEGRA-Life (contract # 315997) to GL and VZ; European Structural and Investment Funds grant for the Croatian National Centre of Research Excellence in Personalized Healthcare (contract # KK.01.1.1.01.0010) to GL and VZ; Croatian Science Foundation grant EpiGlycoIgG (contract # 3361) to VZ; FEDER COMPETE 2020 POCI, Portugal 2020, and Portuguese funds through FCT (contracts # POCI-01/0145-FEDER-016601 and PTDC/DTP-PIC/0560/2014) to SP; and FTC (contract # PD/BD/105982/2014) to AMD.

Background Due to common evolutionary origins, mitochondrial DNA (mtDNA) shares many similarities with immunogenic bacterial DNA. MtDNA is recognized as a pro-inflammatory damage-associated molecular pattern (DAMP) with a pathogenic role in several inflammatory diseases. We hypothesised that mtDNA is released during active disease, serving as a key pro-inflammatory factor in inflammatory bowel disease (IBD). Methods Between 2014 and 2015, we collected plasma separated within 2 hours of sampling from 97 prospectively recruited IBD patients (67 ulcerative colitis [UC] and 30 Crohn’s disease [CD]) and 40 non-IBD controls. We measured circulating mtDNA using quantitative polymerase chain reaction (amplifying mitochondria COXIII/ND2 genes) and also in mouse colitis induced by dextran sulfate-sodium (DSS). We used a mass spectometry approach to detect free plasma mitochondrial formylated peptides. Furthermore, we examined for mitochondrial damage using electron microscopy (EM) and TLR9 expression, the target for mtDNA, in human intestinal IBD mucosa. Results Plasma mtDNA levels were increased in UC and CD (both P < 0.0001) compared with non-IBD controls. These levels were significantly correlated to blood (C-reactive protein, albumin, white cell count), clinical and endoscopic markers of severity, and disease activity. In active UC, we identified 5 mitochondrial formylated peptides (the most abundant being fMMYALF with known chemoattractant function) in plasma. We observed mitochondrial damage in inflamed UC mucosa and significantly higher fecal MtDNA levels (vs non-IBD controls [P < 0.0001]), which supports gut mucosal mitochondrial DAMP release as the primary source. In parallel, plasma mtDNA levels increased during induction of acute DSS colitis and were associated with more severe colitis (P < 0.05). In active IBD, TLR9+ lamina propria inflammatory cells were significantly higher in UC and CD compared with controls (P < 0.05). Conclusions We present the first evidence to show that mtDNA is released during active IBD. MtDNA is a potential mechanistic biomarker, and our data point to mtDNA-TLR9 as a therapeutic target in IBD.

BACKGROUND Acute appendicitis remains the most common indication for emergency abdominal surgery in the United Kingdom. Although laparoscopic appendicectomy has demonstrable advantages over open appendicectomy, uptake has not been universal. The aims of this study were to describe trends in laparoscopic appendicectomy in a District General Hospital in Scotland. METHODS Retrospective review of appendix histopathology records within NHS Fife between 2003 and 2010. Note review of cases of acute appendicitis managed with laparoscopic appendicectomy was performed. Perioperative variables in perforated and nonperforated appendicitis were compared. A multivariate logistic regression analysis to determine factors associated with developing complications was performed. RESULTS Between 2003 and 2010, 237 laparoscopic appendicectomies were performed. The rate of laparoscopic appendicectomy increased from 2.5% in 2003 to 78% in 2010. In 50% of cases, the trainee surgeon was the primary operator. Complications occurred in 9.6% and the mortality rate was 0.4%. No factors on multivariate logistic regression predicted development of complications. CONCLUSIONS We describe a change in practice towards laparoscopic appendicectomy for the treatment of acute appendicitis over a 7-year period. Furthermore, laparoscopic appendicectomy is associated with acceptable morbidity rates.

Response to corticosteroid treatment in acute severe ulcerative colitis (ASUC) has changed very little in the past 50 years. Predicting those at risk at an early stage helps stratify patients into those who may require second line therapy or early surgical treatment. Traditionally, risk scores have used a combination of clinical, radiological and biochemical parameters; established indices include the 'Travis' and 'Ho' scores. Recently, inflammatory bowel disease genetic risk alleles have been built into models to predict outcome in ASUC. Given the multifactorial nature of inflammatory bowel disease pathogenesis, in the future, composite scores integrating clinical, biochemical, serological, genetic and other '-omic' data will be increasingly investigated. Although these new genetic prediction models are promising, they have yet to supplant traditional scores, which remain the best practice. In this modern era of rescue therapies in ASUC, robust scoring systems to predict failure of ciclosporine and infliximab must be devised.

Background & Aims Biomarkers are needed for early detection of Crohn’s disease (CD) and ulcerative colitis (UC) or to predict patient outcomes. Glycosylation is a common and complex posttranslational modification of proteins that affects their structure and activity. We compared plasma N-glycosylation profiles between patients with CD or UC and healthy individuals (controls). Methods We analyzed the total plasma N-glycomes of 2635 patients with inflammatory bowel diseases and 996 controls by mass spectrometry with a linkage-specific sialic acid derivatization technique. Plasma samples were acquired from 2 hospitals in Italy (discovery cohort, 1989 patients with inflammatory bowel disease [IBD] and 570 controls) and 1 medical center in the United States (validation cohort, 646 cases of IBD and 426 controls). Sixty-three glycoforms met our criteria for relative quantification and were extracted from the raw data with the software MassyTools. Common features shared by the glycan compositions were combined in 78 derived traits, including the number of antennae of complex-type glycans and levels of fucosylation, bisection, galactosylation, and sialylation. Associations of plasma N-glycomes with age, sex, CD, UC, and IBD-related parameters such as disease location, surgery and medication, level of C-reactive protein, and sedimentation rate were tested by linear and logistic regression. Results Plasma samples from patients with IBD had a higher abundance of large-size glycans compared with controls, a decreased relative abundance of hybrid and high-mannose structures, lower fucosylation, lower galactosylation, and higher sialylation (α2,3- and α2,6-linked). We could discriminate plasma from patients with CD from that of patients with UC based on higher bisection, lower galactosylation, and higher sialylation (α2,3-linked). Glycosylation patterns were associated with disease location and progression, the need for a more potent medication, and surgery. These results were replicated in a large independent cohort. Conclusions We performed high-throughput analysis to compare total plasma N-glycomes of individuals with vs without IBD and to identify patterns associated with disease features and the need for treatment. These profiles might be used in diagnosis and for predicting patients’ responses to treatment.

In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn’s disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD.

IntroductionThere is an unmet need for novel blood based biomarkers that offer timely and accurate diagnostic and prognostic testing in Inflammatory Bowel Diseases (IBD). We aimed to investigate the diagnostic and prognostic utility of serum calprotectin (SC) in IBD.MethodsA total of 171 patients (n=96 IBD, n=75 non-IBD) were prospectively recruited. A multi biomarker model was derived using multivariable logistic regression analysis. Cox proportional hazards model was derived to assess the contribution of each variable to disease outcomes.ResultsSC correlated strongly with current biomarkers including faecal calprotectin (FC) (n=50, rho= 0.50, p=1.6x10-437 ). SC was the strongest individual predictor of IBD diagnosis (odds ratio (OR): 9.37(95%CI: 2.82-34.68), p=4.00×10-438 ) compared with other markers (CRP: OR 8.52(95%CI: 2.75-28.63), p=2.80×10-439 ); albumin: OR 6.12(95%CI: 1.82-22.16), p=0.004). In a subset of 50 patients with paired SC and FC, the area under receiver operating characteristic discriminating IBD from controls was better for FC than SC (0.99, (95% CI 0.87-1.00) and 0.87 (95% CI:0.78-0.97) respectively; p=0.01).43 At follow up (median 342 days; IQR: 88-563), SC predicted treatment escalation and/or44 surgery in IBD (HR 2.7, 95% CI: 1.1-4.9), in particular CD (HR 4.2, 95% CI 1.2-15.3).Page 2 of 73ScholarOne, 375 Greenbrier Drive, Charlottesville, VA, 22901American Journal of GastroenterologyFor Peer Review3A model incorporating SC and either CRP or albumin has a positive likelihood 45 ratio of 24.1446 for IBD. At 1 year, our prognostic model can predict treatment escalation in IBD in 65% of47 cases (95% CI: 43-79%) and 80% (95% CI: 31-94%) in CD if 2 or more blood marker48 criteria are met.49 Conclusions50 A diagnostic and prognostic model that combines SC and other blood-based biomarkers51 accurately predicts the inflammatory burden in IBD and has the potential to predict disease52 and its outcomes. Our data warrants further detailed exploration and validation in large multi53centre cohorts.

Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression., Epigenetic perturbations may be an important factor in diseases where both genes and environment play a role. Here, Ventham and colleagues show that DNA methylation changes in inflammatory bowel disease are related to the underlying genotype, and are associated with cell-specific changes to gene expression.

INTRODUCTION Parastomal herniation occurs in 30–50% of colostomy formations. The aim of this study was to radiologically evaluate the mechanical defects at stoma sites in patients who had previously undergone a permanent colostomy with or without mesh at the index operation for colorectal cancer. METHODS A study was performed of all colorectal cancer patients (n=41) having an end colostomy between 2002 and 2010, with or without Prolene® mesh plication, with blinded evaluation of the annual follow-up staging computed tomography (CT) for stomal characteristics. The presence of parastomal hernias, volume, dimensions, grade of the parastomal hernia and abdominal wall defect size were measured by two independent radiologists, and compared with demographic and operative variables. RESULTS In those patients with radiological evidence of a parastomal hernia, Prolene® mesh plication significantly reduced the incidence of bowel containing parastomal hernias at one year following the procedure (pCONCLUSIONS Prophylactic mesh placement at the time of the index procedure reduces the diameter of abdominal wall aperture and the incidence of parastomal hernias containing bowel. Future studies should use both objective radiological as well as clinical endpoints when assessing parastomal hernia development with and without prophylactic mesh.

As surgical trainees across multiple disciplines, it is our collective aim for all surgical patients to have the opportunity to participate in at least one clinical trial during their hospital episode.1 We recognise that most patients wish to have this option,2 and we want our training to facilitate this. Because patients have the right to be involved in improving surgical …

Article first published online 17 April 2015. Supplemental Digital Content is Available in the Text., Background: Glycobiology is an underexplored research area in inflammatory bowel disease (IBD), and glycans are relevant to many etiological mechanisms described in IBD. Alterations in N-glycans attached to the immunoglobulin G (IgG) Fc fragment can affect molecular structure and immunological function. Recent genome-wide association studies reveal pleiotropy between IBD and IgG glycosylation. This study aims to explore IgG glycan changes in ulcerative colitis (UC) and Crohn's disease (CD). Methods: IgG glycome composition in patients with UC (n = 507), CD (n = 287), and controls (n = 320) was analyzed by ultra performance liquid chromatography. Results: Statistically significant differences in IgG glycome composition between patients with UC or CD, compared with controls, were observed. Both UC and CD were associated with significantly decreased IgG galactosylation (digalactosylation, UC: odds ratio [OR] = 0.71; 95% confidence interval [CI], 0.5–0.9; P = 0.01; CD: OR = 0.41; CI, 0.3–0.6; P = 1.4 × 10−9) and significant decrease in the proportion of sialylated structures in CD (OR = 0.46, CI, 0.3–0.6, P = 8.4 × 10−8). Logistic regression models incorporating measured IgG glycan traits were able to distinguish UC and CD from controls (UC: P = 2.13 × 10−6 and CD: P = 2.20 × 10−16), with receiver–operator characteristic curves demonstrating better performance of the CD model (area under curve [AUC] = 0.77) over the UC model (AUC = 0.72) (P = 0.026). The ratio of the presence to absence of bisecting GlcNAc in monogalactosylated structures was increased in patients with UC undergoing colectomy compared with no colectomy (FDR-adjusted, P = 0.05). Conclusions: The observed differences indicate significantly increased inflammatory potential of IgG in IBD. Changes in IgG glycosylation may contribute to IBD pathogenesis and could alter monoclonal antibody therapeutic efficacy. IgG glycan profiles have translational potential as IBD biomarkers.

Transcalcaneal talonavicular dislocation is a rare injury, with very few reported cases. Of these, most have been the result of high-energy mechanisms such as road traffic collisions or falls from a height. The management of this injury is challenging, and treatment is fraught with a high rate of disability, infection, and amputation. We describe the successful management of the first reported case of a low-energy transcalcaneal talonavicular dislocation in a 71-year-old female. Combined external and internal fixation was used to reduce and maintain the injury, with a resultant good functional and complication-free outcome at 1 year after the injury. Our experience highlights the prevalence of these devastating injuries caused by relatively benign mechanisms in an increasingly older population with osteoporotic bone. It also indicates that operative stabilization of a low-energy injury can be more successful than that with the traditional high-velocity trauma.

Background Exploring DNA methylation in inflammatory bowel disease might provide an insight into the complex gene–environment interactions in disease pathogenesis. Our study aimed to characterise disease-associated methylation changes in newly diagnosed inflammatory bowel disease and explore its association with germline variation and gene expression. Methods Samples were obtained from new onset inflammatory bowel disease in six European centres (IBD-Character project). Genome-wide methylation was measured (450k platform, Illumina, San Diego, CA, USA) in 641 whole blood DNA samples (298 controls, 150 Crohn's disease, 167 ulcerative colitis, 26 inflammatory bowel disease unclassified). Genotyping and gene expression were performed using HumanOmniExpressExome-8 BeadChips (Illumina) and Ion AmpliSeq (ThermoFisher, Waltham, MA, USA) platforms, respectively. Correlation and pathway analyses were performed between the top differentially methylated regions and gene expression. Findings M195 probes exhibited Holm-significant inflammatory bowel disease-associated methylation differences, including MIR21 (p=3·7 × 10 − 20 ) and RPS6KA2 (p=1·1 × 10 −19 ) with only one probe differentiating Crohn's disease from ulcerative colitis ( NAV2 , p=6·82 × 10 −8 ). Paired genetic and methylation data showed 1037 significant methylation quantitative trait loci indicating a genetic influence on several key loci: RPS6KA2 (p=8·6 × 10 −34 ) and MIR21 (rs8078424, p=4·4 × 10 − 25 ; rs10853015, p=7·4 × 10 −21 ). 1543 differentially methylated regions (DMRs) were identified and included MIR21 , RPS6KA2 , and TNF . These DMRs mapped to 8214 mRNA profiles of which 1916 showed Holm-significant correlation with methylation such as IL32 (seven probes: r =–0·50 to −0·66, p=6·0 × 10 −76 ). GO term analyses of these highly correlated genes revealed pathways that regulate cell–cell adhesion and immune cell differentiation. Interpretation Our data provide a comprehensive multicentre genome-wide profile of the circulating methylome and give an insight into the complex interplay between differential methylation, germline variation, and gene expression in immune mediated disease. Funding RK and AA are funded by IBD-Character (a European Union 7th Framework Programme project).

A number of genetic and immunological studies give impetus for investigating the role of glycosylation in IBD. Experimental mouse models have helped to delineate the role of glycosylation in intestinal mucins and to explore the putative pathogenic role of glycosylation in colitis. These experiments have been extended to human studies investigating the glycosylation patterns of intestinal mucins as well as levels of glycans of serum glycoproteins and expression of glycan receptors. These early human studies have generated interesting hypotheses regarding the pathogenic role of glycans in IBD, but have generally been restricted to fairly small underpowered studies. Decreased glycosylation has been observed in the intestinal mucus of patients with IBD, suggesting that a defective inner mucus layer might lead to increased bacterial contact with the epithelium, potentially triggering inflammation. In sera, decreased galactosylation of IgG has been suggested as a diagnostic marker for IBD. Advances in glycoprofiling technology make it technically feasible and affordable to perform high-throughput glycan pattern analyses and to build on previous work investigating a much wider range of glycan parameters in large numbers of patients.

BACKGROUND National Scottish data were used to compare 3-year mortality in patients hospitalized for Crohn's disease (CD) between 1998-2000 and 2007-2009. METHODS The linked Scottish Morbidity Records database was used to identify patients admitted with CD during two periods: Period 1 (1998-2000) and Period 2 (2007-2009). 3-year mortality and standardized mortality ratio (SMR) were determined and multivariable logistic regression analysis of associated factors was performed. Mortality was determined following four admission types: surgery-elective, surgery-emergency, medical-elective and medical-emergency. 3-year mortality was compared between study periods using age-standardized rates. RESULTS The number of patients per 100,000 population hospitalized with CD per year was unchanged (15.7 [Period 1]; 14.4 [Period 2]). Overall crude and adjusted 3-year mortality rates were also unchanged (crude mortality 9.0%-9.1%, adjusted mortality odds ratio [OR]=0.87, 95% confidence interval [CI] 0.65-1.17; p=0.36). The adjusted 3-year mortality increased following elective surgery (Period 1: 1/303 [0.3%]; Period 2: 9/261 [3.4%]); OR=13.5 [CI 1.66-109.99]) and decreased following emergency medical admission (Period 1: 99/779 [12.7%]; Period 2:86/802 [10.7%]; OR=0.68 [CI 0.47-0.97]). Directly age-standardized mortality rates were similar (Period 1:338/10,000 person years [CI 282-394]; Period 2:333/10,000 person years [CI 276-390], p=0.2). On multivariable regression, age, deprivation status, comorbidity and the length of hospital stay were associated with mortality in both periods. High 3-year mortality was observed during both periods in patients between 50 and 64years (Period 1: 33/298 [11.1%, SMR=4.8 [CI 3.44-6.63], Period 2: 33/296 [11.1%, SMR=5.9 [4.14-8.22]) and over 65years(Period 1: 94/275 [34.2%, SMR=2.78 [CI 2.42-3.62], Period 2: 78/251 [31.1%, SMR=3.31 [2.64-4.11]). CONCLUSION Nationwide linkage data demonstrate that overall 3-year mortality after hospitalization for CD is high, especially in patients over 50years, and has not altered between the time periods 1998-2000 and 2007-2009.

Background Scottish nationwide linkage data from 1998 to 2000 demonstrated high 3‐year mortality in patients hospitalised with ulcerative colitis (UC). Aim To compare 3‐year mortality, and factors related to mortality, in Scottish patients hospitalised with UC between 1998–2000 and 2007–2009. Methods The Scottish Morbidity Records and linked datasets were used to assess 3‐year mortality, standardised mortality ratio (SMR) and multivariate analyses of factors associated with 3‐year mortality. The 3‐year mortality was determined after four admission types: surgery‐elective or emergency; medical‐elective or emergency. Age‐standardised mortality rates (ASR) were used to compare mortality rates between periods. Results Ulcerative colitis admissions increased from 10.6 in Period 1 to 11.6 per 100 000 population per year in Period 2 (P = 0.046). Crude and adjusted 3‐year mortality fell between time periods (crude 12.2% to 8.3%; adjusted OR 0.59, CI 0.42–0.81, P = 0.04). Adjusted 3‐year mortality following emergency medical admission (OR 0.58, CI 0.39–0.87, P = 0.003) and in patients >65 years (38.8% to 28.7%, P = 0.02) was lower in Period 2. The SMR in period 1 was 3.04 and 2.96 in Period 2. Directly age‐standardised mortality decreased from 373 (CI 309–437) to 264 (CI 212–316) per 10 000 person‐years. On multivariate analysis, increasing age (50–64 years OR 7.11 (CI 2.77–18.27, P < 0.05); 65–74 years OR 14.70 (CI 5.65–38.25 P < 0.05); >75 years OR 46.42 (CI 18.29–117.78, P < 0.001) and co‐morbidity (OR 3.02, CI 1.72–5.28, P < 0.001) were significantly associated with 3‐year mortality in Period 2. Conclusions Comparisons of crude and adjusted mortality rates suggest significant improvement in outcome over the last decade – however, mortality remains high, and older age and co‐morbidity are important predictors of outcome.

Laparoscopic mesh repair is becoming an increasingly popular method of ventral and incisional hernia repair. Entrapment neuropathy is a recognised complication when tacks are used to fix the mesh, particularly below the inguinal ligament and laterally in the abdominal wall. We describe a novel method of ventral hernia repair, which employs transabdominal extra-peritoneal dissection to create a pocket for mesh placement with complete avoidance of tacks in the postero-lateral abdominal wall. This technique is particularly useful for incisional hernias arising through old stoma wounds or appendicectomy incisions, and for Spigelian and lumbar hernias.

Omental infarction is a rare cause of acute abdomen in childhood. We describe a case of omental infarction mimicking acute appendicitis occurring in a child with cyclical neutropenia. Neutropenic enterocolitis, a serious cause of the acute abdomen, has been linked with cyclical neutropenia. In neutropenic patients, omental infarction when diagnosed pre-operatively can be managed conservatively with the focus on improving the neutrophil count. If after imaging the diagnosis is in doubt, there should be a low threshold for laparoscopy. The low incidence of omental infarction will continue to mean that it is a diagnosis made at operation for suspected appendicitis. In these cases, the infarcted tissue may be removed by the laparoscopic or open technique.

Introduction There is an unmet need for novel blood based biomarkers that offer timely and accurate diagnostic and prognostic testing in Inflammatory Bowel Diseases (IBD). We aimed to investigate the diagnostic and prognostic utility of serum calprotectin (SC) in IBD Methods A total of 156 patients (82 IBD and 74 non-IBD) were sampled within 90 days from diagnosis (median 0 days; IQR 0–7). A multibiomarker diagnostic and prognostic model was derived using multivariable logistic regression analysis. Treatment escalation was defined as the need for escalation and establishment of 2 or more immunomodulatory therapies and/or surgery for disease flare after initial induction of disease remission (criteria previously used by Lee et al) (1). Cox proportional hazards model was derived to assess the contribution of each variable to disease outcomes Results SC correlated strongly with current biomarkers including CRP (rho = 0.60, p = 1.4x10−16) faecal calprotectin (FC) (rho = 0.51, p = 1.6x10−4). Paired FC was available within 30 days (median 0 days, IQR: -4 to5 days) of SC in 50 patients (IBD n = 30, non-IBD n = 20).The area under receiver operating characteristic discriminating IBD from controls was similar for FC and SC(0.95, 95% CI 0.87–1.00 and 0.89, 95%CI 0.81–0.98 respectively;p = 0.36). SC was the strongest individual predictor of IBD diagnosis (odds ratio (OR): 12.33 (95% CI 4.48–38.33, p = 3.5×10−6) compared with other markers (CRP: OR 4.44, CI 1.58–12.90; albumin: OR 5.65, CI 1.98–17.16). At follow up (median 342 days; IQR: 88–563),a total of 1 (2%), 16 (47%),23 (51%) patients required treatment escalation in the IBDU, CD and UC group respectively.SC predicted treatment escalation and/or surgery in IBD (HR 2.4, 95% CI: 1.1–4.9), in particular CD (HR 4.1, 95% CI 1.1–14.7). A model incorporating SC, CRP and albumin has a positive likelihood ratio of 20.03 for IBD.At 1 year, our prognostic model can predict treatment escalation in IBD in 65% of cases (95% CI: 43–79%) and 80% (95% CI: 31–94%) in CD if 2 or more blood marker criteria are met. Conclusion Sampling faeces can be a hurdle for patients and some individuals can decline FC testing. These factors impact on the practical utility of FC.SC shows promise as a diagnostic and prognostic biomarker in IBD. Our findings warrant further exploration and validation within large multicentre cohorts. Reference 1 Lee JC, et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest 2011;121:4170–9. Disclosure of Interest None Declared

Breast cancer in men is rare. Breast cancer presenting initially as an abscess has been described only a handful of times in the literature. We present the first described case of invasive adenocarcinoma presenting as an abscess in a man. An 80-year-old diabetic man presented with symptoms typical of a breast abscess. The abscess failed to respond to percutaneous therapy and excision of breast abscess was performed. Histology revealed an invasive carcinoma. He went on to have a mastectomy. Histology should be obtained from breast abscesses not resolving within 2 months of initial percutaneous therapy. Histology could be obtained by ultrasound-guided fine-needle aspiration (FNA), core or vacuum assisted biopsy, or by formal incision and drainage.

Introduction Epigenetic alterations including DNA methylation may provide important insights into gene-environment interaction in complex immune diseases such as inflammatory bowel disease (IBD). Whilst whole tissue methylation changes may provide clinically useful biomarkers, epigenetic changes are cell-type specific. This study aimed to characterise the circulating methylome in IBD, and relate changes seen in whole blood to the methylation profile in separated leucocytes, gene expression data, as well as our previous data in childhood-onset disease. 1 Method The Illumina 450k array was used to assess whole blood leucocyte DNA methylation at over 485,000 CpG sites across the genome in 240 patients (121 Crohn’s disease [CD], 119 ulcerative colitis [UC]) and 191 controls. Differentially methylated sites discovered in whole blood were investigated in immunomagnetically separated leucocytes (CD4 + and CD8 + lymphocytes, CD14 + monocytes). Results There were 439 differentially methylated positions (DMPs) meeting epigenome wide significance as defined as a Holm corrected p value of –7 ) in IBD cases versus control. No markers were significantly different between CD and UC. There were 55 differentially methylated regions (DMRs) with unidirectional methylation change in 3 or more adjacent markers each achieving False Discovery Rate significance of p There was significant enrichment of methylation alteration around known susceptibility loci. 2 Linear Discriminant analysis using two CpG sites discriminated IBD cases and controls with high accuracy (area under curve 0.87). Established as well as novel pathways pertinent to disease pathogenesis are strongly implicated. The most significantly DMP in whole blood (RPS6KA2 [corrected p = 1.2 × 10 –16 ] was also hypomethylated in monocytes in UC (uncorrected p = 3.5 × 10 –6 ). The most significant DMR,VMP1/miR21 (most significant probe corrected p = 2 × 10 –14 ) strongly replicates the same finding in our previous study. The gene encoding Beta-2 Integrin (ITGB2) was a hypermethylated DMR in IBD and more specifically CD (most significant probe corrected p = 3.3 × 10 –5 ) compared with controls. Conclusion This is the most detailed characterisation of the epigenome carried out in IBD to date and includes novel data exploring the circulating methylome in UC. The findings strongly validate this approach in complex disease, replicate and expand previous data, and provide clear translational opportunities. Disclosure of interest N. Ventham Grant/Research Support from: EC grant IBD-BIOM, Conflict with: Abbvie, MSD speakers fees, N. Kennedy Grant/Research Support from: Wellcome Trust, Conflict with: Abbvie, MSD, Warner Chilcott, Ferring speakers fees. Shire Travel bursay, A. Adams: None Declared, R. Kalla: None Declared, K. O’Leary: None Declared, IBD BIOM consortium: None Declared, D. Wilson Grant/ Research Support from: MRC, CICRA, and EC grant IBD-BIOM, Consultant for: Pfizer, Conflict with: MSD investigator grant, MSD speaker fee, and Ferring speaker fee, E. Nimmo Grant/ Research Support from: EC grant IBD-BIOM, CSO, J. Satsangi Grant/ Research Support from: EC grant IBD-BIOM, Wellcome, CSO, MRC, Consultant for: Takeda, Conflict with: MSD speaker fees. SHire travelling expenses. References Adams AT, et al . IBD 2014;20(10):1784–93 Jostins L, et al . Nature 2012; 491(7422):119–24

Introduction Advances in protein profiling using proximity extension assays (PEA) have transformed our ability to compare concentrations of multiple proteins across biological samples. PEA utilises the specificity of antibody proximity and the sensitivity of polymerase chain reaction (qPCR) to detect proteins of interest. As part of the EC funded IBD Character initiative to discover biomarkers for clinical use using multiomic technologies, we performed high-throughput prospective case-control serum profiling to identify protein biomarkers that can predict Inflammatory Bowel Disease (IBD). Method Utilising Proseek Multiplex panels (Olink Bioscience, Sweden), serum profiling was performed in patients with a new diagnosis of IBD. Our control group consisted of symptomatic individuals. Phenotypic data was captured including age, sex, diagnosis and IBD medications. Statistical analysis was performed using R. Data were normalised and then batch corrected using ComBAT. Linear models were created for each protein including age and sex as covariates. After quality control, data from 186 proteins was available for analysis. Results A total of 245 patient serum samples (n = 153) newly diagnosed IBD, n = 92 symptomatic controls) from 4 IBD centres from Norway, United Kingdom and Sweden were included in the study from December 2012 to June 2014. 70 had Crohn’s disease (CD), 70 ulcerative colitis (UC) and 13 Inflammatory Bowel Disease Unclassified (IBDU). The mean age of the entire cohort was 33 years (range 0–79 years) and 54% were female. Multivariable analysis identified a set of 48 protein markers that were significantly associated with IBD. The 5 most significant protein markers were MMP-12 (Holm-adjusted p = 3.3 × 10 –13 ), OSM (p = 2.4 × 10 –12 ), CXCL9 (p = 1.7 × 10 –9 ), MMP10 (p = 1.7 × 10 –9 ) and EGFR (p = 1.8 × 10 –9 ). Of these five, all except EGFR were upregulated in IBD. The top 2 markers, MMP-12 and OSM were able to discriminate IBD from controls with an area under the receiver operator characteristics curve of 0.81 and 0.75 respectively. Using linear discriminant analysis, a combined biomarker consisting of MMP-12 and OSM was able to discriminate IBD from controls with a sensitivity and specificity of 80% and 72% respectively. Conclusion We have identified serum biomarkers that can predict IBD. These data demonstrate a potential for a PEA multiplex technology in IBD diagnostics and its ability to identify novel proteins that may be relevant in disease pathogenesis. Disclosure of interest R. Kalla Grant/Research Support from: IBD Character, N. Kennedy Grant/Research Support from: Wellcome Trust, Conflict with: Abbvie, MSD, Warner Chilcott, Ferring speaker fees, F. Hjelm: None Declared, E. Modig: None Declared, M. Sundell: None Declared, J. Soderholm: None Declared, B. Andreassen: None Declared, D. Bergemalm: None Declared, N. Ventham Grant/Research Support from: IBD BIOM, H. Hjortswang: None Declared, R. Petr: None Declared, M. Vatn: None Declared, J. Halfvarson: None Declared, M. Gullberg: None Declared, J. Satsangi Grant/Research Support from: EC Grants, Wellcome, CSO, MRC, Consultant for: Takeda, Conflict with: MSD speaker fees.

Background: Although endoscopy is the gold standard for the assessment of activity in Crohn's disease (CD), it should be integrated with clinical, laboratory, and radiological data. In particular, it is still unclear when MRI should be performed. Aim: To evaluate the advantages and limitations of endoscopy and MRI to assess disease activity and severity in a series of CD patients. Material and methods: 50 consecutive patients with endoscopically provenCD underwentMRI enterography for the staging at diagnosis or follow-up. Endoscopic activity was measured by SES-CD (range 0-40) with active mild,moderate ad severe disease defined as a scores 4-10,11-19 and >20 respectively. MRI activity was measured by a validated quantitative score which integrates both mural and extramural involvement (Magnetic Resonance Enterography global score,MEGS,range 0-296), with active disease present for a ≥ 1 score. CDAI, CRP and fecal calprotectin (FC) were measured in all participants (positivity cut-off respectively >0,50 mg/dl and >150 μg/gr). Results: We enrolled 20 males and 30 females (diagnosis in 62%, follow-up in 38%), mean age 38±15 years,mean disease duration 5,4±5 years. SES-CD and MEGS were well correlated (r=0,42, p=0.001); both SESCD andMEGS show correlation with clinical (CDAI r=0,51,r=0,59, p

The bottom line Crohn’s disease is a chronic inflammatory disorder that can affect any part of the gastrointestinal tract. Although the disease most commonly presents at a young age, it can affect people of all ages. Patients often present with persistent diarrhoea, abdominal pain, and weight loss. Crohn’s disease has a global impact on patients’ education, work, and social and family life. High quality multidisciplinary care, of which primary care is a key aspect, can attenuate relapse, prevent long term complications, and improve quality of life. In this review we provide a practical approach to the diagnosis, management, and long term care of patients with Crohn’s disease. #### Sources and selection criteria We carried out an electronic search of PubMed, the Cochrane Library, and Ovid databases for articles using the term “Crohn’s disease”. We limited studies to those in adults and focused on high quality randomised control trials, meta-analyses, and systematic reviews. Crohn’s disease is an idiopathic, chronic relapsing immune mediated disease, the pathogenesis of which remains incompletely understood, although the condition is thought to arise from environmental priming and …

Introduction We have previously demonstrated concerningly high 3-year mortality following hospitalisation with ulcerative colitis (UC) between 1998 and 2000 in Scotland. 1 We have extended these studies by examining 3-year mortality following hospitalisation with UC in Scotland between 2007–2009, providing an opportunity for comparison with our earlier results. Aim To compare 3-year mortality, and factors related to mortality, in Scottish patients hospitalised with ulcerative colitis (UC) between Period 1 (1998–2000) and Period 2 (2007–2009). Methods The Scottish Morbidity Records and linked datasets were used to assess 3-year crude mortality, standardised mortality ratio (SMR) and multivariate analyses of factors associated with 3-year mortality. The 3-year mortality was determined after four admission types: surgery-elective or emergency; medical-elective or emergency. Age-standardised mortality rates (ASR) were used to compare mortality rates between periods. Results The admission rate with UC increased from 10.6 per 100,000 of the Scottish population per year in Period 1 to 11.6 in Period 2 (p = 0.046). Among those admitted with UC, the proportion aged 65 yrs age group crude 3-year mortality fell (38.8% to 28.7%, p = 0.02). The overall SMR in period 1 was 3.04 and 2.96 in Period 2. Directly age standardised mortality decreased from 373 (CI 309–437) to 264 (CI 212–316) per 10,000 person years. On multivariate analysis, older age and co-morbid remained associated with 3-year mortality in Period 2. Conclusion Although the mortality associated with admission remains high at 3 years, crude and adjusted rates suggest significant reductions over the last decade. Reference Nicholls RJ, Clark DN, Kelso L, et al . Nationwide linkage analysis in Scotland implicates age as the critical overall determinant of mortality in ulcerative colitis. Aliment Pharmacol Ther 2010;31:1310–21 Disclosure of Interest N. Ventham: None Declared, N. Kennedy: None Declared, A. Duffy: None Declared, D. Clark: None Declared, A. Crowe: None Declared, A. Knight: None Declared, J. Nicholls Grant/research support from: A grant was obtained from AbbVie Ltd to be administered by the North West London Hospital Trust (NWLHT) on behalf of Prof Nicholls, to allow funding of ISD and Corvus Communications for their work on the project. In the context of the work presented in this manuscript and in consideration of BMJ guidance, none of the authors have any competing or other conflict of interest, J. Satsangi: None Declared.

in the CD4+aEb7 compartment (p < 0.001). IL-10 was not differentially expressed between CD4+aEb7+ and CD4+aEb7 lymphocytes in controls or UC, and a low frequency of aEb7+FOXP3+ cells was observed by IHC. qPCR array confirmed higher mRNA levels of IFNg (p < 0.001), TNFa (p < 0.01) and IL-17A (p < 0.01), and lower transcription of FOXP3 (p < 0.0001) in CD4+aEb7+ cells compared to CD4+aEb7 cells. Conclusions: aEb7 expression was associated with an enrichment of pro-inflammatory Th17, Th1 and Th17/Th1 T lymphocytes, and not associated with a regulatory phenotype. These data suggest therapeutic interventions targeting aE expressing T cells and the aEb7 integrin itself may be viable approaches for reducing aberrant inflammatory responses in UC.