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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.

Aims Within this region, Upper GI and Colorectal subspecialties are located at separate hospitals. This study aims to determine outcomes of critically unwell patients undergoing emergency colorectal surgery off-site at the non-colorectal specialist centre. Methods An observational retrospective study of emergency colorectal laparotomies at a major acute teaching hospital (non-colorectal specialist centre) between January 2016 and August 2020 was performed. The primary outcome was 30-day mortality. Secondary outcomes included rate of primary anastomosis, complications and overall mortality. The NELA predicted mortality risk was obtained from notes or retrospectively calculated. Subgroup analysis of colorectal surgeon involvement was performed. Results One hundred and eighteen patients were included (median age 64 years, 55% female). The median NELA mortality score was 5.8% (IQR 1.9 – 14.7%). The 30-day mortality rate was 22% (26/118). The rate of primary anastomosis was 31%. Patients having an anastomosis had a lower median NELA score compared those patients who did not (1.6% vs. 7.85%). Forty five (38%) patients had Clavien-Dindo grade IV-V complication. Colorectal Surgeon involvement in the operation (23/118), was associated with a lower 30-day mortality (17.4% colorectal surgeon vs. 23.2% emergency general surgeon alone) albeit in patients with a lower median NELA score (4.5% vs. 6.7%) and a similar rate of primary anastomosis was achieved (31.6% vs. 30.9%). Conclusions The high mortality rate highlights a specific group of acutely unwell patients unfit for transfer to the subspecialist unit. Good outcomes were seen where a colorectal surgeon was involved, however a similar rate of primary anastomosis was demonstrated.

Aims This audit aimed to assess pre-operative NELA risk score documentation and subsequent specialist peri-operative critical care involvement. Methods This complete audit cycle retrospectively reviewed notes (electronic patient records, anaesthetic charts and CEPOD booking forms) of all patients undergoing emergency laparotomy between March and May 2019. The NELA score was calculated retrospectively if not documented. Following the initial audit, the following multi-disciplinary interventions were instituted: alteration of the physical CEPOD booking form to include NELA score (Surgical); a sticker added to anaesthetic charts to prompt NELA calculation (Anaesthetic), formal recording of NELA score during theatre brief (Theatre staff); and by increasing awareness of NELA via departmental education (All). The audit cycle was completed by reassessment between October and November 2020. Results The initial cycle included 34 patients, with only 2 (6%) having a NELA documented. The repeat cycle included 35 patients, with 29 (83%) having a NELA documented. Regarding post-operative critical care admissions, both cycles found that 100% of patients with a NELA of ≥ 5%, were admitted to either surgical HDU or ICU (n = 17 in first cycle, n = 17 in second cycle). For those with a high-risk NELA of ≥ 10% (n = 11 in first cycle, n = 7 in second cycle), only 2 (18%) were admitted to ICU in the first cycle vs 7 (100%) in the second cycle. Conclusions This complete audit cycle demonstrates improved NELA score calculation following institution of several multidisciplinary interventions. The improved NELA score uptake was associated with increased critical care review and admission to ITU in high-risk cases.

A blood-based prognostic biomarker to guide clinical decision-making at diagnosis of inflammatory bowel disease (IBD) would be immensely helpful. We investigated a composite serum N-glycomic biomarker to predict future disease course in 244 newly diagnosed IBD patients. Forty-seven 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 a HR of 5.1 (p = 1.1×10− 5; 95% CI, 2.54–10.1). These data demonstrate the predictive capacity of serum N-glycan biomarkers and represent a step towards personalized medicine in IBD.

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.

The European Union offers opportunities for high-level of funding of collaborative European research. Calls are regularly published: after the end of the FP7 funding programme the new round of Horizon 2020 calls started in 2015. Several topics are relevant to inflammatory bowel disease (IBD) challenges, including chronic disease management, biomarker discovery and new treatments developments. The aim of this Viewpoint article is to describe the new Horizon 2020 instrument and the project submission procedures, and to highlight these through the description of tips and tricks, taking advantage of four examples of successful projects in the field of IBD: the SADEL, IBD-BIOM, IBD Character and BIOCYCLE projects.

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 The Montgomery ruling has had a wide-ranging impact on the consent process and has been the subject of new guidelines by bodies, including the Royal College of Surgeons (RCSEng). This is the first study to examine the current standard of consent for surgical procedures at a national level. Method A national collaborative research model was used, with prospective data collection performed across hospitals in Scotland. Variables associated with the consent process were audited across three surgical specialities (general surgery, urology and orthopaedics) and measured against standards set by RCSEng, the Scottish Public Services Ombudsman and medical defence organisations. Results A total of 289 cases were identified from 12 hospitals. The majority of patients were reviewed by a consultant surgeon in clinic (79.9%) or on the day of surgery (55.4%). The clinic consent rate was 27.0%, while a copy of the documented discussion was only provided to 4.2% of patients. On the day of surgery, the benefits, risks and alternatives to the planned procedure were discussed in less than half of cases. This rate was similar across different clinician grades, while marked variation was seen across hospitals. Conclusion In this prospective multi-centre study we have demonstrated wide variation in the consent processes in many surgical specialities across Scotland. Following the Montgomery ruling, we have demonstrated the current consent process in elective surgery is likely to be substandard, and may require additional steps to be taken by clinicians to ensure patients are fully informed to make decisions regarding their treatment.

Placement of sterile multiholed wound catheters can provide continuous administration of local anaesthetic (LA) via an elastomeric pump, thereby extending the duration of action of LA beyond the first post-operative day. The relative simplicity of placement under ultrasound guidance or under vision at the time of closure of the operative wound is an advantage, and may avoid some of the incumbent risks of landmark-based neuraxial and nerve block techniques. An accumulating body of evidence suggests an improved overall quality of recovery with LA continuous wound infusion (CWI) with earlier return of gut function and shorter hospital stay, probably due to the opioid sparing effect. In the context of abdominal surgery,wound catheters should be positioned pre-peritoneally in the subfascial or transversus abdominis plane to provide effective analgesia. Long acting LA with an adequate flow-rate is advocated to maintain adequate dispersion across the subfascial plane. CWI is generally safe, although more research is required to better understand pharmacodynamics/kinetics and to avoid LA toxicity from systemic absorption. CWI with LA is efficacious as part of a multimodal analgesic regimen to facilitate enhanced recovery after major abdominal surgery .

Background A liver resection under low central venous pressure (CVP) has become standard practice; however, the benefits beyond a reduction in blood loss are not well reported. Moreover, the precise method to achieve CVP reduction has not been established. A systematic review and meta analysis of randomized controlled trials (RTCs) was performed to assess the effects of CVP on clinical outcome and to identify the optimum method of CVP reduction. Methods EMBASE, Medline, PubMed and the Cochrane database were searched for trials comparing low CVP surgery with controls. The primary outcome was post operative complications within 30 days. Secondary outcomes included estimated blood loss (EBL), blood transfusion rates and length of stay (LOS). Sub group analysis was performed to assess the CVP reduction method on the outcome. Results Eight trials were identified. No difference was observed in the morbidity rate between the high CVP and control groups [odds ratio (OR) = 0.96 (95% confidence interval (CI) 0.66, 1.40) P = 0.84, I 2 = 0%]. EBL [weighted mean difference (WMD) = −308.63 ml (95% CI −474.67, −142.58) P = I 2 = 73%] and blood transfusion rates [OR 0.65 (95% CI 0.44, 0.97) P = 0.040, I 2 = 37%] were significantly lower in the low CVP groups. Neither anaesthetic nor surgical methods of CVP reduction were associated with a reduced post operative morbidity. Conclusion Low CVP surgery is associated with a reduction in EBL; however, this does not translate into an improvement in post operative morbidity. The optimum method of CVP reduction has not been identified.

Intravenous (IV) lidocaine has analgesic and anti-inflammatory properties. This study aims to evaluate the efficacy of IV lidocaine in controlling postoperative pain following laparoscopic surgery. A meta-analysis of randomised controlled trials (RCTs) comparing IV lidocaine versus placebo/routine treatment for postoperative analgesia following laparoscopic surgery. The primary outcome was opiate requirement at 24 h. Secondary outcomes included cumulative opiate requirement, numerical pain scores (2, 12, 24, 48 h at rest and on movement), recovery indices (nausea and vomiting, length of stay, time until diet resumption, first flatus and bowel movement) and side effects (cardiac/neurological toxicity). Subgroup analyses were performed according to operation type and to compare IV lidocaine with intraperitoneal lidocaine. Fourteen RCTs with 742 patients were included. IV lidocaine was associated with a small but significant reduction in opiate requirement at 24 h compared with placebo/routine care. IV lidocaine was associated with reduced cumulative opiate requirement, reduced pain scores at rest at 2, 12 and 24 h, reduced nausea and vomiting and a shorter time until resumption of diet. The length of stay did not differ between groups. There was a low incidence of IV lidocaine-associated toxicity. In subgroup analyses, there was no difference between IV and intraperitoneal lidocaine in the measured outcomes. IV lidocaine has a multidimensional effect on the quality of recovery. IV lidocaine was associated with lower opiate requirements, reduced nausea and vomiting and a shorter time until resumption of diet. Whilst IV lidocaine appears safe, the optimal treatment regimen remains unknown. Statistical heterogeneity was high.

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.

Intravenous (IV) fluid administration continues to be a mainstay of care in General Surgery. Yet if they are prescribed incorrectly significant morbidity including electrolyte abnormalities, renal impairment and cardiac failure can develop. Despite this, it is frequently the responsibility of the most junior staff to prescribe IV fluids. We aim to analyse the understanding of IV fluid prescribing amongst junior doctors and to describe variability in clinical practice.We undertook a multicentre questionnaire study. Foundation doctors and specialty trainees were invited to undertake a two part paper-based questionnaire. Part one analysed baseline knowledge of the concentration of commonly prescribed fluids. Part two consisted of four clinical vignettes requiring a IV fluid prescribing decision by the surveyed doctor.A total of 143 Doctors working in 8 hospitals were recruited. 65 (45.5%) doctors correctly stated the daily maintenance fluid requirements of water for an adult (25-30 mls/kg/day), while only 54 (37.8%) knew the sodium concentration of 0.9% NaCl. Lack of postgraduate experience (p = 0.011), qualifying from a medical school outside the United Kingdom (p 0.0001) and working in one of the eight hospitals in this study (p 0.0001) were associated with a lower knowledge level. There was limited consensus in prescribing in the responses to the 4 clinical scenarios, with 69 unique combinations of fluid choice, rate and volume prescribed.Knowledge of the constituents of common IV fluids and routine requirement for fluid and common electrolytes is poor across junior doctors of all grades, driving large variation in clinical practice.

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.

Aim Reduced opioid use in the immediate postoperative period is associated with decreased complications. This study aimed to determine the effect of transversus abdominis plane (TAP) block on morphine requirements 24 h after abdominal surgery. Secondary outcomes included the effect of TAP block on morphine use 48 h after surgery, incidence of postoperative nausea and vomiting (PONV) and impact on reported pain scores (visual analogue scale). Method A systematic review of the literature was conducted for randomised controlled trials (RCTs) evaluating the effects of TAP block in adults undergoing abdominal surgery. For continuous data, weighted mean differences (WMD) were formulated; for dichotomous data, odds ratios (OR) were calculated. Results were produced with a random effects model with 95% confidence intervals (CI). Results Nine studies, including published and unpublished data, containing a total of 413 patients were included. Of these 205 received a TAP block and 208 a placebo. Cumulative morphine utilization was statistically significantly reduced at 24 h. [WMD = 23.71 mg (38.66–8.76); P = 0.002] and 48 h [WMD = 38.08 mg (18.97–57.19); P

INTRODUCTION Reducing exogenously administered opioids in the post-operative period is associated with early return of bowel function and decreased post-operative complication rates. We evaluated the effectiveness of a surgeon-delivered open transversus abdominis plane (TAP) block as a method to reduce post-operative opioid requirements, sedation and inpatient stay. METHODS The patient cohort was identified from those who had undergone a right hemicolectomy for colonic cancer. Patients received either an open TAP block and post-operative patient controlled anaesthesia (PCA) (n=20) or were part of a control group who received subcutaneous local anaesthetic infiltration and PCA (n=16). RESULTS PCA morphine use was reduced within the first 24 hours post-operatively in the TAP block group compared with controls (42.1mg vs 72.3mg, p=0.002). Sedation was also reduced significantly in the early post-operative period (pCONCLUSIONS Open TAP blocks are safe and reduce post-operative opioid requirements and sedation after right hemicolectomies. They should be considered as part of a multimodal enhanced recovery approach to patients undergoing abdominal surgery via a transverse incision.

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 …

Serum N-glycans have been identified as putative biomarkers for numerous diseases. The impact of different serum sample tubes and processing methods on N-glycan analysis has received relatively little attention. This study aimed to determine the effect of different sample tubes and processing methods on the whole serum N-glycan profile in both health and disease. A secondary objective was to describe a robot automated N-glycan release, labeling and cleanup process for use in a biomarker discovery system.25 patients with active and quiescent inflammatory bowel disease and controls had three different serum sample tubes taken at the same draw. Two different processing methods were used for three types of tube (with and without gel-separation medium). Samples were randomised and processed in a blinded fashion. Whole serum N-glycan release, 2-aminobenzamide labeling and cleanup was automated using a Hamilton Microlab STARlet Liquid Handling robot. Samples were analysed using a hydrophilic interaction liquid chromatography/ethylene bridged hybrid(BEH) column on an ultra-high performance liquid chromatography instrument. Data were analysed quantitatively by pairwise correlation and hierarchical clustering using the area under each chromatogram peak. Qualitatively, a blinded assessor attempted to match chromatograms to each individual.There was small intra-individual variation in serum N-glycan profiles from samples collected using different sample processing methods. Intra-individual correlation coefficients were between 0.99 and 1. Unsupervised hierarchical clustering and principal coordinate analyses accurately matched samples from the same individual. Qualitative analysis demonstrated good chromatogram overlay and a blinded assessor was able to accurately match individuals based on chromatogram profile, regardless of disease status.The three different serum sample tubes processed using the described methods cause minimal inter-individual variation in serum whole N-glycan profile when processed using an automated workstream. This has important implications for N-glycan biomarker discovery studies using different serum processing standard operating procedures.

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.

Serum N-glycans have been identified as putative biomarkers for numerous diseases. The impact of different serum sample tubes and processing methods on N-glycan analysis has received relatively little attention. This study aimed to determine the effect of different sample tubes and processing methods on the whole serum N-glycan profile in both health and disease. A secondary objective was to describe a robot automated N-glycan release, labeling and cleanup process for use in a biomarker discovery system.25 patients with active and quiescent inflammatory bowel disease and controls had three different serum sample tubes taken at the same draw. Two different processing methods were used for three types of tube (with and without gel-separation medium). Samples were randomised and processed in a blinded fashion. Whole serum N-glycan release, 2-aminobenzamide labeling and cleanup was automated using a Hamilton Microlab STARlet Liquid Handling robot. Samples were analysed using a hydrophilic interaction liquid chromatography/ethylene bridged hybrid(BEH) column on an ultra-high performance liquid chromatography instrument. Data were analysed quantitatively by pairwise correlation and hierarchical clustering using the area under each chromatogram peak. Qualitatively, a blinded assessor attempted to match chromatograms to each individual.There was small intra-individual variation in serum N-glycan profiles from samples collected using different sample processing methods. Intra-individual correlation coefficients were between 0.99 and 1. Unsupervised hierarchical clustering and principal coordinate analyses accurately matched samples from the same individual. Qualitative analysis demonstrated good chromatogram overlay and a blinded assessor was able to accurately match individuals based on chromatogram profile, regardless of disease status.The three different serum sample tubes processed using the described methods cause minimal inter-individual variation in serum whole N-glycan profile when processed using an automated workstream. This has important implications for N-glycan biomarker discovery studies using different serum processing standard operating procedures.

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).