SummaryBackgroundThe omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer chemoprevention, aligned with an excellent safety profile. Therefore, we aimed to test the efficacy of EPA and aspirin, alone and in combination and compared with a placebo, in individuals with sporadic colorectal neoplasia detected at colonoscopy.MethodsIn a multicentre, randomised, double-blind, placebo-controlled, 2 × 2 factorial trial, patients aged 55–73 years who were identified during colonoscopy as being at high risk in the English Bowel Cancer Screening Programme (BCSP; ≥3 adenomas if at least one was ≥10 mm in diameter or ≥5 adenomas if these were <10 mm in diameter) were recruited from 53 BCSP endoscopy units in England, UK. Patients were randomly allocated (1:1:1:1) using a secure web-based server to receive 2 g EPA-free fatty acid (FFA) per day (either as the FFA or triglyceride), 300 mg aspirin per day, both treatments in combination, or placebo for 12 months using random permuted blocks of randomly varying size, and stratified by BCSP site. Research staff and participants were masked to group assignment. The primary endpoint was the adenoma detection rate (ADR; the proportion of participants with any adenoma) at 1 year surveillance colonoscopy analysed in all participants with observable follow-up data using a so-called at-the-margins approach, adjusted for BCSP site and repeat endoscopy at baseline. The safety population included all participants who received at least one dose of study drug. The trial is registered with the International Standard Randomised Controlled Trials Number registry, number ISRCTN05926847.FindingsBetween Nov 11, 2011, and June 10, 2016, 709 participants were randomly assigned to four treatment groups (176 to placebo, 179 to EPA, 177 to aspirin, and 177 to EPA plus aspirin). Adenoma outcome data were available for 163 (93%) patients in the placebo group, 153 (85%) in the EPA group, 163 (92%) in the aspirin group, and 161 (91%) in the EPA plus aspirin group. The ADR was 61% (100 of 163) in the placebo group, 63% (97 of 153) in the EPA group, 61% (100 of 163) in the aspirin group, and 61% (98 of 161) in the EPA plus aspirin group, with no evidence of any effect for EPA (risk ratio [RR] 0·98, 95% CI 0·87 to 1·12; risk difference −0·9%, −8·8 to 6·9; p=0·81) or aspirin (RR 0·99 (0·87 to 1·12; risk difference −0·6%, −8·5 to 7·2; p=0·88). EPA and aspirin were well tolerated (78 [44%] of 176 had ≥1 adverse event in the placebo group compared with 82 [46%] in the EPA group, 68 [39%] in the aspirin group, and 76 [45%] in the EPA plus aspirin group), although the number of gastrointestinal adverse events was increased in the EPA alone group at 146 events (compared with 85 in the placebo group, 86 in the aspirin group, and 68 in the aspirin plus placebo group). Six upper-gastrointestinal bleeding events were reported across the treatment groups (two in the EPA group, three in the aspirin group, and one in the placebo group).InterpretationNeithe...

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

ObjectiveLow adenoma detection rates (ADR) are linked to increased postcolonoscopy colorectal cancer rates and reduced cancer survival. Devices to enhance mucosal visualisation such as Endocuff Vision (EV) may improve ADR. This multicentre randomised controlled trial compared ADR between EV-assisted colonoscopy (EAC) and standard colonoscopy (SC).DesignPatients referred because of symptoms, surveillance or following a positive faecal occult blood test (FOBt) as part of the Bowel Cancer Screening Programme were recruited from seven hospitals. ADR, mean adenomas per procedure, size and location of adenomas, sessile serrated polyps, EV removal rate, caecal intubation rate, procedural time, patient experience, effect of EV on workload and adverse events were measured.Results1772 patients (57% male, mean age 62 years) were recruited over 16 months with 45% recruited through screening. EAC increased ADR globally from 36.2% to 40.9% (P=0.02). The increase was driven by a 10.8% increase in FOBt-positive screening patients (50.9% SC vs 61.7% EAC, P<0.001). EV patients had higher detection of mean adenomas per procedure, sessile serrated polyps, left-sided, diminutive, small adenomas and cancers (cancer 4.1% vs 2.3%, P=0.02). EV removal rate was 4.1%. Median intubation was a minute quicker with EAC (P=0.001), with no difference in caecal intubation rate or withdrawal time. EAC was well tolerated but caused a minor increase in discomfort on anal intubation in patients undergoing colonoscopy with no or minimal sedation. There were no significant EV adverse events.ConclusionEV significantly improved ADR in bowel cancer screening patients and should be used to improve colonoscopic detection.Trial registration numberNCT02552017, Results; ISRCTN11821044, Results.

Background Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0•9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0•9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.

Background The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer (CRC) chemoprevention, aligned with an excellent safety profile. Objectives The objectives were to determine whether or not EPA prevents colorectal adenomas, either alone or in combination with aspirin, and to assess the safety/tolerability of EPA, in the free fatty acid (FFA) form or as the triglyceride (TG), and aspirin. Design This was a randomised, blinded, placebo-controlled, 2 × 2 factorial trial. Setting The NHS Bowel Cancer Screening Programme (BCSP). Participants Patients (aged 55–73 years) identified as ‘high risk’ (i.e. those who have five or more colorectal adenomas of < 10 mm in size or three or more colorectal adenomas if one is ≥ 10 mm in size) at screening colonoscopy. Interventions The interventions were capsules containing 2000 mg of 99% EPA–FFA or 2780 mg of 90% EPA–TG (equivalent to 2000 mg of FFA) taken daily, or identical placebo capsules; and 300 mg of aspirin taken daily, or an identical placebo, enteric-coated tablet. Both were taken for ≈1 year until surveillance colonoscopy. All participants and staff were unaware of treatment allocation. Main outcome measures The primary outcome was the number of participants with one or more colorectal adenomas [adenoma detection rate (ADRa)] at surveillance colonoscopy. Outcomes were analysed for all participants with observable follow-up data by an ‘at-the-margins’ approach, adjusted for BCSP site and by the need for repeat baseline endoscopy. Secondary outcome measures – these included the number of colorectal adenomas per patient [mean adenomas per patient (MAP)], ‘advanced’ ADRa and colorectal adenoma location (right/left) and type (conventional/serrated). Results Between November 2011 and June 2016, 709 participants were randomised, with 707 providing data (80% male, mean age 65 years). The four treatment groups (EPA + aspirin, n = 177; EPA, n = 179; aspirin, n = 177; placebo, n = 176) were well matched for baseline characteristics. Tissue EPA levels and tolerability were similar for FFA and TG users. There was no evidence of any difference in ADRa between EPA users (62%) and non-users (61%) [risk difference –0.9%, 95% confidence interval (CI) –8.8% to 6.9%] or for aspirin users (61%) versus non-users (62%) (risk difference –0.6%, 95% CI –8.5% to 7.2%). There was no evidence of an interaction between EPA and aspirin for ADRa. There was no evidence of any effect on advanced ADRa of either EPA (risk difference –0.6%, 95% CI –4.4% to 3.1%) or aspirin (risk difference –0.3%, 95% CI –4.1% to 3.5%). Aspirin use was associated with a reduction in MAP [incidence rate ratio (IRR) 0.78, 95% CI 0.68 to 0.90), with preventative efficacy against conventional (IRR 0.82, 95% CI 0.71 to 0.94), serrated (IRR 0.46, 95% CI 0.25 to 0.87) and right-sided (IRR 0.73, 95% CI 0.61 to 0.88) lesions, but not left-sided (IRR 0.85, 95% CI 0.69 to 1.06) adenomas. There was evidence of chemopreventive efficacy of EPA on conventional (IRR 0.86, 95% CI 0.74 to 0.99) and left-sided (IRR 0.75, 95% CI 0.60 to 0.94) adenomas, but not on total MAP (IRR 0.91, 95% CI 0.79 to 1.05) or serrated (IRR 1.44, 95% CI 0.79 to 2.60) or right-sided (IRR 1.02, 95% CI 0.85 to 1.22) adenomas. EPA and aspirin treatment were well tolerated, with excess mild/moderate gastrointestinal (GI) adverse events (AEs) in the EPA alone group. There were six GI bleeding AEs. Conclusion EPA and aspirin treatment were not associated with a reduction in ADRa. However, both agents displayed evidence of chemopreventive efficacy, based on adenoma number reduction, which was specific to adenoma type and location, and is compatible with known anti-CRC activity of aspirin. Limitations Limitations of the trial included the failure to recruit to the target sample size of 853, and an unexpected switch of EPA formulation mid-trial. Future work A future objective should be to understand the mechanism(s) of action of EPA and aspirin using the trial biobank. Established trial infrastructure will enable future trials in the BCSP. Trial registration Current Controlled Trials ISRCTN05926847. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.