Study CONSORT diagram detailing the flow of control and Barrett's esophagus patients (cases) through the study.

<p>Patients who were unable to swallow the Cytosponge or whose Cytosponge sample failed processing were excluded from the study. Exact numbers of control and BE patients who successfully completed the study are noted.</p

Sensitivity of the Cytosponge-TFF3 in different groups of patients (full dataset in S2 and S3 Tables).

<p>C, Circumferential length; IMC, intramucosal carcinoma; LGD, low grade dysplasia; M, maximal length; NDBE, non-dysplastic BE.</p><p>Sensitivity of the Cytosponge-TFF3 in different groups of patients (full dataset in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001780#pmed.1001780.s005" target="_blank">S2</a> and <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001780#pmed.1001780.s006" target="_blank">S3</a> Tables).</p

Modeling of Cytosponge-TFF3 testing and risk stratification in the primary care population with reflux symptoms.

<p>Extrapolation of findings to a hypothetical population of 10,000 individuals with reflux symptoms using a sensitivity and specificity of 79.9% and 92.4%, respectively, for the TFF3 screen, and a sensitivity and specificity of 86% (95% CI of 65%–96%) and 100% (95% CI of 94.6%–100%), respectively, for <i>TP53</i> mutation screening for detection of HGD. The assumed prevalence of BE was 3%. In patients found to be high risk, endoscopy within 6–8 wk would be recommended. For low-risk patients, a repeat Cytosponge-TFF3 test would be performed at an interval of several years (exact timing to be determined) in case they had become TP53 positive over this time period. In the TFF3-negative arm, the repeat Cytosponge testing might not be necessary. If it took place, repeat testing would be recommended within 6 to 8 wk of the delivery of the TFF3-negative results.</p

Clinical covariates have no impact on sensitivity and specificity of the test.

<p>Clinical covariates have no impact on sensitivity and specificity of the test.</p

Acceptability of endoscopy and the Cytosponge test.

<p>Patients were asked to rate the procedures using a visual analogue acceptability scale after swallowing the Cytosponge and after endoscopy. The colors representing the different acceptability scores are shown on the right-hand side, with 0 representing the worst experience ever, 5 representing a neutral experience, and 10 representing the best experience ever. The dotted red line marks the boundary between mildly unpleasant or worse (left of the line, score of 0–3) and acceptable scores (right of the line, score of 4 or more), for ease of comparison between the two procedures.</p

TFF3 immunohistochemical staining of Cytosponge samples.

<p>TFF3 staining was performed on all Cytosponge samples to test the sensitivity and specificity of the Cytosponge-TFF3 test for diagnosing BE. TFF3 was scored in a binary fashion, with samples with one or more TFF3-positive goblet cells being classed as positive. Shown are immunohistochemical images illustrating examples of TFF3-negative and-positive staining at low magnification (100×) and high magnification (400×).</p

Demographics of the BEST2 Study patient cohorts.

<p>^aBE defined as endoscopically visible columnar-lined esophagus that measured at least 1 cm circumferentially or at least 3 cm in non-circumferential tongues (Prague classification ≥C1 or ≥M3).</p><p>^bSex ratio rounded to the nearest tenth.</p><p>n/a, not applicable.</p><p>Demographics of the BEST2 Study patient cohorts.</p

Disentangling oncogenic amplicons in esophageal adenocarcinoma

Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons’ origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

BackgroundTranexamic 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.MethodsWe 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.FindingsBetween July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).InterpretationWe found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial.</div