Additional file 1: of Functional characterization of enhancer evolution in the primate lineage

Figure S1. Tiling Across Large Enhancer Regions. Figure S2. Reproducibility of Tiling Scores. Figure S3. Reproducibility of Functional Scores for Orthologs. Figure S4. Permuted Species’ IDs. Figure S5. Confidence of Ancestral Reconstructions. Figure S6. Sequence vs. Functional Divergence. Figure S7. Number of Prioritized Mutations per Tile. (DOCX 514 kb

Additional file 2: of Functional characterization of enhancer evolution in the primate lineage

Table S1. Tiling Scores. Table S2. TF motif enrichment. Table S3. gkm-SVM Prediction of Tiles. Table S4. Ortholog Scores. Table S5. Orthologs normalized to Human. Table S6. gkm-SVM Predictions of Orthologs. Table S7. Orthologs normalized to N2. Table S8. Enhancer Groups from Fig. 4. Table S9. Prioritized Mutations. (XLSX 974 kb

Genome Sequencing of Idiopathic Pulmonary Fibrosis in Conjunction with a Medical School Human Anatomy Course

<div><p>Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF). Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP), as opposed to IPF <i>per se</i>. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP), rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The <i>MUC5B</i> promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD) adjacent to <i>MUC5B</i>, nor did we discover other likely risk-contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with <i>MUC5B</i> dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education.</p></div

Variants associated with IPF that were also seen in this individual. Allele frequencies accessed 4/16/2014.

A<p>Discovery and ^Breplicate GWAS.</p><p>Variants associated with IPF that were also seen in this individual. Allele frequencies accessed 4/16/2014.</p

Integrated Genomics Viewer (IGV) screenshot of the rs35705950 variant.

<p>Integrated Genomics Viewer (IGV) screenshot of the rs35705950 variant.</p

Genes previously associated with familial IPF.

<p>Genes previously associated with familial IPF.</p

Sequencing coverage and variant distribution within the <i>MUC5B</i> locus.

<p>(<b>A</b>) Sequence coverage of the <i>MUC5B</i> gene. (<b>B</b>) Rare variants neighboring the <i>MUC5B</i> promoter variant rs35705950. Variant track is colored by allele frequency (blue: AF<2%, red: AF<5%, black: AF<10%). No other rare variants in this region overlap with putative transcription factor binding sites, consistent with the hypothesis that the rs35705950 is causative of <i>MUC5B</i> dysregulation. Plots were generated using the UCSC genome browser (<a href="http://www.genome.ucsc.edu" target="_blank">http://www.genome.ucsc.edu</a>).</p

Histological demonstration of the NSIP pattern of IPF in the patient's lungs. Microscopic examination of the lungs.

<p>(<b>A</b>) 40×; (<b>B</b>) 400×. Note uniform fibrotic thickening of the alveolar septae and type II pneumocyte hypertrophy. There was no histologic evidence of sarcoidosis, hypersensitivity pneumonitis, organizing pneumonia, or diffuse alveolar damage.</p

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