Robb Le (knotcanada38)

SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online. © The Author(s) (2020). Published by Oxford University Press. All rights reserved. For Permissions, please email journals.permissions@oup.com.BACKGROUND Rapid blood culture diagnostics are costly and of unclearbenefit for patients with Gram-negative bacilli (GNB) bloodstream infections (BSIs). We conducted a multicenter, prospective, randomized controlled trial comparing outcomes of patients with GNB BSI who had blood culture testing with standard of care (SOC) culture and antimicrobial susceptibility testing (AST) versus rapid organism identification (ID) and phenotypic AST using the Accelerate Pheno™ System (RAPID). METHODS Patients with positive blood cultures with Gram stains showing GNB were randomized to SOC testing with antimicrobial stewardship review (AS) or RAPID with AS, at two medical centers between 10/2017-10/2018. The primary outcome was time to first antibiotic modification within 72 hours of randomization. RESULTS Of 500 randomized subjects, 448 were included (226 SOC, 222 RAPID). Mean (S.D.) hours to results was faster for RAPID than SOC for organism ID [2.7 (1.2) vs 11.7 (10.5), p less then 0.001] and AST [13.5 (56) vs. 44.9 (12.1), p less then 0.001]. Median (IQR) hours to first antibiotic modification was faster in the RAPID vs. SOC arm for overall antibiotics [8.6 (2.6, 27.6) vs. 14.9 (3.3, 41.1), difference 6.3, p=0.02] and Gram-negative antibiotics [17.3 (4.9, 72) vs. 42.1 (10.1, 72), difference 24.8, p less then 0.001]. Median (IQR) hours to antibiotic escalation was faster in the RAPID vs. SOC arm for antimicrobial-resistant BSIs [18.4 (5.8, 72) vs. 61.7 (30.4, 72), difference 43.3, p=0.01]. There were no statistically significant differences between the arms in patient outcomes including mortality and length of stay. CONCLUSION Rapid organism ID and phenotypic AST led to faster changes in antibiotic therapy for Gram-negative BSIs. (Funded by the U.S. NIH UM1AI104681; ClinicalTrials.gov number, NCT03218397.). © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.CONTEXT Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not. OBJECTIVE To test whether genetically determined variation in normal-range thyroid function is causally associated with the risk of stroke and Coronary Artery Disease (CAD), and investigate via which pathways these relations may be mediated. DESIGN Setting and ParticipantsMendelian Randomization (MR) analyses for stroke and CAD using genetic instruments associated with normal-range TSH and FT4 levels or Hashimoto's disease and Graves' disease. The potential mediating role of known stroke and CAD risk factors was examined. Publically available summary statistics data were used. MAIN OUTCOME MEASURES Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels. RESULTS A one SD increase in TSH was associated with a 5% decrease in the risk of stroke (OR=0.95, 95% CI= 0.91 to 0.99, p=0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation (AF). MR analyses did not show a causal association between normal-range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto's Disease and a 7% increased risk of CAD (OR=1.07, 95% CI= 1.01 to 1.13, p=0.026), which was mainly mediated via body mass index. CONCLUSION These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke and CAD. We identify variation in normal-range thyroid function and Hashimoto's Disease as risk factors for stroke and CAD, respectively. © Endocrine Society 2020. All rights reserved. For permissions,