Podcasts about Randomization

N Engl J Med 2001;345:1667-1675Background: Angiotensin II is a peptide hormone that is part of the renin–angiotensin–aldosterone system (RAAS). Angiotensin II is a potent vasoconstrictor and growth-stimulating hormone. Data suggested that it plays a role in ventricular remodeling and progression of heart failure. Although treatment with angiotensin-converting enzyme inhibitors (ACEi) reduce angiotensin II levels, physiologically active levels of angiotensin II may persist despite long-term therapy.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.The Valsartan Heart Failure Trial (Val-HeFT) sough to assess whether the angiotensin-receptor blocker valsartan, could reduce mortality and morbidity when added to optimal medical therapy in patients with systolic heart failure.Patients: Eligible patients had left ventricular ejection fraction less than 40% and left ventricular dilation, in addition to having clinical heart failure for at least 3 months with NYHA class II, III or IV symptoms. Patient also had to have been receiving a fixed-dose drug regimen for at least two weeks, that could include ACEi, diuretics, digoxin, and beta-blockers.There were many exclusion criteria. We mention some here: Postpartum cardiomyopathy, acute myocardial infarction within 3 months, coronary artery disease likely to require intervention, serum creatinine >2.5 mg/dL and life expectancy less than 5 years.Baseline characteristics: Patients were recruited from 302 centers in 16 countries. The trial randomized 5,010 patients – 2,511 randomized to receive valsartan and 2,499 to receive placebo.The average age of patients was 63 years and 80% were men. The average left ventricular ejection fraction was 27%. Cardiomyopathy was ischemic in 57% of the patients. The NYHA class was II in 62% of the patients, III in 36% of the patients and IV in 2%.Approximately 26% had diabetes and 12% had atrial fibrillation.At the time of enrollment, 86% were taking a diuretic, 67% were taking digoxin, 35% were taking beta-blockers, and 93% were taking ACEi.Procedures: The trial was double-blinded. The trial had an initial run-in period for 2 - 4 weeks where patients received placebo twice daily. This was performed to confirm patients' eligibility, clinical stability and compliance.Patients were assigned in a 1:1 ratio to receive valsartan or placebo. Randomization was stratified according to whether or not they were receiving a beta-blocker.Valsartan was started at a dose of 40 mg twice a day, and the dose was doubled every two weeks to the target dose of 160 mg twice a day. Placebo doses were adjusted in a similar way.Follow up occurred at 2, 4, and 6 months and every 3 months thereafter.Endpoints: The trial had two primary end points. The first was all-cause mortality. The second was the combined end point of mortality and morbidity, which was defined as cardiac arrest with resuscitation, hospitalization for heart failure, or administration of intravenous inotropic or vasodilator drugs for four hours or more without hospitalization.The estimated sample size was 5,000 patients. The sample size calculation assumed 20% relative risk reduction in mortality with valsartan assuming 906 patients would die during the trial. This sample size would provide the trial 90% power at 0.02 alpha. Alpha was 0.02 instead of the traditional 0.05 since the trial had two primary endpoints and to adjust for the interim analyses.Results: The target valsartan dose of 160 mg twice a day was achieved in 84% of the patients. The reduction in systolic blood pressure was greater with valsartan vs placebo – mean of 5.2 ± 15.8 mm with valsartan compared to 1.2 ± 14.8 mm Hg with placebo, at 4 months.All-cause mortality was not different between both groups (19.7% with valsartan vs 19.4% with placebo, RR: 1.02, 95% CI: 0.88 – 1.18; p= 0.80). The second co-primary endpoint was reduced with valsartan (28.8% vs 32.1%, RR: 0.87, 95% CI: 0.77 – 0.97; p= 0.009). This was driven by reduction in hospitalizations for heart failure (13.8% vs 18.2%). Cardiac arrest with resuscitation was 0.6% with valsartan and 1.0% with placebo. All-cause hospitalization was numerically lower with valsartan, however, this was not statistically significance (2,856 vs 3,106; p= 0.14). The mean change in ejection fraction was higher with valsartan (4.0% vs 3.2%; p= 0.001). More patients had improvement in NYHA classification with valsartan (23.1% vs 20.7%; p

Stratified Randomization Study to Compare Different Duration of Dual Antiplatelet Therapy After Coronary Stenting in Either High or Low Bleeding Risk Population

Join Jay Gunkelman, QEEGD (the man who has read over 500,000 brain scans), Dr. Mari Swingle (author of i-Minds), and host Pete Jansons for one of the most entertaining and eye-opening episodes of the NeuroNoodle Neurofeedback Podcast to date. This week's guest is David Siever, founder of Mind Alive and creator of the DAVID Premier device — a revolutionary audiovisual entrainment tool designed to combat brain fog, burnout, and post-COVID crashes. From pirate anthems to cutting-edge neuroscience, we explore cerebral spinal fluid, mood recovery, detoxification, and why traditional sleep aids may be making things worse. Packed with science, storytelling, and a few sea shanties, this is an episode you don't want to miss.Topics Discussed

Timestamps:00:10: Introductions00:45: Where there is power, there's abuse. 03:05: Imbalance of power is inevitable. If we don't share power, we hoard it04:05: Can power ever be positive? To take action, we need power. It has the capacity to create good, but without any checks and balances, it goes too far06:45: Institutional power as a result of individual power. We willingly give up power to the institution09:05: How do we get the power back? Only collectively, large scale efforts can shift the power balance12:00: January 6th as a display of power, even if it's misguided14:30: How can we utilize power to make positive strides of change?17:15: Power-seekers aren't those who should have it. Perverse incentives20:30: Randomization as a potential solution to power hoarding21:15: How do we account for lack of knowledge in the randomization scenario? Town halls, bureaucracy, and trial and error24:00: Advisors as the lynchpins of powerSupport the showTwitter: @talkpopc Instagram: @talkpopc

N Engl J Med 2009;360:2503-2515Background: Type 2 diabetes increases the risk of cardiovascular events and death. Previous trials comparing revascularization versus medical therapy included patients with diabetes, however, a large-scale trial specifically focusing on patients with type 2 diabetes was lacking.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial sought to assess the optimal treatment strategy for patients with type 2 diabetes and stable coronary artery disease.Patients: Eligible patients had type 2 diabetes and stable coronary artery disease. Coronary artery disease was defined as a stenosis in a major coronary artery of 50% or more and a positive stress test or 70% or more and classic angina. Patients had to be candidates for percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) without further specification.Patients were excluded if they had left main disease, prior PCI or CABG within 12 months, class III or IV heart failure, hepatic dysfunction, creatinine> 2 mg/dL or glycated hemoglobin> 13%.Baseline characteristics: The trial randomized 2,368 patients – 1,176 randomized to the revascularization arm and 1,192 to the medical therapy arm. Among the 1,176 patients in the revascularization arm, 32% were planned to undergo CABG and 68% planned to undergo PCI.The average age of patients was 62 years and 70% were men. The mean glycated hemoglobin was 7.7% and the mean duration of diabetes was 10.4 years. Approximately 32% had prior myocardial infarction, 7% had congestive heart failure and 24% had peripheral artery disease. Approximately 18% had no angina or angina equivalent. Angina class within 6 weeks was 1-2 in 43% of the patients and 3-4 in 9%.The mean left ventricular ejection fraction was 57%. Approximately 31% had three-vessel disease and 13% had proximal left anterior descending artery disease.Baseline characteristics were well balanced between the revascularization arm and the medical therapy alone arm. However, patients who were in the CABG stratum had more three-vessel disease (52% vs 20%) and more proximal left anterior descending artery disease (19% vs 10%).Procedures: The trial was a 2 x 2 factorial design and patients were randomly assigned to two treatment strategies. The first was randomization to revascularization or medical therapy. The second was randomization to insulin-sensitization therapy or insulin-provision therapy. Randomization was stratified based on the method of revascularization (PCI vs CABG) which was determined by the treating physician.In this review, we will focus on the first strategy of revascularization vs medical therapy.For patients randomized to the revascularization arm, the procedure was to be performed within 4 weeks after randomization. Patients in the medical arm could receive revascularization on follow up for any of the following: Progression of angina, acute coronary syndrome or severe ischemia.Patients were seen monthly for the first 6 months and every 3 months thereafter.Endpoints: The primary endpoint was death from any cause. Secondary end point was a composite of death, myocardial infarction, or stroke.Analysis was performed based on the intention-to-treat principle. The original sample size of 2,800 patients was not met, and therefore, the average follow up time was increased by 1.5 years to become 5.3 years. Using the new follow up duration, the study had 88% power to detect a 33% relative risk reduction of death (from 14.0% to 9.8%), and a 95% power to detect a 25% relative risk reduction in the secondary composite endpoint (from 24.0% to 18.0%).Results: Among the patients randomized to the revascularization arm, 95.4% underwent revascularization at 6 months compared to 13.0% of the patients randomized to the medical arm. At 5-years, 42.1% of the patients randomized to the medical arm had undergone revascularization. Among patients who underwent PCI in the revascularization arm, procedures were attempted on average of 1.5 lesions and 56.0% received a bare metal stent. Among patients who underwent CABG in the revascularization arm, 94.2% received an internal mammary artery graft and the mean number of distal anastomoses was 3.0.The average follow up time was 5.3 years.There was no significant difference in the primary outcome of all-cause death. Survival was 88.3% in the revascularization arm and 87.8% in the medical arm (difference: 0.5%; 95% CI: −2.0 - 3.1; p=0.97). There was also no significant difference for the secondary composite endpoint. Freedom from events for the secondary endpoint was 77.2% in the revascularization arm and 75.9% in the medical arm (difference: 1.3%; 95% CI, −2.2 - 4.9; p=0.70).Survival was not significantly different between both treatment strategies in the CABG stratum (86.4% with revascularization vs 83.6% with medical therapy; p= 0.33). However, patients in the CABG stratum had more freedom from the secondary composite endpoint (77.6% vs 69.5%; p= 0.01).In the PCI stratum, revascularization did not improve survival (89.2% with revascularization vs. 89.8% with medical therapy; p= 0.48) or freedom from the secondary composite endpoint (77.0% with revascularization vs 78.9% with medical therapy; p= 0.15).Conclusion: In patients with type 2 diabetes and stable coronary artery disease, revascularization compared to medical therapy did not improve the primary outcome of all-cause death, or the composite secondary outcome of death, myocardial infarction or stroke over an average follow up time of 5.3 years.The observed benefit of revascularization within the CABG stratum should be viewed as hypothesis-generating rather than conclusive evidence that CABG is superior to PCI in this patient population.One potential limitation of this trial is that the authors included patients who were candidates for either PCI or CABG without providing enough details on what makes someone not a candidate. This lack of clarity limits physicians' ability to fully understand which patients would have been suitable for inclusion.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

In this World Shared Practice Forum podcast, Dr. Mark Peters discusses the Oxy-PICU trial, published in The Lancet in January 2024, which compared conservative to liberal oxygenation targets in critically ill children. The study highlighted the importance of pragmatic trial design and the need for larger trials to confirm these findings. LEARNING OBJECTIVES -Discuss the background driving the investigation of oxygenation in critically ill children -Summarize the study design of the Oxy-PICU Trial -Present the outcomes and challenges of the Oxy-PICU Trial -Identify the key characteristics of pragmatic trial design and the implication of pragmatic trial results AUTHORS Mark Peters, MBChB, MRCP, FFICM, FRCPCH, PhD Professor of Paediatric Intensive Care NIHR Senior Investigator UCL Great Ormond St Institute of Child Health Hon. Consultant Paediatric Intensivist Paediatric Intensive Care Unit and Children's Acute Transport Service Great Ormond St Hospital Jeffrey Burns, MD, MPH Emeritus Chief Division of Critical Care Medicine Department of Anesthesiology, Critical Care and Pain Medicine Boston Children's Hospital Professor of Anesthesia Harvard Medical School DATE Initial publication date: November 26, 2024. ARTICLES REFERENCED AND ADDITIONAL RESOURCES Peters MJ, Gould DW, Ray S, et al. Conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU): a UK multicentre, open, parallel-group, randomised clinical trial [published correction appears in Lancet. 2024 Jan 27;403(10424):354. doi: 10.1016/S0140-6736(24)00100-4]. Lancet. 2024;403(10424):355-364. https://pubmed.ncbi.nlm.nih.gov/38048787/ Fan E, Del Sorbo L, Goligher EC, et al. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome [published correction appears in Am J Respir Crit Care Med. 2017 Jun 1;195(11):1540. doi: 10.1164/rccm.19511erratum]. Am J Respir Crit Care Med. 2017;195(9):1253-1263. https://pubmed.ncbi.nlm.nih.gov/28459336/ Peters MJ, Ramnarayan P. Randomized Trials to Reduce Clinical Uncertainty: Gold Standard or Fool's Gold? Pediatr Crit Care Med. 2024;25(8):775-777. https://pubmed.ncbi.nlm.nih.gov/39101806/ Darnell R, Brown A, Laing E, et al. Protocol for a Randomized Controlled Trial to Evaluate a Permissive Blood Pressure Target Versus Usual Care in Critically Ill Children with Hypotension (PRESSURE). Pediatr Crit Care Med. 2024;25(7):629-637. https://pubmed.ncbi.nlm.nih.gov/38629915/ Taccone FS, Rynkowski Bittencourt C, Møller K, et al. Restrictive vs Liberal Transfusion Strategy in Patients With Acute Brain Injury: The TRAIN Randomized Clinical Trial. JAMA.Published online October 09, 2024. https://pubmed.ncbi.nlm.nih.gov/39382241/ Jones GAL, Eaton S, Orford M, et al. Randomization to a Liberal Versus Conservative Oxygenation Target: Redox Responses in Critically Ill Children. Pediatr Crit Care Med. 2023;24(3):e137-e146. https://pubmed.ncbi.nlm.nih.gov/36728001/ UK-ROX: https://www.icnarc.org/research-studies/uk-rox/ MegaROX: https://www.anzics.org/current-active-endorsed-research/mega-rox/ ICU-ROX: https://www.thebottomline.org.uk/summaries/icm/icu-rox/ TRANSCRIPT https://cdn.bfldr.com/D6LGWP8S/as/rq7kgwqkh4hk4nk67584pfj/202411_-_WSP_-_Less_is_more_Oxygenation_Targets_in_Critically_Ill_Children_-_Transcript?position=2 CITATION Peters MJ, Burns JP. Less is More: Oxygenation Targets in Critically Ill Children. 11/2024. OPENPediatrics. https://soundcloud.com/openpediatrics/less-is-more-oxygenation-targets-in-critically-ill-children-by-m-peters-openpediatrics.

N Engl J Med 2016;375:2223-2235Background: Smaller randomized trials have shown that outcomes are not significantly different when patients with left main disease are treated with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). In the subgroup of patients with left main disease in the SYNTAX trial, outcomes were similar between PCI and CABG in patients with low or intermediate SYNTAX score but PCI was associated with worse outcomes in patients with high SYNTAX score.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial sought to assess if PCI was noninferior to CABG in patients with left main coronary artery disease.Patients: Eligible patients had left main stenosis of 70% or more. Patients with stenosis of 50% to 69% were enrolled if the stenosis was hemodynamically significant as determined by non-invasive or invasive testing. Patients were also required to have low or intermediate SYNTAX score defined as a score of 32 or less.Patients were excluded if they had prior PCI to the left main coronary artery, PCI to any other coronary artery within 1 year, prior CABG, a need for a concomitant cardiac surgery, elevated CK-MB, or life expectancy less than 3 years due to non-cardiac conditions.Baseline characteristics: The trial randomized 1,905 patients – 948 randomized to PCI and 957 to CABG.The average age of patients was 66 years and 77% were men. Approximately 74% had hypertension, 70% had hyperlipidemia, 29% had diabetes, 17% had prior myocardial infarction and 22% were current smokers. The average left ventricular ejection fraction was 57%.The clinical presentation was myocardial infarction within 7 days in 14% of the patients, unstable angina in 24%, stable angina in 53%, and silent ischemia or other in 8%.Distal left main bifurcation or trifurcation disease was present in 81% of the patients, and 2- or 3-vessel coronary artery disease was present in 51%. SYNTAX score based on a core laboratory evaluation was low (22 or less) in 36% of the patients, intermediate (23-32) in 40% and high (33 or more) in 24%. However, based on site assessment, SYNTAX score was low in 61% of the patients and intermediate in 39%.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo CABG or PCI using fluoropolymer-based cobalt–chromium everolimus-eluting stents (XIENCE, Abbott Vascular). Randomization was stratified based on the presence of diabetes, SYNTAX score (low vs intermediate) and study center.Dual antiplatelets were given for at least 12 months following PCI.CABG was performed with or without cardiopulmonary bypass based on the operator discretion. The use of arterial grafts was recommended.Endpoints: The primary endpoint was a composite of death from any cause, myocardial infarction and stroke at 3 years. Secondary endpoints included the components of the primary endpoint as well as repeat revascularization.Analysis was performed based on the intention-to-treat principle. Sample size was calculated based on non-inferiority. The sample size to provided 80% power with one-sided alpha of 0.025 was 1,900 patients. This calculation was based on an assumed 11% event rate in each study group and 4.2% absolute difference non-inferiority margin.The original sample size was 2,600 patients which would have provided 90% power. However, both were adjusted due to slow enrollment.Results: Among the 948 patients assigned to the PCI arm, 99% underwent the procedure. The mean number of stents implanted per patient was 2.4. Among the 957 patients assigned to the CABG arm, 96% underwent the surgery. The mean number of grafts per patient was 2.6. An internal mammary artery graft was used in 99% of the patients. The median follow up time was 3 years.The primary composite endpoint was not significantly different between CABG and PCI (14.7% with CABG vs 15.4% with PCI, absolute difference: 0.7%, upper bound of the 97.5% CI: 4.0%; p= 0.02 for non-inferiority). There was no significant difference in death from any cause (5.9% with CABG vs 8.2% with PCI; p= 0.11), myocardial infarction (8.3% with CABG vs 8.0% with PCI, p= 0.64) or stroke (2.9% with CABG vs 2.3% with PCI; p= 0.37). Ischemia-driven revascularization was higher with PCI (12.6% vs 7.5%; p

Lancet 2016;388:2743-52Background: PCI was commonly used for the management of patients with left main coronary artery disease and favorable pathology (i.e., absence of complex lesions). This was recommended by the guidelines at the time and based mainly on the prespecified subgroup of 705 patients with left main disease in the SYNTAX trial. The NOBLE trial sought to more rigorously test the hypothesis that PCI with drug eluting stents was non-inferior to CABG in patients with unprotected left main coronary artery stenosis.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients: Inclusion criteria for study enrollment were stable angina pectoris, unstable angina, or acute coronary syndrome with a left main lesion with visually assessed stenosis diameter >/= 50% or fractional flow reserve I. The number of target lesions was 2 in both groups. The average SYNTAX score was 22.5 (for reference, it was 28.7 in the SYNTAX trial). The percentage of patients with stable angina was 82% and acute coronary syndrome was 18%. Patients were enrolled from 36 different centers but 5 centers contributed 42% of them. A screening log from these 5 centers was presented in the main paper. For these centers, the enrolled/screened ratio was 52%. The most common reasons for exclusion were unsuitable coronary anatomy for PCI.Procedures: Patients were assigned 1:1 to undergo PCI with drug eluting stents or CABG. After treatment of 73 patients with PCI, the Biolimus-eluting stent became the recommended study stent. Randomization was stratified by sex, the presence of a distal left main bifurcation lesion, and diabetes.The intent was to achieve complete revascularization of all vessels with significant lesions. The techniques for CABG and PCI as well as post-treatment medicines were chosen based on local practice but included 75-150 mg of aspirin lifelong. In both groups, patients with acute coronary syndrome received 75 mg of clopidogrel daily for 12 months. All patients in the PCI group also received 75 mg clopidogrel daily for 12 months and prasugrel or ticagrelor could be substituted at the discretion of the PCI operator.Endpoints: The primary endpoint was a composite of death from any cause, non-procedural myocardial infarction, repeat revascularization, or stroke.Analysis was performed based on the intention-to-treat principle. The primary analysis was a non-inferiority analysis. The main hypothesis tested was non-inferiority of PCI to CABG, assessed as the upper limit of the 95% CI of the hazard ratio (HR) of PCI to CABG, not exceeding 1.35 at median 3 years of follow-up. It should be noted that the sample size calculation for NOBLE was based on 1 year event estimates from the SYNTAX trial that were extrapolated to 2 years. The sample size of 1,200 patients came from the original hypothesis test of non-inferiority corresponding to a total of 275 events at median 2 years of follow-up. However, due to slow accrual of events, assessment of the primary endpoint could not be reached within the limit of the study and so the primary endpoint assessment was pushed back to 3 years of follow-up. Despite this, the prespecified event total (275 events) was not reached.Results: 1,201 patients were enrolled, which included 598 in the PCI group and 603 in the CABG group; however, only 592 patients in each group were entered into the final intention-to-treat analysis. Compared to CABG, PCI increased the primary composite endpoint (28% vs 18%; HR 1.51; 95% CI 1.13-2.00). Since the upper bound of the 95% CI was >1.35, PCI did not pass the test for non-inferiority. The primary outcome was driven mainly by differences in non-procedural MI (6% vs 2%; HR 2.87; 1.40-5.89) and repeat revascularization (15% vs 10%; HR 1.50; 1.04-2.17), which favored the CABG group. There was no difference in all-cause mortality (11% vs 9%; HR 1.08; 0.67-1.74) or its sub-component of cardiovascular mortality (3% vs 3%; HR 0.92; 0.44-1.90). The outcome of stroke was numerically higher with PCI but the difference was not statistically significant (5% vs 2%; HR 2.20; 0.91-5.36). When examining the Kaplan-Meier curves for the primary outcome, the curves start to diverge at 1 year.PCI was associated with significantly lower 30 day morbidity compared to CABG exemplified by 3 outcomes: duration of index treatment admission (2 vs 9 days; p

N Engl J Med 2009;360:961-972Background: After its introduction in 1968, the use of coronary artery bypass grafting (CABG) in patients with coronary artery disease grew rapidly. Although early trial results were mixed (see the Veterans Administration Cooperative study, the European Coronary Surgery Study and the CASS study), advancements in surgical techniques and the use of arterial conduits improved survival and reduced graft occlusion rates. In 1977, percutaneous coronary intervention (PCI) was introduced, and subsequent improvements in PCI techniques and stents have led to fewer complications and better stent patency. Large trials comparing CABG to PCI using drug-eluting stents were lacking.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial sought to assess the optimal revascularization strategy for patients with left main or three-vessel coronary artery disease.Patients: Eligible patients had three-vessel or left main coronary artery disease. Patients had to have 50% or more stenosis in the target vessels and either chest pain or evidence of myocardial ischemia. Exclusion criteria were previous PCI or CABG, acute myocardial infarction or the need for concomitant cardiac surgery.Baseline characteristics: The trial randomized 1,800 patients – 903 randomized to PCI and 897 to CABG.The average age of patients was 65 years and 78% were men. The average body mass index was 28 kg/m2. Approximately 67% had hypertension, 78% had hyperlipidemia, 25% had diabetes, 33% had prior myocardial infarction, 5% had congestive heart failure, and 20% were current smokers.The number of target lesions was approximately 4 in both groups. The SYNTAX score was 28.4 in the PCI group and 29.1 in the CABG group.Note to readers: The SYNTAX score is an anatomical score to grade the complexity of coronary artery disease with higher scores indicating more complex disease. A score of 22 or less is considered low whereas a score of 33 or more is considered high (this scoring was a prespecified secondary endpoint). Procedures: Patients were assigned in a 1:1 ratio to undergo CABG or PCI using Taxus Express paclitaxel-eluting stents (drug-eluting stent). Randomization was stratified by the presence or absence of left main disease and diabetes.The intent was to achieve complete revascularization in all coronary arteries of at least 1.5 mm diameter with 50% or more stenosis. The techniques for CABG and PCI and post procedural medications were chosen based on local practices.Endpoints: The primary endpoint was a composite of death from any cause, stroke, myocardial infarction, or repeat revascularization up to 12 months after randomization.Analysis was performed based on the intention-to-treat principle. The primary analysis was a non-inferiority analysis. The estimated sample size was 1800 patients assuming 13.2% event rate in the CABG group, 14.0% in the PCI group and 6.6% absolute risk difference non-inferiority margin. This sample size would provide 96% power at 5% one-sided alpha.Results: Revascularization was complete in 56.7% of the patients in the PCI group and 63.2% in the CABG group. In the CABG group, one or more arterial grafts were used in 97.3% of the patients. In the PCI group, the average number of stents implanted per patient was more than four.At 12 months, the primary outcome was lower in the CABG group (12.4% vs 17.8%, RR with PCI: 1.44, 95% CI: 1.15 – 1.81; p= 0.002). The absolute difference was 5.4% with an upper bounds of the 95% CI of 8.3%; thus not meeting non-inferiority. Stroke was lower with PCI (0.6% vs 2.2%; p= 0.003) while repeat revascularization was lower with CABG (5.9% vs 13.5%; p< 0.001). There was no significant difference in death from any cause (4.4% with PCI vs 3.5% with CABG; p= 0.37) or myocardial infarction (4.8% with PCI vs 3.3% with CABG; p= 0.11).There was a significant interaction based on the SYNTAX score where patients with high SYNTAX scores (>/=33) had significant benefit with CABG while patients with low or intermediate SYNTAX scores did not (14.7% with CABG vs 13.6% with PCI for low SYNTAX score, 12.0% with CABG vs 16.7% with PCI for intermediate SYNTAX score, and 10.9% with CABG vs 23.4% with PCI for high SYNTAX score; p for interaction= 0.01).In the subgroup of patients with left main disease, the rate of the primary outcome at 12 months was not significantly different between both treatment groups (13.7% with CABG vs 15.8% with PCI; p= 0.44). In patients with three-vessel but no left main disease, the primary outcome was significantly higher in the PCI group (19.2% vs 11.5%; p< 0.001).Stent thrombosis was 3.2% in the PCI group and graft occlusion was 3.1% in the CABG group.Conclusion: In patients with stable three-vessel or left main coronary artery disease, PCI did not meet non-inferiority compared to CABG in reducing the composite endpoint of death from any cause, stroke, myocardial infarction, or repeat revascularization over 12 months of follow up. The number of patients needed to treat with CABG to prevent one primary endpoint was approximately 19 patients, which was mainly accounted for by repeat revascularization. There was no significant difference in death or myocardial infarction and stroke was higher in the CABG group.The subgroup analysis based on SYNTAX score demonstrated a strong signal that CABG is more effective than PCI in patients with complex coronary artery disease. In patients with stable coronary artery disease, meeting the inclusion criteria of this trial, the risk of repeat revascularization with PCI should be carefully weighed against the increased stroke risk and invasiveness of CABG. Considerations regarding patient selection are crucial. It is reasonable to anticipate that less robust patients will have higher morbidity with CABG versus PCI.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

Lancet 1997;350(9076):461-468Background: In the ACME trial, percutaneous transluminal coronary angioplasty (PTCA) improved symptoms in patients with single-vessel stable coronary artery disease, but it did not lead to reduction in myocardial infarction or mortality, which were not primary endpoints and the study was under powered for these endpoints. The available data on the efficacy of PTCA for reducing hard endpoints were limited. Moreover, the findings from surgery trials had been inconsistent, as discussed in prior reviews.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The second Randomized Intervention Treatment of Angina (RITA-2) trial sought to test the hypothesis that coronary angioplasty compared to medical therapy improves outcomes in patients with coronary artery disease.Patients: Eligible patients were recruited from the United Kingdom and Ireland. Patients had to have significant stenosis amenable to dilation, in at least one major coronary artery. A significant coronary lesion was defined as a 50% or greater diameter stenosis in at least two radiographic projections or at least 70% diameter stenosis in one projection.Patients were not required to have current symptoms. Patients with multivessel coronary disease, occluded coronaries or who had abnormal left ventricular function were allowed to be enrolled, as well as patients with unstable angina if the most recent episode was at least 7 days before randomization. Patients were excluded if they had left main disease, prior revascularization procedure or recent myocardial infarction.Baseline characteristics: There were about 70,000 patients who underwent coronary angiogram during the recruitment phase. Around, 2,750 patients were eligible and among them 1,018 were randomized – 504 randomized to the PTCA arm and 514 to the medical therapy arm. The main reasons for not randomizing eligible patients were clinician's decision or patient's refusal.The average age of enrolled patients was 58 years and 82% were men. Approximately 47% had prior myocardial infarction and 9% took medications for diabetes.Approximately 20% reported no angina at the time of randomization. Single-vessel coronary artery disease was present in 60% of the patients, 2-vessel in 33% and 3-vessel in 7%.Approximately 87% were taking aspirin, 13% were taking lipid lower drugs, 67% were taking beta-blockers, 50% were taking calcium channel blockers, and 44% were taking long acting nitrates.Procedures: Patients were randomized to coronary angioplasty or medical therapy. Randomization was stratified by center, extent of coronary disease and the presence of recent unstable angina. PTCA was to be performed within 3 months of randomization. In patients with multivessel disease, not all lesions had to be dilated. Multivessel dilatation could be staged over more than one procedure. Conventional balloon dilatation was the intended strategy, but stents were permissible if the initial angioplasty result was unsatisfactory.Aspirin was recommended in all patients. Lipid lowering drugs were prescribed at the discretion of the treating physician.Patients were followed at 3 months, 6 months, then yearly.Endpoints: The primary endpoint was a composite of all-cause death or non-fatal myocardial infarction at 5-years. Secondary endpoints included unstable angina, heart failure, arrhythmias, angina based on the Canadian Cardiovascular Society classification, anti-anginal drug use, and exercise duration on a symptom-limited treadmill test.Analysis was performed based on the intention-to-treat principle. The sample size to achieve 80% power at an alpha level of 0.05 was 1,400. This was based on the assumption that the event rate of the primary outcome is 15% at 5-years in the medical arm, and that PTCA would reduce the primary outcome by 33%. The study enrolled less patients than planned due to slow recruitment.Results: The median follow up time was 2.7 years. Among the 504 patients randomized to PTCA, the procedure was performed in 417 (93%) patients. Among the 514 patients randomized to medical therapy, 118 (23%) underwent PTCA or coronary bypass surgery.PTCA increased the risk of the primary composite outcome (6.3% vs 3.3%, RR: 1.92, 95% CI: 1.08 – 3.41; p= 0.02). This difference was primarily driven by more non-fatal myocardial infarction with PTCA (4.2% vs 1.9%; p value not provided). All-cause death was not significantly different between both groups (2.2% with PTCA vs 1.4% with medical therapy; p= 0.32).No significant differences noted in unstable angina (9.9% with PTCA vs 9.1% with medical therapy; p value not provided), heart failure (1.6% with PTCA vs 2.9% with medical therapy; p= 0.15) or arrhythmias (3.0% with PTCA vs 1.4% with medical therapy; p= 0.08).Symptoms improved significantly in both treatment groups. The improvement in symptoms was greater with PTCA at 3 months (16.5% more patients with grade 2+ angina in the medical arm; p< 0.0001) but the difference was smaller at 2 years (7.6% more patients with grade 2+ angina in the medical arm; p= 0.02). These differences disappeared at 3 years. More patients in the PTCA arm were not taking anti-anginal medications at 3 years (36.2% vs 13.8%). PTCA led to greater improvement in exercise time compared to medical therapy but the differences were small (mean difference favoring PTCA was 35s at 3 months and 25s at 1 year).No subgroup analysis was provided for the primary outcome.Conclusion: In patients with coronary artery disease without recent myocardial infarction, PTCA compared to medical therapy worsened the primary outcome of all-cause death or non-fatal myocardial infraction with a number needed to harm of approximately 33 patients over 2.7 years follow up. This difference was largely due to more non-fatal myocardial infarction in the PTCA arm. PTCA led to greater improvement in symptoms at 3 months but there were no significant differences at 3 years.Read the results above and compare our conclusion with the authors' conclusion: [In patients with coronary artery disease considered suitable for either PTCA or medical care, early intervention with PTCA was associated with greater symptomatic improvement, especially in patients with more severe angina. When managing individuals with angina, clinicians must balance these benefits against the small excess hazard associated with PTCA due to procedure-related complications].Medical and percutaneous interventions for coronary artery disease have advanced since the publication of this trial. However, reviewing older trials remains crucial to understand the evolution of the cardiology field and why certain interventions are no longer used. Studying the history of these treatments is important because it sheds light on how current practices have been shaped.This trial serves as a reminder that a bias toward interventions exists in medicine; the authors' conclusion downplayed the harms associated with PTCA while emphasizing its potential benefits for symptom relief, even though this was not the primary outcome and is highly subject to bias based on the study design. The trial also has reporting bias; subgroup analysis was not provided for the primary outcome but rather for the secondary endpoints of symptom relief and exercise tolerance. Additionally, the effects of PTCA on symptom relief and exercise tolerance were reported at various time points that seem to have been chosen to emphasize the protentional benefits of PTCA.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

Circulation 68, No. 5, 939-950, 1983Background  Coronary artery bypass surgery (CABG) had grown in popularity through the 1970s and 1980s. By 1981, approximately 159,000 bypass surgeries had been done.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.The goal of the CASS trial was to rigorously evaluate the effect of surgical vs medical therapy on total mortality in well-defined subsets of patients with coronary artery disease.Patients Eligible patients had to be 65 years of age or below and have angina that was Canadian Cardiovascular Society class I or II with or without a history of myocardial infarction, or had to have a well-documented MI more than 3 weeks before randomization. Clinical criteria for exclusion were prior CABG, unstable or progressive angina, angina more severe than class II (angina occurring after climbing one flight of stairs or walking two blocks is class III), congestive heart failure (New York Heart Association class III or IV), a coexisting illness that would increase the likelihood of death within 5 years, and a variety of practical exclusions that might limit active participation during follow-up.Angiographic requirements for participation in the trial included the presence of significant operable coronary artery disease, defined as either 70% or greater reduction in the diameter of the right, left anterior descending, or left circumflex coronary artery, or 50% or greater reduction in the diameter of the left main coronary artery. Patients with 70% or greater luminal diameter reduction of the left main were excluded. Also excluded were patients with LVEF (measured by left ventriculography) of less than 35% or those patients who required valve surgery or LV aneurysm repair.Baseline Characteristics There were 390 patients randomized in both the surgical and medical arm. The mean age was 51 years; 90% were males and 98% were White. Approximately 60% had previous MI, 30% had hypertension and only 3% had congestive heart failure. About 40% were smokers.Angiographic criteria were well matched—27% had one-vessel disease, 38% had two-vessel disease, and about a third had three-vessel disease. Nearly a third of patients in both groups had proximal LAD disease. The LVEF was more than 50% in 73-74% of patients in both groups. The LVEF was less than 50% in a fifth of patients in both arms.Procedures CASS authors were quite clear in the screening and randomization process. Slightly more than 16,600 patients were screened for participation in the trial at 11 centers. Figure 1 in the manuscript shows the reasons for exclusion, which included normal or minimal coronary disease (28%), Class 3 or 4 angina (36%), and left main disease more than 70%n (1.5%). Other exclusions totaled 16%.Ultimately there were 2099 patients eligible to be randomized, however, 1319 patients were not included in the trial due to physician preference.Randomization was stratified by clinical site, number of diseased vessels, and ejection fraction within three different clinical subgroups. Patients with angina and ejection fractions of at least 0.50 were randomized within group A (n =514), those with angina and EF less than 0.50 were randomized within group B (n=106) and those free of angina after well-documented MI were randomized within group C (n=160).A total of 954 distal anastomoses were constructed in 357 patients in the surgical group, an average of 2.7 per patient. A total of 334 distal anastomoses were evaluated in the 129 patients; 90% of the grafts were open, 97% of patients had at least one open graft, and in 81% of patients all grafts were patent. Medical therapy consisted mostly of nitrates, and beta-blockers. Statin drugs were not available during the trial. Endpoint The primary endpoint was all-cause mortality. It was assessed with the intention-to-treat method. Results There were no significant differences in mortality.At 5 years, the average annual mortality rate in patients assigned to surgical treatment was 1.1%. The annual mortality rate in those receiving medical therapy was 1.6%. Expressed differently, the rate of death at 5 years was 9.2% in the medical group versus 7.4% in the surgical group. Annual mortality rates in patients with single-, double-, and triple-vessel disease who were in the surgical group were 0.7%, 1.0%, and 1.5%; the corresponding rates in patients in the medical group were 1.4%, 1.2%, and 2.1%.There were also no significant differences in survival when patients were grouped according to degree of coronary artery disease (number of vessels) or EF or by a combination of diseased vessels and EF.Crossovers did occur. Approximately 23% of the 390 patients assigned to the medical group had surgery during the follow-up period (4.7% per year). Of the patients assigned to surgery, 31 of 390 patients (8%) did not have surgery.Conclusions The CASS authors write in the abstract of the manuscript that they observed excellent long-term survival in both groups and that for patients similar to those in the trial, surgery could be deferred until symptoms worsen.The CASS trial had caveats. First was that the 780 patients enrolled in the trial were highly selected from a total of more than 16,000 patients in the registry. The CASS registry revealed widely disparate annual mortality in patients managed medically, ranging from 1.3% for those with single-vessel disease and normal EF to 12.5% in those with three-vessel disease and impaired EF. Another caveat was the lower-than-expected annual mortality in the medical arm of only 1.6%. This was lower than previous surgery trials (3.3% noted in the European Collaborative Study and 4.3% reported in the Veterans Administration Study). CASS authors estimated a 2-4% annual mortality. This reduces the power to find differences in the two groups.It is interesting however, that for the 1319 patients in whom their physician declined randomization, the outcome in those treated medically was similar to that reported in the randomly assigned patients who received medical therapy.In conclusion, as early as the 1980s, the CASS study showed that stable coronary artery disease was quite stable, and that revascularization in selected patients did not improve survival over medical therapy. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

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This podcast is published open access in Infectious Diseases and Therapy and is fully citeable. You can access the original published podcast article through the Infectious Diseases and Therapy website and by using this link: https://link.springer.com/article/10.1007/s40121-024-00932-3. All conflicts of interest can be found online. This podcast is intended for medical professionals.  Open Access This podcast is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The material in this podcast is included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

N Engl J Med 2019;380:752-762Background: Growing body of evidence suggests the role of inflammation in atherosclerosis. The CANTOS trial, discussed earlier, provided further evidence for that hypothesis. In the CANTOS trial, canakinumab a monoclonal antibody that neutralizes interleukin-1β led to fewer myocardial infarctions compared to placebo.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Cardiovascular Inflammation Reduction Trial (CIRT) sought to test the hypothesis that an alternative approach to reduce inflammation using low-dose methotrexate, also lowers cardiovascular events compared to placebo. Low-dose methotrexate was chosen since it's widely used, inexpensive and was shown, in observational studies, to lower cardiovascular events in patients with rheumatoid arthritis and psoriatic arthritis compared to other drugs or placebo.Patients: Patients were enrolled if they had history of myocardial infarction or multivessel coronary artery disease and had either type II diabetes mellitus or metabolic syndrome. Patients had to be medically stable and had completed any planned revascularization. Exclusion criteria were many and included patients with chronic liver disease, chronic inflammatory conditions, chronic infectious diseases, HIV positive, chronic use of immunosuppressive therapy or women of childbearing potential.Baseline characteristics: The trial randomized 2,391 patients to the low-dose methotrexate arm and 2,395 patients to the placebo arm. The average age of patients was 66 years with 81% being men. The median body mass index was 31 kg/m2. About 61% had prior myocardial infarction, 34% had diabetes, 32% had metabolic syndrome and 13% had congestive heart failure. The median total cholesterol was 141 mg/dL, median LDL was 68 mg/dL and the median hs-CRP was 1.5 mg/L.Procedures: The study had a run-in phase in which patients were administered 1 mg of oral folic acid daily in addition to oral methotrexate once weekly, initially at 5 mg, then increased to 10 mg, and finally to 15 mg. This phase was conducted in an open-label manner, and patients were excluded from further participation if they experienced adverse events, including laboratory abnormalities related to the treatment.Patients who were able to tolerate the 15 mg dose of methotrexate for 2 consecutive weeks without adverse events, were randomized in 1:1 fashion to receive methotrexate at a dose of 15 mg or placebo in a double-blinded fashion. All patients took folate daily. At 4 months, the dose of methotrexate was increased to 20 mg. Symptoms and laboratory variables were assessed every 2 months and the dose of methotrexate, or placebo, was adjusted as needed. Randomization was stratified based on the type of index event, time since the index event and metabolic syndrome alone or diabetes.Endpoints: Initially, the primary endpoint of the trial was a composite endpoint of the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Approximately 5 years into the trial, the composite end point was expanded to include hospitalization for unstable angina that led to urgent coronary revascularization. This increased the statistical power and allowed for smaller sample size. Death from any cause was included as a secondary endpoint.Statistical analysis was performed based on the intention-to-treat principle. Based on the new composite primary endpoint, it was estimated that a total of 5,500 patients and 634 primary endpoint events would give the trial 90% power to detect 23% relative reduction of the new composite primary endpoint, with methotrexate compared to placebo. The data safety and monitoring board recommended early termination of the trial for futility.Results: Out of 6,158 patients who entered the open label run-in phase, 997 (16.2%) patients were excluded due to symptoms or adverse events, 129 (2.1%) patients were excluded due to laboratory values out of range, and 4,786 (77.7%) patients were randomized.At 8 months, methotrexate compared to placebo, did not result in greater reduction in hs-CRP, interleukin-1β, or interleukin-6.After a median follow-up time of 2.3 years, the rate of the final composite primary endpoint was similar in both treatment groups [8.4% (4.13%/ year) with methotrexate vs 8.6% (4.31%/ year) with placebo, HR: 0.96, 95% CI: 0.79 – 1.16; p= 0.67]. There was no significant difference in death from any cause [4.0% (1.80%/ year) vs 3.5% (1.55%/ year)], cardiovascular death [2.0% (0.92%/ year) vs 1.8% (0.80%/ year)], nonfatal myocardial infarction [4.7% (2.29%/ year) vs 4.8% (2.32%/ year)], nonfatal stroke [1.2% (0.55%/ year) vs 1.3% (0.60%/ year)], or hospitalizations for unstable angina that led to urgent revascularization [1.7% (0.81%/ year) vs 2.1% (1.01%/ year)].Mouth sores and oral pain were more common with methotrexate [4.0% (1.95%/ year) vs 2.3% (1.13%/ year); p= 0.001]. Non-basal-cell skin cancer was also more common with methotrexate [1.3% (0.61%/ year) vs 0.4% (0.20%/ year); p= 0.002]. Serious infections [4.6% (2.24%/ year) vs 5.1% (2.47%/ year); p= 0.50] and serious bleeding [1.3% (0.63%/ year) vs 1.0% (0.50%/ year); p= 0.44] were not significantly different between both treatment groups.Data on subgroup analysis was not provided in the main paper or supplement.Conclusion: In patients with history of myocardial infarction or multivessel coronary artery disease, low-dose methotrexate did not reduce cardiovascular events compared to placebo.The authors proposed several reasons why the results of CIRT contrast the results of CANTOS in which canakinumab, a monoclonal antibody targeting interleukin-1β was used. First, CANTOS limited enrollment to patients with elevated hs-CRP while CIRT did not require that. Consequently, the median hs-CRP was significantly higher in CANTOS at 4.2 mg/L compared to 1.5 mg/L in CIRT. Furthermore, canakinumab in CANTOS lowered interleukin-6 and hs-CRP levels by 35-40% compared to placebo, while methotrexate in CIRT did not lower interleukin-6, hs-CRP or interleukin-1β. This suggests that the effectiveness of reducing atherosclerosis risk may vary depending on the specific pathway targeted. Other notable findings are higher LDL levels in CANTOS compared to CIRT (82 mg/ dL vs 68 mg/ dL). In addition, all patients had history of myocardial infarction in CANTOS compared to 61% in CIRT.Another important teaching point from this trial is the use of a run-in period with the active drug, methotrexate. Although employing a run-in period is beneficial for assessing adherence and eliminating early dropouts, it can introduce selection bias. This can occur by excluding patients who experience adverse events from the study drug, methotrexate in this case, and thereby favor the balance of benefits and harms in favor of the study drug.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

- How fully digitalized, real-time temperature monitoring through integration with Randomization and Trial Supply Management (RTSM), leads to better oversight, quicker decision-making, a reduction of human error and increased patient safety - Showcase the application of in-transit monitoring of a Highly Advanced, Personalized and temperature sensitive drug, requiring real-time tracking of temperature, light, tilt, and location - Showcase how automated real-time communication solutions between on-site logger technology and the RTSM system transform drug supply management and oversight, whilst reducing the administrative burden on site users

bleu noir. First and foremost, a friendship composed of Edouard-Marc and Bastien. Two companions who, in their distinct singularities, come together to converge towards a common universe. Complementarity is created from the beginning of the project to the finishing touches of their musical collaborations. A sincere, imaginative, and heartfelt approach. Random but shared experiences, such as numerous musical events ranging from concerts to festivals, inspire them. All of this leads to beautiful creations like this EP named: Naviguer à vue. “Naviguer à vue” is the story in a fictitious and picturesque imagination, of a collective adventure taking place on a boat. The construction and launching of it, welcoming "Hordes" of people, are represented by "Recherche hivernale". A long aquatic journey through "Brume épaisse", filled with “Emergences of details”, as beautiful as they are stressful. Presented to the people on the boat is an internal and collective struggle, "Psychomachia". A battle between vice and virtue, between the humble human and the one of a self-centered and selfish society. “Inno”, floating on the surface and swimming, between two worlds, unable to leave the fluid and yet aware that it exists. A track that could have been called “Innolude”. The sound translations of these different emotions and sensitivities, vectorized by “Diversions currents then landscapes”, make this EP a true journey. Today's premiere is the second track from this great release, "Brume épaisse." This eerie, aquatic techno odyssey is defined by a powerful bassline that builds tension like The Marin, bringing thick coastal fog over a southern seaside city. "Brume épaisse" boasts a delicate yet murky atmosphere, perfectly grasping the essence of a late-night after-hours track. “Naviguer à vue” EP is set for release in the second half of April. https://soundcloud.com/lowvolumerandomization https://soundcloud.com/user-676721263 https://www.instagram.com/lowvolumerandomization/ https://www.instagram.com/bleunoirr/ Follow us on social media: https://soundcloud.com/itsdelayed https://linktr.ee/delayed https://www.itsdelayed.com https://www.facebook.com/itsdelayed https://www.instagram.com/_____delayed https://www.youtube.com/@_____delayed

Support the showVideo version available on YouTubeDo We Need Probability?Causal inference lies at the very heart of the scientific method. Randomized controlled trials (RCTs; also known as randomized experiemnts or A/B tests) are often called "the golden standard for causal inference".It's a less known fact that randomized trials have their limitations in answering causal questions.What are the most common myths about randomization?What causal questions can and cannot be answered with randomized experiments? Finally, why do we need probability? Join me on a fascinating journey into clinical trials, randomization and generalization. Ready to meet Stephen Senn? About The GuestStephen Senn, PhD, is a statistician and consultant specializing in clinical trials for drug development. He is a former Group Head at Ciba-Geigy and has served as a professor at the University of Glasgow and University College London (UCL). He is the author of "Statistical Issues in Drug Development," "Crossover Trials in Clinical Research," and "Dicing with Death". Connect with Stephen: - Stephen on Twitter/X- Stephen on LinkedIn- Stephen's web pageAbout The HostAleksander (Alex) Molak is an independent machine learning researcher, educator, entrepreneur and a best-selling author in the area of causality.Connect with Alex:- Alex on the InternetLinksFind the links hereCausal Bandits TeamProject Coordinator: Taiba MalikThe Code of Entry PodcastThe Code of Entry Podcast, hosted by the insightful Greg Bew, delves deep into the...Listen on: Apple Podcasts SpotifySupport the showCausal Bandits PodcastCausal AI || Causal Machine Learning || Causal Inference & DiscoveryWeb: https://causalbanditspodcast.comConnect on LinkedIn: https://www.linkedin.com/in/aleksandermolak/Join Causal Python Weekly: https://causalpython.io The Causal Book: https://amzn.to/3QhsRz4

Impact of Cardiac Arrest Before Randomization on the Efficacy of ECLS in Patients With Infarct-Related Cardiogenic Shock. A Sub-Analysis of the Prospective EClS-Shock Trial (AHA 2023)

In part 1 of this episode, Libbi and Siobhan delve into the escalating intricacies of clinical trials, shedding light on the challenges and solutions within the realm of Randomization and Trial Supply Management (RTSM) build for clinical trial protocols. As the pharmaceutical and biotech industries evolve, so does the demand for adaptive and nuanced approaches to address the growing complexity in trial designs. The conversation unfolds as they explore the delicate nuances involved in tailoring the RTSM build directly to the specific needs of the protocol. Siobhan, drawing from her extensive experience, emphasizes the critical role of having a proficient team of RTSM experts. Together, they dissect the importance of this expertise in supporting end-users and, ultimately, ensuring the well-being of patients throughout the clinical trial journey.

In this journal club episode, my guest is Dr. Peter Attia, M.D., a Stanford and Johns Hopkins-trained physician focusing on healthspan and lifespan and the host of The Drive podcast. We each present a peer-reviewed scientific paper chosen because it contains novel, interesting, and actionable data. First, we discuss a paper on how bright light exposure at sunrise and throughout the day and dark exposure at night independently improve mental health and can offset some of the major symptoms of mental health disorders such as depression and anxiety. Then, we discuss an article that explores a novel class of immunotherapy treatments to combat cancer. We also discuss some of the new data on low-calorie sweeteners and if they are safe. This episode should be of interest to listeners curious about maximizing their vitality and longevity and to anyone seeking science-supported ways to improve mental health and lifespan. For show notes, including referenced articles and additional resources, please visit hubermanlab.com. Thank you to our sponsors AG1: https://drinkag1.com/huberman Eight Sleep: https://www.eightsleep.com/huberman BetterHelp: https://betterhelp.com/huberman Joovv: https://joovv.com/huberman LMNT: https://drinklmnt.com/huberman Momentous: https://livemomentous.com/huberman Timestamps (00:00:00) Dr. Peter Attia, Journal Club (00:02:40) Sponsors: Eight Sleep, BetterHelp & Joovv (00:07:14) Light, Dark & Mental Health; Retina (00:11:16) Outdoor vs. Indoor Light, Cataracts, Sunglasses (00:16:17) Tools: Sunrise & Sunsets, Circadian Rhythm; Midday Light (00:24:55) Tools: Night & Light Exposure; Waking Before Sunrise (00:31:05) Article #1, Light/Dark Exposure & Mental Health (00:36:50) Sponsor: AG1 (00:38:18) Odds Ratio, Hazard Ratio (00:45:43) Night vs. Daylight Exposure, Mental Health Disorders (00:51:35) Major Depression & Light Exposure; Error Bars & Significance (00:59:15) Sponsor: LMNT (01:00:39) Prescriptions; Environmental & Artificial Light; Red Lights (01:08:14) Nighttime Light Exposure; Sleep Trackers & Belief Effects (01:13:54) Light Directionality, Phone, Night (01:17:21) Light Wavelengths & Sensors; Sunglasses (01:20:58) Hawthorne Effect, Reverse Causality, Genetics (01:26:26) Artificial Sweeteners, Appetite (01:31:16) Natural Light Cycles, Circadian Rhythm & Mental Health (01:39:53) Article #2, Immune System & Cancer (01:43:18) T-Cell Activation; Viruses (01:50:41) Autoimmunity; Cancer & Immune System Evasion (02:00:09) Checkpoint Inhibitors, CTLA-4 (02:06:45) Anti-CTLA-4 Study Drug (Ipilimumab), Melanoma (02:12:07) Patient Population, Randomization, GP100 (02:18:09) Response Rate (02:22:52) Overall Survival & Response (02:28:38) Median Survival vs. Overall Survival, Drug Development (02:35:45) Gender & Dose (02:40:32) Adverse Events; Autoimmunity (02:46:42) Pancreatic Cancer; Aging & Immune System Health (02:53:57) Melanoma; Lynch Syndrome, Keytruda (02:58:43) Immunotherapy & Cancer Treatment; Melanoma Risk (03:06:26) Zero-Cost Support, Spotify & Apple Reviews, YouTube Feedback, Sponsors, Momentous, Social Media, Neural Network Newsletter Disclaimer

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. Jean-Marc Classe to discuss the CHIPOR Trial. Dr. Classe is a surgeon and former head of the surgical department of the Institute of Surgical Oncology of Nantes, France. He is a professor in oncology and president of the French Society of Surgical Oncology.   Highlights: The CHIPOR phase III RCT studied the use of HIPEC in 1st PSROC who underwent complete cytoreductive op after 2nd-line platinum-based chemo. Randomization was performed during complete cytoreductive surgery. The primary endpoint was OS. Results showed HIPEC significantly improved OS, HR 0.69, p=0.020. This study suggests that HIPEC can be a beneficial addition to the tx strategy for women with 1st PSROC when used in conjunction with 2nd-line platinum-based chemo and complete cytoreductive surgery.

In this Episode we talk about reasons why you should play, continue to play and do somewhat of an evergreen episode that goes over what is shatterpoint 0:00 Intro and basics - from squads to deployment 14:00  - The Table 101: struggle(s) & terrain 29:00 - Randomization & Agency 101: Order deck, dice & damage trees 43:10 - Abilities 101: Character abilities and keywords 55:10 - COJ - Randomization our discord here! https://discord.gg/kc59N2cbEX  Want to become a Patreon? check out here! https://patreon.com/RogueSupport790?utm_medium=clipboard_copy&utm_source=copyLink&utm_campaign=creatorshare_creator&utm_content=join_link -- Watch live at https://www.twitch.tv/roguesupportswsp

Dr. Darrin Dodds shares his years of experience managing ag data and statistics. He talks about side-by-side and small plot trials – which provides better statistics? Know the right questions to ask and how to make more informed decisions with data.    To discover the latest crop nutrition research visit nutrien-eKonomics.com

Henry and Finn paint a picture of the horribleness of this episode.THIS WEEK'S TOPICM.E. Time (Brooklyn Nine-Nine: S1, E4): while on a case, Jake sabotages Boyle's case by starting a relationship with a medical examiner. Santiago tries to get Holt into a better mood by having Terry paint his picture.USEFUL INFORMATION AND LINKSPlease listen to our explainer “What is Schurt?” episode. It will explain the show in only three minutes.Schurt: A Collection of Enjoyable PodcastsThe Office (American TV Series)Parks and RecreationBrooklyn Nine-NineThe Good PlaceRutherford FallsSchurt Numbers Spreadsheet for Randomization and Charts (alternatively, view as a pdf)The music is created by me, Henry, with help from my very good music teacher, Brian Ajjan.Contact us at henry@tunklecast.com (NOT welcome.everythingis@schurt.site)

On today's show, we discuss how to optimize operations within your organization. Tommy Yionoulis has been in the restaurant industry for nearly his entire adult life. He has a BSBA from University of Denver's Hotel Restaurant school in addition to an MBA. This former stand-up comic turned SaaS founder, has extensive experience helping businesses become more efficient and profitable through process, accountability, and data.  He's currently the Managing Director of OpsAnalitica, an Operations Analytics platform that focuses on managing and measuring daily team activities for large multi-unit businesses.  Tommy believes that the next big technological disruptor event for many businesses is going to be implementing Operations Management software to shape the future of work and beat our competitors through better, more consistent daily operations. Key Takeaways: Why do we need to optimize our operations? We are not suffering from a lack of knowledge, but too much information and too many things to track. The human brain can only keep a few things in mind at a time. Leaders have already identified the things that they know they should do to stay on top of things, but they cannot translate that knowledge into consistent action at the location level. Often, an employee missing one step in the middle of a multi-step process will cause the process to fail. What are the symptoms that indicate a problem? What is the trigger point?Unfortunately, without implementing operations management software, an organization may not realize they have a problem. KPI indicators will lag. For instance, by the time the sales numbers indicate a problem, the business has been suffering for a while, and it may take years to win customers back. How does the solution get you more instantaneous feedback? What is being measured and how does an organization know what action to take?At the location level - It takes the guesswork out of running the business by scheduling a series of tasks and checklists.At the upper level - It allows teams to be more effective and efficient. Corporate brings on people to manage multiple locations. The solution allows these managers to watch what's happening in real-time. When there are issues, the solution alerts the managers.  How do you avoid "death by checklist"?Checklists often need to be done at busy times, so they need to be focused and smart. Real-time collaboration can allow several people to check things together and be more efficient. Randomization helps ensure good coverage over a series of things that need to be checked as well.  How can a business promote adoption of the system?Adoption is dependent upon the priority structure of the business. Part of the systems can be time-based to ensure things are done at the optimum time and promote accountability. Process and systems-driven businesses are the ones that succeed.  Top Takeaways:Operations management is the next technological battlefield that we will all be in. In the multi-location business of the future, you'll be collecting data from 5 places: POS Internet - social media Checklist platform Robots Sensors The key will be to bring all of that information together and turn it into real-time actions that solve the problems that are affecting the customers. Jump in on an ops program to get the data and take it seriously.Get started soon. Let the data influence you over time to make it better. Don't wait to figure it all out. Connect with Tommy YionoulisWebsite: https://opsanalitica.com/

Today's episode is about Pseudo Random Number Generators and how we can achieve Randomization. We also explain how applications can suffer big time when they don't have random values generated in their crypto systemsTwitter: @almorabeaTwitter: @CyberRiddlerWebsite: https://thecyberriddler.com

Today's episode is about Pseudo Random Number Generators and how we can achieve Randomization. We also explain how applications can suffer big time when they don't have random values generated in their crypto systemsTwitter: @almorabeaTwitter: @CyberRiddlerWebsite: https://thecyberriddler.com

Arden is back in the “studio” along with Ben and his lovable pod-cats to discuss the word chaos… a concept that Mango personifies.  Predictably the conversation starts with Bash causing an avalanche in the Himalayas and then gains entropic momentum.  Ben shares information on his favorite movie True Romance, chaos theory models, the band Luscious Jackson, the Kids in the Hall skit “Jazz Schmazz,” a Flash Gordon “deep cut,” and his work experience with software development.  Arden talks about chaos as it relates to his time playing Call of Duty: Modern Warfare 2 and Elden Ring, the band Mr. Bungle, the “hell in space” movie Event Horizon, and the Risk of Rain game franchise.    00:00:20 - Arden is crushing noobs and finding rings; Ben rolled credits on Cult of the Lamb 00:02:35 - Causing avalanches, comprehending the universe, and sharks in Lake Michigan 00:06:00 - Shark tornado, Summer snowstorms in Ohio, and how can chaos be plural? 00:08:35 - The fake mom, Arden shares the etymology of chaos, and hot hail 00:11:00 - The impactful nature of chaos, making life interesting, and a suitcase full of cocaine 00:14:15 - From Dusk Till Dawn, no lap time for Mango, and does chaos make movies better? 00:16:50 - Christopher Nolan movies, and Ben tries to convince Arden to see Tenet 00:20:50 - “Hell in space” movies and games, Ben in a nutshell, and Contra on a quarter 00:25:30 - Looking like a pelvis, Edward Lorenz's deterministic chaos, and basic science 00:29:05 - The Butterfly Effect, probability warping superpowers, luck, and determining odds 00:33:34 - Models illustrating chaos, Ben doesn't like Muppets, and Daughters of the Kaos 00:36:40 - Luscious Jackson, Mr Bungle, and Ben reads a bit from Jazz Schmazz  00:42:07 - Arden's experiences with Call of Duty: Modern Warfare 2 00:45:20 - Proximity chat and Reddit user Crescendummain starts an in game taxi service 00:48:23 - Arden talks about his issues with COD:MW2 and “out of touch” game companies  00:52:55 - Ben's software development experiences and thoughts on “crunch culture” 00:55:10 - Hate speech in COD:Modern Warfare 2, gender bias today, and GamerGate 00:58:25 - “Actual entropy” and the results of aligning with the Three Fingers in Elden Ring 01:00:50 - A discussion about procedurally and/or randomly generated game content 01:05:00 - Randomization in Risk of Rain, closing wisdom on chaos, and ladder not latter

The top ten stories of the year plus a few honorary mentions. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I Annual Wrap Ups on Medscape - Mandrola's Top 10 Cardiology Stories of 2022 https://www.medscape.com/viewarticle/985607 - 2022 in Review Through a Cardiology Lens https://www.medscape.com/viewarticle/984505 - Top Cardiology Trials of 2022 https://www.medscape.com/viewarticle/985647 II REVIVED BCIS2 - Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction https://www.nejm.org/doi/full/10.1056/nejmoa2206606 - PCI Fails in Stable Disease Again: REVIVED-BCIS https://www.medscape.com/viewarticle/979862 - PCI Fails to Beat OMT in Ischemic Cardiomyopathy: REVIVED-BCIS2 https://www.medscape.com/viewarticle/979853 III GUIDE HF - Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial https://doi.org/10.1016/S0140-6736(21)01754-2 - CardioMEMS Remote HF Monitoring: Resist the Spin and FOMO https://www.medscape.com/viewarticle/970278 - GUIDE-HF: CardioMEMS-Guided Meds Fall Short in Mild to Moderate Heart Failure https://www.medscape.com/viewarticle/957390 IV DECAAF II - Effect of MRI-Guided Fibrosis Ablation vs Conventional Catheter Ablation on Atrial Arrhythmia Recurrence in Patients With Persistent Atrial Fibrillation The DECAAF II Randomized Clinical Trial https://jamanetwork.com/journals/jama/fullarticle/2793452 - DECAAF II: AF, Fibrosis Ablation Technique Falls Short, but Signs of Hope https://www.medscape.com/viewarticle/957469 V DANCAVAS - Five-Year Outcomes of the Danish Cardiovascular Screening (DANCAVAS) Trial https://www.nejm.org/doi/full/10.1056/NEJMoa2208681 - DANCAVAS Misses Primary Endpoint but Hints at Benefit from Comprehensive CV Screening https://www.medscape.com/viewarticle/979854 - Judicious CVD Screening May Work in Men: DANCAVAS https://www.medscape.com/viewarticle/980153 - DANCAVAS: Might Cardiovascular Screening Extend Men's Lives? https://www.medscape.com/viewarticle/979632 VI SODIUM HF - Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial https://doi.org/10.1016/S0140-6736(22)00369-5 - Low-Sodium Diet Did Not Cut Clinical Events in Heart Failure Trial https://www.medscape.com/viewarticle/971482 - Sodium Restriction in Heart Failure: Another Dogma Felled by Randomization https://www.medscape.com/viewarticle/971697 - SODIUM-HF Simplifies Message to Patients on Diet https://www.medscape.com/viewarticle/971547 VII STRONG-HF - Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial https://doi.org/10.1016/S0140-6736(22)02076-1 - Rapidly, Fully Optimize HF Meds After Hospital Discharge: STRONG-HF https://www.medscape.com/viewarticle/983870 - STRONG HF: More Beats Less After Discharge for Heart Failure https://www.medscape.com/viewarticle/983698 VIII Health Insurance Access - Health Care Access and Management of Cardiovascular Risk Factors Among Working-Age Adults With Low Income by State Medicaid Expansion Status https://doi.org/10.1001/jamacardio.2022.1282 - Medicaid Expansion: Good First Step, but No Panacea for CV Care https://www.medscape.com/viewarticle/975141 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

Host: Richard Young, VP, Strategy, Veeva Vault CDMS Guest: Natalie Townsend, VP, Strategy, Veeva RTSM This week, Richard Young speaks to Natalie Townsend, the global lead for Randomization and Trial Supply Management (RTSM) strategy at Veeva. They discuss the evolution of ‘digital' clinical trials from the early days of phone-based and spreadsheet-centered activities to the role technology is playing today. Will data management clash, combine, or sit comfortably with the world of site supplies and randomization? And how can technology help with challenges faced by both sides? Subscribe to State of Digital Clinical Trials, a Veeva podcast to get new episodes as soon as they are released. Spotify: https://lnkd.in/e5pJ7saP Youtube: https://bit.ly/3quY9FY Apple Podcasts: https://lnkd.in/efMTxybk

Picture of the Week. Breach of Customer Information Meta-targeted Malware Uber's Chief Security Officer Found Guilty More Cryptocurrency Chaos The UK to drop GDPR Summer Internship with the NSA Many Incident Responders are Stressed Out Microsoft's newest dual 0-day Exchange Fumbles SpinRite news ZimaBoard Closing the Loop Source Port Randomization We invite you to read our show notes at https://www.grc.com/sn/SN-892-Notes.pdf Hosts: Steve Gibson and Leo Laporte Download or subscribe to this show at https://twit.tv/shows/security-now. Get episodes ad-free with Club TWiT at https://twit.tv/clubtwit You can submit a question to Security Now! at the GRC Feedback Page. For 16kbps versions, transcripts, and notes (including fixes), visit Steve's site: grc.com, also the home of the best disk maintenance and recovery utility ever written Spinrite 6. Sponsors: Secureworks.com/twit newrelic.com/securitynow bitwarden.com/twit

Picture of the Week. Breach of Customer Information Meta-targeted Malware Uber's Chief Security Officer Found Guilty More Cryptocurrency Chaos The UK to drop GDPR Summer Internship with the NSA Many Incident Responders are Stressed Out Microsoft's newest dual 0-day Exchange Fumbles SpinRite news ZimaBoard Closing the Loop Source Port Randomization We invite you to read our show notes at https://www.grc.com/sn/SN-892-Notes.pdf Hosts: Steve Gibson and Leo Laporte Download or subscribe to this show at https://twit.tv/shows/security-now. Get episodes ad-free with Club TWiT at https://twit.tv/clubtwit You can submit a question to Security Now! at the GRC Feedback Page. For 16kbps versions, transcripts, and notes (including fixes), visit Steve's site: grc.com, also the home of the best disk maintenance and recovery utility ever written Spinrite 6. Sponsors: Secureworks.com/twit newrelic.com/securitynow bitwarden.com/twit

Picture of the Week. Breach of Customer Information Meta-targeted Malware Uber's Chief Security Officer Found Guilty More Cryptocurrency Chaos The UK to drop GDPR Summer Internship with the NSA Many Incident Responders are Stressed Out Microsoft's newest dual 0-day Exchange Fumbles SpinRite news ZimaBoard Closing the Loop Source Port Randomization We invite you to read our show notes at https://www.grc.com/sn/SN-892-Notes.pdf Hosts: Steve Gibson and Leo Laporte Download or subscribe to this show at https://twit.tv/shows/security-now. Get episodes ad-free with Club TWiT at https://twit.tv/clubtwit You can submit a question to Security Now! at the GRC Feedback Page. For 16kbps versions, transcripts, and notes (including fixes), visit Steve's site: grc.com, also the home of the best disk maintenance and recovery utility ever written Spinrite 6. Sponsors: Secureworks.com/twit newrelic.com/securitynow bitwarden.com/twit

Picture of the Week. Breach of Customer Information Meta-targeted Malware Uber's Chief Security Officer Found Guilty More Cryptocurrency Chaos The UK to drop GDPR Summer Internship with the NSA Many Incident Responders are Stressed Out Microsoft's newest dual 0-day Exchange Fumbles SpinRite news ZimaBoard Closing the Loop Source Port Randomization We invite you to read our show notes at https://www.grc.com/sn/SN-892-Notes.pdf Hosts: Steve Gibson and Leo Laporte Download or subscribe to this show at https://twit.tv/shows/security-now. Get episodes ad-free with Club TWiT at https://twit.tv/clubtwit You can submit a question to Security Now! at the GRC Feedback Page. For 16kbps versions, transcripts, and notes (including fixes), visit Steve's site: grc.com, also the home of the best disk maintenance and recovery utility ever written Spinrite 6. Sponsors: Secureworks.com/twit newrelic.com/securitynow bitwarden.com/twit

Picture of the Week. Breach of Customer Information Meta-targeted Malware Uber's Chief Security Officer Found Guilty More Cryptocurrency Chaos The UK to drop GDPR Summer Internship with the NSA Many Incident Responders are Stressed Out Microsoft's newest dual 0-day Exchange Fumbles SpinRite news ZimaBoard Closing the Loop Source Port Randomization We invite you to read our show notes at https://www.grc.com/sn/SN-892-Notes.pdf Hosts: Steve Gibson and Leo Laporte Download or subscribe to this show at https://twit.tv/shows/security-now. Get episodes ad-free with Club TWiT at https://twit.tv/clubtwit You can submit a question to Security Now! at the GRC Feedback Page. For 16kbps versions, transcripts, and notes (including fixes), visit Steve's site: grc.com, also the home of the best disk maintenance and recovery utility ever written Spinrite 6. Sponsors: Secureworks.com/twit newrelic.com/securitynow bitwarden.com/twit

Picture of the Week. Breach of Customer Information Meta-targeted Malware Uber's Chief Security Officer Found Guilty More Cryptocurrency Chaos The UK to drop GDPR Summer Internship with the NSA Many Incident Responders are Stressed Out Microsoft's newest dual 0-day Exchange Fumbles SpinRite news ZimaBoard Closing the Loop Source Port Randomization We invite you to read our show notes at https://www.grc.com/sn/SN-892-Notes.pdf Hosts: Steve Gibson and Leo Laporte Download or subscribe to this show at https://twit.tv/shows/security-now. Get episodes ad-free with Club TWiT at https://twit.tv/clubtwit You can submit a question to Security Now! at the GRC Feedback Page. For 16kbps versions, transcripts, and notes (including fixes), visit Steve's site: grc.com, also the home of the best disk maintenance and recovery utility ever written Spinrite 6. Sponsors: Secureworks.com/twit newrelic.com/securitynow bitwarden.com/twit

Picture of the Week. Breach of Customer Information Meta-targeted Malware Uber's Chief Security Officer Found Guilty More Cryptocurrency Chaos The UK to drop GDPR Summer Internship with the NSA Many Incident Responders are Stressed Out Microsoft's newest dual 0-day Exchange Fumbles SpinRite news ZimaBoard Closing the Loop Source Port Randomization We invite you to read our show notes at https://www.grc.com/sn/SN-892-Notes.pdf Hosts: Steve Gibson and Leo Laporte Download or subscribe to this show at https://twit.tv/shows/security-now. Get episodes ad-free with Club TWiT at https://twit.tv/clubtwit You can submit a question to Security Now! at the GRC Feedback Page. For 16kbps versions, transcripts, and notes (including fixes), visit Steve's site: grc.com, also the home of the best disk maintenance and recovery utility ever written Spinrite 6. Sponsors: Secureworks.com/twit newrelic.com/securitynow bitwarden.com/twit

Picture of the Week. Breach of Customer Information Meta-targeted Malware Uber's Chief Security Officer Found Guilty More Cryptocurrency Chaos The UK to drop GDPR Summer Internship with the NSA Many Incident Responders are Stressed Out Microsoft's newest dual 0-day Exchange Fumbles SpinRite news ZimaBoard Closing the Loop Source Port Randomization We invite you to read our show notes at https://www.grc.com/sn/SN-892-Notes.pdf Hosts: Steve Gibson and Leo Laporte Download or subscribe to this show at https://twit.tv/shows/security-now. Get episodes ad-free with Club TWiT at https://twit.tv/clubtwit You can submit a question to Security Now! at the GRC Feedback Page. For 16kbps versions, transcripts, and notes (including fixes), visit Steve's site: grc.com, also the home of the best disk maintenance and recovery utility ever written Spinrite 6. Sponsors: Secureworks.com/twit newrelic.com/securitynow bitwarden.com/twit

Peralta may be in a slump, but Henry and Finn are definitely in a pmuls today.THIS WEEK'S TOPICThe Slump (Brooklyn Nine-Nine: S1, E3): Jake is in a slump. Amy and Rosa attempt to give a seminar to teenagers. Terry is having trouble with a gift for his daughters.USEFUL INFORMATION AND LINKSPlease listen to our explainer “What is Schurt?” episode. It will explain the show in only three minutes.Schurt: A Collection of Enjoyable PodcastsThe Office (American TV Series)Parks and RecreationBrooklyn Nine-NineThe Good PlaceRutherford FallsSchurt Numbers Spreadsheet for Randomization and Charts (alternatively, view as a pdf)The music is created by me, Henry, with help from my very good music teacher, Brian Ajjan.Contact us at henry@tunklecast.com (NOT welcome.everythingis@schurt.site)THINGS THAT WE MENTIONShe-Hulk: Attorney at Law

THIS WEEK'S TOPICDiversity Day (The Office: S1, E2): Michael tries to prove that he is an expert on racial diversity, while Jim repeatedly attempts to make a sale.USEFUL INFORMATION AND LINKSPlease listen to our explainer “What is Schurt?” episode. It will explain the show in only three minutes.schurt.siteTunkle CastsThe Office (American TV Series)Parks and RecreationBrooklyn Nine-NineThe Good PlaceRutherford FallsSchurt Numbers Spreadsheet for Randomization and Charts (alternatively, view as a pdf) (this PDF will be reflective of last week's charts, because the current version was lost)The music is created by me, Henry, with help from my very good music teacher, Brian Ajjan.Contact us at welcome.everythingis@schurt.siteTHINGS THAT WE MENTIONRon and Tammy (Parks and Recreation: S2, E8)Ron and Tammy 2 (Parks and Recreation: S3, E4)Ron and Jammy (Parks and Recreation: S7, E2)Buckheart Lodge (Rutherford Falls: S1, E2)Green GoblinThe Amazing Spider-Man (1963) #122The WizardME Time (Brooklyn Nine-Nine: S1, E4)Halloween (Brooklyn Nine-Nine: S1, E6)EPISODES THAT WE MENTIONScott's Totts (S6, E12)Angry Andy (S9, E21)Broke (S6, E25)

The past two episodes we've explored the importance of habits. But on this episode J.R. looks at the flip side of the coin and talks about randomization rituals. Leonard Sweet lives his life by putting himself in a position where he can experience things in a new – and sometimes strange – ways in order to have fresh eyes. The Russian term for this is ‘ostranenie' – seeing the familiar in unfamiliar ways in order to understand it better or more deeply. When we experience ‘ostranenie' we can become more resilient leaders.. . .If you haven't signed up for my every other week FREE newsletter 5 Things in 5 Minutes (5 valuable nuggets that can be read in 5 minutes or less), check outwww.kairospartnerships.org/5t5mI'd love to hear from you. Drop me a line at jrbriggs@kairospartnerships.orgKairos Partnerships: www.kairospartnerships.orgContact: www.kairospartnerships.org/contactConnect with me on LinkedIn: https://www.linkedin.com/in/kairospartnerships**Resilient Leaders is produced by the incredibly gifted Joel Limbauan. Check out his great video and podcast work at On a Limb Productions: www.onalimbproductions.com

Finn and Henry find this week's episode more enjoyable than the last few. Boyle's B plot isn't great, but it's at least partly made up for by Peralta's comedy. That's right. This episode had actual funny jokes. Who could have guessed?THIS WEEK'S TOPICThe Tagger (Brooklyn Nine-Nine: S1, E2): Jake continues trying to adjust to the new captain, while dealing with a vandalism case. Boyle meets Gina's psychic.USEFUL INFORMATION AND LINKSPlease listen to our explainer “What is Schurt?” episode. It will explain the show in only three minutes.Schurt: A Collection of Enjoyable PodcastsThe Office (American TV Series)Parks and RecreationBrooklyn Nine-NineThe Good PlaceRutherford FallsSchurt Numbers Spreadsheet for Randomization and Charts (alternatively, view as a pdf)The music is created by me, Henry, with help from my very good music teacher, Brian Ajjan.Contact us at henry@tunklecast.com (NOT welcome.everythingis@schurt.site)THINGS THAT WE MENTIONDoctor Strange in the Multiverse of MadnessEverything Is Fine (The Good Place: S1, E1)Pilot (Rutherford Falls: S1, E1)Somehow I Manage: Rewatching the OfficeAvenue 5Agents of SHIELDStar Wars: The Clone WarsGreg Pikitis (Parks and Recreation: S2, E7)Glory (1989)Episodes that we mentionCharges and Specs (S1, E22)Christmas (S1, E11)

THIS WEEK'S TOPICPilot (The Office: S1, E1): Michael and the office find out about potential downsizing, as well as a merge with Stamford.USEFUL INFORMATION AND LINKSPlease listen to our explainer “What is Schurt?” episode. It will explain the show in only three minutes.Schurt: A Collection of Enjoyable PodcastsThe Office (American TV Series)Parks and RecreationBrooklyn Nine-NineThe Good PlaceRutherford FallsSchurt Numbers Spreadsheet for Randomization and Charts (alternatively, view as a pdf)The music is created by me, Henry, with help from my very good music teacher, Brian Ajjan.Contact us at welcome.everythingis@schurt.siteTHINGS THAT WE MENTIONPilot (Rutherford Falls: S1, E1)Tuesday TechTunkle CastsThor (1966) #361Power Pack (1984) #15U-MenInfinite IssuesBonoBob HopeDisenchantmentSeveranceM.E. Time (Brooklyn Nine-Nine: S1, E4)EPISODES THAT WE MENTIONThe Job (S3, E24)Business School (S3, E17)Weight Loss (S5, E1)The Merger (S3, E8)Branch Closing (S3, E7)Special Project (S8, E14)The Convention (S3, E2)Health Care (S1, E3)Search Committee (S7, E26)Scott's Tots (S6, E12)Goodbye Michael (S7, E22)Money (S4, E7)

Big Loans to Small Businesses: Predicting Winners and Losers in an Entrepreneurial Lending Experiment, Mental Health Therapy as a Core Strategy for Increasing Human Capital: Evidence from Ghana, Randomization for Causality, Ethnography for Mechanisms: Illiquid Savings for Liquor in an Autarkic Society, and Pathways out of Extreme Poverty: Tackling Psychosocial and Capital Constraints with a Multi-faceted Social Protection Program in Niger Scientific Sense ® by Gill Eapen: Prof. Dean Karlan is Professor of Economics and Finance at Northwestern University, and the Founder and President of Innovations for Poverty Action, a non-profit organization dedicated to discovering and promoting solutions to global poverty problems. Join this channel to get access to perks: https://www.youtube.com/channel/UCo2wiIHPM35xPawotek2IDA/join --- Send in a voice message: https://anchor.fm/scientificsense/message Support this podcast: https://anchor.fm/scientificsense/support

This week, please join author Andrew Chapman and Guest Editor Harvey White as they discuss the article "Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Greg Hundley: Well, Carolyn, this week's feature on April 19th refers to coronary artery and cardiac disease in patients with type two myocardial infarction. And we will have more to learn about that, but how about we grab a cup of coffee and get started with some of the other articles in the issues. Dr. Carolyn Lam: Please? You first. Dr. Greg Hundley: Thanks Carolyn. So Carolyn, this team investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity based proteomic assays to estimate their association with incident heart failure. And so to accomplish this, the team, led by Dr. Thomas Lumbers from University College of London, utilized a fixed effect meta-analysis of four population-based studies comprising a total of 3,000 plus participants with 732 heart failure events. Now, the causal effects of heart failure associated proteins were then investigated by Mendelian randomization using CIS protein, quantitative loci, genetic instruments identified from genome-wide association studies or GWAS and over 30,000 individuals. Dr. Carolyn Lam: Wow! Big study, important stuff. So what did they find? Dr. Greg Hundley: Right Carolyn, several things. So 44 of 90 proteins were positively associated with the risk of incident heart failure. Now, among these eight proteins had evidence of a causal association with heart failure that was robust to multiverse sensitivity analysis. Higher CSF1, Galectin-3 and KIM-1 or kidney injury molecule one were positively associated with the risk of heart failure, whereas higher adrenomedullin chitinase-3 like-protein-1, cathepsin L1, and fibroblast growth factor 23, and matrix metalloproteinase 12 were protective. And so Carolyn in summary, the team identified 44 circulating proteins that were associated with incident heart failure of which eight showed evidence of a causal relationship, and seven were identified as being drugable, including adrenomedullin, which represents a particularly promising drug target. Dr. Greg Hundley: Additionally, Carolyn, this is a really interesting study as the teams approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases. Dr Carolyn Lam: Wow! Super cool. Yeah, indeed the methodology is significant there too. Thanks Greg. Well, this next paper deals with hypertrophic cardiomyopathy and we know that familial hypertrophic cardiomyopathy is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. But how exactly is the dysregulated sarcomeric force production sensed and how does that lead to pathological remodeling? Dr. Carolyn Lam: Well, today's authors and they are Dr. Qyang from Yale University School of Medicine and colleagues gained insights from a severe phenotype of an individual with hypertrophic cardiomyopathy and a second genetic alteration in a sarcomeric mechanosensing protein. They derived cardiomyocytes from patient specific induced pluripotent stem cells and developed robust, engineered heart tissues to study human cardiac mechanobiology at both cellular and tissue levels. They further used computational modeling for muscle contraction and rescue of disease phenotype via gene editing and pharmacological interventions to identify a new mechanotransduction pathway in hypertrophic cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn! Tell us more about this new pathway. Dr. Carolyn Lam: The study presents a novel biomechanical mechanism by which enhanced myofilament contractile force generation due to sarcomeric mutations, destabilize the muscle limb protein Z-disc mechanosensory complex, and this leads to disinhibition of calcineurin nuclear factor of activated T-cells or NFAT signaling and consequently leads to hypertrophy. Normalization of hypercontractile force in proband cardiomyocytes either with gene editing approaches or with ectomyosin crossbridge inhibitor mavacamten, resulted in an increase in Muscle Lim Protein levels, a decrease in that calcineurin and fat activity and a rescue from the hypertrophic cardiomyopathy defects. Dr. Carolyn Lam: The authors provided evidence that the common Muscle Lim Protein W4R variant is an important modifier that worsens the disease severity of hypertrophic cardiomyopathy, but alone does not appear sufficient to cause disease. All in all, these data established a foundation for developing innovative mechanism-based treatments for hypertrophic cardiomyopathy that stabilize the Z-disc Muscle Lim Protein mechanosensory complex. Dr. Greg Hundley: Oh, wow Carolyn! What a really nice mechanistic study and important new information too. Well, Carolyn, my next paper comes to us from Dr. Anthony Rosenzweig, Massachusetts General Hospital at the Harvard Medical School and Carolyn the LV myocardium increases in mass in response to pathological as well as physiological stimuli. The former or pathologic hypertrophy, often proceeds cardiomyocyte loss and heart failure. The latter or physiologic, paradoxically protects the heart enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Now, while long non-encoding RNAs are important in cardiac development and disease associated with pathologic hypertrophy, less is known about their roles in physiologic hypertrophy or cardiomyogenesis. Dr Carolyn Lam: Oh, interesting! So what did these authors find about link RNAs and physiologic hypertrophy? Dr Greg Hundley: Right, Carolyn. So in this study of mice, the authors identified exercise regulated cardiac link RNAs termed lncExACT and lncExACT1 was evolutionarily conserved and decreased in exercised hearts, but increased in experimental heart failure. Cardiac lncExACT1 over expression caused pathological hypertrophy and heart failure while lncExACT1 inhibition induced physiologic hypertrophy and cardiomyogenesis protecting against cardiac fibrosis and dysfunction. Dr. Greg Hundley: Now, lncExACT1 functioned by regulating microRNA 222 calcineurine signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCH2 over expression in zebra fish induced pathological hypertrophy and impaired cardiac regeneration promoting scarring after this injury. In contrast mirroring DCH2 deletion, induced physiological hypertrophy and promoted cardiomyogenesis. Dr. Carolyn Lam: Oh, wow, Greg! Okay. Could you wrap it up for us? What's the take home message? Dr. Greg Hundley: You bet, Carolyn. These studies identify that lncExACT1 DCHS2 is a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1 DCHS2 acts as a master switch, toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the benefits of exercise. Dr Carolyn Lam: Oh, thank you, Greg. Well, also in this issue is an In-Depth paper by Dr. Luesebrink on “Percutaneous Transvalvular Micro Exhale Flow Pump Support in Cardiology.” There's a Research Letter by Dr. Shekhar on “Age and Racial or Ethnic Disparities in Pediatric Out-of-Hospital Cardiac Arrest.” Dr. Greg Hundley: Right, Carolyn. Well, Carolyn from the mailbag, we have a Letter to the Editor from Dr. Gronda entitled “The Failing Heart and SGLT2 inhibitor Renal Effects: Are They Mutually Engaged in Business?” We also have from Dr. Viskin, an ECG challenge entitled “Sinus Node Dysfunction with a Nice Twist.” And finally, Carolyn, there's a Perspective piece from Dr. Schulman entitled “The Price and Quality of the Generic Pharmaceutical Market.” Well, how about at Carolyn we get on our feature discussion involving type two myocardial infarction. Dr. Carolyn Lam: Yay! Let's go. Dr. Greg Hundley: Well, listeners, welcome to our feature discussion on this April 19th and we have with us today, Dr. Andrew Chapman from Edinburg, Scotland and Dr. Harvey White from Auckland, New Zealand. Welcome gentlemen. And we'll start with you, Andrew. First, could you describe for us some of the background information that went into the preparation of your study? Dr Andrew Chapman: Good morning and good evening and thank you very much for the invitation. So type two myocardial infarction is an interesting diagnosis. It was first introduced in around 2007 in recognition that patients could have heart injury when they were in hospital with other problems that led to an imbalance in myocardial oxygen supply, or an unmet need in myocardial oxygen demand, without the presence of atherothrombotic coronary artery disease. We don't know a great deal about these patients. Dr. Andrew Chapman: There have been a number of observational cohort studies, including from ourselves in Scotland, which have demonstrated the outcomes for this patient group are poor. We know only around one-third of patients with type two MI, survive to five years after diagnosis. And we also know, and previously demonstrated from patients in Scotland that those with underlying coronary artery disease actually had the worst outcomes and were at increased risk of future myocardial infarction events due to plaque rupture. So we hypothesized that patients with type two myocardial infarction may have failed a physiological stress test due to another illness and we wanted to investigate what the prevalence of underlying coronary artery disease and/or structural heart disease was, using a panel of different imaging modalities. Dr. Greg Hundley: And so Andrew tell us the hypothesis that you wanted to address? Dr. Andrew Chapman: So we believed that observational evidence suggested that coronary artery disease was important in patients with type two myocardial infarction and we felt that this was increasing their susceptibility to these events. Our primary hypothesis was that the majority of patients with type two myocardial infarction would have underlying coronary artery disease, which was previously quiescent undetected. Dr. Greg Hundley: Tell us a little bit about the study design and the study population that you use to answer this question. Dr. Andrew Chapman: Demand MI is to our knowledge, the first prospective observational cohort study in which patients who were in hospital with evidence of myocardial injury, so a raised cardiac troponin, were screened for the presence of supplier demand imbalance and the clinical diagnosis of type two MI. Now, in those patients that we were able to recruit, we did obviously have important exclusion criteria, but we designed a series of different investigations depending on individual patient risk factors and the appropriateness of such, but the primary goal was to undertake coronary angiography, ideally using an invasive coronary angiogram, which would allow us to undertake additional testing, such as plaque imaging and pressure wire study, to look for the functional consequences of stenosis. In those not fit for an invasive angiogram, we undertook CT coronary angiography. And in all patients we undertook structural imaging and we aimed to do cardiac MRI in all. Due to the coronavirus pandemic and for other reasons, we used echocardiography where MRI was not available. Dr. Greg Hundley: And so the total number of subjects here was how many? Dr. Andrew Chapman: We recruited 100 patients with a clinical diagnosis of type two myocardial infarction. Dr. Greg Hundley: Very good. And so now, Andrew, what were your results? Dr. Andrew Chapman: It's a really fascinating study, obviously, in my opinion. So we recruited 100 patients with a clinical diagnosis of type two myocardial infarction who had evidence of supplier demand and balance, a raised cardiac troponin concentration and evidence of symptoms and/or signs of myocardial ischemia. So in line with the universal definition criteria. Of 100 patients after undertaking coronary imaging, we reclassified the diagnosis in seven. Dr. Andrew Chapman: In five patients, we found that there was evidence of either plaque rupture or a stent thrombosis. And in two patients, we found evidence of myocarditis and stress cardiomyopathy respectively. The first principle finding is that actually despite careful characterization and really detailed screening, we were correct in 93 of 100 patients and we got the diagnosis wrong in seven. The principle hypothesis related to the prevalence of coronary artery disease and this was, as alluded to, undertaking with invasive and noninvasive imaging. But overall, the prevalence of coronary artery disease was 68% of those with type two myocardial infarction and this was obstructive in 30%. Dr. Andrew Chapman: We also undertook structural imaging as mentioned. We observed evidence of left ventricular systolic dysfunction in 34% of patients, of around a third, and perhaps most surprisingly, although we had a clear diagnosis of myocardial infarction in these patients, we only found imaging evidence of in part pattern late gadolinium enhancement, which is considered the gold standard for its diagnosis of myocardial infarction. We only observed that in 42%, which raises some interesting questions. Dr. Andrew Chapman: One of the principle clinical findings of the study is that these underlying conditions of coronary artery disease and left ventricular impairment, both of which are readily treatable with secondary prevention. These conditions were previously unrecognized in 60% of patients and only one-third were on appropriate evidence-based treatment, which gives me some cause for optimism, that there may be a role here for targeted treatment, which could plausibly, plausibly impact on outcomes. Dr. Greg Hundley: And Andrew, just a clarification point, maybe a subgroup analysis, any differences in your findings in regarding men versus women? Dr. Andrew Chapman: Excellent question. And in most studies of type two myocardial infarction, it's thought that this condition is more prevalent in women than men, but undoubtedly in all observational cohorts, there is selection bias as you will only diagnose a type two myocardial infarction if a clinician requests to test troponin in the first place. In our study, interestingly, we recruited more men than women. We had 56% men and we did not find any differences by sex in our analysis. Dr. Greg Hundley: Well listeners, what an excellent description from Dr. Chapman. A very interesting study. And we now want to turn to one of our editors, guest editors, Dr. Harvey White, and Harvey, we want to thank you for your work here with us at the American Heart Association and Circulation, and you receive many articles to review. What attracted you to this particular article and how do we put in context, these results with others that have been published pertaining to type two myocardial infarction? Dr. Harvey White: Thanks, Greg, it's a pleasure to work for Circulation. This paper is very close to my heart because I introduced the typing system in 2007 and it had minimal support and people said, "Why do we need a typing system? We've got killer class and Canadian class and you've done a troponin release system as well". And people stood up and then I laid out the type one plaque rupture. We know the pathophysiology and we know the treatment. Type two, I'd worked on beta blockers, supply and demand and I thought we should define the pathophysiology and define the treatment. That's 2007, which is 15, 16 years ago. And Andrew's paper is really lovely. As I said, it's close to my heart and he inches things forward. I've written an editorial, which I call "Zooming in on the enigmas of type two MI" and enigma means mystery or it's unclear, uncertain. Dr. Harvey White: And that's for sure we don't have full support for the diagnosis. It's become very practical, used in clinical trials and clinically, but we don't know how to manage it and we don't know how to define the groups. Andrew and colleague study is very nice. It's prospective and it has set out to define the coronary artery disease. I've tried for about 10 years to subdivide type two and to those without coronary disease and those with coronary disease. And you could also have a type C, which hasn't been investigated or unknown. And Andrew has answered one of the enigmas and it's really interesting. Large proportion, normal coronary arteries, diagnosis was changed a little bit based on the finding of thrombus. We're challenged with that finding because all MIs have thrombus at PM and really type one should be ruptured plaque. But Andrew changed the diagnosis in a few where one was an OTC, a marvelous case with marvelous pictures, changed the diagnosis. So I like the study and I like the findings. Thanks. Dr. Greg Hundley: Very nice. Well, Andrew, what a perspective and listeners getting just to listen to Dr. White is really quite exciting for me. Andrew, what do you see as the next study to be performed in this sphere of research? Dr. Andrew Chapman: I think we've gone some way to provide some insights into the underlying pathophysiology of this condition and these coexistent conditions of coronary artery disease and left ventricular impairment, which might increase an individual's susceptibility to a type two myocardial infarction. The question is what can we do about it and does targeted treatment with secondary prevention therapies for coronary disease and treatment for heart failure left ventricular impairment, does that improve outcomes? Dr. Andrew Chapman: The next study for me is clear. The next study for me, needs to be a randomized controlled trial, whereby patients with type two myocardial infarction are randomized to current best practice or risk stratification by a cardiologist with an interest in this condition, followed by targeted investigation for coronary disease and LV impairment and thereafter treatment as appropriate. This will be a trial of a complex intervention. I'm very grateful that we've received funding in Scotland already for this pilot phase of this trial, which we've called Targets Type Two and we'll begin recruitment for that trial in August of this year. Dr. Andrew Chapman: I must acknowledge colleagues in this area are looking at coronary disease and type two myocardial infraction. Professor Derek Chew is leading a study called Act Two, which is already recruiting and that will also provide invaluable information as to the prevalence of coronary disease and the potential benefits of treatment of that coronary disease in patients with this condition. Dr. Greg Hundley: And Harvey. How about your, what is your perspective in terms of the next series of studies perhaps that need to be performed in this space? Dr. Harvey White: There's a number and I like very much, Andrew's suggestion. The study that we're doing is randomizing to angiography or not angiography working with Derek Chew. I think all patients with MI should have coronary angiography. It's simple, it takes about 10 minutes. There's obviously some contraindications, but the information as Andrew has pointed out is really so useful. He found dissection, he found an embolus. Normal coronary arteries that in my view changes the management. Whether you should do an angiogram is very important. Randomization to various treatments. That's important. I would like to get more information about the objective evidence of type two MI, the criteria for low hemoglobin, shortness of breath, low blood pressure, high blood pressure, and so forth. There's a lot to do. As Andrew pointed out, the outcome may be worse than type one that's becoming more common and I think these studies will be very, very important. Dr. Greg Hundley: Very nice well listeners. We want to thank Dr Andrew Chapman as lead investigator and Dr Harvey White as guest editor for bringing us this study using advanced imaging of patients with type two myocardial infarction, which identified coronary artery disease in two-thirds and left ventricular dysfunction in one-third, and also highlighting that unrecognized and untreated coronary or cardiac disease occurs in many patients with type two MI and gives us pause for thought on a series of studies that may be performed in the future. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

ACC Recap: John Mandrola, MD, provides part 1 of an ACC recap in this week's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I – HTN in Pregnancy - Hypertension Control During Pregnancy Validated in Large Trial https://www.medscape.com/viewarticle/971486 - Treatment for Mild Chronic Hypertension during Pregnancy https://www.nejm.org/doi/full/10.1056/NEJMoa2201295 II – Prevention of Bleeding in Non-Cardiac Surgery - POISE-3 Backs Wider Use of Tranexamic Acid in Noncardiac Surgery https://www.medscape.com/viewarticle/971483 - Tranexamic Acid in Patients Undergoing Noncardiac Surgery https://www.nejm.org/doi/full/10.1056/NEJMoa2201171 III – HCM - VALOR-HCM: Novel Drug May Delay, Avert Invasive Therapy in OHCM https://www.medscape.com/viewarticle/971484 IV – Left Atrial Appendage Occlusion - Small Leaks After LAAO Linked to Thromboembolism, Bleeding https://www.medscape.com/viewarticle/971709 V – Low Sodium Diet for HF - Low-Sodium Diet Did Not Cut Clinical Events in Heart Failure Trial https://www.medscape.com/viewarticle/971482 - Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial https://doi.org/10.1016/S0140-6736(22)00369-5 VI – Flu Vaccine and Heart Failure - Flu Vaccines Cut Seasonal Death in Patients With Heart Failure https://www.medscape.com/viewarticle/971619 VII – New Anticoagulant? - Less Bleeding With Factor XI Inhibitor Anticoagulant? PACIFIC-AF https://www.medscape.com/viewarticle/971702 Features: - Sodium Restriction in Heart Failure: Another Dogma Felled by Randomization https://www.medscape.com/viewarticle/971697 - Percutaneous Left Atrial Appendage Occlusion: ACC Data Challenge Promise vs Reality https://www.medscape.com/viewarticle/971512 - Mavacamten in Hypertrophic Cardiomyopathy: Reasons for Both Optimism and Caution https://www.medscape.com/viewarticle/971485 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact: news@medscape.net

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Why randomized controlled trials matter, published by salonium on March 22, 2022 on The Effective Altruism Forum. Hello! I'm Saloni Dattani and I work at Our World in Data. I wanted to share an article I wrote recently for Our World in Data, where I explain how randomized controlled trials (RCTs) work and why (and when) they matter: http://ourworldindata.org/randomized-controlled-trials Since RCTs are considered a high-quality source of evidence for our knowledge of the effects of treatments, policies, and interventions, I think it's important to understand how they work to improve our ability to read scientific literature and to help us make better decisions. I make two main arguments: 1. That RCTs are a powerful source of evidence because of the procedures that they are expected to follow. For each, I illustrate how they work and how they might affect the results of studies with examples. A control group, which gives us the possibility to see a counterfactual (“what might happen otherwise”). Placebos, which can account for placebo effects. For example, people may feel better from taking a pill because they expect it to make them feel better. More generally, these are changes that occur because of the procedure of the treatment rather than the treatment itself. Randomization, which ensures that the two groups (control and treatment) have comparable risks (at the beginning of the study) of developing the outcome, and can enable us to attribute differences between them to whether they received the treatment. Concealment and blinding, which prevent researchers and participants from knowing which group they are allocated to. Pre-registration, a procedure where researchers declare in advance how they are going to carry out the study. This allows us see whether they've deviated from their plans, for example, because they found results that were disappointing. It can store research that is not published in a journal, because of ‘publication bias.' Some other key features of RCTs that I mention but don't detail: experimentation and intention-to-treat analysis. Importantly, this means that when RCTs do not follow these procedures, this makes them less reliable. Sometimes other types of studies (apart from RCTs) follow some of these procedures, which strengthens them as sources of evidence. 2. That RCTs are particularly useful in some circumstances. I illustrate this with two examples. We know that smoking has a large causal effect on the risk of lung cancer, without evidence from RCTs. This is because many lines of evidence converge on this conclusion, and other explanations fall short of accounting for the massive association that we see. In contrast, when scientists looked for treatments for HIV/AIDS, many candidate drugs they expected to work actually failed, while some that worked were unexpected and led to insights about how the virus caused disease. With this, I argue that RCTs matter when: we don't have enough data from other lines of evidence, when we don't know how to rule out other explanations, and when research is affected by biases (of the researcher, of participants, and publication bias). A catchier version is that they matter when we don't know enough, when we're wrong, and when we see what we want to see. As I explain, I think understanding these ideas is very important because we point to evidence from RCTs when we want to evaluate treatments, policies and interventions. Hopefully, the examples that I give are intuitive and help to apply these concepts more widely. If the points in the summary above are already familiar to you, hopefully there are some cool charts or examples that are still new to you. I'm also happy to answer questions or correct errors, if you spot any. You can also contact me at saloni@ourworldindata.org or find me at @salonium on Twitte...

Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief, and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, shares key takeaways from the practice-changing ARASENS trial in mHSPC, featured at the 2022 ASCO Genitourinary Cancers Symposium.   Transcript: ASCO Daily News: Hello, and welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Today in our continuing coverage of the 2022 ASCO Genitourinary (GU) Cancer Symposium. Dr. Neeraj Agarwal, the editor in chief of the ASCO Daily News will share key takeaways from the practice-changing ARASENS trial, which showed promising results in metastatic hormone-sensitive prostate cancer. Dr. Agarwal has no conflicts relating to the topic of this episode and his full disclosures are available in this show notes. Disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts. Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Neeraj Agrawal, the director of the Genitourinary Cancers Program and professor of medicine at the University of Utah Huntsman Cancer Institute. Let's discuss the results of the practice-changing ARASENS trial in patients with metastatic castration-sensitive prostate cancer as presented at the 2022 ASCO GU Symposium. This abstract, Abstract 13, was presented by Dr. Matthew Smith from the Massachusetts General Hospital and Hartford Medical School. ARASENS is a randomized phase 3 trial evaluating the efficacy and safety of darolutamide, a novel hormonal therapy, plus ADT (antiandrogen therapy) plus docetaxel versus placebo plus ADT plus docetaxel in patients with metastatic castration-sensitive prostate cancer. Randomization was stratified by the extent of disease and alkaline phosphatase levels, below versus upper limit of normal or above. It is important to know that this study only included patients that were eligible for ADT and docetaxel chemotherapy, to begin with. The primary endpoint was overall survival with multiple secondary endpoints, including time to CRPC (castration-resistant prostate cancer), time to pain progression, time to first symptomatic skeletal event, and time to start off the next anti-neoplastic therapy, and safety. A total of 1,306 patients were randomly assigned to triplet therapy with darolutamide plus ADT plus docetaxel versus placebo plus ADT plus docetaxel. Baseline characteristics were well balanced between the treatment arms. Analysis of the primary endpoint was pre-specified. After, 533 events had occurred results show the primary endpoint of this study was met with a significant improvement in overall survival and a 32.5% reduction in risk of death for patients on the triplet therapy on for darolutamide plus ADT plus docetaxel versus placebo plus ADT plus docetaxel. It is important to know that the triplet therapy improved overall survival, despite 76% of patients in the control arm having received the next life-prolonging therapy. Subgroup analysis indicates consistent benefit across the 3 specified groups. Secondary endpoints also were favored by the triplet therapy combination over the control arm. While this study offers an additional excellent option for our patients with metastatic cancer-sensitive prostate cancer in older populations, the use of docetaxel may be a significant limitation to this triplet combination. In addition, and importantly, this study did not answer the question of whether adding docetaxel chemotherapy to the ADT plus novel hormonal therapy backbone will also improve survival. With the advent of multiple doublets and triplet combinations in recent years, as we saw in the form of ADT plus enzalutamide ADT plus apalutamide in the recent years, it is very important to find biomarkers that may predict response to these treatment options, which will allow personalization of therapy with that. I would like to conclude this podcast on the ARASENS trial. Thank you very much for your kind attention. ASCO Daily News: You've been listening to Dr. Neeraj Agarwal of the University of Utah's Huntsman Cancer Institute. Thanks for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcasts. Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas Disclaimer: The purpose of this podcast is to educate and to inform this is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this episode Craig and Nathan chat about how to start a song, pros & cons of a DAW template, Song Exploder, Brian Eno's deck of cards, using randomization, and much more. Get our newest library Struck Grand: https://soundiron.com/products/the-struck-grand For more info, visit our website: https://soundiron.com/ Podcast notes: * (0:00) Intro * (0:22) Superbowl Halftime Show * (1:55) How to start a song * (7:54) Abstract Adjectives * (10:08) Struck Grand Piano * (13:24) Song Exploder * (15:46) DAW templates * (20:55) Start with a photograph * (24:04) Brian Eno Oblique Strategies * (33:52) Randomize * (39:35) Recommendations Soundiron is a premium developer of virtual instruments and sample libraries for songwriters, composers and sound designers. They are a team of programmers, engineers, composers and instrumentalists passionate about building beautiful-sounding instrument plugins that are inspiring to play. Whether you're new to music production or a seasoned pro in the film, television, advertising, video game, or music recording industries, They've got you covered. Soundiron serves the best and brightest composers and artists in film & media today. #soundiron #musicpodcast #keepgoing

We attempt to talk about news headlines. Randomly.--- Send in a voice message: https://anchor.fm/therandomkristianshow/messageSupport this podcast: https://anchor.fm/therandomkristianshow/support