Podcast appearances and mentions of David Strauss

In this extended extract from their series 'Conversations in Philosophy', part of the LRB's Close Readings podcast, Jonathan Rée and James Wood look at one of Friedrich Nietzsche's early essays, 'Schopenhauer as Educator'. For Nietzsche, Schopenhauer's genius lay not in his ideas but in his heroic indifference, a thinker whose value to the world is as a liberator rather than a teacher, who shows us what philosophy is really for: to forget what we already know. ‘Schopenhauer as Educator' was written in 1874, when Nietzsche was 30, and was published in a collection with three other essays – on Wagner, David Strauss and the use of history – that has come to be titled Untimely Meditations. Jonathan and James consider the essays together and their powerful attack on the ethos of the age, railing against the greed and power of the state, fake art, overweening science, the triviality of universities and the deification of success.James Wood is a contributor to the LRB and staff writer at The New Yorker, whose books include The Broken Estate, How Fiction Works and a novel, Upstate.Jonathan Rée is a writer, philosopher and regular contributor to the LRB whose books include Witcraft and A Schoolmaster's War.To listen to the rest of this episode and all our other Close Readings series, sign up;In Apple Podcasts: https://lrb.me/nietzscheapplecrIn other podcast apps: https://lrb.me/nietzschesccr Hosted on Acast. See acast.com/privacy for more information.

For Nietzsche, Schopenhauer's genius lay not in his ideas but in his heroic indifference, a thinker whose value to the world is as a liberator rather than a teacher, who shows us what philosophy is really for: to forget what we already know. ‘Schopenhauer as Educator' was written in 1874, when Nietzsche was 30, and was published in a collection with three other essays – on Wagner, David Strauss and the use of history – that has come to be titled Untimely Meditations. In this episode Jonathan and James consider the essays together and their powerful attack on the ethos of the age, railing against the greed and power of the state, fake art, overweening science, the triviality of universities and, perhaps above all, the deification of success.Non-subscribers will only hear an extract from this episode. To listen to the full episode, and all our other Close Readings series, subscribe:Directly in Apple Podcasts: https://lrb.me/applecrcipIn other podcast apps: https://lrb.me/closereadingscipRead more in the LRB:David Hoy on Nietzsche's life:⁠https://www.lrb.co.uk/the-paper/v09/n01/david-hoy/different-stories⁠J.P. Stern on 'Unmodern Observations' (or 'Untimely Meditations'):⁠https://www.lrb.co.uk/the-paper/v12/n16/j.p.-stern/impatience⁠Jenny Diski on Elisabeth Nietzsche:⁠https://www.lrb.co.uk/the-paper/v25/n18/jenny-diski/it-wasn-t-him-it-was-her⁠ Hosted on Acast. See acast.com/privacy for more information.

David Strauss is widely recognized as the world authority on overcoming Energy Vampires: the toxic people and relationships that steal our joy and crush our zest for life. David shares his story that reads like an epic adventure, being a runaway at 15, climbing to the 23,000-foot summit of Aconcagua, Argentina, and recovering from a rockfall to his head, David has emerged as an Author, Transformational Speaker, Philanthropist, and Life Strategist. Learn more about David, his bestselling books as well as his author and speaking services at www.davidstrauss.com

The Supreme Court kicks off its 2023 term on Monday with guns, abortion, and affirmative action potentially coming back—whether the justices are ready for them or not. Advocates and lower courts are emboldened by the high court's recent rulings in key areas and are bringing aggressive claims that the justices might not have anticipated, University of Chicago law professor David Strauss said. The “chickens are coming home to roost,” Strauss said in noting the court has unsettled law in some areas with its rulings. Do you have feedback on this episode of Cases & Controversies? Give us a call and leave a voicemail at 703-341-3690.

Bill Knapp is in his fifth decade as a top Democratic media consultant and is the first K in the mega-media firm SKDK. In this conversation, Bill talks his NYC roots, the 1980 Senate campaign that launched his professional career, lessons from his mentor & eventual partner Bob Squier, key races in his development as a strategist, the '96 Clinton re-elect, 20 years as part of Mike Bloomberg's political orbit, advice for budding media consultants, and much more. IN THIS EPISODEBill's roots on the Upper West Side of Manhattan…The three prominent figures Bill met as a child in his apartment building…Bill dips his toe into politics at Franklin & Marshall College in rural PA…The 1980 Liz Holtzman Senate campaign changes Bill's professional direction…Bill's intersection with mentor and future business partner, the legendary Bob Squier…Bill talks the legacy of Bob Squier…The US Senate race where Bill established himself as a media strategist in his own right…Bill goes deep inside the 1996 Clinton Presidential Re-election…Bill helps elect Mike Bloomberg Mayor of NYC in 2001…Bill's perspective on the Bloomberg 2020 presidential with a few years' hindsight…How Bill's firm, SKDK, grew to the size of 100+ employees…Bill talks the skillset of his prominent business partner Anita Dunn…Bill's advice to the next generation of political media consultants… AND $15 CPP, Adas, Avenue J, Daniel Barash, Bob Bauer, Belmont Stakes, Joe Biden, Rod Blagojevich, Jim Blanchard, Bill Bradley, Jim Brady, broad shoulders, Quentin Burdick, Jimmy Carter, Pia Carusone, Central Park, Chat GPT, cinema verité, Tony Coehlo, The Communications Company,  the crack epidemic, crusty editors, Jennifer Cunningham, the DSCC, Rich Davis, Joe DiMaggio, David Dinkins, David Doak, Bob Dole, Byron Dorgan, Rahm Emanuel, Carter Eskew, F stops, FIFA, Friday Shabbat, David Garth, Newt Gingrich, Al Gore, Bob Graham, Frank Greer, Hal the Doorman, David Halberstam, Patti Harris, the Hinckley Hilton, Harold Ickes, Independent Network News, Josh Isay, Elena Kagan, Keith Kincaid, Samantha Knapp, Stanley Kubrick, JFK, lashon hara, Joe Lieberman, Horace Mann, Minnesota boys, Damon Miranda, Rick Miranda, Mike Moore, Mike Morey, Dick Morris, Jim Mulhall, New Jersey droughts, Jackie Onassis, Mark Penn, Earl Pomeroy, Mark Putnam, Riverdale, Bob Roe, Hillary Rosen, David Sawyer, Doug Schoen, Kevin Sheekey, Oren Shur, Doug Sosnik, Mark Squier, George Stephanopoulos, David Strauss, Earl Strinden, Ray Strother, technocrats, torturing gaffers, Donald Trump, Bradley Tusk, Verrazzano-Narrows Bridge, VW Karmann Ghia, Otto von Bismarck, War and Peace, Lowell Weicker, Elie Wiesel & more!

In this special monthly round-up episode of Transform Talks, Maria looks back at some of the best moments from June. For those of you that are interested in listening back to the full episodes, the excerpts were taken from the following podcasts: #185 - David Strauss on how a connected Supply Chain helps you become resilient #186 - Dr Wayne Visser on why it is time to start reframing sustainability #187 - Meaghan Ziemba on how she became a Maven of Manufacturing #188 - Lynn Torrel on how the True Demand initiative will help improve forecasting  Make sure to like and subscribe to Transform Talks to never miss the supply chain conversations that matter. New episodes are released every Wednesday. ↓ FOLLOW US ON LINKEDIN ↓ Maria Villablanca (Host) https://www.linkedin.com/in/mariavillablanca/ Transform Talks  https://www.linkedin.com/showcase/transform-talks/ ↓ FIND US ONLINE ↓ https://futureinsights.org/ https://futureinsights.org/transform-talks/ Get more on-demand supply chain content https://sctvplus.com/pages/sctv-individual Apply to be a guest on the show https://futureinsights.org/speaker-form/ Apply be a sponsor on the show https://futureinsights.org/sponsor-form/

David Strauss is the VP, Strategic Partner & Enterprise Solutions at e2open, the supply chain software platform that enables the world's largest companies to transform the way they make, move, and sell goods and services. David has over 20 years experience working for international supply chain software companies. In fact, prior to joining e2open David spent nearly a decade supporting the global chemical industry at Elemica. Since joining e2open in 2014 David has been focused on working with the company's strategic partners to bring the value of e2open's best-in-class, end-to-end cloud-based supply chain platform. On this week's episode David and Maria discuss:  The key takeaways from the recent e2open Connect European Summit  How resiliency has become a buzzword in supply chain management  What resiliency actually means in 2023  Make sure to like and subscribe to Transform Talks to never miss the supply chain conversations that matter. New episodes are released every Wednesday. ↓ David Strauss ↓ https://www.linkedin.com/in/david-strausss/ ↓ FOLLOW US ON LINKEDIN ↓ Maria Villablanca (Host) https://www.linkedin.com/in/mariavillablanca/ Transform Talks  https://www.linkedin.com/showcase/transform-talks/ ↓ FIND US ONLINE ↓ https://futureinsights.org/ https://futureinsights.org/transform-talks/ Get more on-demand supply chain content https://sctvplus.com/pages/sctv-individual Apply to be a guest on the show https://futureinsights.org/speaker-form/ Apply be a sponsor on the show https://futureinsights.org/sponsor-form/

In this episode, Pete is joined by David Strauss of Broadband Success Partners, a leading technology advisory firm in the digital infrastructure M&A sector. Pete and David discuss the current market conditions regarding funding, fiber, fixed wireless & cable in the US and globally. Click the link below to listen. Also, subscribe to the Broadband Bunch on your favorite podcast platform so you never miss an episode.

There's no shortage of topics in the world of broadband these days. Fiber network M&A activity and upgrades have not slowed down. Billions of dollars are flowing into rural broadband. Cable operators are considering multiple paths forward on their access network upgrades amid flagging broadband subscriber growth. Meanwhile, fixed wireless access (FWA) seems to be all the rage. To cover that ground and help analyze those various-but-related-topics, two cable industry vets, David Strauss and Jay Rolls, now execs at Broadband Success Partners, recently joined the Light Reading Podcast. Broadband Success Partners, a company founded in 2017, has completed more than 40 technical due diligence engagements from about 25 clients, including a growing number of them outside the US. Heading into 2023, the company is also exploring how it might bring its expertise to the public sector. "When you consider the $65 billion of infrastructure funding – broadband funding – that's coming down the pike here, perhaps there's an opportunity. We're just exploring it at this stage," David Strauss, co-founder and principal of Broadband Success Partners and an exec formerly of Lightpath, Comcast, AT&T and Sprint, explained.Meanwhile, investor interest in fiber "is very strong and not abating," says Rolls, an exec who previously held top engineering slots at Charter Communications and Cox Communications, and now serves as CTO of Broadband Success Partners. "I would even say it might be a little stronger than we saw six months ago." And Broadband Success Partners is seeing the notion of the "open access network," a model already somewhat popular in Europe, get more traction and interest in the US. You can download a lightly edited transcript of the podcast here. If you want to skip around and listen, here are a few topics discussed during this podcast:Background on the market focus of Broadband Success Partners and the number of M&A-related due diligence projects completed so far (0:50) On the opportunities emerging outside the US and, within the US, the potential to engage with the billions of dollars being freed up to bring broadband to unserved and underserved areas (4:15) An update on the current level of investor interest in fiber, and how the notion of an "open access network" built on fiber is becoming an emerging topic in the US (6:45) How active Ethernet, not just PON, is making waves in the world of fiber access networks (9:50) How in-home services, such as managed Wi-Fi, are becoming increasingly important attributes for broadband service providers that are trying to differentiate beyond speeds, feeds and pricing (11:30) A discussion on the various options available to cable operators as they pursue what's next on the access network – DOCSIS 3.1 enhancements, future DOCSIS 4.0 upgrades or overbuilds based on fiber-to-the-premises (FTTP) technology (17:00) An update on potential pricing for DOCSIS 4.0 network upgrades (22:00) As cable faces slowing broadband subscriber growth, what's more important: keeping prices and margins steady amid that slowdown, or driving promos that can rekindle subscriber growth? (27:00) How fixed wireless is factoring into the discussion, particularly in rural areas (31:45)—Jeff Baumgartner, Senior Editor, Light Reading Our GDPR privacy policy was updated on August 8, 2022. Visit acast.com/privacy for more information.

Supply chains snags continue just as U.S. communications companies are working to “rip and replace” Chinese-made equipment from their networks. How can small, rural telecom operators compete with the larger national operators to get the equipment they need? CoBank's Jeff Johnston speaks with David Strauss, senior vice president at Ace Technologies, on effective strategies rural telecom operators can use.

The pharmaceutical quality control laboratory serves one of the most important functions in pharmaceutical production and control. Poor laboratory practice may yield compliance issues, higher costs, increased cycle time, and delayed product introductions. Avoiding all that means consistent lab review processes and good document controls. Here to review effective laboratory review processes, and their importance to regulatory compliance is David Strauss of SciCord.   About Our Guest: David Strauss, CEO and Founder, SciCord David co-founded SciCord LLC in 2014.  SciCord implemented the first production ELN solution in 2015 and has continued to grow both in functionality and customer base.  SciCord's solution has evolved to encompass integrated ELN & LIMS functionality with plug-and-play modules preconfigured to automate many laboratory functions.    Prior to 2014, David created an ELN application for GSK which virtually eliminated paper from the worldwide pre-clinical organization and was credited with a 30% productivity increase. David grew the application over 15 years to service more than 6000 scientists who in turn created over 800,000 experiments. As ELN champion, David was involved and often led the design, development, testing, validation, implementation, and regulatory compliance defense. David started his career with Merck, working in the lab and then specializing in information and laboratory automation.   Voices in Validation brings you the best in validation and compliance topics. Voices in Validation is brought to you by IVT Network, your expert source for life science regulatory knowledge. For more information on IVT Network, check out their website at http://ivtnetwork.com. 

B.J. and Brian are back in action today as they discuss the Wisconsin win over Minnesota! David Strauss (mybookie.ag) joins us to chat some betting as NBA returns and the college basketball season rolls on. Plus, our best tweet comes from a great Mom!

We talk about QB's we'd like to see on the move! David Strauss (mybookie.ag) joins the show to chat about NBA and college hoops betting this weekend! We end the first hour with our best tweet and it comes from Matthew Stafford.

Thursday's show begins with the details behind B.J. paying off part of the pizza bet to Brian that was wagered earlier this year with those two and KB. The fellas kick around some of the rumors surrounding the Bucks and the NBA trade deadline that comes up at 2pm later this afternoon. David Strauss lays out his over 2,200 prop best for the upcoming Super Bowl and we close out the first hour with an interesting conclusion from a mayor in Ohio who believes ice fishing and shanties lead to prostitution.

B.J. and the Bear start the morning with breaking news out of Green Bay as Nathaniel Hackett has accepted the Denver Broncos Head Coaching job! This bring the question of will Aaron Rodgers follow him there? David Strauss (mybookie.ag) joins us to talk some Aaron Rodgers and the playoff games this weekend! We end the first hour with best tweet and it comes from Giannis.

The full squad is back as Brian makes his return this week! We discuss Brian's experience watching the Bucks game last night and his thoughts on the win. We hear from Matt LaFleur as Green Bay gets ready for their playoff contest with San Francisco. David Strauss (mybookie.ag) stops by today to chat NFL Divisional Round weekend and where the money is coming in! Plus, we end the first hour with our best tweet!

B.J. and the Bear are finally back to full strength as Brian is back! We talk about his journey home from Nebraska and catch up from his trip. We hear from Aaron Rodgers as he met with the media yesterday and we play hold up, stop the tape! David Strauss (mybookie.ag) stops by to chat NFL Wild Card weekend and which games are getting the most action! Plus, we end the first hour with our best tweet.

B.J. and Brian have their final show of 2021 and we started it out hearing from Aaron Rodgers as he met with the media yesterday. David Strauss (mybookie.ag) joins the show to discuss the bowl slate and the weekend ahead in the NFL. We end the first hour of the show with our best tweet and it comes from El Presidente at Barstool Sports.

B.J. and the Bear get the show started tonight recapping B.J.'s wild night at golf league! We hear from Davante Adams as he met with the media yesterday. David Strauss (mybookie.ag) joined us to preview the weekend ahead in the NFL and how COVID is changing lines like crazy right now. Plus, we end the first hour with a great best tweet!

B.J. is back! Brian is out for the day but B.J. makes his return from a mini-vacation! He discusses whether he believes if Badgers Hoops is back and why he believes they might be! David Strauss (mybookie.ag) joins the show to chat Week 14 in the NFL and teams you should be zeroing in on! Plus, we end the first hour with our best tweet!

B.J. and the Bear gets off and rolling discussing some Badgers basketball after their win over Georgia Tech! David Strauss (mybookie.ag) joins the show to chat NFL Week 13 and College Football Championship Games! We end the first hour with Giannis' big night!

B.J. and the Bear are back at full strength today as Brian returns! The guys recap Corbin Burnes winning the Cy Young and can they win a World Series with this pitching staff? David Strauss (mybookie.ag) joins the show to chat about the NFL slate and college football lines for the weekend! Plus, we end the first hour with a classic pretzel throw!

David Strauss is a long time Drupal community member, attending his first DrupalCon in Boston in 2008. Since then, he has been a regular contributor to Drupal performance enhancements, the https://www.drupal.org/project/bakery (Bakery Single Sign-On System), and a major Drupal distribution - https://www.pressflow.org/ (Pressflow). During his time, he also was a co-founder of https://www.fourkitchens.com/ (Four Kitchens) and later, also a co-founder of https://pantheon.io/team-member/david-strauss (Pantheon). His focus has been, and continues to be on ensuring the performance and scalability of websites - especially Drupal websites. In this installment of our https://tag1consulting.com/20years (20 years of Drupal series), David joins Tag1 Managing Director Michael Meyers to talk about his experience in making contributions - not just up front contributions like Bakery, but the ones he considers even more important - the behind the scenes performance enhancements and integrations that have helped make Drupal what it is today. David's leadership in modules at the forefront of as well as critical back-end improvements show all the ways that people can add to the community.

We begin Thursday's show with a little 'Hold Up Stop The Tape' with some Aaron Rodgers audio as the Packers QB was pretty loose at the podium when he met with the media on Wednesday. David Strauss pops in to talk about a brutal Thursday Night football matchup in the NFL, what's in store for the weekend and where Adam Schefter may land if he leaves ESPN. Really good insight and inside information on Schefty from David! Also a Butch's Breakdown from Brian that looks at the PAC 12 and B.J. is now a Kendrick Perkins fan after today's 'Best Tweet We Saw' as Perk is sold on Giannis.

Beginning Thursday by trying to move past the Brewers season being over by focusing on Packers v. Bears. The boys play a little "Hold Up Stop the Tape" with some Aaron Rodgers audio from Wednesday's presser. David Strauss swings in to talk Fury Wilder, NLDS game 5 bets for Dodgers/Giants and week 6 action in the NFL. Finally we close out the first hour with another Butch's Breakdown and a spot on take in the 'Best Tweet We Saw' featuring Chargers head coach Brandon Staley.

B.J. and Brian are off and rolling this morning as we hear from Aaron Rodgers as he met with the media yesterday! David Strauss (mybookie.ag) joins us to chat some playoff baseball and also get you ready for a wild weekend in college football/NFL. We end the first hour with Butch's Breakdown and our best tweet!

B.J. and the Bear get the show started this morning talking about Devin Williams breaking his hand after the Brewers won the division. David Strauss (mybookie.ag) joins the show to get you ready for the weekend ahead across college football and the NFL! Plus, we begin our new segment of Butch's Breakdown where we will get you ready for the college basketball season!

B.J. and the Bear are out at Whistling Straits for the 43rd Ryder Cup in Haven, Wisconsin! David Strauss (mybookie.ag) joins us to talk some Ryder Cup and also get you ready for the weekend across college football and the NFL! Plus, we have some fun with our best tweet as it comes from a fake Ryder Cup Presser!

B.J. and the Bear get the show started this morning discussing the Bucks new play-by-play commentator in Lisa Byington! David Strauss (mybookie.ag) joins the show to chat about betting in college football this weekend and the slate of games this weekend in the NFL! Plus, we end the first hour with a Seymour Safari!

The fellas B.J. and the Bear get off and rolling this morning discussing the Ryder Cup selections and what our opinions are on the guys who were picked. David Strauss (mybookie.ag) joins the show today to chat about the upcoming NFL and College football slate with betting and where he is seeing the most money coming in on the Packers vs. Saints! Plus, we end the first hour with three best tweets!

B.J. and the Bear return after a week away from each other!! We discuss the Brewers continued hot run and how impressed are the guys with this team right now? David Strauss (mybookie.ag) joins the show to chat betting on the first week in college football! Plus, we end the first hour with our best tweet!

B.J. DeGroot is out for the day so it's Brian Butch running the helm with Alex Thomas joining us! Alex gives us his reasons on why the Brewers will have trouble contending for a World Series but Brian completely disagrees. David Strauss (mybookie.ag) joins us to talk preseason betting in the NFL and college football betting is officially back!! We end the first hour with our best tweet and it comes from the Little League World Series!

B.J. and the Bear get the morning recapping the Brewers crazy comeback win last night in St. Louis! Plus, we hear from Aaron Rodgers as he spoke to the media yesterday and we do our segment of hold up, stop the tape! David Strauss (mybookie.ag) joins the show to preview the weekend ahead in the MLB and get you ready for the NFL and College Football seasons that are just right around the corner. Our best tweet is all about Christian Yelich throwing down a bunt!

B.J. is out for the day so it's Brian hosting again with Alex Thomas! The guys get rolling breaking down the Brewers continued success against the Cubs. Plus, we discuss if vintage Christian Yelich will ever return for the Brewers and should you worry? David Strauss (mybookie.ag) joins us to chat some gambling as the preseason kicks off tonight and also a preview of college football! Plus, we end the show with our best tweet and this is a great one!

B.J. and the Bear get the show started this morning chatting about some Brewers baseball as they got a nice come from behind win! We hear from Aaron Rodgers after he met with the media and we play hold up, stop the tape! David Strauss (mybookie.ag) joins us to talk some NFL betting and we open the preseason tonight! Plus, we end the first hour with our best tweet!

Will is joined by UChicago Law Professor David Strauss to discuss Congress's power to enforce the Constitution, recognized by Katzenbach v. Morgan, and whether there's still any room today for the principles of the Warren Court.Audio clips are from Oyez.org

Carolyn:                               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editor's. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our Journal this week features important new data telling us that a common genetic variant risk score is associated with risk of drug induced QT prolongation and torsades de pointes.                                                 First, let's give you your summary of this week's journal. The first paper provides both clinical and experimental data to show that the adipokine, retinal binding protein four promotes atherosclerosis. First author, Dr. Liu, corresponding author, Dr. Xia and colleagues from Sun Yat Sen University in Guangzhou, China first evaluated the association between serum retinal binding four levels and the incidents of adverse cardiovascular events in a community based prospective cohort and then examined the effects of retinal protein four gain or loss of function on macrophage foam cell formation and atherogenesis in an apple lipase protein E deficient mouse model. They found, in the clinical cohort study, that base line serum retinal binding protein four level was an independent predictor of incidents of adverse cardiovascular events after adjustment for traditional risk factors.                                                 In the experimental study's, they showed that retinal binding protein four promoted macrophage derived foam cell formation through the activation of scavenger receptor CD36 mediated cholesterol uptake. In turn dependent on June and terminal kinase and signal transducer and activator of transcription one, as well as upstream regulation by the tracing kinase CSRC. These findings, therefore, support the use of retinal binding protein four as a novel biomarker for the prediction of cardiovascular risk. The data also provide insight into the mechanism of action of retinal binding protein four in the path of physiology of atherosclerosis.                                                 The next paper is the first clinical trial, looking at remote ischemic pre conditioning prior to carotid artery stinting in patients with severe carotid artery stenosis. Remote ischemic pre conditioning is a protective, systemic strategy by which cycles of bilateral limb ischemia are applied briefly to confer protection from subsequent severe ischemia and distant organs. First author, Dr. Zhao, corresponding authors, Dr. Ji, and colleagues from Xuanwu Hospital, Capital Medical University in Beijing, China performed a proof of concept, single center, prospective, randomized control trial to assess whether remote ischemic preconditioning was safe and effective in attenuating ischemic injury related to carotid artery stinting in 189 patients with severe carotid artery stenosis. Results show that daily remote ischemic pre conditioning for two weeks, prior to carotid artery stenting, was feasible, safe, well tolerated, and may effectively attenuate secondary brain injury as evidence by a decreased incidence and reduced volumes of new ischemic legions on magnetic residence imaging performed within 48 hours post operation. The clinical implications are that if results are confirmed by future, larger studies, remote ischemic preconditioning may evolve into a nonpharmacological, neuro protective method for inhibiting carotid artery stenosis related cerebral ischemic events.                                                 This potential for clinical translation in discussed in an accompanying editorial by Doctors Bell and Yellen, from University College, London.                                                 The final paper discusses firefighting and the heart. What's the link? Well, cardiovascular events are the leading cause of death amongst firefighters and the risk is known to be substantially increased during fire suppression duties. In the current study, first author Dr. Hunter, corresponding author, Dr. Mills, and colleagues from University of Edinburgh in United Kingdom sought to understand this link better by assessing the effects of simulated fire suppression on measures of cardiovascular health in an open label, randomized cross over study of 19 healthy firefighters. These firefighters performed a standardized training exercise in a fire simulation facility or like duties for 20 minutes. Following each exposure, ex vivo thrombus formation, fibrinolysis, platelet activation and for armed blood flow in response to intra-arterial infusions of endothelium dependent and independent vasodilators were all measured. The authors found that exposure to extreme heat and physical exertion during fire suppression activated platelets, increased thrombus formation, impaired vascular function, and promoted myocardial ischemia and injury in healthy fire fighters. These finding provided pathogenic mechanisms to explain the association between fire suppression activity and acute myocardial infarction in fire fighters.                                                 The implications of these findings for prevention are discussed in an accompanying editorial from Dr. Kales, of Harvard school of Public Health and Dr. Smith from Skidmore College and University of Illinois fire service institute.                                                 Well, those were your summaries. Let's welcome our guests for our feature discussion.                                                 Today's feature paper describes a pilot study that shows that a common genetic variant risk score, is associated with drug induced QT prolongation and torsades de pointes. This paper is so interesting to me because I found that the learning points, at least for me, really extended well beyond the trial itself. I'm so delighted to have with me the co corresponding authors, Dr. David Strauss from the US FDA, as well as Dr. Christopher Newton-Cheh from Massachusetts General Hospital. Welcome, gentlemen. David:                                   Thanks very much, glad to be here. Christopher:                       Thank you, Carolyn. Carolyn:                               So, I've always thought that common genetic variants identified via GWAS, for example, are individually very weak effects on medical traits. For example, systolic blood pressure or in this case, QT interval. But what I'm so impressed with this study is that you show, I think for the first time, that even these small effects can add up to clinically meaningful results that are testable or demonstrable in a trial. David, could you begin by telling us a little bit about this trial and what the primary results were. David:                                   In the study, we tested the hypothesis that a weighted combination of common genetic variants, contributing to the QT interval at base line, identified through prior GWAS studies, can predict individual response to multiple QT prolonging drugs. We performed a genetic analysis of 22 subjects and a secondary analysis of a randomized, double blind, placebo controlled cross over trial, that included three QT prolonging drugs, with 15 tie matched QT and plasma drug concentration measurements. This allowed us to carefully control for the inter individual differences in pharmacokinetics and just focus on the pharmacodynamics so the direct effect of the drug on the heart.                                                 What we found was, there was a significant correlation between the weighted combination of common genetic variants, which we call the genetic QT score, and drug induced QT prolongation. More specifically, we found that the genetic QT score explained 30 percent of the variability in response to dofetilide, 23 percent in response to quinidine, and 27 in response to ranolazine.                                                 We also investigated how response to one QT prolonging drug predicted the response to other QT prolonging drugs. There were significant correlations between all the drug/drug relationships with response to each drug explaining 24 to 29 percent of the variability in response to each of the other drugs. It's important to note that QT prolongation, by itself, is not harmful. The real concern is torsades de pointes, which can degenerate into ventricular fibrillation and cause sudden death. So, the test, irrelevant to the common genetic variants in predicting drug induced torsades, we then went on to examine a previously published, genome wide association study that included 215 patients with drug induced torsades, compared to 771 ancestry match controls and that prior study that was previously published had found that each individual common genetic variant did not reach genome wide significance, as you suggested, Carolyn. However, when we applied the weighted combination of common genetic variants, we found that the genetic QT risk score was associated with significantly increased risk of drug induced torsade, explaining 12 percent of the variation in risk. Carolyn:                               So, my simplistic understanding was more or less there. That these genetic risks of these common variants kind of add up. I'm just curious ... Chris, do you think that this has implications for even other diseases? That's one question. And then secondly, I really appreciated your comment about using an intermediate trait, if you may, of QT interval versus looking at the disease itself of torsade de pointes. Could you give me comments on both these things? Christopher:                       The study of intermediate traits, such as, quantitative traits like QT variability on the EKG are, I think very tractable for the study of genetic bases of underlying physiologic processes because we can study so many people. So the original genome wide association study that detected these individually weak genetic effects could only find them because we studied about 75,000 people who had had genome wide genome typing and QT intervals measured. It requires such large sample sizes to reach p values that are able to distinguish true positive associations from false positive associations, due to the multiple testing burden.                                                 I think a challenge of what to do with these genetic effects once they've been reliably detected is that they do have weak effects and they influence intermediate traits. Nobody really cares whether their QT interval is three milliseconds longer, or three milliseconds shorter. What they care about is hard outcomes, or the likelihood that they'll have a toxic drug response. So, it was a natural follow on to that work to try to test these variants, and we knew that based on their weak effects individually on QT interval in the general population, that it was unlikely that they would individually explain a significant portion of either drug response or torsade. Which is why we aggregated the facts into the weighted score.                                                 I think we tried to examine what we thought were the most proximal, clinically relevant outcomes. Specifically, drug response. QT drug response to drugs that are established to cause QT prolongation and arrhythmias. Whether the QT score will have meaningful or detectable impact on drugs that have much weaker effects on re polarization and risk of torsade, I think, would remain to be seen. Carolyn:                               That's really remarkable.                                                 David, how about your perspective of the implications of this? It's so unique that you're actually from the FDA so, why is this important to the FDA? David:                                   As Chris mentioned, the specific application we studied here, a drug induced QT prolongation and torsade have resulted in the withdrawal of several drugs from the market both in the US and worldwide. Many critical drugs remain on the market that are associated with QT prolongation and torsade…over 100 drugs, likely. What some people may not be familiar with is that at FDA we perform research to move new science into the drug review process and close the gap between scientific innovation and drug review. Like practicing clinicians, we seek to understand inter patient variabilities and we conduct research to better evaluate, benefit, and risk of medications. This is in line with the broader initiative ... the precision medicine initiative, which seeks to move away from the traditional “one size fits all” approach for medical therapy and instead, take into account specific characteristics of individual patients.                                                 People are most familiar with this being applied in oncology and advances in pharmacogenomics have been more limited in other areas with the exception of the genetic bases of metabolism and pharmacokinetics  where the traits are often controlled by one or a few genetic mechanisms, rather than the many mechanisms responsible for complex traits and diseases, as Chris discussed. As I mentioned earlier, what was relatively unique about this study is that we were able to control for the difference in pharmacokinetics and investigate the inter individual differences in the direct effect of drugs on the heart, the pharmacodynamics. We think it's very exciting that a combination of common genetic variants and aggregate can explain a significant portion of the inter individual variability and, as Chris mentioned, this is also important because the incidence of torsade is quite low. Only a small number of patients will develop drug induced torsade. It's possible that in the future analysis of a large number of common genetic variants that can be identified through genome wide association studies as in this case, may help to better define the personalized benefit risk profiles for individual patients. Carolyn:                               You've really articulated that remarkably. That's exactly the excitement I think the entire editorial team shared when we read your paper. Thank you so much for it. Maybe just one last question thrown out to both of you, what's the next step? What's in the future. Christopher:                       I think one next step, based on this proof of principle study, will be to try to test the impact of these genetic risk scores in real world clinical settings where individual patients with the diversity of different comorbidities and different drug exposures are also receiving QT prolonging drugs. Because that will have the biggest relevance for our patients who faced increased risk of drug toxicity. David:                                   The issue of cardiac safety of drugs is something that is very important to us at the FDA and we have some parallel initiatives that, in collaboration with other global drugs ... regulatory agencies and industry and academic collaborators ... we are working to develop new cardiac safety evaluation paradigms for new drugs, or existing drugs, that could even be applied in the preclinical setting and really focus on the mechanistic base, pro arrhythmic risk. So, we should have more exciting work coming forward in the near future for better prediction and individualized prediction of benefit and risk of medication. Carolyn:                               Thank you, listeners, for joining us. You've been listening to Circulation on the Run. Join us next week.  

Supreme ​Court ​Preview: ​ Constitutional ​Interpretation ​at ​the ​Roberts ​Court Hear Professors ​Justin ​Driver, ​Jennifer ​Nou, ​and ​David ​Strauss​discuss ​what ​divides ​the ​current ​Court ​and ​what ​unites ​it. ​Their ​lecture ​will ​be ​followed ​by ​a ​lively ​Q&A ​session ​with ​alumni ​and ​guests ​in ​attendance. This First Monday alumni event was recorded on October 1, 2014 in Washington, DC.

The U.S. Constitution is "the supreme Law of the Land." Of course some of its provisions are vague and must be interpreted. But when the Constitution says something clearly, we follow it. Don't we? Actually things are not that simple. There are several important examples of clear language in the Constitution that we do not follow. (For an example, look at the first word of the First Amendment.) Sometimes, in fact, it would be essentially unthinkable to follow themost obvious meaning of apparently clear language. These are not just slips of the pen by the Framers of the Constitution.Things are more interesting than that: the Framers made deliberate choices that we do not always accept, even though those choices are reflected in the text. The ways in which we ignore apparently clear language in the Constitution can teach us a lot about how American constitutional law actually works. This talk was recorded on February 26, 2014, as part of the Chicago's Best Ideas Lecture Series. David Strauss is Gerald Ratner Distinguished Service Professor of Law at the University of Chicago Law School.