Podcasts about radboud university medical center

Dr Emmy Boerrigter (Department of Pharmacy, Radboud University Medical Center, Netherlands) discusses her Review on dose selection of novel anticancer drugs: exposing the gap between selected and required doses.Read the full article:https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00134-7?dgcid=buzzsprout_icw_podcast_generic_lanoncTell us what you thought about this episodeContinue this conversation on social!Follow us today at...https://twitter.com/thelancet & https://Twitter.com/TheLancetOncolhttps://instagram.com/thelancetgrouphttps://facebook.com/thelancetmedicaljournalhttps://linkedIn.com/company/the-lancethttps://youtube.com/thelancettv

BUFFALO, NY- July 17, 2024 – A new #editorial paper was #published in Oncotarget's Volume 15 on July 2, 2024, entitled, “Using early on-treatment circulating tumor DNA measurements as response assessment in metastatic castration resistant prostate cancer.” In this new editorial, researchers S.H. Tolmeijer, E. Boerrigter, N.P. Van Erp, and Niven Mehra from Radboud University Medical Center discuss metastatic castration resistant prostate cancer (mCRPC). mCRPC is lethal, but the number of life-prolonging systemic treatments available for mCRPC has expanded over the years. Real world data suggest that the most common first-line therapy for mCRPC was treatment with an androgen receptor pathway inhibitor (ARPI), being either enzalutamide or abiraterone, although more patients will nowadays receive ARPI and/or docetaxel already for hormone sensitive prostate cancer (HSPC). Recent clinical trial data suggest potential benefit of adding poly-ADP ribose polymerase inhibitors (PARPi) or lutetium-117-prostate-specific membrane antigen (LuPSMA) to first-line mCRPC treatment with ARPIs in a subset of patients. As these different drug classes are associated with different toxicity profiles and significant costs, it is highly important to identify which patients experience durable benefit from monotherapy ARPI and which patients would potentially benefit from treatment intensification or therapy switch. “Research by Tolmeijer et al. 2023, published in Clinical Cancer Research [13], suggests that the detection of circulating tumor DNA (ctDNA) at baseline and 4-weeks after treatment initiation can predict response durability to first-line ARPIs.” DOI - https://doi.org/10.18632/oncotarget.28599 Correspondence to - Niven Mehra - niven.mehra@radboudumc.nl Video short - https://www.youtube.com/watch?v=DTJ0vEnQ9SY Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28599 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, ctDNA, prostate cancer, liquid biopsy, biomarker, androgen receptor pathway inhibitors About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

The ‘I' (intermediate susceptibility) in a EUCAST-guided antibiogram never meant impending resistance to your antibiotic. It was never meant to make you find the one ‘S' (invariably a carbapenem) and use it instead—even if many clinicians did. In this episode of Communicable, hosts Marc Bonten and Angela Huttner welcome Profs. Christian Giske (outgoing chair) and Sören Gatermann (newly elected chair) of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) to discuss its recent updates, including the new ‘susceptible dose dependent' (SDD) label, and to shed light on common misconceptions around the way it sets breakpoints. Breakpoints for Pseudomonas aeruginosa are discussed, as are intravenous fosfomycin's ‘disappearance' from the breakpoints table and EUCAST's new guidance on it. Episode peer-reviewed by Dr. Suzanne van Asten of Radboud University Medical Center.Literature:The European Committee on Antimicrobial Susceptibility Testing (EUCAST): https://www.eucast.org/EUCAST guidance on use of fosfomycin i.v. breakpoints:https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Guidance_documents/Use_of_fosfomycin_iv_breakpoints_General_advice_20240528.pdfIn vitro synergy between fosfomycin and ceftazidime/avibactam: Kroemer, Martens, Decousser et al. Evaluation of in vitro pharmacodynamic drug interactions of ceftazidime/avibactam and fosfomycin in Escherichia coli. J Antimicrob Chemother. 2023 Oct 3;78(10):2524-2534. doi: 10.1093/jac/dkad264

In this episode, we discuss human genetics and artificial intelligence. In this conversation, we are joined by Head of the Institute for Genomic Statistics and Bioinformatics, Professor Peter Krawitz, Professor Tjitske Kleefstra from Radboud University Medical Center, and Dr. Tanja Zdolsek Draksler, research project manager at the Jožef Stefan Institute. 

Thank you for joining us for another episode of the Low Carb MD Podcast. Luc Hagenaars, Ph.D., M.Sc., is a policy advisor and researcher with a fascination for addressing the social and commercial determinants of health. His scientific expertise concerns the analysis of health policy innovations with case studies, system mapping and applied policy process theory. He has extensive experience in developing health policy through his previous work at the Dutch Ministry of Health. He is Assistant Professor Health Policy Analysis at Amsterdam UMC and a visiting scholar at the University of California, San Francisco. Hagenaars received his Ph.D. from the Radboud University Medical Center, Nijmegen, and his M.Sc. in global health from Maastricht University. In this conversation, Tro and Luc talk about how Luc's interest in the social determinants of health came to be, a recent study looking at why the field of obesity prevention is stuck and how it could be unstuck, the issue of weight stigma and how it relates to the ‘health at every size' movement, finding effective solutions to the obesity problem, how to influence government policy to embrace effective solutions, how companies try to influence your food buying decisions at the grocery store, how big food companies push back against positive health movements, and Dr. Luc's current research projects. For more information, please see the links below. Thank you for listening! Links: Luc Hagenaars, Ph.D., M.Sc.: Research Paper Dr. Brian Lenzkes: Website Twitter Dr. Tro Kalayjian: Website Twitter Instagram Doctor Tro App Join a growing community of individuals who are improving their metabolic health; together. Get started at your own pace with a self-guided curriculum developed by Dr. Tro and his care team, community chat, weekly meetings, courses, challenges, message boards and more. Apple Google Learn more

Welcome to the special episode of our podcast, where we showcase the work of early career scholars in health professions education from around the world. This is part two of a two-part series, where we will hear from three different researchers who have been nominated by colleagues to share their projects and insights with us In this episode, we will learn about the diverse topics and methods that these scholars are using to advance the field of health professions education.We hope that their stories will inspire you to connect with them, explore their work, and pursue your own education scholarship. This episode we are featuring :Natasja Looman, a researcher at Radboud University Medical Center in the Netherlands. Her research focuses on exploring power dynamics and their impact on intraprofessional learning.Abigail Konopasky Director in Medical Education Research and Scholarship and Associate Professor of Medical Education at Giesel School of Medicine, US. Her research is focused on clinical reasoning, linguistics, and narrative analysisJenny Routh veterinary surgeon and a PhD researcher at the School of Veterinary Medicine at the University of Surrey in the UK. She has explored the topic of student preparedness for workplace clinical trainingRead more on the Episode webpage Hosts are: Lara Varpio, Jason Frank, Jonathan Sherbino, Linda SnellTechnical Producer: Samuel LundbergExecutive Producer: Teresa SöröThis is a Production of Unit for teaching and learning at Karolinska Institutet

There's a new and greater understanding of the relationship of Parkinson's disease (PD) and art. Engaging in artistic practices can enhance mood, cognitive function, and enjoyment of life for people with PD. Importantly, how art causes these effects is giving greater insight into the neurobiological basis of how people in general create and respond to art. Central to this insight is the role of the neurotransmitter dopamine. In this episode, Prof. Bas Bloem, Director of the Parkinson's Foundation's Center of Excellence at Radboud University Medical Center in Nijmegen, the Netherlands, explores the emerging importance of incorporating art in the treatment of PD and the role of dopamine for enhancing people's enjoyment and creativity. Dopamine has been called the “happiness hormone,” but it may also be the creativity hormone.

Perhaps the most noteworthy element of Osmosis from Elsevier's Year of the Zebra educational initiative is the new, open-access, peer-reviewed journal Rare. Open Research in Rare Diseases.It joins Elsevier's leading collection of 2,500 publications in science and medicine. Rare is an open journal in multiple senses because, in an unusual step, contributions are being welcomed from patients as well as scientists. “We need the patient's voice to find out what their needs and challenges are every day,” says editor-in-chief, Dr. Wendy van Zelst-Stams. “We really want to have both a clinical impact on rare disease patients and an impact on their well-being in daily life.” Dr. van Zelst-Stams is taking on this new role in addition to her work leading the Clinical Genetics Section in the Department of Human Genetics of the Radboud University Medical Center and the Dutch Society of Clinical Genetics. In this enlightening conversation with host Shiv Gaglani, you'll learn about Europe's efforts to improve care for rare disease patients, the “DNA-first” approach her program takes to reduce the diagnostic odyssey, and the types of content that will be featured in this multidisciplinary scientific journal. Mentioned in this episode: https://www.sciencedirect.com/journal/rare

This week, please join author Vincent Aengevaeren and Associate Editor Jarett Berry as they discuss the article "Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study." Dr. Gregory Hundley: Welcome listeners to this March 28th issue, and I am one of your co-hosts, Dr. Gregory Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo in Norway. And today, Greg, we have such an interesting feature paper. It comes to us from Professor Aengevaeren and it discusses the progression of coronary atherosclerosis in middle-aged and older athletes. They're looking at exercise volume versus intensity in the MARC-2 study. So Greg, this is really something us master athletes are interested in, and I'm really excited to hear this discussion. Dr. Gregory Hundley: Very nice. Well, how about we jump into some of the other articles first, Peder? And I could go first. So Peder, my first article involves pregnancy related complications. And as you know, these pregnancy complications are associated with increased risk of developing cardiometabolic diseases and an earlier mortality. However, much of the prior research has been limited to individuals of White race. So these investigators led by Professor Cuilin Zhang from the National Institutes of Health aimed to investigate pregnancy complications in association with total and cause specific mortality in a racially diverse cohort, and then evaluate whether associations differ between Black and White individuals. And they performed their work using the Collaborative Perinatal Project, which was a prospective cohort study of 48,197 pregnant women across 12 US clinical centers from the period of time of 1959 through 1966. Dr. Peder Myhre: Oh wow, Greg. Almost 50,000 pregnant women. Very huge initiative. So what did they find? Dr. Gregory Hundley: Right, Peder. So overall, 15% of participants had preterm delivery, 5% had hypertensive disorders of pregnancy, and 1% had gestational diabetes or impaired fasting glucose. Now, the preterm delivery was higher in individuals of Black race at 20% relative to those of White race, which were 10%. Now, in relation to all-cause mortality, the following were associated with increase adjusted hazard ratios. One, spontaneous labor; two, induced labor; three, pre-labor cesarean delivery. And all of those, those adjusted hazard ratios in comparison with a full term delivery. Next, in the world of blood pressure, preeclampsia and eclampsia as well as superimposed preeclampsia and eclampsia were all associated with adjusted hazard ratios that were elevated compared to individuals with normal blood pressure. And then finally, in those individuals with gestational diabetes or impaired fasting glucose, their adjusted hazard ratio, again for all-cause mortality, was elevated relative to those with normal glycemia. Now interestingly, in comparing the two racial groups, preterm induced labor was associated with greater mortality risk among those of Black race relative to those of White race. However, or while, preterm pre-labor cesarean delivery interestingly and conversely was associated with a higher adjusted hazard ratio for those of White race as compared to individuals of Black race. So Peder, in summary, within this large diverse US cohort, pregnancy complications were associated with higher mortality almost 50 years later. And the higher incidents of some complications occurred in individuals of Black race. And differential associations with mortality risk indicate that because of these racial differences, there could really be disparities in pregnancy related health. And finally, that these disparities and their relationship with overall health really could have long life implications for earlier mortality in these patients. Dr. Peder Myhre: Well, that is really interesting, Greg. Are you ready for the next paper? Dr. Gregory Hundley: Absolutely. Dr. Peder Myhre: So this paper is about the glucagon-like peptide-1 receptor agonist and large CV outcome trials clearly show that several GLP-1 agonists reduce CV outcomes in patients with Type 2 diabetes. Whether their cardioprotective effects are related to drug dose or potency remains uncertain however, but important due to recent introduction of high dose and high potency agents for diabetes and for weight loss indications. And therefore, Greg, in this paper, the investigators from the AMPLITUDE-O trial led by corresponding author Hertzel Gerstein from McMaster University Hamilton Health Sciences analyzed the effect of the different doses of the GLP-1 agonist efpeglenatide that is four milligram, six milligram compared to placebo. And the effect was assessed on major adverse cardiovascular events. Dr. Gregory Hundley: Interesting, Peder. So what did they find? Dr. Peder Myhre: So Greg, during a median follow-up of 1.8 years, MACE occurred in 9.2 participants assigned to placebo, 7.7 in participants assigned to efpeglenatide four milligrams, and 6.2% in participants assigned to efpeglenatide six milligrams. And participants receiving high dose of this GLP-1 agonist also experienced fewer secondary outcomes, including the composite of MACE coronary revascularizations or hospitalizations for unstable angina, a kidney composite outcome comprising sustained new microalbuminuria, decline in eGFR more than 40%, or renal failure. And there was also a clear dose response relationship noted for all primary and secondary outcomes with a P4 trend that was significant. So Greg, the authors conclude that the graded relationship between efpeglenatide dose and CV outcomes suggests that titrating this drug and potentially other GLP-1 agonists to high doses may maximize their cardiovascular and kidney benefits. Dr. Gregory Hundley: Very nice, Peder. Well, my next paper comes to us and involves the world of bleeding associated with Factor Xa inhibitors. So Peder, andexanet alfa is a modified recombinant inactive Factor Xa designed to reverse Factor Xa inhibitors. ANNEXA-4 is a multicenter prospective phase 3B single group cohort study that evaluated andexanet alfa in patients with acute major bleeding. And the study is led by Dr. Truman Milling of Seton Dell Medical School Stroke Institute and colleagues, and they present the results of their final analyses. Dr. Peder Myhre: Oh, this is really interesting, Greg. So what did they find? Dr. Gregory Hundley: Right, Peder. So first, 479 patients were enrolled. And their average age was 78 years. 54% were men, 86% were White. 81% of the individuals enrolled were anticoagulated for atrial fibrillation. And they had received this drug 11 hours median time since the last dose. 51% of the individuals were on a apixaban, 37% were on rivaroxaban, and 8% were on edoxaban, and then finally 5% were on enoxaparin. Now bleeding, Peder, was predominantly intracranial in 69%, it was GI in 23%. In evaluable apixaban patients, median anti Factor Xa activity decreased from 146.9 to 10 nanograms per milliliter. That's a 93% reduction. In rivaroxaban patients, it decreased from 214 to 10.8 nanograms per milliliter. That's a 94% reduction. In edoxaban patients, it decreased from 121 to 24 nanograms per milliliter; a 71% reduction. And in enoxaparin, it decreased from 0.48 to 0.11 international units per milliliter or a 75% reduction. So Peder, excellent or good hemostasis occurred in 274 of the 342 evaluable patients. So in 80%. In the safety population, thrombotic events occurred in about 10% of patients. And in 16 patients, this occurred during treatment with prophylactic anticoagulation that began after the bleeding event. So no thrombotic episodes occurred after oral anticoagulation restart. So Peder, in conclusion, in patients with major bleeding associated with the use of Factor Xa inhibitors, treatment with enoxaparin and andexanet alfa reduced anti Factor Xa activity and was associated with good or excellent hemostatic efficacy in 80% of patients. Dr. Peder Myhre: Oh wow. That was really impressive. Dr. Gregory Hundley: Yeah, what a very practical study. Well, Peder, we have some other articles in the issue. How about I go first? So first, there's a Research Letter from Professor Eleanor entitled “A Mouse Model of Atrial Fibrillation in Sepsis.” And then from Tracy Hampton we have some Cardiology News. First from Professor Shane et al, a paper on the impact of coffee subtypes on incident cardiovascular disease, arrhythmias, and mortality, long-term outcomes from the UK Biobank study, which is published in the European Journal of Preventive Cardiology. Next from Professor Morashige, there is a paper entitled “Extra Cardiac BCAA Metabolism Lowers Blood Pressure and Protects From Heart Failure.” And that's published in Cell Metabolism. And then finally from Professor Kessler and associates, the paper is entitled “Common and Rare Variant Associations with Colonial Haematopoiesis Phenotypes.” And that particular paper is published in Nature. Dr. Peder Myhre: That's great, Greg. And we also have an exchange of letters by Dr. Ding and Dr. Kirshenbaum regarding the article “Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.” And finally we have On My Mind by Bertram Pitt entitled “Early Implementation of aldosterone Targeted Therapy in Patients with Hypertension.” Now Greg, let's go to the feature paper to discuss the progression of coronary atherosclerosis in middle-aged and older athletes. Dr. Gregory Hundley: Very good. Let's go. Welcome listeners to this feature discussion on March 28th. And we have with us today Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands. And also with us one of our associated editors, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome gentlemen. Well, Vince, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Vincent Aengevaeren: So this specific study is actually a follow-up study of a previous study that we did on the relationship between exercise and coronary atherosclerosis. The original study was published also in circulation in 2017 and it really looked at the association of relationship between exercise volume, lifelong exercise volume and coronary atherosclerosis. And at that time we found that there was actually a sort of paradoxical association between lifelong exercise volume and coronary atherosclerosis that with higher lifelong exercise volumes, there was a dose upon dependent association with the prevalence of coronary atherosclerosis. And there was actually in the same issue, there was another paper in 2017 from a London group shown similar findings. And actually, yesterday on the ACC, there was another paper also showing increased coronary atherosclerosis in athletes. And this study of course there was also some critic like is this caused by confounding, these were observational perceptional studies, could there be other factors playing, but also none of the studies looked at the differentiation between exercise volume and exercise intensity. So the composition of the exercise. So that was the main question actually for this study. We want to do a follow-up study after at least five years do another CT scan, again, get everyone back the questionnaire, exercise habits, and then also specifically look at exercise volume versus exercise and density. Dr. Gregory Hundley: Very nice. So it sounds like in this study you have a cohort that you're following over time. So maybe describe for us a little bit more the specific study design and who is included. Who is your study population here? Dr. Vincent Aengevaeren: The study population is called the MARC study, Measuring Athletes Risk of Cardiac events. And the study was originally designed mainly based on the fact that healthy athletes, mainly male athletes, sometimes suddenly die of coronary atherosclerosis, which is not really recognized beforehand. So the main study idea was to look at healthy male athletes who didn't experience any symptoms and who underwent the screening, including an exercise test with EKG with normal findings and who then subsequently underwent a coronary CT scan. So blank CT scan for corona calcification score, but also contrast enhanced CT scan to look at the degree of coronary atherosclerosis to those of [inaudible 00:15:18] characteristics. So that's how the original study was designed and it included 318 male individuals over the age of 45 with a very heterogeneous exercise exposure. So they all had to do some type of sports, but there was no minimal dose. So it really depended. So we have some very high level athletes, but also some more of the regular people who exercise a lot less. So very heterogeneous exposure. And for this study, so in the follow-up study, we actually included 291 of those 318 individuals after six years, which I was pretty happy with. And for this specific analysis we excluded two individuals due to their PCI in between. So that's pretty much the cohort that we're looking at. And during this follow-up period of six years, they did the equivalent of about 40 MET hours per week, which equates to about five hours of the exercise. Dr. Gregory Hundley: Very nice. And Vince, you said you had a very diverse group. I mean, a lot of times I'll think about the extremes here. Folks that do a lot of aerobic exercise, those that I think about the power weightlifter. What kind of distribution of athlete, maybe just some practical identifiers for our listeners here. Dr. Vincent Aengevaeren: So it's a very important point. So the main type of athletes in this group who are endurance athletes, so mainly runners and cyclists. Of course also some other type athletes and some athletes do multiple type of sports, but mainly runners and cyclists and definitely large proportion of [inaudible 00:16:53] athletes. Dr. Gregory Hundley: Very nice. So Vince, describe for us your study results. Dr. Vincent Aengevaeren: During this follow-up period, and it's important to state that for this follow-up study we used the exercise characteristics during the follow-up period, we found that exercise volume during follow-up was not associated with progression of coronary atherosclerosis, but exercise intensity was. So we defined exercise intensity based on the MET score, the metabolic equipment of task score, which is derived from previous studies. And there's a compendium explaining MET scores for all the different sports and we used that to categorize the different sports. And we've found that vigorous intensity exercise, for example cycling, was associated with less progression of coronary calcification, but very vigorous intensity exercise, for example running was associated with more progression or coronary calcification. And if you then also look at plaque types, we also saw that those who did the most very vigorous exercise also had a bit more calcified plaque progression. So that was the main findings. Dr. Gregory Hundley: And Vince, describe for our listeners, many whom are cardiologists or others fellows, et cetera. Can you give me a specific example of vigorous exercise versus very vigorous exercise? Like, if I'm doing something during the week, describe for me those two categories, examples. Dr. Vincent Aengevaeren: So typically, and of course this is a very typical vigorous exercise was cycling and very vigorous exercise was running. But of course as you do cycling at a higher intensity, for example spinning on a spinning bike, it's traditionally at a higher exercise intensity. So that was counted as a very vigorous intensity exercise. And I have to say this was based on questionnaire data, so I did not have six-year or lifelong heart rate data. So it is based on questionnaire data, the categorization of exercise intensity. That's a good example. Other things of [inaudible 00:19:03] intensives, for example, soccer, hockey, I don't know how popular those sports are in America, but those are pretty popular in Netherlands as well. Dr. Gregory Hundley: When you mean very vigorous for some of our runners out there, I mean for the casual runner that might run two or three miles a day, is that very vigorous or are you talking about someone that's training periodically for marathons and running three or four marathons a year? Dr. Vincent Aengevaeren: That is really more, I guess, about volume. So if people do a lot of marathons, that can actually be at a lower intensity. Like, with intensity, we really, really mean the heart rate intensity and not the intensity of the volume. So I have to specify that. It's really exercise intensity such as for oxygen consumption or heart rate and not the volume in the hours per week. So typically the runners that we had were mostly very vigorous runners. So couple hours per week traditionally they did like trainings of one and a half hour, which is usually at a higher intensity. Dr. Gregory Hundley: Very nice. Well listeners, now we're going to turn to one of our associate editors, Dr. Jarett Berry, who really has some expertise in this area. And Jarett, you see many papers in circulation. What do you find is unique about this particular study and then how do you put its results really in the context of other studies that have focused on exercise both in duration as well as intensity? Dr. Jarett Berry: Yeah, thanks Greg. And Vince, a fantastic paper, such a privilege to be able to visit with both of you today about this important paper. I think if you take a step back here, challenges I think we all have as physicians is dealing with these uncertain questions that arise clinically where you encounter patients who are exercising at these extreme levels. And although it's not super common, we do encounter these scenarios clinically. And what we need in context like this is we need some data and understanding of what's happening clinically to be able to provide guidance. And so we're really in a context like this in a scenario where we have the common clinical problem of incomplete information. And I think it's studies like this that really help us move the needle to help us understand how to think about those patients of ours that exercise at very high levels. I do think it's important to put it into context, about 10% of the participants in this study exercised below 1,000 minutes per week. And so for those of you taking notes at home, that's the guidelines in 500 and 1,000 minutes per week would be, I mean you'd be hitting the guidelines. And two-thirds of these individuals were exercising at 2,000 minutes per week. So I think it's important to put it into context when we think about applying and understanding the question about toxicity of exercise, putting that into context that most of the patients that we encounter are not exercising at these high levels. However, as I mentioned, we do encounter this and we have to know what to do with it. The key here I think is... The other context is with a point that's been raised already in some of the questions and discussion is the heterogeneity that we see in individuals who exercise at these high levels. When you're trying to think about dose of exercise, we have to think about not just intensity but volume. And I think what the study's done here has done a really nice job of trying to parse that out because we can achieve the dose of exercise that's recommended or the dose of exercise that we want to achieve for personal reasons, but we can get there through different ways. We can get there through more hours or we can get there through a higher intensity. And then of course, obviously combinations of the two. And I think this study here does two things for us. Number one, it gives us a delta question. We've seen this before with just looking cross-sectionally and we have all the challenges that come with that with regard to recall of exercise. Here we have a prospective cohort that we're following or that events followed. And secondly, the ability to parse out both volume and intensity over time. And I think that for me, the finding that really sticks out is that in addition to all the complexities that are right here, we see that the story with regard the components of the dose may not be uniform. That intensity or exercising at very high intensity may be a different part of the equation beyond just volume. And I think that as we think about counseling our patients as they are engaging in this type of high level of exercise, I think it's one additional component of our way of interpreting this and providing counsel to these patients about how to think about volume and intensity. And maybe these data suggests the hypothesis that the volume part of the dose equation may be safer or maybe something that's more palatable for the heart perhaps over time than the intensity. I think the big elephant in the room, of course, is the fundamental question is that we're dealing with an intermediate phenotype and we know lots of observational data showing that more atheros bad. We all recognize that, but you can get to athero through different mechanisms here. And I think that these data and others suggest that exercise is one mechanism perhaps that though you can get athero, the question is what is the true clinical significance from a [inaudible 00:24:32] standpoint down the road as we try to extrapolate the intermediate phenotype into the future. And I think there's controversy, I think agreement about what the intermediate phenotype means in these high volume exercisers. And I think that question remains unknown, I think. But in the interim, as I said in the beginning, that as we think about putting all this into context, we don't have perfect information and we do have to take the information that we do have to provide the counsel that we need to provide if these patients. And I think I take away from this that when providing counsel, maybe I lean more towards volume and less towards this really high volume, sorry, this really high intensity for those individuals whose coronary calcium or their athero burden is particularly high. But a fantastic study. Another step in the road and it's really trying to understand an incredibly complex story and one that will continue to unfold. Dr. Gregory Hundley: Very nice, Jarett. And listeners, we're going to turn back to both Vince and Jarett here each in 30 seconds. Vince, what do you see as the next study that your group or others might want to be considering in this sphere of research? Dr. Vincent Aengevaeren: For me personally, the next big thing that we should do is really cardiovascular risk. So what's the clinical relevance of this finding? So coronary calcification is strongly associated with cardiovascular risk, but how that is in these athletes in which we see increased coronary calcification, that's still pretty much the question. I mean, any plaque is worse than no plaque, but how is this for the very vigorous exercisers who may show some more calcification and whether that risk is different. I mean, that's the question that all the athletes that email me after this type of publication have the question. And also the mechanisms. Like, what are the underlying mechanisms? That's also a next lead study for me. Dr. Gregory Hundley: Very nice. And Jarett? Dr. Jarett Berry: Yeah, I think the ultimate question is, I completely agree, is what is the clinical significance. I think that's going to be... That's a challenging question to answer just because of the on average these individuals are more rare. And so following these individuals over time to really tease out the clinical significance of this type of athero in these athletes, I think, is a challenge. I think for me the next step would be more studies like this where we can get more granular with regard to measured exercise intensity. I think wearable devices, things that Vince alluded to with regard to heart rate, really trying to get more quantitative to try to parse out the contribution of more objectively measured exercise intensities, I think would probably, for me, represents kind of probably the next step, is digging a little deeper into the phenotype and being a little bit more precise perhaps with studies like this to help us begin to understand the significance of these findings. Dr. Gregory Hundley: Very nice. Well, listeners, we want to thank Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands, and our own associated editor, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas for bringing us this study highlighting that exercise intensity but not volume was associated with progression of coronary atherosclerosis during a six-year follow-up of this cohort of really trained athletes and intriguingly the very vigorous. So we want to distinguish that. The very vigorous intensity exercise was associated with greater coronary artery calcium calcified plaque progression, whereas simply just vigorous intensity exercise, casual riding of the bike, casual running, et cetera, was associated with less coronary artery calcium progression. Well, on behalf of Peder and Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. 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.

In this episode of CLOT Conversations we interview Dr Saskia Middeldorp and Dr Hanke Wiegers, authors of the groundbreaking Highlow study. This open-label, multicenter, randomized controlled trial aimed to determine the optimal dose of low-molecular-weight heparin (LMWH) for pregnant and postpartum women with a history of venous thromboembolism (VTE). Discover the study's findings on the incidence of recurrent VTE, major bleeding, and death from any cause between the intermediate-dose (ID) and low-dose (LD) LMWH groups. The results may surprise you and highlight the need for individualized dosing strategies for pregnant and postpartum women to balance the risks and benefits of anticoagulant therapy. Don't miss this fascinating episode!Dr Saskia Middeldorp is Professor of Medicine and Head of the Department of Internal Medicine of the Radboud University Medical Center in Nijmegen, The Netherlands. Prior to her transfer to Nijmegen in January 2021, she has been a professor of Medicine at Amsterdam University Medical Centers for over 10 years, leading the clinical thrombosis and haemostasis research lines of the Department of Vascular Medicine. Since January 2023, Saskia Middeldorp is one of the 4 Research Domain Leaders in the Radboudumc Research Institution for Medical Innovation.Her present research focuses on several aspects of hereditary and acquired thrombophilia, women's issues in thrombosis and haemostasis, and the clinical evaluation of new anticoagulants and antidotes.Dr Hanke Wiegers is an MD, PhD student, at the department of vascular medicine at the Amsterdam UMC, location AMC. In June 2019 she started her PhD trajectory under the supervision of Prof. Dr. S. Middeldorp as supervisor and focuses particularly on women & thrombosis. On the 17th of March 2023 she will defend her PhD thesis entitled: “Progress in prevention and prediction of venous thromboembolism in women – focus on pregnancy and the postpartum period.”  Hanke Wiegers started as a gynecologist in training on the 1st of January 2023 Bistervels, I. M., Buchmüller, A., Wiegers, H. M., Áinle, F. N., Tardy, B., Donnelly, J., ... & Zelis, M. (2022). Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial. The Lancet, 400(10365), 1777-1787 Follow us on Twitter:@thrombosiscan@MiddeldorpSSupport the showhttps://thrombosiscanada.caTake a look at our healthcare professional and patient resources, videos and publications on thrombosis from the expert members of Thrombosis Canada

The contribution of adverse events to the deaths of patients in the pediatric ICU (PICU) who die despite a low predicted mortality risk is unknown. Elizabeth H. Mack, MD, MS, FCCM, is joined by Carin W. Verlaat, MD, to discuss adverse events in low-risk nonsurvivors compared with low-risk survivors and high-risk PICU survivors and nonsurvivors and the contribution of adverse events to mortality. The podcast centers around the article, Adverse Events in Pediatric Critical Care Nonsurvivors With a Low Predicted Mortality Risk: A Multicenter Case Control Study (Verlaat C, et al. Pediatr Crit Care Med. 2023;24:4-16). Dr. Verlaat is a pediatric intensivist at Radboud University Medical Center in Nijmegen, Netherlands.

Computational pathology – how did this field even start?In today's episode my guest is Jeroen van der Laak, computational pathology professor at Radboud University Medical Center, who was recently listed on "The Pathologist Power List" in the category “Strange New worlds”Jeroen has been in the field of computational pathology for over 30 years and has seen it being created and evolve. He witnessed how advancements in whole-slide imaging and deep learning have allowed for the practical application of AI in pathology.Throughout the evolution of the field of computational pathology the focus has shifted from research-oriented work to direct collaboration with clinicians to test AI in diagnostic practice.During his tenure Jeroen has seen what it takes to be successful in the field of computational and digital pathology. To be a successful researcher in this field you need to understand the importance of high quality data and understand how the field of pathology works and what you see in the tissue you are analyzing. This is a very collaborative field and a responsibility of an AI researcher is making AI accessible and breaking down technical aspects for pathologists.Jeroen co-leads the Computational Pathology Group at Radboud with two other researchers – Francesco Ciompi and Geert Litjens. Their criteria for choosing successful candidates for a digital pathology group include good team spirit, collaboration, willingness to learn, and understanding of the field.It is just a matter of (not too much) time when AI will become mainstream in pathology labs and will improve the accuracy and speed of patient diagnosis. Just like whole slide scanning is becoming part of the routine pathology workflow, so will AI based image analysis. THIS EPISODES RESOURCESThis episode on YouTube"Bridging the gap between pathology and computer science" - full event on YouTubeSupport the showGet your "Digital Pathology Beginners Guide" E-book for free! Sign up for the waiting list here.

I avansert behandling ved Parkinsons sykdom kan det benyttes flytende levodopa i Duodopa- eller Lecigonpumper, men mange benytter også dopaminagonisten Apomorfin. I denne episoden møter vi den internasjonalt anerkjente parkinsonforskeren professor Andrew Lees fra England, som regnes som «Mr. Apomorfin». Han var en av de første som introduserte nettopp apomorfin i parkinsonbehandlingen. I tillegg kan du høre professor Bastiaan Bloem fortelle mer om viktigheten av tverrfaglighet og ParkinsonNet i oppfølgingen, og mer om stamcellebehandlingen i Sverige. Gjester: Bastiaan Bloem (professor Radboud University Medical Center, Nijmegen), ParkinsonNet. Andrew Lees (professor University College London og National Hospital for Neurology and Neurosurgery) og Håkan Widner (professor Lunds universitet). Med programleder Nils Johan Halvorsen og husnevrolog Espen Dietrichs, professor ved OUS Produsert av Tid og Lyst AS for Norges Parkinsonforbund, med støtte fra Stiftelsen Dam.

Breast cancer is the most common cancer found in women worldwide, and one of the most effective ways to combat it is early detection through screening. However, this faces several challenges, such as limited access to screening, socio-economic issues and the difficulties in getting conclusive results from some tests. Taking screening closer to the people and employing artificial intelligence in diagnostics are two viable solutions that doctors are using to promote early detection. Today, Siemens Healthineers Head of Marketing Women's Health Aline Hambüchen talks with Dr. Brian Englander, Chairman of the Pennsylvania Hospital Department of Radiology, Federica Pediconi, professor of radiology at the University of Rome La Sapienza, Marco Caballo, Ph.D., a biomedical engineer and AI researcher at Radboud University Medical Center in Gelderland, NL and Abby Weldon, Senior Director of Women's Health at Siemens Healthineers.Listen to learn about what breast cancer screening entails and the barriers stopping women from being screened. You'll also find out about mobile mammography trucks and the problems they are solving. Additionally, you'll hear about the role that artificial intelligence (AI) can play in improving the diagnostic process.What You'll Learn in This Episode:How breast cancer gets diagnosed (02:57)Barriers to preventative breast cancer screening (05:16)How a mobile mammogram truck works ( 09:33)The impact that telemedicine is having on healthcare services (12:33)The consequences of canceled and delayed breast cancer screening (13:57)The role that AI can play in the fight against breast cancer (15:35)Connect with Marco Caballo, Ph.D.:LinkedInConnect with Dr. Brian Englander:LinkedInConnect with Aline Hambüchen:LinkedInConnect with Abby Weldon:LinkedInLearn more about breast cancer prevention and self-examination here:https://www.siemens-healthineers.com/company/breastcancer-care Hosted on Acast. See acast.com/privacy for more information.

Eline Giraud and Elise Smolders from the (Radboud University Medical Center, Nijmegen, Netherlands) discuss their Review on QT interval prolongation potential of anticancer and supportive drugs.Read the full Review:The QT interval prolongation potential of anticancer and supportive drugs: a comprehensive overview

The Cochrane Gynaecology and Fertility Group maintains a pair of reviews on the use of antioxidants in the treatment of subfertility. The review for males was updated in May 2022 and we asked Wiep de Ligny from the Radboud University Medical Center at Nijmegen in the Netherlands to tell us about the importance of the review and its latest findings in this podcast.

The Cochrane Gynaecology and Fertility Group maintains a pair of reviews on the use of antioxidants in the treatment of subfertility. The review for males was updated in May 2022 and we asked Wiep de Ligny from the Radboud University Medical Center at Nijmegen in the Netherlands to tell us about the importance of the review and its latest findings in this podcast.

Have you ever wondered what semi-supervised, weekly, and unsupervised artificial intelligence digital pathology models can do to help pathologists?Can we finally stop annotating???This episode's guest Geert Litjens - a member of the computational pathology group at Radboud University Medical Center explains how semi-supervised and weekly supervised artificial intelligence-based image analysis can help pathologists do better, more time-efficient, and data-efficient digital pathology. The supervised deep learning image analysis methods are used often and are well accepted in the digital pathology scientific community, however, they rely heavily on whole slide image annotations. This is very time-consuming and is subjected to annotator to annotator variability. There has been a lot of research going on in the computational pathology community on the semi and weakly supervised approaches. It turns out that those approaches are starting to match the results delivered by the supervised approaches. Are we there yet? Can we stop annotating pathology slides altogether and rely on the slide-level labels? Listen to the full episode to learn more + share with friends!This episodes resources:Aiosyn websiteStreamingCNNPathology streaming pipelineStreaming  CNNs for Multi-Megapixel Images (article)DALL-E-2 network that generates artworks from descriptions in natural language Other podcast episodes you'll enjoy:Bigpicture - the largest whole slide repository for AI model development in pathology. Where do we stand at month 15/72?5 Ways to make histopathology image models more robust to domain shift w/ Heather Couture, Pixel Scientia Labs

Forty percent of people living with Parkinson's disease (PD) are women, but compared to men, they have a longer time to diagnosis, less access to neurologist care, and are underrepresented in research studies. Although PD presents special considerations for women, they are, overall, treated the same as men. Some of the differences are body weight, drug metabolism, symptoms, monthly hormone cycles, hormonal changes across different stages of life, pregnancy, and family and other care giving responsibilities and occupational demands, all of which can affect their disease and its treatment. However, these special needs have largely been underrecognized and under-addressed by the medical profession.    Six women health care professionals, three of whom have PD, authored a paper titled “Unmet Needs of Women Living with Parkinson's Disease: Gaps and Controversies” to bring these issues to the fore, identify current knowledge, gaps, and possible strategies to meet the neglected needs of women with PD.   Some of these areas of need are management of the disease, psychosocial issues, advocacy, research on sex and gender issues, and participation of women in research studies. One of the authors is Annalien Oosterbaan, MD, PhD, who has Young-Onset Parkinson's disease and is an obstetrician/gynecologist, researcher at the Radboud University Medical Center in Nijmegen, The Netherlands, and a mother, and whom we spoke with for this podcast. She said the paper lays out a path forward for medical professionals to recognize the unique needs of women with PD and for women to become educated and empowered to communicate their symptoms and needs, participate in research, and to organize as a community.

This EMG-Health podcast, hosted by Brigitte Scott, explores the treatment landscape and emerging therapies in oesophageal cancer over the last decade, placing an emphasis on novel research and treatment. Scott introduces two leading experts in oesophagogastric cancer: Geoffrey Ku, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, USA, and Peter Siersema, Director of the Endoscopy Center, Co-Director of the Radboud Technology Center, Radboud University Medical Center, Nijmegen, the Netherlands.

The prevalence of long-term mental health symptoms in the family members of COVID-19 ICU survivors is unknown and may differ from the prevalence rate in the family members of non-COVID-19 ICU survivors, given the pandemic circumstances. A better understanding of the impact of COVID-19 ICU admission on family members is needed to provide adequate support during and after the ICU stay. Therefore, the prevalence of mental health symptoms and quality of life in family members of COVID-19 ICU survivors 3 and 12 months after ICU admission was evaluated in the first study ever done. Risk factors associated with mental health symptoms were also explored. Original article: https://pubmed.ncbi.nlm.nih.gov/35103824/ (Mental health symptoms in family members of COVID-19 ICU survivors 3 and 12 months after ICU admission: a multicentre prospective cohort study) Speakers Hidde HEESAKKERS. Radboud Institute for Health Sciences, Department Intensive Care Medicine, Radboud University Medical Center, Nijmegen (NL). Burcin HALACLI. Hacettepe University, Faculty of Medicine, Department of Internal Medicine, Intensive Care Unit, Ankara (TR). ESICM NEXT Committee Member.

In this episode of When Life Gives You Parkinson’s, I am the host of a live event with four leading experts in the Parkinson’s world. Together they wrote a book called “Ending Parkinson’s Disease” and launched a red letter campaign to the White House. It’s been one year since the book was released and it has helped to inspired the movement PD Avengers, which I co-founded. What’s new in Parkinson’s? What have they learned? What’s standing in our way of success? Listen as Dr. Ray Dorsey, Dr. Bas Bloem, Dr. Michael Okun, and Dr. Todd Sherer sit down for one on one interviews with me and learn how, no matter where you are in the world, you can help make a difference.   Thank you for listening. Add your voice to the show and leave a message for us here; https://www.speakpipe.com/WhenLifeGivesYouParkinsons Follow us, Larry & Rebecca Gifford  Twitter: @ParkinsonsPod Facebook: Facebook.com/ParkinsonsPod Instagram: @parkinsonspod Thank you to the following people featured in this episode: Dr. Todd Sherer, CEO Michael J Fox Foundation Dr. Michael Okun, Chair and professor of Neurology, University of Florida Dr. Bas Bloem, Prof. Bas Bloem is the medical director of the Department of Neurology at Radboud University Medical Center. Dr. Ray Dorsey, Prof. Department of Neurology , Director of Center for Health and Technology (SMD)     at the University of Rochester   Buy the Ending Parkinson’s Book or Join the Red Letter Campaign www.endingpd.org Diagnosed with Parkinson’s? You are not alone. Contact presenting partner Parkinson Canada http://www.parkinson.ca/, call the toll free hotline 1-800-565-3000 or on Twitter you can message @ParkinsonCanada. Here is a link to the Parkinson’s Canada Preventing Falls Guide.   Thanks also to our content and promotional partners The Michael J. Fox Foundation Parkinson’s Podcast hosted by Larry Gifford Spotlight YOPD – The only Parkinson’s organization dedicated to raising awareness for Young Onset Parkinson’s disease and funds for the Cure Parkinson’s Trust.  PD Avengers - United to end Parkinson’s. Join us. World Parkinson Congress 2022 –Make plans to join us for #WPC2022 in Barcelona, Spain.   Credits Dila Velazquez – Story Producer Greg Schott – Sound Design   See omnystudio.com/listener for privacy information.

Personalized medicine has garnered a lot of attention over the past decade. Usually it means determining the factors for each person that affect their health, their diseases, and potentially their treatments. Some examples are biomarkers that are found in their blood, their genetic make-up, diet and nutrition, behaviors, and environment. One example is the Parkinson’s Foundation’s PD GENEration initiative that offers free genetic testing and counseling for people with Parkinson’s disease (PD) to determine what genes and gene variants affect the course of their disease and response to treatments.   But despite all the scientific advances that allow these forms of personalized medicine, one crucial aspect of personalized medicine is the voice of the patient, both in each person’s encounters with the medical system and treatment team, as well as to inform the kinds of research that should be done and how to design and perform them. Dr. Bas Bloem, a professor of movement disorder neurology at Radboud University Medical Center in Nijmegen, the Netherlands, a Parkinson’s Foundation Center of Excellence, discusses how people with PD want to be heard and how a new definition of health may best put people’s disease into the overall context of their lives.

Dr. Beth Rymeski (Fetal Surgeon) and Dr. Rachel (Rae) Hanke (Pediatric Surgical Education Fellow) from Cincinnati Children’s Hospital bring you highlights from the 2019 International Fetal Medicine and Surgical Society (IFMSS) meeting. Part II includes interviews focusing on technical and educational innovation. Special guests include: •Stephen Emery, MD, Director of Center for Innovative Fetal Intervention at University of Pittsburgh Medical Center & Associate Professor of Obstetrics and Gynecology at Pittsburgh Magee Hospital, Pennsylvania, USA •Jose Peiro, MD, Director of Endoscopic Fetal Surgery at the Cincinnati Fetal Center and Associate Professor at the University of Cincinnati Department of Surgery, Ohio, USA •Anouk van der Schot, MSc, technical physician at Radboud University Medical Center, Netherlands •Jena Miller, MD, Assistant Professor of Gynecology and Obstetrics at Johns Hopkins Center for Fetal Therapy and Lead of Fetoscopic Spina Bifida Repair Program, Maryland USA IFMSS facilitates international collaboration, networking and exchange of ideas, with the goal of advancing the field of fetal diagnosis and therapy. Check out the Stay Current: Pediatric Surgery app at https://staycurrent.globalcastmd.com/download. Intro and outro tracks are adapted from "I dunno" by grapes, featuring J Lang, Morusque. Artist URL: ccmixter.org/files/grapes/16626.

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 Greg Hundley, Associate Editor at the Pauley Heart Center at VCU Health in Richmond, Virginia.                                                 Well Carolyn, did you ever wonder whether cardiovascular drug effects could be investigated through natural variation in the genes for the protein targets? In our feature discussion today, investigators from the British Isles, Germany, and the United States use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs. Sound interesting? Well listeners, we look forward to the results later in our program, but Carolyn, how about we chat about some of the other papers in this issue? Dr Carolyn Lam:                You bet Greg. So, have you ever asked yourself "What is the role of protein glycosylation in regulating LDL metabolism?" Dr Greg Hundley:             That was going through my mind when we were playing basketball just the other night. Dr Carolyn Lam:                Well this is truly a great study from Dr Holleboom at Academic Medical Center Amsterdam and Dr Lefeber from Radboud University Medical Center, both in the Netherlands. And their colleagues will study 29 patients of the two most prevalent types of Type 1 Congenital Disorder of Glycosylation, and these are the ALG6 and PMM2 types. They also study 23 first and second-degree relatives with a heterozygote mutation and measured their plasma cholesterol levels. LDL metabolism was studied in three cell models. They found that patients with type 1 congenital disorder of glycosylation have hypobetalipoproteinemia through increased LDL receptor expression. Carriers of the mutation in glycosylation enzymes affected in this syndrome had decreased LDL cholesterol levels compared to controls, and defects in glycosylation enzymes could play, therefore, an important role in LDL cholesterol metabolism. Dr Greg Hundley:             Boy, this is pretty insightful I think, Carolyn. So, what are the clinical implications? Dr Carolyn Lam:                Well, given that LDL cholesterol was also reduced in a group of clinically unaffected heterozygotes, the authors propose that increasing LDL receptor mediated cholesterol clearance, by targeting N-glycosylation in the LDL pathway, may therefore represent a novel therapeutic strategy to reduce LDL cholesterol, and of course prevent cardiovascular disease. Dr Greg Hundley:             Very interesting work. You know, we just keep learning more and more about LDL. I'm going to switch and jump back with Empagliflozin. And this is a study in diabetic mice that really has an interesting in-vivo imaging component. As an imager, I was really excited about this. The article is from Dr Kengo Kidokoro from Kawasaki Medical School. And we don't often talk about it, but listeners, if you have a chance, there's a very interesting video-enhanced file associated with this article, and if you can download it, it's really just so cool with multiple image clips demonstrating an operative mechanism of SGLT2 inhibition on renal function. And it really gives us an opportunity to revisit renal function.                                                 Quick quiz Carolyn. In diabetic kidney disease, is glomerular hyperfiltration good or bad? Dr Carolyn Lam:                Bad. Dr Greg Hundley:             Yeah, absolutely. So, hyperfiltration is characteristically observed at earlier stages of diabetic kidney disease and involves activation of the renin-angiotensin-aldosterone system at the efferent arteriole and tubuloglomerular feedback mechanisms, especially at the afferent arteriole. So, as they go through this, just picture in your mind that glomerulus and afferent is arriving, and efferent is leaving.                                                 So, SGLT2 upregulation in diabetes is thought to play an important role in TGF signaling by increasing sodium reabsorption at the proximal tubule, thereby decreasing distal delivery to the sodium sensing macula densa at the juxtaglomerular apparatus. This decline in distal sodium delivery is interpreted as a decline in effective circulating volume, leading to inappropriate afferent vasodilation in an effort to preserve intra-glomerular pressure and GFR.                                                 In diabetes, these TGF effects lead to intra-glomerular hypertension and hyperfiltration. You got that quiz right, Carolyn. Which promotes diabetic kidney disease progression and impaired kidney function, ultimately increasing overall cardiovascular risk and mortality. Conversely, blocking SGTL2 pharmacologically reduces renal hyperperfusion and hyperfiltration in animals and humans, which may preserve renal function, thereby reducing risk associated with diabetic kidney disease progression. Dr Carolyn Lam:                You know what, Greg? I kind of had an unfair advantage in this quiz. I work with a lot with the SGLT2 inhibitors, but I just love that you asked us to picture it and look at that video. Anyways, so this article really allows us to review SGLT2 inhibition at the glomerular level, which is truly hot. So, tell us what did they find? Dr Greg Hundley:             So, this is the first report of changes in renal hemodynamic function by SGLT2 inhibition using direct in-vivo visualization techniques in a diabetic animal model. The videos, they're spectacular, and they're excellent so that you can download them for educational purposes. Afferent arteriolar vasoconstriction, and reduced hyperfiltration occurred within a few hours after a single dose of a SGLT2 inhibitor. And Adenosine signaling, through tubuloglomerular feedback, is a key pathway to prevent diabetic hyperfiltration via SGLT2 inhibition.                                                 Clinically, Carolyn, now I know you would ask me about that, so I got ready, this study highlights another potential mechanism for the benefits of SGTL2 inhibition. The SGLT2 inhibitor-related mechanism's responsible for reducing cardiovascular risk in clinical trials may be due to protection against diabetic kidney disease progression, thereby attenuating risk factors for heart failure, such as volume overload and hypertension. Dr Carolyn Lam:                Ah. That is just so cool, and really just so consistent with the clinical data that's emerging too. Thank you, Greg. So, have you ever asked yourself this other question, what role do platelets play in ischemia reperfusion injury? So, I'm not going to quiz you. I'm actually kind and loving and a good person. And so, I will tell you about ischemia reperfusion injury, which is a common complication of cardiovascular disease.                                                 Now, resolution of the detrimental effects of ischemia reperfusion injury generated prothrombotic and proinflammatory responses, is essential to restore homeostasis. Now, although platelets are known to play a crucial role in the integration of thrombosis and inflammation, their role as participants in the resolution of thrombo-inflammation is really under-appreciated. And hence, this other paper that I chose today, and it's from Dr Gavins from Louisiana State University Health Sciences Center Shreveport, and her colleagues, who used pharmacological and genetic approaches, coupled with murine and clinical samples to uncover key concepts underlying this role for platelets. Dr Greg Hundley:             So Carolyn, what did they find? Dr Carolyn Lam:                Well, they found that exacerbation of thrombo-inflammatory responses occurred in ischemia reperfusion injury mouse models of middle cerebral arterial occlusion, as well as lower plasma levels of the anti-inflammatory pro-resolving protein Annexin A1. And this was a lower plasma level of this Annexin A1 among patients with acute ischemic stroke.                                                 Administration of Annexin A1 promoted cerebral protection against thrombo-inflammation and the development of subsequent thrombotic events post-stroke. Annexin A1 was also able to reduce platelet activation and thrombosis, via the suppression of integrins. So, overall, these data reveal a novel multi-faceted role for Annexin A1 to act both as therapeutic and prophylactic drug via its ability to promote endogenous pro-resolving anti-thrombo, anti-inflammatory circuits in the cerebral ischemia reperfusion injury. And collectively, these results further enhance our understanding in the field of platelet and ischemia reperfusion injury biology. Dr Greg Hundley:             Oh wow. So, another important insight from this author group on platelet activation and thrombosis in key clinically relevant syndromes. Well, my last paper is going to be talking about a risk prediction score for life-threatening ventricular tachyarrhythmias. And they're going to study this in laminopathies, and the lead investigator is Dr Karim Wahabi from Cochin Hospital in France.                                                 To estimate the risk of life-threatening ventricular tachyarrhythmia in patients with LMNA mutations, and thus select candidates for implantable cardiac defibrillators, the investigators evaluated 444 patients of about 40 years in age in a derivation sample. And then, 145 patients that are about the same age, 38 years, in a validation sample, for the occurrence of a) sudden cardiac death or b) ICD-treated or hemodynamically unstable ventricular tachyarrhythmias. Dr Carolyn Lam:                Oh. Very important. These laminopathies are really not that uncommon. So what did they find, Greg? Dr Greg Hundley:             Carolyn, predictors of events included male sex, non-missense LMNA mutations, first-degree and higher AV block, non-sustained ventricular tachycardia, and LVEF. The authors developed a new score to estimate the 5-year risk of life-threatening ventricular tachyarrhythmias in patients with LMNA mutations. And compared to the current standard of care, the proposed risk prediction model offered more accurate prediction of life-threatening ventricular tachyarrhythmias, and correctly re-classified almost 30% of the patients in the study.                                                 Nicely, the authors have made this available, and the score can be derived from readily collected clinical and genetic parameters and estimated using an online calculator that's provided in the journal. But, it's https://lmna-risk-vta.fr.                                                 Future prospective studies should focus on the estimation of the clinical benefit conferred by the use of this score in terms of sudden cardiac death prevention. Dr Carolyn Lam:                That is super cool, Greg. But, I am so excited now to move to our feature discussion. Shall we? Dr Greg Hundley:             You bet. Dr Carolyn Lam:                Can we use natural variations in our genes for the protein targets as a way to look at cardiovascular drug effects? Man, this is going to be such an important and exciting discussion, because this is what our feature paper talks about. I am so pleased to have with us our corresponding author, Dr Dipender Gill from Imperial College London, as well as our Associate Editor, Dr Wendy Post from Johns Hopkins.                                                 So, first of all, Dipender, please, could you give us a background on what you did? This is really very novel in approach. Dr Dipender Gill:               It was also a lot of fun to conduct. I think, currently, we're living in an era where there's been a recent explosion in the availability of genetic data, and this really inspired us to think about how we could use that to learn more about commonly prescribed drugs. The implementation of genetics, or genetic variance, to study drug effects isn't entirely novel. It's actually been undertaken for some years now.                                                 Most of the work has been related to lipid lowering drugs, for example, statins, where people can take genetic variance, or versions of genes, corresponding to the drug effect, and study these to investigate what effects these drugs might have, both on the intended target, but also potential side effects. To my knowledge, this hadn't previously been done for anti-hypertensive drugs. But yet, the data for this was available. And therefore, we thought that actually we could very well go ahead and do this, and perhaps find some interesting things. Dr Carolyn Lam:                Oh, that's so interesting thing, Dipender. You know, there was this term in your abstract, and mentioned multiple times, Mendelian randomization. Now, for those of us that don't think about this every day, could you tell us a little bit what that means? Dr Dipender Gill:               Yeah. So, I'll actually give a little bit of background. One of the main limitations of traditional epidemiological research is that any association, it's sometimes difficult to infer causation. They can be confounded by environmental factors, lifestyle factors. In the Mendelian randomization technique, what we do is we use randomly allocated genetic variants to study the effect to an exposure.                                                 So, we select these genetic variants because they are related to the exposure of interest. And because these genes are randomly allocated at conception, they're not subject to confounding from environmental or lifestyle factors. Whether you have a gene or not, is not necessarily related to your lifestyle or your environment. And therefore, the association of these genetic variants with certain outcomes isn't subject to confounding. Dr Carolyn Lam:                That makes so much sense, and I suppose that, not to allow cause and effect to be determined. So please, tell us, in this particular case of the anti-hypertensive drugs, what did you do and what did you find? Dr Dipender Gill:               First, we decided specifically which drugs we wanted to look at, and we thought, actually, let's start off with the most commonly prescribed anti-hypertensive drugs. So, we short-listed these based on recent consensus guidelines, and we looked at ACE inhibitors, beta-blockers, calcium channel blockers, thiazide type diuretics. And then, we went back to various online databases to identify which genes correspond to the target protein of these drugs.                                                 We took these genes, and we then identified genetic variants at their specific genetic loci, their specific region of the genome, and we identified the variants in these regions that were also related to systolic blood pressure. And in this way, we inferred that genetic variants, at the protein coding targets of these genes, that were also related to systolic blood pressure, likely represented the effect of variations in these proteins that also implicated blood pressure, and therefore, could serve as proxies, or instruments, to study the effect of these drug targets.                                                 We then went ahead to validate the selection of these genetic variants by forming Mendelian randomization, and specifically, we checked whether people that have genetic variants that correspond to, say, ACE inhibitor activity, or beta-blocker activity, or calcium channel blocker activity, if they also have correspondingly lower risk of coronary heart disease and stroke, to the same degree that we would observe in randomized control trials against placebo.                                                 And indeed, we found that actually, the results were fairly similar, and this gave us confidence. And studying these genetic variants that mimic the effect of these drugs could be used as a proxy or as a surrogate to study their clinical effect of taking these drugs. So, that was the first phase. Dr Wendy Post:                 Dipender, congratulations to you and our team. This is a really exciting paper, and the editors were especially interested in the novelty, and the potentially impactful findings, especially of the second part of the study, which I think you'll describe briefly next. And that was using an approach that many who are listening may not have heard about too much before called PheWAS, or a phenome wide association study. And maybe you could tell us briefly what you found in that part of the analysis. Dr Dipender Gill:               The first part, it was very cool, because it allowed us to identify versions of genes that corresponded to the effect of these drugs. But in itself, it didn't tell us anything novel. It didn't tell us anything new. So, the real question was, how could we use this new information to make progress towards helping patients? So, we went back and we thought, "So okay." So, we knew that these drugs are used for certain conditions already to prevent heart disease, to prevent stroke.                                                 But, what about their side effects? What about their repurposing potential? How could we use our new approach to study that a little bit more carefully? As you alluded to, when we used this new technique, relatively new technique called phenome wide association study, and we essentially investigated the association of our genetic variants for each respective anti-hypertensive target with all clinically relevant outcomes throughout the phenome, using the UK bio-back cohort, which was the main population used for this PheWAS, this phenome wide association study.                                                 We were actually able to rapidly investigate over 900 disease outcomes, and their association with our genetic risk score for these drugs. And this was very exciting for us, because it allowed us to very rapidly, efficiently, and cost-effectively explore the potential repurposing opportunity and side effects of these very commonly prescribed drugs, which to our mind, offered significant advantage over previous approaches.                                                 We all know that sometimes randomized control trials can be very expensive and time-consuming, and of course, traditional observational research can be limited by reverse causation, assessment-vise confounding. And so, what we were able to do here had several important advantages, and not to mention the efficiency by which it allowed study of these outcomes. Dr Wendy Post:                 Dipender, tell us what you found in your PheWAS study. Dr Dipender Gill:               We identified genetic variants for 3 commonly prescribed anti-hypertensive targets. The first were ACE inhibitors, second, beta blockers, and the third were calcium channel blockers. When performing PheWAS for all of these drug targets, we identified associations with common cardiovascular disease that are related, or implicated in hypertension, specifically hypertension itself, but also circulatory diseases, things like atrial fibrillation, coronary heart disease. They all came up.                                                 And this actually gave us a lot of confidence because that's exactly what we'd expect. We know that these medications prevent or reduce risk of these diseases, and therefore, this served as kind of a positive control that our approach was doing it what it was supposed to do. The novel finding came when we investigated the genetic risk score, or the genetic variants for calcium channel blockers, in this PheWAS approach.                                                 And we actually identified an association which we weren't expecting. We showed that blood pressure reduction through the genetic risk score for calcium channel blockers was an association with an increased risk of diverticulosis, a condition not conventionally thought to be associated with blood pressure. We were very excited and interested by this, and we went on to investigate it further using some other techniques as well. Dr Wendy Post:                 The really impactful part of this, many things, but especially this association with diverticulosis. So, maybe you can briefly summarize what you think the potential clinical implications are, and what the next step should be. Dr Dipender Gill:               The first question we had was whether this was related to blood pressure alone, the effect of calcium channel blockers, or perhaps some other effect of these drugs. We investigated the genetic risk score for systolic blood pressure generally and found that this itself wasn't associated with risk of diverticulosis, which suggested that the effect isn't really mediated by blood pressure alone, but it's some other property of calcium channel blockers.                                                 We know that sometimes calcium channel blockers can be associated with constipation, and it may be through this mechanism that they're having consequent effects on risk of diverticulosis. Other possible mechanisms might be through effects on blood flow, through the vasa recta in the bowel. But, what was very interesting was that we went forward with this finding, and investigated, observed, drug use in the UK bio-bank.                                                 Specifically, we looked at people taking non-dihydropyridine, and dihydropyridine calcium channel blockers at baseline, and found that those taking non-dihydropyridine calcium blockers only were known to have a higher risk of diverticulosis as compared to those taking other anti-hypertensive classes, which further added support for our findings. The interesting point here is that looking at the genetics doesn't allow us to discriminate between these drug classes.                                                 That was only possible with the observed data, and that was because the genes for these drug classes were the same. Dr Carolyn Lam:                Well, congratulations. Wow. I'm just so intrigued listening to all of this. Wendy, I would love if you could help put all of this in context for us. The US, the novel information, and the approach that could potentially go way beyond just anti-hypertensive. Dr Wendy Post:                 So, this is a very exciting new approach to doing genetic studies that can help us to understand potential targets for therapy in the future, and understanding more about causality, which as Dipender explained, can sometimes be confusing, as it may be confounded by environmental factors. So, using these genetic approaches through Mendelian randomization, and what we heard about today, which is PheWAS, or phenome wide association study, we can learn much more about how the potential observational analyses can be related to new discoveries through mechanisms, or potential side effects, as we heard about here of calcium channel blockers.                                                 So, wanted to congratulate Dipender again with his impactful paper here. Dr Carolyn Lam:                Thanks, Wendy. And then if I could, I'm just going to steal minutes here, because this is so interesting. Where do you think the field's going to go next? And Dipender, with these findings of diverticulitis and diverticulosis, what next? How do we apply this? Dr Dipender Gill:               There's 2 main points to cover here. The first is what we do specifically with the findings we got for calcium channel blockers and diverticulosis. I should emphasize that on their own, I don't think that this should currently change practice. But, I think it should inspire and capitalize further research into this association. If we're able to replicate and validate it further, then perhaps there might be some implications for the drugs that we prescribe with patients at risk of diverticulosis.                                                 The second point I wanted to make is more generally, what does this mean for research, and particularly, genetic research. I think we're living in very exciting times, and there's a lot of really great work that's going to come out using these types of approaches. I think 2 areas that we could expand further is what else we can do with our genetic instruments, or our genetic variants that proxied these drugs. How do we look at other targeted refocusing potential? Can we try and explore other side effects? Can we investigate efficacy for other disease outcomes? Specifically, for these anti-hypertensives.                                                 And the other thing is, which other drugs can we identify genetic variants to proxy? We've been thinking about looking at diabetes medicines. There's a variety of other drugs that correspond to specific gene targets, and proteins. And in theory, these could also be studied using genetics. So, there's a lot more work to come out from this. Dr Carolyn Lam:                Thanks so much, both of you, for joining us today. This was just such an exciting discussion.                                                 Thank you for listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association, 2019.  

This Podcast is brought to you by: Picmonic - USE THIS LINK TO GET 20% OFF ANY PREMIUM MEMBERSHIP: https://www.picmonic.com/affiliate/medspirationLDW19 Picmonic has a visual learning platform that will help anyone in healthcare learn more in less time, so they can rock course exams, boards, and become more competent providers! Using their learning tools has been proven to increase long term memory retention up to 331%! Picmonic helped me with my USMLE Step 1 studies & can help also help student NPs, PAs, Pharm Ds, RNs, LPNs, paramedics & those in premed. We've partnered with them to bring you an INCREDIBLE OFFER:  You can check them out @: Picmonic.com & sign up for FREE & you’ll get instant access to a free video and quiz questions every day - no credit card required.  Use the promo code Medspiration for 20% off any Premium subscription!  According to the Proceedings of the National Academy for Sciences (PNAS) of the United States: It has long been presumed that it was NOT possible to voluntarily influence the Autonomic Nervous System & Innate Immune System. In 2014, a peer reviewed study that was published after Wim Hof demonstrated that through practicing the Wim Hof Method (https://www.youtube.com/watch?v=nzCaZQqAs9I&t=1s), a self developed technique that involves a combination of breathing, cold exposure & meditation, the sympathetic nervous system & immune system CAN indeed be voluntarily influenced. Here is the link to this study:(https://www.pnas.org/content/111/20/7379). In today's episode, we're sitting down with the Ice-Man himself! Wim owns 26 official Guinness World Records, all of which are beyond comprehension to most who hear them! In 2007 he climbed 22,000ft up Mount Everest in only shorts & shoes. In 2009 he ran a full marathon in the Arctic circle in temperatures close to -20°C, wearing only a pair of shorts and having not trained at all. In 2011, Wim broke his own cold-endurance record, remaining submerged neck-deep in an ice bath for 112 minutes. The same year he completed another marathon without training, this time in the Namibian desert in temperatures of up to 40°C, without drinking a drop of water!  I made sure to study EVERY peer-reviewed study ever published on Wim before this interview (links to these studies are below). Wim & I discussed how he is revolutionizing medicine & medical science through meditation; How it is possible to use the mind to control the immune system & nervous system; mental health; epi-genetics; & the Science of the Wim Hof Method. P RESEARCH: 2018 Article: “Brain over body”–A study on the willful regulation of autonomic function during cold exposure Authors: O. Muzik, K. Reilly, V. Diwadkar - Wayne State Univeristy School of Medicine Summary: In this paper, a brain imaging study was conducted to measure the relative contributions of the brain and the periphery that endow the Iceman to withstand the cold using his Wim Hof Method techniques. The results provide compelling evidence for the primacy of the brain (CNS) rather than the body (peripheral mechanisms) in mediating the Iceman's responses to cold exposure. They also suggest the compelling possibility that the WHM might allow practitioners to develop higher level of control over key components of the autonomous system, with implications for lifestyle interventions that might ameliorate multiple clinical syndromes. 2015 Article: The Role of Outcome Expectancies for a Training Program Consisting of Meditation, Breathing Exercises, and Cold Exposure on the Response to Endotoxin Administration: a Proof-of-Principle Study Authors: H. van Middendorp, M. Kox, P. Pickkers, A.W.M. Evers - Radboud University Medical Centre Summary: This paper adds to a previous study, published in 2014, on the ability to voluntarily influence the physiological stress response in healthy men to experimentally induced inflammation, after WHM training. It is a proof-of-principle study that investigated how one’s expectancies might play a role in treatment outcome. Indications were found that generalized outcome expectancy optimism is a potential determinant of the autonomic and immune response to induced inflammation after training. 2014 Article: Voluntary Activation of The Sympathetic Nervous System and Attenuation of the Innate Immune Response In HumansAuthors: M. Kox, P. Pickkers et al. - Radboud University Medical Center (published in PNAS) Summary: In this paper, the effects of the Wim Hof Method on the autonomic nervous system and innate immune response are evaluated. A group of twelve people was trained with the Wim Hof Method before undergoing an experiment to induce inflammation, normally resulting in flu-like symptoms. Compared to a control group who were not trained in the Wim Hof Method, the trained participants showed fewer flu-like symptoms, lower levels of proinflammatory mediators, and increased plasma epinephrine levels. In conclusion, the trained group was able to voluntarily activate their sympathetic nervous system.   Article: Controlled Hyperventilation After Training May Accelerate Altitude AcclimatizationAuthors: G. Buijze, M.T. Hopman Summary: This report deals with the effects of the Wim Hof Method on acute mountain sickness (AMS). During an expedition to Mt. Kilimanjaro, a group of 26 trekkers who were trained in the Wim Hof Method used the breathing techniques to largely prevent and, if needed, reverse symptoms of AMS.   Article: Frequent Extreme Cold Exposure and Brown Fat and Cold-Induced Thermogenesis: A Study in a Monozygotic TwinAuthors: J. Vosselman, W.D. van Marken-Lichtenbeld - Maastricht University Medical Center Summary: This study tested the effects of a lifestyle with frequent exposure to extreme cold on brown adipose tissue (BAT) and cold-induced thermogenesis (CIT). The experiment compared Wim Hof, who is used to extreme cold exposure, to his monozygotic twin brother who isn’t. Both used a g-Tummo like breathing technique. The results showed no significant difference in BAT or CIT between the two subjects. However, Wim’s core temperature dropped less compared to his brother and his subjective response to the cold temperature was more positive. Furthermore, the body heat generated of both brothers was considerably higher than the average person. Thus, it seems that g-Tummo like breathing during cold exposure might cause additional heat production. 2012  Article: The Influence of Concentration/meditation on Autonomic Nervous System Activity and the Innate Immune Response: A Case Study Authors: M. Kox, M. Hopman, P. Pickkers. et al. - Radboud University Medical Center Summary: This case-study research was conducted after Wim Hof claimed he could influence his autonomic nervous system and thereby his innate immune response. His inflammatory response was measured during an 80-minute full body ice immersion and practicing the Wim Hof Method concentration technique. In addition, an endotoxemia experiment was conducted to study Wim’s in vivo innate immune response. The results showed how the techniques of the Wim Hof Method seemed to evoke a controlled stress response. This response is characterized by sympathetic nervous system activation, which seems to attenuate the innate immune system. Here, Wim Hof proved he was able to influence his a 2009 Letter: Blood tests during meditation and breathing exercises in New York led by Dr. K. Kamler & G. Stewart Summary: During Wim’s world record attempt of full ice immersion wearing only shorts, he swallowed a vital sense monitor capsule to measure his core temperature. His core temperature started at 98.6 °F and dropped to 88 °F after 75 minutes of cold immersion. Remarkably, his temperature rose again to 94 °F within the next 20 minutes. Standard medical dogma states that once your core temperature falls below 90 °F, your body is not able to warm itself again. Thus, if no external source of heat is provided, your temperature will continue to spiral downward and you will eventually die of hypothermia. However, Wim proved he was able to raise his core temperature from 88 °F to 94 °F by using the Wim Hof Method techniques (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034215/)   2019 - Research currently being conducted: Motivation and Experiences of WHM PractionersRMIT University in Australia has conducted a survey study, exploring the motivation and experiences of Wim Hof Method practitioners worldwide. This will offer insight into 1) the positive impact of practicing the WHM on health & wellbeing and 2) any potential adverse effects, which in turn improves safety protocols. The data is currently being analyzed. Inflammation & PainIn the Netherlands, Radboud University Medical Center in Nijmegen is completing a new study about the effects of the various components of the WHM on inflammation and pain. Metabolic ActivityKenkodo Metabolomic Discoveries in Germany is working closely with Radboud UMC. They are analyzing blood samples that have been taken by Radboud UMC in previous studies. Using this data, they seek to deepen the understanding of the metabolic activity in blood cells when practicing the WHM. Its various parameters can provide new insight into shifts in metabolic rate. Auto-immune DiseaseThe Amsterdam Medical Centre (AMC) in the Netherlands is conducting a study into the effects of the WHM on inflammation and quality of life of people with Spondylitis. Brain ActivityWayne State University in Michigan, USA, is measuring the effect of the WHM on brain activity. This research consists of 2 parts: 1. Effects of isolated cold exposure 2. Effects of cold exposure combined with WHM breathing exercises and mind-set Hof wore a water perfusion suit, which continuously pumps ice cold water in and out of tubes in the suit, while lying in fMRI and PET machines. They also monitored his heart and metabolic rates. “I was heating the water at first,” he said.  Please subscribe to our podcast & rate it 5 stars!  You can find Wim Hof on Social Media: Instagram: @iceman_hof YouTube: Wim Hof Facebook: Wim Hof Wim's website: https://www.wimhofmethod.com

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 of Circulation on the Run. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I am Greg Hundley, also associate editor from VCU Health Systems in Richmond, Virginia. Dr Carolyn Lam:                So, have you ever wondered in patients with atrial fibrillation and stable coronary artery disease beyond a year of coronary stenting, can you safely just continue on oral anticoagulation without antiplatelet therapy? Well, if you've ever wondered that ... I sure have. I'm sure you have too, Greg. Our feature paper this week does discuss this, so you have to stay tuned. But for now, Greg, what are your picks from this week's issue? Dr Greg Hundley:             I've got a couple to discuss. The first is Patrick Hsieh from Taipei, Taiwan, and really is evaluating the gut microbiota and how that affects cardiac repair after myocardial infarction. I mean, who would've thought to chase an idea like this? But what this investigative team did is they had mice, so this was a basic science experiment, and they treated them seven days prior to ligation of their left anterior descending artery that would induce a myocardial infarction. They treated them seven days prior with ampicillin, metronidazole, neomycin, and vancomycin. What were they trying to do? Totally obliterate any bacterial load within their GI system. Then, they ligated that coronary artery, and at 21 days, they looked at histopathologically what was happening.                                                 And you know what they found? Those where they wiped out the bacterial load, they had increased cardiovascular events. And importantly, myocardial rupture was very high in this group of mice. Also those mice, they had reduced heart rate, and mechanistically what had occurred is there was a reduction in our immune monocytes that were trying to infiltrate the peri-infarct. They weren't there. They were not in those peri-infarct zones. And so, the thought here is that removal of the favorable microbiota in the gut can actually be harmful in the setting of myocardial infarction. Dr Carolyn Lam:                Fascinating. So, microbiome as our pals. But wait a minute. I mean, how can you say it's from elimination of the microbiome versus some kind of effect of the antibiotics itself? Dr Greg Hundley:             Yeah, that's a great question, Carolyn. The way they did this is they took another group of animals, and they supplemented them with lactobacillus probiotic, like the stuff we get in the grocery store. And those animals, they did not suffer any of the adverse cardiovascular effects. So, it really points to an important role of our gut microbiota. You know, and what do they do? They basically ferment these carbohydrates that we ingest, and produce short chain fatty acids that are a substrate for these mononuclear cells to help infiltrate those infarct zones. So, really exciting basic science question that this group examined. Dr Carolyn Lam:                I love that you picked a basic science paper, and I love that you made even me understand it so well. Okay, but what I have is a clinical trial. So, it's the REDUCE-MVI trial, which is the first randomized trial comparing maintenance treatment with ticagrelor or prasugrel after a primary PCI. So, this is from Dr van Royen and colleagues. They're from Radboud University Medical Center in the Netherlands. Basically, they figured that despite successful restoration of epicardial vessel patency with primary PCI, coronary microvascular injury does occur in a large proportion of STEMI patients, and of course, adversely affects outcomes. Now, ticagrelor has been reported to increase plasma adenosine levels, which may have a protective effect on the microcirculation. So, the authors randomize 110 STEMI patients following revascularization to maintenance therapy with ticagrelor versus prasugrel, with the primary outcome being microvascular injury at one month as determined by the index of microcirculatory resistance in the infarct related artery.                                                 What they found was that there was no difference in the extent of microvascular injury and in the extent of infarct size by cardiac MRI at one month after the primary PCI. The attributed pleiotropic benefits of ticagrelor through the adenosine metabolism pathway actually could not be confirmed in the STEMI population, as plasma adenosine levels were actually not increased in the patients treated with ticagrelor. Dr Greg Hundley:             So, what does this mean for the use of adenosine and its role? Dr Carolyn Lam:                I suppose you're also asking, you know, is the adenosine hypothesis really out here? This is a study that really suggests we have to question it, but there are some limitations that we perhaps should keep in mind when we think about this. So first, before primary PCI, all patients were loaded with ticagrelor because this was standard of care in the participating centers. That, of course, could have modified microvascular injury already at the index event. Now, a second important thing is that the study may have been underpowered. There was a greater than anticipated variability in that primary outcome of index on microcirculatory resistance.                                                 The relatively low rates of risk factors, the small infarct size, the preserved ejection fraction could all have influenced this IMR values, as well as the potential effects of the pharmacological intervention. And furthermore, the natural recovery of microvascular dysfunction over time may have diluted the positive effects. And of course, selection bias is inevitable in a trial. And so, you know, although this really questions the adenosine hypothesis, there are still caveats to these results. Dr Greg Hundley:             Very good. So, Carolyn, I've got another study to sort of go over, and this is from Dan Modin from the University of Copenhagen. And it's really addressing this issue. We all in the fall, do we all get our flu shots? And could that be helpful in patients with heart failure? You know, the ACC, the AHA, and the ESC all suggest flu shots, but there's actually no guideline to recommend. So, what did these investigators do? They looked in Denmark, and from the period of January of 2003 to June of 2015, they identified 134,048 subjects. And they looked at the vaccination status for those with a diagnosis of heart failure that were greater than 18 years in age. 55% percent of these were men. And then, they also looked at ICD-10 codes for cardiovascular events.                                                 Now, they examine the dates of when you had your vaccination, how frequently, what were your comorbidities cardiovascular-wise, medication use, etc. And what they observed is that those individuals that had more than one vaccination ... So, basically annual vaccinations for a three year period, they had an 18% reduction in all death, and a 19% reduction in cardiovascular death. Dr Carolyn Lam:                So, is this all heart failure patients? Are there specific subgroups that we should be targeting? Dr Greg Hundley:             At our institution, they really get on us. If we don't have our flu shots in September, I mean, they threaten to withhold everything, or maybe October. Well, interesting that you asked that question. Those individuals that had flu shots in the September to October window did much better than those individuals that had their vaccination November, December, or actually later in January. And the second group that benefited were the individuals that actually had annual vaccinations. So, if periodically you say, "Oh, I'm going to get it this year, but then I'm not going to get it two years from now." Not so good. It was those individuals that had those vaccinations annually. Dr Carolyn Lam:                You know, Greg, it's making me question too, because here I am in a tropical island. We actually don't have seasons. So, what does that mean for us? That's one thing. And then, do we need even randomized trials now? Dr Greg Hundley:             Yeah, I think you're right there, Carolyn, because first of all, you know the investigators targeted this because 50% of heart failure exacerbations are actually triggered by some sort of respiratory infection. So, that was kind of the thought behind this. But we do have to be careful about looking at this longitudinal data and making predictions or developing guidelines. A couple of reasons why. It could be that those that come in for annual vaccinations at the time points, well, maybe they also come in for more frequent heart failure visits with their doctor. So, it's not cause and effect.                                                 And in fact, there was another study, Get with the Guidelines heart failure study, and it actually showed no association. So, more work really needs to be done in this area. And just to point out quickly, there is a current randomized trial going on called Invested, and it's looking at different types of vaccinations, trivalent versus quadrivalent. They're underway in those with heart failure. And so, there's a lot more work in this area. But it was interesting getting it that old "get your flu shot," and it looks like at least longitudinally in cohort studies could be beneficial. And if you are going to do it, do it every year and get that September, October. So, Carolyn, what about your next paper? Dr Carolyn Lam:                So, Greg, my second paper is another trial. It's the radio sound hypertension trial, this time focusing on renal denervation. In fact, it's the first trial to compare three different techniques and technologies for catheter-based renal denervation. It's from Dr Lurz from Heart Center Leipzig in Germany. And what they did is, they randomized 120 patients with resistant hypertension to three arms. Either one, radiofrequency, renal denervation of the main renal arteries. Two, radiofrequency renal denervation of the main renal arteries and the side branches and accessories. Or three, an endovascular ultrasound-based renal denervation of the main renal artery. The primary endpoint was change in systolic daytime ambulatory blood pressure at three months. In the end, endovascular ultrasound-based renal denervation was the winner over radiofrequency ablation of the main arteries, with or without ablation of the side branches. Dr Greg Hundley:             Carolyn, does this mean that renal denervation is coming back? Are we going to actually start thinking about this as a viable option to treat those with longstanding hypertension? Dr Carolyn Lam:                Greg, this was exactly addressed by an editorialist, Dr Ram from UT Southwestern and Apollo Hospitals and Apollo Medical College in India. Beautiful editorial. Basically, even with the publication of these new data, it is difficult to predict whether renal denervation is firmly back on track. You see, some caveats should be mentioned, including that in this trial, only patients with large renal arteries were chosen for this study. And patient enrollment was rather selective.                                                 For example, out of 1,884 patients screened, only 120 patients met the inclusion criteria. And then, importantly, in a few patients, the reduction in systolic blood pressure was really impressive, close to 40 millimeters mercury. But the majority of responders had a more modest effect, and in about 30%, there was no change in blood pressure.                                                 So, one of the ultimate things we need to learn to do is to identify the so-called hyper-responders from the non-responders. So, lots more work needs to be done in renal denervation.                                                 That brings us to a close of our little chat. Can't wait for our feature discussion coming right up.                                                 Our feature paper today deals with a very important topic in a very frequently encountered group of patients. And they're the ones with concomitant stable coronary artery disease and atrial fibrillation. You see, these are patients at high risk of both ischemic and bleeding events, and therefore, it's critical to identify the right antithrombotic regimen with the optimal benefit ratio, since this is going to be lifelong therapy. Now, interestingly, despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation with and without antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond one year of coronary stenting. I mean, Greg, I didn't even realize that we didn't have a randomized control trial. Did you? Dr Greg Hundley:             Absolutely, Carolyn. And, you know, this is an important issue, because we have a lot of patients coming to the cath lab that have atrial fibrillation, and what is going to be the recommended anticoagulant and antiplatelet combination? And so, it's really time for a randomized trial. Dr Carolyn Lam:                I know, and luckily for us, that's exactly what this issue's feature paper does. And I'm so pleased to welcome to the show Dr Satoshi Shizuta from Kyoto University Graduate School of Medicine, Japan, as well as associate editor Dr Shinya Goto from Tokai University in Japan. We're so proud to be publishing the OAC-ALONE trial, even though we understand it was a difficult trial. Tell us, what were the results? Dr Satoshi Shizuta:           As you know, the results were somewhat inconclusive because of pretty much a combination of patient enrollment. Initially, we scheduled to enroll 2,000 patients during 12 months, but patient enrollment speed was extremely slow, much slower than expected. So, we extended the patient enrollment period from 12 months to 38 months. But finally, we could only enroll 696 patients, about one-third of the initially planned patients. The result was around 50% rate of primary end point during 2.5 years of follow up. And the hazard ratio of [inaudible 00:15:01] strategy, as compared with OAC plus APT was 1.16 with a 95 confidence interval of 0.79 to 1.72.                                                 So, in conclusion, our study failed to establish no inferiority of OAC-ALONE to combination therapy of OAC plus antiplatelet therapy in patients with AF and stable coronary artery disease beyond one year after stenting in terms of primary endpoint of death, MI, or stroke. So, this study was underpowered and inconclusive. So, future larger studies require to establish the optimal antithrombotic regimen in this same patient population. Dr Carolyn Lam:                Thanks so much. Shinya, you've been thinking about this, too, and the performance of such a difficult trial. Did you have anything to add or to ask? Dr Shinya Goto:                So, first of all, I would to congratulate Satoshi and the group. They have completed a very interesting randomizing trial. As Greg mentioned, there is two kind of patient who lead to coronary artery disease and atrial fibrillation, especially after, you know, one year after stenting. So, taking a look at coronary artery disease with atrial fibrillation, we don't have the established standard of care yet. So, Satoshi know, it is a long-time study. So, I understand the rich colored nature of the patient in this kind of trial. So, what is the most difficult point increased to encourage the patient in this long-term trial? Dr Satoshi Shizuta:           We think that difficulty reflects substantial reluctance of most cardiologists to withdraw antiplatelet therapy, single antiplatelet therapy from stented patients, even the patients treated with oral anticoagulation for atrial fibrillation. So, that is the most important point. Dr Shinya Goto:                You have already showed in this paper myocardial infarction recurrence of stents thrombosis. Not a huge problem in this kind of patient population, you know? Stroke is a bigger problem, mortality, not including cardiovascular is also the problem. So, you have suggested, you have a strong kind of mind, is it? And single antiplatelet therapy necessary after stenting. Your results are underpowered but still suggest how always you know would be enough in stable CAD patients with atrial fibrillation.                                                 I would congratulate you again. Dr Satoshi Shizuta:           Thank you. Dr Greg Hundley:             Satoshi, I have a quick question. So, in the randomization process, how can you achieve the physicians managing the patients to administer the anticoagulant therapy to guideline levels, particularly when they are also prescribed antiplatelet therapy? I noticed that in the editorial on this manuscript that was a concern, and suggesting that in future studies that the therapy really be defined, and not so much open label administration at the discretion of the prescribing physician. What are your thoughts on that? Dr Satoshi Shizuta:           I agree with you, but in this kind of study, randomizing whether or not to withdraw a drug is very difficult to conduct. Financial support is limited, and in such situation, double blind placebo controlled trial is very difficult to conduct. As you know, several years ago, a loose trial was published in the Lancet. And also in the loose trial, the study design was open level, and also in the PCI and [inaudible 00:19:48], I think the study design was not blinded but open. In this paper figure two, our control level was set as a dependent based on the Japanese guidelines. In the Japanese guidelines, target IR was set as 1.6 to 2.6, a little bit lower than Western golden standard for elderly patients older than 50 years. And same 2.0 to 3.0 in patients younger than 70 years.                                                 And in that criteria, as you can see, if you get 2A of paper, the therapeutic range was extremely high. 76% in the OAC-ALONE group, and also 73% in the OAC plus APD group. We can clearly understand that the intensity of oral anticoagulation was different between the two groups. Most of the OAC-ALONE group, OAC was controlled with ionine level higher than 2.0. On the other hand, in the OAC plus APD group, the ionine level was mostly controlled between 1.6 to 2.2 or .5 or so. So, this is a great big limitation of the study. But even in this limitation, the bleeding events, there was numerical excess in the OAC plus APD group. And, regarding the TEMI major bleeding, there was a trend toward increased major bleeding in the OAC plus APD group. If the intensity of OAC was the same, of course, I am convinced that even in this underpowered sample five, the major bleeding will be statistically higher in the OAC plus APD group. Dr Carolyn Lam:                Thank you so much Satoshi for really taking us under the hood, and showing us all the myriad of considerations that occurred to perform this trial.                                                 This is Greg and Carolyn. Thank you for joining us on Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019.  

Neke žene koje imaju stimulaciju jajnika zbog asistrirane reprodukcije doživjeti će štetni učinak zvan sindrom hiperstimulacije jajnika ili SHJ. Postoji nekoliko Cochraneovih pregleda strategija za sprečavanje ovog i jedan novi pregled iz siječnja 2017., koji spaja rezultate iz ovih sustavnih pregleda. Glavna autorica Selma Mourad s Radboud University Medical Center u Nijmegenu u Nizozemskoj, u razgovoru sažima ovu veliku bazu dokaza. Volonterka Jela Ravnjak je prevela ovaj razgovor, a Irena Zakarija-Grković, iz Hrvatskog Cochranea, će nam ga pročitati.

Digital Healthcare, from Healthcare Innovation Strategist Zayna Khayat’s Point of View. Zayna tackles Digital Health from innovation and business perspectives, having worked with Mars Innovation Hub, University of Toronto, Saint Elizabeth Healthcare & the Rotman School of Business in Canada, as well as REShape at Radboud University Medical Center in the Netherlands. Twitter: @ZaynaKhayat.

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Youth National University of Singapore. Coming right up, we will be discussing fascinating new data on the prevalence of subclinical coronary artery disease in masters endurance athletes but first, here's your summary of this week's journal. The first paper provides insight into ischemic cellular post conditioning. Now, we know that cardiosphere derived cell therapy has been utilized as a strategy to treat ischemic heart disease and reduce chronic scar burden when administered months after myocardial infarction. In the current study, by first author Dr. de Couto, corresponding authors Dr. Marban and Berman from Cedars-Sinai Heart Institute in Los Angeles, California, the authors used rat and pig models of myocardial infarction to show that exosomes, which are nanosize lipid bi-layer vesicles, actually mediate the cardio protective effects of cardiosphere derived cells when administered after reperfusion of myocardial infarction.                                                 They further show that treatment with either cardiosphere-derived cells or their secreted exosomes reduce infarct size and improved functional recovery. Using RNA sequencing to determine exosome content and alterations in gene expression profiles on macrophages from cardiac tissue or bone marrow, they found that a specific micro RNA species miR 181-B within the exosomes, acted on macrophages and was implicated as a key mediator of the cardio-protective benefits. Thus, this study gives new reason to test the idea that allogeneic cardiosphere-derived cells may be efficacious in preventing scar formation and improving cardiac function, when given in the earlier reperfusion period. The data further support that exosomal transfer of miR 181-B from these cardiospheric-derived cells into macrophages underlie the cardio-protective effects after reperfusion.                                                 The next study describes a potential new therapeutic strategy for vasoproliferative retinopathy which can underlie age-related macular degeneration, the leading cause of blindness in industrialized nations. First author, Dr. Bucher, corresponding authors Dr. Yea and Friedlander, from the Scripps Research Institute in La Jolla, California used rodent models of retinal neo-vascular disease to show that Tspan-12, beta-catenin signaling plays an important role in the development of vasoproliferative retinopathy. As background, Tspan-12 belongs to the Tetraspanin family, which mainly includes cell surface proteins characterized by four transmembrane domains and two extra cellular domains.                                                 Members of the Tspan family participate in a diverse cellular processes and act as signaling platforms by forming Tspan-enriched micro domains in plasma membranes. The authors went further to use a novel phage display combinatorial antibody library to specifically design a Tspan-12 blocking antibody which is capable of interacting with human and mouse Tspan-12 antigen. They then provided strong evidence that the Tspan-12 blocking antibody prevents developmental pathological neovascularization in  murine models of vasoproliferative retinopathy. Combination therapy with a known anti-VEGF agent demonstrated significant synergy supporting the potential clinical use of the anti-Tspan-12 antibody as a novel angiomodulatory agent.                                                 The next study addresses the paradox that blacks have higher coronary heart disease mortality compared with whites, but non-fatal coronary heart disease risks may be lower for black versus white men. To address this paradox, first author Dr. Colantonio, corresponding author, Dr. Safford and colleagues from Weill Cornell Medical College in New York, compared fatal and non-fatal coronary heart disease incidents and case fatality among blacks and whites in three studies. The Atherosclerosis Risk in Communities or ARIC study, cardiovascular health study, and reasons for geographic and racial differences in stroke or regards study, all stratified by gender.                                                 They found that the incidents of non-fatal coronary heart disease was consistently lower among black versus white men, although black men have a higher burden of unfavorable social determinants of health and cardiovascular risk factors and a higher fatal coronary heart disease incidents. Following adjustment for social determinants of health and cardiovascular risk factors, black men and women had a similar risk of fatal coronary heart disease, but a lower risk of non-fatal coronary heart disease compared with white men and women respectively. Finally, blacks with incident coronary heart disease had a higher case fatality compared with whites and the difference remained similar after adjustment for social determinants of health and risk factors. Thus, there is an apparent lower risk for non-fatal coronary heart disease among black versus white men and women, which needs to be further studied. Blacks have a higher risk of their initial coronary heart disease event being fatal compared with whites, highlighting the need for reinforcing primary prevention in this population.                                                 The next study provides important information on the burden of re-admissions after hospitalization for critical limb ischemia. First author, Dr. Kolte, corresponding Dr. Aronow and colleagues from Brown University in Providence, Rhode Island, used the 2013/2014 nationwide re-admissions databases to identify almost 61,0000 hospitalizations for primary diagnosis of critical limb ischemia during which patients underwent endovascular or surgical therapy. They found a 30-day re-admission rate of 20.4%. Independent predictors of 30-day re-admission included presentation with an ulcer or gangrene, age above 65 years, females, large hospital size teaching hospital status, known coronary artery disease, heart failure, chronic kidney disease, anemia, coagulopathy, obesity, major bleeding, acute myocardial infarction, vascular complications, and sepsis. Interestingly, mode of revascularization was not independently associated with re-admissions.                                                 The most common reasons for re-admissions included infections, persistent or recurrent manifestations of peripheral artery disease, cardiac conditions, procedural complications, and endocrine issues. Finally, the costs of 30-day re-admissions for critical limb ischemia during the study period were 624 million U.S. dollars. Thus, this study provide knowledge of independent predictors and reasons for re-admissions that will help clinicians and hospitals to identify, develop, and implement strategies to reduce re-hospitalizations and healthcare costs associated with critical limb ischemia. The final study tells us that there may be a direct relationship between life-long exercise volume, and coronary atherosclerosis in athletes. Dr. Aengevaeren and colleagues from Radboud University Medical Center in the Netherlands, studied 284 middle-aged men engaged in competitive or recreational leisure supports, using contrast enhanced CT to assess coronary artery calcification and plaque characteristics.                                                 Participants also reported life-long exercise history patterns and exercise volumes were quantified as metabolic equivalent of task or met minutes per week. They found that participants in the more than 2,000 met minutes per week group had a higher prevalence of coronary artery calcification and atherosclerotic plaques. The most active group did, however, have a more benign composition of plaques with fewer mixed plaques and more often, only calcified plaques. These observations may explain the increased longevity typical of endurance athletes, despite the presence of more coronary atherosclerotic plaques in the most active participants. Well, that wraps it up for your summaries. Now for our featured discussion.                                                 Our current physical activity guidelines recommend 150 minutes of moderate exercise and that's supposed to protect against cardiovascular disease and increase longevity. However, what do we really know about the dose response relationships and the effects of exercises doses that exceed current recommendations. Well, recent data, including a paper in this week's issue, suggests that long-term, high volume endurance exercise may actually accelerate, rather than reduce coronary atherosclerosis. To discuss this exciting paper, we have the corresponding author, Dr. Sanjay Sharma, from Saint George's University of London, as well as editor of digital strategies and associate editor at UT Southwestern who handled this paper, Dr. Amit Khera. Welcome, gentleman. Dr. Amit Khera:                 Good morning. Dr. Sanjay Sharma:          Thanks for having us. Dr. Carolyn Lam:               First, Sanjay, oh yikes! As a runner and as a person who strongly advocates regular exercise, please, please, put us out of our misery. Tell us what you've found and what you think are the possible explanations. Dr. Sanjay Sharma:          I'm a runner too, and I don't think anyone would argue that the benefits of exercise on the cardiovascular system are unrivaled. People who exercise regularly do reduce their risk of an adverse event from a heart attack by 50% when they're in their 5th and 6th decade and they live around three years longer than people who don't exercise at all. Now as you rightly point out, the current recommendation suggests 2 1/2 hours of moderate physical activity per week and by that I would mean, at maximum, a 15-minute mile pace. Clearly, our endurance athletes exercise much, much more than that. They exercise 10 to 20 times greater than that volume and in parallel with this has been the emergence of a large number of people participating in marathon runs. For example, in Europe, there were two million marathon runs per annum and that figure's going up by about 5%.                                                 Coinciding with this burgeoning increase in endurance exercise, is the development of several reports that show that exercise may cause release of biomarkers of cardiac damage. Animal experiments have shown that exercise may cause scaring in the heart and human studies have shown that some marathon runners have more calcium in their coronary arteries compared to relatively sedentary individuals. One of the problems with these studies is firstly, the biomarker release is very transient, it goes away after about two days. Animal experiments cannot really reflect what goes on in human beings because they're artificial and animals are forced to exercise with electrical shocks, et cetera. The studies in human beings have been conducted in runners who have been former smokers.                                                 In fact, the most commonly reported study or cited study, contained individuals of whom 50% had risk factors for coronary artery disease. What we decided to do was to do a clean study, where we took 150 individuals who had none of the risk factors for coronary artery disease and 92 relatively sedentary controls who exercise within the normal limits. We have to exclude a lot of people because we have to exclude anyone that had ever smoked, anyone that had high blood pressure, high cholesterol, or a family history of permanent cardiac disease. We actually subjected them to all sorts of investigations and we found that a small number of male runners had more calcium in their arteries compared to sedentary individuals. Dr. Carolyn Lam:               Wow! Please tell us that there's something good that you can say about that. First of all, I really want to congratulate you on this most elegant study and Amit, I'm sure you put in what the editor's thought but we're just so proud to be publishing such a high quality study here. Amit, is there anything you might want to add of what the editors thought? Dr. Amit Khera:                 Sure, I first want to congratulate Dr. Sharma and his colleagues. This was a carefully done study and we've talked a bit about the coronary calcium but there was extensive investigation and I really think this advanced the field. Sounds like all three of us are runners, so this hit home to all of us and as he mentioned, this has been a very hot area and one that's been very controversial. I think here what we have is a manuscript that really helped move the field forward, helped us better understand the biology. The one thing I'll comment on that we found very interesting was the observation that those that were the masters athletes actually had more of a calcific phenotype, where as those that were not looked like a soft plaque phenotype, if you will. Actually, if you look, we have a companion article in circulation looking at sort of dose dependent finding a similar finding. My question, now turned back to Dr. Sharma is, what do you counsel your patients now with these findings? Has it changed now how you recommend exercise or your thoughts on how you counsel them? Dr. Sanjay Sharma:          Well, we examined 152 different athletes, or masters athletes in 92 controls. These athletes were aged 56 years old, who'd been training for 36 years and had immediate marathon number of 13. Now, what we've found in these individuals is that a small number of males, that's 11%, had a coronary artery calcium score of more than 300. Some men had more plaques than sedentary individuals and these plaques were distributed throughout all three coronary arteries. When we looked at the pathology of the plaques very carefully, we found that the plaques in the athletes were calcified. Indeed, 72% of athletes had very calcified plaques. We know that such calcified plaques are stable, they're less likely to fissure and are less likely to cause coronary thrombosis and therefore, acute myocardial infarction.                                                 This led us to propose that although exercise may be causing some atherosclerosis through the sheering and stressful source during exercise of the bending and kicking of vessels, we believe that the repair mechanism here is different to that seen in people who smoke or who have high cholesterol or high blood pressure. The repair mechanism results in very calcified and stable plaques in athletes and this may actually mitigate the risk of acute myocardial infarction and may explain why the number of people who actually suffer an acute myocardial infarction during a marathon run is very small, around 1 in 50,000, and no different to the number of people who suffer a sudden cardiac arrest playing football or basketball, due to congenital or inherited abnormalities of the heart.  Dr. Carolyn Lam:               Sanjay, those are just such important points to keep in mind as we read your paper. It did strike me as a significant minority, actually, of these long term endurance athletes who develop significant coronary artery calcification and it could potentially be a clinically benign phenotype. At the end of the day, this is a cross-sectional study, isn't it? We can't, I suppose, extrapolate into the clinical events. What are your postulations there and what could be future work that you're planning? Dr. Sanjay Sharma:          Well, you make a good point. This is a cross-sectional study and the demonstration of an increased cardiopathy calcium does not necessarily reflect future cardiac events. We have followed these individuals up for the last 18 months. These masters athletes and have not demonstrated a single one to develop an acute event that would last 18 months. We really don't know what the meaning of these plaques is. I think the only thing to do now, being we've got the liberty of having so many people that do marathon runs and so many people who've been exercising for three or four decades, we can actually do a prolonged follow up study, so the answers will be a while coming. To follow these people up with high calcium, just to see whether they do go on to develop adverse events in the future. All our study has shown is that some male athletes who've exercised lifelong get an increasing number of plaques. These plaques appear to be calcified and stable and the long term effects of such  plaques is unknown. Dr. Carolyn Lam:               Sanjay, just circling back to Amit's question earlier and maybe Amit, you could take it to after this. What do we recommend to our athletes who come in and have a high coronary artery calcium score? Do we tell them to stop? Dr. Sanjay Sharma:          I certainly wouldn't and I'm much less worried about an increase coronary calcium score in a lifelong runner or cyclist than I was 10 years ago. It appears that these plaques are there in some individuals, they are calcified, they appear stable. Given the fact that we know that coronary events during marathon running in experienced runners are very, very low indeed. I don't think I would be keen to do anything about it, not even consider stacking therapy based on our findings at present. As I said before, we do need longitudinal follow up to really identify all ascertain the precise implications of these plaques in masters athletes. Dr. Carolyn Lam:               Right, and this is again recognizing that your particular population was free of traditional cardiovascular disease. Of course, if we were to find these risk factors in our athletes, we would most certainly treat the traditional risk factors. Amit, anything to add there? Dr. Amit Khera:                 I think that was an excellent point about his approach to counseling patients. I will mention on the editorial staff, we felt like this was such an interesting area with emerging data and fast moving, that it was warranting of an editorial. I recommend people to look at the one by Aaron Baggish and Ben Levine. I think they had a very similar conclusion and that was that they don't necessarily proscribe exercise in patients with high coronary calcium but rather, focus on risk mitigation strategy, focusing on risk factors as we normally would do. I think the conclusions are similar and the thoughts in that editorial were insightful, pairing both of these papers and helping us make sense out of this really evolving field. Dr. Carolyn Lam:               Well, thank you Sanjay and Amit for this wonderful discussion. I learned so much as I'm sure our listeners did. You've been listening to Circulation On The Run. Tune in next week.