Podcasts about mendelian

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Take a sneak peek at this month's Fertility and Sterility! Articles discussed this month are:   01:48 Trustworthiness criteria for meta-analyses of randomized controlled studies: OBGYN journal guidelines 06:24 Playing the long game for reproductive rights 08:04 Limiting the number of fresh donor oocytes inseminated with sperm as a strategy to minimize supernumerary embryos 15:38 Effectiveness of degradable polymer film in the management of severe or moderate intrauterine adhesions (PREG-2): a randomized, double-blind, multicenter, stratified, superiority trial 26:37 Aneuploidy rates and likelihood of obtaining a usable embryo for transfer among in vitro fertilization cycles using preimplantation genetic testing for monogenic disorders and aneuploidy compared with in vitro fertilization cycles using preimplantation genetic testing for aneuploidy alone 38:13 Antimüllerian hormone levels are associated with time to pregnancy in a cohort study of 3,150 women 47:50 Racial disparities in the outcomes of euploid single frozen-thawed embryo transfer cycles – analysis of the Clinical Outcome Reporting System of the Society for Assisted Reproductive Technology 2016–2018 data 57:14 No association between celiac disease and female infertility: evidence from Mendelian randomization analysis   View Fertility and Sterility October 2024, Volume 122, Issue 6:  https://www.fertstert.org/issue/S0015-0282(24)X0013-8 View Fertility and Sterility at https://www.fertstert.org/  

In this episode, we discuss instrumental variables with Dr. Rita Hamad of Harvard's TH Chan School of Public Health. This episode is focused on the first part of Chapter 28 of Modern Epidemiology 4th edition on quasi experimental methods. We start with what quasi experimental designs are and why we would want to use them (and whether more epidemiologists are being exposed to them). We also talk about why these methods are more common in economics than in epi. We talk about how these methods try to take advantage of something that approximates randomization to estimate causal effects. We talk about what instrumental variables are and the conditions required to be met for a variable to be an instrument. We focus on the strengths and limitations of the methods and when they make the most sense to use them. We talk about what happens when you violate the assumptions of IV. We talk about weak and strong IVs and we talk about Mendelian randomization and its role in epi. And we ask the age-old question, how do you find the elusive instrumental variable?

IGF-1 (Insulin-Like Growth Factor 1) has emerged as a hot topic in health and nutrition discussions, often linked to longevity, cancer risk, and metabolic health. On one hand, IGF-1 is essential for growth, repair, and metabolic regulation; on the other, it is sometimes associated with disease processes, including cancer and cognitive decline. For those intrigued by the intersection of nutrition, biomarkers, and disease prevention, IGF-1 offers an opportunity to explore how science grapples with these complexities. Claims about manipulating IGF-1 through dietary changes — whether by reducing protein or adopting fasting protocols — are common. But does the evidence support these claims? If you're curious about IGF-1 and the relationships between diet, disease, and healthy aging, in this Premium-exclusive episode Danny and Alan discuss this fascinating topic. To listen to the full episode, subscribe to Sigma Nutrition Premium Timestamps [02:21] IGF-1 and Diet: Examining the Relationship [09:15] IGF-1 as a Biomarker: Challenges with Sensitivity and Specificity [11:54] IGF-1 and Cancer Risk: Insights and Complexities [25:51] IGF-1 in Aging: Cognitive Function and Longevity Considerations [43:38] Key Takeaways: IGF-1, Diet, and Practical Advice Related Resources Join the Sigma email newsletter for free Subscribe to Sigma Nutrition Premium Enroll in the next cohort of our Applied Nutrition Literacy course Murphy et al., 2020 – observational and Mendelian randomization analyses

Recent progress in neurogenetics and molecular pathology has improved our understanding of the complex pathogenetic changes associated with neurodegenerative dementias. In this episode, Katie Grouse, MD, FAAN, speaks with Sonja W. Scholz, MD, PhD, FAAN, an author of the article “Genetics and Neuropathology of Neurodegenerative Dementias,” in the Continuum® December 2024 Dementia issue. Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California. Dr. Scholz is a senior investigator at the National Institutes of Health in Bethesda, Maryland and an adjunct professor of neurology at Johns Hopkins University in Baltimore, Maryland. Additional Resources Read the article: Genetics and Neuropathology of Neurodegenerative Dementias Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Full episode transcript available here:  Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Sonia Scholz about her article on genetics and neuropathy of neurodegenerative dementias, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast, and please introduce yourself to our audience.  Dr Scholz: Thank you so much for inviting me. My name is Sonia Scholz. I'm a neurologist working at the National Institutes of Health. My main focus of research and clinical work are neurodegenerative diseases, and I have a particular interest in using modern genomic tools to understand these diseases and potentially leverage it for new translational applications. Dr Grouse: Sonia, we're really excited to have you today and thanks for joining us.  Dr Scholz: I'm pleased to be here.  Dr Grouse: I'd like to start by asking what you think is the most important message or takeaway point from your article? Dr Scholz: So, this is an article that really captures a very broad and exciting field. So, one thing I wanted to really highlight is that there's a lot of heterogeneity, clinical, pathological, molecular heterogeneity in age-related neurodegenerative dementia syndromes. Our article was really aimed at providing a bird's eye view of the pertinent pathological characteristics, but also important genetic advances and insights and how we can leverage that, particularly in the new physician medicine era, hopefully come up with better treatments and better ways to counsel our patients.  Dr Grouse: What do you think is the most challenging aspect of understanding the genetics and neuropathologic basis of neurodegenerative dementias?  Dr. Scholz: That's a good question. There're many big and challenging questions, but I think one of the things we struggle the most with is really the heterogeneity. I see patients with one and the same Mendelian form of dementia. One patient is in their forties another patient is in their eighties, and the clinical manifestations can be very different from one patient to another. There's a lot of heterogeneity, also, on the pathological level. Not every patient has exactly the same distribution. And so, we're starting to slowly define what the underlying causes are, but it's still quite baffling and quite challenging to put them together and understand them. Dr Grouse: Do you feel that the genome-wide association studies has helped our understanding of these diseases, specifically the heterogeneity? And if so how?  Dr Scholz: That's a great question, but you're talking to a geneticist here. And I definitely would say genome-wide association studies have helped us a lot in identifying what the underlying disease pathways are and what the relationships between neurodegenerative disease entities are. It really also gave us a better understanding of apparently sporadic diseases where genetic factors are still playing a role. And we can leverage that type of knowledge increasingly to highlight high-risk groups, but also, we can increasingly use it to stratify patients for clinical trials, for example. And that's really exciting and there's still a lot of knowledge that we have to garner very quickly, especially in the non-Alzheimer dementia space.  Dr Grouse: You've mentioned, of course, the heterogeneity and these syndromes. And in your article, you go into a lot of the issue of the significant crossover between the genetic links and the neuropathological findings for the various types of neurodegenerative dementias. Do you think that this crossover has been more of a help or a hindrance in better understanding these diseases? Dr Scholz: Yeah, it can be a little bit, you know, challenging to wrap one 's mind around it. But by and large, I think it's actually good news because it highlights that there is a shared biology between many of the neurodegenerative disease entities. And by figuring out which the pathways are that are very often involved, we can prioritize certain targets for therapy development. But we can also be smarter about how we developed treatments. We could repurpose a drug that has been developed for Alzheimer's disease very easily for Lewy body dementia because we increasingly understand the overlap. And we can also leverage new clinical trials design, like basket trials. This is something that has been really transformative in the oncology sphere and now, increasingly, neurodegeneration. We're trying to apply that kind of thinking as well to our patient populations. Dr Grouse: What do you think our listeners will find to be most surprising when they read the article? Dr Scholz: We often present these diseases in our textbooks as these black-and-white entities, but the reality is that there's a lot of overlap. And we also see that co-pathologies are actually the norm and not the exception, and a lot of the molecular risk factors are shared. It's not really surprising. And I think that overlap and crosstalk between the various diseases is something that's a little bit strange to think about, but it actually makes increasingly sense now that we see the genetic risk profiles coming up. Dr Grouse: In reading your article, I was really struck by how many, or how much the prior studies have been lacking in inclusion of different ethno-racial backgrounds in the patients who've been studied. How can this be improved going forward?  Dr Scholz: Yeah, thank you. That's a really important and crucial question, and I think it really takes the collective effort of everybody in the healthcare research community to improve upon that. We need to talk to our patients about genetic testing, about brain donation programs, about referrals to clinical trials, and don't feel shy about reaching out to our colleagues and academic centers, even if you don't have the resources in a smaller institution. We also not only need to engage with the communities, we also need to build up a healthcare research community that has representatives from these various communities. So, it's really a collective effort that we build up and are proactive about building a more equitable healthcare system and research system that works for all of us and that really is going to provide us with the precision medicines that work for everybody. Dr Grouse: What do you think is the biggest debate or controversy related to the genetics and neuropathology of neurodegenerative dementias?  Dr Scholz: Yeah, there are loads of interesting debates, but I think in my field, in particular in the genetics is what to do with risk variance. What is it that I actually communicate to the patient? Obviously, I can learn a lot on the bench and I think I can use a lot of the genetic risk factors for molecular modeling, etc. But to which extent should I share that information? Because genetic information is something that we cannot alter and many of the risk factors are actually mild, that they may never result in disease. And so, communicating risk with patients is something that's very challenging and we used to just steer away from it. But now the discussion is starting to shift a little bit. You know, nowadays we are starting to offer, for example, testing for the APOE4 allele in individuals who are considering antiamyloid therapies. And this really, this is precision medicine in his earliest days because it allows us to stratify patients into those that are high-risk versus low-risk and those that need more frequent follow-up or may be advised not to pursue this treatment. And we're probably going to see more of those discussions and the ethics around it. And it's even harder in an aged population where you know, you may never manifest any of the symptoms despite carrying a lot of these risk deals. Dr Grouse: You mentioned, you know, that testing, APOE4 testing for certain populations when deciding to do the antiamyloid immunotherapies. Apart from that, which I think is a really good example of where genetic testing makes sense, what other scenarios do you think it makes sense at this point in time to recommend genetic testing for symptomatic patients who are concerned about neurodegenerative dementias? Dr Scholz: Yeah. So, I usually have a very frank discussion with patients in whom I suspect the genetic etiology. So those are individuals who have a strong family history, individuals from very early onset of the disease where genetic testing may allow us to establish a molecular diagnosis, individualize and refine our counseling, and potentially get them into targeted clinical trials that may be suitable for that. Those are always very nuanced discussions, but I usually start with those high-risk individuals. Increasingly patients are, even with the apparently sporadic forms, are asking me about it. And then I have a frank discussions about the pros and cons and offer it to the patients who really would like to pursue it.  Dr Grouse: That makes a lot of sense. What about in the case of patients who are asymptomatic but might have high risks because of, well, family members with certain types of neurodegenerative dementias? When would it make sense, if ever, to do genetic testing for them? Dr Scholz: Yeah, that's a that's a tough situation, to be honest. By and large, I would say I would like to understand what the motivation is to learn about the genetic status. If the motivation is something like family planning, future care planning, etc, then it may be a reasonable thing. But I also want to make it very clear upfront that knowing a genetic status, at least aside from APOE status, at least for now, doesn't actually change the clinical management. And I want to make sure patients understand if they are trying to lower their risk, knowing that genetic status is not going to lower their risk. There are other things, brain health habits, that are really important, that patients should double down on: avoiding vascular disease, avoiding traumatic brain injury, excessive alcohol use, etcetera. It's a discussion that really tries to understand the motivations behind the testing. But some patients are very frank and they want to have it. They may want to contribute to the research community, and so in those instances we may offer it, but I also really want to make them understand that knowing a genetic diagnosis may be acceptable to them, but family members who are related to them may not wish to know. And they can really cause a lot of psychological stress that extends beyond the individual. And then that's something to really consider before actually pursuing testing. Dr Grouse: I think that's a really good reminder, especially about how this can even affect people outside of the patient themselves. I think a lot of us don't even think about that. And certainly, our patients may not either. Taking it a step further, thinking about newly available biomarkers, imaging modalities, how should we incorporate the use of these for our patients when we're suspicious of things like Alzheimer's disease or dementia with the Lewy bodies? Dr Scholz: So by and large these biomarkers are used in in the research area, but we can, in a given patient where maybe the clinical presentation is somewhat atypical, we can use it to help with our diagnostic impression. It doesn't get rid of the clinical evaluation, but at least it gives us a little bit more certainty. Here are the you know, the molecular features, the abnormal amyloid tau deposits, for example, that we're there we're detecting supports diagnosis. May also sometimes help in patients where we suspect there could be even the co-pathology going on where we get a mixture of features, where we can counsel the patients and you know, detecting copathologies is something that is certainly challenging. We know that patients who have more pathologies on average are not doing as well as the ones who have relatively pure disease forms. But this is also an area of intense research and as long as it's used judiciously to help with the diagnostic compression, to reduce a diagnostic odyssey, I think there's a lot of potential there to improve the clinical evaluations nowadays. Dr Grouse: It is really exciting to see the options that are opening up as the years go by, which brings me to my next question. There is certainly, as we know, this new category of disease modifying therapies that are available in the form of the anti-amyloid immunotherapies. What else do you think's on the horizon for treatment and prevention, neurodegenerative dementias, going down the road five, ten, fifteen years down the line?  Dr Scholz: Yeah, I think we're entering the era of precision medicine already and we're, we're seeing it already with the anti-amyloid therapies. By and large, I think the standard of care is going to be a multidisciplinary individualized treatment plan that incorporates a more holistic view. It incorporates diet, lifestyle factors, symptomatic management, but also disease modification strategies and potentially even multitarget disease modifying strategies. I think there's a lot more work that we have to do, especially in in the non-Alzheimer's dementia field. But overall, we're becoming much better in refining our diagnostic impression and in treating some of the complications that arise in these very complex diseases.  Dr Grouse: I'm curious, with the future of dementia care and diagnosis being more of a precision medicine model, how do you think this will be possible in an aging population with already, I think, probably a limited access to neurologists even in current state? Dr Scholz: Yeah, this is- these are these are very challenging societal questions. Increasingly, you know, we can use modern technologies such as televisits for follow up, but also, you know, remote monitoring devices. We have to educate the next generation, we need more neurologists, we can't do it alone; but we also need to empower primary care doctors who are usually the first go-to person. And perhaps biomarker testing will become much more common even in the primary care setting. I think overall, you know, we can tackle it by educating the community, empowering participants in various clinical trials, and being flexible of embracing certain new technologies. Dr Grouse: Absolutely. I think that makes a lot of sense and hopefully this will be another call to arms to try to get the word out, get more access to neurology and more people interested and like you said, getting our other colleagues involved and being able to manage it as well.  Dr Scholz: Yeah.  Dr Grouse: I wanted to transition a little bit into learning more about you. How did you become interested in genetics of neurodegenerative dementias? Dr Scholz: Yeah, it's something, it's an interest that has grown gradually. I started out as a neuroscientist in in Austria, where I was fortunate to work with a group that was very strongly involved in Parkinson's disease care. And I was so thrilled to see patients, you know, treated with deep brain stimulation. But yet in the same clinic, I also saw the patients who were not eligible because they had atypical neurodegenerative diseases. And it's the realization that there is such a broad spectrum of diseases that we frankly don't understand very well, that we really need to work with, understand and hopefully develop the treatments with. That's really has resonated with me. And I've since then really built my entire career around it through different countries at the United Kingdom and the United States. And I'm very fortunate to work at the National Institutes of Health, where I can pursue a lot of these research passions and work with interesting patients and colleagues.  Dr Grouse: Well, I've learned a lot today, and I'm sure our listeners would agree. Thank you so much for joining us. It's really been a pleasure speaking with you.  Dr Scholz: Well, thank you so much for allowing me to contribute. And, you know, I hope the review article conveys a lot of the exciting developments in this really challenging field. But there's loads of hope that we will eventually get to the point to tackle these conditions.  Dr Grouse: I encourage all of our listeners to check out Dr Scholz 's article. It is a great overview of these conditions and the genetics and neuropathology underlining them. Again, thank you so much.  Dr Scholz: Thank you for having me. Dr Grouse: Again, today I've been interviewing Dr Sonia Scholz, whose article on genetics and neuropathology of neurodegenerative dementias appears in the most recent issue of Continuum on dementia. Be sure to check out Continuum audio episodes from this and other issues. And thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

Matters Microbial #72: Who is in Your Water? January 2, 2025 Today, Dr. Ameet Pinto, Carlton S. Wilder Associate Professor in Civil and Environmental Engineering at the Georgia Institute of Technology, joins the #QualityQuorum to discuss the microbiome of drinking water and how it can be used to optimize safety and health.  Host: Mark O. Martin Guest: Ameet Pinto Subscribe: Apple Podcasts, Spotify Become a patron of Matters Microbial! Links for this episode A short review of a famous article by Dr. Norman Pace about the microbiome of showers and how microbial populations differed due to chlorination. An old discussion of microbial oligotrophy:  the ability to survive on very low levels of nutrients. The story of John Snow, a water fountain, and cholera in England. The concept of “Live/Dead” staining of microbes. An overview of the concept of metagenomics. An article on the microbiome of shower hoses. A public science outreach program to study the microbiome of showerheads. The Instagram link for Dr. Pinto's wonderful cat, Nessie. A great book describing exceptions to Mendelian genetics using cats:  “Cats Are Not Peas.”  Highly recommended. An article about water supplies and the pathogenic microbe Legionella. An overview of water disinfection techniques. An introduction to a model system of a microbial soil community, called THOR by Jo Handelsman and colleagues. Thinking of water treatment and related technologies as a series of ecological niches, via Tom Curtis and Bill Sloane. Dr. Pinto's faculty website. Dr. Pinto's deeply fascinating research group website. Intro music is by Reber Clark Send your questions and comments to mattersmicrobial@gmail.com

Send us a textLink to Health Type Quiz Link to Living Well, Aging Strong 6-month group experience As the holiday season approaches, the question of how much alcohol is too much becomes ever more pressing. What if the festive cheer of a drink or two could be clouded by the potential for long-term health risks? Dr. Bobby unpacks the complex and often contradictory research around alcohol, helping listeners navigate the decision: is it best to have none, or is a little okay? By exploring the impacts of alcohol on weight/appetite, heart disease, cancer, sleep, and cognitive health, and by considering personal health types, listeners can make more informed choices about their drinking habits. Key Topics Covered:Conflicting Headlines and Research: Discussing the confusion around alcohol's health effects, from Gallup poll insights to studies highlighting both potential benefits and risks.Health Risks Explored: Weight Gain: Alcohol adds calories and increases appetite, contributing to potential weight gain (study on caloric intake). Heart Disease: Early studies suggested moderate benefits for small amounts of alcohol, but advanced analyses, like Mendelian randomization, challenge this assumption, not showing a protective effect (study on genetic analysis). Cancer Risks: Alcohol consumption has been linked to several cancers, including breast and colon cancer.  (WHO fact sheet).Sleep Impacts: Alcohol disrupts sleep quality, even if consumed earlier in the day (small study on sleep effects).Cognitive Decline: Even mild drinking shows potential risks for brain health, with larger consumption exacerbating damage (UK Biobank study).Defining Drinking Levels: Categories from non-drinker to heavy drinking were clarified, helping listeners identify where they stand (National Survey on Drug Use and Health).Personal Stories and Practical Decisions: Dr. Bobby shares his personal experience with holiday indulgence and offers practical strategies for mindful drinking.Role of Health Types: Leveraging your health archetype (e.g., Purposeful Path Planner or Contentment Creator) to guide decisions about alcohol consumption.Takeaways:  Know Your Limits: For most, keeping alcohol under seven drinks per week minimizes risks without eliminating enjoyment.As we navigate the complexities of alcohol's impact on health, I share my personal approach of allowing myself up to seven drinks a week, accepting some level of risk for the sake of balance. With the Living Well Aging Strong program, we provide tools to create personalized health plans, empowering you to make choices that align with your lifestyle. Let's embark on this journey together, equipped with knowledge and support, as we strive for imp

Gregor Mendel was the father of modern genetics. He wrote his most important papers on the topic just a few years after Darwin published the Origin of Species. What people don't realize is that Mendel's papers did not only describe how traits are passed down. He also explained how his ideas of genetics lead directly to an explanation of the origin of species. Was Mendel directly and purposefully contradicting Darwin? Links and notes: Crompton et al. 2024 Mendelian speciation, part 1—what is the abundant source of significant biodiversity, J Creation 37(3):110–120, 2023. Crompton et al. 2024 Mendelian speciation, part 2—latent genetic information, J Creation 38(1):77–86, 2024. Crompton et al. 2024 Mendelian speciation, part 3—fixation and reproductive isolation, J Creation 382):97–104, 2024. Crompton et al. 2024 Mendelian speciation, part 4—adaptive radiations and cis-evolution, J Creation 38(2):105–112, 2024. Gregor Mendel on Wikipedia "They believe in bigger miracles than I do" on YouTube.com Species were designed to change on BiblicalGenetics.com Species were Designed to Change on Creation.com Arguments we think a creationist should not use on creation.com Wort und Wissen

Join us as we welcome back Dr. Veera Rajagopal, a discovery scientist at Regeneron with an interest in human genetics and drug target discovery in neuroscience and psychiatry. If you're a regular listener of The Genetics Podcast, you may be familiar with Dr. Veera's annual round-up episodes, and more recently, his quarterly appearances on the show. We're pleased to bring you the latest quarterly roundup, during which Dr. Veera and Patrick walk through the most recent developments in genetics, drug discovery, and precision medicine. In this episode, Dr. Veera and Patrick dive into a wide variety of topics, including: - The evolution of skin color in humans - The potential of a novel tau isoform for Alzheimer's treatment - Protective mechanisms of tomoregulin-1 against herpes simplex virus - The discovery of a new noncoding Mendelian disease mechanism linked to cardiac arrhythmias - A comparative analysis of whole genome versus whole exome sequencing for gene discovery. Tune in now, and don't forget to check out Veera's substack, GWAS Stories, and his Twitter, @doctorveera. Additionally, we're excited to invite you to an in-person meetup for The Genetics Podcast during the ASHG Annual Meeting in Denver, CO! Over the years, we've had the honor of speaking with leading voices across science, industry, patient advocacy, and policy. Now, we're bringing this incredible community together face-to-face. Join us on the evening of Thursday, November 7. To RSVP, visit: https://lu.ma/geneticspodASHG.

Today, you'll learn about the amazing transformative power of an out-of-body experience, how scientists want to use brain cells to do their computing, and a study that suggests eating cheese might make you live longer. Out-Of-Body Experience “Exploring the transformative potential of out-of-body experiences: A pathway to enhanced empathy.” by Marina Weiler, et al. 2024. “Out of body experiences and their neural basis.” by Olaf Blanke. 2004. Brain Cell Computing “Open and remotely accessible Neuroplatform for research in wetware computing.” by Fred D. Jordan, et al. 2024. “Neuromorphic wetware for artificial neural networks that overcome the limits of traditional computer hardware.” Innovation Toronto. 2023. “How Many Joules Does My Surge Protector Need?” by Karenann Brow. 2024. Cheese & Aging “Eating cheese plays a role in healthy, happy aging - who are we to argue?” by Bronwyn Thompson. 2024. “Mendelian randomization evidence for the causal effect of mental well-being on healthy aging.” by Chao-Jie Ye, et al. 2024. Follow Curiosity Daily on your favorite podcast app to get smarter with Calli and Nate — for free! Still curious? Get exclusive science shows, nature documentaries, and more real-life entertainment on discovery+! Go to https://discoveryplus.com/curiosity to start your 7-day free trial. discovery+ is currently only available for US subscribers. Hosted on Acast. See acast.com/privacy for more information.

Pradeep is a brilliant geneticist and Director of Preventive Cardiology, holds the Paul & Phyllis Fireman Endowed Chair in Vascular Medicine at Mass General Hospital and on faculty at Harvard Medical School and the Broad Institute. His prolific research has been illuminating for the field of improving our approach to reduce the risk of heart disease. That's especially important because heart disease is the global (and US) #1 killer and is on the increase. We didn't get into lifestyle factors here since there was so much ground to cover on new tests. drugs, and strategies.A video snippet of our conversation on ApoB. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to key publications and audioEric Topol (00:06):Well, welcome to Ground Truths. I'm Eric Topol and with me is Pradeep Natarajan from Harvard. He's Director of Preventative Cardiology at the Mass General Brigham Health System and he has been lighting it up on the field of cardiovascular. We're going to get to lots of different parts of that story and so, Pradeep welcome.Pradeep Natarajan (00:31):Thanks Eric, really delighted and honored to be with you and have this discussion.Eric Topol (00:36):Well, for years I've been admiring your work and it's just accelerating and so there's so many things to get to. I thought maybe what we'd start off with is you recently wrote a New England Journal piece about two trials, two different drugs that could change the landscape of cardiovascular prevention in the future. I mean, that's one of the themes we're going to get to today is all these different markers and drugs that will change cardiology as we know it now. So maybe you could just give us a skinny on that New England Journal piece.Two New Lipid Targets With RNA DrugsPradeep Natarajan (01:16):Yeah, yeah, so these two agents, the trials were published at the same time. These phase two clinical trials for plozasiran, which is an siRNA against APOC3 and zodasiran, which is an siRNA against ANGPTL3. The reason why we have medicines against those targets are based on human genetics observations, that individuals with loss of function mutations and either of those genes have reduced lipids. For APOC3, it's reduced triglycerides for ANGPTL3 reduced LDL cholesterol and reduced triglycerides and also individuals that have those loss of function mutations also have lower risk for coronary artery disease. Now that's a very similar parallel to PCSK9. We have successful medicines that treat that target because people have found that carriers of loss of function mutations in PCSK9 lead to lower LDL cholesterol and lower coronary artery disease.(02:11):Now that suggests that therapeutic manipulation without significant side effects from the agents themselves for APOC3 and ANGPTL3 would be anticipated to also lower coronary artery disease risk potentially in complementary pathways to PCSK9. The interesting thing with those observations is that they all came from rare loss of function mutations that are enriched in populations of individuals. However, at least for PCSK9, has been demonstrated to have efficacy in large groups of individuals across different communities. So the theme of that piece was really just the need to study diverse populations because those insights are not always predictable about which communities are going to have those loss of function mutations and when you find them, they often have profound insights across much larger groups of individuals.Eric Topol (03:02):Well, there's a lot there that we can unpack a bit of it. One of them is the use of small interfering RNAs (siRNA) as drugs. We saw in the field of PCSK9, as you mentioned. First there were monoclonal antibodies directed against this target and then more recently, there's inclisiran which isn't an RNA play if you will, where you only have to take it twice a year and supposedly it's less expensive and I'm still having trouble in my practice getting patients covered on their insurance even though it's cheaper and much more convenient. But nonetheless, now we're seeing these RNA drugs and maybe you could comment about that part and then also the surprise that perhaps is unexplained is the glucose elevation.Pradeep Natarajan (03:53):Yeah, so for medicines and targets that have been discovered through human genetics, those I think are attractive for genetic-based therapies and longer interval dosing for the therapies, which is what siRNAs allow you to do because the individuals that have these perturbations, basically the naturally occurring loss of function mutations, they have these lifelong, so basically have had a one-time therapy and have lived, and so far, at least for these targets, have not had untoward side effects or untoward phenotypic consequences and only reduce lipids and reduce coronary artery disease. And so, instead of taking a pill daily, if we have conviction that that long amount of suppression may be beneficial, then longer interval dosing and not worrying about the pill burden is very attractive specifically for those specific therapeutics. And as you know, people continue to innovate on further prolonging as it relates to PCSK9.(04:57):Separately, some folks are also developing pills because many people do feel that there's still a market and comfort for daily pills. Now interestingly for the siRNA for zodasiran at the highest dose, actually for both of them at the highest doses, but particularly for zodasiran, there was an increase in insulin resistance parameters actually as it relates to hyperglycemia and less so as it relates to insulin resistance, that is not predicted based on the human genetics. Individuals with loss of function mutations do not have increased risks in hyperglycemia or type 2 diabetes, so that isolates it related to that specific platform or that specific technology. Now inclisiran, as you'd mentioned, Eric is out there. That's an siRNA against PCSK9 that's made by a different manufacturer. So far, the clinical trials have not shown hyperglycemia or type 2 diabetes as it relates inclisiran, so it may be related to the specific siRNAs that are used for those targets. That does merit further consideration. Now, the doses that the manufacturers do plan to use in the phase three clinical trials are at lower doses where there was not an increase in hyperglycemia, but that does merit further investigation to really understand why that's the case. Is that an expected generalized effect for siRNAs? Is it related to siRNAs for this specific target or is it just related to the platform used for these two agents which are made by the same manufacturer?Eric Topol (06:27):Right, and I think the fact that it's a mystery is intriguing at the least, and it may not come up at the doses that are used in the trials, but the fact that it did crop up at high doses is unexpected. Now that is part of a much bigger story is that up until now our armamentarium has been statins and ezetimibe to treat lipids, but it's rapidly expanding Lp(a), which for decades as a cardiologist we had nothing to offer. There may even be drugs to be able to lower people who are at high risk with high Lp(a). Maybe you could discuss that.What About Lp(a)?Pradeep Natarajan (07:13):Yeah, I mean, Eric, as you know, Lp(a) has been described as a cardiovascular disease risk factors for quite so many years and there are assays to detect lipoprotein(a) elevation and have been in widespread clinical practice increasing widespread clinical practice, but we don't yet have approved therapies. However, there is an abundance of literature preclinical data that suggests that it likely is a causal factor, meaning that if you lower lipoprotein(a) when elevated, you would reduce the risk related to lipoprotein(a). And a lot of this comes from similar human genetic studies. The major challenge of just relating a biomarker to an outcome is there are many different reasons why a biomarker might be elevated, and so if you detect a signal that correlates a biomarker, a concentration to a clinical outcome, it could be related to that biomarker, but it could be to the other reasons that the biomarker is elevated and sometimes it relates to the outcome itself.(08:10):Now human genetics is very attractive because if you find alleles that strongly relate to that exposure, you can test those alleles themselves with the clinical outcome. Now the allele assignment is established at birth. No other factor is going to change that assignment after conception, and so that provides a robust, strong causal test for that potential exposure in clinical outcome. Now, lipoprotein(a) is unique in that it is highly heritable and so there are lots of different alleles that relate to lipoprotein(a) and so in a well powered analysis can actually test the lipoprotein(a) SNPs with the clinical outcomes and similar to how there is a biomarker association with incident myocardial infarction and incident stroke, the SNPs related to lipoprotein(a) show the same. That is among the evidence that strongly supports that this might be causal. Now, fast forward to many years later, we have at least three phase three randomized clinical trials testing agents that have been shown to be very potent at lowering lipoprotein(a) that in the coming years we will know if that hypothesis is true. Importantly, we will have to understand what are the potential side effects of these medicines. There are antisense oligonucleotides and siRNAs that are primarily in investigation. Again, this is an example where there's a strong genetic observation, and so these genetic based longer interval dosing therapies may be attractive, but side effects will be a key thing as well too. Those things hard to anticipate really can anticipate based on the human genetics for off target effects, for example.(09:52):It's clearly a risk signal and hopefully in the near future we're going to have specific therapies.Eric Topol (09:57):Yeah, you did a great job of explaining Mendelian randomization and the fact the power of genetics, which we're going to get into deeper shortly, but the other point is that do you expect now that there's these multiple drugs that lower Lp(a) efficiently, would that be enough to get approval or will it have to be trials to demonstrate improved cardiovascular outcomes?Pradeep Natarajan (10:24):There is a great regulatory path at FDA for approval just for LDL cholesterol lowering and inclisiran is on the market and the phase three outcomes data has not yet been reported because there is a wide appreciation that LDL cholesterol lowering is a pretty good surrogate for cardiovascular disease risk lowering. The label will be restricted to LDL cholesterol lowering and then if demonstrated to have clinical outcomes, the label could be expanded. For other biomarkers including lipoprotein(a), even though we have strong conviction that it is likely a causal factor there hasn't met the bar yet to get approval just based on lipoprotein(a) lowering, and so we would need to see the outcomes effects and then we would also need to understand side effects. There is a body of literature of side effects for other therapies that have targeted using antisense oligonucleotides. We talked about potential side effects from some siRNA platforms and sometimes those effects could overtake potential benefits, so that really needs to be assessed and there is a literature and other examples.(11:31):The other thing I do want to note related to lipoprotein(a) is that the human genetics are modeled based on lifelong perturbations, really hard to understand what the effects are, how great of an effect there might be in different contexts, particularly when introduced in middle age. There's a lot of discussion about how high lipoprotein(a) should be to deliver these therapies because the conventional teaching is that one in five individuals has high lipoprotein(a), and that's basically greater than 75 nanomoles per liter. However, some studies some human genetic studies to say if you want to get an effect that is similar to the LDL cholesterol lowering medicines on the market, you need to start with actually higher lipoprotein(a) because you need larger amounts of lipoprotein(a) lowering. Those are studies and approaches that haven't been well validated. We don't know if that's a valid approach because that's modeling based on this sort of lifelong effect. So I'm very curious to see what the overall effect will be because to get approval, I think you need to demonstrate safety and efficacy, but most importantly, these manufacturers and we as clinicians are trying to find viable therapies in the market that it won't be hard for us to get approval because hopefully the clinical trial will have said this is the context where it works. It works really well and it works really well on top of the existing therapies, so there are multiple hurdles to actually getting it directly to our patients.How Low Do You Go with LDL Cholesterol?Eric Topol (13:02):Yeah, no question about that. I'm glad you've emphasized that. Just as you've emphasized the incredible lessons from the genetics of people that have helped guide this renaissance to better drugs to prevent cardiovascular disease. LDL, which is perhaps the most impressive surrogate in medicine, a lab test that you already touched on, one of the biggest questions is how low do you go? That is Eugene Braunwald, who we all know and love. They're in Boston. The last time I got together with him, he was getting his LDL down to close to zero with various tactics that might be extreme. But before we leave these markers, you're running preventive cardiology at man's greatest hospital. Could you tell us what is your recipe for how aggressive do you go with LDL?Pradeep Natarajan (14:04):Yeah, so when I talk to patients where we're newly getting lipid lowering therapies on, especially because many people don't have a readout of abnormal LDL cholesterol when we're prescribing these medicines, it's just giving them a sense of what we think an optimal LDL cholesterol might be. And a lot of this is based on just empirical observations. So one, the average LDL cholesterol in the modern human is about 100 to 110 mg/dL. However, if you look at contemporary hunter gatherers and non-human primates, their average LDL is about 40 to 50 and newborn babies have an LDL cholesterol of about 30. And the reason why people keep making LDL cholesterol lowering medicines because as you stack on therapies, cardiovascular disease events continue to reduce including down to these very low LDL cholesterol values. So the population mean for LDL cholesterol is high and everybody likely has hypercholesterolemia, and that's because over the last 10,000 years how we live our lives is so dramatically different and there has not been substantial evolution over that time to change many of these features related to metabolism.(15:16):And so, to achieve those really low LDL cholesterol values in today's society is almost impossible without pharmacotherapies. You could say, okay, maybe everybody should be on pharmacotherapies, and I think if you did that, you probably would reduce a lot of events. You'll also be treating a lot of individuals who likely would not get events. Cardiovascular disease is the leading killer, but there are many things that people suffer from and most of the times it still is not cardiovascular disease. So our practice is still rooted in better identifying the individuals who are at risk for cardiovascular disease. And so, far we target our therapies primarily in those who have already developed cardiovascular disease. Maybe we'll talk about better identifying those at risk, but for those individuals it makes lots of sense to get it as low as possible. And the field has continued to move to lower targets.(16:07):One, because we've all recognized, at least based on these empirical observations that lower is better. But now increasingly we have a lot of therapies to actually get there, and my hope is that with more and more options and the market forces that influence that the cost perspective will make sense as we continue to develop more. As an aside, related aside is if you look at the last cholesterol guidelines, this is 2018 in the US this is the first time PCSK9 inhibitors were introduced in the guidelines and all throughout that there was discussions of cost. There are a lot of concerns from the field that PCSK9 inhibitors would bankrupt the system because so many people were on statins. And you look at the prior one that was in 2013 and cost was mentioned once it's just the cost effectiveness of statins. So I think the field has that overall concern.(17:01):However, over time we've gotten comfortable with lower targets, there are more medicines and I think some of this competition hopefully will drive down some of the costs, but also the overall appreciation of the science related to LDL. So long-winded way of saying this is kind of the things that we discussed just to give reassurance that we can go to low LDL cholesterol values and that it's safe and then we think also very effective. Nobody knows what the lower limit is, whether zero is appropriate or not. We know that glucose can get too low. We know that blood pressure can be too low. We don't know yet that limit for LDL cholesterol. I mean increasingly with these trials we'll see it going down really low and then we'll better appreciate and understand, so we'll see 40 is probably the right range.Eric Topol (17:49):40, you said? Yeah, okay, I'll buy that. Of course, the other thing that we do know is that if you push to the highest dose statins to get there, you might in some people start to see the hyperglycemia issue, which is still not fully understood and whether that is, I mean it's not desirable, but whether or not it is an issue, I guess it's still out there dangling. Now the other thing that since we're on LDL, we covered Lp(a), PCSK9, the siRNA, is ApoB. Do you measure ApoB in all your patients? Should that be the norm?Measuring ApoBPradeep Natarajan (18:32):Yeah, so ApoB is another blood test. In the standard lipid panel, you get four things. What's measured is cholesterol and triglycerides, they're the lipids insoluble in blood to get to the different tissues that get packaged in lipoprotein molecules which will have the cholesterol, triglycerides and some other lipids and proteins. And so, they all have different names as you know, right? Low density lipoprotein, high density lipoprotein and some others. But also in the lipid panel you get the HDL cholesterol, the amount of cholesterol in an HDL particle, and then most labs will calculate LDL cholesterol and LDL cholesterol has a nice relationship with cardiovascular disease. You lower it with statins and others. Lower risk for cardiovascular disease, turns out a unifying feature of all of these atherogenic lipoproteins, all these lipoproteins that are measured and unmeasured that relate to cardiovascular disease, including lipoprotein(a), they all have an additional protein called ApoB. And ApoB, at least as it relates to LDL is a pretty good surrogate of the number of LDL particles.(19:37):Turns out that that is a bit better at the population level at predicting cardiovascular disease beyond LDL cholesterol itself. And where it can be particularly helpful is that there are some patients out there that have an unexpected ratio between ApoB and LDL. In general, the ratio between LDL cholesterol and ApoB is about 1.1 and most people will have that rough ratio. I verify that that is the expected, and then if that is the expected, then really there is no role to follow ApoB. However, primarily the patients that have features related to insulin resistance have obesity. They may often have adequate looking LDL cholesterols, but their ApoB is higher. They have more circulating LDL particles relative to the total amount of LDL cholesterol, so smaller particles themselves. However, the total number of particles may actually be too high for them.(20:34):And so, even if the LDL cholesterol is at target, if the ApoB is higher, then you need to reduce. So usually the times that I just kind of verify that I'm at appropriate target is I check the LDL cholesterol, if that looks good, verify with the ApoB because of this ratio, the ApoB target should be about 10% lower. So if we're aiming for about 40, that's like 36, so relatively similar, and if it's there, I'm good. If it's not and it's higher, then obviously increase the LDL cholesterol lowering medicines because lower the ApoB and then follow the ApoB with the lipids going forward. The European Society of Cardiology has more emphasis on measuring ApoB, that is not as strong in the US guidelines, but there are many folks in the field, preventive cardiologists and others that are advocating for the increasing use of ApoB because I think there are many folks that are not getting to the appropriate targets because we are not measuring ApoB.Why Aren't We Measuring and Treating Inflammation?Eric Topol (21:37):Yeah, I think you reviewed it so well. The problem here is it could be part of the standard lipid panel, it would make this easy, but what you've done is a prudent way of selecting out people who it becomes more important to measure and moderate subsequently. Now this gets us to the fact that we're lipid centric and we don't pay homage to inflammation. So I wrote a recent Substack on the big miss on inflammation, and here you get into things like the monoclonal antibody to interleukin-6, the trial that CANTOS that showed significant reduction in cardiovascular events and fatal cancers by the way. And then you get into these colchicine trials two pretty good size randomized trials, and here the entry was coronary disease with a high C-reactive protein. Now somehow or other we abandon measuring CRP or other inflammatory markers, and both of us have had patients who have low LDLs but have heart attacks or significant coronary disease. So why don't we embrace inflammation? Why don't we measure it? Why don't we have better markers? Why is this just sitting there where we could do so much better? Even agents that are basically cost pennies like colchicine at low doses, not having to use a proprietary version could be helpful. What are your thoughts about us upgrading our prevention with inflammation markers?Pradeep Natarajan (23:22):Yeah, I mean, Eric, there is an urgent need to address these other pathways. I say urgent need because heart disease has the dubious distinction of being the leading killer in the US and then over the last 20 years, the leading killer in the world as it takes over non-communicable diseases. And really since the early 1900s, there has been a focus on developing pharmacotherapies and approaches to address the traditional modifiable cardiovascular disease risk factors. That has done tremendous good, but still the curves are largely flattening out. But in the US and in many parts of the world, the deaths attributable to cardiovascular disease are starting to tick up, and that means there are many additional pathways, many of them that we have well recognized including inflammation. More recently, Lp(a) that are likely important for cardiovascular disease, for inflammation, as you have highlighted, has been validated in randomized controlled trials.(24:18):Really the key trial that has been more most specific is one on Canakinumab in the CANTOS trial IL-1β monoclonal antibody secondary prevention, so cardiovascular disease plus high C-reactive protein, about a 15% reduction in cardiovascular disease and also improvement in cancer related outcomes. Major issues, a couple of issues. One was increased risk for severe infections, and the other one is almost pragmatic or practical is that that medicine was on the market at a very high price point for rare autoinflammatory conditions. It still is. And so, to have for a broader indication like cardiovascular disease prevention would not make sense at that price point. And the manufacturer tried to go to the FDA and focus on the group that only had C-reactive protein lowering, but that's obviously like a backwards endpoint. How would you know that before you release the medicine? So that never made it to a broader indication.(25:14):However, that stuck a flag in the broader validation of that specific pathway in cardiovascular disease. That pathway has direct relevance to C-reactive protein. C-reactive protein is kind of a readout of that pathway that starts from the NLRP3 inflammasome, which then activates IL-1β and IL-6. C-reactive protein we think is just a non causal readout, but is a reliable test of many of these features and that's debatable. There may be other things like measuring IL-6, for example. So given that there is actually substantial ongoing drug development in that pathway, there are a handful of companies with NLRP3 inflammasome inhibitors, but small molecules that you can take as pills. There is a monoclonal antibody against IL-6 that's in development ziltivekimab that's directed at patients with chronic kidney disease who have lots of cardiovascular disease events despite addressing modifiable risk factors where inflammatory markers are through the roof.(26:16):But then you would also highlighted one anti-inflammatory that's out there that's pennies on the dollar, that's colchicine. Colchicine is believed to influence cardiovascular disease by inhibiting NLRP3, I say believed to. It does a lot of things. It is an old medicine, but empirically has been shown in at least two randomized controlled trials patients with coronary artery disease, actually they didn't measure C-reactive protein in the inclusion for these, but in those populations we did reduce major adverse cardiovascular disease events. The one thing that does give me pause with colchicine is that there is this odd signal for increased non-cardiovascular death. Nobody understands if that's real, if that's a fluke. The FDA just approved last year low dose colchicine, colchicine at 0.5 milligrams for secondary prevention given the overwhelming efficacy. Hasn't yet made it into prevention guidelines, but I think that's one part that does give me a little bit pause. I do really think about it particularly for patients who have had recurrent events. The people who market the medicine and do research do remind us that C-reactive protein was not required in the inclusion, but nobody has done that secondary assessment to see if measuring C-reactive protein would be helpful in identifying the beneficial patients. But I think there still could be more work done on better identifying who would benefit from colchicine because it's an available and cheap medicine. But I'm excited that there is a lot of development in this inflammation area.Eric Topol (27:48):Yeah, well, the development sounds great. It's probably some years away. Do you use colchicine in your practice?Pradeep Natarajan (27:56):I do. Again, for those folks who have had recurrent events, even though C-reactive protein isn't there, it does make me feel like I'm treating inflammation. If C-reactive protein is elevated and then I use it for those patients, if it's not elevated, it's a much harder sell from my standpoint, from the patient standpoint. At the lower dose for colchicine, people generally are okay as far as side effects. The manufacturer has it at 0.5 milligrams, which is technically not pennies on the dollar. That's not generic. The 0.6 milligrams is generic and they claim that there is less side effects at the 0.5 milligrams. So technically 0.6 milligrams is off label. So it is what it is.CHIP and Defining High Risk People for CV DiseaseEric Topol (28:40):It's a lot more practical, that's for sure. Now, before I leave that, I just want to mention when I reviewed the IL-1β trial, you mentioned the CANTOS trial and also the colchicine data. The numbers of absolute increases for infection with the antibody or the cancers with the colchicine are really small. So I mean the benefit was overriding, but I certainly agree with your concern that there's some things we don't understand there that need to be probed more. Now, one of the other themes, well before one other marker that before we get to polygenic risk scores, which is center stage here, defining high risk people. We've talked a lot about the conventional things and some of the newer ways, but you've been one of the leaders of study of clonal hematopoiesis of indeterminate potential known as CHIP. CHIP, not the chips set in your computer, but CHIP. And basically this is stem cell mutations that increase in people as we age and become exceptionally common with different mutations that account in these clones. So maybe you can tell us about CHIP and what I don't understand is that it has tremendous correlation association with cardiovascular outcomes adverse as well as other system outcomes, and we don't measure it and we could measure it. So please take us through what the hell is wrong there.Pradeep Natarajan (30:14):Yeah, I mean this is really exciting. I mean I'm a little bit biased, but this is observations that have been made only really over the last decade, but accelerating research. And this has been enabled by advances in genomic technologies. So about 10 years or plus ago, really getting into the early days of population-based next generation sequencing, primarily whole exome sequencing. And most of the DNA that we collect to do these population-based analyses come from the blood, red blood cells are anucleate, so they're coming from white blood cells. And so, at that time, primarily interrogating what is the germline genetic basis for coronary artery disease and early onset myocardial infarction. At the same time, colleagues at the Broad Institute were noticing that there are many additional features that you can get from the blood-based DNA that was being processed by the whole exome data. And there were actually three different groups that converged on that all in Boston that converged on the same observation that many well-established cancer causing mutations.(31:19):So mutations that are observed in cancers that have been described to drive the cancers themselves were being observed in these large population-based data sets that we were all generating to understand the relationship between loss of function mutations in cardiovascular disease. That's basically the intention of those data sets for being generated for other things. Strong correlation with age, but it was very common among individuals greater than 70; 10% of them would have these mutations and is very common because blood cancer is extremely, it's still pretty rare in the population. So to say 10% of people had cancer causing driver mutations but didn't have cancer, was much higher than anyone would've otherwise expected. In 2014, there were basically three main papers that described that, and they also observed that there is a greater risk of death. You'd say, okay, this is a precancerous lesion, so they're probably dying of cancer.(32:17):But as I said, the absolute incidence rate for blood cancer is really low and there's a relative increase for about tenfold, but pretty small as it relates to what could be related to death. And in one of the studies we did some exploratory analysis that suggested maybe it's actually the most common cause of death and that was cardiovascular disease. And so, a few years later we published a study that really in depth really looked at a bunch of different data sets that were ascertained to really understand the relationship between these mutations, these cancer causing mutations in cardiovascular disease, so observed it in enrichment and older individuals that had these mutations, CHIP mutations, younger individuals who had early onset MI as well too, and then also look prospectively and showed that it related to incident coronary artery disease. Now the major challenge for this kind of analysis as it relates to the germline genetic analysis is prevalence changes over time.(33:15):There are many things that could influence the presence of clonal hematopoiesis. Age is a key enriching factor and age is the best predictor for cardiovascular disease. So really important. So then we modeled it in mice. It was actually a parallel effort at Boston University (BU) that was doing the same thing really based on the 2014 studies. And so, at the same time we also observed when you modeled this in mice, you basically perturb introduce loss of function mutations in the bone marrow for these mice to recapitulate these driver mutations and those mice also have a greater burden of atherosclerosis. And Eric, you highlighted inflammation because basically the phenotype of these cells are hyper inflamed cells. Interestingly, C-reactive protein is only modestly elevated. So C-reactive protein is not fully capturing this, but many of the cytokines IL-1β, IL-6, they're all upregulated in mice and in humans when measured as well.(34:11):Now there've been a few key studies that have been really exciting about using anti-inflammatories in this pathway to address CHIP associated cardiovascular disease. So one that effort that I said in BU because they saw these cytokines increased, we already know that these cytokines have relationship with atherosclerosis. So they gave an NLRP3 inflammasome inhibitor to the mice and they showed that the mice with or without CHIP had a reduction in atherosclerosis, but there was a substantial delta among the mice that are modeled as having CHIP. Now, the investigators in CANTOS, the manufacturers, they actually went back and they survey where they had DNA in the CANTOS trial. They measured CHIP and particularly TET2 CHIP, which is the one that has the strongest signal for atherosclerosis. As I said, overall about 15% reduction in the primary outcome in CANTOS. Among the individuals who had TET2 CHIP, it was a 64% reduction in event.(35:08):I mean you don't see those in atherosclerosis related trials. Now this has the caveat of it being secondary post hoc exploratory, the two levels of evidence. And so, then we took a Mendelian randomization approach. Serendipitously, just so happens there is a coding mutation in the IL-6 receptor, a missense mutation that in 2012 was described that if you had this mutation, about 40% of people have it, you have a 5%, but statistically significant reduction in coronary artery disease. So we very simply said, if the pathway of this NLRP3 inflammasome, which includes IL-6, if you have decreased signaling in that pathway, might you have an even greater benefit from having that mutation if you had CHIP versus those who didn't have CHIP. So we looked in the UK Biobank, those who didn't have CHIP 5% reduction, who had that IL-6 receptor mutation, and then those who did have CHIP, if they had that mutation, it was about a 60% reduction in cardiovascular disease.(36:12):Again, three different lines of evidence that really show that this pathway has relevance in the general population, but the people who actually might benefit the most are those with CHIP. And I think as we get more and more data sets, we find that not all of the CHIP mutations are the same as it relates to cardiovascular disease risk. It does hone in on these key subsets like TET2 and JAK2, but this is pretty cool as a preventive cardiologist, new potential modifiable risk factor, but now it's almost like an oncologic paradigm that is being applied to coronary artery disease where we have specific driver mutations and then we're tailoring our therapies to those specific biological drivers for coronary artery disease. Hopefully, I did that justice. There's a lot there.Why Don't We Measure CHIP?Eric Topol (36:57):Well, actually, it's phenomenal how you've explained that, but I do want to review for our listeners or readers that prior to this point in our conversation, we were talking about germline mutations, the ones you're born with. With CHIP, we're talking about acquired somatic mutations, and these are our blood stem cells. And what is befuddling to me is that with all the data that you and others, you especially have been publishing and how easy it would be to measure this. I mean, we've seen that you can get it from sequencing no less other means. Why we don't measure this? I mean, why are we turning a blind eye to CHIP? I just don't get it. And we keep calling it of indeterminate potential, not indeterminate. It's definite potential.Pradeep Natarajan (37:51):Yeah, no, I think these are just overly cautious terms from the scientists. Lots of people have CHIP, a lot of people don't have clinical outcomes. And so, I think from the lens of a practicing hematologists that provide some reassurance on the spectrum for acquired mutation all the way over to leukemia, that is where it comes from. I don't love the acronym as well because every subfield in biomedicine has its own CHIP, so there's obviously lots of confusion there. CH or clinical hematopoiesis is often what I go, but I think continuing to be specific on these mutations. Now the question is why measure? Why aren't we measuring it? So there are some clinical assays out there. Now when patients get evaluated for cytopenias [low cell counts], there are next generation sequencing tests that look for these mutations in the process for evaluation. Now, technically by definition, CHIP means the presence of these driver mutations that have expanded because it's detectable by these assays, not a one-off cell because it can only be detected if it's in a number of cells.(38:55):So there has been some expansion, but there are no CBC abnormalities. Now, if there's a CBC abnormality and you see a CHIP mutation that's technically considered CCUS or clonal cytopenia of unknown significance, sometimes what is detected is myelodysplastic syndrome. In those scenarios still there is a cardiovascular disease signal, and so many of our patients who are seen in the cancer center who are being evaluated for these CBC abnormalities will be detected to have these mutations. They will have undergone some risk stratification to see what the malignancy potential is. Still pretty low for many of those individuals. And so, the major driver of health outcomes for this finding may be cardiovascular. So those patients then get referred to our program. Dana-Farber also has a similar program, and then my colleague Peter Libby at the Brigham often sees those patients as well. Now for prospective screening, so far, an insurance basically is who's going to pay for it.(39:51):So an insurance provider is not deemed that appropriate yet. You do need the prospective clinical trials because the medicines that we're talking about may have side effects as well too. And what is the yield? What is the diagnostic yield? Will there actually be a large effect estimate? But there has been more and more innovation, at least on the assay and the cost part of the assay because these initial studies, we've been using whole exome sequencing, which is continuing to come down, but is not a widely routine clinical test yet. And also because as you highlighted, these are acquired mutations. A single test is not necessarily one and done. This may be something that does require surveillance for particular high risk individuals. And we've described some risk factors for the prevalence of CHIP. So surveillance may be required, but because there are about 10 genes that are primarily implicated in CHIP, that can substantially decrease the cost of it. The cost for DNA extraction is going down, and so there are research tests that are kind of in the $10 to $20 range right now for CHIP. And if flipped over to the clinical side will also be reasonably low cost. And so, for the paradigm for clinical implementation, that cost part is necessary.Eric Topol (41:10):I don't know the $10 or $20 ones. Are there any I could order on patients that I'm worried about?Pradeep Natarajan (41:17):Not yet clinical. However, there is a company that makes the reagents for at least the cores that are developing this. They are commercializing that test so that many other cores, research cores can develop it. I think it's in short order that clinical labs will adopt it as well too.Eric Topol (41:36):That's great.Pradeep Natarajan (41:37):I will keep you apprised.What About Polygenic Risk Scores?Eric Topol (41:39):I think that's really good news because like I said, we're so darn lipid centric and we have to start to respect the body of data, the knowledge that you and others have built about CHIP. Now speaking of another one that drives me nuts is polygenic risk score (PRS) for about a decade, I've been saying we have coronary disease for most people is a polygenic trait. It's not just a familial hypercholesterolemia. And we progressively have gotten better and better of the hundreds of single variants that collectively without a parental history will be and independently predict who is at double, triple or whatever risk of getting heart disease, whereby you could then guide your statins at higher aggressive or pick a statin, use one or even go beyond that as we've been talking about. But we don't use that in practice, which is just incredible because it's can be done cheap.(42:45):You can get it through whether it's 23andMe or now many other entities. We have an app, MyGeneRank where we can process that Scripss does for free. And only recently, Mass General was the first to implement that in your patient population, and I'm sure you were a driver of that. What is the reluctance about using this as an orthogonal, if you will, separate way to assess a person's risk for heart disease? And we know validated very solidly about being aggressive about lipid lowering when you know this person's in the highest 5% polygenic risk score. Are we just deadheads in this field or what?Pradeep Natarajan (43:30):Yeah, I mean Eric, as you know, lots of inertia in medicine, but this one I think has a potential to make a large impact. Like CHIP mutations, I said news is about 10% in individuals greater than 70. The prospect here is to identify the risk much earlier in life because I think there is a very good argument that we're undertreating high risk individuals early on because we don't know how to identify them. As you highlighted, Dr. Braunwald about LDL cholesterol. The other part of that paradigm is LDL cholesterol lowering and the duration. And as we said, everybody would benefit from really low LDL cholesterol, but again, you might overtreat that if you just give that to everybody. But if you can better identify the folks very early in life, there is a low cost, low risk therapy, at least related to statins that you could have a profound benefit from the ones who have a greater conviction will have future risk for cardiovascular disease.(44:21):You highlighted the family history, and the family history has given the field of clues that genetics play a role. But as the genome-wide association studies have gotten larger, the polygenic risk scores have gotten better. We know that family history is imperfect. There are many reasons why a family member who is at risk may or may not have developed cardiovascular disease. A polygenic risk score will give a single number that will estimate the contribution of genetics to cardiovascular disease. And the thing that is really fascinating to me, which is I think some of a clinical implementation challenge is that the alleles for an individual are fixed. The genotyping is very cheap. That continues to be extremely cheap to do this test. But the weights and the interpretation of what the effects should be for each of the SNPs are continually being refined over time.(45:18):And so, given the exact same SNPs in the population, the ability to better predict cardiovascular diseases getting better. And so, you have things that get reported in the literature, but literally three years later that gets outdated and those hypotheses need to be reassessed. Today, I'll say we have a great relative to other things, but we have a great polygenic risk score was just reported last year that if you compare it to familial hypercholesterolemia, which has a diagnostic yield of about 1 in 300 individuals, but readily detectable by severe hypercholesterolemia that has about threefold risk for cardiovascular disease. By polygenic risk score, you can find 1 in 5 individuals with that same risk. Obviously you go higher than that, it'll be even higher risk related to that. And that is noble information very early in life. And most people develop risk factors later in life. It is happening earlier, but generally not in the 30s, 40s where there's an opportunity to make a substantial impact on the curve related to cardiovascular disease.(46:25):But there is a lot of momentum there. Lots of interest from NIH and others. The major challenge is though the US healthcare system is really not well set up to prevention, as you know, we practice healthcare after patient's developed disease and prevent the complications related to progression. The stakeholder incentives beyond the patient themselves are less well aligned. We've talked a lot here today about payers, but we don't have a single payer healthcare system. And patients at different times of their lives will have different insurers. They'll start early in life with their parents, their first employer, they'll move on to the next job and then ultimately Medicare. There's no entity beyond yourself that really cares about your longevity basically from the beginning and your overall wellness. That tension has been a major challenge in just driving the incentives and the push towards polygenic risk scores. But there are some innovative approaches like MassMutual Life Insurance actually did a pilot on polygenic risk scoring.(47:33):They're in the business of better understanding longevity. They get that this is important data. Major challenges, there are federal protections against non-discrimination in the workplace, health insurance, not necessarily life insurance. So I think that there are lots of things that have to be worked out. Everybody recognizes that this is important, but we really have to have all the incentives aligned for this to happen at a system-wide level in the US. So there's actually lots of investment in countries that have more nationalized healthcare systems, lots of development in clinical trials in the UK, for example. So it's possible that we in the US will not be the lead in that kind of evidence generation, but maybe we'll get there.The GLP-1 DrugsEric Topol (48:16):Yeah, it's frustrating though, Pradeep, because this has been incubating for some time and now we have multi ancestry, polygenic risk scores, particularly for heart disease and we're not using it, and it's not in my view, in the patient's best interest just because of these obstacles that you're mentioning, particularly here in the US. Well, the other thing I want to just get at with you today is the drugs that we were using for diabetes now blossoming for lots of other indications, particularly the glucagon-like peptide 1 (GLP-1) drugs. This has come onto the scene in recent years, not just obviously for obesity, but it's anti-inflammatory effects as we're learning, mediated not just through the brain but also T cells and having extraordinary impact in heart disease for people with obesity and also with those who have heart failure, about half of heart failure for preserved ejection fraction. So recently you and your colleagues recently published a paper with this signal of optic neuropathy. It was almost seven eightfold increase in a population. First, I wanted to get your sense about GLP-1. We're also going to get into the SGLT2 for a moment as well, but how do you use GLP-1? What's your prognosis for this drug class going forward?Pradeep Natarajan (49:55):As it relates to the paper, I can't claim credit as one of my former students who is now Mass Eye and Ear resident who participated, but we can talk about that. There's obviously some challenges for mining real world data, but this was related to anecdotes that they were observing at Mass Eye and Ear and then studied and observed an enrichment. In general though, I feel like every week I'm reading a new clinical trial about a new clinical outcome benefit as it relates to GLP-1 receptor agonists. This is kind of one thing that stands out that could be interrogated in these other clinical trials. So I would have that caveat before being cautious about ocular complications. But the data has been overwhelmingly beneficial, I think, because at minimum, obesity and inflammation are relayed to myriad of consequences, and I'm really excited that we have therapies that can address obesity that are safe.(50:52):There's a legacy of unsafe medicines for obesity, especially related to cardiovascular disease. So the fact that we have medicines that are safe and effective for lowering weight that also have real strong effects on clinical outcomes is tremendous. We in cardiology are increasingly using a range of diabetes medicines, including GLP-1 receptor agonists and SGLT2 inhibitors. I think that is also the secular changes of what influences cardiovascular disease over time. I talked about over the last 10 years or so with this increase in deaths attributable to cardiovascular disease. If you look at the influences of traditional clinical risk factors today, many of them have decreased in importance because when abnormal, we recognize them, in general we modify them when recognized. And so, many of the things that are unaddressed, especially the features related to insulin resistance, obesity, they start rising in importance. And so, there is a dramatic potential for these kinds of therapies in reducing the residual risks that we see related to cardiovascular disease. So I'm enthusiastic and excited. I think a lot more biology that needs to be understood of how much of this is being influenced specifically through this pathway versus a very effective weight loss medicine. But also interesting to see the insights on how the effect centrally on appetite suppression has profound influences on weight loss as well too. And hopefully that will lead to more innovations in weight management.The SGLT-2 DrugsEric Topol (52:25):And likewise, perhaps not getting near as much play, but when it came on the cardiovascular scene that an anti-diabetic drug SGLT2 was improving survival, that was big, and we still don't know why. I mean, there's some ideas that it might be a senolytic drug unknowingly, but this has become a big part of practice of cardiology in patients with diabetes or with preserved ejection fraction heart failure. Is that a fair summary for that drug?Pradeep Natarajan (53:00):Yeah, I totally agree. I mean, as there has been increased recognition for heart failure preserved ejection fraction, it has been almost disheartening over the last several years that we have not had very specific effective therapies to treat that condition. Now, it is a tremendous boon that we do have medicines interestingly focused on metabolism that are very helpful in that condition for heart failure with preserved ejection fraction. But there is still much more to be understood as far as that condition. I mean, the major challenge with heart failure, as you know, especially with heart failure preserved ejection fraction, it likely is a mix of a wide variety of different etiologies. So in parallel with developing effective therapies that get at some aspect is really understanding what are the individual drivers and then targeting those specific individual drivers. That requires a lot of unbiased discovery work and further profiling to be done. So lot more innovation, but relative to heart failure itself, it is not had widespread recognition as heart failure reduced ejection fraction. So much more to innovate on, for sure.Eric Topol (54:07):Right, right. Yeah, I am stunned by the recent progress in cardiovascular medicine. You have been center stage with a lot of it, and we've had a chance to review so much. And speaking of genetics, I wanted to just get a little insight because I recently came across the fact that your mother here at the City of Hope in Southern California is another famous researcher. And is that, I don't know what chromosome that is on regarding parental transmission of leading research. Maybe you can tell me about that.Pradeep Natarajan (54:41):Yeah, I mean, I guess it is a heritable trait when a parent has one profession that there is a higher likelihood that the offspring will have something similar. So both of my parents are PhDs, nonphysicians. There is a diabetes department at the City of Hope, so she's the chair of that department. So very active. We do overlap in some circles because she does investigate both vascular complications and renal complications. And then sometimes will ask my advice on some visualization. But she herself has just had a science translational medicine paper, for example, just a couple of months ago. So it's fun to talk about these things. To be honest, because my parents are researchers, I was not totally sure that I would be a researcher and kind of wanted to do something different in medicine. But many of my early observations and just how common cardiovascular disease is around me and in my community and wanting to do something useful is what got me specifically into cardiology.(55:45):But obviously there are numerous outstanding, important questions. And as I went through my career, really focused on more basic investigations of atherosclerosis and lipids. What got me excited sort of after my clinical training was the ability to ask many of these questions now in human populations with many new biological data sets, at least first centered on genetics. And the capabilities continue to expand, so now I teach first year Harvard medical students in their genetics curriculum. And when I talk to them just about my career arc, I do remind them they're all doing millions of things and they're exploring lots of things, but when they get to my shoes, the capabilities will be tremendously different. And so, I really advise them to take the different experiences, mainly in an exercise for asking questions, thoughtfully addressing questions, connecting it back to important clinical problems. And then once they start to understand that with a few different approaches, then they'll totally take off with what the opportunities are down the road.Eric Topol (56:51):No, it's great. I mean, how lucky somebody could be in the first year of med school with you as their teacher and model. Wow. Pradeep, we've really gone deep on this and it's been fun. I mean, if there's one person I'm going to talk to you about cardiovascular risk factors and the things that we've been into today, you would be the one. So thank you for taking the time and running through a lot of material here today, and all your work with great interest.Pradeep Natarajan (57:24):Thanks, Eric. I really appreciate it. It's tremendous honor. I'm a big fan, so I would be glad to talk about any of these things and more anytime.***************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informative!Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

An introduction to classical Mendelian genetics, in which we discuss Mendel's experiments with peas and the laws of heredity that he discovered, including inheritance of one allele from each parent, the law of dominance, and the law of independent segregation. We then consider more complex cases of genetic inheritance, including sex-linked traits, incomplete dominance, codominance, and epistasis. The episode concludes with a discussion of quantitative traits determined by many genes, including how genetic variation is described, how sources of variance are identified using genome wide association studies, and the conceptual issues with defining heredity and separating the effects of genes from those of environment.   If you enjoyed the podcast please consider supporting the show by making a PayPal donation or becoming a Patreon supporter. https://www.patreon.com/jamesfodor https://www.paypal.me/ScienceofEverything Check out out youtube channel! The Science of Everything Podcast - YouTube

Discover the connection between muscle mass, lipids, and cardiovascular health with Dr. Richie Kirwan!

Wenig Zeit - trotzdem neugierig? Hier ist Euer Podcast Update für alles, was Ihr zu aktueller Forschung wissen müsst. Kurz, relevant und überraschend. Die Themen in dieser Podcast Folge: (00:00:38) Woher kommt das Wasser auf der Erde? Recurrent planetesimal formation in an outer part of the early solar system https://www.nature.com/articles/s41598-024-63768-4 (00:02:25) Wie Bakterien kommunizieren Pneumococcal competence is a populational health sensor driving multilevel heterogeneity in response to antibiotics https://www.nature.com/articles/s41467-024-49853-2 (00:04:01) Armut und psychische Krankheiten hängen zusammen Investigating the impact of poverty on mental illness in the UK Biobank using Mendelian randomization https://www.nature.com/articles/s41562-024-01919-3 Wir freuen uns, von Euch zu hören: WhatsApp oder iq@br.de

The consumption of red meat, specifically the distinction between unprocessed and processed varieties, has been a subject of considerable debate in nutritional science and public health. There is a fair amount of confusion and lack of clarity surrounding this issue. While the harmful effects of processed meat are well-documented and less controversial, the evidence concerning unprocessed red meat is less consistent. This inconsistency often leads to a gray area in scientific discussions and public perception. In examining unprocessed red meat, we encounter a spectrum of claims, including minimal evidence of harm, context of overall diet and mechanistic concerns. Epidemiological evidence shows varied health outcomes related to red meat consumption across different populations. These variations underline the importance of defining and measuring “high” and “low” intake levels accurately in research. The challenges in nutrition research, including methodological flaws in meta-analyses and the rapid dissemination of simplified study results, can impact public health recommendations. Misinterpretations can arise from comparisons within narrow intake ranges or from studies failing to specify absolute intake levels. This podcast episode's goal is to clarify existing evidence, acknowledge areas needing further research, and explore why this topic is significant in the broader context of nutrition science, aiming to equip healthcare professionals with the knowledge needed to make nuanced and effective dietary recommendations. Links: Receive our free weekly email: the Sigma Synopsis Want to advance your understanding of nutrition science? Check out our course. Go to episode page for this episode Subscribe to Sigma Nutrition PREMIUM Timestamps 01:00 Introduction to the issue 03:16 Processed vs. unprocessed red meat 05:54 Health guidelines and recommendations 06:56 Epidemiological evidence and dose thresholds 09:55 Biological mechanisms and plausibility 21:00 Criticisms and misinterpretations in research 40:42 Substitution analyses and dietary patterns 46:37 Mendelian randomization and genetic studies 56:31 Effect modifiers and confounders 01:13:18 Key Ideas Segment (Premium-only)

A book that reads like a novel; it's humorous, it's a love story. Dr. Christopher Labos, an imaginative cardiologist and epidemiologist at McGill University, takes us through multiple longstanding misconceptions about different foods and drinks, and along the way provides outstanding educational value.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with external links and links to the audio recordingEric Topol (00:07):Hello, it's Eric Topol with Ground Truths, and with me today is a cardiologist, Chris Labos from Montreal, who has written an extraordinary book. I just read it on my Kindle, “Does Coffee Cause Cancer? And 8 More Myths about the Food We Eat. Chris teaches at McGill University. He is a prolific writer at the Montreal Gazette and Canadian broadcast system, CBC, CJAD radio, CTV News. And he also has a podcast on the Body of Evidence and he probably has other stuff, but welcome Chris.Christopher Labos (00:49):Hello. Hello. Hello. Thank you for having me. It is a great honor to be on your podcast. I am in awe of the work that you've been doing, I mean, for all your career, but especially during Covid. So it's a big thrill for me to be on the podcast.Eric Topol (01:03):Well, for me, I have to say I learned about a person who is not only remarkably imaginative but also humorous. And so, have you ever done standup comedy?Christopher Labos (01:16):I have not. Although I was asked to chair the research awards that we did here at McGill one year because I've been doing local media stuff and they said, can you come and be like the MC? And I said, sure. And I said, do you want me to be funny? And they were like, well, if you can. And I went up there and people were laughing and laughing and laughing and then people, like some of my former attendings had come up to me and they're like, Chris, I don't remember you being this funny as a resident. And I was like, well, I guess you come into your own when you start your own career. But I think people were very, it's tough MCing a research awards because you're essentially, it's kind of like a high school graduation where you don't read the names in alphabetical order, right? It's like one name after the other. And I went up there and I tried to throw in a little bit of humor and people seem to like it. So I think that was the first, that was when I started to realize, oh, if you inject a little bit of levity into what you're doing, it tends to resonate a little bit more with people.Eric Topol (02:13):Well, no question about that. And what I love about this book is that it wasn't anything like I thought it was going to be.Eric Topol (02:21):Amazing. It was a surprise. So basically you took these nine myths, which we'll talk to, hopefully we'll get to several of them, but you didn't just get into that myth. You get into teaching medical statistics, how to read papers, all the myths. I mean, you are the master debunker with entertainment, with funny stuff. It's really great. So this is great, before we get into some of these myths and for you to amplify, but this is a gift of communication, science communication that is you get people to learn about things like p-hacking and you throw in love stories and all kinds of stuff. I mean, I don't know how you can dream this stuff up. I really don't.Christopher Labos (03:10):I sort of look back at the inception of this. This book did have sort of a few iterations. And I think the first time I was thinking about it, I mean I wrote it during Covid and so I was really thinking about this type of stuff. It's like how do we educate the public to become better consumers of scientific information? Because there was a lot of nonsense during Covid. So teaching them about confounding, which I think through a lot of people when we started talking about low vitamin D levels and Covid and outcomes and all that. And so, I started like, how do I write this type of book? And I thought, yeah, this should probably be a serious science book. And the first version of it was a very serious science book. And then the idea came and try to make it a conversation. And I think I sort of wrote it.(04:02):There's a book that may not be that popular in the US but it was kind of popular here in Canada. It was called The Wealthy Barber. And it was all about personal finance. And the idea of the book was these people would go into a barbershop and the barber would talk to them about how to save money and how to invest in all that. And it was fairly popular and people liked that back and forth. And I said, oh, maybe I could do something like that. And then I wrote the first chapter of the doctor who goes in to talk to the barista and I showed it to a friend of mine. I said, what do you think? Do you think this would work? And her response to me by email was two lines. It was pretty good period. But I kept expecting him to ask her out at the end. And the minute she said that I thought, oh my God, this is a love story. And so, I reshaped everything to make this a love story. And I don't think the publishers were expecting that either because they were like, the first comment from the editor was, most science books don't have a narrative arc to them in character, but this one does. So there you go.Eric Topol (05:00):This is a unique book. I hope that people who listen or read the transcript will realize that this is a gift. It's a model of communication and it just is teaching things almost like you don't realize it. You're just learning all this stuff. So let's get into some of these because they're just masterful. I guess I should start ask you, you have nine of them. You could have picked 20 more, but which one is your favorite? Or do you have one?Christopher Labos (05:31):I think the one, it's hard to say. I think the first one in the book is the vitamin C one. And I think it's the most interesting one to explain to people, not just because vitamin C to fight the common cold is so pervasive as a product and a thing that people believe. But it also, I think has the greatest opportunity to teach people about what is one of the most important ones, which is subgroup analysis and p-hacking. And it's so easy to bring that back into a comedic level with some of the graphs that I put in there. I think a close second would probably be the coffee one where I was talking about selection bias, because those examples of online dating and then all the jokes that came from it. And it's hard to say how much of it was the subject and how much of it was the character.(06:21):Because I'd always heard stories of authors when they say like, oh, the characters will tell me what to say. And I always thought that sounds like bollocks. How could that be possible? You're the author, you write what's on the page. But then the minute I started actually writing it and started envisaging these characters, all of a sudden the characters took on a life of their own and they were dictating how the story ended up. So the coffee one I think is also good too. And I guess it became the title of the book. So I guess that's a good indication that was popular. But when you can really spin it out and make it obvious to people using common examples, I think those are interesting ones. So the vitamin C and the coffee ones, I think were probably the most interesting.Eric Topol (07:02):Let's take those first because you've mentioned them and then hopefully we'll get into some others. Now in the vitamin C, you're going on a plane and you hook up with this guy, Jim, on the plane. I know none of this stuff really happened, and you're explaining to him the famous ISIS-2 trial about the Gemini and Libra subgroup. So for those of people who are listening, can you review that? Because that of course is just one of so many things you get into.Christopher Labos (07:33):I know it's almost amazing how short a memory we have in medicine, right? And again, this is sort of surprising me. I sort of knew the study and then I went back, and I looked at it and I thought ISIS-2 was in 1988. That's not that long ago. The fact that we didn't give aspirin. So for people who don't know, I mean, we did not give aspirin to people with cardiac disease for a very long time. And it was really from 1988 afterwards. So relatively recently, I mean I realized it's been a couple of decades, but still. So ISIS-2 was really the first trial to show that if you give aspirin to somebodywhen they're having a heart attack, you see a benefit. But what was fascinating in the study was this one subgroup analysis of people in whom it did not work.(08:19):And when I give public lectures, I often use this example because it's such a beautiful teaching case, and I go ask people, what do you think it was? And people are like, oh, hemophiliacs, smokers, people who drink alcohol. And then you find out, no, the subgroup in whom aspirin does not work is Geminis and Libras. And everybody sort of laughs and they think it's funny. And it's a beautiful example because a lot of people think it's like, oh, it was a joke or it was sort of silly science. But no, it was actually done purposefully. And the authors put that in there because they wanted to make the point that subgroup analysis are potentially misleading. And I sort of am a little bit in awe of, I mean the power or the intelligence to actually make it a point with the editors like, no, we're going to put this in here essentially as a teaching tool.(09:09):And it's amazing to me that we're still using it as a teaching tool decades after the fact. But it was just to show that when you have these tables where you have umpteen subgroup analysis, just by random chance, you will get some spurious results. And though our brain understands that Zodiac signs have nothing to do with the effectiveness of aspirin, you do the same subgroup analysis and diabetics and non-diabetics, and everybody was like, oh yeah, that's plausible. And yeah, it might be, but the computer doesn't know the difference, right. To the computer these are all ones and zeros. So if you don't go into it with a healthy skepticism about the limitations of subgroup analysis, you will eventually get fooled. And the problem with vitamin C research is I think a lot of very smart people have gotten fooled on this because they're like, well, overall the data is negative, but if we slice it up, we can find something that's positive. So maybe there's something here. And the number of people who have fallen in that trap over the years is unfortunately quite high.Eric Topol (10:10):No, and it's still happening and it is a famous subgroup story, but I just want to remind everybody that this was in the chapter on vitamin C and it's going into aspirin and subgroups. So each one of these chapters is not confined to the myth. They go into all sorts of other teaching examples in a humorous and fun way through conversations. Here it was with Jim on the plane. Now another one you mentioned, I forgot about this one. In the British Medical Journal, there was a paper, the Miracle of DICE Therapy.Christopher Labos (10:45):Miracle of DICE Therapy. Yeah, that's another brilliant one, because again, you couldn't do a study like this today, but basically for people who aren't aware of the paper, I mean, I think it was published in the Christmas issue. So again, just to show you how sometimes even in medical science, the humor is really, really effective. So what researchers did was they went to this neurology conference and they got all the people to participate in this live study, and they gave them dice and said, you're going to roll these dice. And they had white, red, and green dice and said, the exercise is for all of you to roll this dice and then analyze the data and tell us which color dice is off which one has been weighted. Because if you roll a one, two, three, four, or five, the patient has survived their stroke. If they roll a six, the patient died of their stroke.(11:33):So you go, you roll these dice dozens of times, generate your data. I mean, what we would do today with a random number generator but they were rolling dice. And they said, you figure out which of these dice is skewed. And so, the people at the conference went, they rolled their dice, they crunched their data, and they said, the red dice are skewed. There's a difference between the red dice and the white and green dice. And then the researchers revealed aha jokes on you. All the dice were the same. And the funniest part about that is that a lot of the people in the room didn't believe them. They refused to believe them that the dice were weighted because, and one of my favorite quotes was when student A refused to believe that his days were really loaded, he rolled one six and then a second and then a third, and he said, the room felt eerily quiet as he rolled a fourth six.(12:25):He had never rolled four sixes in a row in his life. And if you're there, I mean, yeah, you're going to be like, how do you doubt the power of your own eyes? You roll four sixes in a row, you think to yourself, gee, this must be the loaded dice. But that thing would happen. You put enough people in a room rolling enough dice, you will eventually get four sixes in a row in the same way that if you put enough monkeys in front of enough typewriters, eventually you're going to get all the works of William Shakespeare. So it's shocking how much our own human biases make us immune to the realization that random things are going to happen. And there was another, I think there was a quote in that paper too, where doctors are very willing to admit that chance affects whether they win a raffle, but they are surprisingly unwilling to admit that chance can affect the results of their medical research. And we don't appreciate it, even though, I mean, the reality is it happens all the time and we don't take the necessary steps to fix it sometimes and to address it, and we keep making the same mistakes over and over again.Eric Topol (13:32):Yeah, no, that's a great paper to illustrate. Again, a lot of important teaching points. Now as we get into the coffee, does it cause cancer? It brings up another theme in the book that I noticed. What you do is you pick up on papers or broadcasts that were decades ago that have become inculcated in our minds and our thoughts. And in this case, it was a famous New England Journal paper in 1981 raising the question about does coffee, if you drink too much coffee is that a risk factor for pancreatic cancer? So maybe you could take us through that, and somehow that gets into the NBA, it gets into H. pylori for ulcer. I mean, but maybe you could help get us through this coffee and cancer story.Christopher Labos (14:23):Yeah, I mean, well, and it's still happening isn't it, right? In 2018 in California, coffee was declared a carcinogen after that court case. I mean, it was ultimately overturned. So I sort of explained that saga in the chapter as well. And of course, we're going through it now with the decaf coffee, right? There are people trying to petition the FDA to get methylene chloride removed from decaf coffee, even though, I mean, I'm fairly dubious that that's a real significant risk factor in the grand scheme of things. And I was a little bit sort of worried when we were trying to pick a title for the books. I was like, are people going to think this is absurd? Are people going to think this is a pseudoscience book? And I was a little bit worried because people are not going to, they're going to think, oh, this is silly.(15:03):Obviously, coffee doesn't cause cancer, and yet we still talk about it. And so, I mean, the 1981 paper just to sort of go way, way back, and this was not a nothing paper. This was in the New England Journal of Medicine with some of heavyweights in the field of epidemiology. And I don't want to discount what these people did. They have more illustrious careers than I will ever have in the field of epidemiology. But this one paper, they made a mistake. What they did was they went around to the local area hospitals, recruited all the patients with pancreatic cancer, recruited controls from the same hospital, and then gave them questionnaires about what they ate, what they drank, how much they smoked, fairly standard stuff. And so, when they were analyzing the data, they saw some associations with tobacco and alcohol, but they saw this really strong association with cancer where the patients who drank a lot of coffee had a near tripling of their risk of pancreatic cancer.(16:02):And so, this made headlines, I mean, this was in all the major US newspapers of the time, interviews people were like, well, maybe we should stop drinking coffee. And they pointed to the Amish and other groups that don't drink coffee and have very low rates of cancer. And what was critical in the critical mistake that they made, which is now taught in intro epidemiology classes we know about it, is that if you pick hospital patients as your control, you have a problem. And it's become so common that actually has a name now it's called Berkson's bias. But the problem with picking hospitalized controls is they are not the same as the general population. And in 1981, why were you going to be admitted to a gastrointestinal ward in a major US hospital? It was probably because you have peptic ulcer disease and you tell this to people now, and of course they have no living memory of this.(16:53):They've forgotten that we used to do partial gastrectomies to treat peptic ulcer disease, which is a shocking thing to say out loud. And then it gives you also the opportunity to teach people about H. pylori and everything that happened. And then the discovery and the famous case of the researcher drinking a broth of H. pylori to make himself sick and his wife having to drag him to the hospital throwing up every morning. And really how it changed the field of medicine because now we treat peptic ulcer disease with you eradicate H. pylori with two weeks of antibiotics, and we give people a proton pump inhibitor. But back in the day, the people who were in hospital had peptic ulcer disease and other gastrointestinal complaints because of those gastrointestinal issues. They didn't drink a lot of coffee because it would upset their stomach, because coffee can upset people's stomach a little bit.(17:48):And so, it wasn't that the pancreatic cancer patients drank more coffee, it's that the control group drank less, and that's why you saw that discrepancy. Whereas if you did the same study in the general population, which was subsequently done, you see no influence of coffee consumption. And so, it's a prime example of how selection bias can happen. And it's a seminal paper because it has become a teaching case, and it's become, for the most part, so well understood that most people are not going to make the same mistake again. And so, the point of highlighting these things is not to make fun of people, which is an unfortunate trend I've started to see online of people being very, very critical and dismissive of the publish research. Like, no, listen, this is how medicine is supposed to work. It's an evolution. We learn from our mistakes and we move on and we have to keep talking about these stories so that people don't make the mistake because choosing the right control group is important.(18:44):And so, that's sort of the message of that chapter because each chapter, you're right, it's about a food, but it's also about an epidemiological concept, be it p-hacking or selection bias or information bias or confounding or reverse causation. So I often joke that if you read this book each chapter, you will become very, very smart at dinner parties. You'll be able to figure out terms that no one's heard of before. They're like, Bob, I know you've heard that red wine is good for you, but are you familiar with the concept of reverse causation? And people are going to be very, very impressed with you and keep inviting you to dinner parties the rest of your life afterwards. So there you go. That's another reason to read the book.Eric Topol (19:20):Yeah, really. Well, I do want to get into the red wine story too, because it exemplifies this time instead of that New England Journal, this was a 60 Minutes segment in 1991, and then a paper, I guess I went along with that about how red wine is great to reduce heart disease. It still, here it is, what, 30 some years later, 34 years later. And people still believe this. They still think that red wine is preventing heart disease or reducing it. So can you set the record straight on that one?Christopher Labos (20:06):Yeah, listen, if you want to drink red wine, you can. I mean, I have nothing against red wine. I mean, I'm drunk right now. No, I'm not.Eric Topol (20:15):By the way, that chapter you were drinking wine with your friend, maybe imaginary friend Alex or Alexi. Anyway, yeah. So it was great to hear you are drinking red wine and you're talking to each other about all the cockamamie stuff about it.Christopher Labos (20:30):I mean, yeah, the thing, if you're going to do a story, if you're going to do a book chapter about red wine, I think one of the important things is to have two friends drinking at a conference. I mean, let's be honest, that's what usually happens. And so, throughout the evening, they're sitting there polishing off the wine, and then they go on almost a drunken pub crawl. Not quite, it's not quite that bad, but it was almost fun to sort of introduce that element to it of the story. But the red wine thing is fascinating. I get this a lot. I mean, I'm still practicing. I'm still seeing patients and patients come up. I've had, this is not rare, I have had patients literally come to me in clinic and say things like, doctor, my blood pressure is good. I'm checking it at home. I got my blood tests.(21:12):My cholesterol is good. I'm eating healthy, I'm exercising. But I find it really hard to drink two glasses of red wine every day. I just don't like red wine all that much. It's like, wow. No, please sir. Please, for the love of God, stop. It's still there. And what's fascinating is that if you ever go back and watch the 60 Minutes clip by today's standards, it's very weird. You go back and again, it was a product of its time. They were very, very focused on cheese and fat, which of course now we have a much more nuanced understanding about with regard to cholesterol. I mean, a lot of it's genetically mediated and all that, but you go back, it was partially about the red wine being good for you, but it was also there was this really strange subplot, if you will, where they were saying that milk was bad for you and that we should stop getting kids in the US to drink milk. And they thought that a lot of the cardiovascular risk in the US was attributed to the fact that children drink milk routinely, which again, weird by modern standards. Again, I was aware of the 60 Minutes story, but I'd never seen it and I hadn't seen it at the time. And going back to watch it, you're like, wow, that's odd. That's odd.(22:26):Again, this idea that, oh, we should be having kids drink wine at a young age. And it was like, really? Do we really want to start having our kids drink alcohol? I'm not so sure about that. It was weird stuff there. But again, it was all part of this French Paradox, which again was a product of its time in the eighties and nineties, this desire to really understand why was heart disease increasing so much in North America and our real failure to really get a handle on it. And with 30 years of hindsight, I think we're in a much better position now to understand why it was the residual effect of all that smoking. It was the residual effect of our more sedentary lifestyle that was starting to happen post World War II. And I think we've largely got a handle on most of those risk factors now.(23:13):But the red wine thing persists because I think people like drinking wine and there are not, what's the word I'm looking for, there is not a significant number of people who still believe this. And we had a change in guidelines up here in Canada where the amount of healthy drinking was really reduced down from 2 drinks a day to 1-2 drinks per week, and it caused a bit of a fury. And there was a local cardiologist here who was going on news and saying is like, I don't believe this, red wine is good for you. And I was a little bit taken a breath like, you're a senior cardiologist at a university hospital. You should not be saying stuff like this. And so, they actually had us on to have a debate, and I think they were expecting us to go at each other.Eric Topol (23:59):Oh, wow.Christopher Labos (24:00):And I was a little bit diplomatic because I've gotten used to this. I know how to bob and weave and avoid the punches. And then at the end, I think it was either me or the reporter asked him, he's like, so what do you tell your patients? And he was like, well, no, I do tell them to drink less because of the AFib risk and the blood pressure and the blood sugar. So I was like, well, you see, you're telling your patients to drink less alcohol for any number of reasons. And irrespective of the U-shaped associations, which is the main statistical argument of the chapter, there's a lot of other reasons to be wary of alcohol. I mean, I think we've proven pretty conclusively the AFib risk. There was that Australian study where if you get people to abstain, you decrease their AFib burden.(24:42):So a lot of sugar in alcohol, I mean the blood pressure and diabetes, there's a lot of reasons to not drink this particular sugary beverage and not to mention sort of the cancer associations too that we've seen as well. So it was an interesting thing to argue with him. But the point of the chapter was really to explain why do we see this U-shaped association? And I'll spoil the chapter for people. The statistical concept is called reverse causation. And that happens because it's not that abstaining from alcohol makes you sick. It's that people who are sick end up abstaining from alcohol. So if you have high blood pressure, diabetes, heart disease, AFib, cancer, you've probably been told don't drink alcohol. And so, if you do just a single cross-sectional study where you ask people, how much do you drink? And they say zero, you're probably identifying a high-risk population because most studies, most, not all, but many studies do not make the distinction between former drinkers and never drinkers. And there's a big difference between somebody who used to drink and then quit and somebody who never drank throughout their whole lives.Eric Topol (25:47):Yeah, no, it's great. And I think I just want to come back on that. I think Norway and several other countries are now putting on their alcohol products. This may cause cancer, and the American Cancer Society has put a warning on this. So the cancer story is still out there, but you also make among hundreds of important good points in the book about how these food diaries are notoriously inaccurate. And you already touched on that with the survey thing, but it's hard to get, we don't have randomized trials of people drink a lot or don't drink. You can't drink with adherence to that. So it's out there, and of course, people like to drink their wine, but there's a risk that I think has been consistent through many of these studies that is a bit worrisome. I don't know what you would, if you'd say it's conclusive or you'd say it's kind of unsettled.Christopher Labos (26:49):I mean, I think it's as settled as it's going to get because I don't see somebody doing a randomized controlled trial on this. And this is the problem. And there has been this trend recently for people to say, well, if there's no randomized controlled trials, I'm not going to believe it. You're like, okay, look, a fair point. And when you're talking about interventions and therapies, then yes, we should absolutely do randomized controlled trials. And I've made that point vociferously when it comes to vitamin D and a lot of the other stuff. The problem is it's going to be very, very hard to do a randomized controlled trial with alcohol. I mean, that was tried. It fell apart and it fell apart for many reasons, not the least of which was the fact that the alcohol industry seemed to be influencing what outcomes people were going to look at.(27:34):So that was problematic. I sort of mentioned it right at the tail end of the chapter as well. So if you're not going to have an NIH funded trial to look at in a randomized fashion, does alcohol effect atherosclerosis or cancer outcomes? You're not going to get it. No private industry is going to do it. You're not going to be able to get it done. So given that we have to live in the real world, and I'm always a firm argument in us basing ourselves in reality and living in the real world, we have to make the best decision we can with the evidence that we have available. And I would say, look, I'm pretty sure alcohol is not good for you. I think it is actually detrimental to your cardiovascular health overall. And I think we can say pretty definitively that any potential benefit that people think exists in terms of myocardial infarction, I think that's all a statistical artifact.(28:26):I think if you were to analyze it properly, it would all sort of vanish. And I think it largely does. And there's been some really interesting genetic studies using instrumental variables. So what the Mendelian randomization studies that really do suggest that there really is a linear relationship and that the more you drink, the worse it is. And there's no plateau, there's no floor, there's no J shaped curve. It really does appear to be linear. And I've been, I think, fairly convinced because I think the Mendelian randomization studies are as good as we're going to get on this issue.Eric Topol (29:01):No, I think it's an important point. And I think there again, the book will hold on so many of these things, but we keep learning all the time. And for example, going back to coffee, there's many studies now that suggest it will reduce type 2 diabetes, it will improve survival, cardiovascular, the mechanism is unknown. Do you think there's, so not only does coffee not cause cancer, but it actually may make you healthier. Any thoughts about that?Christopher Labos (29:35):Well, I can state, again, I'm ruining the book. I can state, I think fairly unequivocally coffee does not cause cancer. I think that is pretty clear. Even protective is harder, I think it's possible that a lot of the benefit that's been seen, because it is very observational, could just be the result of residual confounding. I think that is still possible. And again, we have to learn to live with uncertainty in medical research. And when we talk about Bayesian statistics, which is a subject I love, but probably outside of the topic for today, you have to be able to create a framework for what we're certain about and what we're uncertain about. So if you look at the spectrum of risk, clearly the risk ratio for coffee is not above 1. Is it below 1 or is it really straddling the null value? And I'm a little bit uncertain. I think if there is a benefit, it's probably small. I think a lot of it is residual confounding. The one point that would make though, if we're going to talk about coffee being beneficial, we have to talk about coffee. Not a lot of the stuff they are serving at coffee shops now, which are probably more akin to milkshakes than actual coffee.Eric Topol (30:52):Yeah, that's a really good point. Plus, the other thing is the spike of caffeine at much higher levels than you might have with a standard coffee that is typical, these Grande or super Grande, whatever they are. Now another, since we talked about things that people enjoy like coffee and wine, we have to touch on chocolate. The chapter was fun on chocolate, is it a health food and also about the Nobel Laureates. Can you enlighten us on that one?Christopher Labos (31:26):This is another, I mean, again, people are going to think that I hate the New England Journal of Medicine. I don't just, that they provided such great teaching material over the years. And to be fair, the study that we're going to talk about the Nobel Laureate chocolate study, I mean if you read it, it really feels like it was meant to be satire and it probably should have belonged in the BMJ Christmas issue. When you read it and you read the disclosure statement where the author is like, disclosure the author admits to loving chocolate, and you're like, okay, that's a weird thing to write in a serious article. So it was probably meant to be a satire. And when you read some of the interviews that Messerli had given afterwards, it does seem that he was trying to just make a point. But it seems to have taken off a life of its own.(32:10):What the study was, and it's again, first time I've ever seen a single author on a New England paper, which probably should have been a warning sign for people because generally New England papers don't have single authors on them. But basically, what he did was he was at a conference as the way the story goes, and he was thinking up this idea. So he went on the internet, went onto Wikipedia, and was basically looking up how many Nobel prizes have been won by various countries, looked up the average chocolate consumption on a variety of other websites and basically plotted out a regression line and showed this really linear association between average chocolate consumption per country and number of Nobel prizes per country with the suggested rules that if you eat chocolate, you'll win a Nobel Prize. Except, and notwithstanding all the jokes that came up later, there was another Nobel laureate, and I'm blanking on his name right now, there is in the book. When he was interviewed, he said something like, I believe this is true. Now, milk chocolate might be fine if you want a Nobel Prize in chemistry or medicine, but if you want a Nobel Prize in physics, it really does have to be dark chocolate.Christopher Labos (33:20):He said this to the Associated Press, the Associated Press took the quote and put it on the Newswire, and it got reprinted over and over again. And I think he had to publicly apologize to all the people at his university, which to me seemed ridiculous. He was obviously joking, and people took this study very, very seriously. The explanation for why this study is not true, there's actually a word for this, and it's called the ecological bias. And you have to remember something if you're going to look at chocolate and Nobel prizes and look at it in terms of country as the level of exposure, as the unit of exposure. Countries don't eat chocolate and countries don't win Nobel prizes. People eat chocolate and people eat Nobel prizes. And you can't show that the people eating the chocolate in Switzerland are the ones who are winning the Nobel Prizes.(34:10):Right. That's the point you can't show, and this is a humorous example, but we've made this type of mistake before when people were talking about saturated fats causing breast cancer. You can look at countries and show that countries that eat a lot of saturated fat have more breast cancer. But that's also because western countries with other basic differences are the countries where you eat a lot of saturated fats and where women develop higher rates of breast cancer. But that doesn't mean that the women who eat the saturated fats are the ones who get breast cancer. And so, the chocolate one is funny because again, it's exactly what you said. People like eating chocolate, so they want a reason to believe that it is good for you even when it isn't. And so, they will latch on to the cardiovascular benefits, which have frankly been disproved in the COSMOS study. They will latch on to the neurological, neurocognitive benefits, which have themselves been disproved. And what's fascinating about the whole story is that you would say, oh, we need a large randomized trial. Well, we had that, it was called the COSMOS study. It got published. I mean, maybe it happened during Covid, people didn't notice, but it got published. It was negative. That should have been the end of the story, and it's not, people still believe it.Eric Topol (35:23):Well, there's a lot of confirmation bias there, isn't there? Again, the thread through all the chapters is biases, all the different biases that come in play. And this one, knowing Franz Messerli, he's Swiss, so of course he'd want to, yeah, and he eats a lot of chocolate, by the way. And he also comes into play in the chapter you have on salt. It's really interesting. You have chapters on breakfast. Is it really the most important meal? Were there other chapters that you thought about putting in the book that you didn't wind up there, or if you were to write a second edition that you would add?Christopher Labos (36:01):I wanted to do a chapter on fish oils. Actually, there's a tweet that you did that I use in my teaching material, which is two days apart, fish oils are good for you, fish oils are bad for you. Because again, that's one of those things where it's just the cycle of all these studies showing no benefit, and yet there's one study that shows a thing and it just keeps coming back. And so yeah, fish oils would've definitely been one. If there is a sequel to this book, and I'm hoping to make a sequel to it.Eric Topol (36:30):You should, you should definitely.Christopher Labos (36:32):So fish oils is definitely going to be in there because there were originally going to be ten stories. There's only nine in the book. And because it got to the point where the publisher was like, this book is getting a little long, maybe we've got to wrap it up. Maybe it's time to land the plane. And I was like, okay, fair, fair. So we'll cut it at nine. So we had to drop the fish oil one, but that'll be in the sequel if there is a sequel, I want to do, I have a list. It's just off camera actually. I have a little notepad where I've been jotting down ideas. So like fish oils, artificial sweeteners, I'll throw MSG in there, which is a wild story for anybody who's ever dug into the history of MSG. It is a wild and borderline nonsensical story of why we believe that MSG might be bad for us.(37:14):Although, I mean, that was, again, very much a product of the eighties and the nineties. So yeah, there's a lot of stuff out there, but fish oil is definitely one that I want to tackle just because it's so relevant. And I still have patients coming in that are going to pharmacy and buying over the counter fish oil supplements. I have to tell them, it's like, look, the evidence on this is pretty clear. It doesn't help. If anything, maybe it slightly increases risk your AFib risk. There's some stuff there. So yeah, again, you could be easily tempted into thinking this is sort of frivolous and funny, but it actually has an implication for people's daily lives because the people out there walking around the street, they believe these things go stop a hundred random people.Eric Topol (37:59):Yeah, no, everything in this book is approaching things that are the dogma still, or at least uncertainty, and you get it straight. I mean, you're an epidemiologist as well as a cardiologist in your training, but you don't use that in a way that is trying to teach people. You're doing it really subtly. And then the other thing just to bring up is that obviously you're debunking all this stuff, and we live in a time where we got all this misinformation and blurred truths. I mean, that's one of the reasons why I pick Ground Truths for this podcast. But it's diminished or certainly challenged the role of physicians and scientists because things are not reliable. They're not constant. They're changing. You touched on that earlier, but can you address, I mean, one of the things besides communicating in a way that makes it easily understandable and fun, which you do so well, it's also addressing trust. How do we promote trust?Christopher Labos (39:10):I think you have to, yeah, that's a really challenging question because I think the old model is not going to work anymore. The model of issuing a guideline statement to be like, this is the truth, people will just ignore it because we have issued new guidelines on alcohol consumption. It didn't change behavior. If you want to get people to drink less, you have to address the underlying reason why they do it, and it's this persistent myth. So I think one of the reasons why pseudoscience succeeds as much as it does is because so much of their communication is about storytelling. You can go at people with these large randomized control trials, and yet they will still latch onto an anecdote, right? Because, oh, my friend Bobby had a bad side effect with the Covid vaccine. That's why I'm not getting vaccinated. And so, storytelling is a really, really powerful tool.(40:05):And I think the reason why I thought this type of book format could work is it's a story. Because even if you don't remember the details, I was at a lecture last night and I was speaking to a dermatology friend of mine, which sounds like it's an episode from the book, but it's not. But I was speaking to a dermatology friend of mine, and he had read it. He says, Chris, I read it. I really liked it. He goes, I don't remember a lot of the examples you put up. He is a busy guy. He's got young kids. He read the book, and I was giving a lecture based on this book and exploring all of these concepts. And he was like, I remember when you started talking about the aspirin. I couldn't remember what the example was, but I remembered your point that it's all about subgroups.(40:47):And that's the thing is that even if people don't remember the details, even if people don't remember the New England paper about coughing pancreatic cancer, even if they don't remember the COSMOS study about chocolate, even if they don't remember the Nobel chocolate association, they will remember the take home message, which is that you have to be careful. If somebody is torturing the data, they understand why publication bias is a real problem. So that's the point, is that if you tell a story, it sticks in people's minds. So it's almost very Socratic in a way. If you ever read Plato, he's not writing a philosophical treatise in the same way that other philosophers do. It's a conversation between Socrates and other people, and it's a very one-sided conversation because Socrates is telling everybody why they're wrong. So I tried to sort of nuance that and improve upon that framework, but you take away the general gist of it, and that's what we need to give to people.(41:48):We need to tell them, we need to give them the tool so that they can say it's like, oh, well wait a second. You're telling me that broccoli is going to prevent pancreatic cancer? Was this a food questionnaire thing? And you're giving people that little bit of background knowledge that they can ask intelligent questions. And I think that's what we have to do going forward, because we have to introduce that little bit of skepticism into their thought process so that they can question what they see on the internet. Because the reality is a lot of what they see on the internet is going to be wrong because it's clickbait, it's headlines, it's all the issues that we have with our modern communication strategies.Eric Topol (42:31):Yeah. Well, I think storytelling and what you just described is so darn important. And so, just to wrap up this book, Does Coffee Cause Cancer?: And 8 More Myths about the Food We Eat is much more than what that title says. I hope you're going to do a sequel. You ought to have a Netflix special.Christopher Labos (42:54):Please tell somebody that, I don't how to get a Netflix special, but use your clout and make it happen, and I'll invite you over for dinner.Eric Topol (43:01):Sounds good. We'll have red wine together, and drink a lot of decaffeinated coffee. No, this has been fun. You've definitely had an impact. And I hope everybody takes a chance to get through this book because it's like a novel. A novel, which is somehow you've floated in all this really important stuff in medicine, both content, how to interpret data, how to interpret papers, statistics, somehow invisibly in a novel. You've got it all in there. So congratulations on that. It's a new genre medical book like I've never seen before. And so, we'll be following all your next works, and I'm sure your podcast Body of Evidence must be something along these lines as well. So I'll have to take a look and listen to that too.Christopher Labos (43:56):Thank you so much. That is very, very, you have no idea how much it means to me to hear you say something like that, that has warmed the cockles of my heart.Eric Topol (44:07):Alright, well Chris, thank you.***********************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

We discuss the impact of genetics on society, touching on both the positive and dark aspects of the field. We reflect on the work of Dr. Anthony Fauci in combating infectious diseases like HIV-AIDS, Ebola, Zika, and COVID-19. Dr. Fauci's dedication to saving lives and his experiences with various administrations are highlighted, along with the unfortunate security threats he faces due to political tensions. Then we delve into the history of eugenics, citing examples of how genetics was misused to justify atrocities such as sterilizations and discriminatory practices. We share insights from a lecture by Dr. Adam Rutherford on the dark history of genetics, emphasizing the shift from simplistic Mendelian inheritance patterns to the complex interplay of multiple genes and environmental factors in shaping traits. He critiques the perpetuation of outdated monogenic deterministic thinking in education and media, leading to racial essentialism and misunderstanding of genetic concepts. Rutherford challenges the inaccurate portrayal of genetics in popular culture, debunking sensationalized claims about genes determining complex human behaviors and characteristics. The discussion extends to the distorted application of genetics in eugenics, with examples from Nazi Germany where pseudo-scientific racial hygiene policies led to widespread atrocities. The fraudulent foundation of eugenics, propagated by influential figures like Charles Davenport, is exposed, showcasing how flawed interpretations of genetics can have catastrophic consequences. Rutherford emphasizes the importance of revising genetic education to align with current scientific understanding and avoid reinforcing harmful ideologies rooted in eugenic thinking. By shedding light on the intersection of genetics, eugenics, and societal beliefs, we encourage critical thinking and a nuanced approach to genetic concepts to prevent the reemergence of harmful practices. Through historical analysis and modern perspectives, we underscore the impact of accurate genetic education in shaping informed discussions and ethical considerations surrounding genetic research and applications. This is our 80th episode - thanks for listening all this time. Full Show Notes Subscribe to our free newsletter Check out our merch --- Send in a voice message: https://podcasters.spotify.com/pod/show/glasscityhumanist/message

Mental Health problems are common and there is good evidence for physical activity as an important role to help prevent and treat mental health conditions. The BJSM has collaborated with the PACC programme to help develop this podcast and has invited Professor Brendon Stubbs, a global expert in this space. Brendon is a clinical-academic physiotherapist and has published more than 800 academic papers and has advised the WHO and the World Psychiatric Association.  “The Physical Activity Clinical Champions or PACC programme is a national project delivering physical activity education to professionals working in healthcare to help get patients more physically active. It was previously being led by public health England as part of the moving healthcare professionals programme and funded by the national lottery & Sport England and is now being led by a consortium of The Faculty of Sport and Exercise Medicine, The Advance Wellbeing Research Centre at Sheffield Hallam University and Intelligent Health and is being re-designed with new resources. This podcast forms part of a series to support physical activity education for professionals working in healthcare. For anyone you would like to get involved with PACC project then please do email us at pacc@shu.ac.uk  PAPERS MENTIONED Physical activity Prevention of Mental Health Problems Physical Activity and Incident Depression: A Meta-Analysis of Prospective Cohort Studies - PubMed (nih.gov) Physical activity protects from incident anxiety: A meta-analysis of prospective cohort studies - PubMed (nih.gov) Physical activity and sedentary behaviour:  The association between sedentary behaviour and indicators of stress: a systematic review - PubMed (nih.gov) Testing the causal relationships of physical activity and sedentary behaviour with mental health and substance use disorders: a Mendelian randomisation study - PubMed (nih.gov) Changes in sedentary time are associated with changes in mental wellbeing over 1 year in young adults - PMC (nih.gov) Treatment of Mental Health conditions Exercise and internet-based cognitive-behavioural therapy for depression: multicentre randomised controlled trial with 12-month follow-up - PubMed (nih.gov) Antidepressants or running therapy: Comparing effects on mental and physical health in patients with depression and anxiety disorders - PubMed (nih.gov) Other resources mentioned:  https://movingmedicine.ac.uk Home - Mind

中午好好休息睡個午覺吧 Support this show: https://open.firstory.me/user/ckgk7ej6h3uud081394y4caub 意見回饋：https://forms.gle/WG82GMGhZi22cuSU6 Reference: Dutheil, F., Danini, B., Bagheri, R., Fantini, M. L., Pereira, B., Moustafa, F., Trousselard, M., & Navel, V. (2021). Effects of a short daytime nap on the Cognitive Performance: A Systematic Review and Meta-Analysis. International Journal of Environmental Research and Public Health/International Journal of Environmental Research and Public Health, 18(19), 10212. https://doi.org/10.3390/ijerph181910212 Paz, V., Dashti, H. S., & Garfield, V. (2023). Is there an association between daytime napping, cognitive function, and brain volume? A Mendelian randomization study in the UK Biobank. Sleep Health, 9(5), 786–793. https://doi.org/10.1016/j.sleh.2023.05.002 Leave a comment and share your thoughts: https://open.firstory.me/user/ckgk7ej6h3uud081394y4caub/comments 這是Vitamind專門製作的正念冥想節目，幫你抵抗分心焦慮的情緒。 每週日更新，你隨時服用。 歡迎來找我們合作聊天～ Instagram: @itsvitamind Email: tiffany@itsvitamind.com Powered by Firstory Hosting

In this episode Rob Calder talks to Dr Germán Carrasquilla about his study assessing whether smoking cased increases in abdominal obesity or belly fat. They discuss the implications of this kind of fat and note the importance of the findings for people who struggle to quit smoking. Germán talks about using Mendelian randomisation to identify a causal association between smoking and abdominal obesity. The findings, that 'smoking initiation and higher lifetime smoking may lead to increased abdominal fat', add evidence and important detail to the known health benefits of quitting smoking."People who might be afraid of quitting smoking due to putting on weight find these findings motivating to quit smoking because smoking increases this problematic internal fat which is a risk factor for many other diseases like diabetes, cardiovascular disease."Original article: Estimating causality between smoking and abdominal obesity by Mendelian randomization by Germán Carrasquilla and colleagues. Published in Addiction (2024)The opinions expressed in this podcast reflect the views of the host and interviewees and do not necessarily represent the opinions or official positions of the SSA or Addiction journal.The SSA does not endorse or guarantee the accuracy of the information in external sources or links and accepts no responsibility or liability for any consequences arising from the use of such information. Hosted on Acast. See acast.com/privacy for more information.

BUFFALO, NY- April 24, 2024 – A new #researchpaper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 7, entitled, “Using genetics and proteomics data to identify proteins causally related to COVID-19, healthspan and lifespan: a Mendelian randomization study.” The COVID-19 pandemic poses a heavy burden on public health and accounts for substantial mortality and morbidity. Proteins are building blocks of life, but specific proteins causally related to COVID-19, healthspan and lifespan, have not been systematically examined. In this new study, researchers Jie V. Zhao, Minhao Yao, and Zhonghua Liu from The University of Hong Kong and Columbia University conducted a Mendelian randomization study to assess the effects of 1,361 plasma proteins on COVID-19, healthspan and lifespan, using large GWAS of severe COVID-19 (up to 13,769 cases and 1,072,442 controls), COVID-19 hospitalization (32,519 cases and 2,062,805 controls) and SARS-COV2 infection (122,616 cases and 2,475,240 controls), healthspan (n = 300,477) and parental lifespan (~0.8 million of European ancestry). “We included both COVID-19 and healthspan and lifespan in the outcome, because COVID-19 which occurred in recent years reflects a new threat to longevity, whilst healthspan and lifespan reflect overall morbidity and mortality.” The researchers identified 35, 43, and 63 proteins for severe COVID, COVID-19 hospitalization, and SARS-COV2 infection, and 4, 32, and 19 proteins for healthspan, father's attained age, and mother's attained age. In addition to some proteins reported previously, such as SFTPD related to severe COVID-19, the team identified novel proteins involved in inflammation and immunity (such as ICAM-2 and ICAM-5 which affect COVID-19 risk, CXCL9, HLA-DRA and LILRB4 for healthspan and lifespan), apoptosis (such as FGFR2 and ERBB4 which affect COVID-19 risk and FOXO3 which affect lifespan) and metabolism (such as PCSK9 which lowers lifespan). They found 2, 2, and 3 proteins shared between COVID-19 and healthspan/lifespan, such as CXADR and LEFTY2, shared between severe COVID-19 and healthspan/lifespan. Three proteins affecting COVID-19 and seven proteins affecting healthspan/lifespan are targeted by existing drugs. “Our study provided novel insights into protein targets affecting COVID-19, healthspan and lifespan, with implications for developing new treatment and drug repurposing.” DOI - https://doi.org/10.18632/aging.205711 Corresponding authors - Jie V. Zhao - janezhao@hku.hk, and Zhonghua Liu - zl2509@cumc.columbia.edu Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts About Aging-US Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer's diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases. Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

On today's episode Fei and Nick go back to basics with genetics -- we realized we have never discussed genetics and inheritance patterns! We review single gene inheritance and Mendelian genetics for the first part of this series.  The OB/Gyn Intern Challenge is happening soon for 2024! Go onto our website to get signed up to be part of this innovative text-message course in May of this year absolutely free. www.obgyninternchallenge.com  Twitter: @creogsovercoff1 Instagram: @creogsovercoffee Facebook: www.facebook.com/creogsovercoffee Website: www.creogsovercoffee.com Patreon: www.patreon.com/creogsovercoffee You can find the OBG Project at: www.obgproject.com

Today Dr. Lisa reviews an article that identifies four specific sedentary behaviors that contribute to excess weight. Armed with this information, you'll create unique ways to achieve weight loss that aren't directly related to diet or exercise. The original article link can be found below. Also, be sure to check out Lisa Oldson MD on social media, if you'd like to learn more about our 2024 Women's Wellness Retreat. Early bird registration is now open! Article: Sedentary behavior, physical activity, sleep duration and obesity risk: Mendelian randomization studyIf you'd like more support during your SMART weight loss journey, check out our group coaching program at www.smartweightlosscoaching.comThis episode was produced by The Podcast Teacher.

In this episode of Longevity by Design, Dr. Gil Blander and Ashley Reaver, MS, RD, CSSD, sit down with Dr. Bartek Nogal from InsideTracker to explore the cutting-edge intersections of exercise, genetics, blood biomarkers, health optimization, and longevity. Dr. Bartek Nogal, with a strong background in biological engineering and genomics, dives into how personalized health data can shape our understanding of aging and wellness. He discusses InsideTracker's new innovative approach to using DNA analysis for tailoring health interventions, emphasizing the importance of actionable guidance for optimizing blood biomarkers and extending healthspan and longevity.Dr. Bartek Nogal shares compelling insights into the latest findings from InsideTracker's peer-reviewed published study on the effect of running on blood biomarkers and metabolic health, along with the influence of genetics—highlighting the power of exercise combined with the added value genetics provide for even greater personal health optimization. Dr. Nogal also discusses InsideTracker's new innovative DNA healthspan report and the enhanced information and deeper insights it provides. The conversation is a deep dive into how technology bridges the gap between scientific research and everyday health practices, offering listeners a roadmap to a longer, healthier life. Listeners will leave with a clear understanding of the power of exercise on blood biomarkers and genomics for personal health and practical tips for leveraging their genetic information to make even better-informed lifestyle choices. This episode is a testament to the evolving landscape of health and science, where the fusion of data, technology, and personalized insights paves the way for a future of optimized health and longevity.Listen to all episodes of Longevity by Design at https://info.insidetracker.com/longevitybydesign Episode timestamps:Introduction: 00:00-02:32What led Dr. Bartek Nogal to become a scientist: 02:33-03:27Dr. Bartek Nogal's career at InsideTracker: 03:28-04:02InsideTracker's peer-reviewed study: Dose response of running on blood biomarkers of wellness in generally healthy individuals (https://pubmed.ncbi.nlm.nih.gov/37967046/): 04:03-06:46What is principal component analysis (PCA), and what were the findings using PCA: 06:47-07:56What is the effect of running blood biomarkers? What is the effect of the amount of running on blood biomarkers?: 07:57-09:27What was the effect of running on BMI (body mass index): 09:28-10:44What is Mendelian randomization, and what is the relationship of genetics with exercise and blood biomarkers? : 10:45-12:40What is the influence of genes on the relationship between exercise and diet: 12:41-13:33What are the strengths of Mendelian randomization for understanding the influence of genetics: 13:34-17:05What were the key findings from InsideTracker's study on the effect of running on blood biomarkers 17:06-18:56What is InsideTracker's new DNA report? What was the motivation for developing this new DNA healthspan report: 18:57-20:31What additional information and insights does InsideTracker's new DNA report and scores provide: 20:32-28:41How much do genes or lifestyle influence blood biomarkers and risk of developing diseases:  28:42-32:24How to use InsideTracker's new DNA and healthspan scores to optimize blood biomarkers and health: 32:25-34:28What is the future of genetics research: 34:29-36:36What is the future of genetic testing at InsideTracker: 36

This podcast is called the High Performance Human podcast for a reason. It gives me the opportunity to showcase individuals who excel in their chosen sport, but also in many other areas of their life, while still focussing on basics such as sleep and nutrition.   Next time you take a flight, think about what you would like to know about your pilot - skills at their job (obviously) but also that they prioritise health and fitness, turn up each day having slept well and eaten the right foods to help them concentrate throughout the full duration of your flight. Today's guest, Rick Peters, is an elite swimmer, airline pilot, and high performance human.   He was introduced to me by long time client Toby Baxendale when he and Rick met at the Barbados Open Water swim festival, last November. Rick finished 7th overall in the 5k swim (non wetsuit) in a very impressive time of 1hr 13 (an average pace of 1:28/100m), made even more impressive by the fact that Rick is 60 years old.   Rick still regularly captains long haul flights for Air Canada, and in today's conversation we talk about his daily fitness routine, his love for swimming, and how he stays so fit and healthy. Then we add in the complications of air travel, the impact of time zone changes, and some of the strategies Rick uses to mitigate these. Needless to say, I would be very confident to have Rick Peters as the Captain on my next flight! Some other topics we discuss include: Earthing - to help the body rebalance after crossing time zones Drinking hydrogen water to limit the impact of flying at altitude Finding time to workout when travelling The microbiome and how keeping your gut healthy has a major impact on brain health, sleep and general fitness   Rick doesn't use social media but if you have any questions for him, I'm sure he wouldn't mind me forwarding them on. He did recommend some resources and books.   Books “YOUNGER NEXT YEAR” (Live strong, fit, sexy and smart – until you're 80 and beyond) by Chris Crowley & Henry Lodge. The Psychology of Winning” (Ten qualities of a total winner) by Dr. Denis Waitley.   Video Light as Medicine by Dr. Roger Seheult MD of MedCram who gives a very detailed description of how mitochondria produce ATP and what infrared light can do to optimize your health and immunity.   Research Papers on Gut MicroBiome How gut bacteria balance enhanced exercise performance “Associations between gut microbiota and sleep: a two-sample, bidirectional Mendelian randomization Study”, by J. Wu et al “Gut microbiome diversity is associated with sleep physiology in humans”, by R. Smith et al., in PLoS One, October 2019, PMID 31589627. “Exercise and the Gut Microbiome: A review of the Evidence, Potential Mechanisms, and Implications for Human Health”   To contact Beth regarding Life Coaching, please email her at Info@BethanyWardLifeCoaching.uk. To leave a review of the podcast on Apple podcasts CLICK HERE. Sports Nutrition questions - if you have a sports nutrition question that you would like answered on the podcast, please email it to me via Beth@TheTriathlonCoach.com. Join our SWAT/High Performance Human tribe using this link, with a happiness guarantee! You can watch a brief video about the group by going to our website here, and join our SWAT High Performance Human tribe here. Purchase a copy of my High Performance Human e-book featuring more than 30 top tips on how to upgrade your life. If you would like to help offset the cost of our podcast production, we would be so grateful. Please click here to support the HPH podcast. Thank you! Visit Simon's website for more information about his coaching programmes. Links to all of Simon's social media channels can be found here.  For any questions please email Beth@TheTriathlonCoach.com.

Machine learning models that use DNA markers can estimate the age of biological samples. However, understanding why these markers change with age is challenging because it's hard to prove that these changes cause aging-related traits. In this week's Everything Epigenetics podcast, I speak with Kejun Ying who uses large datasets to find specific DNA markers that directly influence aging traits. We explore his recently published study which found casual CpGs that speed up aging and others that protect against it. Kejun and colleagues created two new models, DamAge and AdaptAge, to measure harmful and beneficial changes related to aging. DamAge, which indicates negative aging effects, is linked to several health risks, including higher chances of dying. AdaptAge, on the other hand, shows positive aging adaptations. Interestingly, only the negative changes seen in DamAge can be reversed by a process that makes aged cells young again.The research findings provide a detailed understanding of the DNA markers that truly affect lifespan and overall health as we age. This helps us develop more accurate aging biomarkers and evaluate treatments aimed at reversing aging, improving longevity, and understanding events that speed up the aging process.In this Everything Epigenetics episode, you'll learn about:Kejun's unique journey into the aging fieldOne of the biggest weaknesses of the epigenetic clocks (separating causation versus correlation)Mendelian randomization Casual inferenceWhy causality matters for aging biomarkersWhy it is  important to separate deleterious and protective changes in agingDamAge (casual aging clock based on damaging sites)AdpateAge (casual aging clock based on protective sites)The applications of DamAge and what AdpateAgeClockBase: a comprehensive platform for biological age profiling in human and mouseThe application of ClockBaseData privacy when using ClockBaseWhere to find Kejun: XLinkedInGoogle ScholarKejun Ying is a 4th year Ph.D. student in Harvard Medical School, Gladyshev lab. His research focuses on understanding cause of aging and develop ML-based aging biomarkers to facilitate the discovery of novel anti-aging interventions.Support the showThank you for joining us at the Everything Epigenetics Podcast and remember you have control over your Epigenetics, so tune in next time to learn more about how.

Dr. Shannon Westin and her guests, Dr. Judy Garber and Dr. Geoffrey Oxnard, discuss the paper "Germline EGFR Mutations and Familial Lung Cancer" recently published in the JCO. TRANCRIPT The guest on this podcast episode has no disclosures to declare.   Shannon Westin: Hello, and welcome to JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for the JCO and Gynecologic Oncologist by trade. And it is my great pleasure to speak today with you about an amazing manuscript entitled, “Germline EGFR Mutations and Familial Lung Cancer.” It was published in the JCO on August 14, 2023.  The authors have no conflicts of interest, and they are Dr. Geoffrey Oxnard, he's a Thoracic Oncologist and Associate Professor, Hematology and Medical Oncology at Boston Medical Center.  Welcome, Geoff. Dr. Geoffrey Oxnard: Hi, Shannon. Thanks. Shannon Westin: And Dr. Judy Garber, the chief of the Division of Cancer Genetics and prevention at the Dana-Farber Cancer institute in Boston. Welcome, Judy. Dr. Judy Garber: Thank you. Hi, Shannon. Hi, Geoff.  Shannon Westin: So excited you both could be here. Let's get started. So first I just want to levelset for our audience. Can you speak just a little briefly about the incidence and mortality of lung cancer and how that's been changing over time? Dr. Geoffrey Oxnard: Sure. Lung cancer is common and it's deadly, more than 200,000 cases a year in the United States, more than 100,000 deaths a year in the United States. But I think importantly, it's evolving. Its biology is evolving as smoking incidence goes down. We've identified these genomic subtypes of lung cancer that are sort of increasingly apparent and important as we think about its treatment. Outcomes are changing with emerging therapies, presentation is changing with lung cancer screening and with a growing ability to now find cancers early and prevent them. And so it's in that setting of a very dynamic disease that we chose to study a really unique little slice of it, which is germline risk. Shannon Westin: So let's take that one step further because I think that's really interesting. You mentioned the genomic aberrations and kind of how you're using that to target. Can you expand upon that a little bit more for me? Dr. Geoffrey Oxnard: Lung cancer that I've long studied is different than breast cancer when Judy has long studied because we think about its somatic alterations, we've always thought about KRAS mutations, EGFR mutations, and smaller and smaller splice limit. ALK, RAS, RET HER2, etc. And so tumor testing in lung cancer has one of the first to be standard across on solid tumor oncology. And the germline genetics was kind of an afterthought and is the flip, I think, of how genetic testing evolved in the breast cancer space for example. Dr. Judy Garber: I might argue a little bit if breast cancer was earlier and it was subtyped some molecularly it doesn't have as many molecular subtypes yet perhaps as lung cancer. But we've all been studying the somatic space to look for targets for therapy. And the germline space, certainly in breast cancer, came much earlier. And everybody knows about BRCA1 and 2. Now, we hope everybody knows about Lynch Syndrome, but certainly not everybody's thinking about inherited lung cancer risk. Dr. Geoffrey Oxnard: Yeah, these have converged. I think 10 years ago when this kicked off, I felt like a super outlier for thinking about, wait a second, what about the genetics behind all this that is leading to this strange variable presentation of lung cancer? For example, we know that in Asian populations, one type of lung cancer, EGFR mutant lung cancer, is more common. There must be some geneticness that leads to that. What explains the sort of pattern of presentation of these genetic subtypes in the populations we see in the US, that's pretty unclear?  Dr. Judy Garber: So, I think, Shannon one of the clues about all this came from the fact that the EGFR mutations were being identified in the tumors. And then I really should let Geoff tell this story, but as the amateur thoracic person in the room here, to me, it was so interesting that there were the EGFR mutations, then there was treatment exploiting EGFR mutations, and the most common resistance mutation was this T790M variant. But when labs started testing EGFR, there was a small group of people who had that resistance variant without ever having been treated at all. So that was the obvious question, what was it doing there? And that's where Geoffrey came in.  Dr. Geoffrey Oxnard: Yeah, this is a patient I met more than a decade ago at my fellowship in MSKCC. She'd been living with a T790M mutation in her tumor for years and years and years. I was like, “Well, I don't understand. Why is this sitting there?” And she had this sort of slightly mysterious history of lung cancer in her family. And we realized, wait a second, this T790M was behind her cancer from the beginning, and in fact, might have been the basis of why she developed lung cancer. And so that actually motivated a career development award I submitted to the Conquer Cancer Foundation of ASCO, a grant I received, and that then led to a program that I led at Dana-Farber under Judy's mentorship, where over the past decade, we sort of focused in and studied this strange, rare syndrome, really to dig into inheritedness as a kind of different flavor of lung cancer genetics.  Dr. Judy Garber: Well, and now it's really a good time to think about this because we're recognizing there are younger cancers, colon cancer, like an epidemic, and lung cancers, and we're not sure how many of them are genetic or come from other exposures. Geoff talked about the differences in Asia, some of which are certainly genetic, some which may be environmental, especially in the lung, where that's such an issue. But trying to sort these things out, you have to be willing to think a little bit differently. And that was fun when Geoff came from the lung program, interested in the germline, we said, “Oh, we have to do this.”   Shannon Westin: Well, let's talk about what you did. I would love to hear and I know the audience would as well about the design of this study, so called INHERIT study. Very good name. I love a good name. This is a good one.   Dr. Geoffrey Oxnard: Yeah. So that stands for Investigating Hereditary Risk of T790M, INHERIT. I forget where we coined that. Let me give you a case example. A patient presents in his 40s. I remember this man. He has an EGFR mutation in his tumor. He has a T790M in his tumor as well. He had routine tumor testing that lung cancer patients were getting. And he says, “Oh, also, my brother had lung cancer in his 40s just a couple of years ago. He was a smoker, though. He never had genetic testing.” And so this patient we test on the study, we hypothesized that when patients present with T790M at diagnosis, that it would be a representation of an underlying germline EGFR mutation. Our hypothesis was that about 50% of the time T790M at diagnosis would be explained by a germline behind the doll. And that that could then empower families like this one to understand the kinds of lung cancer they're getting in their family, the kinds of treatment they should be getting, and the kinds of testing they should be getting to look for lung cancer at risk early on.   It really saddens me that in a family that doesn't know about this condition, the brother would never get testing and would never think that I might be getting or might never get testing, might not be disposed to getting testing, and might not realize there's a therapy available to target that EGFR mutation if he died young without even much treatment. But this individual, we tested his lung cancer, we found him a therapy, we put him on a pill therapy that could last a very long time. And so we set up a program with a consortium alchemy, the Addario Lung Cancer Medical Institute, where we enrolled at three sites, both at Dana-Farber in Boston, Vanderbilt, and Ohio State, with some motivated investigators there that we appreciate their collaboration.  But also, again, this is now more than 10 years ago, set up shop where people could enroll remotely, that if you found a T790M in your tumor, for whatever reason, you could reach out to the team at Dana-Farber centrally and get consented online and even get counseling. And this is one of the early ways of getting this remote participation. And you can imagine, over the course of the study, we quickly ran out of individuals at any given site, but that remote enrollment accelerated and really allowed us to get to the large population of remote study. Dr. Judy Garber: We were lucky that things were happening. The things you don't expect. So EGFR testing was not routine at that time. And the EGFR testing that had developed in Dana-Farber and NGH became standard of care at Dana-Farber so we were finding those patients, and then grew outside as well, at institutions and testing labs. And these people would somehow emerge so we were very lucky that we were able to set up remote testing. We could send and get a saliva sample and be able to test. Or these were people who got tested through their own doctors, found out they had this mutation and then went online and said, “Who knows anything about this?”  I would say that we and our amazing genetic counselors who spoke to all these patients, took their detailed family histories, got their other information, and were able then to really build out these cohorts so we can understand them. And to look at, for example, Geoff's question, it was really his question, “Why did we have such clusters in certain parts of the country? Could it be that there were the so-called founder mutations that somebody had this mutation and they spread their genes around so that they're around the country and that turned out to be true. Shannon Westin: It's so fascinating, and I love how you kind of almost crowdsourced getting these patients to you because I was mystified because it's such a rare aberration and you had so many patients. Let's talk a little bit maybe about your patient population and who volunteered, and is it reflective of kind of you do think, the general population? Dr. Geoffrey Oxnard: I want to give a shout out to the GO2 Lung Cancer Foundation. That really was a lot of the ‘rah rah', getting people to know about this, having some word of mouth and spreading the word. And so certainly there are physicians around the country that have been like found patients that I've got to know because they sent us patients to study over the years. We ended up getting germline testing on 141 individuals who presented eligible for testing because of either a relative or a mutation that was suspicious for inherited. Most of those were enrolled remotely, in the end, as you might expect. We found what you might expect, that this was Mendelian in its inheritance, that if you had a first degree relatives, they had 50% chance of having this. And so we sort of slowly built these pedigrees of individuals who once they were positive, would refer in their relatives and say, “Please go get testing. Let's describe our family and help understand our risk.”   It ended up boiling down to six individuals with a germline EGFR mutation from 39 different families. I remember one family where two different cousins presented separately to the program, not knowing each other was participating. And so, of course, there's not that many of these families around the United states, but we're really very lucky to have touched so many different individuals. What did we find? That if you had a germline EGFR mutation, your tumor almost always had an EGFR mutation. That really is the dominant biology of lung cancer that presents in these affected individuals, that it presents young, that the likelihood of developing lung cancer is around 55% by age 40 to 50. So it really is– I'm trying to make sure I'm quoting that right, actually, Shannon, I'm looking at the numbers here, but it was a really broad range of diagnosis.  We had a 28-year-old who was affected and an 83-year-old who was affected. I saw a family where the grandson had lung cancer, but his father and grandfather who had germline EGFR mutations, did not. So variable penetrance. Judy, of course, told me, “Geoff, this is the way families present. Come on, Geoff.” But other families, incredible penetrance– not everyone having lung cancer, many of them smoking, some of them not smoking. But for these families, what a sense of empowerment to say, “Oh, this helps explain what's going on in our family, why this is happening at a younger age.” And helps explain the therapies that we had some concern about giving these potent EGFR inhibitors originally, understanding every cell in their body has this EGFR mutation. Are we going to somehow cause toxicity? No. These potent therapies can be effective, can be tolerated, and can work for many years. So we really feel hopeful that we've described a syndrome that's out there that people see and that has a distinct presentation, a distinct treatment pattern, and a clear association with lung cancer risk. Dr. Judy Garber: And I think that now the opportunity is to say, can you find these people before they get their lung cancers? Some of them have abnormalities on scans. Think of it's like the APC, the polyposis coli of lung cancer. You can see these adenomas forming, but we can't really predict exactly who's going to develop tumor when. And that, I think, is a challenge that families have to help us with because we need to continue to identify some of these people who have not had cancer. They have children. They want to know what to tell them besides not smoking adamantly and maybe with some hopes that we're going to do some screening.  I am afraid there probably is not good data that EGFR inhibitors could be used for prevention, but it's tempting to think that way. So there's plenty of work to do still to sort out the questions. This is the nature of genetics. We often find inherited susceptibility and people want to know, “Well, why would I want to know? What am I going to do about it?” And here I would say, “We're going to figure out what's your risk more specifically, and how can we help reduce that risk, in addition to telling you not to smoke.” Dr. Geoffrey Oxnard: I do want to allude to Judy's comment about founder effect. I didn't tell you exactly about the presentation, but these families, first off, we only found germline EGFR mutations in Caucasian individuals and in black individuals, and it was mostly in the United States and in fact, enriched in the southeast United States. And don't get me wrong, we had enthusiastic participation from Vanderbilt. But still it seemed like there was more southeast United States prevalence. And even families I met in the Boston area would say, ‘Oh yeah, I have relatives going back to Arkansas.”   And so we ended up with a bit of a suspicion for this geographic enrichment, studying the genomes of these affected individuals, and in fact did find a very large region of chromosome 7 that was shared in more than 90% of the folks we tested, suggesting a founder effect in the southeast United States, probably white and black. And that goes back hundreds of years, maybe 200, 300, 400 years, as far as we can estimate, making me think that this is a fairly unique syndrome that we're seeing in North America, but actually may not be prevalent in other parts of the globe. Though we did identify a single individual in Australia, it might be a unique phenomenon in North America. Dr. Judy Garber: At least more common. But these days, people travel, so hard to know. Shannon Westin: I don't know if you've gotten a chance to do this - any other cancer type seeming to be associated with this mutation? Dr. Judy Garber: No, fortunately not. Shannon Westin: Okay, very interesting. And what about outcome? What was the association, or was there any association of these mutations with cancer related outcomes? Dr. Geoffrey Oxnard: I would say the survival of these cancers isn't that different than EGFR mutant lung cancers. If they get to effective therapy, they can live for years on therapy. If they don't, they can do quite poorly. One interesting finding is that they can present in a multinodular fashion that might be multiple primaries. And so you can kind of use an approach of eliminating individual clones. Sometimes it's been described these different tumors have different mutations, and so you might treat them like a stage IV lung cancer, but actually they lived for a long time because actually they had multiple stage I lung cancers, so it can present a little bit differently. And then we tried to collect CT scans on affected carriers who did not yet have lung cancer to see if they might develop lung cancer. It was not required on study, and it's sort of an area of future investigation. But as you can imagine, lots of lung nodules and certainly anecdotes of individuals where we found early precancers through the screening effort, motivating the investigation that Judy was alluding to. Dr. Judy Garber: I think this is what you expect in inherited predisposition that you have an earlier chance. So some of them are younger, not the 84-year-old, but that they could be younger, that they could have multifocal disease, that their biology could be different, but could be the same, maybe accelerated, maybe not. Some of these are slower. And I think that's why we're excited to be able to continue this work with the group at Dana-Farber.  Now, Jaclyn LoPiccolo is going to lead the INHERIT study, but much of the team is the same. And now the focus will be even more on trying to really quantify the risk and help think about prevention strategies and screening for these patients. It's a little tricky to want to do too much chest CT screening. On the other hand, there are lower dose CTs now, and we hope the guidelines will clarify the role of inherited risk. At ASCO this year there were a lot of talks about inherited lung cancer risk, but nothing is quite as well characterized as, I think, the T790M population. Shannon Westin: Well, thank you all so much. This was fascinating. I learned a ton and I know our listeners did as well. And thank you to our listeners. This was “Germline EGFR Mutations and Familial Lung Cancer.” Again, published in the JCO August 14, 2023. So go check it out and check out our other podcasts on the website or wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. John Vervaeke engages with the multi-talented Ethan Kobayashi-Hsieh in a conversation that oscillates seamlessly between the theoretical and the practical. Known for transforming Vervaeke's theoretical frameworks into tangible practices, Ethan presents his novel Sapiential Processing Framework, a countermeasure to parasitic cognitive biases. The duo also explores the neurobiology of cognition, the intricacies of recursive awareness, and the enigmatic world of spiritual phenomenology. Throughout the conversation, they illuminate the nuances of dialogical rationality, cognitive flexibility, and the transformative power of awareness. Dr. Vervaeke and Ethan delve deep into the mechanics of performance, drawing fascinating parallels to conventional cognitive science theories. Wrapping up the episode, Ethan shares a poignant practice of writing thoughts for his future children, offering a touch of humanism amid cerebral dialogues. Listen in for a thought-provoking blend of philosophy, psychology, and practical wisdom. Resources:   John Vervaeke: Website | Patreon | Facebook | X | YouTube Ethan Kobayashi-Hsieh: LinkedIn   The Vervaeke Foundation   Related Voices with Vervaeke Episodes   Theatre-ritual-movement ecology of practices w/ Ethan Kobayashi-Hsieh & Tamaki Kobayashi-Hsieh. Building Practices to Cultivate Wisdom | John Vervaeke & Ethan Kobayashi-Hsieh | Voices w/ Vervaeke   Books   The Enigma of Reason - Hugo Mercier, Dan Sperber  From Ritual to Theatre: The Human Seriousness of Play - Victor Turner   Publications   In search of insight | ScienceDirect - Simon & Kaplan   Time Codes   00:00:00 — Dr. John Vervaeke introduces returning guest Ethan Kobayashi-Hsieh. 00:01:04 — Ethan discusses transitioning from theoretical to practical work. 00:01:57 — Ethan shares his Sapiential Processing Framework via a screen presentation. 00:03:08 — Ethan talks about the fourth iteration of his framework. 00:04:00 — Discussion on recursive awareness of interpretive bias. 00:08:22 — Vervaeke draws an analogy between Darwinian theory and Mendelian genetics. 00:10:08 — Vervaeke explains dialogical processing as an antidote to confirmation bias. 00:16:13 — Ethan demonstrates an exercise to shift perspectives in actors. 00:17:47 — Vervaeke introduces the notion of the notice invariance heuristic. 00:23:09 — Vervaeke stresses the transformative aspect of spiritual experiences. 00:25:26 — Both discuss the concept of 'notice invariance.' 00:30:16 — Vervaeke talks about his work on rituals. 00:31:40 — Conversation on deliberate critical reflection for self-organizing criticality. 00:38:00 — Ethan delves into the theatrical context of speaking. 00:39:50 — The concept of presence is debated. 00:45:41 — Ethan discusses introspection and adjustment for personal growth. 00:46:37 — Introduction to the default mode network by Ethan. 00:49:06 — Ethan defines his work as part of a meta curriculum. 00:50:28 — Insights on the cognitive mechanics of performance and parasitic processing. 00:54:55 — Kobayashi-Hsieh urges listeners to fight paralysis through self-awareness. 00:55:36 — Vervaeke wraps up with a reminder of Socrates' multifaceted wisdom.  

On this episode, Dr Peter Fish, the CEO of Mendelian joins the show. Their mission is to make it easier for clinicians to diagnose rare diseases. Their AI based platform can sift through medical records to discover more than 100 rare conditions. As a serial entrepreneur, he has built and invested in various tech companies, combining his medical background with his passion for the tech industry. Learn about his investment experience starting at the age of 18, why they created the product, how it works, their journey to development, and their ambitious plans for addressing rare diseases, which seem to be not as rare as we think. On the show, you'll find out: Peter's background and experience in molecular genetics How he became a serial entrepreneur in South Africa at just 18 What Peter learnt from failures and success in entrepreneurship How optimism and a can-do attitude are essential attributes for entrepreneurs How Mendelian began life in California with a few software engineers and a clinician How they decided to tackle the ‘diagnostic odyssey' affecting those with rare diseases How research into disease and genetics mean that rare diseases may become more prevalent in the future How MendelScan is identifying patients with patterns of symptoms to provide better diagnosis and/or treatment How all their algorithms use deep clinical data in their iterations How their NHS pilots have allowed them to scan 700 000 patient files records so far How their work earned them the NHS AI Award 2023 Guest: Dr Peter Fish Website: https://www.mendelian.co/ Host: Dr Vinay Shankar Website: https://www.oncedaily.co

This video is the second in a two-part series that presents an approach to family history and pedigree. In this video, viewers will review the classic patterns of Mendelian inheritance and see how these patterns might look in a pedigree. This podcast was developed by Erinna McMurtry and Jovana Miladinovic in collaboration with Dr. Patricia Blakley, an Associate Professor at the Department of Pediatrics at the University of Saskatchewan with specialization in clinical genetics and developmental pediatrics.

Hi Everyone! In today's episode we go over some basics of Mendelian inheritance and Hardy-Weinberg population genetics. Hope you enjoy!

Today we discuss the link between gastrointestinal disorders and mental health, how the path you take walking through a crowd can be predicted by mathematics, and how we've now witnessed an example of super propulsion in nature for the first time! GERD Anxiety “The causal role of gastroesophageal reflux disease in anxiety disorders and depression: A bidirectional Mendelian randomization study” by Youjie Zeng, Si Cao, and Heng Yanghttps://www.frontiersin.org/articles/10.3389/fpsyt.2023.1135923/full“Linking the Gut and the Mind: New Evidence Shows GERD May Increase Risk of Anxiety and Depression” by Heng Yang, Youjie Zeng, and Si Caohttps://oa.mg/blog/gerd-may-increase-risk-of-anxiety-and-depression/“Gastroesophageal reflux disease (GERD)” by Mayo Clinichttps://www.mayoclinic.org/diseases-conditions/gerd/symptoms-causes/syc-20361940#:~:text=Gastroesophageal%20reflux%20disease%20(GERD)%20occurs,reflux%20from%20time%20to%20time.“GERD (Chronic Acid Reflux)” by Cleveland Clinichttps://my.clevelandclinic.org/health/diseases/17019-gerd-or-acid-reflux-or-heartburn-overviewCrowd Math “Lane nucleation in complex active flows” by KAROL A. BACIK, BOGDAN S. BACIK, AND TIM ROGERShttps://www.science.org/doi/10.1126/science.add8091“Stick to your lane: Hidden order in chaotic crowds” by University of Bathhttps://phys.org/news/2023-03-lane-hidden-chaotic-crowds.html“Mathematicians have discovered the hidden patterns that exist within ‘chaotic' crowds” by Connie Linhttps://www.fastcompany.com/90860429/mathematics-of-crowds-patterns-theoryInsect Catapult  “Droplet superpropulsion in an energetically constrained insect” by Elio J. Challita, Prateek Sehgal, Rodrigo Krugner & M. Saad Bhamlahttps://www.nature.com/articles/s41467-023-36376-5“Insect that flings pee with a butt catapult is 1st known example of 'superpropulsion' in nature” By Charles Q. Choihttps://www.livescience.com/insect-that-flings-pee-with-a-butt-catapult-is-1st-known-example-of-superpropulsion-in-nature“Sharpshooter Insects Use ‘Superpropulsion' to Catapult Their Pee” by Jack Tamisieahttps://www.scientificamerican.com/article/sharpshooter-insects-use-superpropulsion-to-catapult-their-pee1/Follow Curiosity Daily on your favorite podcast app to get smarter with Calli and Nate — for free! Still curious? Get exclusive science shows, nature documentaries, and more real-life entertainment on discovery+! Go to https://discoveryplus.com/curiosity to start your 7-day free trial. discovery+ is currently only available for US subscribers.Find episode transcripts here: https://curiosity-daily-4e53644e.simplecast.com/episodes/gerd-anxiety-crowd-math-insect-catapult

This week, please join author Mikael Dellborg and Associate Editor Gerald Greil as they discuss the article "Adults With Congenital Heart Disease: Trends in Event-Free Survival Past Middle Age." Dr. Greg Hundley: Welcome listeners to this March 21st issue. And I am one of your co-hosts, Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VSU Health in Richmond, Virginia. Dr. Peder Myhre: And I am the other co-host, Dr. Peder Myhre, from Akershus University Hospital and University of Oslo in Norway. Dr. Greg Hundley: Well, Peder, we have a very interesting feature discussion this week. It focuses on adults with congenital heart disease. And as you are aware, over the last 25 to 30 years the survival rate of individuals with congenital heart disease has really improved. And this group, led by Professor Dellborg, will discuss with us more on results from a Swedish registry examining patients after the age of 18 with adult congenital heart disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first? Dr. Peder Myhre: I would love it to, Greg, thank you. So Greg, the first paper is about aortic stenosis and the genome-wide association study looking at aortic stenosis in patients from the Million Veteran Program. And as you know, Greg, calcific aortic stenosis is the most common valve of heart disease in older adults and has no effective preventive therapies. Genome-wide Association studies, GWAS, can identify genes influencing disease and may help prioritize therapeutic targets for aortic stenosis. And in this study, which comes to us from co-corresponding authors, O'Donnell from VA Boston Health System and Dr. Natarajan from Massachusetts General Hospital, both in Boston Massachusetts, performed genetic analysis in 14,451 cases with aortic stenosis and almost 400,000 controls in the Multiancestry Million Veteran Program. And replication for these results was performed in five other cohorts. Dr. Greg Hundley: Wow, Peder, so a very large gene-wide association study. So what did they find? Dr. Peder Myhre: So Greg, the authors found 23 lead variants representing 17 unique genomic regions. And of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. And five replicated genomic regions were previously known risk loci for aortic stenosis, while six were novel. And of the 14 replicated lead variants, only two of these were also significant in atherosclerotic cardiovascular disease GWAS. And in Mendelian randomization, lipoprotein a and LDL cholesterol were both associated with aortic stenosis, but the association between LDL cholesterol and aortic stenosis was attenuated when adjusting for LP a. So Greg, in conclusion this study identified six novel genomic regions for aortic stenosis, and secondary analysis highlighted roles of lipid metabolism, inflammation, cellular senescence and adiposity in the pathobiology of or stenosis, and also clarified the shared and differential genetic architectures of aortic stenosis with atherosclerotic cardiovascular disease. Dr. Greg Hundley: Wow, Peder, what a beautiful description. Very comprehensive study. Well, my study comes to us from the world of preclinical science and, Peder, it involves embryonic heart development. So Peder, placental and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor presentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain really unresolved. So in this study, led by Dr. Suchita Nadkarni from Queen Mary University of London and colleagues, the team used an in vivo neutrophil-driven placental inflammation model via antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy, embryonic day 4.5, 7.5, and then the animals were culled at embryonic day 14.5 to assess placental and embryonic heart development. Dr. Peder Myhre: Oh, wow. Very interesting design. And, Greg, I'm curious to know what did they find? Dr. Greg Hundley: Right, Peder. So they found that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. And consequently, placental inflammatory monocytes of maternal origin become capable of then migrating to the embryonic heart and alter the normal composition of resonant cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Also, they found that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life. So in conclusion, Peder, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development. And this in turn certainly has major implications on cardiac function into the adult life of these animals. And this really warrants further study in larger animal models and perhaps human subjects. Dr. Peder Myhre: Very interesting, Greg. Thank you for summarizing that. And we also have some other articles in the mail bag today. Do you mind going first? Dr. Greg Hundley: Sure, Peder. So what I've got is a very nice exchange of letters from Doctors Deng, Schmidt, and Tabák regarding a prior paper entitled, "Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study." Dr. Peder Myhre: And Greg, we also have a Research Letter from Dr. Niklas Bergh entitled, "Risk of Heart Failure in Congenital Heart Disease: A Nationwide Register-based Cohort Study." And then there is an article summarizing Highlights from the Circulation Family written by Molly Robbins [and Dr. Parag Joshi] where she summarizes, first the characteristics of pleomorphic ventricular tachycardia described in Circulation: A and E, then racial inequities in assessing advanced heart failure therapies reported in Circulation: Heart Failure. Outpatient clinic-based vascular procedure outcomes are compared with those done in a hospital setting in Circulation: Cardiovascular Quality and Outcomes. Then there's a paper about immune cell imaging using nuclear methods from Circulation: Cardiovascular Imaging. And finally, temporal trends in left main PCI from the UK described in Circulation: Cardiovascular Interventions. And then Greg, we have one final very interesting paper, which is a joint opinion from the European Society of Cardiology, American Heart Association, and American College of Cardiology, in addition to the World Heart Federation and it's entitled, "Randomized Trials Fit for the 21st Century." And I'm going to read you a quote from the beginning of this article, Greg. It is, "Randomized controlled trials are the cornerstones for reliably validating therapeutic strategies. However, during the past 25 years, the rules and regulations governing randomized trials and their interpretation have become increasingly burdensome, and the cost and complexity of trials has become prohibitive. The present model is unsustainable, and the development of potentially effective treatments is often stopped prematurely on financial grounds, while existing drug treatments or non-drug interventions, such as screening strategies or management tools, may not be assessed reliably." What do you think about that? Dr. Greg Hundley: Oh, wow, Peder. Very provocative. So it'd be interesting for our listeners to take a gander at that particular paper. Well, what a great issue and how about we get on to that feature discussion? Dr. Peder Myhre: Let's go. Dr. Mercedes Carnethon: Thank you for joining us on this episode of Circulation on the Run Podcast. My name is Mercedes Carnethon. I'm an Associate Editor at the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. I'm thrilled today to be able to host this podcast alongside my colleague at Circulation, Gerald Greil, and with our special guest today, Dr. Mikael Dellborg from the Sahlgrenska Academy at the University of Gothenburg and Sahlgrenska University Hospital. Welcome this morning, Mikael, to our podcast. We're really excited that you shared this important work to us about adults with congenital heart disease, particularly given the burden of the condition and how many more individuals are living to adulthood with congenital heart disease. So I'd love to really just open with asking you to tell us a little bit about your study and what you found. Professor Mikael Dellborg: Well, first thank you for inviting me to talk about these issues. I very much appreciate the opportunity and I appreciate having the paper published by Circulation, which of course is a great honor. Our study included 37,278 patients with congenital heart disease born between 1950 and 1999, and alive at 18 years of age. Follow-up was started in 1968 and at 18 years of age, and went on until the end of 2017 or death. So the mean follow-up was 19.2 years. And for every patient with CHD, we had 10 randomly chosen controls from the general population registry, matched for year of birth and sex and, of course, without CHD, so 37,000 patients and 412,000 controls. During the follow-up, 1,937 patients with CHD died or 5.2%, as compared to 1.6% of controls, a mortality three to four times higher among patients with CHD. Still, at 50 years of follow-up, i.e. at age 68, more than 75% of all patients with CHD were still alive, and I think that is the positive news of this paper. Mortality wise, this could be expected highest among those with the most severe defects, the conotruncal defects, i.e., the transposition of the great arteries, the tetrology patients, double out ventricles and so on. And there the hazard ratio for death was 10.1 times that of controls. But also, for non-com complex conditions such as that we consider very malignant such as atrial septal defect, the ASD, there was a slight but significant increase in risk with the hazard ratio 1.4 times that of controls. We also looked at how the increased risk of mortality changed over time. And when comparing birth year by birth year, we could see that things started to really change in the mid 1970s, where the hazard ratio began to decline. So if you were born around 1950, '60 or '70, once you reached 18 years of age, your risk of dying had not really changed over the years. But once you were born '75, '80, '85 and on, your risk past 18 years of age declined and was lower as compared to those born before that, although still higher than the risk for controls. This decline was dramatic and significant for all patients with complex CHD. For patients with less complex conditions, it was smaller and not statistically significant. Although it trended in the same direction. The excess risk also declined with age. Typically, it declined from 20 to 100 times the risk of controls in the first years after turning 18, to seven to eight times after 30 years of follow-up. In other words, when you were in your fifties the difference between CHD and controls was much smaller, although still existed. Dr. Mercedes Carnethon: Oh, wow. So that really seems to shift over time and that gap got a little smaller with aging. What about these findings surprised you? Professor Mikael Dellborg: What surprised us was to see that there is a... For the CHD population as a group, we can see that the changes in operative techniques, the possibility to operate on much earlier time that became used in the '70s, mid-late '70s, early '80s, that has really changed life for so many patients. When we started the Adult Congenital Heart Unit at our hospital in 1996, there was a belief that either you were cured or you are a sad person to follow. You will only have trouble and you will die in your thirties or you'll get a transplant. That was the three conditions that we could see coming, but that's not true. I mean, again, once you turn 18, once you come to the adult cardiologist, you will most likely be 68, 70 years, 75 years of age. Dr. Mercedes Carnethon: Now, that is fantastic. I want to turn to you, Gerald, because you were obviously the handling editor of this piece and saw a lot of strengths. Can you tell us a little bit about why you wanted this piece for Circulation? Dr. Gerald Greil: Mikael, thank you so much for submitting to Circulation. The numbers of the patients you had for this study, including the controls, is impressive and we all think that it's one of the largest patients areas we looked at. Mikael, obviously this is all exceptional, but can you line out to us what are the strengths and limitations of your study? And how you think the results of your investigations are going to impact patient care in the future? Professor Mikael Dellborg: Thank you, Gerald. I think that the strengths are obviously, like you pointed out, there's 37,000 patients. There is 50 years of patients, there's 20 years of follow-up on average and that's clearly a strength. Also, that we have virtually no patients lost to follow-up. We have many controls and the registers we used are public, mandatory and have been fully operational for CHD care and CHD hospitals and including the death registry since 1968, which is when we really started the follow-up. So it's a broad and complete spectrum of patients with congenital heart disease, excluding none, and I think it's fair to say that our data reflect what you can expect from a population of eight to 10 million people, which is the Swedish population during these years. The weaknesses are clearly, as with any data of this sort, i.e. Large public registers, you will always lack the granularity. The clinical data, the blood pressure, weight, ECG, the echocardiogram, the cath data, et cetera. And also the lifestyle information, smoking, exercise, diet. It's also important to realize that Sweden was, particularly at this time before 2000, it was a fairly homogenous society in terms of ethnicity. One feature, which I'm not sure if it's a strength or a limitation, is that we group patients with CHD into one or sometimes two complex non-complex or at the most six groups. And since CHD consists of about 400 different diagnosis and entities, we paint a broader general picture. But if you want to know more about specific conditions such as say, hypoplastic left heart syndrome, you need to look for other and more specific papers. We're currently working on several more analysis based on this material for more narrow patient groups where we can take into consideration also things such as type of surgery or intervention, timing of intervention, medication and so on. We have a lot of data on this, but it was simply not possible to put everything into one paper. Dr. Gerald Greil: Yeah, I mean speaking about getting more specific, we were fortunate enough having one of your colleagues publishing about patients with congenital heart disease. They looked at the time period from 1930 to 2017 using the same database. And they focused specifically on heart failure in this group of patient describing it in a research letter, actually in the same volume your paper's published. How does this study relate to your work? And how do you think are their results impacting the care of these patients? Professor Mikael Dellborg: I think they relate to our paper in a nice way, because one of the things we also could show was that the morbidities of patients with adult congenital heart disease are significant. The risk of heart failure, atrial fibrillation, stroke, nonfatal MI, diabetes, and so on, is much larger in that group. And the cumulative risk of having any such adverse event is about 75% at age 68 after 50 years of follow-up. The letter by Bergh et al. focuses on, as you say, heart failure. And during a follow-up or 25 years, there was an overall, like you said, 8.7 times higher risk for patients with CHD to develop heart failure. The most, I think, important factor from this is not only that the risk is increased, it has been described before and it's obvious and quite intuitive, but there was a dramatic difference in the age of onset of heart failure, which was about 40 years in patients with CHD compared to 66 years of age for the controls who developed heart failure. And again, it was obvious that it was highest among the most complex CHD. The risk was 20 to 40 times higher. But also among non-complex CHD, the atrial receptor defects, the ventricular receptor defects, the risk was significantly higher, five to 10 times. One thing we saw there was that... That could be seen there was that the risk was particularly high in the youngest age group, the youngest patients, as compared to controls. And not so much, although still significant, it increased also in the higher age groups. We could also see that the risk of heart failure seemed to increase. It was higher among those born after 1970 as compared to those before 1930 to '69. And I have two explanations for that. One is that a lot of patients born in 1930 and so on were not captured by our registers, because they have died before that. But it also reflects that the most complex patients, the most likely to develop heart failure, they survive these days. They did not survive in their thirties, forties, fifties, sixties and early seventies and so on, so that's why. So things haven't been worse, but we do have a much sicker group of patients with congenital heart disease that are alive today. Dr. Mercedes Carnethon: That's very hopeful. When I hear that and I think about the impact that treatment and therapy has had on these improvements in survival, it's really exciting to hear. We were really enthusiastic because our colleagues, Dr. Rosenthal and Qureshi from London, submitted an editorial to discuss your piece as well as Dr. Bergh's piece. And they're discussing in it some of the complexity in providing this care and what it has taken to get us to this point where survival is better. Can you tell us a little bit based on the findings from your study and what you know of the field, how do you envision the future care of adults with congenital heart disease? Professor Mikael Dellborg: Yes, Mercedes, thank you. I think this is a very nice editorial. It summarizes very well where we are today, and I think they see the future very much along the same lines as I do and as we do. But the large number of patients with CHD living into their sixties, seventies, and eighties, they will not only live longer, they will also have more comorbidities. And I think that's what our data shown and what the editorial is discussing. This will require some changes to be made to the care of adults with congenital heart disease. We will clearly, as pointed out, need large, highly specialized, very competent ACHD centers located close to, or at least in close corporation with pediatric centers. There's no doubt about that building such centers need to continue and you need roughly one large complete such center with outpatient clinic, surgical interventions, structured transfer, specialized physicians, physiotherapists, nurses, education research, et cetera. You need about one such center per 5 million people. But over time the need of ACHD patients will also change and this will have impact also on the large specialized centers. For instance, if you have an adult patient with say, tetrology of Fallot, fairly common disease in this setting, well operated on a early childhood, well-functioning, modest right ventricular dysfunction, modest pulmonary valve insufficiency, and it's followed by a large centralized ACHD unit. You will keep track of the right ventricle size waiting for the proper time to intervene and replace the right ventricular outflow tract by surgery or catheter. This waiting is probably 10, 15, maybe 20 years before anything needs to be done. But during that time the patient develops hypertension, type 2 diabetes, AFib, and the chances of this happening at some time are fairly substantial. So either the ACHD unit needs to take care of also these comorbidities and that's not always the case today. And I think it's unrealistic to expect primary care GPs to do this. I mean, would you as primary... As a GP start the SGLT2 treatment? Is that okay for a patient with Fallot? Or the indications for anticoagulation the same as... And that's not easy patients to handle. So on the other hand, if the ACHD unit will take care also of all these comorbidities, they will, I think, have too much to do and I think they will find it difficult to completely cope with this. So as in increasing role for cardiologists who are knowledgeable on ACHD care, but who perhaps spend most of the time caring for the usual patients with heart failure and AFib, post-MI, type 2 diabetes and who are confident in using novel anti-diabetic medications, but at the same time they know about Fallot. They know enough to understand the do's and don'ts, and they can interact on a regular basis with the local ACHD units. So patients will see their general cardiologist twice a year perhaps, and the ACHD center every two years, something like that. I think there's a great need for that. Dr. Mercedes Carnethon: I really appreciate having your insights on that. Do you have anything, Gerald, that you'd like to follow up with? I think the feedback that you've shared with us, Mikael, about where you see the treatment field going for adults has been very comprehensive and it's fantastic to be able to have these conversations with you, because obviously these discussions go beyond what you can share in the original research article, which is why we really enjoy this opportunity with the podcast. So Gerald, I'd really like to turn it to you for a final wrap up, given your expertise in this area. Dr. Gerald Greil: Yeah, I mean, Mikael, thank you so much to you and your colleagues just giving us this great overview, and even more importantly giving us the perspective how this field is going. I think we are getting more and more aware that there are more patients with and adults with congenital heart disease we need to take care of. We need to find new strategies, as you correctly pointed out, to cope with the enormous burden of disease and providing these patients good quality of life and excellent outcome after sometimes a very difficult start in their lives. And we need to be aware of the pediatricians and adult cardiologists and other subspecialties are forming a team and working together and not working as separate entities. So thank you so much for giving us this perspective. And I would hand over to Mercedes to wrap up the whole discussion please. Dr. Mercedes Carnethon: Well, yes, I just really want to thank our listeners for tuning in with us today. It was such a delight to have you here with us, Dr. Dellborg, and thank you as well for sharing your insights. Thank you for joining us again for this episode of Circulation on the Run Podcast. It's meant to whet your appetite and turn you towards the journal so that you can read more. So thank you very much. Dr. Greg Hundley: 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.

A key goal of eugenics in the 20th century was to eliminate genetic defects from a population. Many countries pursued this with state-led programmes of involuntary sterilisation, even murder. We unpick some of the science behind this dark history, and consider the choices and challenges opened up by the science today. In the mid-19th century, an Augustinian friar called Gregor Mendel made a breakthrough. By breeding pea plants and observing how certain traits were passed on, Mendel realised there must be units - little packets - of information determining characteristics. He had effectively discovered the gene. His insights inspired eugenicists from the 1900s onwards. If traits were passed on by specific genes, then their policies should stop people with ‘bad' genes from having children. Mendel's ideas are still used in classrooms today - to teach about traits like eye colour. But the eugenicists thought Mendel's simple explanations applied to everything - from so-called ‘feeblemindedness' to criminality and even pauperism. Today, we recognise certain genetic conditions as being passed on in a Mendelian way. Achondroplasia - which results in short stature - is one example, caused by a single genetic variant. We hear from Professor Tom Shakespeare about the condition, about his own decision to have children despite knowing the condition was heritable - and the reaction of the medical establishment. We also explore how genetics is taught in schools today - and the danger of relying on Mendel's appealingly simple but misleading account. Contributors: Dr Brian Donovan, senior research scientist at BSCS, Prof Tom Shakespeare, disability researcher at London School of Hygiene and Tropical Medicine; and Dr Christine Patch, principal staff scientist in Genomic Counselling in the Society and Ethics Research group, part of Wellcome Connecting Science.

This podcast is a commentary and does not contain any copyrighted material of the reference source. We strongly recommend accessing/buying the reference source at the same time. ■Reference Source (You can purchase the original book from here) https://amzn.to/3VftFFx ■Post on this topic (You can get FREE learning materials!) https://englist.me/48-academic-words-reference-from-the-intellectual-devotional-revive-your-mind-complete-your-education-and-roam-confidently-with-the-cultured-class-week-9-day-4-mendelian-genetics--rodale-books/ ■Youtube Video https://youtu.be/mxn-csNWe-8 (All Words) https://youtu.be/yJSy5MvoLp4 (Advanced Words) https://youtu.be/aCfztVeaOLw (Quick Look) ■Top Page for Further Materials https://englist.me/ ■SNS (Please follow!)

Episode #243. It's time to face the facts on saturated fat. Dr Gil Carvalho returns to examine a bold new study on this controversial topic, breaking down whether you need to reconsider your food choices in the wake of this study's release. We discuss: Intro (00:00) Saturated fat misunderstandings: Is saturated fat bad? (17:20) Principle 1: Dose matters? — How much saturated fat is too much? (22:07) Is no saturated fat the goal? (30:12) Principle 2: Replacement nutrient matters (31:54) Principle 3: Source matters (45:53) Mechanisms: Saturated fat and heart disease (50:48) Saturated fats and genetics (55:47) Target ApoB level (59:40) Importance of lifetime exposure (1:03:02) Statins and heart disease risk: Are statins bad for you? (1:08:53) Mendelian randomization studies (1:10:52) The totality of evidence (1:15:59) Saturated fats and total mortality (1:17:46) Saturated fat and liver health (1:19:51) Gaps in the research (1:20:43) Common arguments against lowering saturated fat (1:23:52) Outro (1:38:36) To explore more of Dr Gil Carvalho's work, you can find him on YouTube. You can also connect with him on Twitter and Facebook, and listen to our previous conversation in Episode #207. Discover more insights and supporting studies in the full show notes. Enjoy, friends. Simon Want to support the show? The best way to support the show is to use the products and services offered by our sponsors. To check them out, and enjoy great savings, visit theproof.com/friends. You can also show your support by leaving a review on the Apple Podcast app and/or sharing your favourite episodes with your friends and family. Simon Hill, MSc, BSc (Hons) Creator of theproof.com and host of The Proof with Simon Hill Author of The Proof is in the Plants Watch the episodes on YouTube or listen on Apple/Spotify Connect with me on Instagram, Twitter, and Facebook Nourish your gut with my Plant-Based Ferments Guide Download my complimentary two-week meal plan and high protein Plant Performance recipe book

A key goal of eugenics in the 20th century was to eliminate genetic defects from a population. Many countries pursued this with state-led programmes of involuntary sterilisation, even murder. We unpick some of the science behind this dark history, and consider the choices and challenges opened up by the science today. In the mid-19th century, an Augustinian friar called Gregor Mendel made a breakthrough. By breeding pea plants and observing how certain traits were passed on, Mendel realised there must be units - little packets - of information determining characteristics. He had effectively discovered the gene. His insights inspired eugenicists from the 1900s onwards. If traits were passed on by specific genes, then their policies should stop people with ‘bad' genes from having children. Mendel's ideas are still used in classrooms today - to teach about traits like eye colour. But the eugenicists thought Mendel's simple explanations applied to everything - from so-called ‘feeblemindedness' to criminality and even pauperism. Today, we recognise certain genetic conditions as being passed on in a Mendelian way. Achondroplasia - which results in short stature - is one example, caused by a single genetic variant. We hear from Professor Tom Shakespeare about the condition, about his own decision to have children despite knowing the condition was heritable - and the reaction of the medical establishment. We also explore how genetics is taught in schools today - and the danger of relying on Mendel's appealingly simple but misleading account. Contributors: Dr Brian Donovan, senior research scientist at BSCS; Professor Tom Shakespeare, disability researcher at London School of Hygiene and Tropical Medicine; and Dr Christine Patch, principal staff scientist in Genomic Counselling in the Society and Ethics Research group, part of Wellcome Connecting Science. Music: Jon Nicholls Presenter: Adam Rutherford Producer: Ilan Goodman

This is a bonus episode featuring a special guest hosted by the NC State Science, Technology, and Society (STS) and GBIRd – Genetic Biocontrol of Invasive Rodents programs. Note, the audio is a little rough due to the way it was recorded. The video is also available here, as well as the PDF of the presentation slides. Dr. Tanja Strive, Senior Principal Research Scientist at Commonwealth Scientific and Industrial Research (CSIRO), Australia's National Science Agency “Prospects for genetic biocontrol of vertebrate pests in Australia” Thursday, December 8, 2022, 3:00-4:30 PM Abstract: Deliberately or accidentally introduced invasive species have cost the Australian economy AUD$390 billion during the past 60 years, with vertebrate pests such as feral cats and rabbits amongst the costliest, and more effective landscape-scale management tools are needed. Novel revolutionary genetic technologies have recently been developed that can force modified genetic traits into an animal population, defying the constraints of normal Mendelian inheritance. Combined with a highly specific gene editing system, this technology has the potential for population control of pests, for example by creating all-male or female infertile offspring which would ultimately lead to the collapse of the target population. Delivered and spread through sexual reproduction the potential of this powerful new technology is unprecedented, making pest eradication theoretically feasible. Proof of concept in a mammalian model system (mice) has recently been achieved, raising the possibility of exploring these technologies for some of Australia's most intractable and damaging vertebrate pests. In line with the Guiding Principles for Sponsors and Supporters of Gene Drive Research (Science, 2017), in addition to technical developments, extensive consultations are currently underway in Australia with key stakeholders including scientists, government regulators, policy makers and public representatives. Moving forward it will be essential to ensure a transparent and informed debate, responsible conduct of science, provide a robust regulatory framework, and to identify key pathways and barriers to adoption of any putative genetic control tools. Related links: CSIRO – Biological Control of Rabbits Tanja Strive on Google Scholar Download event flyer Speaker Bio: Dr. Tanja Strive is a Senior Principal Research Scientist within CSIRO Health and Biosecurity, based in Canberra, Australia. A molecular virologist by training, she joined CSIRO in 2002 following the completion of the PhD at the Philipps University in Marburg, Germany. She has since worked on a series of projects investigating lethal and non-lethal, and both GM and non-GM, biocontrol options for a range of feral animal species, including European foxes, mice, cane toads and rabbits. During the past ten years Tanja has led a project portfolio of both applied science and fundamental research projects aimed at developing a pipeline of biocontrol tools for European rabbits, exploring both classical viral biocontrol approaches and more recently prospects for genetic biocontrol technology. For more information, please contact Dr. Jason Delborne, Director of Science, Technology, and Society (STS) at jadelbor@ncsu.edu.[Talk Description] Genetic Engineering and Society Center GES Colloquium - Tuesdays 12-1PM (via Zoom) NC State University | http://go.ncsu.edu/ges-colloquium GES Mediasite - See videos, full abstracts, speaker bios, and slides https://go.ncsu.edu/ges-mediasite Twitter - https://twitter.com/GESCenterNCSU GES Center - Integrating scientific knowledge & diverse public values in shaping the futures of biotechnology. Find out more at https://ges-center-lectures-ncsu.pinecast.co

This week, please join author Sean Pokorney and Associate Editor Shinya Goto as they discuss the article "Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial." Dr Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and Backstage Pass of the journal and its editors. We're your cohost. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:            And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting topic. In patients that have end stage renal disease that require dialysis, questions emerged should we anticoagulate them to prevent stroke, but of course, there's a risk of excess bleeding. Well, this feature discussion today is a study comparing apixaban and warfarin for anticoagulation in exactly this patient population. But before we get to those results, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first? Dr Carolyn Lam:               Absolutely, Greg. So my first paper is a pre-specified analysis of the Paradise MI trial and knowing you'll likely ask me what that was about, Greg, at least to summarize for everyone, the Paradise MI trial compared sacubitril/valsartan with ramipril and its effect on reducing heart failure events after an MI in more than 5,600 patients with an acute myocardial infarction complicated by LV systolic dysfunction, pulmonary congestion, or both. Now in today's paper, what Dr. Mehran and colleagues found was that among patients with a recent AMI and LV systolic dysfunction, heart failure are both, sacubitril/valsartan decreased the risk of coronary related events by 14% as compared with ramipril over a median follow-up of 22 months. The reduction in coronary events occurred with a favorable safety profile. Dr Greg Hundley:            Wow, Carolyn, very interesting. Another indication perhaps for sacubitril/valsartan, especially relative to ACE inhibitors. So what does this mean for us clinically? Dr Carolyn Lam:               Well, the results really cause us to consider if in addition to antiplatelets and lipid lowering therapies, sacubitril/valsartan may be explored as a potential agent to mitigate the residual risk in survivors of AMI. Of course, dedicated studies are necessary to confirm this finding and elucidate its mechanism. Dr Greg Hundley:            Oh, very nice, Carolyn. Well, my first paper comes to us from the World of Preclinical Science and Carolyn, this study evaluated the scavenger receptors stabilin-1 and stabilin-2, proteins that are preferentially expressed by liver sinusoidal endothelial cells. Now, they mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. And studies suggest that stabilin-1 and stabilin-2 may impact atherosclerosis. So in this study, the investigative team led by Professor Cyrill Géraud from the University Medical Center and Medical Faculty in Mannheim, Heidelberg comprehensively studied how targeting stabilin-1 and stabilin-2 affects atherosclerosis. Dr Carolyn Lam:               Huh. All right, nicely explained. And so what did they find, Greg? Dr Greg Hundley:            Right, Carolyn. So inhibition of evolutionary conserved class H scavenger receptors, stabilin-1 and stabilin-2, reduced aortic plaque burden in preclinical models and athero protection was mediated likely through down regulation on transcriptional factor ERG1 in monocytes by multifaceted plasma protein changes. And then finally, Carolyn transforming growth factor beta induced periostin, reelin, and they are novel ligands of stabilin-1 and stabilin-2 and are implicated in the development of atherosclerosis. Dr Carolyn Lam:               Okay. Wow. Could you give us a take home message, please Greg? Dr Greg Hundley:            Right. Carolyn, I knew you had asked me this. So here we go. Monoclonal, anti-stabilin-1 and anti-stabilin-2 antibodies provide a novel approach for the future treatment of atherosclerosis. And in the future, perhaps the plasma proteome composition may serve as a predictive factor, biomarker or surrogate parameter for cardiovascular disease in patients. Dr Carolyn Lam:               Wow. Thanks Greg. My next paper is a true story of discovery. Now I could ask you what you know about the condition hypertension with brachydactyly type E... Greg, I love that expression. I wouldn't be able to answer that too. So let me tell you the story. So hypertension with brachydactyly type E is an autosomal dominant Mendelian disease resembling essential hypertension. Untreated patients die of stroke by the age of 50 years. Now, these authors had previously demonstrated a gain of function phosphodiesterase 3A gene mutations that caused the condition by increasing peripheral vascular resistance. They studied a large family with the condition earlier and were puzzled that cardiac hypertrophy and heart failure did not occur despite the decades of hypertension. And so they hypothesized that in the heart, this phosphodiesterase 3A or PDE3A mutations could be protective. Isn't that neat? And so corresponding authors, Doctors Bader, Klussmann, Bähring and Hübner, all from the Max Delbruck Center for Molecular Medicine in Berlin, Germany. So they studied new patients as well as CRISPR-Cas9 engineered rat models of this condition of hypertension with brachydactyly type E. And they comprehensively phenotyped all of them with the human induced pluripotent stem cells carrying these PDE3A mutations as well. So analyzing all of this from cells to new patients to CRISPR-Cas9 models. Dr Greg Hundley:            Wow, Carolyn, what an interesting story. So what did they find? Dr Carolyn Lam:               So while in vascular smooth muscle, the PDE3A mutations caused hypertension, in the hearts, they conferred protection against hypertension-induced cardiac damage, hypertrophy and heart failure. The mechanism involved long-term adaptations of mRNA and protein expression as well as calcium cycling. Non-selective PDE3A inhibition was a final short term option in heart failure treatment to increase cardiac cyclic AMP and improve contractility. So the data argued that mimicking the effect of PDE3A mutations in the heart rather than non-selective PDE3 inhibition was cardioprotective in the long term. And these findings could indeed facilitate the search for new treatments to prevent hypertension-induced cardiac damage. This is discussed in a really lovely editorial by Dr. Chiong, Houslay, and Lavandero. Dr Greg Hundley:            Very nice, Carolyn. Wow. What another... we have such great articles from the World of Preclinical Science. Beautiful description as well. Well, we have some other articles in the issue, particularly from the Mailbag. And we have a Research Letter from Professor Thiagarajan entitled “Yield of Cardiac MRI in a pre-participation cohort of Young Asian males with T-Wave inversion.” Dr Carolyn Lam:               Interesting. There's an exchange of letters between Dr. Xu and Huang regarding the article associations of dietary cholesterol, serum cholesterol and egg consumption with overall and cause-specific mortality with a systematic review and updated meta-analysis. There is a Perspective piece by Dr. Marcus on Smart watch detected atrial fibrillation, the value in positive predictive value. Isn't that interesting? And now onto that very, very important question of anticoagulation in patients with kidney disease. Can't wait. Let's go, shall we? Dr Greg Hundley:            You bet. Carolyn. Welcome listeners to our December 6th feature discussion. And we have with us today Dr. Sean Pokorney from Duke University in Durham, North Carolina, and our associate editor, Dr. Shinya Goto from Tokai University in Isehara, Japan. Welcome gentlemen. Well, Sean, we're going to 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. Sean Pokorney:         Yeah, absolutely. Thanks for having me to discuss the renal AF trial. And so I would say that the background information to the study was that we know that atrial fibrillation is an incredibly common condition in patients with chronic kidney disease. And the decision of anticoagulation in patients with end-stage kidney disease, on hemodialysis is really quite complex because these patients are at high risk for stroke and they're at high risk for bleeding. There are concerns with warfarin around calcific uremic arteriolopathy or calciphylaxis and there have been some data including from the original Aristotle trial that apixaban was even more favorable in terms of bleeding reduction relative to warfarin in patients with more advanced chronic kidney disease. Although patients with creatinine clearance less than 25 were excluded from Aristotle and really all patients with endstage kidney disease on hemodialysis have been excluded from all trials of atrial fibrillation in the past. And so we really wanted to evaluate the safety of apixaban versus warfarin in patients with end-stage kidney disease, on hemodialysis. And the hypothesis was that apixaban was going to be non-inferior to warfarin with respect to safety in terms of major or clinically relevant, non-major bleeding in these patients with atrial fibrillation and end stage kidney disease on hemodialysis. Dr Greg Hundley:            Thanks so much, Sean. And you've mentioned the renal AF trial. So could you describe for us, for your, I guess, substudy, what was the study population? Who did you include and describe for us also your study design? Dr. Sean Pokorney:         Yeah, absolutely. So the trial included patients who had end-stage kidney disease, and/or on hemodialysis, as well as having concomitant atrial fibrillation. And the patients had to have a CHA-VASc score greater than equal to two. All of the patients had to be on hemodialysis for at least three months. So these were chronic hemodialysis patients. And the study design was an open label randomized trial that was 1:1 randomization between apixaban and warfarin with blinded outcome evaluation. And again, the primary endpoint of the study was major or clinically relevant non-major bleeding based on ISTH definitions. And there were secondary endpoints looking at stroke, systemic embolism, death, medication adherence, and I think a really important sub-study looking at PK data. And the goal was to have 50 patients where we included PK data that was going to more represent what chronic apixaban dosing data would look like in these patients with end-stage kidney disease on hemodialysis. And originally the goal of the trial was to include over 700 patients. Originally we were trying to include 762 patients based on our initial power calculations to achieve true non-inferiority. Unfortunately, the trial enrollment was low and so the trial was ultimately stopped prematurely at 154 patients, although we were able to include the original targeted 50 patients in the PK substudy. The dosing that we used in the renal AF trial was 5 mg of apixaban twice daily unless patients had a second dose-reduction criteria in addition to chronic kidney disease. So the fact that they had end-stage kidney disease and were on hemodialysis counted as one dose reduction criteria and patients that were under 60 kilograms or less were 80 years of age or older, who had then a second dose-reduction criteria were treated with the 2.5 mg twice daily dosage. And this was important to note because this is different than the dosage that was used in the AXADIA-AFNET trial. Dr Greg Hundley:            Very nice. And so Sean, what did you find? Dr. Sean Pokorney:         Yeah. So again, a lot of this data is really exploratory because of the limited sample size, we weren't really able to definitively conclude anything about the major or clinically relevant non-major bleeding rates. I would say that some of the key findings that we saw was that there were high rates of major or clinically relevant non-major bleeding in both arms of the trial and one year bleeding event rates were 25% in the warfarin arm and 31% in the apixaban arm. And again, there was no statistically significant difference, although again, this is really exploratory. I would say that some of the other interesting findings that we saw was that there were very low rates of ischemic and hemorrhagic stroke in this patient population. Again, there were 82 patients randomized to apixaban, 72 patients randomized to warfarin. And there was a difference in the randomization because of the stratification by site that was performed with the randomization. And so within the 82 patients that were randomized to apixaban, the patients, there was one ischemic stroke and one hemorrhagic stroke. There were no hemorrhagic strokes in the warfarin population and two ischemic strokes. Another key finding was the high rates of mortality in this patient population. So 26% of the apixaban patients experienced a mortality event, 18% in the warfarin arm. So again, the mortality rates in these patient populations were extremely high. I would also emphasize some of the data from the PK analysis. So we looked at the PK analysis in two different ways. For the patients that were treated with the 5 mg dose of apixaban, the PK data showed that there was consistent overlap in the steady state concentration at one month compared to patients in the Aristotle trial that had really mild to moderate, moderate to severe and severe chronic kidney disease. And so there was a consistent overlap in those steady state concentrations between the end-stage kidney disease population on hemodialysis and the chronic kidney disease population who benefited from a apixaban in the Aristotle trial. Similarly, in the 2.5 mg apixaban dose, the patient who had a second dose reduction criteria in addition to chronic kidney disease, those patients had consistent steady state concentrations of apixaban relative to patients with mild to severe chronic kidney disease. Dr Greg Hundley:            Very nice. Well thank you so much, Sean. And listeners, now we're going to turn to our associate editor, Dr. Shinya Goto. Shinya, can you, sort of, highlight for us some of the interesting findings that you see from these study results that Sean just presented? Dr. Shinya Goto:              Thank you, Greg. Thank you, Sean for your wonderful summary of your study. We had a great discussion with an editor for this paper. As Sean pointed out, this is a kind of underpowered trial or just terminated early, hypothesis was not tested in the trial. But this population of patient clearly needs a real-world clinical trial, patient with atrial fibrillation, end-stage kidney disease, on hemodialysis; things a clinician could do. In some country, nephology society defined warfarin contraindicated in this population. As Sean pointed out, whether the development of this trial include this high-risk population patient. So we had a discussion whether the underpowered trial provided something or nothing may be better than something just provided here. Our consensus finally reached was, this limited trial still provide something like, you have to make a decision to use the anticoagulation. I mean, that the apixaban might be still used due to the PK data. That is the kind of interesting point of this trial. Dr Greg Hundley:            Very nice Shinya. Well, Sean, turning back to you and Shinya with that nice lead in really, Sean, what do you think is the next study that needs to be performed in this sphere of research? Dr. Sean Pokorney:         Yeah, absolutely. I think this is a challenging patient population to study. And again, our trial, the renal AF trial stopped early. Unfortunately, the AXADIA-AFNET 8 study also stopped early, which was also looking at apixaban versus warfarin outside the US and Europe. And so again, it is a challenging patient population to study. But again, I also think it's a really important population to study because one of the main unanswered questions in this population is whether or not they should receive anticoagulation. And so I think that ultimately more work and additional studies trying to determine whether or not these patients truly benefit from anticoagulation or stroke prevention, I think is really one of the critical directions that we need to take the field in. Dr Greg Hundley:            And Shinya, do you have anything to add? Dr. Shinya Goto:              Well, I fully agree with Sean. I mean, this is a very challenging area and still raising the question whether anticoagulation is necessary or not by your study. Maybe next generation oral anticoagulant such as Factor XI inhibitor that is more elevated to contact pathway may be beneficial. So we really need a good clinical study in this very important and known answered area. Dr Greg Hundley:            Very nice. Well listeners, we want to thank Dr. Dr. Sean Pokorney from Duke University in Durham, North Carolina and our own associate editor, Dr. Shinya Goto from Tokai University in Japan for bringing us the results of this randomized open-label trial of apixaban versus warfarin in patients with chronic kidney disease on hemodialysis, revealing high rates of bleeding in both groups, but due to low enrollment, was unable to identify its non-inferiority endpoint. It's important to note, however, as both our author and editorialists have identified further research is really needed in this area to really examine the efficacy of anticoagulation for stroke prevention in this high-risk patient population. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On The Run. Dr. Greg Hundley:           This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Qiang Zhang and Matthew Burrage as well as Senior Associate Editor Victoria Delgado as they discuss the article "Artificial Intelligence for Contrast-free MRI: Scar Assessment in Myocardial Infarction Using Deep Learning-Based Virtual Native Enhancement." 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 cohosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre from University of Akershus University Hospital in Norway. Dr. Carolyn Lam: Peder, today's feature discussion is on AI for contrast-free MRI. Isn't that so cool, using AI to perhaps understand what we could see only with contrast, but now in a contrast-free manner. Now I know that sound a bit confusing, but I hope very, very enticing, because everyone's going to have to wait for a little while before we get to that interesting feature discussion. And for now, let's talk about some of the papers we have in today's issue, shall we? Dr. Peder Myhre: Yes, Carolyn, I can't wait for the feature discussion, but we're going to start with some of the other papers in this week's issue, and we're going to start in the world of preclinical science with a paper looking at human cardiac reprogramming, because Carolyn, direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as one of the promising strategies to remuscularize the injured myocardium. Yet it is still insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails and underlying molecular mechanisms are not really well understood. Transcriptional factors often act in concert and form tightly controlled networks featuring with common targets among different transcriptional factors. Therefore, missing one component during heart development could lead to heart function defects and congenital heart disease. And in this study by corresponding author Yang Zhou from the University of Alabama at Birmingham, the authors perform transcriptomic comparison between human induced cardiomyocytes and functional cardiomyocytes to assess additional factors that govern transcriptional activation of gene programs associated with sarcomere contractility. Dr. Carolyn Lam: Wow. Really nicely explained. Thanks, Peder. So what did they find? Dr. Peder Myhre: So Carolyn, through these computational analysis of transcriptomic data, the authors identified TBX20 as the most under expressed transcription factor in human induced cardiomyocytes compared to endogenous cardiomyocytes. They also demonstrated that TBX20 enhances human cardiac reprogramming and improves contractility and mitochondrial function in the reprogrammed cardiomyocytes. Dr. Carolyn Lam: Nice. Could you summarize the clinical implications, please? Dr. Peder Myhre: Yes. So the clinical implications are that enhancing the efficiency and quality of direct cardiac reprogramming for human fibroblast is a critical step in the clinical translation of this technology, and better understanding of this synergistic regulation of key cardiac transcription factors during reprogramming will provide new insights into the genetic basis in normal and diseased hearts. Well, Carolyn, please tell me about your next paper. Dr. Carolyn Lam: Thanks, and we're moving now to kidney disease. Now end stage renal disease is associated with a high risk of cardiovascular events, but what about mild to moderate kidney dysfunction? Is it causally related to coronary heart disease and stroke? Well, today's authors give us a clue, and it's from corresponding author Dr. Di Angelantonio from University of Cambridge and colleagues who took a very unique combined approach to answer this question. They first conducted observational analyses using individual level data from four huge population based data sources, namely the emerging risk factors collaboration, Epic CVD, Jillion Veteran Program and UK Biobank. Can you imagine this comprised almost 650,000 participants with no history of cardiovascular disease or diabetes at baseline, yielding almost 43,000 and 15,700 incident coronary heart disease and stroke events respectively during a 6.8 million person years of follow up. So huge observational study, which they then followed with a Mendelian randomization analyses using a genetic risk score of 218 variants for GFR and involving participants in Epic CVD Million Veterans Program and the UK Biobank. Dr. Peder Myhre: Wow, Carolyn, this is a topic that I think many of us have really been wondering and thinking about. The mild to moderate kidney dysfunction, what does it really mean? And what a beautiful study to answer this. So what did they find? Dr. Carolyn Lam: First, there was a U-shaped association of creatinine-based GFR with coronary heart disease and stroke with higher risk in participants with GFR values below 60 or more than 105 mills per minute per 1.73 meters squared. Mendelian randomization analyses for coronary heart disease showed an association among participants with GFR below 60, but not for those with GFR above 105. Results were not materially different after adjustment for traditional cardiovascular risk factors and the Mendelian randomization results for stroke were nonsignificant but broadly similar to those for coronary heart disease. So in summary, in people without manifest cardiovascular disease or diabetes, mild to moderate kidney dysfunction is causally related to the risk of coronary heart disease, highlighting the potential value of preventive approaches that preserve and modulate kidney function. Dr. Peder Myhre: Thank you, Carolyn, for such a great summary and an important result from that study. I'm going to now take us back to the world of preclinical science and talk about diabetic cardiomyopathy and exercise. And we both know that patients with diabetes are vulnerable to development of myocardial dysfunction, and that exercise, our favorite thing, for maintaining cardiovascular health, especially in patients with diabetes. And despite a wealth of evidence supporting that cardiometabolic benefits of exercise, the precise exercise responsive signals that confer the beneficial effects of exercise in cardiomyocytes to remain poorly defined. And previous studies have identified fibroblast growth factor 21, FGF21, a peptide hormone with pleiotropic benefits on cardiometabolic hemostasis as an exercise responsive factor. And in this study from Aimin Xu from the University of Hong Kong, the authors investigated a six-week exercise intervention program in FGF21 knockout mice and wild-type litter mates that all had diabetic cardiomyopathy induced by high fat diet and injection of streptozotocin. Dr. Carolyn Lam: Nice. So what did they find? Dr. Peder Myhre: Yeah, the authors found that exercise lowers circulating FGF21 levels, therefore remodeling the heart as an FGF21 sensitive target organ. And the protective effects of exercise against diabetic cardiomyopathy are therefore compromised in mice with deficiency of FGF21. They also identified Sirtuin-3 as an obligor downstream effector on FGF21, preserving mitochondrial integrity and cardiac function. Finally, the authors demonstrated that FGF21 induces Sirtuin-3 expression through AMPK-FOXO3 signaling access. Dr. Carolyn Lam: So could you put that together for us better? So what are the clinical implications? Dr. Peder Myhre: So the clinical implications from this paper is that circulating FGF21 is a potential biomarker for assessment of exercise efficacy in improving cardiac functions. And exercise is a potent FGF21 sensitizer in cardiomyocyte and has the potential to enhance the therapeutic benefits of FGF21 analogs in diabetic cardiomyopathy, and selective activation of FGF21 signal in cardiomyocytes may serve as exercise mimetics and represent a promising targeted intervention for precise management of diabetic cardiomyopathy. Dr. Carolyn Lam: Oh my goodness. That is fascinating. Thank you, Peder. Well let's wrap up with what else there is in today's issue. There's an On My Mind paper by Dr. Weir entitled, “The Emperor's New Clothes: Aren't We Just Treating Grades of Heart Failure with Reduced Ejection Fraction.” Dr. Peder Myhre: And there is a Research Letter by Dr. James Martin from Baylor College of Medicine entitled “Gene Therapy Knockdown of Hippo Signaling Resolves Arrhythmic Events in Pigs after Myocardial Infarction.” Dr. Carolyn Lam: Very nice. Thanks, Peder. So wow, let's go onto a featured discussion on AI for contrast-free MRI and a virtual native enhancement here coming right up. Dr. Peder Myhre: Awesome. Dr. Carolyn Lam: Now we all know that myocardial scar is currently assessed non-invasively using cardiac MRI with late gadolinium enhancement as what we would call the imaging gold standard. Wouldn't it be amazing to have a contrast-free approach, which could provide the same information with many advantages such as a faster or cheaper scan, and without contrast associated problems? Well guess what? We're about to discuss that today in a feature publication in today's issue, and I am so pleased to have the co first authors with us today. They are Dr. Qiang Zhang and Dr. Matthew Burridge, both from University of Oxford, and to discuss it as well, our senior associate editor, Dr. Victoria Delgado from Barcelona. So welcome, everyone. Qiang Zhang, could I start with you and ask you, I understand you're a machine learning expert, which means you're probably smarter than all of us here. Could you maybe explain in simple terms what made you and Dr. Burridge do the study? Dr. Qiang Zhang: First? Thank you so much, Carolyn and Victoria, for the invitation. As you have mentioned, late gadolinium enhancement, or LGE, has been the imaging gold standard in clinical practice for myocardial catheterization including scar assessment for patients with myocardial infarction. However, LGE requires the injection for gadolinium contrast, and this is cautioned in some patient groups and increases the scan time and cost. On the other hand, pre-contrast CMR such as Sydney T1-T2 mapping, a gadolinium-free alternative for myocardial catheterization. But their clinical use has been hindered by confounding factors and a lack of clear interpretation. So with our cross deceptor team at Oxford, we developed an artificial intelligence, virtual native enhancement technique VNE. It can produce a sort of a virtual LGE image but without the need for gadolinium contrast. And we have previously tested it in patients with hypertrophic cardiomyopathy as published in this journal last year. And in this new study together with Matt here, we tested in patients with history of chronic or prior myocardial infarction. Dr. Carolyn Lam: Oh wow. Cool. So audience, you heard it. Instead of LGE, we now have VNE, virtual native enhancement. That's super cool. Thank you. Matt, could I bring you in here? So tell us a little bit more about the population you studied and what you both found. Dr. Matthew Burrage: Yeah, absolutely. And thank you so much for the invitation as well. So as Chang has said, this was a single sensor study that we performed at the University of Oxford and specifically targeting assessing myocardial scar in patients with a history of chronic or prior MI. So we had two sources for our population data. Well, first we used our real world clinical service data from our institution. So we screened 11 years worth of patient data for presence of MI. So patients were included. There was a evidence of a previous MI based on an ischemic pattern of LGE, but we specifically excluded patients who had an acute presentation, or if there were features of acute MI on the CMR scan such as presence of myocardial edema or microvascular obstruction. The reason for this is we wanted to keep this as a clean population to avoid the potential confounding effects of myocardial edema or MVO on native T1 values. And so we also excluded other myocardial pathologies such as underlying cardiomyopathies and infiltrative diseases. A second population dataset came from the OX Army study, which is a single center prospective study of patients presenting with acute MI. And for these patients we used their six month follow up scan to again avoid the confounding effects of edema and pathology. So overall we had a total of 912 patients who have contributed over 4,000 image data sets. The patient characteristics, 81% were male, they had a mean age of 64 years and there were cardiovascular risk factors such as diabetes melitis, hypertension, hypercholesterolemia in 20 to 40% of patients, while just over half had a history of previous revascularization. We also separately applied the VNE technology to a pig model of myocardial infarction, which was thanks to our collaborator, Rohan Domakuma in the US. And so those were scans performed eight to nine weeks after an induced MI in the LAD territory in a series of pigs. And so this gave us the ability to provide a direct comparison between LGE, VNE, and histopathology in this model. Dr. Carolyn Lam: Wow. And results? Dr. Matthew Burrage: So what we found and the key results were firstly that VNE provided significantly better image quality than LGE, and this was on blinded analysis by five independent operators from our test data sets. Secondly, the VNE correlated strongly with LGE in terms of quantifying infarct size and the degree of transmurality, so the extent of the MIs in our test data set. We had pretty good overall accuracy of 84% for VNE in detecting scar compared to LGE with no false positive VNE cases. And finally there was also excellent visuospatial agreement with the histopathology in the pig model of myocardial infarction. So really this, we think, is a technology that provides clinicians with images in a format that firstly they're familiar with, which looks like LGE, provides essentially the same information as LGE, but it can be achieved without the need for any gadolinium contrast agents and can be acquired in a fraction of the time. So it takes less than one second to generate the VNE image. So as we've said before, we feel there's a lot of potential here for this technology to potentially eliminate the need for gadolinium contrast in a significant proportion of CMR scans, reduced scan times and costs, increased clinical throughput and hopefully improve the accessibility of CMR for patients in the near future. Dr. Carolyn Lam: Oh wow. That is tremendous. So first of all, congratulations to both of you. Before I ask Victoria for some thoughts, could I also just check with Qiang Zhang, because all AI algorithms need to be externally validated or surely there's some catch to it, or so-called limitations, or something else you may study. Could you maybe round up by saying is there anything that clinicians should not be applying it to or be aware of some limitations or? Dr. Qiang Zhang: Thank you, Carolyn. So a limitation of this study is that the dataset that is used for developing the models, the majority of them are patients around six month after the acute infarction. So where the myocardial infarction is still evolving, which may include residual edema and microvascular obstruction, and that is difficult to assess using the current VNE model. And also we found it challenging to assess small sub endocardial infarction and actually to address those limitations, we are working on improving the VNE models, training it on even larger data sets and training it on LGE to detect small sub endocardial function. And we will further develop it to detect, for example, acute edema and a microvascular obstruction, and in the meantime develop quality control driven AI models to inform the clinical users of and unreliable results. Dr. Carolyn Lam: Wow, thank you. So Victoria, now I'm dying to hear your thoughts. How do you think this fits in the landscape of all AI imaging now? Dr. Victoria Delgado: I think that it's an excellent development and I congratulate the others for the article and the proof of concept that we can move away from the late enhancement and the use of gadolinium enhancement. I think that this is a major step forward because as Matt said, they are going to decrease very much the time of scanning and the post processing because is automatically done as far as I understand. So even if you can interpret yourself the amount of so-called virtual enhancement, the system gives you a value for that extension of the virtual in non-gadolinium enhancement. So that reduces very much the variability that can be in each observer if that is done automatically. But my question to them is also if that can be influenced by the type of scanner that you use, for example on echocardiography, that's much more my field of interest, it depends very much sometimes how the images are processed of which are the vendors that we have used to acquire the images. Is this a limitation for your software? Can you foresee there some variability or is completely independent? Dr. Qiang Zhang: Thank you, Victoria. So we are aware of actually the difference of the data produced by different scan of vendors and the advantage of AI-driven methods is that it is data driven. So we plan to incorporate dataset from other vendors so that the trend that VNE models can work with like multiple scanner vendors. This actually will be done alongside the ongoing standardization program of T1 mapping in our group, which is the underpinned technology for VNE. And this is led by Professor Stephan Pitchnik and Vanessa Farrera. And we actually hope the VNE technology as AI driven methods could contribute to a solution to the CMO standardization between the scanner vendor. Dr. Victoria Delgado: And another question, if I may follow in this CMR, it has been proposed as a very valuable imaging technique to assess infarct size and to see the efficacy of some therapies to reduce the myocardial infarction size. How do you think that this new methods will impact in future trials and the way we have been interpreting the previous trials, like for example, the one that you use for the validation? Dr. Matthew Burrage: Yeah, thanks Victoria. It's a really, really excellent question. I think there's a lot of potential for the new VNE technology to also become a clinical endpoint in some of these trials in terms of reduction in infarct size, because the information that we get is more or less the same as we get from the LGE. So there's lots of potential that we can, again, use this as a biomarker in trials for looking at reduction in infarct size and reperfusion therapies. But it has the benefit that it can be done quicker and without gadolinium contrast. Dr. Victoria Delgado: This is amazing guideline and really I would have a lot of questions for them as well. And knowing the literature, for example, in the Scenic center in Madrid that they have been scanning the evolution of myocardial infarction from 0.02 weeks to see how this would translate with your technique. That will be amazing to understand how this can be done. Dr. Carolyn Lam: Oh wow, there you go. New research idea right there. Well how about if we end with a very quick question for each of the first authors. So maybe Matt, you could start, I mean is this ready for primetime and clinical use? And if it's not, what needs to be done to get there? In other words, where are you headed as the next step? Dr. Matthew Burrage: So again, thank you, Carolyn, that's a really excellent question and I think the next step before this becomes ready for primetime clinical use is validating this technology really across the spectrum of other myocardial pathologies. So the next work that we are developing this on is in patients with acute myocardial infarction, and then extending this to sort of acute inflammatory conditions like myocarditis, other non-ischemic cardiomyopathies, things like amyloidosis as well. So this will be the next step into rollout and we are looking to track things like VNE burden and how that relates to clinical outcomes, similar to the previous LGE papers have done across different myocardial pathologies, but then ultimately aiming towards clinical rollout within the next few years. Dr. Qiang Zhang: Yeah, I think pretty much what Matt has said, we're going to develop the deep learning methods and test it further on pretty much the whole spectrum of commonly encountered diseases, and then more complex pathologies such as acute pathologies like edema, microvascular obstruction, and then we test on large population study like UK Biobank and other prospective clinical trials. And of course the most importantly is to roll out for real world clinical use. And as Matt said, we are aiming to do this within the next two to five years. Dr. Carolyn Lam: Wow, this is amazing. Both Victoria and I said thank you, congratulations on this landmark piece of work. Thank you for publishing it in circulation. Audience, thank you for joining us today from Greg, Peder, myself. You've been listening to Circulation on the Run, and don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

VIDEO: The U.S. secret in Syria EXPOSED in new hidden camera footage | Redacted with Clayton Morris (12:03) The Conservatives Made Everything in Britain Worse – Johnatan Pie  (6:40) Neil Oliver: Persuading generations of children they are a plague upon the earth is unforgivable – 12:27   Purple potato may pack cancer prevention punch – even after cooking Pennsylvania State University, September 1, 2022 Anthocyanin compounds found in purple potatoes may help in the prevention of certain types of cancer, even after cooking, say researchers. The new data, published in the Journal of Nutritional Biochemistry, tested the potential for anthocyanin-containing purple potatoes to block the growth of cancer tumours, even when they have been cooked – after previous research suggested that the polyphenols found in purple potatoes (PP) may help to battle cancer. Led by Venkata Charepalli from Pennsylvania State University, the team used laboratory tests including in vitro cell line investigations and animal modelling to test how PP impacted colon cancer growth, and in particular, colon cancer stem cells (CSCs), which have previously been suggested to be target by dietary bioactives such as curcumin. The team reported that their data from in vitro and mouse models suggests that baked purple-fleshed potatoes suppressed the growth of colon cancer tumours by targeting the cancer's stem cells. They added that there may be several substances in purple potatoes that work simultaneously, and on multiple pathways, to help kill the colon cancer stem cells, including anthocyanins and chlorogenic acid, and resistant starch. “Our earlier work and other research studies suggest that potatoes, including purple potatoes, contain resistant starch, which serves as a food for the gut bacteria, that the bacteria can covert to beneficial short-chain fatty acids such as butyric acid,” said study senior author Professor Jairam Vanamal – also of Penn State. “The butyric acid regulates immune function in the gut, suppresses chronic inflammation and may also help to cause cancer cells to self-destruct.” Boosting physical activity and curbing sitting time are highly likely to lower breast cancer risk Breast Cancer Association Consortium (UK), September 6, 2022 Boosting physical activity levels and curbing sitting time are highly likely to lower breast cancer risk, finds research designed to strengthen proof of causation and published online in the British Journal of Sports Medicine. The findings were generally consistent across all types and stages of the disease, reveals the Mendelian randomization study, prompting the researchers to recommend a stronger focus on exercise as a way of warding off breast cancer. Mendelian randomization is a technique that uses genetic variants as proxies for a particular risk factor—in this case lifelong physical activity levels/sedentary behavior—to obtain genetic evidence in support of a causal relationship. Observational studies show that physical inactivity and sedentary behavior are linked to higher breast cancer risk, but proving they cause breast cancer is another matter. The researchers included data from 130,957 women of European ancestry: 69, 838 of them had tumors that had spread locally (invasive); 6667 had tumors that hadn't yet done so (in situ); and a comparison group of 54,452 women didn't have breast cancer. Researchers estimated overall breast cancer risk, according to whether the women had or hadn't gone through the menopause; and by cancer type (positive for estrogen or progesterone, or HER-2, or positive/negative for all 3 hormones), stage (size and extent of tumor spread), and grade (degree of tumor cell abnormality). These case-control groups comprised: 23,999 pre/peri-menopausal women with invasive breast cancer and 17,686 women without; 45,839 postmenopausal women with breast cancer and 36,766 without. Analysis of the data showed that a higher overall level of genetically predicted physical activity was associated with a 41% lower risk of invasive breast cancer, and this was largely irrespective of menopausal status, tumor type, stage, or grade. Similarly, genetically predicted vigorous physical activity on 3 or more days of the week was associated with a 38% lower risk of breast cancer, compared with no self-reported vigorous activity. These findings were consistent across most of the case groups. Finally, a greater level of genetically predicted sitting time was associated with a 104% higher risk of triple negative breast cancer. These findings were consistent across hormone-negative tumor types. How the mind sharpens the senses Ruhr University Bochum (Germany), August 27, 2022 A study conducted with experienced scholars of Zen-Meditation shows that mental focussing can induce learning mechanisms, similar to physical training. Researchers at the Ruhr-University Bochum and the Ludwig-Maximilians-University München discovered this phenomenon during a scientifically monitored meditation retreat. The journal Scientific Reports, from the makers of Nature, has now published their new findings on the plasticity of the brain. The participants were all Zen-scholars with many years of meditation practice. The retreat was held in complete silence, with at least eight hours of meditation per day. All participants practiced their familiar meditation, which is characterized by a non-specific monitoring of thoughts and surroundings. Additionally, some participants applied a special finger-meditation for two hours per day, during which they were asked to specifically focus on their right index finger and become aware of spontaneously arising sensory percepts in this finger. Subsequent assessment of the group that practiced finger-meditation showed a significant improvement in the tactile acuity of the right index and middle finger. A control group that had maintained their familiar meditation practice for the whole time, showed no changes in tactile acuity. In order to assess the sense of touch quantitatively, researchers measured the so-called “two-point discrimination threshold”. This marker indicates how far apart two stimuli need to be, in order to be discriminated as two separate sensations. After the finger meditation, the performance improved on average by 17 percent. By comparison, tactile acuity of the visually impaired is 15 to 25 percent above that of typical sighted individuals, because their sense of touch is used so intensively to make up for the reduced visual information. Hence, the changes induced by meditation are comparable to those achieved by intense long-term training. It is known for long that extensive training induces neuroplasticity, which denotes the ability of the brain to adapt and restructure itself, thereby improving perception and behavior. Recently, the group of neuroscientists of the Neural Plasticity Lab headed by Hubert Dinse has shown that these processes can be initiated even without training by mere exposure to passive stimulation, which was translated only recently into a stimulating glove, which is used as therapeutical intervention in stroke patients. The fact that merely mental states without any physical stimulation can improve perception has now been shown for the first time. “The results of our study challenge what we know about learning mechanisms in the brain. Our concept of neuroplasticity must be extended, because mental activity seems to induce learning effects similar to active stimulation and physical training,” Dinse suggests. Elderberry extract may improve obesity inflammation University of Connecticut , September 1, 2022 Black elderberry extract may improve obesity-related metabolic disturbances like triglyceride (TAG) levels, inflammation and insulin resistance, research in mice finds. The researchers from the University of Connecticut in the US said dietary anthocyanins had been shown to reduce inflammation in animal models and to improve obesity-related complications – and black elderberry (Sambucus nigra) was one of the richest sources of these types of flavonoids. “Overall, black elderberry extract appeared to attenuate systemic inflammation and insulin resistance that occurs with diet-induced obesity in this mouse model, but further research is warranted on black elderberry consumption and effects in humans,” they wrote in the British Journal of Nutrition. Mice were fed either a low-fat diet, high-fat lard-based diet, a high-fat diet with 0.25% of the extract or a high-fat with 1.25% of the extract for a period of 16 weeks. The black elderberry extracts amounted to an anthocyanin dose of 20–40 mg per kg of body weight for the 0.25% group and 100–200 mg for the 1.25% group. After 16 weeks both extract groups had significantly lower liver weights, serum TAG and serum monocyte chemoattractant protein-1 – a serum marker linked to cardiovascular disease and diabetes – compared to the group given the high fat diet alone. Liver weights were about 13% lower in both extract groups compared to the group given the high fat diet alone. “Obese individuals have shortened life expectancies; however, they do not typically die of obesity itself but rather obesity-related comorbidities, such as cardiovascular disease, diabetes and certain types of cancers,” they said. They said inflammation as a result of adipose fat and excessive accumulation of ectopic lipid in tissues was thought to be a key underlying cause of these obesity-related comorbidities, meaning methods that target and lower inflammation could be effective at preventing obesity-related conditions. First Ground Breaking Study Shows How Rhodiola Rosea Protects People From Viral Infections Appalachian State University August 26, 2022 Also known as arctic root or golden root, Rhodiola Rosea has already been clinically shown to stimulate serotonin, norepinephrine and dopamine activity, and support healthy neurotransmitter balance, but human trials have now shown the the herb protects against viral infection. A 2002 review in HerbalGram, the journal of the American Botanical Council, reported that numerous studies of rhodiola in both humans and animals have indicated that it helps prevent fatigue, stress, and the damaging effects of oxygen deprivation. Evidence also suggests that it acts as an antioxidant, enhances immune system function, and can increase sexual energy. Rhodiola's efficacy was confirmed in a 2011 review of 11 placebo-controlled human studies. The reviewers considered studies that all had study designs rated as moderate to good quality, and the analysis of their combined data concluded that rhodiola might have beneficial effects on physical performance, mental performance, and certain mental health conditions. Nieman's study “Rhodiola rosea exerts antiviral activity in athletes following a competitive marathon race,” which was published July 31 in Frontiers in Nutrition, is the first to show anti-viral activity. In his study, 48 marathon runners participating in the 2012 Thunder Road Marathon in Charlotte were randomly divided into two groups that ingested either 600 milligrams of Rhodiola rosea or a placebo for a month before the race. Blood samples were collected the day before the marathon and 15 minutes and 1.5 hours post-race. Initial studies found no impact on inflammation and oxidative stress. Additional studies used an in vitro assay to measure the ability of the polyphenolic compounds to protect the cells against Vesicular stomatitis virus. The results demonstrated that Rhodiola rosea delayed viral infection for up to 12 hours after the marathon. Nieman was the first scientist to find that marathon runners are prone to viral illnesses such as upper respiratory tract infections after competing. This discovery motivated him to research plant-based compounds that could prevent infection and enhance recovery and overall athletic performance. Since Rhodiola rosea administration appears to impact central monoamine levels, it might also provide benefits and be the adaptogen of choice in clinical conditions characterised by an imbalance of central nervous system monoamines. It also suggests that research in areas such as seasonal affective disorder, fibromyalgia, and chronic fatigue syndrome, among others, is warranted. “Basically after heavy exertion, bacteria and viruses can multiply at a higher rate than normal due to factors in the serum like stress hormones and inflammatory cytokines,” Nieman said. “This is why runners are six times more likely to get sick after a marathon. We showed that in those who used Rhodiola rosea the viruses could not multiply, meaning it was acting as a countermeasure.” Rhodiola both stimulates and protects the immune system by reinstating homeostasis (metabolic balance) in the body. It also increases the natural killer cells (NK) in the stomach and spleen. This action may be due to its ability to normalise hormones by modulating the release of glucocorticoid into the body. How does nature nurture the brain? Max Planck Society, September 6, 2022 After a 60-minute walk in nature, activity in brain regions involved in stress processing decreases. This is the finding of a recent study by the Lise Meitner Group for Environmental Neuroscience at the Max Planck Institute for Human Development, published in Molecular Psychiatry. Living in a city is a well-known risk factor for developing a mental disorder, while living close to nature is largely beneficial for mental health and the brain. A central brain region involved in stress processing, the amygdala, has been shown to be less activated during stress in people who live in rural areas, compared to those who live in cities, hinting at the potential benefits of nature. “But so far the hen-and-egg problem could not be disentangled, namely whether nature actually caused the effects in the brain or whether the particular individuals chose to live in rural or urban regions,” says Sonja Sudimac, predoctoral fellow in the Lise Meitner Group for Environmental Neuroscience and lead author of the study. To achieve causal evidence, the researchers from the Lise Meitner Group for Environmental Neuroscience examined brain activity in regions involved in stress processing in 63 healthy volunteers before and after a one-hour walk in Grunewald forest or a shopping street with traffic in Berlin using functional magnetic resonance imaging (fMRI). The results of the study revealed that activity in the amygdala decreased after the walk in nature, suggesting that nature elicits beneficial effects on brain regions related to stress. “The results support the previously assumed positive relationship between nature and brain health, but this is the first study to prove the causal link. Interestingly, the brain activity after the urban walk in these regions remained stable and did not show increases, which argues against a commonly held view that urban exposure causes additional stress,” explains Simone Kühn, head of the Lise Meitner Group for Environmental Neuroscience. The authors show that nature has a positive impact on brain regions involved in stress processing and that it can already be observed after a one-hour walk. This contributes to the understanding of how our physical living environment affects brain and mental health. Even a short exposure to nature decreases amygdala activity, suggesting that a walk in nature could serve as a preventive measure against developing mental health problems and buffering the potentially disadvantageous impact of the city on the brain.

Support Topic Lords on Patreon and get episodes a week early! (https://www.patreon.com/topiclords) Lords: * Erica * David Topics: * A partnership between you and a tool * Schmalhausen and Vernadsky, my own personal ARG * Stop trying to make "a wedge is a machine" happen. It's not going to happen * https://en.wikipedia.org/wiki/Machine * The Poetry Teacher, by Mary Oliver * https://voetica.com/voetica.php?collection=2&poet=27&poem=5712 * Drinking vinegar * https://en.wikipedia.org/wiki/Short-chainfattyacid Microtopics: * Taking an allergy pill and getting something unexpected. * Nap skeptics. * Non-stop napping. * Wanting to eat nothing but spinach for two days so you go to Disney World and pay extra for all the park employees to tell you that in the happiest place on Earth we only eat spinach. * Who gets to chew the grape next and for how long. * Forgetting a story after you tell it, so you can tell the story back and forth forever. * A plastic grape that dissolves in your nose. * The least favorite thing that you bought during the pandemic. * The collective politico-pandemical nightmare. * A shitty partnership between you and a shitty tool. * Ol' Slicky. * Tools that bring you distress. * Whether it's legal to open carry a claymore in Texas. * A decoration you can put on your truck just in case nobody knows what an asshole you are. * Whether you can open-carry a dildo in Texas if the dildo is also an assault rifle. * Gluing a penis to things you don't like and explaining that "this is a partnership between you and a tool." * Papers that you really approve should've read fifteen years ago. * The parallel world of the Modern Synthesis. * Soviet biologists who were recognized in their time but have since been forgotten. * Stalin's purge of scientists researching Mendelian genetics. * Being evacuated to Kazakhstan and fed only wilted spinach so that you can finally write the book you've been thinking about. * Bringing your adopted pet wolf back with you from Kazakhstan. * Growing up after the Russian revolution in St. Petersburg. * Delegating research by convincing the Game Detectives folks that there is a pop culture reward behind it. * Your own personal ARG that only you care about and doesn't lead to any goal except knowing more facts. * The point of games. * The creativity that exists in fiction that you wish you could capture in nonfiction. * The advantages of reality over fiction. * Becoming disenchanted with capitalism in the 1920s. * The Demon Haunted World. * Escaping from Stalinist Russia into Nazi Germany. * Cheers to a boring life. * A slightly tilted floor. * Electrifying the wedge so it's finally a machine. * The xkcd comic from 15 years ago that lampooned the way Wikipedia articles used to be stereotypically bad. * Being good at math and assuming that also means you'd be good at writing an encyclopedia. * Whether Wildlife Ecology is a different field from Wildlife Biology. * The shittiest source that Wikipedia will accept as a citation. * Citing George W. Bush as a source in your peer-reviewed paper about climate change. * All the dogs arriving at once. * Dogs teaching students how to write thirsty happy poems. * Dog Songs (2013) * Deliberately putting line breaks where they seem least intentional. * The Wedge of the Poetry World. * Dinging the pan to proceed. * The manufacture and use of short-chain fatty acids. * Fixing an ulcer with vinegar. * Fuck you, I'm drinking a shrub. * Drinking balsamic vinegar and then rinsing with baking soda. * Butter and vinegar, together at last.

Episode 27: “The Psychiatry of COVID-19” A Conversation with Dr. Emanuel Garcia “BIGGEST Disaster in Medical History!” ~ Dr Charles Hoffe Gives Riveting Speech In Vancouver, British Columbia, Canada Kim Iversen: Proof IRS Expansion Of 87,000 New Agents Is Designed To Target Middle Class Americans   Study: Regular consumption of citrus fruits can reduce dementia risk by 15% Tohoku University (Japan), August 4, 2022 Dementia continues to affect more people worldwide, and countries with aging populations like Japan are especially vulnerable. To address this matter, researchers from Tohoku University studied the health benefits of eating citrus fruits. According to the study findings, regular consumption of citrus fruits like oranges, grapefruits, lemons or limes could help reduce the risk of dementia among older adults by almost 15 percent. The research team hopes that the dietary approach could be both a simple and effective solution for dementia prevention. Findings from some cell and animal experiments have shown that citrus flavonoids can cross the blood-brain barrier and play a part in antioxidant and anti-inflammatory actions. Earlier studies suggest that this could help reverse and repair some forms of cellular damage. (next) Olive oil consumption found to reduce risk of death due to cancer, heart disease and Alzheimer's Harvard School of Public Health, August 14, 2022 According to a study, replacing butter or full-dairy fat with half a tablespoon or more of olive oil can help increase your chances of living longer. The study was conducted by experts from the Harvard T.H. Chan School of Public Health and published in the American Journal of Cardiology. The study revealed that people who used seven grams or more (at least half a tablespoon) of olive oil as a dressing or with bread had a reduced risk of dying from Alzheimer's disease, cancer, heart disease or respiratory disease compared to those who rarely or never consumed olive oil. Findings also showed that replacing 10 grams a day (about 3/4 tablespoons ) of butter, margarine, mayo or dairy fat with the same amount of olive oil was linked to an impressive eight to 34 percent lower risk of disease-related death. For the study, the researchers analyzed data from 60,582 healthy adult women and 31,801 healthy adult men from the Nurses' Health Study and the Health Professionals Follow-up Study. During the 28-year follow-up, the volunteers had a diet assessment every four years that asked them how often they consumed certain foods, fats and oils on average. The assessment also checked which brand or type of oils they used for cooking or at the table. (next) Cutting 1 gram from daily salt intake could ward off nearly 9 million cases of stroke/heart disease British Medical Journal, August 16, 2022 A modest cut of just 1 gram in daily salt intake could ward off nearly 9 million cases of heart disease and strokes and save 4 million lives by 2030, suggest the estimates of a modeling study published in the open access journal BMJ Nutrition Prevention & Health. Salt intake in China is one of the highest in the world, averaging 11 g/day—over twice the amount recommended by the Chinese government. High salt intake drives up blood pressure and therefore the risk of cardiovascular disease, which accounts for 40% of all deaths in China every year. The researchers set out to estimate the health gains that could be achieved by reducing salt intake across the nation, with the aim of helping to inform the development of a doable salt reduction program. Given that, on average, adults in China consume 11 g/day of salt, reducing this by 1 g/day should lower average systolic blood pressure by about 1.2 mmHg. And if this reduction were achieved in a year and sustained, some 9 million cases of heart disease and stroke could be prevented by 2030—4 million of them fatal. (next) Getting Adequate Amount Of Vitamin D Prevents Harmful Inflammation University of South Australia, August 7, 2022 A little bit of inflammation is integral to the human body's natural healing process. Chronic inflammation, however, can actually have the opposite effect. Constantly high levels increase one's risk of various serious diseases including but not limited to Type 2 diabetes, heart disease, and various autoimmune conditions. Now, a study by scientists at the University of South Australia reports a direct link between low levels of vitamin D and high levels of inflammation. This is the world's first ever genetic research project to focus on this topic. Study authors believe their work establishes an invaluable biomarker for identifying individuals at a higher risk of developing chronic illnesses with an inflammatory component. The research team used Mendelian randomization on the genetic data of 294 ,970 participants enrolled in the UK Biobank project. That analysis revealed a clear association between vitamin D and C-reactive protein levels, considered an indicator of inflammation. (next) Four Natural Options for Chronic Fatigue Syndrome GreenMedInfo, August 16th 2022 Chronic fatigue syndrome (CFS) is a complex long-term disorder affecting over 2 million Americans that is characterized by extreme fatigue and malaise that doesn't improve with rest.[i] A whopping 90% of chronic fatigue sufferers are undiagnosed[ii] and may find it difficult to carry on with normal activities such as work, school and household chores. At least 1 in 4 CFS patients are house-bound or bed-bound for long periods of time due to the disorder. While some studies demonstrate correlation between CFS and autoimmune system dysregulation,[v],[vi] the cause of CFS, also referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is still unknown. There is no known cure for CFS, with treatment generally focusing on symptom relief.We've identified four of the best natural options for chronic fatigue syndrome to provide safe, effective support to revitalize your body and spirit. Nicotinamide Adenine Dinucleotide (NADH) An essential element in the production of energy, nicotinamide adenine dinucleotide (NADH) is a coenzyme found in every cell in the human body. NADH is a critical factor in hundreds of metabolic processes, including healthy cell turnover (antiaging), converting food into energy and maintaining the integrity of DNA,[ix] an important factor in disease prevention. NADH has been studied extensively as a therapeutic for CFS, including a study comparing oral NADH with conventional therapy consisting of nutritional supplements and psychological therapy for a period of 24 months. To rule out specific comorbidities, immunological parameters and viral antibody titers were also evaluated at baseline and each trimester of therapy. Patients who received NADH had a dramatic and statistically significant reduction in symptoms during the first trimester.[x] Another trial on the stabilized oral form of NADH examined 26 qualified patients over a 12-week double-blind, placebo-controlled study. Subjects were randomized to receive either 10 milligrams (mg) of NADH or placebo for a four-week period, followed by a four-week “washout” period, after which subjects were switched to the alternate treatment for a final four-week period. Within this cohort of 26 subjects, eight patients, or 31%, responded favorably to NADH compared to just 8% (two patients) of the placebo group, with no severe adverse reactions related to treatment.[xi] Astragalus Astragalus is a traditional herbal remedy known for its adaptogenic qualities, meaning it can help protect the body from damage due to oxidative stress. A powerful antioxidant, astragalus is used to protect and support immunity, as a preventative against colds and upper respiratory tract infections, and to regulate healthy blood pressure, among other uses.[xii] Astragalus can even be applied topically for wound care thanks to antiviral properties. A 2009 study focused on the herbal formula Myelophil, a combination of two traditional medicinal plants, Astragalus membranaceus and Salvia miltiorrhiza, a member of the sage family. The Myelophil extract was given to the treatment cohort in either low- or high-dose groups of 3 or 6 grams of Myelophil daily. A control group was provided with a placebo and all groups were monitored for four weeks. Patients were surveyed for symptom severity and blood antibody arrays were taken to measure inflammatory cytokines, an important marker of disease symptoms. Results showed that even at low dosage (3 grams), Myelophil significantly decreased fatigue severity compared with placebo, though no changes in cytokine expression were noted.[xiii] Probiotics Probiotics have garnered the health spotlight in recent years, owing to their ability to support and protect the digestive tract. But probiotics can do more than improve gut health — they may also boost your brain and improve your mood. Brain fog is a key side effect of CFS and a potentially devastating one when it comes to impact on daily functioning. The same can be said for depression, another common hallmark of CFS. Studies reflecting the mood-boosting, clarity-producing effects of probiotics are cause for optimism for sufferers of chronic fatigue. A 2018 study in the journal Beneficial Microbes points to the role gut microbiota may play in CFS and fibromyalgia syndrome (FMS), which shares many features of CFS. A systematic review of studies was performed in this meta-analysis, encompassing randomized controlled trials and pilot studies of CFS or FMS conducted between 2006 and 2016. The administration of Lactobacillus casei for eight weeks was found to reduce anxiety scores, while treatment with Bifidobacterium infantis for the same period reduced inflammatory biomarkers.[xiv] Unhealthful intestinal ecology may play a role in CFS, as it plays a part in the health of the immune system. A 2009 study on probiotics' effects on energy level and symptomology for CFS patients found that, after four weeks of probiotic supplementation with strains of lactobacillus, acidophilus and Bifidobacterium, patients reported improved neurocognitive functions, though fatigue and physical activity scores were not significantly affected.[xv] Antioxidant Formulas Supplementing with antioxidants is another way to boost your body's defenses against the damaging effects of free radicals. By increasing the amount of antioxidant enzymes available to your cells, you may be able to prevent or even reverse the effects of oxidative stress that can cause systemic inflammation and fatigue. Oxidative stress as a factor in CFS was studied by researchers using a mouse model that stressed mice via chronic swimming. Mice treated with melatonin — a hormone with antioxidant effects — carvedilol — a medication that is 10 times more potent than vitamin E[xvi] — were observed to have significantly reduced immobilityperiods each day.[xvii] Similar results were observed when mice were administered an oral herbal compound (Withania somnifera (100 mg/kg), quercetin (50 mg/kg) and St. John's wort (10 mg/kg).)[xviii] These treatments further caused a significant reduction in lipid peroxidation, a sign of oxidative stress, and restored the GSH (glutathione) levels decreased by chronic swimming.[xix]

On this week's podcast, John Mandrola, MD discusses fish oil, America's heart health, pharmacists and prescribing and statins This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I - Fish Oil - New Biomarker Data Add to Concerns Over REDUCE-IT Trial https://www.medscape.com/viewarticle/976490 - Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059410 - Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia https://www.nejm.org/doi/full/10.1056/nejmoa1812792 - Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular RiskThe STRENGTH Randomized Clinical Trial https://jamanetwork.com/journals/jama/fullarticle/2773120 - Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial https://academic.oup.com/eurheartj/article/41/40/3925/5898836 II - US Heart Health - New AHA Checklist: Only 1 in 5 Adults Have Optimal Heart Health https://www.medscape.com/viewarticle/976519 - Life's Essential 8: Updating and Enhancing the American Heart Association's Construct of Cardiovascular Health: A Presidential Advisory From the American Heart Association https://www.ahajournals.org/doi/10.1161/CIR.0000000000001078 - Status of Cardiovascular Health in US Adults and Children Using the American Heart Association's New "Life's Essential 8" Metrics: Prevalence Estimates from the National Health and Nutrition Examination Survey (NHANES), 2013-2018 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.060911 III - Pharmacist Prescribing - Paxlovid Is Here: A Pharmacist's Prescribing Pearls https://www.medscape.com/viewarticle/973260 - Coronavirus (COVID-19) Update: FDA Authorizes Pharmacists to Prescribe Paxlovid with Certain Limitations https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-pharmacists-prescribe-paxlovid-certain-limitations IV - Statin Eligibility - New European Guidelines ‘Drastically' Reduce Statin Eligibility https://www.medscape.com/viewarticle/976715 - Statin Eligibility for Primary Prevention of Cardiovascular Disease According to 2021 European Prevention Guidelines Compared With Other International Guidelines https://jamanetwork.com/journals/jamacardiology/article-abstract/2793729 - Time to Revisit Using 10-Year Risk to Guide Statin Therapy https://jamanetwork.com/journals/jamacardiology/article-abstract/2793732 - Mendelian randomization studies: using naturally randomized genetic data to fill evidence gaps https://doi.org/10.1097/mol.0000000000000247 You May Also Like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

July: Recommendations for next generation sequencing data reanalysis of unsolved cases with suspected Mendelian disorders: A systematic review and meta-analysis

CardioNerds Tommy Das (Program Director of the CardioNerds Academy and cardiology fellow at Cleveland Clinic), Rick Ferraro (cardiology fellow at the Johns Hopkins Hospital), and Dr. Aliza Hussain (cardiology fellow at Baylor College Medicine) take a deep dive on the REDUCE-IT trial with Dr. Peter Toth, director of preventive cardiology at the CGH medical center in Sterling, Illinois, clinical professor in family and community medicine at the University of Illinois School of Medicine, and past president of the National Lipid Association and the American Board of Clinical Lipidology.  Special introduction to CardioNerds Clinical Trialist Dr. Jeff Wang (Emory University). Audio editing by CardioNerds academy intern, Shivani Reddy. This episode is part of the CardioNerds Lipids Series which is a comprehensive series lead by co-chairs Dr. Rick Ferraro and Dr. Tommy Das and is developed in collaboration with the American Society For Preventive Cardiology (ASPC). Relevant disclosures: None Pearls • Notes • References • Guest Profiles • Production Team CardioNerds Cardiovascular Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - REDUCE-IT The Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) trial was a large randomized controlled trial that showed a significant reduction in atherosclerotic cardiovascular disease (ASCVD) events with use of icosapent ethyl ester in secondary prevention patients and high risk primary prevention patients with diabetes and residual elevated triglycerides between 135 to 499 mg/dL on top of maximally tolerated statin therapy1. Despite the use of high intensity statin therapy, considerable residual risk for future atherosclerotic cardiovascular disease exists in patients with ASCVD.Elevated triglycerides (TGs) are an important marker of increased residual ASCVD risk2.There are two primary types of Omega-3 fish oils: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omege-3 fish oils have been shown to lower triglyceride levels.Low-dose combination EPA and DHA has not exhibited incremental cardiovascular benefit in either primary prevention and secondary prevention patients on top of statin therapy3-5.REDUCE-IT showed the use of high dose EPA in patients with either ASCVD or DM and one additional risk factor, and relatively well-controlled LDL-C levels on maximally tolerated statin therapy and residual hypertriglyceridemia (TG 135-499 mg/dL) results in significant reductions in cardiovascular events over a median follow-up period of 4.9 years1. Show notes - REDUCE-IT Multiple epidemiologic and Mendelian randomization studies have established elevated triglyceride (TG) levels as an important risk factor for atherosclerotic cardiovascular events6-8. However previous clinical trials using TG-lowering medication such as niacin, fibrates and low dose omega-3 fish oil have not shown to reduce cardiovascular events when added to statin therapy in patients with or without ASCVD,9,10.The JELIS trial first demonstrated a significant reduction in cardiovascular events when 1.8g daily of eicosapentaenoic acid (EPA) was added to low-intensity statin therapy in patients with ASCVD and hypercholesterolemia, However, the trial was limited due to open label design without placebo, use of low doses of background statin therapy, and geographic/demographic limitations to participants in Japan11.In a large international multicenter randomized controlled trial, the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) randomized 8,179 patients with established atherosclerotic heart disease or diabetes and an additional risk factor, on maximally tolerated statin therapy, to 4 gm/day of icosapent ethyl (a highly purified and stable EPA ethyl ester) or miner...

Check out Noeo Science for your homeschooling needs: https://noeoscience.com/ 

Check out Noeo Science for your homeschooling needs: https://noeoscience.com/

This is Part 2 of a 3-part series on genetics. In this episode we will dive into the principles of Mendelian Genetics. Breeding and creating a strain is governed by 3 important laws of nature, such as the environment, nutrition, and the traits they inherit. In other words, genetics. However, just the idea of genetics can be intimidating for many new breeders, and some veteran as well. Many even avoid genetics, mostly because it can seem confusing and difficult to understand and use. It is my hope that we can show you, not only why genetic is important, but also how to use it in the improvement and creation of your strains. Once you understand the basics, many other topics concerning breeding will become clearer. 

* Soviet scientists locked up or killed for accepting Mendelian genetics * E-boats bigger and stronger * Birds – today's link to dinosaurs * David Stewart – 40 years recording bird calls