Podcasts about University Medical Center Groningen

Dr Akila Viswanathan speaks with Dr Robert Coppes from The University Medical Center Groningen, Dr David Jaffray from MD Anderson Cancer Center and Dr Helen McNair from The Royal Marsden NHS Foundation Trust Institute of Cancer Research to look ahead to the future of radiation oncology as they discuss how to improve decision making, incorporating artificial intelligence, adapt to new training methods, improve safety and sustainability and much more for Seminars in Radiation Oncology.

As part of the non-sponsored sporadic "B-sides" series*, Ben and Ben sit down and talk with Dr. David Tabb, University Medical Center Groningen. (* this series is where we put guests we want to talk to but who do not fit within any sponsored series, but is still proteomics.... mostly)

With Jozine ter Maaten, University Medical Center Groningen, Groningen - the Netherlands, Marta Cobo Marcos, Hospital Puerta de Hierro, Madrid - Spain, Mateusz Sokolski, Wroclaw Medical University, Wroclaw, Poland, Aferdita Spahillari, Duke University Hospital, Durham, NC - USA, Laura Cohen, Massachusets General Hospital, Boston, MA - USA, Antonio Cannata, King's College London, London - United Kingdom & Varun Sundaram, Case Western Reserve University, Cleveland, OH, USA This podcast discusses the results of four late-breaking clinical trials presented at the Heart Failure Congress 2024 in Lisbon, Portugal. First, Dr Cobo Marcos shares the results of the SALT-HF study, a randomised trial investigating the addition of hypertonic saline to diuretics in patients with worsening heart failure. Second, Dr Spahillari and Dr Cohen discuss the main findings and echo substudy of the TEAM-HF trial. Thirdly, Dr Sundaram gives us an insight into the results of the PRAISE-HFpEF trial. The podcast concludes with a brief discussion of some of the HFA Young highlights from the congress. This 2024 HFA CardioTalk podcast series is supported by Novartis in the form of an educational grant. The discussion has not been influenced in any way by its sponsor.

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. Maaike Oonk to discuss the ESGO Vulvar Cancer Guidelines for 2023. Dr. Oonk is a gynaecological oncologist in the University Medical Center Groningen in the Netherlands. Her research focuses on new treatment options for vulvar cancer patients to improve quality of life. She is PI of the GROINSS-V studies and was chair of the 2023 ESGO vulvar cancer guidelines working group.   Highlights: Inguinofemoral radiotherapy is a safe alternative for a lymphadenectomy in patients with micrometastasis in the sentinel node. In case of unilateral sentinel node involvement, it is probably safe to omit treatment of the contralateral (sentinel node negative) groin. Studies are ongoing on application of the sentinel node procedure in locally recurrent disease, tumors > 4cm or multifocal tumors: outside these studies, the sentinel node procedure should only be applied in patients with unifocal primary squamous cell vulvar cancer < 4cm. In advanced disease, both primary chemoradiation and radical surgery are treatment options. The Vulcanize study is investigating the role of neoadjuvant chemotherapy in these patients. Given the rareness of this disease, treatment of vulvar cancer should be centralized in specialized centers.

Our coverage of the 18th World Congress of Anaesthesiologists (WCA 2024) continues. In this piece we cover assisted fluid management in anesthesia. Using AI in anesthesia and its potential impact on anesthesiologists. The validity of the hypotension prediction index in academic debate. Reducing hypertension in surgical patients using HPI. Desiree Chappell and Monty Mythen speak with Thomas Scheeren, Senior Director Medical Affairs, Edwards Lifesciences and Paul Van Beest, Anaesthesiologist, Medical Center Leeuwarden, University Medical Center Groningen.

In January we saw experts from across the genomics ecosystem, including patients and those with an interest in genomics, gather at the Festival of Genomics - the UK's largest annual life sciences event. In this episode, our host, Vivienne Parry, Head of Engagement at Genomics England, speaks to Louise Fish, CEO of Genetic Alliance UK, and Professor Matt Brown, Chief Scientific Officer at Genomics England, to discuss the event and emerging future trends in genomics.  In this episode you'll also hear some exciting future advances in genomics research from some eminent speakers at the Festival: Harold Sneider, Professor of Genetic Epidemiology, University Medical Center Groningen sheds light on the "Identification of methylation markers for Type 2 diabetes up to 10 years before disease onset." Nagy Habib, Professor of Surgery, Imperial College London, delves into "The future of saRNA therapeutics and its potential for treatment".  Lennard Lee, National Clinical Advisor on innovation and cancer vaccines, presents his perspectives on "The Future of Cancer Vaccines," offering a glimpse into the promising advancements in this critical field. "The scientific breakthroughs that are being made are absolutely incredible and they're really exciting, but from the point of someone living with a genetic condition, what they want to see is those scientific breakthroughs making a real difference in the clinics...For some conditions, it's about treatments, but it's also about being able to get a diagnosis faster, to be able to understand what condition is impacting on you, how it might affect you over your lifetime and your wider family, and to be able to work with NHS services to understand and plan for the care and treatment that you'll need throughout your lifetime."   You can read the transcript below or download it here: https://files.genomicsengland.co.uk/documents/Podcast-transcripts/Insights-from-the-Festival-of-Genomics.docx   Vivienne Parry: Hello and welcome to the G Word. Vivienne Parry: The Festival of Genomics is the UK's biggest genomics event, and it's become an essential part of our year. It's free for 90% of its delegates, it's in person, and with more than 5,000 people expected, it's now so big that it's had to move to ExCel's cavernous Dockland Halls. It's the place to hear top science and to spot new trends, but actually for me the joy of the festival is the people you meet. Of course, it's great to catch up with old friends, but it's the new collaborations sparked by random encounters at the festival which I think are the lifeblood of the genomics ecosystem, and everyone with an interest in genomics is here, patients, clinicians from the NHS, researchers, industry, policymakers, and the G Word. What we thought we'd do is bring you a flavour of this great event from the floor of the ExCel halls, and give you a quick soundbite from three of the speakers that we felt best exemplify the future of genomics. With me to discuss the event and future trends in genomics, Professor Matt Brown, Genomic England's chief scientific officer, and Louise Fish, CEO of the Genetic Alliance UK, which as its name suggests, is an alliance of over 200 organisations reflecting the needs and concerns of those affected by genetic conditions. My name's Vivienne Parry, I'm head of public engagement at Genomics England, and I'm delighted to be your host for today's pod from the Festival of Genomics. Welcome to you both. So, let's start with you, Matt. How important is the Festival of Genomics for genomics in the UK? Matt Brown: Well, the Festival of Genomics has become a really key meeting for the genomics community in the UK, and I think increasingly in Europe as well. It's a really large, high quality event that brings together commercial and academic and biotech companies in the one forum, and I think it's a really exciting programme. Vivienne Parry: And of course, Louise, it's open to patients as well, which makes it an unusual event. Louise Fish: Absolutely, and it's brilliant to have patients and families here. So, people living with genetic conditions clearly need to be part of the debate when we're talking about developing new services, and developing new treatments and diagnostics, so it's absolutely fantastic to be able to come together in one room with people from the NHS and the broader sector. Vivienne Parry: And it's grown enormously, and I guess that reflects, as much as anything else, just how exciting genomics is. Matt, I'm going to pin you to the ground [laughter] and say, why is it so exciting in genomics at the moment? Matt Brown: Look, the field's really hitting its tracks. We're seeing advances in technology, analytics, application in the clinical space, and of course booming commercial activity associated with that. But from a situation ten years ago, where we had research capability for using genomics to assist in diagnosis and cancer profiling, now we're in a situation where we have multiple different approaches to assist with both of those things, transcriptomics, proteomics, spatial, single cell methods, optical mapping, a whole monopoly of different technologies that have developed out of the research world but are pretty close to being ready for clinical application. Of course, in analytics, the rise of AI and the potential that has for improving interpretation of genomes and improving personalised medicine prediction in cancers and in multivariant data, those are absolutely massive things. But aligned to that, there's also, you know, the growing worldwide application of genomics in clinical spaces, of course led through the UK and the NHS Genomic Medical Service, which has really shown the way for the world about how this might make a difference. Vivienne Parry: And Louise, that's the really exciting thing is we're now seeing not just talk about therapies, we are seeing the therapies for rare disease actually going into clinical trials and into services even. Louise Fish: Yeah, absolutely, and that's why people living with genetic conditions and their families want to see the change. The scientific breakthroughs that are being made are absolutely incredible and they're really exciting, but from the point of someone living with a genetic condition, what they want to see is those scientific breakthroughs making a real difference in the clinics. And that's sometimes about treatments, you know. For some conditions, it's about treatments, but it's also about being able to get a diagnosis faster, to be able to understand what condition is impacting on you, how it might affect you over your lifetime and your wider family, and to be able to work with NHS services to understand and plan for the care and treatment that you'll need throughout your lifetime. So, treatment's one part of it, but actually that ability to better understand what the future will hold for you, and to plan ahead for the care and support that you will need to live your life to the full is what really excites people living with genetic conditions and their families. Vivienne Parry: Now, let's hear the first of our three clips. The programme is absolutely vast, but these were three presentations that we just thought were terrific. Let's hear the first one. Nagy Habib: My name is Professor Nagy Habib. I'm a consultant surgeon at Hammersmith Hospital, Imperial College, London. We are going through a very exciting time, where we know what is the problem with the diseases, and so far we couldn't do anything about it, but suddenly the door is opening and it all came with the RNA vaccine, because we had to go very fast to get a vaccine for covid, to protect the population, and that pushed the science to go very fast, and now we can apply it to other areas apart from covid, like cancer and rare genetic diseases. And these therapeutics are what you and I and everybody else have received during vaccination. There has been six billion injections around the world, so you can imagine that everybody had an RNA injection. And RNA is that molecule between our genome, the DNA, and the protein. For anything to happen in our body, it requires the protein, but there must be an RNA in between. In the past, it was all about DNA, but now it is RNA. Why can't we get a vaccine against cancer? And so now the field is growing very fast for a vaccine for cancer. Now, the way we think about it is that we can have an injection so that we don't develop cancer of the prostate or cancer of the breast and so on, but in actual fact today what we can say is that if we take out a tumour with surgery, and we can take the RNA from the tumour and inject it in the patient, the early clinical trials tell us that this might work, and to stop the tumour coming back. It is very important to make sure that, once the tumour is out, it doesn't come back. And I think there is hope that we can have RNA vaccines in cancer. Now, to treat cancer without surgery, still we have some way to go, but again, now we know that the problem with cancer is that some of our immune cells that are there to defend us from cancer, they change their mind and suddenly they collaborate with the enemy. So instead of helping us, they are destroying our immune system, and we are developing drugs that can stop that from happening to our immune systems. Now, when you really think about what are the diseases that kill people, cancer is definitely very high up. The second one, not in a particular order, but cardiovascular system, we get heart attacks and we die from heart failure, or we get stroke and we die from stroke, and that's because we eat too much. The food is very tasty [laughter]. So, now we have injections, and the injection can make us lose weight, and we lose weight very fast. The problem is again it's very expensive. Who can afford £600 a week? And when you stop the injection, you put on weight again. So, now we are working again with RNA, and we have found a way where you inject only once every six months. And then the final thing, which is really the dream of everybody, is to stop Alzheimer's disease. So, Alzheimer's disease, as we get old, there are toxic materials that are accumulating in our brain cells, and only this year we've got two drugs coming along that can help stopping Alzheimer's disease at an early stage. Now, what we need to do is to bring that it works on all types, even the advance type of Alzheimer's disease, and now there are [inaudible 0:09:26] where we can take it from the nose. So, you inhale it from the nose and it goes straight to the brain, because there is sort of a motorway that connects the roof of the nose with the base of the brain, which is very simple. It doesn't even need an injection in the arm vein. So, it's all very, very exciting. Vivienne Parry: That is so fascinating. It's real future casting. Matt, I mean, I say it's future casting, but tell me a bit about the Rare Therapies Launchpad, because, you know, that picks up some of what Nagy has outlined. Matt Brown: Yeah, so DNA and RNA therapeutics are absolutely booming, and that's one of the big excitements is that we're not only being able to diagnose people, but we're coming up with new ways of actually providing treatments for patients with rare diseases and cancers through nucleic acid therapeutics. For rare diseases, the type of clinical trials that are involved are really quite different, and you can't just basically translate what was used for common diseases into the rare disease space. It just doesn't work, and that's really held back the field a lot. So, to try and enable rare therapies to actually make that leap from a research setting into actual clinical practice, Genomics England, in partnership with the Medical Health Regulatory Authority and others, have set up a Rare Therapies Launchpad, to provide an end to end solution for people to be able to run clinical trials for rare and ultra rare diseases, particularly focusing on nucleic acid therapies, and linking that with both the regulatory authorities and health funding authorities so that we can get these ultimately into clinical practice. I think we need these sorts of initiatives so that we don't continue to see rare therapies falling over because they're being assessed and made to go through the hurdles that common therapies do nowadays. Vivienne Parry: So Louise, we really are in the area of what people call N of 1 medicines. Louise Fish: Yeah, absolutely. So, these are medicines that are made specifically for one person and will help that one person, and obviously that brings a whole heap of possibilities for people living with genetic conditions, but also a load of challenges that we understand for decision makers within the MHRA and NICE and the NHS. And so I think there are some real challenges that we're really aware of from the decisions that are already being made by those decision making authorities about treatment. Obviously, putting it at the most basic level, you don't have the same evidence base for treatment that's just available for one person that you do from a clinical trial, where thousands of people will have taken part in a trial to understand how it affects a whole host of people. So, we know that the decision making bodies are going to need to take a different approach to evidence, so are going to need to be willing to look at evidence that is just from a trial involving one person. They're going to need to be able to extrapolate the benefits of that treatment across someone's lifetime, and that can be challenging, and we've seen that before in rare disease medicines and the new treatments that have come along in recent years. So, there are definitely some challenges, and we're really glad to see those challenges being acknowledged upfront by Genomics England, the MHRA and others, and being debated and discussed, and trying to find solution now rather than waiting for those treatments to come along later, and then trying to retrofit and decide how to manage them. So, it's great to see this debate taking place early, and we're really keen to make sure that the voices of people living with rare conditions and their families are part of that discussion. Vivienne Parry: And the really cheering thing that we're hearing from Professor Habib is that he thinks that the cost is going to be much less, because some of these things, you know, have million pound price tickets, so to have something that will be cheap is really going to be I think the gamechanger.   Louise Fish: One of the challenges with that is understanding the lifetime costs of someone living with a genetic condition and all of the complexities that are involved, and not just the medical care that they need, but the social care and the wraparound care that they'll need, the extra support from schools and colleges, the extra support from employers if they're able to go in employment. So, I think we're constantly trying to help the government and decision makers have a better understanding that those lifetime costs of living with a genetic condition are the things that should be taken into account when they're making decisions about a new treatment that could be totally game changing for someone's health and their future. Vivienne Parry: Cheaper treatments on the way, Matt? Matt Brown: So, I think we absolutely need to work on reducing the costs of these treatments, because at the moment the costs are so high that, were we to extrapolate that out to try and treat the thousands to tens of thousands of different rare diseases that there are out there, we couldn't possibly afford it. I think it's very promising that we will get cheaper treatments. This might come about through reducing the development costs, in particular reducing the clinical trial programmes, and the level of safety and efficacy evidence that you require before you can actually make these treatments available. I think that will make a massive difference, if we can simplify that. And another thing is, by better collaboration between the different rare disease communities and genetic medical services around the world, to make sure that what might be an N equals 1 condition in the United Kingdom, when you consider it around the world, might actually be an N equals 100 people, and then basically the cost per patient drops substantially. To achieve that, we need much better coordination between the national genomic medical services. Vivienne Parry: At the end there, you heard talk of using RNA therapies for obesity and Alzheimer's, and we principally talk, particularly in Genomics England, not just about cancer and rare disease. But I wanted to present to you another presentation, which I just thought was extraordinary, which comes from the Netherlands, and it's about picking up signs of diabetes using genomics ten years in advance. Just listen to this. Harold Sneider: Hi, I'm Harold Sneider, I'm a genetic epidemiologist working at the University Medical Centre in Groningen in the Netherlands, and my focus is on cardiometabolic disease, and I have a great interest in hypertension, for example, obesity, but also type two diabetes. So, one of my major interests is to try and identify genes for common complex, mostly cardiometabolic diseases, so our approach is to do genome-wide association studies using genetics, but also epigenetics. And epigenetics can be screened for so-called methylation markers, and those methylation markers have an effect on expression of the genes, and we can look at this all over the genome. Then a very interesting question came up, whether these types of epigenetic signals or methylation markers could actually be used to predict disease in people that are still healthy. So, the goal of this type of work always consists of two parts. First, it's that we try to find out which genes are highlighted by these DNA methylation markers, because they are located at certain positions on the genome, so we know which genes are involved in those regions and we can learn more about the underlying biological mechanisms that play a role in the development of the disease. Because we found those signals up to ten years before the disease occurred, so that tells us something about changes that already happen at an early stage. It's like an early detection mechanism. At the same time, a combination of these markers together lets you calculate what's called a methylation score that can be used for the prediction of the disease, and the ultimate goal here is that even in healthy individuals, when you have those measurements, you can calculate such a score to improve the prediction and identify people with a higher probability to develop such a disease. I definitely think we can apply this general approach also to other – for example, cardiometabolic diseases, such as coronary artery disease or also hypertension. Vivienne Parry: Harold Sneider there from Groningen. And extraordinary, the idea that you might be able to pick up not just diabetes perhaps ten years in advance, but also he was talking about potential for other lifestyle diseases, like cardiovascular disease, for instance. What are your thoughts about that, Matt? Matt Brown: Look, I think it's always been an aspiration of the clinical community to move treatments from treating patients with established disease to actually working in really early or preclinical spaces, where you've got a much better chance of preventing end organ damage, and secondly you've got a much better chance of actually inducing remissions or potentially actually curing diseases. And I think not just in diabetes, but also in a range of immune mediated diseases, there's pretty good evidence now that you can, by intervening early, really make a massive difference to the natural history of diseases, and new methods are coming about to identify those patients, be it polygenic risk scores or other biomarkers, to enable us to sort of flip the approach of medicine from being reactive to pre-emptive. Vivienne Parry: And rare conditions, as they do so often, Louise, are leading the way in understanding the issues, which will then spill out into a much wider area of the population. Louise Fish: Yeah, absolutely, and rare conditions obviously is the space that we work in. So, Genetic Alliance UK, as you say, is an alliance of around 230 charities that support people largely with rare genetic conditions, and many of those charities are condition specific or look after groups of conditions, like metabolic rare diseases. So, that's the kind of space that we come from, and obviously in our space, the excitement is around the work that we're doing with Genomics England around the Generation Study, and trying to use that to understand whether it's possible to screen babies to understand whether they have a rare genetic condition, and if so to identify that condition and intervene early. And again, excitingly, that's not just about treatment, it's about whether there's a way of helping that child and their family, if you can identify very early to help really improve their lifestyle choices. And one of the best examples we have is identifying children with brittle bone disease, where if you pick them up through screening, you'd be able to teach their parents to handle them safely, so they didn't have breaks in their bones as babies, which is what we see now. So from our perspective, it's obviously different to the polygenic risk scoring, but again it's that idea of using genomics as a way of identifying conditions very early, and intervening before signs and symptoms start, to try and improve the life chances of the person living with that condition, and help their wider family to help them, which is really exciting from our perspective. Vivienne Parry: But the experience and knowledge that you've gained as rare disease organisations actually is enormously valuable to other people. I mean, rare has always been at the forefront. I mean, in cancer, for example, it was chronic myeloid leukaemia, which was a rare cancer, that kind of unlocked cancer targeted treatments for everybody else. And it always seems to me that rare is at the forefront. Although it's often seen to be behind, it actually is the key to unlocking so many other things, and the experiences that you have all had are so valuable for much wider populations. Louise Fish: Yeah, absolutely, and one of the reasons we run Genetic Alliance UK is so our member organisations can learn from one another, ‘cos there's always one of the rare patient organisations which is surging ahead in a particular space, doing something really exciting, doing something really new, and we try and make sure that our members can learn from one another and don't have to kind of reinvent that wheel. But I know that spills out into the wider cancer space and beyond, which is fantastic. Vivienne Parry: And Louise, do you think there are particular conditions which, if I can put it like this, are on a roll at the moment, where genomics is really advancing fast for them? Louise Fish: Oh goodness, that's a really good question. There are lots of conditions where genomics is making a significant difference really quickly. For us, I think we go back to the Generation Study, and at the moment we only screen in this country for nine conditions, soon to be ten with the addition of a new condition, but the Generation Study's looking at 200 conditions and whether it's possible to screen for them. And for all of those 200 conditions, it's a really exciting opportunity to see if we can learn more, both about the potential to understand and develop treatments early, but also just about the chance to understand the natural history of that condition so much earlier than we do at the moment. And I think that's it, it's that understanding of the natural history of the condition really early, and understanding how a family can be helped through all the aspects of the condition, which is giving people most excitement, I think, alongside the potential to develop treatments. And I know we talk about treatments a lot, but at the moment only five percent of rare diseases have a condition specific treatment available, so we really try and balance, within Genetic Alliance UK, that hope for the small number of conditions that do have treatments, which is really exciting, or have treatments in development, and actually making sure that the scientific breakthroughs in genomics are something that all conditions can benefit from, whether there's a treatment or not. The potential for early identification of people with a condition, understanding the natural history better, and wrapping a package of support and care around people that is not just about a drug itself, is really important to us and to all of our members. Vivienne Parry: Matt, are you seeing any particular areas where there's a really rapid success? Matt Brown: Look, I think there have been some absolute standout successes in nucleic acid therapies in recent years. So, one is the treatment of familial hypercholesterolemia, with siRNAs for PCSK9, so the Inclisiran type approach, which has absolutely revolutionised management of that disease. In recent times, I'd highlight, for example, the treatment of sickle cell disease, an absolutely massive global problem, and now we've got a therapy which can really control sickling crisis and make a big difference to a disease which isn't just a disease of developed countries, in fact it's particularly a disease of Africa, of course. On a global level, that's just going to have a huge effect. But I think, yeah, I just would like to come back to that comment you made about things starting with rare diseases. So, in genomics, rare disease genomics has taught us a heck of a lot about what drives common diseases as well, and to my mind, gold dust for drug development companies is where you have genes that are associated with both rare and common forms of the same type of disease. And that tells you that basically you're very likely, through your treatment, to be able to actually influence the disease, and that it will influence a large proportion of patients with the disease. So, I'm really enjoying seeing this division between rare diseases and common diseases broken down a little bit, and a lot more learning in therapies going from one to the other. Vivienne Parry: Let's move to a completely different area, one that's very important to Genomics England and less important, Louise, at the Genetic Alliance UK, which is cancer. We're going to hear from Lennard Lee about cancer vaccine. Lennard Lee: I'm Dr Lennard Lee, I'm a medical oncologist, so I practice as an NHS doctor, treating cancer, and I'm an associate professor at the University of Oxford. We've come to a position whereby vaccines can be developed quicker than anyone thought. In the last few years, we've realised that the technology has moved on rapidly, MRNA technology, and you can make vaccines and update them really, really quickly. We've now come to a situation where vaccines can be made against cancer, and this is where genomics is really starting to supercharge this technology. If you can sequence a cancer then what we're finding now is that the technology now exists for you to print off an MRNA vaccine for that patient, a truly personalised product. And it's amazing because the genetic basis of the cancer, what the genomics sequencing shows then becomes a vaccine itself. The vaccine is designed based on that sequence, and that's why genomics has really supercharged this field of vaccinations for cancer. One of the possible things we just need to clarify and be aware of is that when people talk about cancer vaccines, they mean a number of things. Ultimately, what it involves is getting a new treatment for people with cancer, because it's based on their genetic sequence, so it's used to treat people with cancer. The future's an exciting one, truly personalised medicine based on genomics. Genomics is going through so many different phases in the field of cancer. Firstly, we were starting to understand why cancer happened and what patients outcomes were. The second phase started to kick off where genomics would help patients select the right drugs at the right time for them, which is amazing. And now we've entered the final evolution of genomics, where it now becomes the actual drugs that we treat people with. And cancer vaccine is one of the first potential areas where genomics will start to form the basis of the treatments going ahead. In five years' time, we're going to know if it works or not, where an individual vaccine based on the genomic abnormality seen in that cancer is going to give better outcomes for patients than an off the shelf product. We know that every cancer's different, so genomics has showed us this, but all of a sudden that sequence could become that vaccine, which then primes that immune system, truly personalised therapy. And it is so exciting that we're going to be talking about this in this festival, and it's being driven as from the UK, which has got so much strength in terms of genomic capabilities as we're developing vaccines. Vivienne Parry: So Lennard Lee there, absolutely confident of the importance of cancer vaccines. Matt, what are your thoughts on that?  Matt Brown: I think it's a tremendously exciting field. The early data on cancer vaccines with melanoma, for example, showed that for a cancer which previously had been resistant to virtually all of our approaches, is actually quite responsive to novel cancer vaccine approaches. We are yet to see across what diversity of cancers this is actually going to work, so there's clearly a huge clinical trial programme that's going to be required to drive this, and the UK is playing a really central role through the Cancer Vaccines Launchpad that Lennard's involved with running, in creating the evidence base about whether these are going to achieve the promise that they hold. I also think that they've got a lot of possibility for inherited cancer types. For example, I think the programme's looking at cancer vaccines for Lynch syndrome, to try and prevent colorectal cancer in that group of patients. So, I think they've got lots and lots of opportunities, and it's nice to see something positive actually coming out of the pandemic like this, for what was a pretty bleak episode worldwide otherwise. Vivienne Parry: They are a small part, I know, of your organisation, Louise, but in some ways, those people with inherited cancers in their families are seeing the benefits of genomics on both sides, both in that earlier diagnosis, picking up right from the very beginning, and of course in the promise of these new treatments. Louise Fish: Yeah, absolutely, and you're right, it's a small part of our remit. We do have some organisations in our membership who specifically support people with rare inherited cancers, and we work very closely with an organisation called Cancer 52, who also represent organisations with rare cancers. I'll just give them a quick shoutout in case anyone listening is not aware of them and their amazing work. But you're right, I think there are a couple of things going on that are really exciting in the cancer space. It's that ability to better understand why some people are likely to inherit cancers, how that pattern works within families, and to support those families and help them understand like the risk that they have, and to make informed decisions about their own treatment and care in the future. And also about whether they want to have children, and if they do want to have children, kind of how they want to approach that to try and reduce the risk of passing on that heritability. So, that's a really important part for everybody. I think there's also potential to develop new treatments, which is absolutely amazing and really exciting, and it is really exciting to hear about the potential for cancer vaccines. The other area where I think people living with inherited cancers are interested to find out more is what impact it might have on better understanding which treatments will work for which people. And we know, for example, that there are some cancer treatments that only work for one in four people with that particular kind of cancer, but it's been really hard to understand why that's the case. And I think the potential for genomics to identify which people could benefit from a particular cancer treatment would have two huge benefits. A, cancer treatments, many of them are really horrible, you know. They're horrible things to go through, and if you had a better confidence that a particular treatment was going to work for you because of your genetic makeup, that would make you a lot more confident about deciding to try that treatment, and taking on board the side effects of the treatment and how it's going to impact on you. That would also obviously massively impact on the cost effectiveness of that treatment. At the moment, we might give it to four people and only one of them would benefit, but you're paying for the cost of giving it to all four people. If you could identify in advance which people were more likely to benefit then you'd give it to fewer people, they'd be more likely to benefit, and the cost would come down. So, I think that there is real potential in this field of genetics and genomics to help in all kinds of ways that people living with these conditions are really excited to see and explore. Vivienne Parry: So Matt there, it's not of course simply about identifying, you know, what the cancer is like and its genomic makeup, but actually it's that wider field of pharmacogenomics, which is a big feature of the programme at the Festival of Genomics this year. And we're very much involved in that, aren't we? Matt Brown: Yeah, we are. So, pharmacogenomics is one of those areas where genomics is about to make a big difference in clinical practice. What we're hoping to get to is the point where we have people who are not yet treated with a medication actually already have the genetic profiling done, so that when they go to a general practitioner or a physician and be prescribed a medication, the data will already be there to say what the appropriate dose should be, and whether they're at risk of getting adverse reactions to those medications, so we could avoid them or use alternate medications. So, that sort of pre-emptive pharmacogenomics is just over the horizon, and if we can achieve that, we're going to significantly improve patient care and reduce the risk of adverse drug reactions, which are a major cause of morbidity and hospital admissions not just in the UK but worldwide. Vivienne Parry: So Matt, perfect segue into our next question, which was, you've already identified one area which you think is going to be big in the next few years. You're both absolutely in the centre of the genomics ecosystem. What do you think we're going to be seeing at next year's Festival of Genomics? What do you think is going to be the big thing that's coming up on the inside rail? Matt Brown: So look, I'd like to say what I think's going to be in next year and what I think's going to be in ten years. Next year, I think the big things are going to be advances in AI and genomic analytics. That's really ramping up fast, and I think we're going to see it in clinical implementation a lot more next year. I think the cancer therapy vaccines are going to be really big next year, as are nucleic acid therapies. Multiomics for rare disease diagnosis and cancer personalised medicine, I think is also ramping up very fast. In ten years' time, the two areas that we've not discussed so far where I think genomics is going to make a big difference are going to be in infectious diseases and in pathology services. In infectious diseases, genomics I think has a fair chance of replacing to a large extent culture based practice, or serology based diagnosis of infectious diseases, which will be done by sequencing instead. And that will be a massive change to the practice there, because you'll be able to rapidly work out, even if people have been treated with antibiotics already, what the infections are and what the likely treatment responses are going to be. Louise Fish: So from my perspective, next year what I hope to see is people getting just as excited about the differences that some of the technology we hear about this year are actually making when they're being applied in clinical practice. So I think from my perspective, it's all about that move from being excited about the science to seeing people just as excited about the difference that science is actually making when it's benefiting people living with rare conditions and their families through clinics across the UK and the NHS. Next year, I'd like to hear that excitement when people are talking about how it's actually affecting real lives. In ten years' time, I hope we'll be talking about the massive difference that some of the amazing techniques we've heard about here this year have made to the lives of people living with genetic and rare conditions. So, you know, in ten years' time, I hope that some of the treatments and the opportunities and the tests we hear about today, we can see how they've affected the natural history of the condition across ten years of lives, and that we can really see that people are living their lives to the full as a result of the fantastic technological breakthroughs that we're hearing about today. Vivienne Parry: Fantastic. It's been great to talk to you both, and it has been a fantastic festival. Vivienne Parry: So, thank you to you again, and also thank you to Frontline Genomics, who organised the Festival of Genomics, because it really has been a wonderful, wonderful event. And if you're interested in things genomic, you can subscribe to the G Word on your favourite podcast app, and if you're new to our podcast, and we always welcome our new listeners, do check out our back catalogue. You'll find it's really extensive. There's a wonderful set of genomic listening available to you, in which even spatial transcriptomics gets explained. I've been your host, Vivienne Parry. This podcast was edited by Mark Kendrick at Ventoux Digital, and produced by Naimah Callachand, and it's very good to have had you with us. Bye for now, and hope to see you at the Festival of Genomics next year.

The year 2023 has come and gone, and we figured that now is the perfect time to look back on some of the top cancer-related stories from the year.  Vitamin D May Impact Colorectal Cancer Outcomes In June, we spoke to an expert about research that analyzed 14 studies on vitamin D and colorectal cancer outcomes. Findings showed that people who had a vitamin D deficiency tended to have poorer mortality outcomes than those who supplemented with vitamin D.  Laura Bolte, of the department of gastroenterology and hepatology at the University of Groningen and University Medical Center Groningen, explained that the use of corticosteroids and being underweight or malnourished — which are all things that can happen during cancer treatment — can increase the risk of vitamin D deficiency, so it is essential that patients speak with their health care team to determine if a vitamin D supplement will be appropriate and beneficial to them.  Jimmy Buffett Dies of Cancer at 76 Every now and then, major celebrity news makes cancer headlines. On Sept. 1, “Margaritaville” singer, Jimmy Buffett died of cancer at the age of 76.  Buffett had a rare and aggressive type of skin cancer called Merkel cell carcinoma, which is much more common to spread to other parts of the body, and can be very difficult to treat if it spreads, according to the American Cancer Society.  Shortly after Buffett's death, we spoke to Dr. Manisha Thakuria, who is the director or Merkel cell carcinoma at the Dana-Farber Cancer Institute. She said, “It's always hard to see any silver linings in losses. I am glad to see Merkel cell having a little bit of a spotlight on it, and I hope that (the media interest) will increase research funding for Merkel cell carcinoma and help more patients,” said Thakuria. Chemo Drug Shortage Requires a ‘Holistic Solution'  Perhaps one of the biggest headlines in the cancer space from 2023 was the chemotherapy shortage. The shortage of cisplatin and carboplatin required a “holistic solution,” according to Dr. Anjan J. Patel.  In a June article, I spoke with Dr. Patel and other oncology experts about the shortage, what it meant for patients taking these drugs and what was needed from a systemic level to ensure that these types of shortages never happened again.  Patients Using Cannabis Experienced Worse Symptoms, Perceive Less Harm Patients with cancer who use cannabis reported more severe symptoms and perceived less potential harm from cannabis than patients with cancer who did not use the drug within the last 30 days, according to study findings published this summer.  Findings showed that study participants who used cannabis experienced significantly poorer physical and social functioning as well as higher pain intensity, pain interference, fatigue and sleep disturbances.  “People are using it, we should study it, and we need to know more to be able to guide physicians and cancer patients and survivors as well,” Gregory Giordano of the department of psychology and neuroscience at the University of Colorado Boulder told CURE® For more news on cancer updates, research and education, don't forget to subscribe to CURE®'s newsletters here.

BUFFALO, NY- November 1, 2023 – A new research perspective was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 20, entitled, “Cholinergic centro-cingulate network in Parkinson disease and normal aging.” In their new perspective, researchers Nicolaas I. Bohnen, Sygrid van der Zee and Roger Albin from University of Michigan, Veterans Administration Ann Arbor Healthcare System, University of Groningen, and the University Medical Center Groningen discussed Parkinson disease (PD). Decreased cholinergic binding within the recently identified centro-cingulate brain network has been shown to robustly correlate with the severity of cognitive impairment in PD. This network with key hubs within the cingulum, operculum and peri-central cortical regions also correlates with elements of parkinsonian motor impairments, including postural instability and gait difficulties, such as falls or freezing. “We recently reported novel data-driving findings suggesting that cholinergic innervation deficits in centro-cingulate brain regions may be an important contributor to cognitive impairments in PD [1].” MRI neuroimaging studies have shown that the anterior midcingulate cortex is a key node for cognitive aspects of movement generation, i.e., intentional motor control. Recent evidence also suggests a novel aspect of organization of primary motor cortex, describing “effector” regions for fine movement control intercalated with interlinked “inter-effector” regions devoted to whole-body control. A distinguishing feature of inter-effector regions is tight linkage to the cingular and opercular regions. Such inter-effector regions have been proposed to be part of a greater somato-cognitive action network necessary for integration of goals and movement. Recent evidence also points to vulnerabilities of cholinergic nerve terminals in the centro-cingulate network in older non-PD adults. These features of normal aging underscore that cortical cholinergic terminal losses in age-associated neurodegenerative disorders are likely not exclusively the result of disease-specific etiologies but also related to otherwise normal aging. “Practical implications of this overlap are that addressing disease-specific and general aging etiologies involved in neurodegeneration, may be of benefit in age-associated neurodegenerative disorders where significant cholinergic systems degeneration is present.” DOI - https://doi.org/10.18632/aging.205209 Corresponding author - Nicolaas I. Bohnen - nbohnen@umich.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205209 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, centro-cingulate network, cholinergic, cognition, motor, Parkinson disease About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-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/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Janneke Koerts is an associate professor in Clinical Neuropsychology and has been working at the University of Groningen, the Netherlands, since 2007. Janneke obtained her PhD in Medical Sciences in 2009 at the University Medical Center Groningen. Her current research is looking at the financial well being and difficulties that affect people with certain psychological conditions such as adults with ADHD. --- Support this podcast: https://podcasters.spotify.com/pod/show/out-of-the-blank/support

With Henrike Arfsten, University of Vienna, Vienna - Austria, Juan Pablo Kaski, University College London, London - United Kingdom, Mateusz Sokolski, Wroclaw Medical University, Wroclaw - Poland, Jozine ter Maaten, University Medical Center Groningen, Groningen - the Netherlands, Peter van der Meer, University Medical Center Groningen, Groningen - the Netherlands, Antonio Cannata, King's College London, London - United Kingdom & Theresa McDonagh, King's College Hospital, London, United Kingdom. This podcast discusses two new guidelines and the results of two hot line presentation all presented at the ESC congress 2023 in Amsterdam, the Netherlands. First, Prof. Kaski shares highlights from the new and first ESC cardiomyopathy guidelines. Second, Prof. van der Meer discusses the results from the STEP HFpEF study in which semaglutide showed beneficial effect on weight, 6MWT and a win ratio compared to placebo in patients with the obesity phenotype of HFpEF. Next, Dr. ter Maaten discusses the results of the first randomized trial investigating the effect of natriuresis guided diuretic therapy in acute heart failure, as already incorporated in the guidelines. Finally, Prof. McDonagh walks us through the update of the ESC heart failure guidelines. The podcast is concluded with a brief discussion of some HFA Young highlights at the congress. 

Hosted by: S. Diane Yamada, MD, Deputy Editor of Gynecologic Oncology Featuring: Maaike Oonk, MD, University Medical Center Groningen, University of Groningen, The Netherlands Akila Viswanathan, MD, MPH, Johns Hopkins Medicine Editor's Choice Paper: Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe Editorial:When is it safe to omit contralateral groin management in unilateral sentinel node-positive early stage vulvar cancer?

In this episode of the podcast, Dr Andrew Perry is joined by Professor Michiel Rienstra of the University Medical Center Groningen in the Netherlands. They discuss his paper “Prevalence and determinants of atrial fibrillation progression in paroxysmal atrial fibrillation” recently published in Heart. It is an interesting piece in the investigation to understand the pathobiology of atrial fibrillation. If you enjoy the show, please subscribe. Also, please consider leaving us a review at https://itunes.apple.com/gb/podcast/heart-podcast/id445358212?mt=2 Link to published paper: https://heart.bmj.com/content/early/2022/07/20/heartjnl-2022-321027

This month—two studies on COVID-19! Daniel R. Goldstein, MD, Editor-in-Chief of JHLT, is taking a short break, so the episode is hosted by Digital Media Editor Erika Lease, MD. Both COVID-19 studies come from the September issue of The Journal of Heart and Lung Transplantation, and in the episode, you'll learn more about each study and their authors.   First, the editors speak with Yael Peled, MD, Medical Director of the Heart Transplant Service at the Sheba Medical Center in Ramat Gan, Israel. She's the first author on a paper entitled “Fourth BNT162b2 vaccination neutralization of omicron infection after heart transplantation.” Dr. Lease and Marty Tam, MD, interview Dr. Peled about the study, which examples how IgG and neutralizing antibodies responded to a fourth BNT162b2 dose in heart transplant recipients against the omicron and delta variants versus the wild-type virus.   Next, we hear from C.T. Gan, MD, PhD, Consultant in Respiratory Medicine and Lung Transplantation at University Medical Center Groningen, on his study, “The effect of COVID-19 on transplant function and development of CLAD in lung transplant patients: a multicenter experience.” Dr. Lease and Van-Khue Ton, MD, discuss the study with Dr. Gan, including questions on management strategies for COVID-19 in lung transplant patients, lung function improvements after COVID-19 recovery, and potential follow up studies.   Follow along in the September issue at www.jhltonline.org/current, or, if you're an ISHLT member, log in at ishlt.org/journal-of-heart-lung-transplantation.  Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.   This episode of JHLT: The Podcast, but not the studies within, is sponsored by Bayer Pharmaceuticals.

Historically, echo analysis has been too expensive or inaccessible for many heart disease patients to receive the care they need. Today's guests, James Hare and Dr. Carolyn Lam of Us2.ai, are changing that.  Us2 is a decision support tool that uses artificial intelligence to automate reading any DICOM (Digital Imaging and Communications in Medicine), anytime, from any device.  It is FDA-cleared, vendor-agnostic, and delivers peer-reviewed results that are shown to be interchangeable with expert human sonographers.  Us2's mission is to give everyone full access to their heart health with easy, mobile echo analysis. Today, James and Dr. Lam discuss why echos can be tricky even for medical experts to get right, how Us2 supports both physician and patient use across a variety of cardiac conditions and the healthcare democratization movement.  Notable Quotes “It should be accessible to everybody to look at the heart. Why shouldn't you be able to look at the heart and see you've got a hole in your heart or a part of the heart that's not working well or a valve is not working well? I mean, we should be able to do that everywhere.” – Dr. Carolyn Lam (04:02) “There's a lot of well merited skepticism about new AI technologies and the burden is on us to prove that what we have done is useful and it works. But once we push beyond that, once people actually see it, it's just the best feeling in the world. And the reality is that everybody in this, as skeptical as they are, everyone knows what the future is. It's just a matter of how soon we're gonna get there.” – James Hare (18:37) In This Episode (03:36) Us2's origins  (15:20) How it works (19:40) Use cases and the intricacies of heart failure that Us2 can identify  (25:38) Us2 uses beyond heart failure (31:30) Us2's commercial outlook  (33:25) The biggest challenge during Us2's development (35:13) Finding a shared language across business, medicine and tech (39:05) The future of Us2 in hospitals and physician offices Our Guests Us2.ai CEO and Co-founder James Hare previously served as the Co-founder and President of eDreams, which IPO'd in 2014 and has become one of the world's most successful e-commerce sites. Before starting Us2, James worked at organizations including EFI, UbiSoft and Netscape, and earned his MBA from Stanford and BA from Harvard. Dr. Carolyn Lam is the Co-founder & Non-Exec Head of Medical Affairs, and is a tenured Professor at Duke-National University in Singapore, where she founded and continues to run the first Women's Heart Clinic. Dr. Lam received her Masters from the Mayo Clinic, graduated from the Stanford Executive Program and then earned her PhD from the University Medical Center Groningen in the Netherlands. Resources & Links Mike Moore LinkedIn James Hare LinkedIn Dr. Carolyn Lam LinkedIn Us2.AI  Website LinkedIn The Bleeding Edge of Digital Health Apple Podcasts Google Amazon Spotify YouTube LinkedIn

"Hypotension is always a problem..." This piece is provided 'as live' from the European Society of Anaesthesiology and Intensive Care (ESAIC). Presented by Desiree Chappell, Monty Mythen and Sol Aronson with their guest Thomas Scheeren, Professor of Anesthesiology, Department of Anesthesiology, University Medical Center Groningen, Groningen, the Netherlands. Our guest has featured on TopMedTalk before, worth checking it out here: http://www.topmedtalk.com/euroanaes2019-thomas-scheeren/ -- Get all the headlines and information about the hot topics and major events of this conference exclusively from TopMedTalk, thanks to our partners in GE Healthcare. Go now to www.twitter.com/topmedtalk Go now to https://www.youtube.com/channel/UC-HYQmeIwcFCYO1hoQ8jShQ Go now to https://www.facebook.com/TopMedTalk1 Go now to https://www.linkedin.com/company/topmedtalk/ Find out more about The ESAIC here: https://www.esaic.org/ Find out more about GE Healthcare here: https://www.gehealthcare.com/

Eating prunes may help protect against bone loss in older women Penn State University, February 9, 2022 It's already well known that prunes are good for your gut, but new Penn State research suggests they may be good for bone health, too. In a research review, the researchers found that prunes can help prevent or delay bone loss in postmenopausal women, possibly due to their ability to reduce inflammation and oxidative stress, both of which contribute to bone loss. “In postmenopausal women, lower levels of estrogen can trigger a rise of oxidative stress and inflammation, increasing the risk of weakening bones that may lead to fractures,” said Connie Rogers, associate professor of nutritional sciences and physiology. “Incorporating prunes into the diet may help protect bones by slowing or reversing this process.” (NEXT) Can correcting micronutrient deficiencies help treat heart failure?  University Medical Center Groningen (Netherlands), February 9, 2022 A review published in the Journal of Internal Medicine provides convincing evidence that micronutrients—including iron, selenium, zinc, copper, and coenzyme Q10—can impact the function of cardiac cells' energy-producing mitochondria to contribute to heart failure. The findings suggest that micronutrient supplementation could represent an effective treatment for heart failure. “Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation, moving our view of the failing heart away from “an engine out of fuel” to “a defective engine on a path to self-destruction,” said co–lead author Nils Bomer, PhD, of the University Medical Center Groningen. (NEXT) Could meditation reduce brain aging? University of California-Los Angeles   February 7, 2022  It is common knowledge that the brain deteriorates as we age, causing functional impairments. You may be surprised to learn that this process usually begins during mid-to-late-20s. But before you panic, a new study suggests a potential way to reduce such deterioration: meditation. The research team at the Brain Mapping Center at the University of California-Los Angeles (UCLA), found meditation may be associated with better preservation of gray matter in the brain – the neuron-containing tissue responsible for processing information. The researchers recruited 100 subjects to the study aged 24-77. Of these, 50 had meditated for between 4 and 46 years and 50 had never engaged in the practice. Both groups were closely matched for age. (NEXT) The Power Of Tea Washington University, February 6, 2022 A compound found in green tea could have life saving potential for patients with multiple myeloma and amyloidosis, who face often-fatal medical complications associated with bone-marrow disorders, according to a team of engineers at Washington University in St. Louis and their German collaborators. Jan Bieschke, assistant professor of biomedical engineering  says the compound epigallocatechine-3-gallate (EGCG), a polyphenol found in green tea leaves, may be of particular benefit to patients struggling with multiple myeloma and amyloidosis. These patients are susceptible to a frequently fatal condition called light chain amyloidosis, in which parts of the body's own antibodies become misshapen and can accumulate in various organs, including the heart and kidneys. (NEXT) Changing your diet could add up to a decade to life expectancy, study finds University of Bergen (Norway), February 8, 2022 A young adult in the U.S. could add more than a decade to their life expectancy by changing their diet from a typical Western diet to an optimized diet that includes more legumes, whole grains and nuts, and less red and processed meat, according to a new study published  in PLOS Medicine. For older people, the anticipated gains to life expectancy from such dietary changes would be smaller but still substantial. In the new study, researchers used existing meta-analyses and data from the Global Burden of Diseases study to build a model that enables the instant estimation of the effect on life expectancy (LE) of a range of dietary changes. (VIDEOS) Every news media who secretly took Trudeau's $61M pre-election pay-off – (13 minutes) Mary Holland – Protect Our Children (3:44 minutes) Canadian truckers are ‘doing something wonderful for the world' says Brendan O'Neill (OTHER NEWS) How Fact Checking Is Controlled and Faked Epoch Times, February 09, 2022 Prior to 2015 or 2016, you could still read what you wanted online without much interference. This has since changed, as propagandists have infiltrated the media and, along with other major players, like Big Tech and government, set out to control information. Fact-checking — a once-obscure term that's since gone mainstream — is one part of the campaign to control what you see online, and therefore what you think and how you perceive reality — but it's all a ruse. Speaking with Jan Jekielek, The Epoch Times senior editor and host of the show “American Thought Leaders,” investigative journalist Sharyl Attkisson explains how virtually everything you see and hear online has been co-opted, or taken over to serve a greater agenda:1 “One has to understand that nearly every mode of information has been co-opted, if it can be co-opted by some group. Fact checks are no different either, they've been coopted in many instances or created for the purpose of distributing narratives and propaganda. And your common sense is accurate when it tells you that the way they chose this fact check and how they decided to word it so they could say this thing is not true when at its heart it really is true, but the message they're trying to send is that you shouldn't believe it, your common sense is right. That's been created as part of a propaganda effort by somebody, somewhere, as part of a narrative to distribute to the public so virtually every piece of information that can be co-opted has been.” The Information Landscape Is Being Controlled Attkisson calls out several common online sources that are heavily manipulated — Wikipedia, Snopes and most “fact” checkers to name a few, along with HealthFeedback.org, which is a fake science group used by Facebook and other Big Tech companies to debunk science that is actually true. Fact checkers are often referred to as scientists, but this, too, is “part of a very well-funded, well-organized landscape that dictates and slants the information they want us to have.” While there have always been efforts to shape the information being given out by the media, it used to be that news reporters would push back against organizations to ensure the public had the other side of the story. Beginning in the early 2000s, Attkisson noted a shift from efforts to simply shape information to those that attempt to keep certain information from being reported at all. This was particularly true among the pharmaceutical companies she was covering at that time. Attkisson described “efforts by these large global PR firms that have been hired by the pharmaceutical industry, by government partners that work with the pharmaceutical industry, to keep the story from being reported at all.”2 Now, instead of real journalists and reporters, the media is infiltrated with propagandists who dictate what's “fake news” and what's not. Many believe that fake news is a product of Trump, but Big Tech was brought into the campaign early on. A lobby campaign by behind-the-scenes propagandists met with Facebook and said you've got to start censoring and “fact” checking information, Attkisson said. Attkisson states that it goes much deeper. A lot of propagandists have become part of the media, and while there used to be a firewall between reporters and the people they reported on, “that's long gone.” She says:6 “We've not just invited them to influence what we report, but we've hired them, not just as pundits and analysts but they are reporters. They are editorial presences within our newsrooms. Now we are one and the same. It's hard to say that there's a distinctive difference in many instances between the people trying to get out a message and the messengers in the media who should be doing a more independent job of reporting accurately.” Reality Is Being Altered in Real Time As it stands, information is being changed in real time to meet the common agenda. This includes definitions in dictionaries and on official government websites. Examples of definitions that have been changed recently include those for pandemic, herd immunity, vaccines and anti-vaxxer. Attkisson reiterates:17 “Virtually every form of information and sourcing that can be co-opted has been. That includes the dictionary definitions; that includes everything because these are important ways to influence thought. Language is very powerful. People don't want to be affiliated with certain names and labels. It reminds me of ‘1984,' the George Orwell story about the futuristic society, under which history was being rewritten in real time to jive with the version that the government wanted or the party wanted it to be. Definitions now are being rewritten and changed in real time to fit with the vision that the establishment wants people to think.” The Truth Finds a Way To Be Told While there are powerful forces at play to control information, all is not lost. Attkisson is aware of three entities that are actively working on a solution, which include: Investors who want to invest in independent news organizations Technical people trying to invent platforms that can't be controlled and deplatformed by Big Tech Journalists who want to work or contribute to these efforts Outlets like Substack newsletters and the video platforms Rumble, Bitchute and Odysee, which don't censor videos for ideological reasons, are actively getting around the censorship of Big Tech, and Attkisson believes that these efforts will accelerate in the next couple of years. Further, she says, “The propagandists may have overplayed their hand by being so heavy-handed and obvious about the control of information and the censorship. It's no longer deniable. Even people who want their information curated, they can't always be happy with the notion that they're not going to be able to get the full story, or that they're only getting one side of something.”24 Ultimately, she adds, “I think the truth finds a way to be told … it may take some time and there may be a lot of people that don't want the truth out, but we inherently as humans seek it.”25 On a personal level, you can go a long way toward finding the truth by following your own common sense and reason, and Attkisson agrees. “I always say, do your own research, make up your own mind, think for yourself. Trust your cognitive dissonance, use your common sense. You're going to be right more often than you think, but open up your mind, read a lot, think a lot and don't buy into the prevailing narrative at face value.” (NEXT) Opioid Overdose Deaths Cost U.S. Economy $1 Trillion A Year, Study Finds Forbes, February 8, 2022 Opioid overdose deaths cost the U.S. economy $1 trillion a year, the U.S. Commission on Combating Synthetic Opioid Trafficking said Tuesday, a “staggering amount” it says underlines the “direct and escalating threat” the opioid epidemic poses to the economy, public health and safety and national security. The panel came up with the estimate based on a White House Council of Economic Advisors' 2018 report that determined the cost of overdose fatalities amounted to $696 billion a year at a time when the death toll was about two thirds of today's. Between June 2020 and May 2021, 100,000 Americans died from drug overdoses, 30% higher than the year before and more than double the number of deaths caused by car accidents or gun violence during that period. About two thirds of those deaths involved synthetic opioids like fentanyl and primarily affected victims between the ages of 15 and 45, the report says. The loss of productivity and increases in healthcare and criminal justice costs tied to opioid overdose deaths amounted to a cost of about $700 billion per year in 2016 and 2017, according to the report. More fatal opioid overdoses. More than 1.2 million Canadians and Americans will die from opioid overdoses by 2029 if the epidemic is not tamed, a group of leading health experts wrote in a report published last week. 

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez, is joined by Drs. Ate van der Zee and Brian Slomovitz to discuss the GROINSS-V-II/GOG 270 Trial. Dr. Brian Slomovitz is a Gynecologic Oncologist at Broward Health and Professor of Obstetrics and Gynecology at the Wertheim College of Medicine at Florida International University. He is an internationally recognized leader in gynecologic oncology clinical trials, specifically in immunotherapy and novel biomarker therapeutics. He also is a leader in sentinel lymph node detection for gynecologic malignancies. Dr. Ate Van der Zee is Chairman of the Board of Directors at the University Medical Center Groningen and professor of Gynaecological Oncology. His current research focuses on translational and clinical research in vulvar cancer. Together with Dr. Oonk he leads a world-wide consortium (GROINSS-V), which performs landmark clinical studies in vulvar cancer. Dr. van der Zee combines his current position chairman position with clinical work and academic research. Highlights •Radiotherapy instead of inguinofemoral lymphadenectomy is a safe treatment option for vulvar cancer patients with a metastasis < 2 mm in the sentinel node •Radiotherapy instead of inguinofemoral lymphadenectomy is associated with less treatment-related morbidity in vulvar cancer patients with a metastasis < 2 mm in the sentinel node •Prospective phase II treatment trials with stopping rules are excellent tools to explore new diagnostic and therapeutic options and to provide evidence-based medicine in rare tumors such as vulvar cancer. •Leading a world-wide consortium (GROINSS-V) is very rewarding and great fun! Ate van der Zee and Brian Slomovitz (@AteZee / @gyncancermd / @umcg / @browardhealth, @FIU)

In this episode, sports physical therapist specialist, Dr. Alli Gokeler, talks about motor learning. Today, Alli tells us about the process of motor learning, how patient autonomy is advantageous to rehabilitation, and how to motivate patients. How does Alli measure motor learning outcomes? Alli elaborates on his on-field rehabilitation model, and the importance of incorporating cognition in ACL injury rehabilitation. Alli talks about RTS from a motor learning perspective, how to continue motor learning on the field, and he gives his younger self some advice, all on today’s episode of The Healthy, Wealthy & Smart Podcast.   Key Takeaways Alli defines motor learning: “In order to acquire motor learning, you need to practice. If you don’t practice, you can’t learn something.” “The learning process itself cannot be measured directly. It’s only something you can measure indirectly.” “What motor learning should result in is: it should lead to relatively permanent improvement of motor skills.” “Be careful how you interpret this process. Quite a few clinicians have a tendency to provide feedback because they intuitively try to correct a patient.” “Be a little bit patient with your patient, because learning takes time. Don’t interrupt the learning process too soon.” “Motor learning, as well as learning a language or math, is a non-linear process.” “One of the strong drivers of learning is intrinsic motivation.” “We provide our patients with a significant amount of autonomy, which means the patient gets a certain level of control over the exercises.” “Providing autonomy during rehab enhances learning.” “Around 70% of people prefer to receive feedback after a good performance of an exercise. What happens in most clinical situations, with all good intentions, we typically give corrective feedback, which typically means you didn’t do something according to the standards of the therapist. This may affect their motivation.” “If you look at the brain activity of someone that is instructed to do something, or the brain activity of a person who has some control over what they’re going to do, you have completely different brain patterns. When you give them some control, they are much more engaged, and this is a prerequisite in order to learn something.” “If you want to be certain that learning has taken place, you need to measure, otherwise you can’t be sure that the patient has learnt something.” “If you’re good at something, it’s not challenging anymore. If it’s too difficult, then it’s overreaching.” “One-on-one training is not what’s needed for a football player. They are team athletes.” Alli’s on-field rehabilitation model: Neurocognition: Reaction time, decision-making, selective attention, inhibition and working memory. Motor component: Strength, range of motion endurance, and speed. Sensory: Visual, auditory, and environmental factors. “We need cognition during our motor control, and if we only work on pre-planned activities, we miss something from the on-field situation.” “An ACL injury isn’t just a peripheral injury, but it’s also a neurophysiological lesion, and that needs to be considered in rehab.” “With colleagues that work with paediatric patients, some of the motor learning principles that they use could be very beneficial for us working with orthopaedic, sports-related injuries.”   Suggested Keywords Motor Learning, RTS, PDCA, ACL, Rehabilitation, Neurocognition, Therapy, Physiotherapy, PT, Training, Injuries, Sport, Wellness, Health, Recovery, Injury-Prevention,   More about Dr. Gokeler Dr. Alli Gokeler has 28 years of experience as a sports physical therapist specialist. In 1990, Alli graduated with a degree in Physical Therapy from the Rijkshogeschool Groningen. Following his graduation, he worked in both the US and Germany as a physical therapist. In 2003, he earned his Sports Physical Therapy Degree from the Utrecht University of Applied Science. In 2005, he started a PhD project at the University Medical Center Groningen, Center for Rehabilitation. He is a researcher-clinician and a clinician-researcher with a passion for multidisciplinary injury prevention. He has over 40 peer-reviewed publications, and he regularly gives lectures worldwide. In his free time, he loves to do mountain biking.   To learn more, follow Alli at: Facebook:       Motor Learning Institute Instagram:       @motorlearninginstitute Twitter:            @Motor_Learning YouTube:        Motor Learning Institute Website:          https://www.motorlearninginstitute.com ResearchGate:           https://www.researchgate.net/profile/Alli_Gokeler   Subscribe to Healthy, Wealthy & Smart: Website:                      https://podcast.healthywealthysmart.com Apple Podcasts:          https://podcasts.apple.com/us/podcast/healthy-wealthy-smart/id532717264 Spotify:                        https://open.spotify.com/show/6ELmKwE4mSZXBB8TiQvp73 SoundCloud:               https://soundcloud.com/healthywealthysmart Stitcher:                       https://www.stitcher.com/show/healthy-wealthy-smart iHeart Radio:               https://www.iheart.com/podcast/263-healthy-wealthy-smart-27628927   Read the Full Transcript Here:  Speaker 1 (00:07): Welcome to the healthy, wealthy, and smart podcast. Each week we interview the best and brightest in physical therapy, wellness, and entrepreneurship. We give you cutting edge information. You need to live your best life. Healthy, wealthy, and smart. The information in this podcast is for entertainment purposes only and should not be used as personalized medical advice. And now here's your host, Dr. Karen Litzy. Hey everybody. Speaker 2 (00:37): Welcome back to the podcast. I am your host, Karen Litzy and today's episode is brought to you by net health. So net health is hosting a three-part mini webinars series on Tuesday, March 9th, entitled from purpose to profits. How to elevate your practice in an uncertain economy after 2020. I think you're going to want to sign up for this. So you're going to hear from a panel of guests that have over 50 years of combined experience working in the PT industry sign up will begin tomorrow, which is Tuesday the 23rd, February 23rd for this mini webinars series. So head over to net health.com/litzy to sign up once again, that's net health.com forward slash L I T Z Y. So check it out and sign up now. Oh, and it's free. Okay. So this whole month we've been talking about ACL injury and rehab. So today's episode is with Dr. [inaudible]. Speaker 2 (01:41): He has 28 years of experience as a sports physical therapist specialist. In 1990, he graduated with a degree in physical therapy from I'm not even going to pretend to try and pronounce this. So you can just go onto the podcast website to find out where he went to school. Cause I'm not even going to attempt it following his graduation. He worked in both the us and Germany as a physical therapist in 2003 here in does sports physical therapy degree from you trick university of applied science in 2005, he started a PhD project at the university university medical center, grown again, center for rehabilitation. He is a researcher, clinician, and a clinician researcher with a passion for multidisciplinary injury prevention. He has over 40 peer reviewed publications and he regularly gives lectures worldwide in his free time. He loves to mountain bike and you can check out more from him and his research@motorlearninginstitute.com. Speaker 2 (02:46): Okay. So today we talk about just that we talk about motor learning. So the process of motor learning, how patient autonomy is advantageous to rehab, how to motivate, how to measure low motor learning outcomes on field rehab models and the importance of cognition and ACL rehab. And we talk about Allie's brand new model for Mona motor learning, which will be out hopefully in a month or so. So a big thanks to Allie. And of course, thank you all for listening to this month on ACL injury and rehab. Hey, Alli, welcome back to the podcast. I am happy to have you on once again. Speaker 3 (03:31): Thank you for inviting me. Yeah. It's been awhile pleasure to be here today. Speaker 2 (03:34): Yes. And so, as people, if you've been listening to the podcast, you know, that this month has been all about ACL injury and rehab. And so what better person to have on the new to talk about kind of the rehab process after an ACL injury and your specialty, which sort of motor motor learning. So the first thing I want to ask you is can you define motor learning? Speaker 3 (04:02): Yeah, that's it, that's a very good question. And I I've taken three, I think important aspects of motor learning that I think are relevant for clinicians that listen to this podcast. The first one is in order to acquire motor learning, you need to practice. If you don't practice, you can't learn something and that may be pretty straight forward, but I still think it's important. The second one, and that's a little bit of a vague one, but the learning process itself cannot be measured directly. It's only been some been something that you can measure indirectly. And I I'll touch back on that a little bit later. What I mean by that? And the third point is what model learning should result in is that it should lead to relatively permanent improvement of motor skills. And last year I gave the example of writing how to ride a bicycle for this year. Speaker 3 (05:03): I thought, Hey, maybe skiing is a good example. And so if you've taking ski lessons as a teenager and you became quite proficient in skiing, it could be for many different reasons for job or any other reason that you haven't been going to the Rocky mountains, but at the age of, let's say 35, you have some time again, and you have some financial resources and you'd, Hey, let's spend the week again in Vermont or the Rockies and maybe a little bit of rusty at the beginning, but perhaps after a day or two, you get the hang of it again. So this is I think a great example of what motor learning means. It means that you acquire something and it sustains over time. Now that needs to be distinguished from performance. And this is, I think one of my key messages that I would like to point out to clinicians when you work with your patient in the clinic and you have your patient doing an exercise. Speaker 3 (06:11): And this relates to my second point is that motor learning is not directly observable. What you see in the here and now is performance. Now I get, I can give you two examples. So let's say you have a patient after an ACL injury six weeks post-op and you want to have your patient work on balance, not patient number one comes in and stands on one leg. And actually what you're seeing, you're very happy, very stable not any excessive movements is able to maintain balance for 30 seconds. Okay. You're you might be happy with that. Now, your second patient comes in from the same surgeon, also six weeks post-op and when you have this patient perform the same exercise, you see that a patient sometimes needs to take the hands of the hips or needs to hold onto something, or puts the other foot down to maintain balance. Speaker 3 (07:16): And from these two examples, you may draw the conclusion that the first patient has better motor skills and has better learning potential. And the second one has poor motor skills and is not such demonstrating good learning potential. We don't know. We only, we only know that performance in patient one is better for sure. Performance in patient B is not as good for sure, but that doesn't mean that the dis says anything about the learning potential. In fact, it may be that the learning potential in patient one is, or has already been reached because this is at the max of his abilities, various for the second patient with poor performance, there may be a large learning potential. So that that's that's I think very important. And what you need to consider as a clinician is be careful how you interpret this process, because what I know from my early days, and also when I teach courses, is that quite a few clinicians have a tendency to provide feedback because they would intuitive to literally try to correct patient too, because you see that it's not able to maintain balance. Speaker 3 (08:40): So we need to say something. So we will usually do that in with feedback. And we typically do this with corrective feedback. And my second take home message would be, be a little bit patient with your patient because learning takes time. So maybe unless you feel that there is an unsafe situation, but if that's not the case, let the patient practice and re evaluate in the week or in two weeks time. But don't interrupt the learning process too soon. Because when I go back to the skiing example, remember when you haven't been skiing for for like 15 years or when you started to ski, it, it, it was probably something like this first day, quite difficult. Second day, still difficult. You might even get frustrated third day, no improvement. However, on the fourth day snow not being able to ski ski lift is closed. Speaker 3 (09:55): And on the fifth day means there was no one day without any skiing lessons on the fifth. There you go out again, Hey, and all of a sudden you feel like, Hey, I I'm, I'm better than I was on day three, although you haven't practiced in the day in between. So this is what I mean, learning is not only happening as you practice, but there's also some processing afterwards going on in your brain that helps to acquire those motor skills now. And if you interrupt that process like vote by providing a lot of corrective feedback you may actually, although with all good intentions, I don't want to disqualify that, but maybe it's better to leave the process happening and evolve and then provide feedback later on. Speaker 2 (10:50): Yeah. It kind of reminds me of have you ever heard the term helicopter parent? So it's the parent that's always hovering over the child, making the decisions, not allowing them any autonomy for themselves. And so it reminds me of that helicopter therapist who's on top like, Oh, I see that if you use the example of balance, Oh, I see that you struggled a lot with your balance. Why don't you try and do this? Well, why don't you do this, try this, try this, try this. And, and in that as the therapist, are you taking away the autonomy for the patient and what kind of, how can that affect the outcomes for that patient? Speaker 3 (11:31): Yeah, that's an excellent point. Karen C motor learning, as well as learning a language or learning math is a nonlinear process, which means how you learn how to ride a bicycle was probably different from how I learned it. So, but what we typically do as clinicians, we have this, this, this clinical guidebook in our, in our mind map that we think based on our experience or based on our beliefs, how we need to guide our patients from simple skills to more advanced skills from single task skills to do a test skill, whatever. However, we don't know how this patient is actively engaged in this process, actually, by example, that you were provided the, the patient is directed by the, by the parent or, or the child is directed by the parent and is actually a passenger. Now, I think one of the strong drivers of learning is intrinsic motivation. Speaker 3 (12:41): So what role do you give your patient if you direct them, where to go, what to do, and also you give them corrective feedback are these all strong drivers for self-organized learning? I'm putting a question Mark behind it. So people need to think about them for themselves. I can tell you what we do in, in, in our clinical situation. And that's based also on our research we provide our patients or in ACL injury prevention, we provide a significant amount of autonomy, which means an athlete or a patient gets a certain level, not complete control, but a certain level of control over the exercises. So they can choose, for example, out of 10 exercises, they can pick three exercises that they would like to do on that particular day, in an order they would like to do. And we know from a substantial body of research that providing autonomy during during rehab enhances enhances learning. Speaker 3 (13:59): And I can tell you this from a research point, but it can also give you a brief insight from a recent survey that we've done among patients that completed their rehab. And we sent them an open questionnaire about their experience in in the entire process of rehabilitation. And one thing that two things that really stood out were a positive environment, a positive environment with relatedness of the therapist towards the patient, and not as a patient, but as a person that's quite important. So it's not a ne it's not an ACL patient. No, it's, it's, it's a person with an ACL injury. That's quite, quite, quite an important distinction. And the second thing that stood out was and you, you touched on that before is the autonomy some self-control over the rehabilitation process. And this was a qualitative study that we did my PhD student while surveilling ran the study. Speaker 3 (15:10): So it's not something that I'm just saying as a scientist, but this is also what we get back from our patients. And when we ask them so going back to the clinical situation this is what we apply also by providing our patient with the opportunity, instead of me always providing the feedback I'm asking them, or I'm giving them the opportunity please let me know when you want me to give you feedback. That is a great example of of autonomy, the thing, easy question. Yeah. And, and, you know, what's, what's, what's what's quite important to understand is if w if we think how humans preferably like to receive feedback if we, if we, if we ask a healthy population and the same applies to to an injured population, it turns out that around 70% of the power of the people prefer to receive feedback after a good performance of an exercise, what happens in most clinical situations with all good intentions? I really don't want to question that, but we typically give corrective feedback, which typically means you didn't do something according to the standards of the therapist. That means that maybe seven out of the 10 people that you provide feedback to may not really like this, and this may affect their motivation. This may affect their learning potential because they like to receive feedback when something went well, they, they conversely they already know when something didn't go well and they don't need us to rub it in or to remind them they already know. Speaker 2 (17:15): So you, you touched on a word that I was just going to ask you about, and that is motivation. So why is motivation key in motor learning? Speaker 3 (17:28): If you look for example, at the brain activity of a person that is instructed to do something, or you look at the brain activity of a person who has some control over what they're going to do, you have completely different brain patterns. And I can tell you that the second one, the second example, when you give them some, and when they can choose, they are much more engaged, and this is a prerequisite in order to learn something. Speaker 2 (17:59): Yeah. And, and I think we can probably all look back on our own personal experiences of learning, whether that be academic learning, or learning a physical task. I think we all like to have a little bit of control over that versus just have stuff thrown at us without our IM without our input or without our thoughts on it. So I think that makes perfect sense. And now, so we spoke about how motor learning is, non-linear why motivation and autonomy is so important. Now let's talk about, we've got this patient with who had an ACL repair and they want to get back to sport. They, they are, they are ready mentally. So we'll put that to one side. They're ready mentally. So let's talk about the return to sport from a motor learning perspective. Speaker 3 (19:02): In my opinion, return to sports is we first need to define what we mean. And I think the 2016 consensus meeting gave us some leeway in that direction. And I think one of the most important things that stood out is that it's a continuum. It is not one moment in time. And I think what I read in the literature often is is that it's such a that coma to choice yes or no at at six months or nine months, whatever you're, you're, you're, you're believing in. I think what we need to understand is certainly in light of the high number of secondary ACL injuries, particularly in the young population, in, in, in pivoting type sports, that's number one. But also the second one is that, you know, only, I think a disappointed percentage of people reach their pre-injury level. Speaker 3 (20:00): So their performance is not up to par. So do those two factors. When we, when we look at that, I think it all starts prior to the surgery. So the rehabilitation, I think is one of the key factors that we need to, that we need to consider anything that's left. Unaddressed will show up even in higher magnitude, after the ACL reconstruction, which was the second trauma to the knee. And, and then in, during the entire rehabilitation process, something very simple. And I can't stress that enough if, if walking is not normal and how do, how do many clinicians assess a normal gait pattern? They usually ballpark it, but, you know, even a slight deficit of five degrees is clinically meaningful. And now, now just follow some logical sense. If you're walking is not normal, what do you think will happen with the running? Speaker 3 (21:01): W what do you think, what would you expect? How, how the squat will be executed by the patient and how will the single leg up will be done or a drop foot, a good jump. So that's why I think that all these elements from a motor learning perspective, and also we'll touch back on that a little bit later, of course, sound strengthening program, you know, no question about it, very important, but I think it is, it is very important to also incorporate the model learning process so that we make sure that the patient is learning or relearning those motor skills, but Mo and I can also stress enough. It's also important that we as clinicians really, really measure and boarding and, and I, we just completed and published a study among Flemish physiotherapist. And one of the things that came out of this study is that many don't use the evidence-based principles, meaning also they don't use two criteria as they don't assess and in order, and that's also coming down to model learning. If you want to a certain that learning has taken place, you need to measure, otherwise you can't, you can't be sure that the patient has learned something. Speaker 2 (22:22): And how do you, what are some examples that you can maybe give the listeners of how you measure these motor learning outcomes? Because I think that's important to let people kind of wrap their heads around that. And on that note, we're going to take a quick break to hear from our sponsor and be right back Speaker 4 (22:41): On Tuesday, March 9th, net health is putting on a three-part mini webinars series entitled from purpose to profits, how to elevate your practice in an uncertain economy after 2020, you're going to want to sign up for this. You're going to hear from a panel of experts that have over 50 years of combined experience working in the PT industry, signup will begin tomorrow for this mini webinars series. So head over to net health.com/litzy to sign up once again, that's net health.com forward slash L I T Z Y. Speaker 3 (23:16): Yeah. So I use, then that's something from, from the business that you probably know that the PDCA cycle, the plan do check act and the P and the plan, which means you do a baseline test. So first you need to let's say balance. So there's the patient have a balance deficit yes or no. You can use the star balance says you can use th the balance error scoring system. That's your baseline test. Now, it's up for you as, as a physiotherapist with your clinical reasoning. Does the patient need an intervention to target a balance? Yes or no, or are we happy with, but let's assume now there is a balance deficit. Now we go to the do, which means what is my intervention? So my intervention could be, I'm planning to do balance training for four weeks, with two therapy sessions in the clinic, and four sessions at home consisting of those and those exercises. Speaker 3 (24:21): And then AF in between I'm doing an interim evaluation, is the patient going on track as I'm expecting or not? I can still find tune my my intervention program, a training program. And then I do a final assessment after, after two weeks and preferably even one little bit later on as well to make sure that the effects of the balanced training are really sustained over time. Remember what I said about riding a bike or skiing and that's a very simple procedure you can use. It doesn't take a lot of time but it's, it needs to be integrated in your daily practice because if you don't measure, you don't know. Speaker 2 (25:09): Yeah, absolutely. And I love that. I think people can get behind that PDCA cycle and cause, you know, PTs love things that are regimented and you know, things that sort of follow a plan. So I think this is a really easy, and I think people can get behind it. And I also think that it will keep your patient on track and keep you on track and organized versus just like throwing whatever up against the wall and seeing what sticks, if you measure it, you're, you know, you're, you kinda know where this patient is going and that makes all the difference. Speaker 3 (25:51): Yeah. Which, which th that's a good point that you I, I forgot to mention it actually in the, in the, in the planning cycle, I'm incorporating my patient. So I'm discussing the baseline tests and I'm asking in my patients, so you have a balanced deficit. What do you think is needed for you to improve your score? What do you think is could be if you score eight out of 10, so zero would be no balanced error. 10 would be the maximum errors that you can acquire. So you have an eight, what do you think is reasonable to achieve in two weeks time, for example, and then the patient could say, yeah, I think I'm I can reach a seven. Hey, that's the interesting information. Why, why are you so conservative? Why can't, why can't you challenge yourself from, from an eight to a four, for example? Speaker 3 (26:42): So I always creating this interaction with my patient. You know, I can in conjunction with, with, with me and my patient, I can set goals that, and that's quite important as well. That need to be challenging for the patient, because if you, if you already a good or something, you're not challenging and it's not challenging anymore, if it's too difficult, then you then it's overreaching. But it, it has to be something that the patient sees. Okay. I really got to put some effort into this is again, which is, again, something for important for learning. Speaker 2 (27:22): I was just going to say that I said from a motor learning standpoint, if you do nothing that gives a substantial challenge to your patient, are they really going to see the benefits of those exercise or of your plan? Exactly. Yeah, yeah. Yeah. That makes perfect sense. Okay. Speaker 3 (27:45): And also going back to to the first example where the two patients with the balance exercise, if, if I give my patient an exercise, it is usually an exercise that creates difficulty for them. So if I see a perfect demonstration, then I'm kind of thinking, yeah, what is the learning potential here? So I purposely make the exercise a little bit more difficult right away. And I explained that to them, I'm explaining to them, don't expect to, to master this exercise today or tomorrow. And I always give that example of, of riding a bike and, and a lot of patients like that because, Oh yeah, I remember that I fell down quite a few times and and that that's in ACL rehab. It's, it's more or less the same process. Speaker 2 (28:37): Yeah. And, and I also want to switch, well, this isn't really switching gears just moving forward. So yes, we know that return to sport is a continuum you've got returned to sport and returned to performance, different things. And one of the things that I spoke about with Nicole [inaudible] is the importance of on-field rehab. So I know that's something that you're also passionate about. So do you want to kind of tie that into what, what therapists can do on field to continue to foster this motor learning within their sport, whatever that sport may be? Speaker 3 (29:20): Yeah. I think that's, that's something that's underappreciated and, and maybe that's because we haven't really integrated the motor learning processes in our rehab. And one of the things that we have to consider is when you observe your patient in the clinic and you a certain motor behavior, that's all what it means. It stems down to the interaction between the environment. The task at hand could be a jumping exercise, could be a single lag, actually, whatever. And, and, and, and to behavior that you're seeing. So there is a task athlete, environmental interaction, which means the movement that you see from that interaction only is valid for that interaction. You cannot extrapolate a jump landing strategy from a box in a physiotherapy clinic. And imagine how this athlete would play lacrosse or American football or soccer. It's completely different game, completely different worlds. Speaker 3 (30:37): So I think that's where one of the main reasons why single leg hop test and accessed by, by, by Kate Webster and, and, and Tim, you, it were shown not to be valid predictors of secondary ACL injury, because a hop test is something completely different than how an athlete performs on the field. So, in, in, in that regards I think we need to take the patient to the field and to see how the patient is performing based on that interaction that I just refer to the tasks, the environment, and the athlete interaction. And then you get meaningful information where the, where that patient is is add, which for example also means that one-on-one training is not what's needed for a football player. They are team ball athletes. So you need to do something with the ball. You need to be on the turf and you need to do something with teammates Speaker 2 (31:43): That yes, when you're working with someone with a team sport, you have to have those other I don't want to say distractions, but you know, other people, a ball scanning a field versus just going one to one with you. Speaker 3 (32:02): Yeah. And we, we've just completed an analysis of 47 non-contact ACL injuries in Italian professional football. Just this work that I've done with Francisco Della Villa from the ISO kinetic group. And what we did is we, we looked at the injury mechanism through a different lens and what we the lens we use was a neurocognition lens. So we looked at the inciting events that happened before the ACL injury took place, because so far the literature is predominated by the dynamic valgus collapse. And I totally agree. I totally agree. However, it doesn't tell you what led to the injury. It just tells you what the end point is. That's dynamic velvets now. And what we've done now is what are now some typical events occurring during a match play in which a non-contact ACL injuries took place. And we took two neurocognitive factors. One is the selective attention. So are you able to maintain attention to the relevant information in this regard and filter out irrelevant information? And the other one is, did we see some impulsive behavior of defenders? And they were running into a situation in which basically the attacker waiting for them to approach. And then at the last moment, they made a deceiving action that the defender did not entail. Speaker 2 (33:40): And now in the very small timeframe, Speaker 3 (33:43): The defender had to change the movements in a timeframe that you don't have enough time to coordinate those movements well. So if you think about this as a framework, how injuries may happen, we also need to consider this framework, how we integrate that in our rehabilitation process. And this is what I do from day one. And certainly this is what I do re related back to your question for the on-field this framework we use for the on-field rehabilitation. And I've created a model for that. Speaker 2 (34:19): Yeah. So I was just going to say, I know that you've created a model and it's going to be published soon. So let's talk about what that model is. And if you can kind of walk us through that, that would be great. Speaker 3 (34:31): So the model is consists of three main pillars. The first one is neurocognition and neurocognition, you need to think about reaction time. Decision-Making selective attention, as I mentioned before, but also your ability to control impulsive behavior. That's called inhibition. Can you, can you change your intended movement? Yeah. That's something to control your impulses. Very important. Working memory is another aspect. So those are the neurocognitive components. Then we have the motor component, and I think that's where most physios will be quite familiar with. So we think about strength, range of motion endurance speed, things like that. Yeah. That that's, that's I think pretty straightforward. Then we have the sensory part. So in the sensory part, we can have the visual components so we can alter the visual input, maybe quite relevant for ACL rehab as Dustin grooms has already shown. And also my colleague and part of borne, Tim layman has demonstrated that with EEG, that the patient may have some visual reliance, but also things like, do you have your patient do training with shoes on is, are you playing on the hard surface, soft surface lighting conditions, auditory information. Speaker 3 (36:06): Now those three factors, neurocognitive motor, and the sensory part. What I did in my model, I created like a gauge, so I can create an exercise combination in which I have a relatively simple motor skill. So not so demanding, standing on one leg, for example, but what happens now, if I, and more cognitive load, for example, by having them do math subtractions, or working on the synaptic sensory station by doing motion tracking. Now I can see what the influences is of an added neurocognitive load on my motor art, because those three shape my functional movement coordination. Likewise, I can turn back. My neurocognition lit and stay with the same exercise and do now something on the sensory part. And this is what we all do as clinicians. So we do a single leg balance exercise, and we have the patient stand on on the, on the foam surface, or we have them close their eyes. Speaker 3 (37:14): So we already doing this, but I think the model can help you. How do I plan my exercises within one rehab session? And I'm changing that from week two week. And why would this be important? Well, first of all, we all always need to consider that we have, we need cognition during our motor control. And if we only work on pre-planned activities that, that are often in happened, we miss something exactly what you pointed out already from the on-field situation. They have to perceive a lot of information. They have to process that information and then execute the movement. And here's where cognition comes in. And we do this by being aware of that, we can use these gauges. What we do is we actually create a rehab environment that we call in part a board. And we call that an enriched environment in which we constantly provide different stimuli to the patient. Speaker 3 (38:22): That means the rehab from week one to week two is not the same, which means variation, something new, something I haven't done before. Again, this could already motivation so significantly, and I can tell you from experience, patients love this. The second benefit would be since you're providing different stimuli, you actually confronting the brain every time with a new situation and the brain has to find solutions. And this is I think very important also from the motor learning perspective that we need to consider to enhance the neuroplasticity of the brain, because an ACL injury is not just a peripheral ligamentous injury. It is also a neurophysiological lesion and that's, I think, needs to be considered and rehab. Speaker 2 (39:19): I mean, I, I have to say for me, I really liked this model because it, it gives you a great way. Like you said, to plan out your session so you can maybe enlarge the motor component one day or take it back another day, do more, neurocognition move that back, do more sensory, do sensory motor, maybe not so much neuro do a little bit of all three. So it's sort of like, I just sort of see the Venn diagram, just expanding and contracting with all three of those bubbles, which I think is really great. And like you said, it gives you, it's almost from a therapist standpoint, a clinician standpoint, I feel like it gives me permission to play around and come up with some fun things and be a little more original. Speaker 3 (40:06): Yeah. And I think what it also does it, it, it may help you as a therapist to get a better understanding where some underlying deficits may be because we only, we T we typically like to measure the outcome. So let's say I'm doing an agility course, and I'm just looking at at the time. And then I see, Oh, the patient is not so fast. So I need to do more training. Well, what you could maybe do is try to untangle a little bit and to see if the patient from the motor perspective has all the necessary requirements in order to be fast. Maybe there's a deficit there, but let's assume it's not the case. So all, all the strength, all the rate of force development, all these parameters are satisfactory. That must mean that there's something else in the system that can't cope with the demands. And that could quite well be that there is an underlying neurocognitive deficit, and this may help you as a therapist to work more on those neurocognitive elements with the intended goal that the patient becomes faster, but maybe not so much, but we're doing more plyometrics and, and doing more speed now working on the neurocognitive aspect. Speaker 2 (41:30): Yeah. So it's, it's a, a treatment as well as an evaluative tool to kind of see where some deficits are and how you, you and your patient together can plan to move forward. Sounds great. When when will this be widely available? Speaker 3 (41:49): I hope we have it out in a month, the time from that pending on, on the, on the publication process, but please stay tuned. Speaker 2 (41:58): Okay, perfect. And we will let, we will let people know. I will put it on social media when that is out. So that sounds great. Well, I mean, thank you so much for coming on and talking about this, I've been taking copious notes. I think this was great. Before we get into where people can find you, I have one last question and I ask everyone this, and that's knowing where you are now in your life and in your career. What advice would you give to your, to your younger self? Speaker 3 (42:23): Good question. I think what would have helped me if I would have spent more time in the neurological field, I think in, in what I still see, or with colleagues that work with pediatric patients, I think some of the motor learning principles that they use could be very beneficial for us working with more orthopedic sports related injuries. That's something I did not understand back then, because my interests were solely in the, in the sports domain, but in retrospect, I should have spent more time in, in the neurological and pediatric field. Speaker 2 (43:04): Great advice and great advice for anyone who is maybe at that starting point in the sports or orthopedic rehab world and trying to figure out, Hey, what is there something I'm missing here? So I think that's great advice now, where can people find you and find all this great stuff, all your great info. Speaker 3 (43:24): All right. So we have a website from our company and our company's serves as the hopefully as the intermediary between academics and the clinical field. I, I work in both fields. I'm, I'm a clinician, I'm a researcher. And with our platform, actually our community model learning Institute, we want to create a bridge between the academic field and the clinical field, because I think we can all improve, but we need to find each other and we need to speak the same language and have respect mutual respect for one another. And if we engage in in such a culture by exploring, by facilitating one another, I think we can create a lot of new things and approaches with the overall purpose to help our patient. This website will be updated in a month from from now. So we will we will be offering completely new courses, which are also have the opportunity to get coaching from us. So it's not frontal education, but we offer for every course participant to receive life or written feedback on their progress during the course, because our premise is that we want to create a course in such a way that you can apply it into your setting after you've completed the course. Speaker 2 (44:58): That sounds amazing. And we will have links to to the website. We'll have also put the link up to your research gate profile so that if people want to look at some of the papers that you mentioned today, they can just go there and see all the papers that you have authored and co-authored do. I think it would be really helpful. And if people want to find you on social media, where's the best place to reach out to you there Speaker 3 (45:26): Would be Twitter, Instagram, or Facebook. Speaker 2 (45:30): Perfect. And what are the handles if you know them off hand motor learning Institute. Perfect. Perfect. Okay. So thank you so much. And like I said, I will have everything available up on the website at pod podcast at healthy, wealthy, smart.com. So Allie, thank you so much for coming on again. I really appreciate it. Speaker 3 (45:55): Thank you, Karen. And I really want to say, thank you so much for setting this up. I think this is exactly what we also stand for, that we create a platform in which we can exchange our ideas. We can ask one another question that that's the best way I think, to move forward. So really thankful for you to organize this and yeah. Speaker 2 (46:16): And so everyone, thank you so much for listening. Have a great couple. I have a great week and stay healthy, wealthy and smart. Well, a big thank you to Allie for coming on and sharing all this great information about motor learning as it relates to ACL injury and rehab. And of course thank you to our sponsor net health. So remember on Tuesday, March 9th, net health is putting on a three-part mini webinars series entitled from purpose to profits, how to elevate your practice in an uncertain economy. You're going to hear from a panel of guests that have over 50 years of combined experience working in the PT industry, signups will begin tomorrow, which is February 23rd for this mini webinars series. So head over to net health.com/ let's say to sign up once again, that's net help.com forward slash L I Speaker 1 (47:04): T Z Y. Thank you for listening and please subscribe to the podcast at podcast dot healthy, wealthy, smart.com. And don't forget to follow us on social media.  

This week feature a Double Feature of Discussions. In our first discussion, author Larry Allen and Associate Editor Justin Grodin discuss the article "An Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction: The EPIC-HF Trial." Then in our second discussion, author Benjamin Scirica and Associate Editor Sandeep Das discuss the Research Letter "Digital Care Transformation: Interim Report From the First 5000 Patients Enrolled in a Remote Algorithm-Based Cardiovascular Risk Management Program to Improve Lipid and Hypertension Control." TRANSCRIPT BELOW Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Dr. Greg, I really love these double features that we have in 2021. Let me tell you about the first one. We are going to be talking about the EPIC heart failure trial. That's the electronically delivered patient activation tool for intensification on medications in HFrEF. Very important results. Dr. Greg Hundley: Yes, Carolyn. And the second feature is going to evaluate an algorithm based cardiovascular risk management program to improve lipid and hypertension control. But before we get to the double feature, how about we grab a cup of coffee and start with some of the other articles in the issue? Dr. Carolyn Lam: My coffee is right here and I want to talk about, guess what? SGLT2 inhibitors again for this first paper. Dapagliflozin, as we know, reduces the risk of end stage renal disease in patients with chronic kidney disease. We saw that in the DAPA-CKD trial. However, the primary and secondary preventive effects of SGLT2 inhibitors on cardiovascular outcomes have not been studied in patients with chronic kidney disease, with and without diabetes. Dr. Greg Hundley: Well Carolyn, remind us a little bit, what were the end points in the DAPA-CKD trial? Dr. Carolyn Lam: Okay, well yes. DAPA-CKD as a reminder, randomized more than 4,000 participants with chronic kidney disease to dapagliflozin, 10 milligrams daily or placebo. The primary endpoint was a composite of sustained decline in GFR of more or equal to 50% or end stage kidney disease or kidney or cardiovascular death. The secondary end points were a kidney composite outcome, the composite of hospitalization for heart failure or cardiovascular death and all cause death. Now the current paper is a pre-specified subgroup analysis where authors led by Dr. John McMurray from University of Glasgow, divided patients into primary and secondary prevention subgroups according to the history of cardiovascular disease. And results showed that dapagliflozin reduced the risk of the primary composite outcome to a similar extent in the primary and secondary prevention groups. This was also true for the composite of heart failure hospitalization or cardiovascular death and all cause mortality. The combined cardio renal benefits of SGLT2 inhibitors in patients with chronic kidney disease with and without diabetes therefore are substantial, whether there is history of cardiovascular disease or not. Dr. Greg Hundley: Not very nice, Carolyn. Well, my paper comes from Dr. Pradeep Natarajan and his colleagues at the Massachusetts General Hospital. And Carolyn, this study evaluated whether premature menopause is associated with CHIP. For our listeners, CHIP stands for clonal hematopoiesis of indeterminate potential and it is the age related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy. And previously it's been shown associated with accelerated atherosclerosis. Dr. Carolyn Lam: Yikes. Greg, is pretty much our menopause associated with CHIP? Dr. Greg Hundley: Well Carolyn, the investigators, among 19,606 women, they identified 418 or 2.1% with natural premature menopause and 887 or four and a half percent with surgical premature menopause. Premature menopause, especially the natural premature menopause was independently associated with CHIP among post-menopausal women. Natural premature menopause, therefore may serve as a risk signal for predilection to develop CHIP and CHIP associated cardiovascular disease. Dr. Carolyn Lam: Interesting. Okay. Well, my next paper really provides the first evidence for endogenous induction of type-1 protein kinase A disulfide formation in the heart and this occurring after ischemia and re-profusion in both humans and mice. Dr. Greg Hundley: Ah Carolyn, so tell us more about this interesting paper. Dr. Carolyn Lam: Well, this is from Dr. Simon from University of Oxford and colleagues who used high spatial and temporal resolution imaging modalities in conjunction with an interesting redox dead type-1 protein kinase A knock-in mouse model and demonstrated that disulfide modification targets this type-1 protein kinase A to the lysosome where it acts as a gatekeeper for two poor channel mediated calcium release and prevents inappropriate triggering of calcium release from the sarcoplasmic reticulum. In the post ischemic heart, they found that inhibition of lysosomal calcium release by these oxidized molecules was crucial for limiting infarct size and preserving cardiac function during re-profusion. All this thus offering a novel target for the design of cardio-protective therapeutics. This is discussed in an editorial by Doctors Westenbrink, Nijholt, and deBoer from University Medical Center Groningen. Dr. Greg Hundley: Thanks, Carolyn. Very nice. Well, my last paper comes from Dr. Nicholas Marston and colleagues from the TIMI study group at Brigham and Women's Hospital of the Harvard Medical School. Carolyn, genome wide association studies have identified single nucleotide polymorphisms or SNIPs that are associated with an increased risk of stroke. The authors sought to determine whether a genetic risk score could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors across five trials involving the spectrum of cardiometabolic disease. Dr. Carolyn Lam: Interesting. And these genetic risk scores are very hot. What did they find? Dr. Greg Hundley: Thanks, Carolyn. Among 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up of two and a half years. Across a broad spectrum of subjects with cardiometabolic disease, a 32 SNIP genetic risk score was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation, but lower CHA2DS2-VASc two scores, the genetic risk score identified patients with risk comparable to those with higher CHA2DS2-VASc two scores. Dr. Carolyn Lam: Wow, that really is impressive. Well, guess what? We've got some other articles in today's issue. There's a beautiful White Paper about the definitions and clinical trial design principles for coronary artery chronic total occlusion therapies and this from the CTOARC consensus recommendations by Dr. Rinfret and colleagues from McGill University. There's a Research Letter entitled, The Randomized Control Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients with Type II Diabetes. And this is from Dr. Hong and colleagues from Yonsei University College of Medicine in Korea. Dr. Greg Hundley: Thanks, Carolyn. Well I have an exchange of letters from Doctors Albiero and Xie regarding the previously published paper, Patent Foramen Ovale Could be a Source of Paradoxical Embolism and Lead to Adverse Outcomes in Hospitalized Patients with COVID-19 Pneumonia and DVTs.” There's also a Perspective piece to the 2020 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease from Dr. Bavry. And finally Carolyn, Dr. Tung has an ECG Challenge entitled, “Narrowing the Differential Diagnosis for a Wide Complex Tachycardia.” Well, how about we get on to both of our double features. Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Well listeners, we are here for our first feature discussion and we have with us today, Dr. Larry Allen from University of Colorado and our own associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical School in Dallas, Texas. Welcome gentlemen. Larry, could you walk us through the background that really formulated your hypothesis? And then what was the hypothesis that you wanted to test with your study? Dr. Larry Allen: Well, thanks again for having me. I'm a heart failure doctor. The research group that I work with has spent a lot of time on patient empowerment and think about medication prescribing for HFrEF as shared decision making. Thinking about this as a discussion between the patient and me, rather than me deciding what to do. As you know, patients are now coming into the office because they've seen direct to consumer advertising around medications, but typically those are very biased. They're advertisements that are for only patented drugs. And what I'm really trying to think about is what is my patient's overall regimen in terms of heart failure? Dr. Larry Allen: And so we developed a tool which was a three minute video to tell patients that they should come into their visit and be excited to have discussions about their medicines and then a one page checklist that basically said, "Here's what an optimal regimen of medicines looks like for a patient with heart failure and reduced ejection fraction and nobody's really on a perfect regimen, but these are all the possibilities that you could have." Our hypothesis was that if we delivered that to patients before the clinic visit, that it would lead to better prescribing of these drugs. Essentially we imparted on a randomized trial within our healthcare system to do that and that's what we're discussing today, the results of the EPIC heart failure trial. Dr. Greg Hundley: Very nice, Larry. Tell us a little bit, what patients did you enroll in your trial? And then what outcomes did you work to assess? Dr. Larry Allen: We're part of the UC Health System, which has 12 hospitals, but a number of cardiology clinics across the front range of Colorado. Our entire system is on a single instance of the EPIC electronic health record so we're now able to essentially automatically identify all the patients in our system who have HFrEF. We generated lists of patients who had HFrEF who were going to see a cardiology provider in clinic and then we identified them ahead of time, enrolled them in the study prospectively. And the enrollment was for them to agree to be randomized in the study and then for us to be able to collect data on them. Dr. Larry Allen: The patients were kind of a wide range of HFrEF. They were an average of 65 years old, about 70% of the patients were male and reflected the race and ethnicity of Colorado with 11% Blacks and about 7% Hispanics. And everybody in the study had an ejection fraction of 40% or less on their last echocardiogram or other recent cardiac study. And then they were randomized to either get this three minute video sent to them as an email or as a text link that kicked them over to the one page checklist. And then we had them come in. A 145 patients came to clinic having got the information and a 145 patients just came to clinic like usual. Dr. Greg Hundley: Very nice. What did you find, Larry? What were your results? Dr. Larry Allen: Yeah, so we found not surprisingly that the majority of patients who were in usual care had no change to their medical regimen. What we found in the patients who received the EPIC heart failure three minute video and checklist, we saw about a 19% absolute increase in intensification of guideline directed medical therapy. And then we found that most of that was actually an increase in beta blocker dose prescribing. To some extent, the cheapest therapy that could be increased on a drug that people are already on. Dr. Greg Hundley: Very good. Well Justin, we'll turn to you. Help us put the results from Larry's work in the context of A, management of patients with heart failure and reduced ejection fraction and then also B, tell us a little bit about what attracted you to this article and maybe even where you see some of this going next. Dr. Justin Grodin: Thanks, Greg. And Larry, obviously I want to echo Greg's comments by thanking you for your submission. This was a paper that we thought obviously very highly of. Greg, for your first point, we've got novel therapies, but really one of the major issues now is not can we find a newer, better drug? I think we've all come to this realization, it's scalability and implementing these therapies into our regular practice, like beta blockers, RAS inhibitors and mineralocorticoid receptor antagonists. And as Larry said, the problem now is not the quality of our therapies, it's really scaling it and getting it to everyone. It's also increasing these therapies to optimum dosages in patients that can tolerate it over time. Dr. Justin Grodin: And then, to answer your second question, I think some of the things that struck us by this was that this is a wonderfully simple intervention that truly does empower patients. The majority of our interventions to optimize medical therapy has been targeting the physicians, the APP, the nurses, et cetera. This is beautiful in that it empowers the patient and we are putting the ball in their court. And I think to kind of dovetail with your third question, this is a health system clinical trial and I think that tells us a few things. I think one, it provides the framework on how one could perhaps implement that in their health systems. And we'll have to see if this is something that could translate to other health systems across the country or multiple centers. But I think really the intrigue with this work is that it all comes back to empowering the patients. Dr. Greg Hundley: Very nice. Dr. Larry Allen: Greg, I wanted to just add one thing that in the heart failure community, there's this argument going back and forth about whether the lack of optimization of guideline directed medical therapies is due to intolerance or whether it's due to therapeutic inertia. And one of the things I like about this study is on face value, we're empowering patients, but the fact that by asking patients to get involved in prescribing decisions, I think one of the take home messages is that this is partially about therapeutic inertia and that as clinicians, we have a lot of things we're dealing with. And if patients come in to the clinic visit and they're motivated to make these changes actually, we can intensify the therapy. Dr. Greg Hundley: Very good. Larry and Justin, both one at a time here quickly, in the last minute that we have, what do you see as the next study, Larry, that needs to be performed in this space? Dr. Larry Allen: I see two things quickly. One is, as Justin mentioned, validating that this kind of intervention, while simple can be pragmatically deployed in other health systems and in other contexts. The second thing is how do we integrate this kind of small intervention with the larger overall care of patients? One of the concepts that I've talked a lot about over the years with others, including Len Stevenson, is this concept of an annual heart failure review, where rather than seeing people on multiple short visits where we tackle small issues, we actually create a little bit of time to stand back and take a global view of heart failure therapy and how that heart failure therapy fits into the goals of care for the patient, the other medical problems they have and where they're headed. Dr. Greg Hundley: Very good. Justin, anything? Dr. Justin Grodin: Greg, I have to agree with Larry. I think he hit the nail on the head with his first comment. At least for me from an editorial standpoint is really we like to see how generalizable this is and really this implemented in other health systems. I think that's the logical next step. I can tell you, at least from our discussions at our medical center about this manuscript since it's been published at Circulation is, is there something like this we could implement in our own health system? Or in the health systems that we're affiliated with? Dr. Larry Allen: And I would just add that this research and the intervention was funded by the American Heart Association under the strategically focused research network for heart failure and so we've made the interventions public they're online at the research website we have, patientdecisionaid.org. Dr. Greg Hundley: Well fantastic. Well listeners, we want to thank Dr. Larry Allen from University of Colorado and our associate editor, Dr. Justin Grodin from UT Southwestern, for bringing us this article, demonstrating a process that facilitates patient physician interactions to improve the administration of guideline based therapy to patients with heart failure and reduced ejection fraction. And so we're going to wind up this feature discussion and we will head to our next feature. Dr. Greg Hundley: And we have with us Dr. Benjamin Scirica from Brigham and Women's Hospital and our own associate editor, Dr. Sandeep Das from UT Southwestern. Benjamin, could you tell us a little bit about the background information that you used to formulate your hypothesis that you wanted to test for this study? Dr. Benjamin Scirica: Thanks so much first for the invitation. It's a great honor to obviously be in Circulation and to be part of this podcast. We started with the recognition that in our practice, which is similar, I think to a lot of the United States, we are not doing as good a job as we could in terms of care for a lot of the chronic cardiovascular conditions we see. And hypertension and high cholesterol are one of those clear areas where we know there are very good guidelines with clear indication for therapy in specific situations and that these drugs that are available are predominantly generic. But when we looked at our registries, we found that we were not doing as well as we thought. We felt that there are a lot of reasons for that. Dr. Benjamin Scirica: A lot of it was based on the fact that for something good to happen, the right thing to happen, you have to have a patient and a doctor in the same room, the doctor has to recognize that there's a problem. They have to know that there is something they can do about it. They have to be able to convince the patient or educate the patient that they should start this new therapy. They have to know how to start the therapy and then have the ability to follow up and make sure that there is longitudinal care for these chronic diseases. Dr. Benjamin Scirica: And that's a lot to ask for any of us when we have 15 minutes to see the patient, we may only see the patient a couple times a year at most. And so we felt that our hypothesis is, could we design a program, would be delivered remotely, that would not require a doctor in the middle of all of these decisions and that we could scale by using lower cost resources, non-licensed healthcare coordinators or navigators and pharmacists who could follow very clear treatment algorithms to be able to identify patients and prescribe the right medicines to patients at the right time, based on their cardiovascular risk. Dr. Greg Hundley: What was your study design? And what was your study population? Dr. Benjamin Scirica: This is an active, ongoing quality improvement program where our hypothesis is that by doing this, we could improve patients' lipids and cholesterol prescriptions compared to prior. And we did some analysis and we saw that a lot of these patients had not been on optimal therapy for many years, even though they've been in our system. With the limitations of not having randomization, we identified these patients and through different clinics in the different hospitals, and would either have patients referred to us by providers or more commonly go and find them within the registries and identify the patients and contact them and have them enter our program where they would usually take somewhere between eight to 12 weeks to be actively managed, to get to their goals and then they'd enter a maintenance program. The report that we do now is that the story of the first 5,000 patients who we enrolled in our program of whom about 35% were still in management at the time we presented these ongoing results. Dr. Greg Hundley: Roughly how old were these participants? And what was the breakdown in terms of gender or sex distribution? Dr. Benjamin Scirica: We found that about 12% were over 75 years old, a little over half were female. We had 71% who are non-Hispanic Caucasian and 8% who were non-English speaking. In terms of their cardiovascular risks, about a third of the patients had established cardiovascular disease, about a quarter of the patients had diabetes and about a third had an LDL of more than 190 milligrams per deciliter, but no history of ASCVD or diabetes. And then for hypertension, we really would take anybody whom the physician felt required further blood pressure management, because their blood pressure was over 130 over 85. Dr. Greg Hundley: And what did you find? Dr. Benjamin Scirica: We found that of the 5,000 patients that we enrolled, about 4,000 were in the lipid program, a little over 1,400 we're in the hypertension program, so some patients were in both programs and in the lipid patients, in those patients who achieved maintenance, we increased lipid therapy, any lipid lowering therapy, from about 78% up to 97%. And that was predominantly through statins but we doubled the use of ezetimibe from 9% to 17%. We saw a small increase in PCSK9 inhibitor use from 1% to 3%. And if we looked at LDL reductions, it was a 52 milligram per deciliter reduction in LDL from an average LDL of a 125 down to 73 in those folks who achieved maintenance. For blood pressure, again, in those patients whom we successfully treated who are about 600 patients, we saw a 14 millimeter systolic blood pressure reduction and a seven millimeter mercury diastolic blood pressure reduction. Dr. Greg Hundley: Wow. Well Sandeep, what drew your attention to this? And then also, how do you put the context of these results with others that really are working in this wing of data science in cardiovascular medicine? Dr. Sandeep Das: Great question. We have a large body of literature that suggests that the use of these fantastic evidence based therapies like statins, like blood pressure medications is poor and we really struggle to improve those numbers. I wanted to applaud Ben and his group for really taking on, in a robust way, an important topic and subject. The other thing that really attracted me to this study, there was a hypertension expert here named Ron Victor back when I first started as a fellow. Fantastic researcher and he did a project called Colloquia called the Barbershop Project about leveraging pharmacists and barbers to improve the blood pressure control of African American men in the community. Dr. Sandeep Das: The idea is that you get out there, you got to go to where the patients are rather than expecting them to come to you. And you got to figure out ways to engage them, activate them, get them to participate in their own care. A fantastic study, but the one thing that always, we discuss that study, the thing that always jumps out is, well how do you scale it? How do you use it in a real practice? To me was also a very exciting aspect to this. The goal is to take steps to generalize from clinical trials to real world practice, because we got to get this to patients. Dr. Greg Hundley: Very nice. Well Ben, coming back to you, what do you see as next steps for your research here? And then even in the field? Dr. Benjamin Scirica: The first is, are there other disease areas we can do this in? I think the second part is how to test different techniques to try to improve the ability to scale it to broader populations and keep the cost down. And I think it is a combination of trying to find the right tools, whether they're digital or not and the right techniques to be able to activate patients, educate them, such that they are asking the question, "How come I'm not on these medicines? How come I'm not on this?" And I think we could do a lot in terms of AB testing in there. The part that I think is challenging in these healthcare studies and quality improvement studies, is that randomization would be great. How can we do it streamline? Do we need to get consent? Can it just be that approved drug A can be tested against approved drug B because there is clear equipoise. And I think by doing that, we could lower the bar for really pragmatic randomization in practice and be able to have much more rapid cycles of improvement and optimization on therapy. Dr. Greg Hundley: Very good. Sandeep, do you have anything to add? Dr. Sandeep Das: I'll echo Dr. Scirica's called arms here that we need to have a way to do this, do trials in this space pragmatically. I agree with that strongly. I did have a few thoughts on next directions. I work in a population of the urban poor of Dallas County with a lot of my clinical time and these patients have poor health literacy so I think that one question, not question but suggestion or comment to Ben and his group would be to think hard about how you would expand this to lower resource setting or to people that would be a little harder to reach. And even as sort of an aspirational goal, how do you expand it into the community? The other question that I would have is how much of this can we get by with adherence interventions? It's one thing to prescribe, but it's another thing to figure out how to get people to adhere to meds. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Ben Scirica for Brigham and Women's and Dr. Sandeep Das from UT Southwestern, bringing us this really interesting research that has been providing early results of a remotely delivered pharmacist led lipid and hypertension management strategy that dramatically increased medication compliance and improved hypertension control and lipid management. Dr. Greg Hundley: 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, 2021.  

In this episode, Alexandra Smink joins Monica Westley to discuss her research in the type 1 diabetes space. Dr. Smink's research focuses on polymer scaffolds for pancreatic islet transplantation. In 2018, Dr. Smink was awarded the young investigator JDRF award and most recently was awarded the EASD Rising Star Award.Using so-called extracellular matrix, which can be used to wrap the islets up and, thus, protect them from the outside world where the immune system lurks, Dr Smink from the Netherlands has designed a device capable of communicating with this outside world but doing so safely, in order to get the nutrients, oxygen and other molecules that the islets need to survive.

In this 18th episode, Alex Friedrich is with us. He is a professor of Medical Microbiology & Infection Control at the University Medical Center Groningen. Wim, Tina and Arjen talk to him about the corona crisis, relaxing the measures and his personal experience in dealing with COVID-19. Also, Arjen gives some historical perspective on reopening the university in relation to the opening of the academic year in September. Guest: prof. dr. Alex Friedrich Hosts: Wim Brons, Tina Kretschmer, Arjen Dijkstra The Crowdfunding for Corona initiative.

Jane Ferguson:                  Hi there. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson, and this is Episode 36 from February 2020.                                                 First up, we have “Identification of Circulating Proteins Associated with Blood Pressure Using Mendelian Randomization” from Sébastien Thériault, Guillaume Paré, and colleagues from McMaster University in Ontario. They set out to assess whether they could identify protein biomarkers of hypertension using a Mendelian randomization approach. They analyzed data from a genome-wide association study of 227 biomarkers which were profiled on a custom Luminex-based platform in over 4,000 diabetic or prediabetic participants of the origin trial.                                                 They constructed genetic predictors of each protein and then used these as instruments for Mendelian randomization. They obtained systolic and diastolic blood pressure measurements in almost 70,000 individuals, in addition to mean arterial pressure and pulse pressure in over 74,000 individuals, all European ancestry with GWAS data, as part of the International Consortium for Blood Pressure.                                                 Out of the 227 biomarkers tested, six of them were significantly associated with blood pressure traits by Mendelian randomization after correction for multiple testing. These included known biomarkers such as NT-proBNP, but also novel associations including urokinase-type plasminogen activator, adrenomedullin, interleukin-16, cellular fibronectin and insulin-like growth factor binding protein-3. They validated all of the associations apart from IL-16 in over 300,000 participants in UK Biobank. They probed associations with other cardiovascular risk markers and found that NT-proBNP associated with large artery atherosclerotic stroke, IGFBP3 associated with diabetes, and CFN associated with body mass index.                                                 This study identified novel biomarkers of blood pressure, which may be causal in hypertension. Further study of the underlying mechanisms is required to understand whether these could be useful therapeutic targets in hypertensive disease.                                                 The next paper comes from Sony Tuteja, Dan Rader, Jay Giri and colleagues from the University of Pennsylvania and it's entitled, “Prospective CYP2C19 Genotyping to Guide Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Pragmatic Randomized Clinical Trial”.                                                 They designed a pharmacode genomic trial to assess effects of CYP2C19 genotyping on antiplatelet therapy following PCI. Because loss of function alleles in CYP2C19 impair the effectiveness of clopidogrel, the team were interested in understanding whether knowledge of genotype status would affect prescribing in a clinical setting. They randomized 504 participants to genotype guided or usual care groups and assessed the rate of prasugrel or ticagrelor prescribing in place of clopidogrel within each arm. As a secondary outcome, they assessed whether prescribers adhere to genotype guided recommendations. Of genotyped individuals, 28% carried loss of function alleles. Within the genotype guided group overall, there was higher use of prasugrel or ticagrelor with these being prescribed to 30% of patients compared with only 21% in the usual care group. Within genotype individuals carrying loss of function alleles, 53% were started on prasugrel or ticagrelor, demonstrating some adherence to genotype guided recommendations.                                                 However, this also meant that 47% of people whose genotype suggested reduced effectiveness were nevertheless prescribed clopidogrel. This study highlights that even when genotype information is available, interventional cardiologists consider clinical factors such as disease presentation and may weight these more highly than genotype information when selecting antiplatelet therapy following PCI.                                                 The next paper is about “Deep Mutational Scan of an SCN5A Voltage Sensor and comes to us from Andrew Glazer, Dan Roden and colleagues from Vanderbilt University Medical Center. In this paper, the team aim to characterize the functional consequences of variants and the S4 voltage sensor of domain IV and the SCN5A gene using a high throughput method that they developed. SCN5A encodes the major voltage gated sodium channel in the heart and variants in SCN5A can cause multiple distinct genetic arrhythmia syndromes, including Brugada syndrome, long QT syndrome, atrial fibrillation, and dilated cardiomyopathy, and have been linked to sudden cardiac death.                                                 Because of this, there's considerable interest in understanding the functional and clinical consequences of different variants, but previous approaches were time consuming and results were often inconclusive with many variants being classified as uncertain significance. This newly developed deep mutational scanning approach allows for simultaneous assessment of the function of thousands of variants, making it much more efficient than low throughput patch clamping. The team assessed the function of 248 variants using a triple drug assay in HEK293T cells expressing each variant and they identified 40 putative gain of function and 33 putative loss of function variants. They successfully validated eight of nine of these by patch clamping data. Their study highlights the effectiveness of this deep mutational scanning approach for investigating variants in the cardiac sodium channel SCN5A gene and suggests that this may also be an effective approach for investigating putative disease variants and other ion channels.                                                 The next article is a research letter from Connor Emdin, Amit Khera, and colleagues from Mass General Hospital in the Broad Institute entitled, “Genome-Wide Polygenic Score and Cardiovascular Outcomes with Evacetrapib in Patients with High-Risk Vascular Disease: A Nested Case-Control Study”. In this study, the team set out to probe the utility of using polygenic risk scores to predict the risk of major adverse cardiovascular events within individuals already known to be at high cardiovascular risk and to assess whether genetic scores can identify individuals who would benefit from the use of a CETP inhibitor such as Evacetrapib. They analyze data from the ACCELERATE trial which had tested Evacetrapib in a high risk population, and they found no effect on the incidents of major adverse cardiovascular events overall. Within a nested case-control sample of individuals experiencing major CVD events versus no events, they applied a polygenic risk score and found that the score predicted major cardiovascular events.                                                 Patients in the highest quintile of the risk score were at 60% higher risk of a major cardiovascular event than patients in the lowest quintile. There was no evidence of any interaction between the genetic risk score and Evacetrapib. These data suggest that genetic risk scores may have utility in identifying individuals at high risk events but may not have utility in identifying individuals who may derive more benefit from CETP inhibition. The next letter concerns “Epigenome-Wide Association Study Identifies a Novel DNA Methylation in Patients with Severe Aortic Valve Stenosis” and comes from Takahito Nasu, Mamoru Satoh, Makoto Sasaki and colleagues from Iwate Medical University in Japan. They were interested in understanding whether differences in DNA methylation could underlie the risk of aortic valve stenosis. They conducted an EWAS or epigenome-wide association study of peripheral blood mononuclear cells or PBMCs from 44 individuals with aortic stenosis and 44 disease free controls.                                                 They collected samples at baseline before a surgical intervention in the individuals with aortic stenosis and collected a follow-up sample one year later. They found that DNA methylation at a site on chromosome eight mapping to the TRIB1, or tribbles homolog one gene, was lower in the aortic stenosis group than in the controls at baseline. They replicated the association in an independent sample of 50 cases and 50 controls. TRIB1 MRNA levels were higher in the aortic stenosis group than the controls. When they looked at methylation status one year after aortic valve replacement or a transcatheter aortic valve implantation in patients with stenosis, they found that DNA methylation had increased in the cases while TRIB1 MRNA decreased. These data suggests that methylation status of TRIB1 and expression of TRIB1 may relate to the disease processes in aortic stenosis such as hemodynamic dysregulation and they can be reversed through surgical intervention. Changes in the methylation status of TRIB1 could be a novel biomarker of response to aortic valve replacement.                                                 The next letter comes from Niels Grote Beverborg, Pim van der Harst, and colleagues from University Medical Center Groningen and is entitled, “Genetically Determined High Levels of Iron Parameters Are Protective for Coronary Artery Disease”. Their study addresses the conflicting hypotheses that high iron status is either deleterious or protective against cardiovascular disease. The team constructed genetic predictors of serum iron status using 11 previously identified snips and tested the genetic association with CAD in UK Biobank data from over 408,000 white participants. Overall, the genetic score for higher iron status was associated with protection against CAD. Ten of the snips suggested individual neutral or protective effects of higher iron status on CAD, while one iron increasing snip was associated with increased risk of disease but this was thought to be likely through an iron independent mechanism. Overall, these data suggest that a genetic predisposition to higher iron status does not increase risk of CAD and is actually protective against disease.                                                 The final letter is entitled, “Confidence Weighting for Robust Automated Measurements of Popliteal Vessel Wall MRI” and comes from Daniel Hippe, Jenq-Neng Hwang, and colleagues from the University of Washington. They were interested in assessing whether images of popliteal artery wall incidentally obtained during knee MRI as part of an osteoarthritis study could be used to study the development and progression of atherosclerosis. They developed an automated deep learning based algorithm to segment and quantify the popliteal artery wall in images obtained over 10 years in over 4,700 individuals. Their approach, which they named FRAPPE, or fully automated and robust analysis technique for popliteal artery evaluation, was able to reduce the average time required for segmentation analysis from four hours to eight minutes per image. They applied weights based on confidence for each segment to automatically improve the accuracy of aggregate measurements such as mean wall thickness or mean lumen area. Their data suggest that this automated method can rapidly generate useful information on atherosclerosis from MRI images obtained as part of other studies. When combined with other data. This approach may facilitate novel discovery in secondary analyses of existing studies in an efficient and cost effective way.                                                 And that's all for issue one of 2020. Come back next time for more of the latest papers from Circulation: Genomic and Precision Medicine. Speaker 2:                           This podcast is copyright American Heart Association 2020.  

Jane Ferguson:  Hi, everyone. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. It's May 2019, and this is episode 28. So let's see what papers we have in the journal this month.                              First up, a paper from Mengyao Yu, Nabila Bouatia-Naji and colleagues from the Inserm Cardiovascular Research Center in Paris, entitled GWAS-Driven Gene-set Analyses, Genetic and Functional Follow-Up Suggest Glis1 as a Susceptibility Gene for Mitral Valve Prolapse.                              In this paper, they set out to characterize the genetic contributions to mitral valve prolapse, or MVP, to better understand the biological mechanisms underlying disease. They applied the gene-set enrichment analysis for QWAS tool and the pathway enrichment tool DEPICT to existing GWAS for MVP in a French sample to identify gene sets associated with MVP. They find significant enrichment of genes involved in pathways of relevance to valve biology and enrichment for gene expression in tissues of relevance to cardiovascular disease.                              They zeroed in a Glis family zinc finger gene Glis1 with consistently strong pattern of evidence across the GWAS enrichment and transcription analyses. They replicated the association between Glis1 and MVP in a UK biobank sample. They found that Glis1 is expressed in valvular cells during embryonic development in mice, but is mostly absent at later times. They targeted two Glis1 orthologs in zebrafish and found that knockdown of Glis1 B was associated with a significant increase in the incidence of severe atrioventricular regurgitation. These data highlight Glis1 as a potential regulator of cardiac valve development with relevance for risk of mitral valve prolapse.                              Next up is a paper from Gina Peloso, Akihiro Namuro, Sek Kathiresan and colleagues from Boston University, Kanazawa University, and Mass General Hospital. In their paper, Rare Protein Truncating Variance in APOB, Lower LDL-C, and Protection Against Coronary Heart Disease, the team was interested in understanding whether protein truncating variance in APOB underlying familial hypobetalipoproteinemia confer any protection against coronary heart disease.                              They sequenced the APOB gene in 29 Japanese families with hypobetalipoproteinemia as well as in over 57,000 individuals, some with early onset CHD and some without CHD. They found that presence of an APOB truncating variant was associated with lower LDL cholesterol and lower triglycerides, and also with significantly lower risk for coronary heart disease. This study confirms that variance in APOB, leading to reduced LDL and triglycerides are also protective against coronary heart disease. :                            The next paper entitled Mortality Risk Associated with Truncating Founder Mutations in Titin comes to us from Mark Jansen, Dennis Dooijes, and colleagues from University Medical Center Utrecht. They analyzed the effect of titin truncating variance on mortality in Dutch families. Titin truncating variants are associated with dilated cardiomyopathy, but have a very variable penetrance.                              In this study, the authors looked at three titin truncating variants, established to be founder mutations, and traced the pedigrees back to 18th century ancestors. They looked at 61 individuals on the transmission line and 360 of their first-degree relatives. They find no evidence for excess mortality in variant carriers overall. However, when they restrict it to individuals over 60 years of age, they did find a significant difference in mortality, which was also observed in individuals born after 1965. What these data tell us is that these titin truncating variants have a relatively mild phenotype with effects on mortality only manifesting later in life in many carriers. Given increases in life expectancy over the past several decades, the prevalence of morbidity and mortality attributable to titin truncating variants may increase. Genetic screening may identify genotype-positive, phenotype-negative individuals who would benefit from preventative interventions.                              Continuing on the theme of genetic variance, we have a paper from John Giudicessi, Michael Ackerman, and colleagues from the Mayo Clinic, Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. In this paper, they aim to find a better way to classify variants of unknown significance, of VUS, in the RYR2 gene. Variants in this gene are commonly associated with catecholaminergic polymorphic ventricular tachycardia, or CPVT.                              They examined 72 distinct variants in 84 Mayo Clinic cases and find that 48% were classified as VUS under ACMG guidelines. The rate was similar in a second sample from the Netherlands, with 42% of variants originally classified as VUS. They developed a diagnostic scorecard to incorporate a pretest clinical probability of CPVT, which included various clinical criteria, including symptoms and stress test results. Application of the phenotype enhanced ACMG criteria brought the VUS rate down to 7% in Mayo Clinic and 9% in the Dutch samples. The majority of VUS were reclassified as likely pathogenic.                              This study highlights how incorporation of disease-specific phenotype information can help to improve variant classification and reduce the ambiguity of reporting variants of unknown significance.                              We also have a number of research letters in the journal this month. From Karine Ngoyen, Gilbert Habib, and coauthors from Marseilles, we have a paper entitled Whole Exome Sequencing Reveals a Large Genetic Heterogeneity and Revisits the Causes of Hypertrophic Cardiomyopathy, Experience of a Multicentric study of 200 French Patients. In this study, they examined the genetic contributions to hypertrophic cardiomyopathy, or HCM, in 200 individuals as part of the HYPERGEN study and compared the benefits of whole exome sequencing compared with targeted sequencing of candidates' sarcomeric genes. All subjects had HCM documented by echocardiography.                              In the whole exome sequencing data, they first looked for mutations within 167 genes known to be involved in cardiomyopathies or other hereditary diseases. Of these 167 virtual panel genes, they find variants in 101 genes. Following whole exome sequencing, over 87% of the patients had an identified pathogenic, or likely pathogenic, mutation compared with only 35% of patients who only had targeted sequencing of sarcomeric genes.                              This highlights the generic heterogeneity of HCM and suggests that whole exome sequencing has utility in identifying variants not covered by sarcomeric gene panels.                              The next letter is from Wouter Te Rijdt, Martin [Vandenberg] and colleagues from University Medical Center Groningen and states that [dissynchronopathy] can be a manifestation of heritable cardiomyopathy. They hypothesized that left bundle branch block, also designated as dissynchronopathy, may be a manifestation of familial cardiomyopathy.                              They analyzed patients from a database of cardiac resynchronization therapy and identified super-responders whose left ventricular dysfunction was normalized by therapy. They carried out targeted sequencing in 60 known cardiomyopathy genes in 16 of these super-responder individuals and identified several variants, including a pathogenic variant in troponin T in one individual and variants of unknown significance in nine individuals. Pedigree analysis identified multiple family members with dilated cardiomyopathy.                              This study highlights that dissynchronopathy can be a manifestation of DCM, but that affected individuals may still benefit from cardiac resynchronization therapy.                              The next letter entitled Targeted Long-Read RNA Sequencing Demonstrates Transcriptional Diversity Driven by Splice-Site Variation in MYBPC3 comes from Alexandra Dainis, Euan Ashley, and colleagues from Stanford University. They set out to understand whether transcriptome sequencing could improve the diagnostic yield over genome sequencing in patients with hypertrophic cardiomyopathy. In particular, they hypothesized that long-read sequencing would allow for identification of alternative splicing linked to disease variance. They used long-read RNA and DNA sequencing to target the MYBPC3 gene in an individual with severe HCM who carried a putative splice-site altering variant in the gene. They were able to obtain heart tissue for sequencing and included several HCM and control subjects in addition to the patient with the MYBPC3 variant.                              They identified several novel isoforms that were only present in the patient sample, as well as some additional isoforms, including retained introns, extended exons, and an additional cryptic exon, which would not have been predicted based on the DNA variant. While the effects on protein function is not known, the transcripts are predicted to be translated.                              This analysis highlights the effect of a rare variant on transcription of MYBPC3 and provides additional evidence to link the variant to disease. This is a really nice approach, which could be used to probe causality and mechanisms, not only for cardiovascular disease, but for other rare variants in many disease settings.                              We finish with a perspective piece from Nosheen Reza, Anjali Owens, and coauthors from the University of Pennsylvania entitled Good Intentions Gone Bad, The Dangers of Sponsored Personalized Genomics. They present a case of a 23-year-old woman who presented for genetic counseling and evaluation after discovering she carried a likely pathogenic MYH7 variant associated with cardiomyopathy. She had no significant medical history, but had participated in employer-sponsored genetic testing motivated to identify potential variants related to cancer given a family history of cancer.                              After receiving her results, she experienced considerable anxiety and stopped exercising out of fear of cardiac complications. She visited an ER after experiencing chest pain, something she had not experienced previously. There was no appropriate counseling available at her institution for her genetic test results, leading her to seek out the additional counseling. Thus, while she was initially motivated to complete genetic testing because her employer offered it free of change, she ended up incurring costs related to the followup evaluation and counseling. Ultimately, she had no significant clinical findings. Although the variant had been listed as likely pathogenic, other sources consider it to be of unknown significance.                              This story highlights the psychological and financial impact that genetic testing can have on individuals, particularly when carried out without any pretest counseling or accessible post-test support when variants are identified.                              Despite the considerable promise of personalized medicine, there are many complexities to be considered, particularly with direct-to-consumer testing and employer-sponsored testing. This perspective highlights the ethical considerations and urges caution to maintain the best interests of patients.                              That's all for this month. Thanks for listening. I look forward to bringing you more next month.                              This podcast was brought to you by Circulation Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.  

Dr. Jason Busse is an Associate Professor in the Departments of Anesthesia and Clinical Epidemiology & Biostatistics, McMaster University. He is the co-Principle Investigator for the TRUST trial, one of the world’s largest orthopedic randomized controlled trials.TrainingDr. Busse completed an MSc in Medical and Molecular Genetics at the University of Toronto, a Doctorate in Chiropractic at CMCC, training in Cognitive Behavioral Therapy at McMaster University, and a PhD in Health Research Methodology at McMaster University.Dr. Busse has been active clinically in the management of disability secondary to chronic pain and other medically unexplained syndromes since 1999 and currently serves as the Clinical Director for Prisma Health Canada – a private company that manages chronic claimants (5+ years on disability) referred by private disability insurers. From 2001 to 2010 Dr. Busse was the Director of the Complex Claims Division for ATF Canada, a private company that provided assessment and treatment for patients in receipt of long-term disability benefits.ResearchDr. Busse has published over 150 peer-reviewed articles in scientific journals with a focus on chronic pain, orthopedic trauma, insurance medicine and methodological research. In 2011 Dr. Busse co-formed the evidence-based insurance medicine research group, an international collaboration with members from McMaster University, the University Medical Center Groningen, and the Academy of Swiss Insurance Medicine. He is a Director of the Cochrane Insurance Medicine Field Group (http://insuremed.cochrane.org/our-team). Current research projects include:FORESITE– a prospective cohort to establish factors associated with persistent post-surgical pain following heart surgeryUpdate and revision of the Canadian Guideline regarding opioids for chronic non-cancer painTeaching and Promotion of Evidence-Based Clinical PracticeSince 2011, Dr. Busse has been a tutor for the McMaster Evidence-Based Clinical Practice workshop, and an editor for the Newsletter of the International Society for Evidence-Based Health Care since 2009.Awards and Honours2015: McMaster University, HRM Mentoring/Supervision Award in the Full-Time/Joint Category2010: Outstanding Thesis Award, McMaster University, Faculty of Health Sciences Graduate Programs2009: New Investigator Award, Canadian Institute of Health Research2003: PhD Training Fellowship, Canadian Institute of Health Research

The 2018 Barbara Dicker Oration was presented by Professor Iris Sommer. Professor Sommer is a best-selling author and Professor of Cognitive Aspects of Neurological and Psychiatric Disorder at the Department of Neuroscience at the University Medical Center Groningen, Netherlands. Entitled The phenomenon of hallucinations, Professor Sommer offered a holistic view into the research and experiences of hallucinations. It’s actually more common than you might think but what happens in our brains when we hallucinate? And what does this mean for new treatments and interventions? This Barbara Dicker Oration was held on 13 September, 2018.

The 2018 Barbara Dicker Oration was presented by Professor Iris Sommer. Professor Sommer is a best-selling author and Professor of Cognitive Aspects of Neurological and Psychiatric Disorder at the Department of Neuroscience at the University Medical Center Groningen, Netherlands. Entitled The phenomenon of hallucinations, Professor Sommer offered a holistic view into the research and experiences of hallucinations. It’s actually more common than you might think but what happens in our brains when we hallucinate? And what does this mean for new treatments and interventions? This Barbara Dicker Oration was held on 13 September, 2018.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 Current guidelines recommend measurement of one of the cardiac specific isoforms of cardiac troponin complex. However, what's the utility of combining measurements of troponins I and T in the early diagnosis of acute myocardial infarction? Well, you have to wait for our upcoming feature discussion, but it's coming right up after these summaries.                                                 The first original paper this week sheds light on the genetic basis and mechanisms of bicuspid aortic valve, the most common congenital heart defect in the population. We know that bicuspid aortic valve is an autosomal dominant trait with variable expression and incomplete penetrants suggestive of genetic and environmental modifiers. In the current study, first author Dr Gharibeh, corresponding author Dr Nemer from University of Ottawa, and authors of the Bicuspid Aortic Valve Consortium assessed cardiac structure and function in mice, lacking a GATA6 allele. They found that GATA6 heterozygous mice had a highly penetrant type of bicuspid aortic valve with right and left leaflet fusion, which is the most frequent type found in humans. GATA6 transcript levels were lower in human bicuspid aortic valve as compared to normal tricuspid valves. Mechanistically, GATA6 haploinsufficiency disrupted valve remodeling and extracellular matrix composition through dysregulation of the importance in the molecules including matrix metalloproteinase nine. Cell-specific inactivation of GATA6 reveal that an essential rule for GATA6 in secondary heart field myocytes. Thus, the study identifies a new cellular and molecular mechanism underlying bicuspid aortic valve.                                                 In the field of cardiac regeneration, c-Kit positive adult progenitor cells were initially reported to produce new cardiomyocytes in the heart. However, more recent genetic evidence suggests that such events are exceedingly rare. Today's paper provides insights into this discrepancy and it is from first author Dr Maliken, corresponding author, Dr Molkentin from Howard Hughes Medical Institute Cincinnati Children's Hospital Medical Center. The authors took a novel approach of deleting the necessary cardiogenic transcription factors, GATA4 and GATA6, from c-Kit expressing cardiac progenitor cells to determine whether true de novo cardiomyocyte formation would occur. They found that deletion of the necessary cardiogenic transcription factors, GATA4 and GATA6, from these c-Kit+ cardiac progenitor cells remarkably resulted in greater apparent cardiomyocyte derivation from the c-Kit+ cells. Deletion of GATA4 from c-Kit–derived endothelial progenitors altered the integrity of the endothelial cell network in the heart, resulting in greater c-Kit+–derived leukocytes entering the heart and fusing with cardiomyocytes.                                                 Thus, they demonstrated a new role for GATA4 in endothelial differentiation, specifically showing for the first time that GATA4 is essential for vascular development by the c-Kit lineage. The study shows that leukocyte to cardiomyocyte fusion is the primary basis for path lineage tracing results, incorrectly suggesting that c-Kit+ cardiac progenitor cells generated de novo cardiomyocytes in the heart.                                                 Lecithin–cholesterol acyltransferase, or LCAT, is the sole enzyme that esterifies cholesterol in the plasma. Its role in the supposed protection from atherogenesis remains unclear, because mutations in LCAT can cause more or less carotid atherosclerosis. Addressing this conundrum, co-first authors Drs. Oldoni and Baldassarre, co-corresponding authors Dr Kuivenhoven from University Medical Center Groningen, Dr Holleboom from Academic Medical Center Amsterdam, and Dr Calabresi from University of Milano in Italy hypothesized that genetic mutations causing complete LCAT deficiency versus partial LCAT deficiency would be differentially associated with carotid atherosclerosis in carriers of LCAT mutations. To study this, they looked at 74 heterozygotes for LCAT mutations who are recruited from Italy and the Netherlands and who were assigned to complete versus partial LCAT deficiency. These were also compared to 280 controls. Using carotid intima-media thickness as a measure of atherosclerosis, the authors demonstrated that carriers of LCAT mutations leading to complete LCAT deficiency exhibited less carotid atherosclerosis, indicating a reduced risk of cardiovascular disease.                                                 By contrast, however, carriers of LCAT mutations leading to partial LCAT deficiency showed marginally more atherosclerosis. The association of mutations in LCAT with subclinical atherosclerosis appeared to be related to the capacity of LCAT to esterify cholesterol on apoB-containing lipoproteins since the abnormal LCAT present in the partial deficiency was only active on this class of lipoproteins. These important findings bear relevance for pharmaceutical strategists that target LCAT.                                                 After a bioprosthesis aortic valve replacement, what is the incidence, correlates, and outcomes of hemodynamic valve deterioration? First author Dr Salaun, corresponding author Dr Pibarot from Quebec Heart and Lung Institute and their colleagues studied 1,387 patients who underwent bioprosthetic aortic valve replacement and found that hemodynamic valve deterioration identified by Doppler echocardiography occurred in one-third of patients and was associated with a 2.2-fold higher adjusted mortality. Diabetes and renal insufficiency were associated with early hemodynamic valve deterioration whereas female sex warfarin use and stented bioprosthetic valve versus the stentless ones were associated with late hemodynamic valve deterioration. These findings suggest that following bioprosthetic valve replacement, a systematic echocardiographic follow-up may be considered to ensure adequate detection and quantitation of hemodynamic valve deterioration.                                                 That wraps up on the summaries this week. Now for our feature discussion.                                                 We are recognizing the critical role that cardiac troponins play for the early diagnosis of acute myocardial infarction. We also know that there are different isoforms of cardiac troponins, the cardiac troponins T and I. Now, have you ever considered combining the two? How does that help the early diagnosis of acute myocardial infarction? Well, I am delighted to have with us the corresponding author of our feature paper today, Dr Christian Mueller from University Hospital Basel in Switzerland, a very familiar voice on this podcast. Welcome, Christian, and thank you so much for publishing yet another wonderful paper with us. Dr Christian Mueller:      Thank you very much for highlighting this important work and allowing me to comment on it in the podcast. Dr Carolyn Lam:                Christian, first of all, could you paint the background to help us understand what's the difference between the two isoforms, I mean, in terms of diurnal variation, the way that they may be released earlier or later, the way they may or may not be impacted by comorbidities like renal dysfunction or hemolysis? Could you help us understand why there may be rational to combine the two in looking at their impact on the diagnosis of acute myocardial infarction? Dr Christian Mueller:      The measurement of cardiac troponin as a structural protein unique to the heart clear is a central piece in our early diagnosis of acute myocardial infarction, so both for the early rule out in patients who present with chest pain and are finally found to have more benign disease as well as the early ruling. In general, I think it's important to highlight that there are two isoforms exactly as you have mentioned, so there is cardiac troponin T and cardiac troponin I. So these two proteins are cardiac specific and are used in the diagnosis of acute myocardial infarction. Now with the development of high-sensitivity methods or measurements of both cardiac troponin T and cardiac troponin I concentrations, we have been able to get a little bit of a better understanding of in fact differences in the pathophysiology as well as analytical details between cardiac troponin T and I.                                                 Before I start highlighting the differences, I think it's important, I mean, both signals show a very strong correlation, so still very, very similar to each other. However, the small differences that have begun to emerge kind of allow to suggest that possible we could use them together as two pieces of information in the diagnosis.                                                 So, what are the differences? First, exactly as you have highlighted, that if in fact that diurnal rhythm with cardiac troponin T, which means that cardiac troponin T concentrations are higher in the morning hours as compared to the evening, we still have no clue why that's the case, but it's a relevant difference about 25% and it has been shown in two cohorts and a group from Maastricht who was the first one highlighting this. This rhythm has not been found for cardiac troponin I. The second difference is that, again, probably understood in many, many population studies cardiac troponin T concentrations are even stronger predictors of death as compared to cardiac troponin I concentration. Then the third difference it seems that if we measure it with high-sensitivity assays, for example high sensitivity, it seems to rise or if you released from injured cardiomyocytes even slightly earlier as compared to T and possibly even less injuries necessary to release I as compared to T.                                                 Then you mentioned renal function. Cardiac troponin T concentration shows slightly higher correlation with renal function as compared to I. Also, other pre-analytical issues, hemolysis seems to affect T and I concentration in a different way. So a lot of small tiny differences that have emerged and that underlie the hypothesis that possibly by combining the two signals we could be even more accurate in the diagnosis rather than relying on one on its own. Dr Carolyn Lam:                That's good. That really sets up the rational very well. I think in and of itself is a learning lesson, because I think most clinicians sort of take the two equivalently. So could you tell us what you found? Dr Christian Mueller:      I would like to of course thank the fantastic team that has allowed us to generate this data. It's a collaboration between the APACE investigators, the ADAPT investigators and experts in clinical chemistry from Maastricht University and Noreen Fandalin and Karen Villa of the first office. So we used two large diagnostic studies, APACE and ADAPT. We measured high-sensitivity cardiac troponin T and I and both of them and compared the diagnostic performance as compared to the final adjudicated diagnosis by two independent cardiologists who, of course, had all information, cardiac imaging and whatever you need to adjudicate.                                                 So, what we found is that in general if you look at diagnostic accuracy, overall is quantified by the area under the curve. Combining the two signals did not consistently increase overall diagnostic accuracy as compared to the individual isoforms. However, we were able to document some improvement for the rule out for the very early rule out of acute myocardial infarction. So the concept that is extremely attractive of course from a medical as well as from an economic perspective is to rule out the presence of acute myocardial infarction with a single blood draw. So, we can do this if we assess the ECG. The ECG doesn't show relevant changes. Then if the troponin concentration measured with a high-sensitivity assay is very low, then the likelihood that the patient would have an acute myocardial infarction again is extremely low or in scientific term sort of a negative predictive value approach is 99 to 100%. By combining very low concentration for high-sensitivity T and very low concentration for I, we were able to increase the efficacy of the early rule out and that seemed to be the most likely possible clinical utility of combining the two signals. Dr Carolyn Lam:                Even that so-called neutral findings are very important. It's an important question to ask and important answer to get. Could you give us an idea for the rule-out part? How much do we gain? How much exactly do we gain by using both assays instead of just one? Dr Christian Mueller:      So, the efficacy of the early rule-out depends to some extent on the assay used and the cut off applied. So the current you see algorithm uses cut-off that has been shown to be very safe. However, they are regarding their efficacy not very high. So the current you see recommended cut-offs and approach, allows the rule-out only in about perhaps 10 or 15% of patients. That number can be significantly increased, likely doubled or perhaps even increased threefold by using the combination approach. So this has been consistently showed both in the derivation and the validation cohort. Dr Carolyn Lam:                Yeah. Do you think this is ready for prime time? I noticed a very balanced discussion actually calling for future studies, but perhaps you could state it better now. Dr Christian Mueller:      The main limitation regarding prime time is the fact that currently manufacturers either of a high-sensitivity TSA or of a high-sensitivity high method, which means that the vast majority of hospitals at this point in time do only have one method available. It would require quite substantial investment in both hardware as well as changing of the logistics in the lab to implement measurement of both assays. So I think it's likely feasible, but it would be associated with relevant investment from a hospital perspective. In addition, I mean, also the rule-out approaches that use of only one assay also there are studies ongoing in trying to further increase the efficacy of the single marker approach. So I think it's the best tool marker strategy that we were able to come up with recently, because many of the other biomarkers that we had tested really didn't work out. Still, as you mentioned, I think it's also important to be very, very honest that it will be difficult to implement tomorrow in most institutions. Dr Carolyn Lam:                Yeah, and perhaps a little bit more work needs to be done to sort first identify perhaps special situations where these may be particularly helpful. I supposed like you just said when we're thinking of the ESCs to review one-hour type algorithm, who knows maybe we should be having that extra insurance of the second test in those that test it negative in the first or something like that. Do you plan further work? I always ask you because you're always in the forefront of these things and we just love touching your work. Dr Christian Mueller:      We have several additional analyses ongoing. Again, I think the main part is for just to go ... I go back from a clinical perspective. So I think for many hospitals that are using T at the moment, it's important to have I available for certain situations. So for example if you have a patient in whom you have evidence of chronic skeletal muscle disease, most of these disorders are rare but some of them have been shown to be associated with increasingly highly troponin T that do not seemed to be related for cardiac diseases but from skeletal muscle. This is rare but if you have a patient with that kind of history, then the dual mark measurement is I think mandatory.                                                 The same applies to iso that the other reasons to have false positive results for iso whenever you are ... If your hospital is using I, you should have the T method also available because once in a while you will identify patients in whom you have an I result that doesn't really match the clinical setting, then it's so easy and often so helpful to get the T result to decide on the most appropriate measurement of patient.                                                 For which patients are kind of a standard that measures T and I would be justified, I think that's something to tease out in future study. I think that the rational is there and likely it will depend also on kind of which T or which I method we might use in the future. So at the moment, we have one method for high-sensitivity T, but there are several other methods in development and kind of applying for FDA approval for high-sensitivity I and possibly combination of these might be even more beneficial regarding the single measurements and I think that has to be teased out in future studies. Dr Carolyn Lam:                Exactly, but what great insights for us to consider as clinicians now for specific cases where we may consider find those if we have those in our institutions. At the end of the day, I supposed cost-effectiveness analysis will need to be done. Agree? Dr Christian Mueller:      Absolutely, absolutely. The good thing about troponin, it's extremely inexpensive. So as compared to most of the new fancy biomarkers that are usually, rather prices of troponin is a routine marker. It's inexpensive. It's there for very likely that if we are able to document some clinical value that also the cost-effectiveness study that's definitely unnecessary will show also some economic benefit. Dr Carolyn Lam:                Oh, Christian, thank you for publishing yet another impactful and clinically relevant paper with us here in Circulation. I mean, it's exactly the kinds of papers that we really treasure here, because they directly inform clinicians and open our eyes to actually things that we should be considering in our everyday practice. Clod I ask you maybe cheekily to share about your experience with publishing at Circulation? Someone like you will be the best person to tell the world what it's like. Dr Christian Mueller:      Oh, of course. I mean, for us as a research group and for me as a researcher, it's fantastic. It's perfect to have some of our work published in Circulation that has fantastic impact factor, fantastic readership and ensures that the research catch the attention that's fantastic. Also, I think for us as a research group, the recognition of being able to publish in Circulation is outstanding and it helps us continue in the research group that we do. The comments made to large extent also by the editors. Also, on this manuscript, I think we're incredibly insightful and definitely had a major contribution to the final product to make it as attractive and also as balanced and insightful I think as it is at this point in time. Dr Carolyn Lam:                Thank you so much for providing that feedback, because it is our aim, explicit aim to put a partner authors in getting the best of the manuscript and working really closely with you. So thank you once again, Christian, for your time today. Audience, I know you've heard many times from this favorite person that we have on our podcast.                                                 Do share this podcast with all your colleagues and don't forget to tune in again next week.  

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke-National University of Singapore.                                                 We know that excessive sedentary time is bad in terms of health outcomes, but does it matter how that sedentary time is accrued, whether in short or long bouts? Today's feature paper gives us some answers. More soon, right after the summary of this week's journal.                                                 The first original paper in this week's journal provides insights into the mechanisms underlying neointima formation in arterial restenosis. Co-first authors, Dr. Cheng and Shi, corresponding author Dr. Li from Wuhan University in China, and their colleagues, performed an elegant series of experiments in which they demonstrated that interferon regulatory factor 4, or IRF4, which is a member of a family of key, innate, immune regulators known to play a role in cardiometabolic disease, actually protects arteries against neointima formation.                                                 They further probed the mechanism underlying this protective effect and found that IRF4 promoted the expression of Krüppel-like factor 4 by directly binding to its promoter. Genetic over-expression of Krüppel-like factor 4 in smooth muscle cells reversed the neointima promoting effect of IRF4 ablation. Whereas, ablation of Krüppel-like factor 4 abolished the protective function of IRF4, thus indicating that the protective effects of IRF4 against neointima formation were Krüppel-like factor 4 dependent.                                                 These findings suggest that the previously undiscovered IRF4 Krüppel-like factor 4 axis plays an important role in vascular proliferative pathology and thus may be a promising therapeutic target for the treatment of arterial restenosis.                                                 The next paper highlights that high-spacial resolution in gene expression signatures can reveal new regulators, genetic pathways, and transcription factors that are active in well-defined regions of the heart.                                                 Now we know that traditional genome-wide transcriptome analysis has been disadvantaged by the fact that the signals are derived from tissue homogenates. Thus, the authors of this current paper, including Co-First authors Dr. Lacraz and Junker, corresponding author Dr. Van Rooij from University Medical Center Utrecht in the Netherlands used tomo-seq to obtain genome-wide gene expression signature with a high spacial resolution, spanning from the infarcted area to the remote areas to identify new regulators of cardiac remodeling.                                                 Using this technique, they identified SOX9 as a potent regulator of cardiac fibrosis. In vivo loss of SOX9 reduced the expression of many extracellular matrix genes, which coincided with a blended cardiac fibrotic response upon ischemic injury.                                                 These data therefore were able to unveil currently unknown relevance of SOX9 as a key regulator of cardiac fibrosis, thus underscoring that tomo-seq can be used to increase our mechanistic insights into cardiac remodeling, and to help guide the identification of novel therapeutic candidates.                                                 The next paper reports the primary results of the effect of ferric carboxymaltose on exercise capacity in patients with iron deficiency and chronic heart failure, or EFFECT-HF study, which is a randomized control trial of intravenous ferric carboxymaltose, compared to standard of care on the primary end point of change in peak Vo2 from baseline, to 24 weeks in patients with symptomatic, chronic heart failure with reduced ejection fraction and iron deficiency.                                                 In this report from Dr. van Veldhuisen from University Medical Center Groningen and colleagues, intravenous ferric carboxymaltose was shown to significantly increase serum ferritin and transferrin saturation. At 24 weeks, peak Vo2 had decreased in the control group, but was maintained in the group receiving intravenous ferric carboxymaltose.                                                 Although a favorable effect on peak Vo2 was observed with ferric carboxymaltose, compared to standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak Vo2 among patients who died.                                                 They also reported that patient's global assessment and functional class, as assessed by New York Heart Association, improved on ferric carboxymaltose compared to standard of care.                                                 Whether ferric carboxymaltose is associated with an improved outcome in these high risk patients, deserves further study.                                                 The final study provides important long term clinical data to guide lead management decisions in patients with cardiac implantable electronic devices.                                                 Dr. Pokorney from Duke University Medical Center in Durham, North Carolina, and colleagues, analyzed over 6,000 Medicare patients and found that device extraction was associated with a lower adjusted five year infection rate, compared with a cap and abandon strategy. There was a lower absolute five year mortality with extraction, but after adjustment there was no association between extraction and a lower five year mortality.                                                 In summary, therefore, elective lead extraction for non-infectious indications in this Medicare cohort had similar long term survival, but lower risk of device infections at five years, compared to capping and abandoning leads.                                                 Patient and provider preferences are critical to decision making when considering extraction versus capping and abandonment of leads.                                                 Well, that wraps it up for your summaries. Now for our feature discussion.                                                 For today's feature discussion, we are talking about sedentary time and a metabolic risk of having too much of it. But, today's paper is so interesting because it tells us that it's not just the total amount of sedentary time that may matter, but how we accrue the sedentary time. Very, very novel concept in my point of view and I'm so pleased to have the first and corresponding author of this paper, Dr. Keith Diaz from Columbia University Medical Center with us, as well as Associate Editor from Johns Hopkins, Dr. Wendy Post.                                                 So pleased to have you both. Keith, could we just dive right into it? Tell us what population you were looking at, and what you found. Dr. Keith Diaz:                    Sure, so we were studying a population of participants enrolled in the Hispanic Community Health Study, so it's a US populations of over 16,000 Hispanic adults. And essentially what we found was that sitting for prolonged bouts, so sitting for one, two hours at a time, was associated with poor glucose regulation. Dr. Carolyn Lam:               Well, yikes. I've actually been sitting for a few hours in a row right now, actually. I think these results are phenomenal, but could you maybe expand a little bit on the details, like how long is too long? And, how often a break needs to happen for you to see differences in the metabolic risk? Dr. Keith Diaz:                    It's a good question and, to be honest, we don't know. I think that's where the research needs to head, but right now it seems to be that taking a break every 30 to 60 minutes could be beneficial. I think that's what we've found thus far. Dr. Wendy Post:               Keith, we were really excited to get your paper in. I think everyone on the Associate Editorial Board was especially interested in it because we can all relate. As Carolyn said, she's been sitting for a long time and when we have these meetings we have two hour meetings at a time and maybe we need to start saying that in the middle we should all stand up and take a break. So we can all relate to this.                                                 But I think one the biggest questions that we had related to data itself, was the association between the total sedentary time and the sedentary bout duration. Maybe you can tell us a little bit more about those correlations in the interaction and tell us also how you also measure sedentary bout duration and total sedentary time in this observational cohort. Dr. Keith Diaz:                    Sure, so I'll start with that latter question. So, we measured sedentary time [inaudible 00:09:32] subjectively. So we actually used an activity monitor called an accelerometer to see how sedentary they are. And how we quantified sedentary bouts is we just looked at how long consecutively a person sat without moving. That was considered sedentary bout. In terms of correlation, what we found is that there are very closely linked. So, people who sit for long hours during the day for total volume, also sit in long bouts. And so what we wanted to do was try to figure out and piece apart, which one is more important? When we're trying to ... If we're thinking about guidelines and what we should be doing about our sedentary time, is it important to reduce our volume or interrupt our bouts? And so what we found is that they're not independent, and that they're in many ways synergistic. And that the association of prolonged sedentary bouts with glycemic biomarkers varied according to how much total volume you sit and vice-versa. Dr. Wendy Post:               Can you expand a little bit more on that? So tell us about the interaction that you found between sedentary bout duration and total sedentary time. Dr. Keith Diaz:                    Sure, so we did find that there was a specifically significant interaction between the two variables and so what we tried to do is actually categorize people as to whether they were high for both characteristics or high for just one of them. And so what we found was that those participants who are high for both, so they had high volume and sat in long bouts, they had the worst glucose regulation, and that those individuals that were high for just one of the characteristics had a little bit better glucose regulation. And so really what we thought the take home message was when thinking about how do we improve our sedentary behaviors is that it's targeting both. It's not sitting for large volumes during the day, but also making sure to take frequent breaks every 30 or 60 minutes. Dr. Wendy Post:               And tell us about the glucose measures that you included in your study. Dr. Keith Diaz:                    Yep, we had a couple glucose measures. One we had people do a two hour glucose tolerance test, so they took a glucose drink and then we measured their blood sugar levels two hours after having that drink. We also measured their H1Ac levels as well as their fasting glucose and fast to link insulin measures from which we can then derive measures of something called HOMA IR, which is a measure of insulin resistance. Dr. Wendy Post:               And the associations that you saw were primarily with the HOMO IR and the two hour glucose levels but less with the hemoglobin A1c? Dr. Keith Diaz:                    Correct. Dr. Wendy Post:               So it really appears to be that insulin resistance that's most affected by the total sedentary time and sedentary bout duration. Tell us about potential confounders and how you factored that into your analysis. Dr. Keith Diaz:                    Yeah, there was quite a number of potential confounders between this relationship of sedentary behavior and glycemic biomarkers. One of them in particular that we were concerned about most were things like body mass index or exercise or physical activity levels. And so we took a look at what we adjusted for those confounders how the relationship changed. And what we did find was that there was an attenuation and association between sedentary behavior and the glucose markers, but there was also ... were still statistically significant. So suggestive that maybe they're partly in the pathway of body mass index or exercise but they didn't make the relationship go away. I should add that we looked at a couple other confounders, we looked at things like inflammation, C-reactive protein, as well as whole bunch of other measures of cardiovascular risk factors. I'll stop there. Dr. Wendy Post:               And what about the fact that study is cross-sectional, are there any caveats related to the study design that you'd like to point out to the audience? Dr. Keith Diaz:                    Yeah, I think that's an important point, that this is cross-sectional, so by no means can we infer causality that sedentary behavior causes glucose dysregulation, it's just purely an association. So I think anyone listening to this podcast should keep that in mind when reading this paper or listening to this podcast. Dr. Wendy Post:               So if you were writing the next set of guidelines what would you recommend in terms of how you implement these findings into guidelines? Not to imply that we think that these cross-sectional observational data mean that we're ready to change guidelines but, if these were replicated in randomized trial or some other more objective data study design, how do you think we should use these results to change our behaviors? Dr. Keith Diaz:                    I think these guidelines point ... or, with the current guidelines are, sit less, move more, where the guidelines that came out from AHA in October of 2016. In part, they were not as specific because we don't have quite the quality of guidelines or data that we need for more qualitative guidelines, or quantitative guidelines. I think if we're able to replicate these data with [inaudible 00:14:10] or point us towards at least is, also, that we should be interrupting our sedentary bouts. And so what I'd like to see hopefully if we can replicate something I'd like guidelines that say every 30 minutes or every 60 minutes of sitting you should stand up and move. And hopefully with future studies that are coming out that we can make them even more specific and something along the lines of every 30, 60 minutes you stand up and walk for 5 minutes or you just stand up for 1 minute. That's where I'd like to see the science head and I think this study points us in the that direction of maybe we have to start thinking about breaking up our sedentary bouts. Dr. Carolyn Lam:               All right you guys, I don't know about you, but I am literally standing up right now while I'm listening to you both. This is so interesting and I love the way, Wendy, you reflected the robust discussions we had as team when we were working through this paper. Congratulations again, Keith, for just this remarkable paper. Actually, maybe I could just ask, Wendy, what do you think? What do you think our next steps that may need to get these kinds of recommendations, perhaps into guidelines? Dr. Wendy Post:               I think as was alluded to before, these are observational data so they're important for hypothesis generation, but really to have evidence that would lead to changes in guidelines maybe having a randomized trial, where obviously you can't have very hard outcomes, but randomized trials of some duration that could potentially lead to changes and important outcomes, would then maybe lead to changes in guidelines. But there isn't anything that we would lose from trying to implement these kinds of behavior, changes into our lifestyle since the downside and the risk is pretty low. So even if they don't make the strongest level of evidence at this point, I think we can still all be mindful of this and so.                                                 One thing that we've been trying to do in our preventive cardiology group at Hopkins is trying to implement walking meetings. In fact, I just had an email discussion with one of my colleagues about meeting tomorrow and she said, "Well, where do you want to meet?" And I said, "Well, why don't we go for a walk? The weather should be nice." And so I think if we're all mindful of trying to, not only increase our amount of physical activity, but trying to limit the sedentary bout duration by being creative and trying to change, sort of, long standing traditions of having meetings sitting in an office, then that could be helpful.                                                 So, just something for our audience to think about as well. Dr. Carolyn Lam:               That's brilliant. You know, the one thing that I was thinking, though, just thinking about the reception of these data in my country, in where I practice, in Asia. This was a purely Hispanic or Latino population. I suppose there is a perception that that population may be predisposed to cardiometabolic disease and so on, and so you know, what's the applicability to us in Asia? So, I'm really happy, particularly to hear how you've taken it on. I mean, it's a simple thing, why not, right? Just to be more active. There's surely can't be something wrong with that. What do you think of that? Dr. Wendy Post:               Totally, I think it's important to emphasize the unique nature of these data and that they come from a Hispanic study, which is a really important addition to our literature in epidemiology and cardiovascular disease and certainly there are significant differences in lifestyle among different communities within the United States and across the globe, as you've experienced having lived in different countries. And so, I think we need obtain more data about how there might be differences based on various traditions and different lifestyles, and try to target those who are at greatest risk. Dr. Carolyn Lam:               Keith, did you have anything to add to that? Dr. Keith Diaz:                    Yeah, I think Wendy is right on and certainly I don't think we have any reason to suspect that sedentary behavior acting differently in Hispanics versus other populations, and so I still think going forth with this notion that we all should be reducing our sedentary behaviors is important to highlight. Dr. Carolyn Lam:               Fantastic. Well, thank you both for a really wonderful discussion. This is really cool, I think a lot of people will be talking about this.                                                 Listeners, you've heard it first, though, in Circulation on the Run. Thank you for joining us today and don't forget to tune in next week.  

On this episode of the Healthy Wealthy and Smart Podcast, Dr. Alli Gokeler joins me to discuss motor learning following ACL injury. Alli has a special interest in motor control. He’s currently working on the development of prevention programs designed to reduce primary and secondary ACL injury rate and optimization of return to sports and performance. In this episode, we discuss: -The 4 principles of motor learning -How to facilitate neuroplasticity with principles of motor learning -Self-controlled feedback and how it enhances learning and motivation -Dr. Gokeler’s take on the timetable for returning to sport following ACL injury -And so much more!   The way clinicians guide and cue their patients can impact their patients’ success in learning motor skills. Dr. Gokeler outlines important considerations for clinicians and suggests, “A very simple change in wording can have a significant effect on learning.”   Incorporating motor learning principles into your treatment is not a one-sized fit all approach and can be dependent on the learning style of the patient, the task and the environment. Dr. Gokeler reiterates, “There is no motor learning principle that is the gold standard.”   Despite widely accepted ACL injury rehabilitation practices, patients continue to display high incidence of re-injury and altered movement patterns. Dr. Gokeler believes, “We need to step up and come up with better rehab approaches.” To improve long term outcomes, Dr. Gokeler advises all clinicians to, “Make rehab challenging, fun but attainable.”   For more information on Dr. Gokeler: Alli Gokeler was born on 18 September 1967 in Groningen, the Netherlands. He obtained his degree in Physical Therapy in 1990 from the Rijkshogeschool Groningen. From 1991-2001 he worked as a physical therapist in the United States and Germany. Upon return to the Netherlands, he obtained a degree in Sports Physical Therapy from the Utrecht University of Applied Science in 2003. In 2005 he started on his PhD project at the University Medical Center Groningen, Center for Rehabilitation. Alli has a special interest in motor control. He’s currently working on the development of prevention programs designed to reduce primary and secondary ACL injury rate and optimization of return to sports and performance.   Resources discussed on this show: Motor Control and Motor Learning---5th-Edition Human Performance by Fitts and Posner Richard Masters: The theory of reinvestment Tim Gabbett Twitter Alli Gokeler Twitter Alli Gokeler Facebook aclrehabilitation.com   Thanks for listening and subscribing to the podcast! Make sure to connect with me on twitter, instagram and facebook to stay updated on all of the latest! Show your support for the show by leaving a rating and review on iTunes!   Have a great week and stay Healthy Wealthy and Smart!   Xo Karen   P.S. Do you want to be a stand out podcast guest? Make sure to grab the tools from the FREE eBook on the home page! Check out my blog post on the Top 10 Podcast Episodes of 2016!  

Carolyn: Welcome to Circulation On The Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, associate editor from the national heart center and Duke National University of Singapore.     In just a while, we will be discussing patients with familial hypercholesterolemia after acute coronary syndrome, and the new data in this week's issue that suggests we still need to pay special attention to this group of patients even in the current era of the widespread use of high intensity satins. First here's your summary of this weeks issue.     The first paper suggests that we may need to look at thyroid function in our risk assessment sudden cardiac death in the general population. This paper is from co primary authors Dr. Chacker in Van Der Burgh and corresponding author Dr. Strecker and colleagues from the Erasmus University medical center in water dom.     The authors studied the association of thyroid function with sudden cardiac death in more than 10,000 participants of the population based Water Dom study. They found the higher levels of 3T4 were associated with an increased risk of sudden cardiac death even in the normal range of thyroid function. The estimated hazard ratio was 2.28 per one nano-gram per deciliter of 3T4, and these risk estimates did not change substantially even after stratification by age or sex or sensitivity analysis excluding participants with an abnormal 3T4. The absolute 10 year risk of sudden cardiac death increased in youth thyroid participants from 1 to 4% within increasing 3T4 levels.     Thus this study suggests that 3T4 and additive marker in risk stratifications for sudden cardiac death in the general population. Further research is needed to assess the possible additional benefit of using 3T4 levels to re stratify and prevent sudden cardiac death.     The next study reminds us that therapies to reduce ischemic events in patients undergoing percutaneous coronary intervention are still really important even in the current era of changing definitions of periprocedural myocardial infarction. This study is from first author Dr. Cavender of University of North Carolina chapel hill and corresponding author Dr. Bach Brigham women's hospital and colleagues.     The authors looked at more than 11,000 patients randomized to cangrelor or clopidogrel int the champion phoenix trial.     Cangrelor is an intravenous P2Y-12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention who are not pretreated with with a P2Y-12 inhibitor.     The authors explored the effects of cangrelor on myocardial infarction using different definitions of myocardial infarction and perform sensitivity analysis on primary endpoint.     They found that 4.2 percent of patients had a myocardial infarction defined by the second universal definition within 48 hours after undergoing PCI. When the sky definition of periprocedural MI was used, there were fewer total myocardial infarction, but the effects of cangrelor remain significant.     Finally similar effects were seen when MI's were restricted to those defined with large bio marker elevations or by symptoms of ECG changes. Very importantly patients who had an MI regardless of the definition, were at increased risk of death at 30 days.     In summary changes in the definition of MI used in the primary endpoint did not affect the overall findings from the champion phoenix trial. This study also reminds us that periprocedural MI remains an important clinical event in the current era. Being associated with increased risks of death at 30 days, and therefore reducing ischemic events in patients undergoing PCI remains very important.     The final paper describes experimental evidence of a novel treatment approach to hypertension using micro RNA's. This paper is from first author Dr. Lee and corresponding authors Dr. Chinn and Wang from Tong G medical college and Whadrom University of Science and Technology in Wuhan China.     Micro RNA's are a class of small non-coding RNA's that regulate gene expression at a post transcriptional level. These authors compared the expression of key neucler genoman coded and mitochondrial genoman coded genes involved reactive oxygen species production in spontaneous hypertensive rats and wistar rats. They then used bioinformatics to predict the micro RNA targets followed by biochemical validation using real time PCR and immunial precipitation.     They first found that there was down regulation of mitochondrial DNA encoded sitoca B in the spontaneous hyper intensive rats, which appeared to directly contribute to the increased mitochondrial reactive oxygen species.     Next they found that mere 21 a key micro RNA induced into hyper spontaneous rats, was able to trans-locate into mitochondria to counteract the mitochondria pseudonym B down regulation. Finally, they showed that exogenous mere 21 delivered by recombinant adeno associated virus was able to lower blood pressure and attenuate cardiac hypertrophy in the spontaneously hypertensive rat model.     These findings are striking because they provide experimental support for developing micro RNA based treatments for hypertension.     Those were your summaries of original papers but before I go, I just have to highlight this in depth review paper in this week's issue, and it is regarding sodium glucose co transported to inhibitors or SLG2 inhibitors in the treatment of diabetes, discussing the cardiovascular and kidney affects potential mechanisms and clinical applications.     It is a beautiful review article written by first author Dr. Heresphink of the University Medical Center Groningen, corresponding author Dr. Churney from Toronto general hospital and colleagues. Truly a must read, but now here is our featured paper.     Our featured paper today is on patients with familial hypercholesterolemia after acute cornery syndromes. Today I have with us the first and corresponding author David Nan chin university of Lausanne in Switzerland.     Hi David, thanks for joining us.   David: Hi, I'm very happy to be here.   Carolyn: As the associate editor who managed this paper we have Dr. Amat Kira and you will recognise him as the digital strategies editor as well from UT Southwestern. Welcome back Amat.   Amat: Thank You Carolyn, happy to be here.   Carolyn: I am really curious about this paper because it speaks of familial hypercholesterolemia that most of us would assume is very rare.     Now David, I know that you actually published prevalence in a prior paper last year, but could you maybe start by telling us why we should, how common is this in our patients with acute coronary syndrome?   David: In fact we studied patients who is hospitalized with acute coronary syndrome in several university hospitals in Switzerland. Of course we try our best to include all classifications in the study in order to be very protective of the acute coronary syndrome population.     We found that among patients with acute coronary syndrome, familial hypercholesterolemia was not a rare disease. We found a prevalence of 2-5% which is in fact 10 times higher than what is thought to be in the general population.     The important point here is that we use very simple clinical catatonia to assist the prevalence of adage. This catatonia includes unbelievable[inaudible 00:08:50] and the family of Bethany of coronary heart disease. This criteria are very easy to use and implement in a clinical practice in the sitting in acute coronary syndrome to detect patients with familial hypercholesterolemia.   Carolyn: Exactly. You did not use molecular diagnosis in your paper, but yet, with these simple criteria there was a very important clinical take home message. Could you tell us about those findings?   David: The question we wanted to answer here is wanted to know what happened to this patient with familial hypercholesterolemia after hospital discharge. We found that patients with familial hypercholesterolemia were an increased risk of recurrence of cornea events within the year after discharge, and this is despite the use of idol science.     In fact, one year after the coronary syndrome, 7 people found a patient with adage were still using idle studies, which is very good we were quite impressed by these numbers, but they mean[inaudible 00:09:57] one year after the acute coronary syndrome, with one in twenty become affected later.     Most of these patients were not able to decrease their added cholesterol to lower evens.     I really think there is clear room for infestation of leamington therapy among these patients. In any of those drugs available from my seeing and very effective to decrease and [inaudible 00:10:25] to substance, but they are very expensive.     Maybe the best initial strategy, to prescot these drugs, is to target patients with familial hypercholesterolemia after acute coronary syndrome. Because these patients are at high risk of recurrence and most of them cannot achieve their cholesterol level with our studies.   Carolyn: Congratulations for being really the first to show that. This is common and it affects recurrent events. I think actually the first step is to recognize this in our patients which very few of us really do I think.     Amat from your point of view, knowing the results of this paper how has it changed your clinical practice?   Amat: Absolutely Carolyn. First I congratulate Dr. Nan chin and his colleagues. This was an incredibly important paper, and I think as you pointed out, one of the first to really show us why it is irrelevant to show us why it is relevant to identify FH at the time of an ACS.     Generally even when I work with my trainees when we talk about FH, everyone is thinking, "Well, we'll just put everyone on statins," and it's well appreciated. We can think about cascades swinging and why it's important to their offspring, but what Dr. Nan chin and his colleagues have certainly highlighted, is that these patients are at higher risks for recurrent ACS and recurrent events, and that's incredibly important as mentioned that tells us that maybe the routine treatment post ACS with high dose statins is not sufficient.     What's next is the tricky part, do we initiate PCS canine initially, do we add a zedemi upfront. Sort of the next step is the part that's a little bit more tricky, but I certainly see a potential for augmented therapy in these patients up front.   Carolyn: I like the way you said tricky, and that's usually when we call for an editorial isn't it?   Amat: That is correct as we will see with this article.   Carolyn: I really like the title of it, "Diagnosis and Management of Petra Zygas familial hypercholesterolemia too little and too late."     That was very interesting, but are there any other take home messages from your end David?   David: Maybe one thing we can add ... We are currently trying to change our practice regarding these reasons that we have now. We have now implemented in our casualty department a system that's explaining strategy to identify this patient, to identify patient with asage.     We have a prevention team that can provide very early during hospitalization additional information for this patient about asage. That's one very important point is to encourage family testing especially for the children of the patient and also to provide concerning for other cardiovascular risk factors. Because we also found that half of these patients with asage were smokers in fact and 40% of them had hypertension.     Certainly to address the other cardio risk factor in patients with asage so certainly very important. At the end part of what we are doing is we are assured of the patient will an appropriate medical follow up in the primary care setting because it's also very important for management of asage and circular prevention in the primary care setting after discharge.   Carolyn: Wow. Those are excellent points. Very practical advice on screening, management, and really just applying the results of what you found. Congratulations once again.     Amat I'm going to switch tracks a little bit now. Since we've got you online I really have to ask you a couple of things with your hat as a digital strategies editor.     Has it been two months since we first chatted even about this podcast which is part of the digital strategies. Let's take stock of it. How are things going?   Amat: Well, so far I think excellent and frankly one of the highlights of our digital strategies is your podcast. It's gotten rave reviews and certainly appreciate all your enthusiasm and your unique take on how to do this. We've also had some excellent work with our social media. We have a revised website which has a lot more real estate for some novel offerings, and I think we certainly can't rule out traditional print media, but those articles that come out online.     It's been really an exciting time and thinking of novel ways to share new information in a modern era.   Carolyn: Right. Thanks to you really Amat and I would really want to bring out one of the strategies that we may have not talked about so often yet, and that's the "on my mind" vlogs.     The reason I'm going to bring it up is because last week I was struck by the on my mind article by Milton Packer and it's entitled, "Heart Failure's Dark Secret. Does anyone really care about optimal medical therapy?" That's just awesome. Could you tell us a bit more about this vlog.   Amat: I think you hit the nail on the head there it certainly an edgy and controversial title, and if you think about it that's the purpose of this in most of our academic writing. It's a little bit stiff in following certain para dines, and more formal para view. The purpose here for the on my mind was literally that for someone who is a thought leader to free associate various ideas they have that would be controversial or edgy or may not be accepted down the main stream.     That's a bit on purpose because we hope to create a dialog around that. If you look on our webpage, there's actually a place where people can add comments or start a dialog saying whether they agree or disagree, or begin an important conversation around these edgy topics.   Carolyn: I think that's the really cool part when we can actually start interacting with our readers and listeners online that way.     Thank you to my wonderful guests and thank you listeners for listening this week. Don't forget to tune in next week for more highlights and features.    

In this podcast Catherine Otto speaks to Dr P G Pieper, Associate Professor of Cardiology, University Medical Center Groningen, the Netherlands, about the recent paper in Heart on assessing the risk of pregnancy for women with congenital heart disease. This study compared three different scoring systems and found that the WHO score provided the most accurate risk prediction. The importance of this issue is illustrated by the approximately 10% risk of maternal complications in this patient group. This podcast was recorded at the European Society of Cardiology Annual Scientific Sessions, Barcelona Spain, August 31, 2014. Read the original article: Prospective validation and assessment of cardiovascular and offspring risk models for pregnant women with congenital heart disease http://heart.bmj.com/content/100/17/1373

Host: Jason Birnholz, MD These interviews were recorded at the Radiological Society of North America's 95th Scientific Assembly and Annual Meeting, which took place November 29th through December 4th in Chicago. Host Dr. Jason Birnholz talks with Dr. Rozemarijn Vliegenthart, from the University Medical Center Groningen in the Netherlands, who presented at the conference a paper entitled, "High Prevalence of Treatable Severe Coronary Artery Disease: Findings in a Randomized Controlled Trial in Cardiac Asymptomatic Peripheral Arterial Disease Patients." Dr. Birnholz also sits down with Dr. Asim F. Choudhri, from Johns Hopkins University in Baltimore, to talk about tele-radiology and smartphones.

Hosted by: S. Diane Yamada, MD, Deputy Editor of Gynecologic OncologyFeaturing:Maaike Oonk, MD, University Medical Center Groningen, University of Groningen, The NetherlandsAkila Viswanathan, MD, MPH, Johns Hopkins MedicineEditor's Choice Paper: Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe Editorial: When is it safe to omit contralateral groin management in unilateral sentinel node-positive early stage vulvar cancer?