Podcasts about leiden university medical center

Hosts Mitsuaki Sawano, MD, Kentaro Ejiri, MD, and Nobuhiro Ikemura, MD, welcome Yuki Obayashi, MD, of Leiden University Medical Center, to discuss findings from the STOPDAPT-3 trial. Dr. Obayashi highlights that, among ACS patients—including those with HBR or STEMI—aspirin and clopidogrel monotherapy after 1 month of DAPT resulted in similar rates of ischemic and bleeding events. These results support flexible, patient-centered antiplatelet strategies beyond the acute phase.

Hosts Mitsuaki Sawano, MD, and Nobuhiro Ikemura, MD, welcome Yoshitaka Kimura, MD, PhD, of Leiden University Medical Center, to discuss proactive ablation strategies in patients with repaired Tetralogy of Fallot (rTOF). Dr. Kimura presents data from a long-term, single-center study evaluating electroanatomical mapping and preventive ablation of slow-conducting anatomical isthmuses (SCAI) in rTOF patients without prior ventricular tachycardia (VT). The findings show that identifying and successfully ablating SCAI significantly reduced VT incidence, with all VT events occurring in patients where ablation failed. Moreover, this approach reduced the proportion of patients qualifying for ICD implantation from 25–51% under current guidelines to just 11%. Dr. Kimura underscores a paradigm shift in congenital heart disease management—from treating VT reactively to preventing it proactively—highlighting the value of data-driven, tailored care strategies that avoid unnecessary device implantation and better target high-risk individuals.

In this episode of the Vital Health Podcast, host Duane Schulthess speaks with two key voices driving the PRIME-ROSE initiative: Gro Live Fagereng, Project Manager of the EU-project PRIME-ROSE and Coordinator of Precision Cancer Medicine at Oslo University Hospital, and Henk van der Pol, Ph.D. Candidate at Leiden University Medical Center. They explain the DRUP (Drug Rediscovery Protocol) trial approach, which repurposes existing oncology drugs for new off-label uses, and discuss how this can widen treatment options for patients with rare or underserved tumor types. They also describe the complexities of consolidating small patient cohorts across multiple sites and countries, shedding light on how data models like OMOP help standardize clinical information. Listeners will learn about the unique challenges of data harmonization and the importance of building robust evidence in real-world settings. Gro Live and Henk share how PRIME-ROSE is helping healthcare systems coordinate more efficiently, reduce barriers to cutting-edge treatments, and ultimately improve patient outcomes. Tune in for a closer look at how forward-thinking collaborations and adaptive trial designs are reshaping the landscape of precision oncology in Europe.See omnystudio.com/listener for privacy information.

Send us a textShort Summary: Thyroid biology, offering insights into its role in metabolism, development, and longevity, making it a fascinating listen for those interested in how our bodies manage energy and health across the lifespan.Guest: Diana van Heemst, PhD is a biologist at Leiden University Medical Center, specializing in gerontology and geriatrics. Her research focuses on the neuroendocrine biology of aging and longevity in humans, particularly involving thyroid functions.Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and to everyone on YouTube. Partial versions are available elsewhere. Full transcript and other information on Substack.Full Summary: Dr. Diana van Heemst explores the thyroid's critical role in metabolism, growth, development, and transitions across life stages. It discusses the thyroid's evolutionary history, its location in the neck, and how it functions through hormone secretion, specifically T3 and T4. The conversation covers the importance of nutrients like iodine and selenium, the impact of thyroid hormone on various bodily functions, and the implications for health conditions like hypothyroidism and hyperthyroidism. It also touches on how thyroid activity might relate to longevity.Key Takeaways:Thyroid Hormones: T3 and T4 are crucial, with T3 being the active form that regulates metabolism, heart rate, and cognitive functions.Iodine and Selenium: Essential for thyroid hormone synthesis; iodine is unique to thyroid hormones, while selenium is vital for the enzymes that regulate hormone availability.Hypothyroidism vs. Hyperthyroidism: Hypothyroidism is more common, especially in older age due to autoimmune issues, leading to symptoms like fatigue and cold sensitivity. Hyperthyroidism can result from iodine excess or autoimmune conditions like Graves' disease.Developmental Role: Thyroid hormones are vital for major developmental transitions, from birth to puberty, impacting brain development and metabolic adaptation.*Not medical advice.Support the showAll episodes, show notes, transcripts, etc. at the M&M Substack Affiliates: Lumen device to optimize your metabolism for weight loss or athletic performance. Use code MIND for 10% off. Readwise: Organize and share what you read. Use your phone's link. Athletic Greens: Comprehensive & convenient daily nutrition. Free 1-year supply of vitamin D with purchase. KetoCitra—Ketone body BHB + potassium, calcium & magnesium, formulated with kidney health in mind. Use code MIND20 for 20% off any subscription. MASA Chips—delicious tortilla chips made from organic corn and grass-fed beef tallow. No seed oils or artificial ingredients. Use code MIND for 20% off. For all the ways you can support my efforts

With Doctor Stefan Simovic, Faculty of Medical Sciences, University of Kragujevac, Kragujevac - Serbia, Serge Trines, Leiden University Medical Center, Leiden - The Netherlands and Philip Moore, St Bartholomew's Hospital, London - UK This episode focuses on the EHRA Updated Core Curriculum.

Join host Duane Schulthess on the Vital Health Podcast as he explores the groundbreaking Prime Rose Project, an initiative redefining the use of off-label drugs in oncology. Featuring insights from Dr. Hans Gelderblom, Chair of Medical Oncology at Leiden University Medical Center, and Sahar Barjesteh van Waalwijk van Doorn-Khosrovani, a member of the Dutch National Payers Evaluation Committee, this episode delves into the challenges and opportunities of drug rediscovery protocols. Learn how this innovative approach balances accessibility, affordability, and evidence-based treatments, transforming the landscape of personalized medicine across Europe.See omnystudio.com/listener for privacy information.

Adding to the Cochrane Reviews of screening for breast cancer, a new review was published in May 2024 looking at the research into shared-decision making for this screening. In this podcast, Dr. Marleen Kunneman from Leiden University Medical Center in the Netherlands and Mayo Clinic in the US talks with lead author Dr. Paula Riganti from Hospital Italiano de Buenos Aires in Argentina about the review and its findings.

Adding to the Cochrane Reviews of screening for breast cancer, a new review was published in May 2024 looking at the research into shared-decision making for this screening. In this podcast, Dr. Marleen Kunneman from Leiden University Medical Center in the Netherlands and Mayo Clinic in the US talks with lead author Dr. Paula Riganti from Hospital Italiano de Buenos Aires in Argentina about the review and its findings.

Check out “Heard on the Street” recorded during Day 3 of the nPOD 2024 scientific meeting. Hear from Dr. Bart Roep at Leiden University Medical Center as he shares his thoughts on the key points of the nPOD meeting.

BUFFALO, NY- January 3, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 24, entitled, “Mapping of the gene network that regulates glycan clock of ageing.” Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. In this new study, researchers Azra Frkatović-Hodžić, Anika Mijakovac, Karlo Miškec, Arina Nostaeva, Sodbo Z. Sharapov, Arianna Landini, Toomas Haller, Erik van den Akker, Sapna Sharma, Rafael R. C. Cuadrat, Massimo Mangino, Yong Li, Toma Keser, Najda Rudman, Tamara Štambuk, Maja Pučić-Baković, Irena Trbojević-Akmačić, Ivan Gudelj, Jerko Štambuk, Tea Pribić, Barbara Radovani, Petra Tominac, Krista Fischer, Marian Beekman, Manfred Wuhrer, Christian Gieger, Matthias B. Schulze, Clemens Wittenbecher, Ozren Polasek, Caroline Hayward, James F. Wilson, Tim D. Spector, Anna Köttgen, Frano Vučković, Yurii S. Aulchenko, Aleksandar Vojta, Jasminka Krištić, Lucija Klarić, Vlatka Zoldoš, and Gordan Lauc from Genos Glycoscience Research Laboratory, University of Zagreb, Novosibirsk State University, Lomonosov Moscow State University, University of Edinburgh, University of Tartu, Leiden University Medical Center, Delft University of Technology, Helmholtz Zentrum Muenchen, German Center for Diabetes Research (DZD), King's College London, Guy's and St Thomas' Foundation Trust, University of Freiburg, University of Rijeka, German Institute of Human Nutrition Potsdam-Rehbruecke, University of Potsdam, Harvard T.H. Chan School of Public Health, Chalmers University of Technology, University of Split School of Medicine, Algebra University College, Johns Hopkins Bloomberg School of Public Health, and Institute of Cytology and Genetics SB RAS performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. “Here, we conducted a GWAS of IgG galactosylation phenotypes in a study that almost doubles the sample size (N=13,705) compared to previous GWAS of IgG N-glycome [33] and focused on the genes with in silico evidence for involvement in the IgG galactosylation process.” Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system, the researchers manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system. “Further research is needed to fully elucidate [the] functional mechanism behind their role in ageing and to reveal the complete network of gene interactions regulating the complex process of IgG glycosylation.” DOI - https://doi.org/10.18632/aging.205106 Corresponding authors - Azra Frkatović-Hodžić - afrkatovic@genos.hr, and Gordan Lauc - glauc@genos.hr 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@IMPACTJOURNALS.COM

Dr. Shannon Westin and her guest, Dr. Nanda Horeweg and Dr. Carien Creutzberg, discuss the paper "Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer" recently published in the JCO. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host Shannon Westin, Social Media Editor for the JCO and GYN Oncologist by trade. And I'm so excited about today's topic because it is a GYN Oncologist dream. Before I start, please note that none of the authors have any conflict of interest. We are going to be discussing molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. And this was published in the JCO on September 20th, 2023. And we're going to be speaking to two of the lead authors. First is Nanda Horeweg. She's a senior researcher in the Department of Radiation Oncology at the Leiden University Medical Center in the Netherlands. Welcome. Nanda Horeweg: Thank you. Happy to be here. Shannon Westin: And Dr. Carien Creutzberg. She's professor at the Department of Radiation Oncology at the Leiden Medical Center as well. Carien Creutzberg: Thank you. Shannon Westin: So, let's get into it. And I want to really level set because we have a mixed audience here. So, why don't you start by speaking about the incidents and mortality of endometrial cancer? Nanda Horeweg: Yes, of course. Endometrial cancer is the sixth most common cancer in women with around 400,000 new diagnoses made globally each year. And a woman's lifetime risk to get endometrial cancer is around 3%, and the median age, the diagnosis is 61 years. Most of the women who are diagnosed with endometrial cancer are diagnosed at an early stage, around two thirds, and they have an excellent prognosis. Actually, the five-year survival rates are around 92%. For stage 2 disease, this is actually already going down a bit to 74%. Therefore, stage 3 disease is only 48%. Women that are diagnosed with advanced disease have only a five-year survival, 15%. Shannon Westin: So, given that we know the majority of endometrial cancers are diagnosed at this early stage, prior to your evaluation, what was known about the optimal way to treat this early-stage patient population? Carien Creutzberg: Well, of course, the PORTEC trials were done … were started PORTEC-1 in the 19th of the last century, and PORTEC-2 in 2002. So, at that time, there were still many, many women treated adjuvantly with external beam radiation therapy. And we just developed risk factors to decide on their risk and the incidents for radiotherapy. And in PORTEC-2, because in PORTEC-1 we had seen that most of the recurrences in these early stage cancers were in the vaginal fold, we compared local vaginal brachytherapy only three sessions within full course of pelvic radiotherapy and showed that it had similar pelvic control and survival. Of course, this study, which Nanda conducted, was a long-term analysis with many new factors known from the translational research in the tissue samples of these patients who participate in PORTEC-1 and 2. And in the meantime, we've developed much more knowledge on the molecular factors and other important factors such as LVSI, which tell us much more about the individual prognosis to patients. So, the treatment has been developing greatly in the past 20 years. Shannon Westin: Yeah, and I think this is a great case of less is more, right? We were doing so much for so many people that really didn't need it. And so, really tailoring who needs less treatment, who doesn't need any treatment, and then also, conversely, who may need more treatment that would be missed by the traditional risk factors that you're speaking of. So, I think that brings us right into my next question, which is just bringing the audience up to date on the cancer genome atlas and how that's changed the way we classify endometrial cancer. Nanda Horeweg: Yes, I think the molecular classification of the TCGA has shaped the way we think about endometrial cancer, and has huge impact on decisions on adjuvant treatments in the years to come. The TCGA performed an extensive characterization of the endometrial cancers and found that in fact, this disease exists of four different groups. And the first of the groups I'd like to discuss is the ultra-mutated group, which is characterized by POLE mutations. And this group is shown to have an excellent prognosis in many independent studies. A second group that also has a high mutational burden is characterized by microsatellite instability, and mismatch repair deficiency and has shown to have an intermediate prognosis. Then there's another group that has a low mutational burden with high copy number alterations and frequent TP53 mutations, and these have a poor prognosis. And then lastly, there's a group that does not have any of the classifying features and is often called non-specific molecular profile or TP53 wild type. And this group also has an intermediate prognosis. And then finally, there's a small group of cancers that has more than one of these classifying features, the so-called multiple classifiers. And the WHO 2020 has developed an algorithm which can be used to classify them into the four groups. And that's first on the POLE status. And for the POLE wild type tumors, they are assigned according to mismatch repair deficiency status. And for those that are mismatch repair proficient than POLE wild type, they are classified according to the TP53 status into NSMP or p53 abnormal. Carien Creutzberg: Yeah, that is because of in the ultra-mutated and hyper mutated groups, many of the other mutations are secondary mutations in the context of the ultra-mutated stage, and they behave like the first molecular group. Shannon Westin: Yeah. So, that POLE mutation is going to trump anything else, and it's so important. And I will just say as a sidebar, it's been challenging with the price of next gen sequencing sometimes to get that for everyone. So, sometimes for us when we see a p53 mutation, we actually go back and do the full next gen sequencing to make sure that we're not going to act on that core prognostic feature when it really is in the setting of that more simplistic or that more positive prognostic place. So, this is great, we already kind of highlighted a little bit PORTEC-1 and 2, but if you don't mind, I would love to get the audience a little bit more information just maybe about the populations that were included as we were figuring out how aggressive to be with radiation just to remind people of that, or to teach them that if they haven't gotten a chance to look at those studies. Carien Creutzberg: Yeah, that's important to know because PORTEC-1 was still in the era that we also treated intermediate risk stage 1 endometrial cancer patients. So, deep invasion with grade 1 and 2 or superficial invasion with grade 2 and 3. That's what we defined at that point. Then we compared external beam radiation or no further treatment, showing no survival difference, but a higher risk of recurrence with higher risk being older age over 60, grade 3 for deep myometrial invasion. And we kept those high intermediate risk factors as also similarly found by GOG-99 at the time to do PORTEC-2. So, at the time, about 50% of patients did not have an indication for adjuvant therapy anymore, and with a high intermediate risk population for PORTEC-2, we compare external beam or vaginal brachytherapy and found the benefit of vaginal brachytherapy. A simple outpatient treatment, very short with almost no side effects ensuring local control. And nowadays, using the molecular classification of PORTEC-4a, we've compared achieving treatment with or without use of the molecular factors to designated treatment. So, the standard arm is vaginal brachytherapy and investigational arm is first, a molecular risk profile. And then we give no radiotherapy for those with a favorable profile, then a brachytherapy for the intermediate ones, and for the small group is either extensive LVSI or TP53 mutation or L1 chem overexpression external beam. And we hope to show that less overtreatment and less undertreatment will benefit these patients. Shannon Westin: Yeah, I'm very much looking forward to the results of PORTEC-4a. But let's circle back and talk a little bit about your amazing work here. So, how did you leverage those patient populations from PORTEC-1 and 2 for the current study? Nanda Horeweg: Yes. Well, the PORTEC-1 and 2 study provided a unique opportunity to look into differential treatment effects for radiotherapy. And that is because these are randomized trials, so the groups are comparable, and we have long-term follow-up data that's of very high-quality. In addition, as Carien said earlier, she had the vision already back in the nineties to directly ask the patients permission for the collection of the tissue. So, we have a broader complete biobank for both of these trials, which is quite unique. And our colleagues, Professor Smit and also Charlene Goseff from the pathology department, they have done extensive work on molecular classification, and have molecularly characterized all these cases. So, this allowed us to include 880 patients in this study, which is the largest so far. And besides like the very good starting point that we have of PORTEC-1 and 2 is that we also chose a design that was optimized to conduct like real causes, the causal effects of the molecular class on radiotherapy response. So, we tried to preserve this randomization effect, the exchangeability of the groups as much by working with the intention to treat population and not excluding any patients, except for when they did not have the molecular classification assessed. And also, we looked at areas in the body that were irradiated in one group and not in the other one to really observe the effect of radiotherapy as much as possible. So, looking to the entire pelvis, so local and regional recurrences in PORTEC-1 and looking at pelvic recurrences in PORTEC-2. Shannon Westin So, how were the intervention outcomes in this study different based on the TCGA classifiers? Nanda Horeweg: Before I tell you the results of biomolecular group, I think it's good to have the starting point of the analysis here. So, the no hypothesis of my study was to see whether there was any difference, and no hypothesis is that there's no difference. So, if we find a significant effect, then we can actually say that we found something. And if we start with the POLE group, we did not find any significant difference between the groups allocated to radiotherapy or not. But we did see not a single recurrence in any of the patients that we included from both of these trials. So, technically speaking, we did not find a predictive effect of the molecular classifier, but a prognostic effect. There's no one's having recurrence, so we can deduct from that, that radiotherapy is probably over treatment. Then for the MMRd group, we did observe some recurrences, but these were not significantly different between these three groups. So, based on this study, we cannot draw conclusions on which type of radiotherapy we should give to the patients or whether we should give radiotherapy at all. This was very different for the p53 group. There, the patients had lots of recurrences, unfortunately, as we expected, but we saw a big difference in outcome compared between no radiotherapy at all if it's vaginal brachytherapy where we still had lots of recurrences, and EBRT where we hardly saw any recurrences in the pelvis. And that difference was significantly different. So, that's an indication that these patients need more than just vaginal brachytherapy, even though it's only stage 1 endometrioid endometrial cancer. And then in the last group, the NSMPs, we saw even a different pattern where patients who had had external beam radiotherapy or vaginal brachytherapy, both had an excellent local regional control, and the ones that did not receive any treatments had more recurrences. And this was also very significant. So, there, you would conclude that both therapies are appropriate, but of course, the toxicity profile for vaginal brachytherapy is much more favorable than that of EBRT. Shannon Westin: We really are getting kind of consistent data around p53 needing more treatment. And I think the natural question that comes here, for me at least, and I know we can't answer it with the work, is would chemo be — would that be that extra treatment, when we saw with PORTEC-3 that the group needed the chemotherapy the most. So, I think we'll have to continue to work through that and determine is any more treatment what we need or specific treatments really the best. So, this is so intriguing and it's nice that it's consistent, that we're seeing that across these different studies that really kind of lends strength and validity, I think to what we're finding. So, one of the actions that we're kind of moving towards and that you advocate certainly in your paper is omitting therapy for patients with POLE mutations. Are there any ongoing studies around that that will help us confirm that this is safe for our patients? Nanda Horeweg: Yeah, that's a very good point. I think the evidence is strong enough now to conduct prospective trials. And of course, these are ongoing, the PORTEC-4a trial was already briefly mentioned there. The patients with poor mutations will be randomized between observation and vaginal brachytherapy. So, that will give us a good indication whether in this high intermediate risk early-stage group omission is safe. And in addition to that, we are also conducting with the RAINBO Consortium, the RAINBO-BLUE trial, wherein patients also with high-risk features, so non-endometrioid isotypes, LVSI and higher stages are included. And also in those patients, we investigate whether the de-escalation of treatment is safe. So, we're definitely looking forward to those results to be able to transfer this knowledge to clinical practice later on. Carien Creutzberg: And maybe it's nice to add that RAINBO BLUE is connected to the Canadian Taper trial. Taper being a general de-escalation trial where the POLE patients in that trial are also feeding into the RAINBO-BLUE. And I know that in North America, many centers will participate in the Taper trial. Shannon Westin: Yes, I think everyone is very excited and I think it'll be nice to have these two very strong studies that will help us really confirm that that is 100% a test that needs to be done, cost are not — and that will help avoid overtreatment of patients. So, in line of that, have you all experienced any challenges with implementing molecular testing across patients with endometrial cancer? Any thoughts on how we could potentially simplify? You talked about the rational promise algorithm, which I think is excellent, but I'm just curious to hear your thoughts on this. Nanda Horeweg: The implementation of the molecular classification can be challenging. We have to be honest about that. And usually, it's the assessment of the POLE status that's causing the problems because that's usually done with NGS, which is quite expensive. It requires a lot of knowledge in the laboratory and it's also a bit time-consuming. So, that is the bottleneck for most laboratories and for most settings. But this is already changing in a couple of places, like in the UK and the Netherlands, it's being reimbursed by healthcare insurances, and also, in many tertiary care centers in other countries, they're already systematically performing this test. But of course, there will always be places where this is not feasible. And luckily, there are also cheaper alternatives coming up and are already available at the moment. So, one of them is, for example, standard sequencing, which is not so expensive, but a bit labor intensive. Some colleagues we work with from India have implemented that in their clinical practice and are perfectly able to molecularly classify the endometrial cancers in daily practice. Another alternative is a test that we've developed in Leiden that's called the QPOLE test, which is based on qPCR, so that's a technology which we use for our COVID test around the world, so that can be done almost anywhere. And with that, you have a very high accuracy to detect unknown pathogenic variants. And this is also published in JCO Global Oncology, and can be implemented in any center after a local validation step. And even like more companies nowadays are realizing that this is important. So, I think commercial tests are already becoming available and very more on the market soon. So, I am really hoping that it'll be more available to endometrial cancer patients. Carien Creutzberg: And they'll offer them at a very low cost and also a rapid turnaround because NGS can take like 10 days. But realizing on a more national level, if you have found one patient with a POLE mutation, the omission of cycles of chemotherapy with all of the patient care around in the hospital is worth much more than just a few POLE tests. So, we have to look at this and that's I think why our healthcare reimbursement came through that if you look at a population level, it is cheaper, and we'll do an extensive cost analysis in PORTEC-4 just to show this. Shannon Westin: That is such a good point. I love that and all of the downstream issues that happen potentially with radiotherapy or with chemotherapy, that's really brilliant. And I'm going to take that back, I love these podcasts. I always learn stuff that I immediately start to use. So, I guess then the last question is, what's next for this particular research and how might we validate what you found? Nanda Horeweg: Yes. Well, as mentioned earlier, for POLE, we have already put the next step in place. So, PORTEC-4a has completed accrual almost two years ago, and we're very much looking forward to do the final analysis within one to one and a half years. So, that will be one of the important next step. And of course, the POLE-BLUE trial is open at the moment, and within a couple of years, we also hope to learn more about this group. So, that's very exciting. Then for the mismatch repair deficient group, while we did not find any particular sensitivity for radiotherapy, and I also don't think that we will conduct another large randomized radiotherapy trial in this group — I think the results that we've observed in the metastasized setting, were really impressive results with immunotherapy are the way forward for this molecular class. And I think the next thing we should do now is prove whether this works or not in the adjuvant setting. And if that's starting with the high-risk patients, which is something we are currently doing in the MMRd-GREEN trial, which is ongoing in the Netherlands, and soon, will open internationally. And from there on, we can work forward if we see that also in this setting the immunotherapy works well. Shannon Westin: And I think GY020 also — NCI trial is also looking at the addition of immunotherapy to radiotherapy in that irony at risk. Carien Creutzberg: Absolutely. Nanda Horeweg: Yeah. And the KEYNOTE-B21 as well — oh, well, already complete accrue. Shannon Westin: The B21, yeah. So, I think those are good. Yeah, that's a really good point for that MMRd group that the immunotherapy really is the way to go, and then more work to be done with the no specific molecular profile. Nanda Horeweg: The NSMP, I think like for the early-stage group, it's quite clear that vaginal brachytherapy is a therapy of choice. But you can of course, try to identify those at such a low risk that you could deescalate treatment. And that's of course what's being done in the Taper trial and also in part, investigated in the PORTEC-4a trial. Carien Creutzberg: And those with higher risk NSMP that we are revisiting hormonal treatments because 90% are estrogen receptor positive, and they have a clearly better prognosis than those with estrogen receptor negative tumors. So, those with estrogen receptor positive tumors can in RAINBO-ORANGE, which will be run led by the UK group, see if we can improve quality of life with less intensive adjuvant treatment. And then you came to the p53 group, that's a good one to stop with. Nanda Horeweg: Yeah, we have very good indications that radiotherapy and chemotherapy is working well for this group. And this is also in line with the guidelines that have been issued in the last few years by many societies. So, I don't think we should change this base of the treatment consisting of radiotherapy and chemotherapy. But since the prognosis is still rather poor, we need to add systemic agents to reduce the risk of metastasis. And preferably, this should be like well-designed based on a proper biological underpinning, plus something that's not too toxic since we're combining the three therapies together. So, this is what we try to do in the RAINBO-RED trial where we will investigate the addition of a PARP inhibitor to chemoradiation in the p53 group. Shannon Westin: Oh, I love that. That's been my whole career, is adding PARP inhibitors wherever I can. Carien Creutzberg): We might also want to mention the HER2 inhibitors, which are also in about 20% of the p53 group has HER2 overexpression. And there is a trial being set up in NCI with trastuzumab and pertuzumab. Shannon Westin: My only concern with that one is I think that the antibody drug conjugates are so much more powerful, the TDX data that we just saw from DESTINY is so impressive. And so, I do wonder, like if we need to move on from kind of some of the older HER2, and get with the program and use some of these more powerful drugs. But with that, I just want to thank Dr. Creutzberg and Horeweg. This was such a great discussion, and obviously, near and dear to my heart talking about endometrial cancer, but I hope our audience enjoyed as well. Just as a reminder, this was a discussion on molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early stage endometroid endometrial cancer, published in the JCO on 9.20.23. I am your host, Shannon Westin, and I hope you'll check out more JCO After Hours wherever you get your podcasts. Have an awesome day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

We all know that sleep is important, but sometimes we just don’t get enough. We also know the normal side effects from lack of sleep, but are there other, metabolic, and neuronendocrine effects from short sleep that we don’t know about. Host Aaron Lohr talks about this with Iris CM Pelsma, an academic researcher at Leiden University Medical Center in the Netherlands. She and her colleagues presented a study earlier this year, at ENDO 2023, titled, “Metabolic and Neuroendocrine Adaptability Following One Night of Partial Sleep Restriction in Dutch Males.” Show notes are available at https://www.endocrine.org/podcast/enp80-metabolic-and-neuroendocrine-effects-of-short-sleep — for helpful links or to hear more podcast episodes, visit https://www.endocrine.org/podcast

We all know that sleep is important, but sometimes we just don’t get enough. We also know the normal side effects from lack of sleep, but are there other, metabolic, and neuronendocrine effects from short sleep that we don’t know about. Host Aaron Lohr talks about this with Iris CM Pelsma, an academic researcher at Leiden University Medical Center in the Netherlands. She and her colleagues presented a study earlier this year, at ENDO 2023, titled, “Metabolic and Neuroendocrine Adaptability Following One Night of Partial Sleep Restriction in Dutch Males.” Show notes are available at https://www.endocrine.org/podcast/enp80-metabolic-and-neuroendocrine-effects-of-short-sleep — for helpful links or to hear more podcast episodes, visit https://www.endocrine.org/podcast

We all know that sleep is important, but sometimes we just don’t get enough. We also know the normal side effects from lack of sleep, but are there other, metabolic, and neuronendocrine effects from short sleep that we don’t know about. Host Aaron Lohr talks about this with Iris CM Pelsma, an academic researcher at Leiden University Medical Center in the Netherlands. She and her colleagues presented a study earlier this year, at ENDO 2023, titled, “Metabolic and Neuroendocrine Adaptability Following One Night of Partial Sleep Restriction in Dutch Males.” Show notes are available at https://www.endocrine.org/podcast/enp80-metabolic-and-neuroendocrine-effects-of-short-sleep — for helpful links or to hear more podcast episodes, visit https://www.endocrine.org/podcast

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Carien Creutzberg, Nanda Horeweg, and Alexandra Leary to discuss the RAINBO trials. Carien Creutzberg is Professor of Radiation Oncology at Leiden University Medical Center, the Netherlands. She specializes in research and treatment of gynecological cancers and has been the initiator and principal investigator of the four PORTEC trials and the TransPORTEC consortium. She is current chair of the GCIG Endometrial Cancer Committee and past Council member of ESGO and IGCS. Nanda Horeweg is senior researcher at the department of Radiation Oncology of Leiden University Medical Center, the Netherlands. She is one of the principal investigators of the PORTEC team and the international coordinator of the RAINBO program of clinical trials. Alexandra Leary, MD, PhD, is a medical oncologist specializing in gynecological cancers at Gustave Roussy Cancer Center in France. She is the CI for the RAINBO-RED trial and member of the TransPORTEC Consortium. She is current chair of the GCIG Phase II committee, gyne track chair for ESMO Asia, and past gyne track chair for ESMO.    Highlights: - The RAINBO program includes 4 international clinical trials of molecular class-directed novel adjuvant targeted treatment strategies for women with high-risk endometrial cancer. - Women with completely resected invasive stage IA-III endometrial cancer may participate in the RAINBO trial that matches with the molecular class of their tumor. - RAINBO aims to either increase cure rates through the addition of novel targeted therapies or safely reduce toxicity and improve quality of life through treatment de-escalation. - Uniform data collection and central biobanking will enable overarching and translational RAINBO research projects.

 Chronic pain is difficult to treat and affects the individual's quality of life, often leading to severe disability.  Ketamine was initially used in anaesthesia, but since the 1990s it has also been used in a much lower dose as a treatment for acute and chronic pain. and also works as an antidepressant Professor Albert Dahan and  colleagues at the Leiden University Medical Center  managed to unlock some of ketamine's previously unknown mechanisms of action against pain, its psychedelic effects,  and also new actions on the heart and breathing mechanism. Read the original research: https://doi.org/10.1097/ALN.0000000000004176Read more in Research Outreach

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Carien Creutzberg, Nanda Horeweg, and Alexandra Leary to discuss the RAINBO trials. Carien Creutzberg is Professor of Radiation Oncology at Leiden University Medical Center, the Netherlands. She specializes in research and treatment of gynecological cancers and has been the initiator and principal investigator of the four PORTEC trials and the TransPORTEC consortium. She is current chair of the GCIG Endometrial Cancer Committee and past Council member of ESGO and IGCS. Nanda Horeweg is senior researcher at the department of Radiation Oncology of Leiden University Medical Center, the Netherlands. She is one of the principal investigators of the PORTEC team and the international coordinator of the RAINBO program of clinical trials. Alexandra Leary, MD, PhD, is a medical oncologist specializing in gynecological cancers at Gustave Roussy Cancer Center in France. She is the CI for the RAINBO-RED trial and member of the TransPORTEC Consortium. She is current chair of the GCIG Phase II committee, gyne track chair for ESMO Asia, and past gyne track chair for ESMO.

Dr. Paul-Peter Tak, M.D., Ph.D., FMedSci ( https://www.candeltx.com/our-team/paul-peter-tak-m-d-ph-d-fmedsci/ ), is President, Chief Executive Officer and member of the Board of Directors of Candel Therapeutics, a biotech company developing and commercializing novel viral immunotherapies to induce immunogenic cell death in cancer cells at the site of injection, with a focus on unmasking tumor neo-antigens within an activated microenvironment, leading to a systemic, durable immune response against the tumor, with the potential to change disease outcomes across a variety of indications. Dr. Tak received his medical degree cum laude from the Free University in Amsterdam and was trained as an internist, rheumatologist and immunologist at Leiden University Medical Center, where he also received his Ph.D. Dr. Tak has been Clinical Associate Professor of Medicine at the University of California San Diego as well as Professor of Medicine and founding Chair of the Department of Clinical Immunology and Rheumatology at the Academic Medical Center/University Medical Center Amsterdam, during this time, where he founded Arthrogen b.v., a biotech company focused on gene therapy. Dr. Tak has published over 580 papers in peer-reviewed journals, received numerous awards, and been elected Fellow of the Academy of Medical Sciences (U.K.). Dr. Tak previously served as Senior Vice President, Chief Immunology Officer, and Global Development Leader at GlaxoSmithKline from 2011 to 2018 where he oversaw a cluster of Therapy Area Units including Dermatology, Immuno-Inflammation, Infectious Disease, and Oncology, where he oversaw the creation of a portfolio of new medicines. He was also the President and CEO of Tempero Pharmaceuticals, which was integrated into GSK in 2015. From 2018 to 2020, Dr. Tak served as venture partner at Flagship Pioneering and also as President and CEO of Kintai Therapeutics (Senda Biosciences). In addition, he has served as board director of Galvani Bioelectronics, ViiV Healthcare, and Omega Therapeutics. Currently, he is also on the Board of Sitryx Therapeutics (co-founder), Levicept, and Citryll. He is a 2021 PharmaVOICE100 honoree (100 most inspiring people in life sciences). Dr. Tak has also been a member of the Scientific Advisory Boards of Index Life VI and Medicxi Ventures funds. Support the show

Frederick Delfin leads one of two human population-based genomics projects under the Filipino Genomes Research Program (FGRP) at the DNA Analysis Laboratory of the UP Natural Sciences Research Institute (UP-NSRI). His research focuses on human population genetics, evolutionary genetics and molecular anthropology. He has a bachelor's degree in Biology from the University of the Philippines Baguio, and a Master's degree from the Molecular Biology and Biotechnology Program (now the National Institute of Molecular Biology and Biotechnology) of UP Diliman. His doctoral fellowship training was through the International Max Planck Research School for Human Origins at the Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany and through the Leiden University Medical Center, the Netherlands. We talked about why genomics is an important field of study, the DNA of the Filipino, the benefits we enjoy from studying genetics, the process of conducting human genomics research, why some people reject scientific ideas despite the existence of evidence, and more. How to contact Frederick: Email: fcdelfin@up.edu.ph Facebook (UP-NSRI DNA Analysis Laboratory): fb.com/DNAForensicAndEthnicity The Filipino Genomes Research Program (FGRP) is searching for partner-volunteers for the National Capital Region and other Filipino groups from different regional population centers. Interested individuals may refer to photos on the DAL FB page (fb.com/DNAForensicAndEthnicity) for more details.

Autoantibodies against post-translationally modified proteins (PTM) are described in various rheumatic diseases and facilitate diagnosis and patient stratification. Researchers from the Leiden University Medical Center analysed the presence of autoantibodies against six different post-translational modifications in a cohort of patients with neuropsychiatric lupus. In this podcast, Leendert Trouw, Rory Monahan and Michelle van den Beukel discuss the results of their study with the ARD/RMDopen social media advisor Caroline Ospelt. Read the Open Access related paper: https://rmdopen.bmj.com/content/8/1/e002079 Listen to more episodes of RMD Open: https://podcasts.apple.com/gb/podcast/rmd-open-rheumatic-and-musculoskeletal-diseases/id1237127864

In this edition we discuss a large scale study on aortic aneurysm in The Netherlands called ‘the RADAR study', to bring aortic aneurysm on the Radar of researchers and clinicians. The goal of the RADAR study is to predict development of an aortic aneurysm in the course of life, to predict growth of an existing aneuryms and to predict aortic dissection or rupture to support timely intervention. In this episode I have two special guests. PhD-student Joe Juffermans and associate professor Jos Westenberg from the Leiden University Medical Center, The Netherlands. --- Send in a voice message: https://anchor.fm/radiologica/message

Blog summary of a trending research paper published in Volume 14, Issue 18, entitled, "The association between continuous ambulatory heart rate, heart rate variability, and 24-h rhythms of heart rate with familial longevity and aging." ______________________________________ A normal resting heart rate (HR) for adults should be anywhere between 60 and 100 beats per minute. A low resting heart rate has been associated with better overall health and fitness. Crosswise, a higher resting heart rate appears to have a strong correlation with mortality. Heart rate variability (HRV), the beat-to-beat changes in heart rate, is indicative of the heart's ability to respond to changes in physical and emotional stress. Low HRV has been shown to be a risk factor for heart disease, while high HRV has been associated with good heart health. Although HR and HRV are frequently studied, these parameters are not often investigated continuously or over long periods of time in healthy, middle-aged individuals. “Parameters of HR and HRV are often investigated during a short electrocardiogram (ECG) measurement at the study center or in the hospital, but not continuously over a longer period while individuals continue with their daily lives.” In a new study, researchers Janneke M. Wiersema, Annelies E.P. Kamphuis, Jos H.T. Rohling, Laura Kervezee, Abimbola A. Akintola, Steffy W. Jansen, P. Eline Slagboom, Diana van Heemst, and Evie van der Spoel from Leiden University Medical Center and Catharina Hospital used continuous ambulatory ECG measurements collected over a period of 24 to 90 hours to investigate the relationship between heart rate parameters and familial longevity and chronological age. On August 16, 2022, their research paper was published in Aging's Volume 14, Issue 18, and entitled, “The association between continuous ambulatory heart rate, heart rate variability, and 24-h rhythms of heart rate with familial longevity and aging.” Full blog - https://aging-us.org/2022/10/does-a-link-exist-between-longevity-aging-and-heart-rate-parameters/ DOI - https://doi.org/10.18632/aging.204219 Corresponding author - Evie van der Spoel - e.van_der_spoel@lumc.nl Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204219 Keywords - aging, longevity, continuous ambulatory measurements, heart rate, heart rate variability 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/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

In today's Brain Talk, we'll be looking at the role technology currently plays in neurosurgery. We are joined by Dr Pieter Kubben, a neurosurgeon at Maastricht University Medical Center and the founder of the Neuromind App and Dr. Marike Broekman, a neurosurgeon in the Department of Neurosurgery at Leiden University Medical Center. She is the first female board member of the European Association of Neurosurgical Associations or EANS, and her main clinical and research interests focus on Neuro-Oncology and Ethics.

Listen to a blog summary of an editorial published in Volume 14, Issue 14 of Aging (Aging-US), entitled, "Restoring rhythm to prevent age-related fractures.” ________________________________ The circadian rhythm is a daily cycle (24 hours) of biological activity that is driven by an internal biological clock. A regular circadian rhythm is important for maintaining numerous facets of human life. Aging-related changes to this delicate rhythm have demonstrated negative consequences in many aspects of health, including bone health. “Among the many risk factors for osteoporosis, a new kid on the block is disruption of the biological clock.” On July 19, 2022, an editorial paper was published in Aging‘s Volume 14, Issue 14, entitled, “Restoring rhythm to prevent age-related fractures.” In this editorial, Annelies E. Smit, Maaike Schilperoort and Elizabeth M. Winter from Leiden University Medical Center discuss the treatment of osteoporosis by way of restoring the circadian rhythm. The researchers review the use of both medical and lifestyle interventions that aim to restore the circadian rhythm to minimize the risk of aging-related osteoporotic fractures. Full blog - https://aging-us.org/2022/08/osteoporosis-linked-to-age-related-changes-in-circadian-rhythm/ DOI - https://doi.org/10.18632/aging.204192 (PDF Download) Corresponding author - Elizabeth M. Winter - e.m.winter@lumc.nl Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204192 Keywords - aging, circadian rhythm, fractures, osteoporosis, glucocorticoids, chronotherapy 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/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Models are important tools: they resemble, they mimic, they imitate something to a greater or lesser extent. How similar models are to the 'real thing' is usually a challenging  issue. And it's a big issue with stem-cell derived models of the human embryo.These embryo models, models of the embryo's 8-cell stage, of the blastocyst or of the gastrula are emerging and they are ones that labs can use to characterize the molecular and physiologic events that take place during early embryogenesis. My story in Nature Methods about some of these embryo models is here. For this story, I spoke with Christine Mummery, a researcher in the anatomy and embryology department at Leiden University Medical Center. In this podcast, she talks about models of the blastocyst and the gastrula, about the updated International Society for Stem Cell Research (ISSCR) guidelines, and shares some thoughts about about what is involved when assessing a model. "If I'm claiming this is a liver cell, what does it have to show? And this is a tricky, tricky thing," says Christine Mummery. 

Join A Cure in Sight on The Eye Believe Podcast and various research experts and clinicians who attended American Society of Clinical Oncology (ASCO) Conference early June 4-6, 2022, as well as the 20th Congress of the International Society of Ocular Oncology (ISOO), June 17-21, 2022. A Cure in Sight attended both to gather updates in research and present a united, collaborative front for the sake of patient advocacy in the field of ocular melanoma. In this episode, you'll hear from the experts about what's new in ocular melanoma and uveal melanoma. You'll also hear news of new clinical trials, and upcoming expanded access programs for treatments for metastatic uveal melanoma. Tune in for updates from: Jerry Wu with Ascentage Pharma, focused on an abstract from Dr. Meredith McKean of the Sarah Cannon Cancer Center in Nashville discussing a novel cancer treatment for uveal melanoma called APG-115. Search “APG-115 melanoma” on ascentage.com, or listed on clinicaltrials.gov. Dr. Johnny John from Delcath discusses the presentation of data from the FOCUS Trial at ASCO and the opening of Delcath's Expanded Access Program for patients with Metastatic Ocular Melanoma. Information on EAP sites may be found on  https://delcath.com/clinical-trials/expanded-access-program/ Karin Hellsvik with Foghorn Therapeutics, discussing uveal melanoma patient advocacy, as well as the existing study for uveal melanoma patients, found by searching FHD-286 on clinicaltrials.gov.   Dr. Justin Moser with HonorHealth Research and Innovation Institute in Scottsdale AZ, discussing a new West Coast clinical trial for metastatic uveal melanoma patients. Info on this trial can be found here: https://clinicaltrials.gov/ct2/show/NCT05004025 Danet Peterson, sharing about her personal ocular melanoma journey in a brief ASCO interview with i3Health.   Dr. Cadmus Rich with Aura Biosciences discussing the AU-011 (belzupacap serotalocan) program, including an upcoming pivotal study for primary choroidal melanoma treatment. Search AU-011 on clinicaltrials.gov for more info. Dr. Johnny John from Delcath along with Dr. Ellen Kapiteijn and Dr. Thaïs Tong from the Leiden University Medical Center discusses the presentation of data from the Chopin Trial in which Delcath's percutaneous hepatic perfusion treatment is combined with immunotherapy for patients with Metastatic Ocular Melanoma. Preliminary data from the trial was presented at the ASCO conference and was also presented at the ISOO conference.   Steven Katz, Chief Medical Officer at TriSalus Life Sciences discussing early safety data from the PERIO-01 clinical study. See www.periotrial.com for more info. ANNOUNCEMENTS: Lookin' For a Cure Arizona 5K Walk for Ocular Melanoma  COMING UP September 24, 8 AM  Register here and be sure to bring friends and family to walk with us! (Virtual option coming soon) Eye Believe Survivorship Seminar in Nashville, Tennessee October 14-15. REGISTER HERE! (Welcome reception for in person attendees on October 13, 6:00 PM) (Virtual and in person options.) Lookin' For a Cure TEXAS 5K Walk for Ocular Melanoma  NOVEMBER 5, 2022; 8 AM  Register here and be sure to bring friends and family to walk with us! (Virtual option available) Email contact@acureinsight.org for questions regarding the event! ********* Be sure to follow us on Facebook, Twitter, Linked In, or  Instagram @acureinsight, for more stories, tips, research news, and ideas to help you navigate this journey with OM! *A Cure in Sight is a 501c3 organization. All donations made can help fund our podcast to educate patients, fund research, aid patients, and more! Donate $10 $15 $20 today to help A Cure in Sight in their quest to find a cure. Contribute via  PAYPAL OR VENMO or reach out directly to contact@acureinsight.org  The Eye Believe Podcast is brought to you by Castle Biosciences. Castle Biosciences is a leading diagnostics company improving health through innovative tests that guide patient care. The Company aims to transform disease management by keeping people first: patients, clinicians, employees and investors.  This podcast was hosted by Danet Peterson and produced by Agora Media.

Welcome to this episode of Physician's Weekly podcast. I am your host, Dr. Rachel Giles, from Medicom Medical Publishers in collaboration with Physicians Weekly. Today we have 2 very interesting and timely interviews to share with you. Later in this podcast, Physician's Weekly's Senior Editor Julia Ernst interviews Dr. Karla O'Dell, from the University of Southern California, about tracheostomy procedures, in particular how you can do open bedside tracheostomies at a low cost without extra risks in safety outcomes. This is of course particularly relevant for this COVID-19 pandemic, and she also reflects on what she thinks those long-term implications will be.But first, we speak with Professor Frank Staal, from the Dept of Immunology at the Leiden University Medical Center, the Netherlands, who was in the news this week because he co-led a team who treated the first baby with severe congenital immune deficiency (SCID) with gene therapy in the Netherlands, and the first time gene therapy has been used to treat this particular form of SCID worldwide. Have you ever heard of the 1976 movie “The Boy in the Plastic Bubble”? That was based on the story of David Vetter, who was born with SCID and lived in a plastic sterile bubble because he had essentially no immune system. New gene therapy techniques are offering alternatives to bone marrow transplants. The treatment in the news this week was effective and the baby is well with a competent immune system. Enjoy listening!Further readingTang L, West J, Lee E, Kharidia K, Hasday S, Chambers T, Kokot N, Swanson M, O'Dell K. Open Bedside Tracheostomy: Safe and Cost Saving but Underutilized Nationally. Otolaryngol Head Neck Surg. 2022 Apr 5:1945998221091905. doi: 10.1177/01945998221091905. Epub ahead of print. PMID: 35380905.Zheng M, Arora N, Chambers T, O'Dell K, Johns MM. Comparison of Treatment for Recurrent Respiratory Papillomatosis at a Public County Versus Private Academic Hospital. J Voice. 2022 Feb 20:S0892-1997(22)00018-2. doi: 10.1016/j.jvoice.2022.01.019. Epub ahead of print. PMID: 35197218.Klaver-Flores S, Zittersteijn HA, Canté-Barrett K, Lankester A, Hoeben RC, Gonçalves MAFV, Pike-Overzet K, Staal FJT. Genomic Engineering in Human Hematopoietic Stem Cells: Hype or Hope? Front Genome Ed. 2021 Jan 22;2:615619. doi: 10.3389/fgeed.2020.615619. PMID: 34713237; PMCID: PMC8525357.

Erik van Zwet (@erikvanzwet) is an Associate Professor in the Department of Biomedical Data Sciences of the Leiden University Medical Center where he has been since 2009. He joined the school wanting to do more applied work in the areas of statistics and data analysis and has since published a paper in Significance Magazine which was the focus of our previous episode.

A randomized controlled trial is viewed as the golden standard in medical research, particularly as it relates to treatments or interventions. But there may be pitfalls to trusting that approach too much. That's the focus of this episode of Stats and Stories with guest Erik van Zwet. -Timestamps- What is a RCT? (1:15), What are characteristic of a well designed trial? (2:00), How did you get interested in this research?(3:45), Data you obtained from Cochrane Database? 5:18), Power and how you got results (7:05), How does affect the laymen (9:49), Coverage of RCTs (12:00), Trends of exaggeration (14:17), What goes into exaggeration? (16:54), What needs to be done? (18:56), Across other fields (21:58) Erik van Zwet (@erikvanzwet) is an Associate Professor in the Department of Biomedical Data Sciences of the Leiden University Medical Center where he has been since 2009. He joined the school wanting to do more applied work in the areas of statistics and data analysis and has since published multiple papers in Significance Magazine including the main focus of today's episode, “Addressing exaggeration of effects from single RCTs”.

This series of two podcasts leads you on a journey through the main clinical and therapeutical aspects of Cutaneous T Cell Lymphomas (CTCLs), a heterogeneous group of lymphoid neoplasms characterized by primary cutaneous localization. Albeit rare, CTCLs have peculiar clinical characteristics, requiring a multidisciplinary approach and a strict collaboration between different specialists, allowing for a timely and precise diagnosis, critical for the good outcome of these patients. Join dermatologist Prof Maarten Vermeer (Dept. of Dermatology, Leiden University Medical Center) and hematologist Dr Erik Marijt (Head of the Central Laboratory of Clinical Hematology and the Interdivisional Flowcytometry Core Facility, Leiden University Medical Center) as they exchange their views and expertise on the diagnosis and management of patients with CTCLs. In this first episode, listen to Prof Vermeer and Dr Marijt illustrating the dermatologic and hematologic approaches to the diagnosis and staging of CTCLs, including the different clinical presentation and prognosis of the most common types of CTCLs. Hosts: Prof Maarten Vermeer; Dr Erik Marijt What did you think of this podcast? Share your opinions with us in this short feedback survey. https://forms.monday.com/forms/d02e52896815eef59ecae09fb74dd78f?r=use1 (Provide Feedback) Would you like to explore more eLearning or podcasts? Please visit the EHA Campus. https://ehacampus.ehaweb.org/ (https://ehaedu.org/Campus) Subscribe, share, and review this podcast to be able to address topics you enjoy and like to listen to. Follow EHA on Instagram: https://www.instagram.com/EHA_Hematology/?utm_medium=podcast&utm_source=bcast&utm_campaign=eha-unplugged (https://www.instagram.com/EHA_Hematology/) Facebook: https://e-h-a.link/facebook?utm_medium=podcast&utm_source=bcast&utm_campaign=eha-unplugged (https://e-h-a.link/facebook) LinkedIn: https://www.linkedin.com/company/eha/?utm_medium=podcast&utm_source=bcast&utm_campaign=eha-unplugged (https://www.linkedin.com/company/eha/) Email us: education@ehaweb.org Subscribe to receive the EHA Educational Updates via https://eha.news/subscribe?utm_medium=podcast&utm_source=bcast&utm_campaign=eha-unplugged (https://eha.news/subscribe) 

This series of two podcasts leads you on a journey through the main clinical and therapeutical aspects of Cutaneous T Cell Lymphomas (CTCLs), a heterogeneous group of lymphoid neoplasms characterized by primary cutaneous localization. Albeit rare, CTCLs have peculiar clinical characteristics, requiring a multidisciplinary approach and a strict collaboration between different specialists, allowing for a timely and precise diagnosis, critical for the good outcome of these patients. Join dermatologist Prof Maarten Vermeer (Dept. of Dermatology, Leiden University Medical Center) and hematologist Dr Erik Marijt (Head of the Central Laboratory of Clinical Hematology and the Interdivisional Flowcytometry Core Facility, Leiden University Medical Center) as they exchange their views and expertise on the diagnosis and management of patients with CTCLs. In this second episode, listen to Prof Vermeer and Dr Marijt discussing how CTCL patients with localized and diffuse disease can be effectively treated, and how new targeted agents and allogeneic transplantation can be integrated into the management algorithm. Hosts: Prof Maarten Vermeer; Dr Erik Marijt What did you think of this podcast? Share your opinions with us in this short feedback survey. https://forms.monday.com/forms/d02e52896815eef59ecae09fb74dd78f?r=use1 (Provide Feedback) Would you like to explore more eLearning or podcasts? Please visit the EHA Campus. https://ehacampus.ehaweb.org/ (https://ehaedu.org/Campus) Subscribe, share, and review this podcast to be able to address topics you enjoy and like to listen to. Follow EHA on Instagram: https://www.instagram.com/EHA_Hematology/?utm_medium=podcast&utm_source=bcast&utm_campaign=eha-unplugged (https://www.instagram.com/EHA_Hematology/) Facebook: https://e-h-a.link/facebook?utm_medium=podcast&utm_source=bcast&utm_campaign=eha-unplugged (https://e-h-a.link/facebook) LinkedIn: https://www.linkedin.com/company/eha/?utm_medium=podcast&utm_source=bcast&utm_campaign=eha-unplugged (https://www.linkedin.com/company/eha/) Email us: education@ehaweb.org Subscribe to receive the EHA Educational Updates via https://eha.news/subscribe?utm_medium=podcast&utm_source=bcast&utm_campaign=eha-unplugged (https://eha.news/subscribe) 

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. David Gaffney, Dr. Carien Creutzberg, and Dr. Anuja Jhingran to discuss this month's special issue on radiation oncology. Dr. Gaffney, MD, PhD, Senior Director of Clinical Research, is Professor and Vice-Chair of the University of Utah (U of U) Department of Radiation Oncology. Dr. Gaffney is a distinguished clinician and a long-standing leader in clinical research, and he is also a past president of the American Brachytherapy Society. Dr. Carien Creutzberg is Professor of Radiation Oncology at Leiden University Medical Center, the Netherlands. She specializes in research and treatment of gynecological cancers and has been initiator and principal investigator of the four PORTEC trials and the TransPORTEC consortium. She is current chair of the GCIG Endometrial Cancer Committee and past Council member of ESGO and IGCS. Dr. Anuja Jhingran is a Professor of Radiation Oncology in the Section of Gynecology at The University of Texas MD Anderson Cancer Center. She is the present treasure/secretary for IGCS. She is highly active in GCSC, GCIC, ASCO, and SGO. Her passion is to improve treatment for all women with gynecological cancer throughout the world and she does this through mentoring physicians in underserved regions throughout world. Highlights: Stereotactic body radiation therapy (SBRT) is useful in gynecological cancers. Brachytherapy improves survival in cervix cancer. Image guidance in radiation oncology decreases morbidity. Patients with small volume disease and long disease-free interval may be good candidates for SBRT. Immunotherapy can be combined with radiation therapy.

Chronic obstructive pulmonary disease is one of the most common lung conditions and there are several Cochrane reviews of possible treatments. One of these, dealing with integrated disease management, was updated in September 2021 and we asked lead author Charlotte Poot from the Leiden University Medical Center in the Netherlands to tell us about the latest findings.

Chronic obstructive pulmonary disease is one of the most common lung conditions and there are several Cochrane reviews of possible treatments. One of these, dealing with integrated disease management, was updated in September 2021 and we asked lead author Charlotte Poot from the Leiden University Medical Center in the Netherlands to tell us about the latest findings.

Dr. Christine Mummery is a Professor of Developmental Biology at the Leiden University Medical Center and the former President of the International Society for Stem Cell Research. She pioneered studies on cardiomyocytes from human embryonic stem cells and was among the first to inject them in mouse hearts after myocardial infarction. She talks about her recent research developing multi-lineage cardiac model systems like microtissues and organ-chips.

In this episode Drs. Peter Loskill and Christine Mummery join the podcast to talk about the intersection of stem cells, microphysiological systems and organs-on-a-chip technology in understanding disease, screening drugs and personalized medicine. Drs. Loskill and Mummery are guest editors of a special issue on this topic appearing now in Stem Cell Reports. GuestsPeter Loskill, PhD W3-Professor for Organ-on-Chip Research at the Eberhard Karls University Tübingen and the Natural and Medical Sciences Institute as well as Vice-Chair of the European-Organ-on-Chip-Society (EUROoCS). Twitter: @pe_loskChristine Mummery, PhD, Professor of Developmental Biology at Leiden University Medical Center and heads the iPSC & organ on a chip facility at the LUMC. She is also the recent past president of the ISSCR.HostMartin Pera, PhD, Editor-in-Chief, Stem Cell Reports and The Jackson Laboratory Twitter: @martinperaJAXSupporting DocumentsSpecial Issue: Organs-on-ChipAbout Stem Cell ReportsStem Cell Reports is the Open Access journal of the International Society for Stem Cell Research (ISSCR) for communicating basic discoveries in stem cell research, in addition to translational and clinical studies. Stem Cell Reports focuses on original research with conceptual or practical advances that are of broad interest to stem cell biologists and clinicians.Twitter: @StemCellReportsAbout ISSCRWith nearly 4,000 members from more than 65 countries, the International Society for Stem Cell Research is the preeminent global, cross-disciplinary, science-based organization dedicated to stem cell research and its translation to the clinic. The ISSCR mission is to promote excellence in stem cell science and applications to human health.Twitter: @ISSCRWebsite: https://www.cell.com/stem-cell-reports/homeAcknowledgementISSCR StaffKeith Alm, Chief Executive OfficerBethany Almon, Senior Manager of Integrated MarketingYvonne Fisher, Managing Editor, Stem Cell ReportsKym Kilbourne, Director of Media and Strategic CommunicationsJack Mosher, Senior Manager of Scientific AffairsVoice WorkBen SnitkoffMusic@Konovalov

My guest today is Dr. Paul Peter Tak. Dr. Tak received his medical degree cum laude from the Free University in Amsterdam and was trained as an internist, rheumatologist, and immunologist at Leiden University Medical Center, where he also received his PhD. He has been a Clinical Associate Professor of Medicine at the University of California San Diego. Next, he served as Professor of Medicine and founding Chair of the Department of Clinical Immunology and Rheumatology at the Academic Medical Centre/University of Amsterdam (AMC). During this time, he founded Arthrogen b.v., a biotech company focused on gene therapy. He has published extensively in peer-reviewed journals (> 570 publications, H-index 130, >75,000 citations) and received numerous awards. He has been elected Fellow of the Academy of Medical Sciences (U.K.) At GlaxoSmithKline he served as Senior Vice President, Chief Immunology Officer, and Global Development Leader. He oversaw the creation of a portfolio of new medicines for immune-mediated inflammatory diseases, cancer, infectious disease and pain, including anti-OSM antibody, anti-LAG3 antibody, ESM-BET inhibitor, RIP1 kinase inhibitor, anti-GM-CSF antibody, anti-CCL17 antibody, Benlysta sc, gepotidacin, molibresib (BET inhibitor), belantamab mafodotin (anti-BCMA antibody-drug conjugate), and NY-ESO1 SPEAR T cell therapy. He was the Chair of the Scientific Review Board, the governing body accountable for the scientific assessment of GSK's R&D portfolio. During 2018-2020 Paul Peter served as Venture Partner at Flagship Pioneering and also as President and CEO of Kintai Therapeutics, a start-up focused on enteric signaling networks, where he oversaw the creation of a portfolio of proprietary small molecules called precision enteric medicines for the treatment of obesity, neurological disease, and cancer. In addition, he has served as President and CEO of Tempero Pharmaceuticals, Board Member of Galvani Bioelectronics, ViiV Healthcare, Sitryx Therapeutics (co-founder), Omega Therapeutics, Levicept, and Citryll.

Fat! This curious, wonderful and often misunderstood organ is the subject of today's podcast with Professor Liesbeth van Rossum, MD PhD and Dr Mariëtte Boon MD PhD authors of the incredible book “Fat. The Secret Organ”. And yes it is an organ.Professor Liesbeth van Rossum, MD, PhD is internist-endocrinologist at the Erasmus University Medical Center, Rotterdam. She is co-founder of the Obesity Center CGG, and has an internationally leading position in the field of obesity and biological stress research.Dr Mariëtte Boon, MD, PhD is an internal medicine specialist in training. Her research, per- formed at the Leiden University Medical Center, focuses on fat metabolism. Today's pod is a whirlwind of a conversation running through a fantastic variety of topics all to do with fat. You'll learn about:Why fat is an organWhat mechanisms drive hunger and satietyWhy too little as well as too much fat can be detrimentalHow you can stimulate your satiety to eat lessHow stress can cause fatThe number and size of fat cells and if they change throughout your lifeWhy liposuction doesn't workWhat brown fat is and how to increase itFat on inflammation, immune health and fertilityThe 6 categories of what causes weight gain from genetics and sleep to food and stressIf a virus can cause obesity?Their book “Fat. The Secret Organ” is a must read for anyone as interested in this subject. We didn't get time to properly dive deep into some other topics in the book, such as the evidence based lifestyle recommendations and how you can use simple hacks to increase metabolism as well as nutrition, so do grab a copy. I highly recommend it!Check out The Doctor's Kitchen website for full show notes and information on this and all other episodes. See acast.com/privacy for privacy and opt-out information.

Osteoarthritis pain remains a large unmet clinical need. One common tool in the clinician's armamentarium has been a steroid injection. They are widely used but recent evidence has questioned their efficacy for pain relief and potentially associated ongoing structural changes, including accelerating the underlying structural progression. On this episode of Joint Action, we will hear from Ali Guermazi and Margreet Kloppenburg about the harms and benefits of steroid injections for osteoarthritis. Dr. Margreet Kloppenburg, MD PhD, is Professor of Rheumatology in the Department of Rheumatology at the Leiden University Medical Center. She is a rheumatologist and epidemiologist. Since 2000 she is appointed both at the departments of Rheumatology and of Clinical Epidemiology of the LUMC. Her research interest includes osteoarthritis with focus on two topics, 1) unravelling underlying pathways in development and progression of osteoarthritis, aimed at inflammatory, metabolic and genetic mechanisms, and 2) optimization of methodology to measure osteoarthritis symptoms and signs, to enable development of disease modifying drugs. She is PI of several cohorts and randomized clinical trials in patients with osteoarthritis. She uses imaging modalities, as radiography, ultrasonography and MR imaging and basic science tools, including immunohistochemistry and metabolomics to characterize and study osteoarthritis patients. She has special interest for hand osteoarthritis. Dr. Guermazi is a French board-certified radiologist. Dr. Guermazi's interest is musculoskeletal diseases, in particular note are his scientific contributions in the diagnosis and disease progression assessment of osteoarthritis using MRI. His work has focused on identifying structural risk factors for developing and worsening osteoarthritis. He has been involved in developing several original and widely accepted radiological methods to assess osteoarthritis disease risk and progression, including the WORMS, BLOKS and MOAKS for the knee, HOAMS for the hip and fixed-flexion radiography for measuring joint space width. Dr. Guermazi has been involved as an MRI reader for the past 14 years in several large U.S. studies. He is author of over 275 peer-reviewed publications and Investigator on numerous research grants related to MRI reading for Osteoarthritis RESOURCESVideosOA summit debate series on steroid injections - video recordingMore Research Needed to Determine Safety of Hip and Knee Steroid InjectionsJournal articlesIntra-articular Corticosteroid Injections in the Hip and Knee: Perhaps Not as Safe as We Thought?Effects of Intensive Diet and Exercise on Knee Joint Loads, Inflammation, and Clinical Outcomes Among Overweight and Obese Adults With Knee OsteoarthritisThe IDEA Randomized Clinical TrialCONNECT WITH USTwitter: @ProfDavidHunter @jointactionorgEmail: hello@jointaction.infoWebsite: www.jointaction.info/podcastIf you enjoyed this episode, don't forget to subscribe to learn more about osteoarthritis from the world's leading experts! And please let us know what you thought by leaving us a review! See acast.com/privacy for privacy and opt-out information.

Dr. Wouter van Furth is a neurosurgeon at Leiden University Medical Center in the Netherlands who is interested in better clinical results with the help of evolving surgical techniques and technological advancements. In this episode he shares information on the education and healthcare systems in the Netherlands, medical technology breakthroughs and challenges in neurosurgery, breaking habits and the difficulty of change, why education when any change to a device is critical, and a burning question he asked the Mastering Medical Device community to explore.Links from this episode:Dr. Wouter van Furth LinkedInLeiden University Medical CenterMastering Medical Device:WebsitePat Kothe LinkedIn

Hand osteoarthritis is a common musculoskeletal disease and associated with hand pain, stiffness, functional limitation and quality of life. For a long time, hand osteoarthritis was a "forgotten disease", resulting in a paucity of good quality clinical trials to help guide the management. However, in more recent years, hand osteoarthritis has gained more attraction and new data to support treatments has become available. On this episode we discuss:what is hand osteoarthritis and which joints are most commonly affected why does hand osteoarthritis occurrecommended treatments for hand osteoarthritisProfessor Margreet Kloppenburg is heading the Osteoarthritis Research Group of the Rheumatology Department of the Leiden University Medical Center, Leiden, the Netherlands. She started research in the field of Osteoarthritis in the department of Rheumatology and made it one of its key research areas. The work of her group focusses on the causal role of systemic factors in osteoarthritis and on methodology to evaluate the course of osteoarthritis by MRI and radiographs, with special attention for hand osteoarthritis. Professor Kloppenburg has published over 200 peer-reviewed papers in the national and international literature.RESOURCESJournal articlesEULAR recommendations for the use of imaging in the clinical management of peripheral joint osteoarthritisEfficacy and safety of non-pharmacological, pharmacological and surgical treatment for hand osteoarthritis: a systematic literature review informing the 2018 update of the EULAR recommendations for the management of hand osteoarthritis2018 update of the EULAR recommendations for the management of hand osteoarthritis2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and KneeYouTube videoHand exercises for hand osteoarthritisCONNECT WITH USTwitter: @ProfDavidHunter @jointactionorgEmail: hello@jointaction.infoWebsite: www.jointaction.info/podcastIf you enjoyed this episode, don't forget to subscribe to learn more about osteoarthritis from the world's leading experts! And please let us know what you thought by leaving us a review!This episode was produced in partnership with The Arthritis Foundation. See acast.com/privacy for privacy and opt-out information.

In today’s episode, Chase DiMarco talks with Renée Hendriks, a PhD candidate at the Center of Innovation for Medical Education at the Leiden University Medical Center. Renée has done a great deal of research into MOOCs (Massive Open Online Classes) and what makes them effective. Together they discuss the evolution of online learning, the importance of course design and the future of the medium for medical education. When it comes to online learning, it is becoming more prevalent and Renée saw a need to look at its effectiveness. Chase talks about the push back he has seen against online learning and Renée acknowledges this by explaining that with proper design and implementation, online courses are just as effective as face-to -face learning. Speaking about her research, Renée tells us that she has examined 33 different medical MOOCs on a variety of subjects to see what they offer. As well as quality, range of topics and assessment methods, she noticed that they often had teaching modes that facilitated construction of knowledge. This is something often missing in other MOOCs. An important factor in any MOOC is creating active learning. Renée believes that to be effective, the courses have to include activation and motivation. There is also scope for creating greater personalization of learning experiences through student data analysis. Staying on the topic of student issues, Chase and Renée end the episode by discussing how utilizing the 11 principles of course design can allow for educators to create engaging, trackable learning. Renée hopes that the future of education is geared towards a greater emphasis on self-regulated learning to create a strong knowledge base. Find Renée’s article here: Twelve Tips for Integrating Massive Open Online Course Content into Classroom Teaching

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart center and Duke National University of Singapore. Dr Greg Hundley: And I'm associate editor, Dr Greg Hundley, from VCU Health, the Pauley Heart Center, in Richmond, Virginia. Well Carolyn, our feature discussion, are results from the Odyssey study and they're presented by Professor Wouter Jukema from Leiden University Medical Center, regarding the relationship between ultra-low LDL levels in both ischemic and hemorrhagic stroke. The study really seeks to answer the question related to concerns that ultra-low LDL levels, less than 15 milligrams per deciliter, in patients treated for ischemic heart disease could increase the risk of hemorrhagic stroke, but more to come on that intriguing question. Carolyn, how about your first paper? Dr Carolyn Lam: It's from doctors Condorelli and Kallikourdis from Humanitas Clinical and Research Center and Institute of Genetic and Biomedical Research respectively in Rozzano Milan in Italy. Now, these authors used single cell RNA sequencing to map the cardiac immune composition in the standard Murine non ischemic pressure overload heart failure model. They then integrated their findings using multi parameter flow cytometry, immunohistochemistry and tissue clarification immunofluorescence in both the mouse and the human. And they found that despite the absence of infectious agents or an autoimmune trigger, induction of disease led to immune activation that involved far more cell types than previously thought. And that included neutrophils, B cells, natural killer cells, and mast cells. And this really opens up the field of cardio immunology to further investigation using toolkits that have already been developed to study these immune subsets. Dr Greg Hundley: Ah, so Carolyn, do they have any specific examples? Dr Carolyn Lam: Hmm, indeed they did. They found that activation lead to up regulation of key subset specific molecules such as pro inflammatory cytokine onco statin M in pro-inflammatory macrophages, and PD1 in T regulatory cells. Now these are significant because they may help to explain clinical findings such as the refractivity of heart failure patients to anti TNF therapy and cardio toxicity during anti PD1 cancer immunotherapy respectively, for the more these subset specific molecules may become useful targets for the diagnosis or therapy of heart failure. Dr Greg Hundley: Oh, beautiful. Well Carolyn, my next article is from Ambarish Pandey from University of Texas Southwestern Medical Center and it's entitled Incorporation of Biomarkers into Risk Assessment for Allocation of any Hypertensive Medication, According to the 2017 ACC, AHA High Blood Pressure Guidelines, a Pooled Cohort Analysis. Dr Carolyn Lam: So I suppose asking does consideration of troponin or BNP inform cardiovascular risk in those with hypertension? Dr Greg Hundley: Great question Carolyn. So in this study, the authors included participant level data from 12,987 participants across three cohort studies, ERIC, the Dallas Heart Study and MESA. And they were pooled excluding individuals with prevalent cardiovascular disease and those taking antihypertension medications at baseline. Participants were analyzed according to blood pressure treatment group from the 2017 ACC AHA Blood Pressure Guideline and those with high blood pressure, 120 to 159 millimeters of mercury, were further stratified by biomarker status. Dr Carolyn Lam: Okay. So what did they find Greg? Dr Greg Hundley: Participants with elevated blood pressure or hypertension, not recommended for any hypertensive medication with versus without either elevated high sensitivity, cardiac troponin T or N terminal pro BNP, had a 10-year cardiovascular incidence rate of 11% and 4.6%, with a 10-year number needed to treat to prevent one event for intensive blood pressure lowering of 36 and 85 individuals respectively. In addition, among participants with stage one or stage two hypertension recommended for antihypertensive medication with a blood pressure less than 160 over a hundred millimeters of mercury, those with versus without an elevated biomarker had a 10-year cardiovascular incidence rate of 15.1% and 7.9% with a 10-year number needed to treat, to prevent one event of 26 individuals and 49 individuals respectively. Dr Carolyn Lam: Wow, Greg, those are impressive numbers. So does this mean we should be checking biomarkers in everyone? Dr Greg Hundley: Great question again Carolyn. These results suggest that a biomarker based approach to cardiovascular risk assessment may help identify high risk individuals with elevated blood pressure or stage one hypertension who are currently not recommended for any hypertensive medication, according to the 2017 ACC AHA Blood Pressure Guideline, but who may benefit from blood pressure lowering therapy. And it seems the more we research blood pressure measures, the more we learn regarding individualizing targets for blood pressure lowering. Dr Carolyn Lam: Very interesting Greg. Thanks. So my next paper sought to understand to what extent do drug costs, which are potentially actionable factors, contribute to medication non-adherence? A very interesting and relevant question, and this is from Dr Nasir from Yale New Haven Health System and colleagues who identified more than 14,000 US adults with a reported history of atherosclerotic cardiovascular disease in the national health interview survey from 2013 to 2017. Now participants were considered to have experienced cost related non-adherence if in the preceding 12 months they reported either skipping doses to save money or taking less medication to save money or delaying filling a prescription to save money. And they used survey analysis to obtain national estimates. Dr Greg Hundley: Okay, Carolyn. So what did they find? Dr Carolyn Lam: Listen to this. So they found that one in eight patients with atherosclerotic cardiovascular disease reported non-adherence with medications due to cost, representing nearly 1.5 million estimated patients missing doses, 1.6 million taking lower than prescribed doses and 1.9 million intentionally delaying a medication fill to save costs, all in the United States. Patients less than 65 years of age, had a three fold higher rate of medication noncompliance due to cost, with significantly higher rates in women and among patients from low income families and those without health insurance. Now the take home message I think is that the removal of financial barriers to accessing medications, particularly among vulnerable patient groups, may help improve adherence to essential therapies to reduce atherosclerotic cardiovascular disease, morbidity and mortality. Dr Greg Hundley: Great paper, Carolyn. We've got a couple other articles in this issue. Let's just run through so our listeners get a synopsis. So Dr Javed Butler from University of Mississippi Medical Center has a nice white paper regarding heart failure endpoints in cardiovascular outcome trials of SGLT2 inhibitors in patients with type two diabetes. Dr Brahmajee Nallamothu in a perspective piece, discusses issues related to the legal prosecution of stent cases and the 70/30 rule. Remember Carolyn, the 70/30 rule, the operator may say a stenosis is 70% of an intracoronary luminal narrowing, but in review, others seem to think it's less than 30% and often these cases are prosecuted for performing coronary artery interventions on these lesions, but what Dr Nallamothu argues is perhaps, these definitions are really related to how that stenosis was measured. Are you taking approximately dilated segment or a distantly dilating segment as your reference point? Really interesting perspective piece. The next article is from Dr Prateeti Khazanie at the University of Colorado in Denver and provides an on my mind piece with Dr Mark Drazner regarding ethical issues that arise during cardiac transplant allocation process. They review some of the pitfalls associated with current physician subjective assessments used for heart transplants in the United States. Dr Neil Kay presents another EKG challenge related to T, a new wave alternans and consumption of alcohol in association with combinations of antiarrhythmic drugs. Dr Dipan Shah from Houston Methodist provides new data in a letter, a research letter, regarding the association of extracellular volume fraction and MRI measure of interstitial fibrosis in the setting of chronic mitral regurgitation. And finally, Carolyn, Dr Nirvik Pal and colleagues write a letter referring to an earlier publication related to LVAD adverse outcomes and cardiac transplantation. Well, shall we move on to that feature discussion? Dr Carolyn Lam: Yeah, let's do that, Greg. Dr Greg Hundley: Welcome everyone to our feature discussion and we're very excited today to have Dr Wouter Jukema from Leiden University Medical Center who's going to tell us about the utility of PCSK9 inhibitors on the impact of both ischemic and hemorrhagic stroke. A large study that comes from the Odyssey study. Welter, we are so glad that you're with us this morning, afternoon, evening, wherever you may be in the world. Could you tell us, what were the thoughts behind putting this study together? Dr Wouter Jukema: As we all know that patients with acute coronary syndromes, ACS, are at an increased risk for a subsequent stroke. And we also do know that lowering of atherogenic lipoproteins, including LDL cholesterol of course, reduces the risk of ischemic stroke in chronic atherosclerotic cardiovascular disease or recent ACS. However, concerns have been raised about very low LDL cholesterol levels and the potential risk and increased risk of hemorrhagic stroke. So the effect of lipid lowering by PCSK9 inhibition, both ischemic and hemorrhagic stroke is actually not fully determined. So what we therefore did to better investigate this is that in the obviously outcomes trial, the main publication was of course in New England Journal of Medicine already, we did a pre-specified analysis. We was designed to assess the effect of LRO come up on the ischemic as well as on the hemorrhagic stroke in patients with a recent ACS in obviously outcomes, all patients had a recent ACS and we have hypothesized that for patients treated with LRO come up that would be one, A, a reduction in risk of ischemic stroke, B, without an increase in hemorrhagic stroke. And we also hypothesize that the results would be irrespective of baseline LDL cholesterol and the history of cerebral vascular disease. So that was our background and objectives and we investigated this in urology outcomes trial a huge, huge trial. If you may all recall post ACS patients one to 12 months post ACS, they all had a run in period two to 16 weeks of high intensity or maximum tolerated dose of atorvastatin or rosuvastatin, and then you had to meet certain lipids criteria and then you were randomized to LRO come up circuitously every two weeks or placebo. And of course all the patients and investigators were blinded to lipid levels and treatment location. So this was a design. Dr Greg Hundley: Wouter that was a fantastic description of why we're studying this particular series of issues as both ischemic and hemorrhagic strokes. Tell us a little bit about your study results? Dr Wouter Jukema: We looked at the entire population of the Odyssey outcomes trial. This is almost 19000 patients and then we looked if they had a history of prior cerebral vascular disease or we have no history of cerebral vascular disease. The majority, almost 18000 did not have a history of cerebral vascular disease and over 900 did have a history of cerebral vascular disease. And we've also looked at our baseline LDL cholesterol levels. Well, if you can of course, be sure we appreciate people with history of cerebral vascular disease or way out, there are a different study population. So that's of course what you may expect anyway. And that's what we saw. But regardless if you have the history of a vascular disease or you didn't have that, we saw a reduction of any stroke and actually it was 28% reduction of any stroke, which is quite impressive, in my opinion, as highly significant with a P value of point 0.05 and then afterwards of course, we tried to split it in ischemic stroke and hemorrhagic strokes. So as I told you, any stroke was reduced with 28% and if you then look at ischemic stroke, it was 27%. Also significant at the P value of 0.01. And then of course, the big question, what would happen with hemorrhagic stroke. And actually this was numerically less also in the LRO come up group. So there was not only a reduction in any stroke, but also in ischemic stroke. But also in hemorrhagic stroke, but this was 17% and then of course you are in the low numbers. So the ischemic ratio for hemorrhagic stroke was 0.83 in favor of LRO come up. And of course that by itself is not significant to the low numbers, but numerically there were less hemorrhagic strokes on top of that, there were less ischemic strokes and that was, I think a very reassuring finding. And the interesting part is that these results were more or less independent. If you have a history of cerebral vascular disease are not, so people without a price were benefiting and with a price were benefiting. And it was also statistically independent of your baseline LDL cholesterol level. So the results were basically the same. If you had a baseline LDL starting below 80 between 80 and 100 and over 100 the results were the same. LRO come up was always better than placebo. If you look at the data, you could see that it was perhaps doing slightly even better if you had a slightly higher cholesterol from the start, which is conceivable. But the formal test returned 80 did not say show any difference. So you could say the beneficial effect of other LRO come up on stroke in post ACA patients is independent of your history of cerebral vascular disease, is independent of your baseline LDL. LRO come up is just better for ischemic strokes as well as for hemorrhagic strokes at least there was no sign. Never mind add to that, we did even go one step further and we looked at the risk of hemorrhagic stroke in relation to the HG LDL cholesterol level. So not your baseline LDL cholesterol level, but the achieved LDL cholesterol level in the LRO come up group because there you find the, of course very low numbers and we divided them and below 25 milligrams per deciliter, which we could continue really low between 25 to 15, 15 to 17 over 17 and the numbers of hemorrhagic strokes were exactly the same, always 0.1, 0.2, 0.3%. So very low. And it was certainly not the case that they do very low numbers. We saw more hemorrhagic strokes. So this is again very reassuring data. So even at very low levels of LDL during the trial. Of course we should realize that this trial is of course only a medium duration of two per date, but we didn't see more erratic strokes. So in my opinion, this is very reassuring data. Dr Greg Hundley: Very good. I loved all that analysis of subgroups. I want to ask you one quick subgroup question. Was there any difference in outcomes related to gender or age? Dr Wouter Jukema: As far as we could see there was no differential effect in gender nor in age. Of course you should realize that in very advanced age, of course the numbers get small and if you then start dividing them again in the history of stroke or not, then of course the numbers will get low. But in general there is no age or gender difference. Dr Greg Hundley: Fantastic. So where do you think, does this field progress from here and what do you think will be the next study that we need related to PCSK9 inhibitors and adverse effects? Dr Wouter Jukema: I think we have shown now that patients with a recent ACS and dyslipidemia, despite incentive therapy, they do benefit from the PCSK9 LRO Come up, which is reflected by a decrease in the risk of stroke. You should of course realize that this is a post ACS population, so it was not targeted in a post stroke population. This is a atherosclerotic disease population, so the results are applying for an atherosclerotic population of course, many people that have a stroke in the past may have and also from embolic processes from a FIP or whatsoever, and those results may be the same but may of course they may also be different. So that situation was not tested here. This is a atherosclerotic post ACS population. Of course you may be interested in what would happen with strokes in an embolic population with a FIP and that would of course be a very nice trial to do as well. But then you have to do an entirely new trial. And some of these trials are of course underway, but I cannot, with my publication circulation, I cannot provide you with the answer. Dr Greg Hundley: Well listeners, we've had a great discussion on our feature article today from Dr Wouter Jukema from Leiden university medical center and really some important insights related to PCSK9 inhibitors and the fact in this study, a large study, a sub study from Odyssey that indicates really no increase incidents of both hemorrhagic or ischemic stroke in patients that receive these agents and had previously sustained acute coronary syndromes. I want to wish you all a great week and on the half of Carolyn and myself. Hope to see you next week. Take care now. This program is copyright American heart association 2019.  

In this episode of humanOS Radio, Dan speaks with Sander Kooijman. Sander is a post-doctoral researcher at Leiden University Medical Center, where he is investigating brown adipose tissue activation as a therapeutic target to attenuate obesity, type 2 diabetes, and atherosclerosis in humans. He and his colleagues recently published a paper examining how light exposure and environmental temperature affect measures of glucose and lipid metabolism in two large population-based European cohorts. It is well established that exposure to bright light at night is linked to metabolic perturbations. A number of studies have found positive associations between artificial light exposure in the evening and risk of type 2 diabetes. In particular, one experiment from Phyllis Zee's lab at Northwestern showed that just a single night of blue light exposure during sleep increased insulin resistance in healthy adults. But what about bright light during the day? Now that's a different story altogether. Observational evidence suggests that light exposure - particularly sun exposure - may in fact be beneficial for glucose metabolism. For example, a cohort study found that participants who received a lot of sunlight exposure during the day had a 30% lower risk of developing type 2 diabetes, compared to those who didn't get much sun. In the study discussed on this show, the researchers collected data from a combined cohort of more than 10,000 healthy middle-aged subjects enrolled in the Oxford Biobank study (OBB) and the Netherlands Epidemiology of Obesity study (NEO). Participants in these studies have provided body composition measurements (weight, body mass index, body fat percentage) as well as bloodwork (fasting glucose, insulin, fasting lipid concentrations, insulin resistance, etc). However, these studies do not assess temperature or light exposure. To capture the impact of these variables, Sander and his team very cleverly collected data on mean outdoor temperature and hours of bright sunlight (defined as global radiation >120 W/m2) from local weather stations. From this information, they were able to calculate mean outdoor temperature and bright sunlight duration during a 7-day and 30-day period before the date of blood sampling. Sure enough, increased bright sunlight exposure was found to be associated with lower fasting insulin (−1.27% per extra hour of bright sunlight), lower triglyceride levels (−1.28%), and reduced insulin resistance (HOMA-IR; −1.36%). After adjustment for bright sunlight, there was no association between outdoor temperature and measures of glucose and lipid metabolism, suggesting that it was indeed the light that was responsible here. But why? What mechanisms mediate this relationship? To find out why Sander thinks bright sunlight might enhance cardiometabolic health, and more about his fascinating work, check out the podcast!

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                So Greg, have you ever wondered what is the clinical significance of exercise induced cardiac troponin eye release with regards to mortality and cardiovascular events? Dr Greg Hundley:             Well, being a runner, and you are too, I actually have wondered about that. Dr Carolyn Lam:                Well guess what? I'm not going to tell you the answer because you're going to have to wait for our feature discussion coming right up after we chat about a few wonderful papers in this week's issue. And I want to start. So the first paper I chose really sought to discover new and effective drug treatments for ischemic stroke. And it did this by integrating genetic and proteomic data through Mendelian randomization analysis. Dr Greg Hundley:             So Carolyn, what is Mendelian randomization analysis? Dr Carolyn Lam:                Well, I would have loved to quiz you on that, but since you already asked me, I'll tell you. So Mendelian randomization is a statistical genetics framework that's used to assess causality between an exposure and an outcome. So similar to how randomized controlled trials randomly allocate an intervention to test its causal effect on an outcome. Well, Mendelian randomization represents a sort of natural randomized control trial that leverages the random allocation of exposure influencing genetic alleles.                                                 Now previously, this technique of Mendelian randomization was applied in a hypothesis driven manner to assess causality of selected biomarkers on stroke risk, for example. However, there has been no systematic scan of the human proteome for novel causal mediators of stroke. And beyond drug target prioritization, Mendelian randomization can actually also be applied to predict target mediated side effects to reveal unanticipated adverse effects and opportunities for drug re-purposing. Hence, in the current paper, the authors led by Dr Paré from Hamilton Health Sciences, McMasters University and colleagues, use Mendelian randomization to firstly systematically screen 653 circulating proteins to identify novel mediators of ischemic stroke subtypes.                                                 Secondly, examine the relationship between identified biomarkers and the risk of intracranial bleeding. And thirdly, predict target mediated side effects through phenome wide analysis. They found that among these 653 proteins, seven were causal mediators of ischemic stroke, including two established targets, apolipoprotein allele and coagulation factor 11. As well as two novel mediators of cardioembolic stroke, which were scavenger receptor class A5, or SCARA5, and tumor necrosis factor weak inducer of apoptosis.                                                 They further showed that targeting SCARA5 was predicted to also protect against subarachnoid hemorrhage with no evidence of it for side effects. Some biomarkers mediate at risk of multiple non-stroke disorders. So in summary, integrating genomic, proteomic and phenomic data through Mendelian randomization facilitated discovery of drug targets and their side effects. Their findings provide confirmatory evidence for pursuing clinical trials of coagulation factor 11 and apolipoprotein allele. Furthermore, SCARA5 represents a new therapeutic target. Neat, huh? Dr Greg Hundley:             You bet. Well, my basic paper, Dr Carolyn Lam, focuses on the border zones of infarcts. And it comes to us from Vincent Christoffels from the Academic Medical Center in Amsterdam. So surviving cells in the post infarction border zone is subjected to intense fluctuations of their microenvironment. We can imagine that. And recently border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here in this study, the investigators define their unique transcriptional and regulatory properties and comprehensively validated new molecular markers, including NPB or encoding B-type natiriuretic peptide after infarction.                                                 So, in the study, transgenic reporter mice were used to identify the NPB positive border zone after mitochondrial infarction, and transcriptome analysis of remote border and infarct zones, and of purified cardiomyocyte nuclei was performed using some RNA sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. So like these great papers we have in basic science, there is a fundamental mouse and then human subject validation. Dr Carolyn Lam:                 Nice. A lot of work. So what did they show? Dr Greg Hundley:             So Carolyn, the investigators identified the border zone as a spatially confined region transcriptionally distinct from remote myocardium. The transcriptional response of the border zone was much stronger than that of that remote ventricular wall involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling and sarcomere function, and activation of the stress response program.                                                 Analysis of infarcted human hearts revealed that the transcriptionally discrete border zone is conserved in humans and led to the identification of novel conserved border zone markers including NPBB and a whole list of others. So in conclusion, cardiomyocytes in a discrete zone bordering the infarct switch gene expression programs, this post switch program is conserved between mouse and humans, includes the NPPB expression, which is required to prevent acute heart failure after infarction. Dr Carolyn Lam:                Wow, really interesting. Well, my next paper is also really just novel information, and it's a promising clinically-relevant approach for immune modulation in transplantation medicine. And that is by selectively targeting notch one. Dr Greg Hundley:             Tell us a little bit about notch signaling. Dr Carolyn Lam:                Well, I'm glad you asked me before I asked you again because notch signaling is a highly conserved pathway, pivotal to T cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell mediated immunity. Now this is relevant in transplantation since, despite advances in immunosuppression, long-term outcomes remain suboptimal and is hampered by drug toxicity and immune mediated injury, the leading cause of late graph loss.                                                 So, the development of therapies that promote regulation while suppressing effector immunity is imperative in improving graph survival and minimizing conventional immunosuppression. In today's paper, Dr Riella and colleagues from Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts investigated the pattern of notch one expression and effector and regulatory T cells in both murine and human recipients of a solid organ transplant. They further examine the effect of notch one receptor inhibition in full murine cardiac and lung transplant models as well as in a humanized skin transplant model, and also in T regulatory cells. They found that notch one is a potent novel target to modulate aloe immunity. Blockade of notch one signaling prolongs allograph survival and enhances tolerance in animal transplant models in a regulatory T-cell dependent manner.                                                 So, in summary, these data suggests that notch one signaling pathway is a potentially clinically relevant target to control effector function and promote immune regulation after transplantation. Dr Greg Hundley:             Oh wow. A lot of intense work, and I learned about notch pathways. I am going to switch and talk about a clinical situation that's really emerged over the last five years, particularly in our scientific literature. And that's tricuspid regurgitation. And this paper comes to us from Dr Jeroen Bax from Leiden University Medical Center in the Netherlands. So in patients with moderate and severe tricuspid regurgitation, the decision to intervene is often influenced by right ventricular size and function. And right ventricular remodeling in significant secondary TR however been under explored. And so in this study the investigators characterize right ventricular remodeling in patients with significant secondary tricuspid regurgitation, and they investigated its prognostic implications. Dr Carolyn Lam:                 Indeed, very important topic. So please tell us what they found. Dr Greg Hundley:             Okay, so they use transthoracic echo-cardiography, and it was performed in 1,292 patients with significant secondary tricuspid regurgitation with patients having an average or median age of 71 years. Half were men, half were women. They had four patterns of right ventricular remodeling, and they were defined according to the presence of RV dilation with the tricuspid annulus of greater than 40 millimeters and RV systolic dysfunction. So pattern one was normal RV size and normal RV systolic function. Pattern two was a dilated RV with preserved systolic function. Pattern three, normal RV size with systolic dysfunction. Pattern four was a dilated RV and systolic dysfunction.                                                 So the primary end point was all caused mortality and event rates were compared across these four patterns of remodeling. So what did they show, Dr Carolyn Lam? The five-year survival rate was significantly worse in patients presenting with either pattern three or pattern four remodeling compared to pattern one, which was normal. And they were independently associated with poor outcome in multivariable analysis. Thus, in patients with significant secondary tricuspid regurgitation, patients with RV systolic dysfunction have worse clinical outcomes regardless of the presence of the magnitude of RV dilation. So really helps us as we're trying to decide what going to do with that tricuspid valve and modifying the severity of tricuspid regurgitation. Very nice work. Dr Carolyn Lam:                 Yeah. Very interesting. Now let's get to our feature discussion. Dr Greg Hundley:             You bet. Dr Carolyn Lam:                Our feature discussion today is all about cardiac troponin increases after endurance exercise. Is it a new marker of cardiovascular risk? What should we think of it? Is it associated with cardiovascular events? Now I know many of us has thought of this many times and we're going to get some beautiful answers with today's feature paper. I'm so glad to have the corresponding author, Dr Thijs Eijsvogels, from Radboud Medical Center that's in Nijmegen. And I also have our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo. So welcome gentlemen, and if I could please start. Thijs, I think a good place to start would be for you to tell us about this four-day march of Nijmegen. Tell us about that and how your study builds on that. Dr Thijs Eijsvogels:           The Nijmegan four-day marches is actually the largest walking march in the world, so it's hosted every year in July in the Netherlands, and about 45,000 people walk for four consecutive days. And this gave us the opportunity to collect some research data during this great exercise event. What we did over the past couple of years is that we've collected blood samples and participants of this Nijmegan marches. We did a before exercise and also directly after exercise. Within those blood samples we determined the concentration of cardiac troponin eye, which is a marker of mitochondrial damage. And what we subsequently did is that we followed this group of walkers over time and we collected data about diverse events that occurred, and also whether they survived or whether they died over time. Dr Carolyn Lam:                Thijs, it's such a clever setup for a study. Now give us some idea though. We're saying walking for four days; how many kilometers is covered? And when you say before and after your troponin sampling, give us an idea of how many hours of walking that would be. Because I believe you did it only on the first day, right? Dr Thijs Eijsvogels:           Yeah, that's correct. So the distance that they must cover is dependent on sex and on age. So for example, if you're a male older than 50 years old, you can walk 30 kilometers per day, but then for four days in a row. But if you are a young individual like me, then you have to cover 50 kilometers per day. So that's a lot more. Typically, they walk about four to five kilometers per hour. So that means that if you walk the shorter distances then you are done within six to seven hours of walking. But if you walk for a longer period of time, then you need 10, 11, and sometimes even 12 hours to complete the distance. Dr Carolyn Lam:                Okay, there you heard it everybody. So we've got a stress test of a mean, I'm reading from your paper, 8.3 hours of walking at almost 70% of maximum heart rate. So that's really cool. Now before you go on further too, tell us a little bit about the population because everybody's wondering, oh no, does this apply to me? Dr Thijs Eijsvogels:           So the population participating in this walking event, I would almost say it's about a representation of the general population. So we have very healthy and very trained individuals. So you could say athletes. But we also have people with cardiovascular disease or cardiovascular risk factors. And even obese individuals. So it's a very mixed population, and it's not like the typical athlete population that you see at a runner’s event, for example. Dr Carolyn Lam:                Great. That's important. So now with that backdrop, please tell us your main findings. Dr Thijs Eijsvogels:           We measured this cardiac troponin and eye concentration, and we determined the number of individuals that were above the clinical threshold, which is the 99 percentile. And then we've compared the event rate. So major at first cardiovascular events and mortality with those walkers who had a cardiac troponin above the 99 percentile and those below it. And then we found that it was way higher in the walkers with the high troponin concentration. So they had an event rate of 27%, whereas the reference group they only had an event rate of 7%. So that was quite a marked difference. Dr Carolyn Lam:                That's huge. So first data of its kind and it's so scary because I think, Torbjørn, as you discussed in your editorial, a lot of us have sort of excused the rises in troponin that we know have been reported at the marathons and all that. So how do you put it all together, Torbjørn? what are your thoughts? Dr Torbjørn Omland:      So I would just like to congratulate Dr Eijsvogels with a very interesting article. And the findings are, as you say, very novel and significantly enhances our understanding of the prognostic implications of exercise induced increase in cardiac troponins. That transient increase in cardiac troponin concentrations may occur in many circumstances, and it's usually considered to reflect acute mitochondrial injury. And thus it has been considered to reflect harmful pathophysiological processes.                                                 But there has to be in one notable exception and that has been the rise in cardiac troponin after endurance exercise, which has commonly been considered a benign phenomenon. But until this study, definitive data relating post exercise troponin concentrations, or the magnitude of the cardiac troponin response following exercise have been lacking. So with Dr Eijsvogels' study we now have clear data showing that these are associated with increased risk. Dr Carolyn Lam:                That's amazing. So thank you for that in context. Thijs, do you agree? I mean that is a beautiful summary, but what is the take home for listeners? What should we be thinking about now first pertaining to our own exercise I suppose, but also then how do we interpret this clinically? Dr Thijs Eijsvogels:           I think that Dr Omland made a great point. So for a long period of time we thought that it wasn't a benign phenomenon, that everybody had those increases in cardiac proponents following exercise and also the pattern that was way different from what we see in clinical populations. So we thought, it's just a physiological phenomenon and it doesn't hurt the heart. But clearly our study now shows that there is an association between high post-exercise troponin concentrations and clinical outcomes. So this is an important finding.                                                 And basically there are two hypothesis I guess that could explain those findings. So first of all, it could be that participants with higher troponins have subclinical or underlying disease. And due to this walking exercise, that could be a stress test for the heart. And then those with vulnerable hearts, they demonstrate a greater increase in cardiac troponins. On the other hand, we should also acknowledge the hypothesis that even though it's moderate intensity exercise, it could be some damage to cardiomyocytes. And those individuals with the greatest or the highest troponin concentrations, they could have more cardiomyocyte damage compared to individuals with lower troponin concentrations. And if you then have repetitive exposures to exercise bouts, it could be harmful in the long run as well. Dr Carolyn Lam:                And so, Torbjørn, you discuss this along with several different mechanisms by which troponin could be increased. Do you have anything else to add to that? Dr Torbjørn Omland:      No, I think it's very right what the Dr Eijsvogels point out. So on one hand we can consider this like a stress test. And there are some data suggesting that that could be the main effect, in that those who had the higher baseline troponin in the trifocal study also demonstrated the highest increase. So in one way you could consider this as a long-term exercise test. Of course that makes it less applicable in clinical practice. So because we can't have exercise test that last for so many hours, but I think that should be an impetus to have more standardized tests that could be applied to the clinical practice. Dr Carolyn Lam:                There's also a comment that you made about the kind of troponin tests that we're applying here, that people should understand that we're using the high sensitivity ones, right? Is that correct? Dr Torbjørn Omland:      Actually, it is not the high sensitivity, but it is a contemporary essay, but it had quite good sensitivity even though it is not classified as a high sensitivity test. Dr Carolyn Lam:                Thank you for clarifying that. I know you made a point about that, that we should know what kind of tests we're talking about. The other thing is what are the remaining unanswered questions then? Like you said, we can't do an eight-hour walking test. Should we be measuring troponins now in our exercise stress? Which kinds? What time? No, it's not time yet? What are the next steps? I'd like to hear from both of you, actually. Dr Thijs Eijsvogels:           First of all, indeed it's not possible in clinical practice to do an eight-hour tests whatsoever. But I think that it could be interesting to explore that maybe with some small modifications to current stress tests, if we do it maybe on a little bit lower intensity. For example, moderate intensity exercise, but we do it for a fixed amount of time and then collect blood sample to determine a highly sensitive correct proponents., then maybe also the Delta, so the increase in proponents could be predictive sign of underlying disease. Because what you see in studies that have been published so far is that the duration of most stress test is too short to induce any substantial changes in aortic troponin concentrations. So I think if we modified a protocol a little bit, we can see greater increases in cardiac troponins, and that could provide us with more information, of course. Dr Torbjørn Omland:      I completely agree. And I think like all great studies, this study raises many new questions, and of course how we should use this clinically is very important one. And as such Eijsvogels pointed out, standardized tests will be required. And I think how much the Delta information we get from measuring the Delta to just the baseline should be one topic for future studies.                                                 And then of course we know that the cardiac troponin increase is a risk factor. But what we also would like to know is whether the at risk is modifiable in some way. So there are some studies that have suggested that increasing your physical activity over time can actually decrease your sort of chronic cardiac troponin concentration. And it would be interesting to see whether increased physical activity over time will also reduce the increase that you observe after a stress test like in Nijmegan march. Dr Carolyn Lam:                That's such great points. And if I could add too, not to forget that the study population here, would I be right to say the majority are middle aged individuals and they do have cardiovascular risk factors or even prior cardiovascular disease in a sizeable proportion? So to what extent these findings generalized to a really, like the young, athletic, competitive, athletic population? Could you comment on that Thijs? Dr Thijs Eijsvogels:           I think that's a very good point, that we cannot compare this population where the fit population competing in running events or cycling events or triathletes or whatsoever. So I think we definitely need follow up studies that reproduce our findings in different cohorts with different training modalities, with different age categories, and so on. So that's definitely a topic of interest for future studies. Dr Carolyn Lam:                Thank you so much. I mean, you've inspired me on so many levels. You've been listening to Circulation On The Run. Don't forget to tune in again next week. Dr Carolyn Lam:                 This program is copyright American Heart Association 2019.  

James is joined by Dr. Paul-Peter Tak, Venture Partner at Flagship Pioneering and CEO of Kintai Therapeutics. Over a more than 25-year career in the life sciences, Paul-Peter has created and led multiple companies. From 2011 until 2017, Paul-Peter founded and served as senior vice president and head of the immuno-inflammation therapy area unit at GSK. Under Paul-Peter's leadership, this unit brought more than 10 new mechanisms of action into the clinic. From 2016 until 2018, Paul-Peter was senior vice president of R&D pipeline, chief immunology officer, development leader, and co-chair of GSK's scientific review board. He oversaw the creation of a new portfolio of medicines in oncology, with a focus on immuno-oncology, epigenetics, and cell and gene therapy. Trained as a general internist, rheumatologist, and immunologist, Paul-Peter has held multiple professorships and has published extensively, with more than 550 papers in his name. He served as professor of medicine and chair of the department of clinical immunology and rheumatology at the Academic Medical Centre/University of Amsterdam for twelve years. He is a professor of medicine at the Amsterdam University Medical Center, honorary professor of rheumatology at Ghent University, and honorary senior visiting fellow at the University of Cambridge. He is a fellow of the Academy of Medical Sciences in the U.K. Paul-Peter received his medical degree cum laude from the Free University in Amsterdam and his Ph.D. from Leiden University Medical Center. https://www.flagshippioneering.com/ For more information and content, check out our website www.hs.ventures. You can follow us on Twitter @HSVenture, on Instagram @hs.ventures, on Linkedin at HS. and you can email us at info@hs.live You can get our host, Dr. James Somauroo, at www.jamessomauroo.com and you can follow him on Twitter @jamessomauroo, on Instagram @j_soms and on Linkedin at james-somauroo

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:             I'm Greg Hundley, Associate Editor for Circulation and Director of the Pauley Heart Center in Richmond, Virginia at VCU Health. Dr Carolyn Lam:                So Greg, ever wondered if prophylactic use of ICDs would help prevent sudden cardiac death in dialysis patients? Well, guess what? We're going to be discussing it in the feature discussion of the ICD II trial coming right up. First, I hear you've got a very interesting probabilistic paper. Dr Greg Hundley:             Yes. It's very sweet. This is from Renata Micha at Tusk University and it's examining the cost effectiveness of the US Food and Drug Administration added sugar labeling policy for improving diet and health. So Carolyn, in this study, investigators used a validated micro simulation US impact food policy model to estimate cardiovascular disease and type II diabetes mellitus cases averted, quality adjusted life years, policy costs, health care, informal care, and loss productivity in health related savings and cost effectiveness of two different policy scenarios.                                                 First, the implementation of the US Food and Drug Administration added to your labeling policy or just the sugar label. And second, further accounting for corresponding industry reformulation the sugar label plus reformulation. The models used nationally represented demographic and dietary intake data from the national health and nutrition examinations survey and diseased data from the centers for disease control and preventive wonder data base and policy affects in diet disease effects from meta-analysis and policy and health related costs from established sources. Probabilistic sensitivity analysis accounted for model parameter uncertainties and population heterogeneity. Dr Carolyn Lam:                Sweet indeed, so tell us all about probabilistic analysis Greg. Dr Greg Hundley:             Okay Carolyn, so between 2018 and then forecasting out into the future, so this is probabilistic, in the year 2037. The sugar label would prevent 354,400 cardiovascular disease cases, and 599,300 diabetes mellitus cases, gain 727,000 quality adjusted life years, and save 31 Billion dollars in net health care costs. Or 61.9 Billion dollars in societal costs incorporating reduce loss productivity and informal care costs and similar findings were accomplished for the sugar label plus reformulation scenario, both scenarios were estimated with greater than 80% probability to be cost saving by the year 2023.                                                 Thus, the results of this simulation exercises indicated that implementing the FDAs added sugar labeling policy could generate substantial health gains and cost savings for the US population particularly if the new label stimulates industry reformulation. The authors point out that the compliance date for updating the nutrition facts label including the added sugar perversion has been continuously delayed. And the authors believe, their findings highlight the need for timely implementation of this label so as to maximize health and economic gains.                                                 An excellent editorial was written by Elizabeth Magnuson at Saint Luke's Mid America Heart Institute revealing the strengths of this work and explains some of the variants that could occur in the results based on assumptions that were used in the authors micro simulation model. Dr Carolyn Lam:                That is so interesting Greg, thanks. So from policy to guidelines and this time on cardiopulmonary resuscitation or CPR, now we know that an out of hospital cardiac arrest, chest compression only CPR has emerged as an alternative to the standard CPR where we use both chest compressions and rescue breathes. Since 2010, CPR guidelines recommend chest compression only CPR for both untrained bystanders and trained bystanders who are unwilling to preform rescue breaths.                                                 The current study really aimed to describe the changes in the rate and type of CPR perform before the arrival of emergency medical services doing three consecutive guideline periods with gradual adoption of compression only CPR and this was in Sweden. Now these were authors led by Dr Hollenberg from The Center of Resuscitation Science, Karolinska Institute in Stockholm, Sweden and colleagues and basically, they study all bystander witness out of hospital cardiac arrest reported in the Swedish register for CPR from 2000 to 2017. They found that there was a six fold higher proportion of patients receiving compression only CPR and a concomitant almost double rate of CPR before emergency medical services arrival, and these changes occurred over time. Any type of CPR was associated with doubled survival rates in comparison with cases not receiving CPR, and this association was observed in all time periods studied. They also found a small but significantly higher chance of survival after CPR with compression and ventilation in comparison with compression only CPR. Dr Greg Hundley:             So Carolyn, does this mean we should go back to standard CPR? Dr Carolyn Lam:                Well, remember these we observational findings, albeit really amazingly done and nationwide. But the findings really support continuous endorsement of the compression only CPR as an option and that's because its associated with higher CPR rates and overall survival of the no CPR skill. The authors ended up calling for randomized controlled trials, which are really needed to answer the question of whether or not CPR with compression and ventilation is superior to compression only CPR, especially in cases where bystanders have had the previous CPR training. Now, this is discussion in a wonderful editorial by Drs. Hsu and Neumar from University of Michigan Medical School. Dr Greg Hundley:             Very nice, so you're going to tell us a little bit about troponin? Dr Carolyn Lam:                Well, the question is "Is Plasma Troponin I measured by the high sensitivity assay associated with incident cardiovascular disease in the community?" Well, Dr Ballantyne from Baylor College of Medicine and colleagues decided to answer this question by looking at the ARIC Study participants age 54 to 74 years without base line cardiovascular disease and what they found was that elevated high sensitivity troponin I was strongly associated with increased global cardiovascular disease incidents in this general population, and this was independent of traditional risk factors. They also found differences between black and white individuals and between men and women. Dr Greg Hundley:             What kind of differences? Dr Carolyn Lam:                Well high sensitivity troponin I had a stronger association with incident global cardiovascular disease events in white compares to black individuals and a stronger association with incident coronary heart disease in women than in men. The authors also did a comparative association of high sensitivity troponin I vs. troponin T, they found that the high sensitivity troponins I and T show only moderate correlation with each other but were complementary rather than redundant in risk assessment for incident cardiovascular events in individuals without known clinical cardiovascular disease at base line. The bottom line is, adding biomarkers to traditional risk prediction models presents a potentially effective approach for future risk prediction algorithms for cardiovascular disease in the general community. Dr Greg Hundley:             You know, think I might read that paper looking at that complimentary risk assessment. That sounds really interesting Carolyn. Well, I'm going to go back to the world of basic science and discuss a paper from Kun Wang discussing the long non encoding RNA regulation of cardiomyocyte proliferation and cardiac repair. Carolyn, post mitotic cardiomyocytes in the adult heart exit from the cell cycle and cease to proliferate, and that's the basis for their poor regenerative capacity and defective repair in response to say a myocardial infraction. Interestingly, the nonmammalian vertebrates such as our friend the zebra fish, their heart exhibits a robust capacity for regeneration. And it can efficiently regenerate its lost cardiac tissue throughout life due to this retain cardiomyocyte proliferation capability. Dr Carolyn Lam:                Interesting indeed Greg about our friend the zebra fish. So what did the authors find? Dr Greg Hundley:             Okay, in this study, Wang and associates investigated whether long non-encoding RNAs had a role in the regulation of cardiomyocyte proliferation and cardiac repair. Using bioinformatics and initial analysis, the identified a long coding RNA named Cardiomyocyte Proliferation Regulator or CPR that was comparatively higher in the adult heart as opposed to hearts in the fetal stage. The silencing of the Cardiomyocyte Proliferation Regulator or CPR significantly increased the cardiomyocyte proliferation in the postnatal in adult hearts, more over CPR deletion restored the heart function after myocardial injury which was evident from increased cardiomyocyte proliferation, improvement of myocardial function and reduce scar formation. Also, neonatal cardiomyocyte proliferation in cardiac regeneration where markedly suppressed in CPR overexpressing heart cells, therefore CPR acts as a negative regulator of cardiomyocyte proliferation and regeneration in fetal hearts.                                                 So, Carolyn the conclusion of this paper is that the inactivation or silencing of CPR accelerates cardiomyocyte proliferation along with significant restoration of cardiac structure and function after myocardial injury in adult hearts. And as such, further studies may investigate whether the therapeutic inter fashion of CPR could be a useful strategy to trigger the expansion of cardiomyocyte populations and myocardial repair. Dr Carolyn Lam:                Nice Greg, so we've talked about CPR as in Cardiopulmonary Resuscitation to CPR as in Cardiomyocyte Proliferation Regulator, how about that? Well, that's as much as we go for now, let’s get to our feature discussion.                                                 Dialysis patients are known to have a high mortality rate, a large proportion of which have been attributed to sudden cardiac death and yet compared to patients with heart failure, these patients with dialysis have been either excluded or only nominally enrolled in all previous trials of implantable defibrillators or ICDs. Now that's why our feature paper this week is so important, and it is the Cardioverter-Defibrillator in the prevention of sudden cardiac death in dialysis patients that prospective randomized controlled ICD to trial. So pleased to have with us, the corresponding author Dr Wouter Jukema from Leiden University Medical Center as well as associate editor Dr Mark Link from UT South Western to discuss this very important paper. Wouter, congratulations, this is a very difficult, very important to do the study though, could you tell us a bit about what you did and what you found? Dr J. Wouter Jukema:     Actually, you just referred to it as a very difficult study to perform and indeed it was. Many years ago, actually, twelve years ago, we noticed that now a lot of death in dialysis patients was attributed to sudden cardiac death, before we tried to make these type of patients better with all types of medications, but did not really work and suddenly the idea was, that came also from death certificates and death records that they have sudden cardiac death and we said we should monitor it and we should treat it in a prospective randomized study. We initiated the study after careful thoughts and we thought we would do it in 4-6 years but it took us 12. So it was quite an effort to set up this rightly and spread it around the Netherlands and activate a Nephrologist and a Cardiologist to take part in this prospective randomized controlled study in dialysis patients.                                                 Of course, you can easily imagine that you could have great benefit from this ICD devise, but you could also easily imagine that you would have complications of the implication of the device. So explaining that we should show it out, I think was the most important job we had to do and think that was a great effort, and it was not easy to do. Dr Carolyn Lam:                And that in it of itself is very important observation. Dr Mark Link:                     So you picked patients without doubts, which is great I mean this is a difficult study, but you also picked with an LDF greater than 35% and traditionally, ICDs are indicated for under 35%, can you give us a little explanation on why you chose the greater than 35% population? Dr J. Wouter Jukema:     Yeah, I think this is perhaps the most important remark on the study, because when we designed the study we had to choose at that time we had guidelines in general that under 35% of injection fraction you were entitled to receive an ICD, however of course almost never dialysis patients were included so there was no formal recommendation on that not to include them or not to exclude them, but dialysis patients have a death rate at that time to sudden cardiac death, anyway regardless of the injection fraction and we thought okay, the patient population that is first at high risk of sudden cardiac deaths so any dialysis patients but also they are entitled to have a meaningful extension of the lives because the prognosis of patients that are on dialysis with an injection fraction under 35% is in general so poor that it would be unfair to start there and most of the Nephrologists also would not allow it anyway, these patients are at the end of life and if you extended for two or three months its useless.                                                 Anyway, so we thought we'd pick the high-risk population and we prove that there were still on high risk but when we could do something meaningful to extend their lives, so we thought we do not pick the worst patients we pick the patients that we think we can really help. We screened them well, we treated them well and we see if an ICD on the patient will benefit them. And that's why we picked the over 35% rage. You need another study to do below 35%, but I don't think that our results are substantiating such an effort. Dr Mark Link:                     The population with EFs was 6-50%, which also has a high risk of sudden death in patients with dialysis but it’s still not looking with the population of less than 35%. Dr J. Wouter Jukema:     No, I completely agree, and we acknowledge that in the manuscript, it was always in the manuscript within the revision that was also pointed out to us that it should be more clearly acknowledged, why we choose this patient population and finally, we can of course not make a formal recommendation on dialysis patients with an injection fraction of less than 35%. You can extrapolate data but we have no formal prof of course for this type of population. I fully agree. Dr Carolyn Lam:                Before we go further, could you first describe, what did you find? Dr J. Wouter Jukema:     Basically, the conclusions are the prophylactic ICD therapy in patients on chronic dialysis with an injection fraction of 35% or higher was not associated with a reduced rate of sudden cardiac death nor of all cause of mortality and besides that the preference of sudden cardiac death in this type of patients on dialysis was actually significantly lower compared to its reports from literature, so that's what we very often see of course if you fill out a death certificate, you have to fill out a cause of death and of course in many patients the heart stops, and you say it's a sudden cardiac death. But that's not what this study actually showed and finally it's also no authority that this population was not too healthy to see any benefit, if you look at the results over the years, then you'll see that after five or six years more than half of the patients are dead anyway, but due to all kind of causes and not to a sudden cardiac death.                                                 So, I think that this is from a pathophysiological background, this is also a very interesting study because we now have finally data, real data on sudden cardiac deaths in these types of patients. Dr Carolyn Lam:                Indeed, and Mark, I know that you invited the editorial from Rod Passman, just discussing why did we see the results that we did. Not quite what we expected I suppose, what do you think Mark? Dr Mark Link:                     First, I want to congratulate Dr Jukema for finishing this study, this was a massive task and a difficult and long one. I think I was surprised, there has been reported to be a very high rate of sudden death in dialysis patients regardless of their LDF. The ICD is very good at preventing sudden deaths, but not good at preventing other types of deaths, so I would extrapolate to say, well you can prevent sudden death in dialysis patients, you should prolong their life and this study did not show that at all. And I was surprised, and it just goes to what Dr Jukema was telling us, that what's reported on a death certificate as sudden death is not necessarily sudden death and could be other types of death and at the end all death is sudden. Dr J. Wouter Jukema:     I fully agree with that remark because that makes is cumbersome to have the right interpretation of the data, so you have to feel like something and then finally your heart stops. Dr Carolyn Lam:                What seems that most of the reasoning seems to be maybe a lower rate of sudden cardiac death than we expected, but there were also other factors that were considered, for example, if you could clarify by dialysis did you mean both hemodialysis as well as peritoneal dialysis, do you think that made a difference? For example, do you think ICDs work differently in presence of uremic precipitant of arrhythmias vs. not and so on, what do you have to say about those factors? Dr J. Wouter Jukema:     We include on purpose both types of patients, the peritoneal dialysis and the hemodialysis patients because you could easily in-visit that there could be a difference, for instance to fluid or electrolyte sheaths that are more sudden in the hemodialysis patients than in peritoneal dialysis and we did a sub-analysis where we looked at both types, but the results are essentially the same, it doesn't seem to matter a great deal of what type of dialysis you have, the amount of sudden cardiac is lowered and expected. By the way occasionally, of course the ICD did work in sudden cardiac death, was aborted. So, it’s not that the apparatus doesn't function it does, it takes it properly and if functions properly. But finally, it doesn't prolong the life and you will die of something else, mostly infections in general well-being when finally, the nephrologist will say this is end of life you have to stop the dialysis procedures anyway. Dr Carolyn Lam:                Right, great points, now in the last few minutes, I'm dying to ask, what do you think of the next steps from here. Mark, what do you think first? And then perhaps I'll give the last word to Wouter? Dr Mark Link:                     I'll start with a question to Wouter myself, the question is what are we going to do now with the individuals on dialysis that are under 35%? I think this study has pretty clearly said that were not going to extend our CDs to people on dialysis with greater than 35%. But we still have a population that currently fits indication for a ICD if their expected longevity is greater than a year. And currently those people are included in the guidelines for ICDs, I think this study gives us some pause about what to do with our population. And many of that population are getting our CDs and I'd be curious to what Dr Jukema thinks about that population and whether that population warrants some randomized trial or whether we should continue with our current guidelines that recommend implantation of an ICD in any individual less than 35%, as long as their expected life span is greater than a year. Dr J. Wouter Jukema:     I think these are excellent questions with excellent remarks, of course, finally, we do not know because we didn't investigate it, I can only imagine the difficulties we would have if we were to do a new additional trial with injection fractions patients less than 35%. I could tell you we had great great difficulty in persuading Nephrologists to take part in the study, because many of them were very reluctant, this is their principal, these are very ill patients, and a lot of them are more or less going towards the end of their lives so you cannot do this when we have Nephrologists telling us that they considered it an unethical study. A lot of them did not want to participate they said, "You shouldn't do this to this patient, they have troubles enough, they suffer from infections and all kinds of things."                                                 Having said this, I do not advocate that you should never implant an ICD in a dialysis patient, I think in our study we also clearly show that in dialysis patients, implantation of an ICD is feasible within acceptable although better complication risk and infection risk, so if you have a patient on dialysis where you feel this patient has a good life expectancy, for instance, he already suffers an episode of arrhythmia, I think you are entitled to discuss this with the patient and have it a try, it might work and prolong their life. So I would not say never do it, I think our studies show that you can do it, yes, it sometimes works but do not expect too much of it. You will never hear me say that in general you should not do it, if you have a clear indication for it you may do it, secondary effect may require a good reason, but primary prophylactic indication, that's a difficult one I think and to do this study in patients that are even more ill, with injection fraction of less than 35%, I feel will be exceeding the difficult. Dr Mark Link:                     One other comment I have is the issue of the SUBCU ICD I think changes the equation in a bit because the risk of infection is much lower with a SUBCU IDC in patients on dialysis, did you have any SUBCU ICDs in your study or was it all transvenous? Dr J. Wouter Jukema:     We don't have any data, when we designed and the developed study, the such a device was not even there so we couldn't do that, and during the study we did not adapt that but of course there is also no formal proof yet that it's a lot safer, a lot better, and once again this time of subcutaneous ICD I think you can do it at an acceptable complication rate. But it’s not effective enough, it's not that the patients were dying from infections of their ICD, they were dying of all kinds of infections and malignancies. Infections due to the ICD were facing procedures, real complications were rare. Dr Carolyn Lam:                Great! Thank you Wouter, thank you Mark, what an important study and what a lot of lessons that we learned here.                                                 Thank you very much audience for listening as well, you've been listening to Circulation on the Run, don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019  

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, from National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor for circulation from VCU Health Systems in Richmond, Virginia. Dr Carolyn Lam:                What does cardiac autoimmunity, glycemic control, and cardiovascular disease risk and Type I diabetes have in common? Well, you've got to wait for our feature discussion. This one's such a hot one, don't you agree, Greg? We could hardly finish talking. Dr Greg Hundley:             Absolutely, and Myra, you're just going to love listening to her. Dr Carolyn Lam:                Yep, but stay tuned. First, we're going to discuss a couple of papers each. Greg. Dr Greg Hundley:             Thanks Carolyn. So, the first paper I've got is from Professor Van Rein at Leiden University Medical Center. And basically he's getting at the issue of bleeding in patients with atrial fibrillation. So this is a retrospective cohort that evaluates different anticoagulation strategies for atrial fibrillation. They examined 272,315 patients that had a median age of 75 years and followed them longitudinally over time. These individuals experience 31,459 major bleeding events, and what he did is he evaluated whether they were not taking anticoagulant therapy, whether they were on a vitamin K antagonist, a DOAC, antiplatelet therapies, and then all combinations of the above, including single, double and triple therapy.                                                 What he observed is relative to taking a vitamin K antagonist alone. The hazard ratios range from 1.13 to 3.73 in those that were receiving dual antiplatelet therapy of vitamin K antagonist plus antiplatelet therapy, a DOAC plus antiplatelet therapy, and then of course triple therapy, which had that highest hazard ratio. Dr Carolyn Lam:                But were there particular combinations within these groups that had particularly high bleeding risk? Dr Greg Hundley:             Well, yeah, Carolyn. As we might expect, triple therapy was the worst, but those that were receiving triple therapy, there were two subgroups that were particularly susceptible to having a bleeding episode. First, those that were greater than 90 years of age, and second, those that had CHADS-VASc 2 scores greater than six. Of course, these are very complicated patients, often particularly that latter group. So there are clinical implications. I mean, clearly, this isn't a randomized trial, but what we should take away from this is that if we have one of those two patient groups, age greater than 90, CHADS-VASc score greater than six, that we ought to minimize the time that those individuals are on that triple therapy. Dr Carolyn Lam:                Talk about and bleeding, I've got a paper, and it's on the performance of the ABC scores for assessing the risk of stroke and systemic embolism or bleeding in patients with atrial fibrillation. This is a study that actually looked at the performance of these scores in an external cohort, which actually hasn't really been done. Now, as a reminder, the ABC score is actually the age biomarker clinical history stroke score, which helps to estimate the risk of stroke or systemic embolism. The ABC bleeding risk score incorporates biomarkers along with the clinical variables to estimate the risk of bleeding.                                                 All of these were tested in the ENGAGE AF-TIMI 48 trial, which was that multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS-VASc 2 score of two and above. Now, this was from Dr Morrow and the TIMI study group in the Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts. Basically what they found was that the ABC stroke and ABC bleeding risk scores performed well in stratifying the risk for stroke or systemic embolic events or major bleeding in this multinational trial.                                                 Compared to the CHADS-VASc score, the ABC stroke score provided both correct upward and downward reclassification of the stroke systemic embolism risk. Compared with the HAS-BLED score, the ABC bleeding score resulted in a predominantly correct downward reclassification of the bleeding risk. Dr Greg Hundley:             So, this new ABC score, do we integrate it with HAS-BLED? Do we integrate it with CHADS-VASc 2? How do we use this clinically? Dr Carolyn Lam:                So first of all, there are some important remaining unanswered questions, and this was really nicely discussed in an accompanying editorial by Dr Hylek from Boston University School of Medicine. Among this, first of all, the ABC scores need to be validated in patients outside of a clinical trial. Remember, this was a clinical trial cohort. Then there are questions about the timing of measurements of the score, the different settings, hospital and otherwise. Do these scores perform equally well across different vascular beds and in diverse patient populations at the same thresholds used?                                                 So, all these things still need to be addressed. And really, in Dr Hylek's words, the work has just begun. Dr Greg Hundley:             This is an issue with the theme that might be bleeding, and I'm going to talk about a study from Professor Huisman from Leiden University again, and this is the RE-VERSE AD study. Again, patients that are receiving dabigatran and that may have a GI bleed or patients that are on this therapy and unexpectedly need an emergent surgical procedure, this investigative team evaluated the utility of idarucizumab on reversing that anticoagulant dabigatran. So what did they do? They administered 2.5 milligrams of idarucizumab twice separated by 15 minutes.                                                 And again, the study population was uncontrolled GI bleeding or those in need of an emergent procedure. The types of GI bleeds that were involved in this study, a third were upper GI bleeds, a third lower, and then a third, it was either unknown, or there was a mixture of both upper GI or lower GI bleeding. So how do we know that dabigatran is effective? We use a DTT time, and 98% of those with an elevated diluted thrombin time had that reduced after receiving these two twin 2.5 milligram doses at a time point of four hours after administration. Dr Carolyn Lam:                Okay, but were there any complications? Dr Greg Hundley:             Yeah, there were. So first of all, something to think about is that this is a high-risk group. In this study, 14.6% of the cohort actually later died either from the bleeding or what have you. Then another thing we need to be thinking about is when we reversed this anticoagulant, do patients experience thrombotic events? So what this group reported is 4.4% did within 30 days. What were those? Myocardial infarction, deep venous thrombosis, and subsequent PE. Then also at the 30-day time point, one patient experienced an ischemic event.                                                 Another question is once you've administered this, you've gone through the procedure. You stopped the GI bleeding, or you've had the surgery. In this particular study, 66% of those individuals had restarted their DOAC. Those events occurred on top of that. So, interesting information. Looking at administration of idarucizumab, and we'll be using this I think frequently as DOACs are used more frequently in the population, particularly dabigatran, so some important data in guiding us on what we might expect when we administer this therapy. Dr Carolyn Lam:                I think going back to atrial fibrillation though, this is my other selected paper, and it's actually results from the GARFIELD-AF Registry. It's from Dr Bassand from University of Besançon in France, and colleagues, and basically, they looked at the early risks of death, stroke, systemic embolism and major bleeding in patients with newly diagnosed atrial fibrillation in the GARFIELD-AF Registry. They basically found that the rates of all three major clinical events was significantly higher during the first month than in the subsequent period set following up to 12 months.                                                 The leading causes of early death were heart failure, sudden death, acute coronary syndromes, infection or sepsis, and respiratory failure. Dr Greg Hundley:             So, what's the take-home message here? Dr Carolyn Lam:                This is observational, so the key thing to understand here, it's a registry. It's observational. We can't really tell chicken from egg with regards to its newly diagnosed AF verses events, which comes first, which causes what. But nonetheless, the increased hazards of an early event and especially cardiovascular mortality in these newly diagnosed AF patients really point to the importance of comprehensive care for such patients and really should alert physicians to detect warning signs of possible early mortality in these newly diagnosed patients. Dr Greg Hundley:             Very good, Carolyn. Dr Carolyn Lam:                I think that wraps it up. Let's hop to our feature discussion, shall we? I'm so super excited about today's feature paper because it may explain that strong link between hyperglycemia and cardiovascular disease in type one diabetes and all by revealing a potential novel pathway that may have been hiding in plain sight. And yes, I'm stealing the words of editorialists and our associate editor, Dr Naveed Sattar from University of Glasgow, and we're all so pleased to have with us the corresponding author of today's feature paper, Dr Myra Lipes from Joslin Diabetes Center in Boston, Massachusetts. Myra, start us off by telling us a little bit about your study please. Dr Myra Lipes:                   Sure. So we were interested in examining the role of whether chronic hyperglycemia could trigger cardiac autoimmunity in type one diabetes, because chronic hyperglycemia is associated with subclinical myocardial damage, and we had actually previously observed just unexpectedly in a young adult cohort that ... Actually from Italy, where unexpectedly, we noticed that patients with the poorest glycemic control expressed cardiac antibodies. There's a lot of interesting people who are autoimmune-proned may overreact to injury of certain tissues.                                                 So, type one diabetes, it's a classical autoimmune disorder. So we examined, really tested this hypothesis, in stored samples from the DCCT/EDIC study, and this is a very landmark study where patients were randomized to tight glycemic control, intensive glycemic control. Then another group had just conventional control, and this was done over an average of six and a half years. So during this time, the samples were stored. Every year samples were stored from participants, and this was quite a rich data set that is publicly available. So we studied the development of autoimmunity in two groups that had very distinct separations of the A1C level.                                                 We specifically excluded people who developed kidney disease or cardiovascular disease events during the study. So this is a cohort that had relatively recent onset type one diabetes. They're relatively healthy, and again, groups were matched with cardiovascular risk factors at the beginning and the end of this DCCT period. And of course with our studies, we've also looked genetically because your HLA immune response genes can influence susceptibility to autoimmunity.                                                 These patients were actually matched in HLA genotypes. So what we found was that patients with poor glycemic control, there was expression over time. You could see a time course relationship between expression of antibodies over time on the levels of the antibodies that were different in the two A1C groups. The number of antibodies were different in that with the high group expressing more antibodies, more different types of antibodies. These are antibodies ... might say antibodies as like proteins in the blood, and they're actually directed against parts of the myocytes, the myofibrillar complex, and a major target is cardiac myosin heavy chain.                                                 We saw the different parts of the myosin heavy chain retarded, and the presence of two or more antibodies, different types of antibodies, different regions of the myosin to different isoforms. Also, we saw antibodies, the troponin, troponin I. So the number of antibodies with different ... with almost a complete absence of antibodies in a tightly controlled group. I might mention the A1C average was 6.5%, so this is a very tightly controlled group whereas the poorly controlled group is at the opposite extreme, the average A1C during DCCT. The mean updated A1C was about 10%.                                                 So, it was a very clean group, two different groups, and we could see that the number of the types, the number over time, very different in the two groups. In fact the profiles of these antibodies were almost very similar to patients with Chagas cardiomyopathy. That was our positive control group. Chagas cardiomyopathy is possibility to be a form of chronic myocarditis directed against cardiac myosin. So the profiles are almost indistinguishable. So on one hand, you have relatively healthy patients with type one before glycemic control, and that was very unexpected that this would look pretty similar.                                                 But very interestingly, and I might say unexpectedly, we saw ... It was very clear that the people with the highest titers of antibody and the most different types of antibodies, particularly two or more, were subsequently ... We noticed that those patients were at high risk for developing CVD events. And that's while the number of events was slow, we noticed that all the patients, some 60%, had two or more antibodies and developed cardiovascular events. Perhaps one more striking example is a single patient in the study could die of cardiovascular death, had a positivity for all five antibodies at highest titer.                                                 Then we looked at coronary calcification just to measure subclinical atherosclerosis. We noticed that the same numbers, two or more, and also the same antibody specificities that were the highest predictors of CVD events were also predictive of coronary ... had detectable coronary calcification. In addition, we looked at the levels trying to find mechanistically what could explain the link between cardiac autoimmunity and an increased risk for atherosclerosis. We looked at CRP, high sensitivity CRP levels.                                                 Again, these were measured about a decade after the antibody samples were obtained, and we saw that the positivity for multiple antibodies was also associated with markedly elevated ... subsequently elevated high sensitivity CRP levels with levels of six versus something like 1.4 in a group with one or less antibody. So these were very intriguing findings, suggesting a role for autoimmune pathways as a susceptibility to cardiovascular disease in type one diabetes. Dr Greg Hundley:             Myra, that was absolutely incredible description of the study and all the particulars of the findings. I wonder if I could ask both you and Naveed, where do you see the next steps moving forward with this research in the future? Number one. And number two, is this in any way can be used to segregate patients that may need, for example, really aggressive glucose control with an insulin pump or something of that nature? Naveed Sattar:                  I think we left this study as beautifully described as you see by Dr Lipes. I think the context ... We looked at this from editorial perspective ... is that most people don't realize if you have a middle-aged person with type one, their hazard ratio for cardiovascular risk is about somewhere between four to six fold for men and women respectively, which is much higher than type two. It's often thought that it's the area under the curve for hyperglycemia. But what this paper throws up is actually maybe there's another pathway, which we just didn't understand that this wasn't a permanent autoimmunity closing subclinical myocardial disease and inflammations.                                                 But potentially, for me though, there's a saying in British that one swallow does not make a summer. So, it would be nice for other groups to replicate this. I think the findings are, as they stand in isolation, fantastically well done. But it would be lovely if other groups had accessible samples, and I knew of several groups that have up towards tens of thousands of samples, maybe even not 10,000. Certainly 10,000 or so plus or minus samples for type and prospective outcomes to potentially validate the findings and extend them.                                                 And really, if the antibodies do help protect people at higher risk in a meaningful way and improve beyond what we can already do, then you're right. Absolutely. If we can pick up early people who are going to have substantially higher risk, you would want to potentially improve glycemic control, potentially pumps, CGM, closed-loop systems or more intensive statins or lower blood pressure targets or other types of antihyperglycemic agents, which seem to be being tested in type one as well. So that's really one example.                                                 And for me, the other thing would be really nice is to pull up any inflammation. Is this high systemic inflammation? Is it IL-6 level? Is it something else? What about troponin and BNP levels, et cetera. I'd be interested to hear what Dr Lipes thinks and how do you think to take it forward as well. Dr Myra Lipes:                   So, this is something Dr Sattar said and I completely agree. Actually, right now, we're looking at the DCCT cohort as a whole for already. It's relatively small compared to the population-based studies. But there's 1,400 patients, and the subjects had CMR studies that were published in Circulation. So we're going to actually study next whether we see CMR evidence of systolic dysfunction and looking at the broader DCCT cohort. So, those studies are underway. But of course the ultimate test would be looking at if there were samples available from the Swedish NDRs, Scottish registry.                                                 I think it's something that's not often done prospectively. So that would be incredibly exciting, and that's the important thing. I'd say with type one diabetes, for screening for type one diabetes, the use of autoantibodies and particularly two or more different types of islet autoantibodies, and this is just putting things in a broader context, is the entry criteria for type one diabetes prevention trials and something cardiologists wouldn't be aware of but this particular thing. So in decades, people, researchers, in the field has spent decades optimizing islet antibody assays.                                                 So by analogy, it would be really important to standardize assays so that they can be done in Sweden and Scotland and so that other groups could confirm this, and I'm confident that this could be done, since the setting up of our assays was really built on the experience of people of developing standardized assays and rigorous cutoff points for antibody positivity. So it would be really important to work internationally to try to tap into this. Dr Carolyn Lam:                Oh, my goodness. Myra, Naveed, these are such insightful comments. I think as Greg said earlier, I think we could go on forever discussing this paper, but I'm so sorry. Our time is up. Before we go though, I must point all readers to look at figure five of this marvelous paper. It puts together the whole schema of how autoantibodies can play a role both in myocardial and atherosclerotic cardiovascular disease and type one diabetes.                                                 Thank you so much. Greg and I loved having you. Listeners, don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019.  

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.                                                 Our featured paper this week reports the five-year clinical outcomes and valve durability in the largest available cohort to date of consecutive high-risk patients undergoing transcatheter aortic valve replacement. You must listen up for this discussion, coming right up after these summaries.                                                 The first original paper describes a personalized risk assessment platform that promotes the implementation of precision medicine by helping us with the evaluation of a genomic variant of uncertain significance. A genomic variant of uncertain significance is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded and thus cannot be definitively annotated. These variants therefore pose critical challenges to the clinical interpretation and risk assessment. New methods are therefore urgently needed to better characterize their pathogenicity.                                                 Co-first authors, Dr Ma, Zhang, and Itzhaki, corresponding author Dr Wu from Stanford University School of Medicine and colleagues recruited a healthy, asymptomatic individual lacking cardiac disease clinical history and carrying hypertrophic cardiomyopathy associated genetic variant in the sarcomeric gene, MYL3, which has been reported by ClinVar database to be likely pathogenic.                                                 Human-induced pluripotent stem cells or IPSCs were derived from the heterozygous carrier, and their genome was edited using CRISPR/Cas9 genome editing to generate karyo-specific IPSCs. Extensive essays, including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic IPSC-derived cardiomyocytes, and together, the platform was shown to elucidate both benign and pathogenic hypertrophic cardiomyopathy-functional phenotypes.                                                 Thus, this paper demonstrates for the first time the unique potential of combining IPSC-based disease modeling and CRISPR/Cas9 genome editing technology as a personalized risk assessment platform for determining the pathogenicity of a variant of unknown significance for hypertrophic cardiomyopathy in a patient-specific manner.                                                 Transcatheter aortic valve replacement is increasingly being used for the treatment of severe aortic valve stenosis in patients at intermediate risk for surgical aortic valve replacement. The next paper provides real world data comparing indications and clinical outcomes of patients at intermediate surgical risk undergoing isolated transcatheter vs. surgical aortic valve replacement.                                                 Co-first and corresponding others, Dr Werner and Zahn from Clinical Ludwigshafen in Germany compared clinical characteristics and outcomes of more than 7,600 patients with intermediate surgical risk who underwent isolated transcatheter or conventional surgical aortic valve replacement within the prospective all-comers, German aortic valve registry between 2012 and 2014.                                                 Multi-variable analyses reveal that factors that were associated with performing transcatheter instead of surgical aortic valve replacement included advanced age, coronary artery disease, New York Heart Association class three or four, pulmonary hypertension, prior cardiac decompensation, and elective procedure, arterial occlusive disease, no diabetes mellitus, and a smaller aortic valve area.                                                 Unadjusted in-hospital mortality rates were equal for transcatheter and surgical aortic valve replacement, whereas unadjusted one-year mortality was significantly higher in patients with transcatheter aortic valve replacement. After propensity score matching, the difference in one-year mortality was no longer significant. Thus, this large registry analysis suggests that both transcatheter and surgical aortic valve replacement are reasonable treatment options in a real world population with aortic stenosis and intermediate surgical risk.                                                 The next paper demonstrates a key role of vascular endothelial growth factor receptor 1 in hemorrhagic telangiectasia type 2. Now, this is an inherited genetic disorder where haplo-insufficiency of the activin receptor-like kinase 1 gene, ACVRL1, results in blood vessels that are prone to respond to angiogenic stimuli, leading to the development of telangiectatic lesions that can bleed.                                                 First author, Dr Thalgott, corresponding author, Dr Lebrin from Leiden University Medical Center and colleagues used ACVRL mutant mice and found that vascular endothelial growth factor, or VEGF receptor 1 levels were reduced, causing increased VEGF receptor 2 signaling that promoted sprouting angiogenesis, correcting the abnormal VEGF gradient, by expressing membranal-soluble VEGF receptor 1 in embryonic stem cells or blocking VEGF receptor 2 with antibodies in mutant mice, normalized the phenotype both in vitro and in vivo.                                                 Importantly, VEGF receptor 1 was reduced in the blood and skin blood vessels of patients with hemorrhagic telangiectasia type 2 compared with H match controls, demonstrating an important role of VEGF receptor 1 in these patients and explaining why their blood vessels might respond abnormally to angiogenic signals. These findings support the use of anti-VEGF therapy in hemorrhagic telangiectasia type 2.                                                 The next study suggests that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease following acute rheumatic fever. First author, Dr Kim, corresponding author, Dr Wicks from Walter and Eliza Hall Institute of Medical Research and University of Melbourne and their colleagues analyzed the immune response to group A streptococcus in peripheral blood mononuclear cells from an Australian Aboriginal acute rheumatic fever cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing.                                                 They then tested the widely used immunomodulatory drug, hydroxychloroquine for its effects on this response. They found that group A streptococcus activated persistent IL-1 beta production and selective expansion of a specific group of T helper 1 cells that produce GMCSF. Furthermore, hydroxychloroquine limited the expansion of these group A streptococcus-activated, GMCSF-producing T helper cells in vitro.                                                 Gene transcriptional profiling of peripheral blood mononuclear cells from patients with acute rheumatic fever showed dynamic changes at different stages of disease. Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis where GMCSF plays a pivotal role, the authors therefore proposed that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart fever following acute rheumatic fever.                                                 The next paper identifies a new anchoring B genetic variant in unrelated Han Chinese probands with ventricular tachycardia. In this paper from co-first authors, Dr Zhu, Wang and Hu, co-corresponding authors, Dr Hong from Second Affiliated Hospital of Nanjing University, Dr Mohler from Ohio State University Wexner Medical Center and colleagues, the authors identified the first anchoring B variant, Q1283H, localized to the ZU5C region in a proband with recurrent ventricular tachycardia.                                                 Knocking mice with this variant showed an increased susceptibility to arrhythmias associated with abnormal calcium dynamics. The variant was associated with loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed after depolarization-mediated trigger activity, and arrhythmogenesis. Furthermore, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias, representing potential therapies for anchoring B variant-associated arrhythmias.                                                 Does variability in metabolic parameters affect health outcomes? First author, Dr Kim, corresponding author, Dr Lee from Seoul Saint Mary's Hospital College of Medicine and Catholic University of Korea and their colleagues used nationally representative data from the Korean National Health Insurance system, consisting of more than 6.7 million people who are free of diabetes, hypertension, or dyslipidemia and who underwent three or more health examinations from 2005 to 2012 and were followed to the end of 2015.                                                 Variability and fasting blood glucose and total cholesterol, systolic blood pressure and body mass index was measured using the coefficient of variation, standard of deviation, variability independent of the mean, and average real variability. They found that a high variability in fasting glucose and cholesterol, systolic blood pressure and body mass index was associated with a higher risk for all-cause mortality, myocardial infarction, and stroke. Variabilities in several metabolic parameters had additive associations with the risk of mortality and cardiovascular outcomes in the general population.                                                 These findings suggest that treatment strategies to reduce fluctuations in metabolic parameters may be considered another goal to prevent adverse health outcomes.                                                 How much exercise over a lifetime is necessary to preserve efficient ventricular arterial coupling? First author Dr Hieda, corresponding author Dr Levine from Texas Health Presbyterian Hospital Dallas and University of Texas Southwestern Medical Center and colleagues studied 102 seniors and grouped them based on their 25 years of exercise training history. The dynamic Starling mechanism was estimated by transfer function gain between beat-by-beat changes in diastolic pulmonary artery pressure and stroke volume index.                                                 They found that there was a graded dose-dependent improvement in ventricular arterial coupling with increasing amounts of lifelong regular exercise in healthy older individuals. Their data suggested that the optimal does of lifelong endurance exercise to preserve ventricular arterial coupling with age appeared to be at least four to five sessions per week. The sufficient lifelong endurance exercise was effective for maintaining the normal dynamic Starling mechanism, left ventricular compliance, and arterial compliance with aging, all of which may lead to favorable effect on cardiovascular stiffness or function.                                                 And that brings us to the end of our summaries this week. Now, for our feature discussion.                                                 Transcatheter aortic valve replacement is taking over the interventional world. It's really rapidly growing, and we're increasingly using it for the treatment of aortic stenosis. It was initially used for inoperable and high-risk patients but now is indicated even in the treatment of intermediate-risk patient, and even low-risk patients are being enrolled into current trials.                                                 So, with TAVR being used for low- and intermediate-risk patients, the longer-term results of this treatment involved your abilities becoming more and more important. Well, gratefully, we have today's feature paper, and it describes the five-year clinical outcomes and valve durability of the FRANCE-2 Registry.                                                 I'm so pleased to have with us the corresponding author, Dr Martine Gilard from University Hospital of Brest in France, we have our editorialist, Dr Anita Asgar from Montreal Heart Institute, and we have our associate editor, Dr Dharam Kumbhani from UT Southwestern.                                                 Martine, congratulations on this largest cohort of high-risk patients and long-term outcomes. Could you please tell us what you found? Dr Martine Gilard:            Yes, and I'll just quote, actually, to have a follow-up of five years. We have 1,200 patients arrive at five years after rotation of TAVI. Each patient was a high-risk patient because it was at the beginning of each treatment, and in this time, it's only the high-risk patient was implanted with TAVI, and actually, we can follow this 1,200 patients, 50% of these patients of these patients have an echography because when we analyze these patients, we have an echography at five years, and the patients who have not echography at five years, the only difference is the age.                                                 It's very old patient. It's very difficult to make this echography on this patient to come back in our center, so it's why there is not all the patient who have an echography at five years.                                                 But our patients who have an echography, we can see that it's a very, very good result at five years. There is always the same area, just after before, of the valve. There is the same gradient. There is not a sign of deterioration.                                                 As you know, we have some guidelines published last year about how we asked to define deterioration of the valve, surgical or TAVI, and if we apply this new recommendation, we saw that in this largest cohort, at five years, there is only 13% of patient who have some sign of deterioration, and of these patients, we never need to make another valve in valve because the deterioration was not so important, and patient leave with this valve like that. There is no necessity to make a new valve in valve, so at five years of this very high-risk patient treated by TAVI, there is no necessity to implant a second valve because the valve deterioration. It's a very, very important message. Dr Carolyn Lam:                Thank you, Martine. Indeed, an important message. And Anita, you wrote a beautiful editorial about it. First, could I ask you to frame the issue? I mean, is there any reason we would expect the durability to be any different from a surgical replacement? Dr Anita Asgar:                  I think that's a great question, Carolyn, and I congratulate again Martine and her team for doing a fantastic job to add some very important results to the clinical literature on TAVI. Five years is relatively early to see structural valve deterioration, so in a sense, it's not surprising, and we would consider this sort of medium-term follow-up rather than really long-term durability, but very reassuring that in a high-risk population of patients, that TAVR performs very well in this population of patients and as mentioned, is very low to the dynamic structural valve deterioration.                                                 One question I have for Martine is, as you mentioned, there was only about 12% that had some evidence of structural valve deterioration hemodynamically, but this didn't result in another procedure, and I wonder if you could explain a little bit about that, whether it's the hemodynamic dynamic value, and yet there's a clinical indication for re-intervention. How do you incorporate the two? Dr Martine Gilard:            It's actually hemodynamic deterioration, there is some form of regurgitation. However, there is no need or clinical indication to make another intervention. So, if you compare this research to the bioprostheses surgical paths, the only one who have, at five years, no need to make a re-intervention appearing rotated, which is a valve, a surgical valve we have a longer bioprostheses surgical path.                                                 So, if we compare this best bioprostheses surgical valve, we have sustained results at five years. At five years, we have no need to make a re-intervention because the deterioration was not so important or as needed for clinical evidence as a need to make a new intervention. Dr Anita Asgar:                  So, there were some increased rates of heart failure in those patients with structural valve deterioration in your paper, and I know that in the paper you did mention that this is not an adjudicated outcome, and there wasn't a VARC definition for heart failure, but what's your interpretation of increasing heart failure events in these patients with structural valve deterioration? Dr Martine Gilard:            We have no real definition about that. We know that there is another registry. We say that there is an increasing of heart failure, and during the follow-up, and the result of this heart failure increase in mortality. There is an increasing of heart failure, but the number of these patients, there is more. So I don't know if this due to because patient is a high-risk patient, or it's because of the TAVI, but it's very difficult actually to have a real explanation about that. Dr Carolyn Lam:                Thanks, Anita and Martin. Dharam, could you share some of the thoughts and the discussions that were going on behind the scenes with the editors when we saw this paper? Dr Dharam Kumbhani:   Professor Gilard, this was a really excellent paper. We really appreciated you sending it to us, and I think for us, the fact that this was a very large cohort, the largest published cohort that has gotten to five years in a TAVR population, in a multicenter study, and having very good follow-up up to five years, with these patients is always this competing hazard that you want to know what the valve is doing at five years from an echocardiographic and hemodynamic perspective, but there's such a high competing hazard of death, just given the population that you're enrolling, and still, you had one of the largest echo follow-ups on these patients, so we want to congratulate you on the study and really a monumental endeavor, and so really great, great work there.                                                 And I think this is, exactly some of the questions that I think we had and I'm sure that the audience would have as well, I guess the one other question I have, and it's not really a question about your paper. So the median Euro score is 21 in this study, approximately 21, so that's obviously gonna, consistent with the patients that are being enrolled at that time between 2007 and 2012, which were predominantly high-risk and inoperable patients. Can you talk to us a little bit about the landscape of, how is TAVR practice in France as a society or from the regulatory standpoint, what are the benchmarks that you have achieve as you move towards low-risk now? Because intermediate-risk, I'm assuming is a [inaudible 00:20:16], so could you talk to us a little bit about the landscape there? Dr Martine Gilard:            Yes. In France, it's difficult because we have the authority to follow, not immediately, the ESC recommendations, so actually in France, we are allowed to implant only patients with high risk, patients with complication of surgery, and actually just since one year, patients with automatic risk, but we have no authorization to implant patient with low risk.                                                 However, the most important fact is the heart team, and if they write. Because we need to have something written, and if they write, if they explain that it's necessary to implant a patient at low risk because of some point while not including the risk score or it's very difficult to explain, for example, frailty or something, we can implant a patient with low risk.                                                 But normally actually, it is only for complication or high risk and for intermediate risk like the recommendation of the ESC.                                                 So the rate of implantation in France increased because we implant only 2,000 people per year, but actually, in 2017, we have implanted 10,200 patient, and this year, we think that we implant 12,800 patients, so as the number of patients increase, the number of patients who have a very high risk decrease because there is a futile indication, and we have a lot of futile indication, so we doesn't implant patient while too high-risk, and we select the most majority of patient implanted in France was high-risk but also intermediate-risk. Dr Dharam Kumbhani:   So, you think you're implanting more intermediate, like that is a bigger population that is getting TAVIs right now in France? Dr Martine Gilard:            Yes, exactly. Dr Carolyn Lam:                How about perspectives from Montreal? What do you think the implications of this findings from today's paper in relation to the types of patients that you might perform this in now? Dr Anita Asgar:                  For us, this is exceptionally reassuring, and as Martine has said, I mean, we have transitioned as well away from that very inoperable cohort C type of patient to more your higher-risk patient or intermediate, and to be honest, everyone over the age of 80 in Canada essentially is getting a TAVR. Dr Carolyn Lam:                Oh, wow. Dr Anita Asgar:                  Because regardless of their risk, and we've been very aggressive with that because trying to get patients back to an appropriate quality of life is very important, and to seeing this very reassuring data is telling us that, as she has already mentioned, we have reached the standard, at least in midterm follow-up as the gold standard of surgical valve replacement, and so structural valve deterioration is not as big a concern.                                                 I think we still however need longer-term data when we're looking at lower-risk patients, and lower-risk patients, let's remember, are not 60-year-olds. They're the 75-year-old, perhaps. But we're still gonna need some more data, but it's very reassuring, and patients are asking for it and are really advocating on their behalf to have a less invasive approach, and I think we can say now with more certainty that we know after five years, your chance of structural valve deterioration is actually quite low, and so I think that's very helpful from our point of view. Dr Carolyn Lam:                I love that, Anita, and it's so consistent with the title of your editorial, "Closing in on the Finish Line". Love it, love it, and recommend all listeners pick it up and have a good read. Dharam, I want to leave the last words to you. What do you think are the implications of this paper? Dr Dharam Kumbhani:   Well, I think that, as Anita said, this is very encouraging results that, in this kind of extreme and high-risk patient cohort, that there appear to be no medium- to long-term signals of structural valve degeneration, that the biggest hazard from this procedure is all upfront, and after that, it's pretty much, it's as we have seen with surgery, that after that, the actuarial rates come back to what you would expect.                                                 If they didn't have aortic stenosis and then they would die from whatever causes they had. Now obviously, that wasn't tested, but it seems like looking at the curves, that that seems like what's going on, so I think they've done a great service to our TAVR community in terms of showing us these results in very large, multicenter cohorts from France. Dr Carolyn Lam:                Thank you so much for joining us today. Thank you, listeners. You've been listening to Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association, 2018.  

A systematic literature review on imaging techniques for diagnosis, outcome prediction and disease monitoring in large vessel vasculitis informing the European League Against Rheumatism recommendations is discussed in this podcast by two of the authors of the paper: Dr. Christina Duftner, rheumatologist at the Medical University Innsbruck, Austria, and Dr. Sofia Ramiro, rheumatologist at Leiden University Medical Center, The Netherlands. Read the paper on the RMD Open website: https://rmdopen.bmj.com/content/4/1/e000612.

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. Will artificial intelligence replace the human echocardiographer? Aha, well to find out the answer, you have to wait for the incredibly exciting discussion of today's feature paper coming right up after these summaries.                                                 The clinical benefits of the cholesterol ester transfer protein, or CETP inhibitor dalcetrapib depends on adenylate cyclase type 9, or ADCY9 genotype. However, what are the underlying mechanism responsible for the interactions between ADCY9 and CETP activity? In the first paper from today's journal first author Dr Rautureau, corresponding author Dr Tardif from Montreal Heart Institute, and colleagues used a mouse atherosclerosis model inactivated for ADCY9 and demonstrated that loss of ADCY9 protected from atherosclerosis and was associated with improved endothelial function, but only in the absence of CETP. ADCY9 in activation increased weight gain, adipose tissue volume, and feed efficiency, but only in the absence of CETP.                                                 This mouse model reproduced the interactions between ADCY9 and CETP activity observed in patients, and offers new mechanistic insights for the importance of ADCY9 in determining the responses to CETP inhibition. For example, the dal-GenE clinical trial is currently testing prospectively whether patients with coronary disease and the favorable ADCY9 genotype will benefit from dalcetrapib.                                                 The next study addresses the controversy around the cardioprotective effects of Omega-3 polyunsaturated fatty acids, and uncovers signaling pathways associated with eicosapentaenoic acid, or EPA supplementation that may mediate protective effects in atherosclerosis. First author Dr Laguna-Fernandez, corresponding author Dr Bäck from Karolinska Institute, and their colleagues showed that EPA supplementation significantly attenuated atherosclerotic lesion growth. They performed a systematic plasma lipidomic analysis and identified that 18 monohydroxy eicosapentaenoic acid was a central molecule formed during EPA supplementation. 18 monohydroxy eicosapentaenoic acid was a precursor for the plural resolving lipid mediator called resolvent E1.                                                 In the present study, a resolve in E1 was shown to regulate critical atherosclerosis related functions in macrophages through its downstream signaling receptor to transfuse protective effects in atherosclerosis.                                                 Are there racial differences and long-term outcomes among survivors of in-hospital cardiac arrest? In the next paper first and corresponding officer Dr Chen from University of Michigan and her colleagues performed a longitudinal study of patients more than 65 years of age who had an in-hospital cardiac arrest and survived until hospital discharge between 2000 and 2011 from the National Get With The Guidelines Resuscitation Registry whose data could be linked to Medicare claims data. They found that compared with white survivors of in-hospital cardiac arrest, black survivors had a more than 10% lower absolute rate of long-term survival after hospital discharge. This translated to a 28% lower relative likelihood of living to one year, and a 33% lower relative likelihood of living to five years after hospital discharge for black versus white survivors.                                                 Nearly one-third of the racial difference in one-year survival was dependent on measured patient factors. Only a small proportion was explained by racial differences in hospital care, and approximately one-half was the result of differences in care after discharge, or unmeasured confounding. Thus, further investigation is warranted to understand to what degree unmeasured, but modifiable factors, such as post-discharge care may account for the unexplained disparities.                                                 The next study provides insights into a novel mechanism of atherogenesis that involves protease-activated receptor 2, a major receptor of activated factor 10, which is expressed in both vascular cells and leukocytes. Co-first authors Dr Hara and Phuong, corresponding author Dr Fukuda from Tokushima University Graduate School of Biomedical Sciences, and their colleagues showed that in ApoE-Deficient deficient mice, protease-activated receptor 2 signaling activated macrophages and promoted vascular inflammation, increasing atherosclerosis.                                                 Furthermore, they showed that in humans, plasma-activated factor 10 levels positively correlated with the severity of coronary artery disease, suggesting that the signaling pathway may also participate in atherogenesis in humans. Thus, the protease-activated receptor 2 signaling pathway may provide a novel mechanism of atherogenesis and serve as a potential therapeutic target in atherosclerosis.                                                 The next paper tells us that biomarkers may help to predict specific causes of death in patients with atrial fibrillation. First and corresponding author Dr Sharma and colleagues from Duke Clinical Research Institute evaluated the role of biomarkers in prognosticating specific causes of death among patients with atrial fibrillation and cardiovascular risk factors in the ARISTOTLE trial.                                                 They looked at the following biomarkers: high sensitivity troponin T, growth differentiating factor 15, N-terminal pro-B-type natriuretic peptide, and interleukin 6. They found that sudden cardiac death was the most commonly adjudicated cause of cardiovascular death, followed by heart failure and stroke or systemic embolism deaths. Biomarkers were some of the strongest predictors of cause-specific death, and may improve the ability to discriminate among patients' risks for different causes of death.                                                 How do the complement and coagulation systems interact in cardiovascular disease? Well in the final original paper this week, first author Dr Sauter, corresponding author Dr Langer from Eberhard Karls University Tübingen, and their colleagues used several in vitro, ex vivo, and in vivo approaches as well as different genetic mouse models to identify the anaphylatoxin receptor C3AR and its corresponding ligand C3A as platelet activators that acted via intra -platelet signaling, and resulted in activated platelet fibrinogen receptor GP2B3A. This in turn mediated intravascular thrombosis, stroke, and myocardial infarction. This paper, therefore, identifies a novel point of intersection between the innate immunity and thrombosis with relevance for the thrombolic disease of stroke and myocardial infarction.                                                 That wraps up with week's summary. Now for our featured discussion.                                                 Can we teach a machine to read echocardiograms? Well today's feature paper is going to be all about that. I am so excited to have with us the corresponding author of an amazing, and I think, landmark paper, Dr Rahul Deo from the One Brave Idea Science Innovation Center and Brigham and Women's Hospital in Boston, as well as our associate editor Dr Victoria Delgado from Leiden University Medical Center in The Netherlands. Now let me set the scene here. We know that echocardiography is one of the most common investigations that we do in cardiology, and in fact even outside of cardiology, and it is hands down the most accessible, convenient tool to image the heart.                                                 Now let's set this up by remembering that echocardiograms are performed with machines, but led by echocardiologists like me. Now this is really scary Rahul because I think your paper is trying to say ... Are you trying to put people like me out of business? Dr Rahul Deo:                    Definitely not. I think what I'm hoping to do is actually two things. One of them is, despite the fact that it's an accessible and safe tool, because it needs people like us, it's probably not used as often as ideally it could be. So part of our hope was to democratize echocardiography by being able to take out some of the expenses from the process so that we can hopefully get more simpler studies done at an earlier stage in the disease process. Because in many ways, at least from my experiences being an attending, it feels like if we could just have gotten to these patients earlier we may have been able to start therapy that could've changed the disease course, but our system can't really afford to do huge numbers of echoes on asymptomatic patients. Really we were trying to find some way of facilitating this by at least helping out on trying to quantify some of the simple things that we do with echocardiography. Dr Carolyn Lam:                I love that phrase, democratizing echo. And you're absolutely right, if we could put it in the hands of non-experts and help them interpret them, we could really lead to detecting disease earlier, and so on and so forth. Wow. But everyone's wondering, how in the world do you go about doing that? Dr Rahul Deo:                    One of the things that's really been amazing in these last five years or so is that the field of computer vision, so the field by which computers are trained to mimic humans in terms of visualizing, recognizing, identifying images, has really advanced, and incredibly rapidly. And one of the reasons for that is that the video game type of computing system, the same things that go into Playstations and such, have resulted in much, much more rapid computing. And that's allowed us to train more complex models.                                                 So that's one of the things that's changed, and also, it's just much easier to get our hands-on training data. So machines can be trained to do things, but they need lots of examples. And the harder the task, the more examples they need. So the widespread availability of digital data has made that easier, though I would say that it wasn't that easy to get our hands on enough echocardiography data to be able to train. But in general, almost any task where there's enough data has been solved on the computer vision side. So this has really been an exciting advance in these last few years. So we thought we could very well just used these same technologies on a clinical problem. Dr Carolyn Lam:                Okay, but Rahul what are you talking about here? Like the machine's actually going to recognize different views, or make automated measurements? That's the cool thing, frankly, that you've written about because we know that the machines can already kind of do EF, ejection fraction, but you're talking about something way bigger. So tell us about that. Dr Rahul Deo:                    Yeah, so there are many cute examples in the popular press about machines being able to recognize the differences between cats and dogs, or some breeds of dogs. And so if you think about things that way, it really shouldn't be that much more difficult to imagine recognizing between different views, which probably are much more dramatically different than different breeds of dogs. So you could really just take the same models, or the same approaches, give enough examples, label them, and then say figure out what the differences are.                                                 And I think one of the challenges with these systems is they're often black boxes. They can't tell us exactly what it is that they're using, but when it comes to something like recognizing whether something is an apical four chamber view or a parasternal long axis view, we actually don't care that much as to how it is that the computer gets there. We just wanted them to do it accurately, and that's one of the places for some of these computer vision models. It's a field broadly called deep learning, and it's just great at achieving complex tasks.                                                 So, once you recognize views, then the other thing that computers have been shown to be able to do is recognize specific objects within an image. For example, you could give an entire football field and you could find a single player within it. You could recognize where the players are, where the ball is, where the grass is. So computers can distinguish all those things too. And then once you know where something is, you can trace it and you can measure it. So in that sense it's very similar to what a human reader would do, it's just broken down into individual steps, and each one of those needs to be trained. Dr Carolyn Lam:                You put that so simply so that everyone could understand that. That's so cool. You mentioned, though, accuracy. I could imagine that a machine would likely interpret one image the same way again and again, and that addresses something that we really struggle with in echo doesn't it? Because, frankly, one reader against another, we always know. Ejection fraction has got a plus minus seven or something, and then even within the same reader you could read the same thing and say something one day, and say something the other. So this is more than just automating it, is it? Dr Rahul Deo:                    Yeah, so it's certainly making it more consistent, and the other thing that we were able to do, I mean once you can teach it to identify and traces the contours of the heart in one image you can have it do it in every single image within the video, and every single video within the study. So now, I mean it's quite painful. I know this from my own experience in terms of tracing these things, so a typical reader can't trace 150, 200, 300, 500 different hearts, that's not going to happen. So instead, they'll sort of sift through manually, pick one or two, and if there's variability from one part of the study to the other, that really won't be captured.                                                 And in this case, the computer will very happily do exactly what you ask it to do, which is to repeat the same thing again and again and again, and then be able to average over that, capture variability. So that's one of the tasks that is much more easy to imagine, setting a computer who won't talk back to you and won't resist and won't refuse to actually taking on the mundane aspect of just getting many, many, many more measurements. And that could happen not only in a single study, but also could happen more frequently. So you could imagine that, again, there's just not that resistance that's coming from having to have an individual do these things. Dr Carolyn Lam:                Oh, my goodness, and not only does he not ... well he, machine, not say no, I mean they don't need to take time off or weekends off. We could get immediate reports directly. Oh my goodness. Victoria I have to bring you in on this. We knew as editors when we found this paper that this is something we just have to publish in Circulation that's going to be groundbreaking. Could you tell us a little bit more about what you think the implications of this is? Victoria Delgado:              I think that this is a very important paper because it's a very large study and it's sets, I would say, three important questions that we deal every day in clinical practice. One is how to reduce burden in very busy echo labs by facilitating the reporting of the echoes and the interpretation of the echoes. Second: to have an accurate measurement and quantification of the images that we are acquiring, and third: this is recognition of the pattern.                                                 And I think that this very important, particularly in primary care because, for example in Europe here, echocardiography is not really in the primary care and the patients are being referred to secondary level hospitals or third level hospitals. That means that the waiting days sometimes is too long. If we train the general practitioners, for example, to do simple echocardiograms with the handheld systems which are also the technologies that are coming and are really available in your iPhone, for example, on your phone, you can get an echocardiographic evaluation of a patient that comes to a general practitioner.                                                 And if you don't have too much knowledge on interpretation, these tools that can have recognition of the pattern of the disease can trace a red flag and say, okay this patient may have this disease or may have this problem, you should consider sending or referring this patient to us at Leiden Hospital where he's going to have a regular check-up and a complete echocardiogram. That could lead to less burden in very busy labs and only refer the patients in a timely manner to the centers when they have to be referred, when the others can wait of can be referred much later.                                                 I think that that's important, and next two technologies that are coming now and it will be very important, some groundbreaking technologies. One is the handheld systems, the ones that you can have in your phone, the ones that you can have in your tablet for example. And the other one is going to be the artificial intelligence to, if not diagnose completely, at least to recognize the pattern that there is a pathology where we need to focus, and we need to act earlier. Dr Rahul Deo:                    I think that one place we would like to see this used is in a primary care setting where you have individuals who have risk factors that we know would be risk factors, for example, for let's say heart failure with preserved ejection fraction. But really, my experience in that phase of clinical practice is there's a lot of resistance from patients to get on the medications. So hypertension is, at that point, often, I just got worked up because I had a hard time finding parking, and so on, and so on, where there's just a natural resistance.                                                 So if you could imagine having objective measures describing, let's say how their left atrium is doing at that point, how it looks the next year, what the change in therapy is doing, all these things, you actually can bring in that quantification at a low enough cost that makes it actually practical, then that would be one place we could imagine motivating or intensifying therapies on the basis of something like this.                                                 And I think one area we have to admit we didn't solve is we haven't solved the ability to facilitate getting the data in the first place. We do know that there are these focused workshops around trying to get some simple views, and more and more of our internal medicine residents are able to get some of these, but we can't dismiss that this is still an important challenge in terms of being able to get the images. What we want to do is say, well you can get some images and we can help you interpret them and quantify in an effort to try to motivate therapies being initiated or intensified in a way that's sometimes difficult to do in the current system. Dr Carolyn Lam:                So, Rahul and Victoria, you both mentioned that one of the key aspects is the acquisition of the echo. Not just the machine that does it, but also who takes the images that will then be automatically analyzed. So, Rahul, do you think that sometimes you're going to invent something that will replace even the acquisition, or maybe even simplify it so that we may not need Doppler anymore? Dr Rahul Deo:                    One of the things that we thought about was, we wanted to limit ourselves to views that might be easier to acquire, in part because we wanted to reduce the complexity of the study and yet still try to capture as much information as possible. And getting back to the first part of your question, you could imagine that recognizing a view is not that different from recognizing that a view is 10 degrees off from where it should be. You could imagine training a computer to do just that very same thing too. It could recognize a slightly off axis apical four chamber view and guide you into correctly positioning the probe, and you could even imagine a robotic system that does this and just takes the person out of it all together. In part because a very skilled sonographer can quickly look at something and say, oh I just need to tilt my wrist this way and move it this way. I was always humbled by that because I never could quite do that myself.                                                 But in the same way, and in the way, that's happening is that an image is recognized, and then the reference image is held in one's brain, and then they just know from experience what needs to be done to turn one into the other. But that very well-oiled machine could very well be taught to do that exact same thing too. Dr Carolyn Lam:                Oh wow. That is just totally amazing. I know the listeners are being blown away by this just as I am. Let me just end by asking for any last words, Victoria and Rahul, of the clinical application of this. When are we going to have this primetime? What do you think? Victoria Delgado:              I think that this is coming. This is one, for example, of the first studies showing the feasibility of this technology. In terms of accuracy, probably we need improvement, but that depends very much on the quality of the echocardiographic data that we obtain. And in the future, I think that we are going to rely more and more on this technology, and we will have the expert view for those cases that are ambiguous or where the technology has limitations. But in terms of accuracy, for example, I can imagine one of the clinical scenarios that we face in everyday clinical practice is the evaluation of the effect of the treatment in heart failure patients for ejection fraction, and in patients, for example, treated with chemotherapy to see changes in ejection fraction.                                                 That, if we do it manually as we do now, we know that we have limitations in terms of the own viability of the observer. If you leave it for artificial intelligence, maybe that viability may be reduced, and you may be better in terms of adjusting the medication if needed. Because you removed completely what would be the individual viability. So these are the fields that probably I see more and more application of this technology in order to improve the reproducibility of the measurements and accuracy. But yeah, for that we need probably very good image quality, and I see in echocardiography we always tend to say, yeah the image quality is not that good. I'm sure that echocardiography can give you much more than just using through the echocardiography. You can use contrast, you can use many other techniques in order to improve the image quality. And artificial intelligence, the better the image quality is, probably the better it's going to be as well, the accuracy of the measurements and the recognition of disease. Dr Carolyn Lam:                Wow, and Rahul? Dr Rahul Deo:                    I completely agree with Victoria. I think that we're going to have to be clever about where we incorporate something like this into the current clinical workflow. You have to choose your problem carefully, you have to understand it. Any system like this is going to make some mistakes. To figure out how to minimize the impact of those mistakes, and at the same time add benefit and potentially enable things that wouldn't even be done. So I think that the fun stuff is yet to come here in terms of really incorporating this in a way that can really change clinical practice.                                                 I want to add one thing that I really haven't mentioned. And we, at this point, really just focused on trying to mimic the stuff that we're already doing. Part of the motivation of this work is to try to potentially see things that we can't even see right now and try to potentially predict onset of disease or early latent forms of something that would really be difficult to detect by the human eye. And we've seen examples of that in some of the other fields around radiology, and I think that's going to be a place that would be augmenting beyond what we're even doing currently.                                                 But of course, the challenge is that the system has to be interpretable enough that we understand what it is that it's seeing, because otherwise I'm sure we'll be reluctant to embrace something clinically that we don't understand. Dr Carolyn Lam:                You've been listening to Circulation on the Run. 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.                                                 FDG-PET CT was recently introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, can we improve on its diagnostic performance? Well, to learn more you have to listen to the upcoming featured discussion, right after these summaries.                                                 Our first original paper this week describes a potential novel therapy for hypertension. In this study from first author Dr Hu, corresponding author Dr Soong, from Yong Loo Lin School of Medicine National University of Singapore, authors showed that galectin-1 is a key regulator for proteasomal degradation of CaV 1.2 channels. L-type CaV 1.2 channels are known to play crucial roles in the regulation of blood pressure. In a series of elegant in vitro and in vivo experiments, the authors showed that galectin-1 promotes CaV 1.2 degradation by replacing CaV-beta and thereby, exposing specific glycines for polyubiquitination. This mechanistic understanding provided the basis for targeting CaV 1.2 galectin-1 interaction and demonstrated the modulatory role that galectin plays in regulating blood pressure. The study, therefore, offers a potential novel approach for the therapeutic management of hypertension.                                                 Direct oral anticoagulants or DOACs, are surpassing warfarin as the anticoagulant of choice for stroke prevention in non-valvular atrial fibrillation. However, DOACs outcomes in elective peri-procedural settings have not been well elucidated and remain a source of concern for clinicians.                                                 The next paper in today's issue was a meta-analysis designed to evaluate the peri-procedural safety and ethicacy of DOACs versus warfarin. For author Dr Nazha, corresponding author Dr Spyropoulos, from the Feinstein Institute for Medical Research in Northwell Health at Lenox Hill Hospital in New York, reviewed the literature for data from phase three randomized controlled trials comparing DOACs with warfarin in the peri-procedural period among patients with non-valvular atrial fibrillation. Sub study from four trials were included namely RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF. The short-term safety and ethicacy of DOACs and warfarin were not different in patients with non-valvular atrial fibrillation peri-procedurally. Under an uninterrupted anticoagulation strategy, DOACs were associated with a 38% lower risk of major bleeds compared to warfarin.                                                 The next paper presents results from the Sarcomeric Human Cardiomyopathy Registry or SHARE, which combined longitudinal data sets curated by eight international hypertrophic cardiomyopathy specialty centers to provide a better understanding of the factors that contribute to heterogeneous outcomes in lifetime disease burden in patients with hypertrophic cardiomyopathy. First and corresponding author Dr Ho from Brigham and Women's Hospital and colleagues analyzed longitudinal clinical information on 4,591 patients with hypertrophic cardiomyopathy. By examining the data set spanning more than 24,000 patient-years, the mortality of patients with hypertrophic cardiomyopathy was shown to be 3-fold higher than the general population at similar ages. The lifetime cumulative morbidity of hypertrophic cardiomyopathy was considerable, particularly for patients diagnosed before age 40 years and patients with sarcomere mutations. Atrial fibrillation and heart failure were the dominant components of disease burden. Thus, young age of diagnosis and the presence of sarcomere mutations are powerful predictors of adverse outcomes in hypertrophic cardiomyopathy. These findings highlight the need for close surveillance throughout life and the need to develop disease-modifying therapies.                                                 The final original paper this week provides molecular insights into atherosclerosis and it shows that defective base excision repair of oxidative DNA damage in vascular smooth muscle cells promotes atherosclerosis. Now, we know that atherosclerotic blocks demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine lesions. In today's paper, first author Dr Shah, corresponding author Dr Bennett from University of Cambridge and colleagues studied levels of 8-oxoguanine and its regulatory enzymes in human atherosclerosis. They found that human plaque vascular smooth muscle cells showed defective nuclear 8-oxoguanine repair, associated with reduced acetylation of the base excision repair enzyme 8-oxoguanine-DNA-glycosylase-1. Furthermore, correcting the base excision repair defect in vascular smooth muscle cells alone markedly reduced plaque formation, thus indicating that endogenous levels of oxidative DNA damage in vascular smooth muscle cells promoted plaque development.                                                 And that brings us to the end of this week's summaries. Now for our feature discussion.                                                 Prosthetic valve endocarditis is a life-threatening complication. However, making a timely diagnosis of prosthetic valve endocarditis before the occurrence of severe complications is really difficult. Now, FDG-PET CT has recently been introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, previous studies reported only modest diagnostic accuracy and may have been hampered by confounders. But today's study, our feature study in Circulation, addresses this issue. We have none other than the corresponding author, Dr Ricardo Budde from Erasmus Medical Center in Rotterdam, the Netherlands, and our dear associate editor, Dr Victoria Delgado, who is in Leiden University Medical Center, also in the Netherlands.                                                 So please tell us, how does your study help us address this issue of the accuracy of FDG-PET CT Dr Ricardo Budde:           What we actually did is that of course endocarditis is a relatively rare disease, so we had six hospitals in the Netherlands that collaborated on this study and in each of the hospitals we searched for PET CT scans that were performed in patients with a prosthetic heart valve, either because they were suspected of having endocarditis, or if they were meant for other purposes, for example oncological follow-up. Then we grouped all those CT scans together, interpreted the PET CTs anew by dedicated interpreters, and then compared the findings with the actual diagnosis in the patient, which of course is always difficult in endocarditis because to make the diagnosis is difficult. So, also, one year follow-up period was included in that to be absolutely certain whether the patient had endocarditis or not. By taking this whole cohort of patients, we were able to determine the diagnostic accuracy of PET CT, as well as by using a logistics model, identify confounders which influence the diagnostic accuracy of PET CT.                                                 I think the study that we did addresses several important aspects and the way it helps physicians in actually interpreting and implementing PET CT to diagnose endocarditis is two-fold. First of all, we identified confounders that have to be taken into account when interpreting and using the PET CT. For instance, low inflammatory activity at the time of imaging and the use of surgical adhesive during a prosthetic heart valve implantation are confounders which should be taken into account when interpreting the PET CT. Furthermore, the guidelines have always insisted on not to use or use it very cautiously PET CT within the first three months after prosthetic heart valve implantation. However, we showed that actually this period after implantation does not necessarily have to be taken into account as also a good diagnostic accuracy can be obtained within the first three months after implantation. Dr Carolyn Lam:                Ricardo, that's wonderfully put. I don't do a CT, PET CT, routinely. In fact, I am echocardiologist and it used to be that infective endocarditis was diagnosed with echo. So Victoria, tell us, how does echo stand now with this information? Dr Victoria Delgado:        That's a very good question but I think the guidelines set a very clear figure of how the diagnostic workup of patients with prosthetic valve endocarditis should be performed. An echocardiography is the first imaging technique. The point is that transthoracic echocardiography in patients with suspicion of prosthetic valve endocarditis is very challenging. In terms of ideal, echocardiography is probably the best imaging technique to do first to evaluate whether it is endocarditis or not. It's difficult, we have to take into account that for a specific prosthetic valve, particularly mechanical, the shadowing can make that we don't see the [inaudible 00:10:22] and sometimes it's difficult, particularly in the early phase immediately after implantation, all the inflammation can be confounder for presence of endocarditis. In those cases, I think that this study provides additional and important data highlighting which are the confounders when you use PET CT to evaluate depressions of endocarditis. I think that, when you take into account those confounders, the accuracy of this technique is very good in order to make or help in the diagnosis of these patients. So, echocardiography, I think that will remain as our first imaging technique to rule out [inaudible 00:11:10] we can see but in those cases where the diagnosis is not confirm or rule out with transthoracic and transesophageal echocardiography this study provides additional data and important data showing that PET CT is a valuable complementary imaging diagnostic test for these patients. Dr Carolyn Lam:                Ricardo, would you agree with that because I think your study also emphasized that perhaps FDG-PET CT should be implemented early in the diagnostic workup to prevent the negative confounding effect of the low inflammatory activity? So how do we put this all together? Dr Ricardo Budde:           Well actually, I agree with Dr Delgado that echocardiography is and should be the first-line test that you do if you have a patient that has a suspicion of endocarditis. I mean, the advantages of echocardiography are many and it's non-invasive, it's bedside-available if needed, it's patient-friendly, and it provides a huge amount of information so you should always start with echocardiography. However, sometimes it can be difficult by echocardiography, for the reasons just explained by Dr Delgado, and I think then PET CT should be considered. And when you want to do a PET CT, then you should do it early within the diagnostic workup.                                                 Actually, in the article, one of the figures is a flow chart which we provide, and it provides information on how we think PET CT can best be implemented in the workup of endocarditis. In this flow chart we also start with doing an echocardiography and also, importantly, consult the endocarditis time to make initial classification of whether it's a rejected, possible, or definite prosthetic heart valve endocarditis. After that, you can follow the flow chart and see when you can best implement PET CT, in our opinion. Dr Carolyn Lam:                Indeed Ricardo, I am so glad you brought up this figure and listeners, you have to take a look at it. I can imagine that everybody will be using this and discussing it and how to incorporate this in the workflow. And indeed you do start with either transthoracic or transesophageal echo and blood cultures, so thank you for clarifying that.                                                 Now, for our clinicians out there, are there any situations you may be telling us to be a little more careful? Could you put it simply for us when it comes to the FDG-PET? Dr Ricardo Budde:           You mean when not to perform a PET CT? Dr Carolyn Lam:                Yeah, or when we have to be really careful about inaccuracies. Dr Ricardo Budde:           I think, of course, the confounders that we indicate in the article, especially if bioglue has been used by the surgeon during the initial surgery. We know that bioglue can be seen on a PET CT as a false positive uptake of FDG and it's also important to note that this is a phenomenon that can persist for a very long time after a valve implantation. It could be for years, so especially that I think is a very important confounder to take into account and be careful when you interpret PET CT or use the PET CT and always read the original surgical report if it is available to obtain this information. Dr Carolyn Lam:                That's wonderful advice. Victoria, do you have anything to add? Dr Victoria Delgado:        No, I think that Dr Budde explained perfectly this figure that is key in the article and also how to evaluate patients with suspected endocarditis of prosthetic valve. One thing that sometimes we forget is starting from the first step that is a good clinical history which includes also a good evaluation of previous history and, if possible, what has been done in the patient. I think that this key information to understand the findings on the echocardiography, transthoracic or transesophageal, and the subsequent investigations that you are going to perform. Either CT which is considered, for example, when you have a definitive prosthetic valve endocarditis and you want to rule out potential complications such as abscess, for example, and if you perform a PET CT or other imaging modalities that then also indicate the presence of infection like, for example, [inaudible 00:15:26] leukocytes with PET, for example. Dr Carolyn Lam:                And I just want to end up with one little point. Ricardo, how about the fact that part of your results don't corroborate the ESC guideline recommendations that they say you have to avoid FDG-PET in the recently implanted prosthetic valve. How do you feel it's going to play out for clinicians? Dr Ricardo Budde:           Well, I think the 2015 ESC guidelines on endocarditis are a very important document. One must take into account that the inclusion of PET CT in the ESC guidelines was a major step, and some might say that it was a little premature to include the use of PET CT because the number of data that was out there were still relatively limited. I think it's something that we are learning along the way. Now that we are using PET CT more often we are more aware of what we do to findings that we get and also the findings that we have within specific timeframes after the implantation of a prosthetic heart valve. One of the things that I think is desperately needed also at the moment is to have a prospective study where we would do PET CT in patients after implantation of a prosthetic heart valve that do not show any signs of endocarditis where we do PET CT just to determine these normal uptake values. I think that would be a major contribution to the whole learning experience that we're currently having with implementing PET CT within prosthetic heart valve endocarditis. Dr Carolyn Lam:                Indeed, and Ricardo your paper has added significantly to our understanding. Readers, remember, it's Figure 6 of our feature paper this week. It is a beautiful figure. Pick it up, take a look. In the meantime just thank you so much Ricardo and Victoria for joining me today.                                                 Listeners, don't forget to tune in again next week.  

RMD Open Editor-in-Chief Professor Bernard Combe talks to Professor Annette van der Helm from Leiden University Medical Center about the use of MR imaging in the diagnosis and classification of rheumatic and musculoskeletal diseases. Professor van der Helm briefly summarises the pros and cons of MR imaging in comparison with the use of CT images, and highlights some of the technical challenges of this technique. For further information on this topic please read this viewpoint article published in RMD Open: https://rmdopen.bmj.com/content/4/1/e000728.

Guest: Dr. Valeria Orlova is the Principal Investigator at the Leiden University Medical Center. Dr. Orlova’s lab uses stem cells to study the blood vessels and vasculature. She joins us to talk about her work…

Full text - http://bit.ly/2ocULhq Interview with Dr. Raz with the Department of Orthopaedics, Leiden University Medical Center, in the Leiden Netherlands talking about their featured cover paper in Oncotarget Volume 7 Number 8 "Molecular signatures of age-associated chronic degeneration of shoulder muscles" Facebook - http://bit.ly/2xznxjV Twitter - http://bit.ly/2xzWvsu LinkedIn - http://bit.ly/2xzJ6kc Pintrest - http://bit.ly/2xzX8SS Reddit - http://bit.ly/2hoxI0N www.Oncotarget.com

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 Centre and Duke-National University of Singapore. Our featured discussion today relates to 20 year outcomes after mitral valve repair versus replacement for severe degenerative mitral regurgitation.                                                 But first, here's your summary of this week's issue. The first paper suggests that agonistic angiotensin receptor autoantibodies may be biomarkers of adverse outcomes. In this study from first author Dr. Abadir, corresponding author Dr. Fedarko, and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland, authors developed a quantitative immunoassay for measuring agonistic angiotensin AT1 receptor autoantibodies in the serum.                                                 They then assessed its operating characteristics in a discovery group of 255 community dwelling adults from Baltimore and validated these findings in a second group of 60 individuals from Chicago. They found that AT1 receptor autoantibody levels were significantly associated with higher levels of inflammatory cytokines, weaker grip strength, slower walking speed, higher risk for frailty, more falls and increased mortality.                                                 Furthermore, chronic treatment with angiotensin receptor blockers, it attenuated the AT1 receptor autoantibody association with decline in grip strength and increased mortality. These results therefore suggest that followup studies and intervention trials in chronic inflammatory diseases should test whether AT1 receptor autoantibody levels can be used to stratify patient risk and whether they can be used to identify patients who may benefit from angiotensin receptor blocker treatment.                                                 The next paper suggests that baseline target mismatch on CT perfusion imaging may predict the response to tenecteplase in ischemic stroke. Dr. Bivard and colleagues from John Hunter Hospital University of Newcastle in Australia pooled two clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke.                                                 Baseline CT perfusion was analyzed to assess if patients met the diffused two target mismatch criteria. These criteria are absolute mismatch volume of more than 15 mL, mismatch ratio of more than 1.8, baseline ischemic core less than 70 mL and volume of severely hypoperfused tissue less than 100 mL.                                                 Among 146 pooled patients, 71 received received alteplase and 75 received tenecteplase. Overall tenecteplase treated patients had greater early clinical improvement by NIH Stroke Scale change and less parenchymal hematoma, but did not show a significant difference in three month patient outcome by the Modified Rankin Scale.                                                 74 of the 146 patients met target mismatch criteria. It was only among these patients with target mismatch that treatment with tenecteplase result in greater early clinical improvement and better late independent recovery than those treated with alteplase. In summary, tenecteplase may offer an improved efficacy and safety profile versus alteplase, benefits that are possibly exaggerated in patients with baseline CT perfusion defined target mismatch.                                                 The next study is the first to provide a comprehensive analysis of circulating metabolite levels and relate these to clinical outcomes in patients with pulmonary arterial hypertension. First author Dr. Rhodes, corresponding author Dr. Wilkins and colleagues from Imperial College London conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry in 365 patients with idiopathic or heritable pulmonary arterial hypertension and 121 healthy controls.                                                 They found that increases in circulating modified nucleosides originating from transfer RNAs, energy metabolism intermediates, tryptophan and polyamine metabolites and decreased steroids, sphingomyelins and phosphatidylcholines independently discriminated pulmonary arterial hypertension from controls and predicted survival. Furthermore, correction of metabolite levels overtime was linked to better clinical outcomes and patients who responded well to calcium channel blocker therapy had metabolic profiles comparable with healthy controls, thus these findings suggest that monitoring plasma metabolites overtime could be useful to assess disease progression and response to therapy in pulmonary arterial hypertension. Therapeutic strategies targeted against metabolic disturbances, particularly translational regulation and energy metabolism, may merit further investigation in pulmonary arterial hypertension.                                                 The final study takes a contemporary look at age associated changes in left ventricular diastolic function. Dr. Shah and colleagues from Brigham and Women's Hospital in Boston, Massachusetts related diastolic measures including tissue Doppler E prime, E to e prime and left atrial size, to the risk of heart failure hospitalization or death in 5801 elderly participants in the ARIC study. They further defined sex-specific 10th percentile limits in 401 participants free of cardiovascular disease or risk factors. They found that each diastolic measure was robustly associated with incident heart failure hospitalization or death. Reference limits for E to e prime and LA size were generally in agreement with existing guidelines, whereas limits for tissue Doppler E prime were substantially lower at 4.6 for septal E prime and 5.2 for lateral E prime in the ARIC study compared to 7 and 10 respectively in international guidelines. Compared to the guideline cut points, the ARIC base limits improved risk discrimination and reclassified over one-third of the study population as having normal diastolic function. These findings were further replicated in the Copenhagen City Heart Study.                                                 In summary, this study suggests that a decline in left ventricular longitudinal relaxation velocity occurs maybe as part of healthy aging and is largely prognostically benign. This supports the use of age-based normative values when considering an elderly population.                                                 Well, that wraps it up for the summaries, now for our featured discussion.                                                 Today we are discussing the very important result of the mitral regurgitation international database and we have with us today no other than the corresponding author Dr. Jean-Louis Vanoverschelde, and he is from University of Louvain in Brussels. Welcome Jean-Louis, I made it. Dr Jean-Louis Vanoverschelde:  Hey, how are you? Dr Carolyn Lam:                Thank you so much for joining us. Also joining us today is Dr. Victoria Delgado, associate editor from Leiden University Medical Center in the Netherlands. Welcome Victoria. Dr Victoria Delgado:        Hello. Thank you very much for having me in this podcast. Dr Carolyn Lam:                So, severe degenerative mitral regurgitation with flail leaflets, a very important condition and your study, Jean-Louis, really provides important clinically applicable information. Could you please address our clinicians out there with a take home message from your paper. Dr Jean-Louis Vanoverschelde:  Well, the take home message is very easy, once this condition needs to be operated on, there are really two options, one which is to repair the valve and keep the native tissue and the other is to replace the valve and trash the native tissue if I can say so. The results of the study are really clear. There is a major survival advantage by repairing the valve as opposed to replacing it. So for everyone of those who have degenerative mitral regurgitation with flail leaflets, the best treatment option is mitral repair. Dr Carolyn Lam:                Now these results came from a multi-center registry of thousands of patients. I was really struck with the duration of the study. I think that's something that's really novel. You had a 20 year follow up but also patients were recruited from 1980 all the way to 2005, am I right? So could you expand a little bit about the possibility of techniques changing during that period? Dr Jean-Louis Vanoverschelde:  Although there has been subtle changes in the practice, the basic principle have remained the same. So we have not really accounted for these changes in the practice over time, with regard to what happened to mitral valve replacement, clearly the prostheses that were there 30 years ago are not the same as the ones that are currently implanted to the patients, but none the less when we performed an analysis, a sensitivity analysis to look at whether the results were different from 20 years ago compared to those that were more recent, we found exactly the same result. Dr Carolyn Lam:                Yes, I thought that was a very important sensitivity analysis. Tell us a bit more about the propensity score matching as well because another thing people will be thinking is, you know, this is a registry, huge numbers very important but obviously there would be differences in indication for repair versus surgery. Dr Jean-Louis Vanoverschelde:  For sure, the fact is that there are statistical means that allow you to mimic not to be the exactly the same as, but to mimic randomization and it is the propensity score matching. That means that you perform a prior analysis that will identify similar patients in the two cohorts and match them so that you are basically having the same kind of patients that are treated with two different ways. So it's not randomization but it's getting close to randomization when you use cohorts like the one from the MIDA registry. Dr Carolyn Lam:                Perfect. Victoria, did you take the same take home messages and are you applying this clinically? I noticed that you invited an editorial, a lovely editorial on this paper as well, so please share your thoughts. Dr Victoria Delgado:        Yeah, I share the same take home message that Dr. Vanoverschelde has outlined. I think that this is very important article, it's a landmark article highlighting one of the most important things that mitral valve repair should be probably the standard of care for patients with severe mitral regurgitation without degenerative cause with a flail and the article basically what it does is also endorsing the recommendations of current guidelines highlighting the value of mitral valve repair. Of course that mitral valve repair should be performed in centers with experience and with good durability of these repairs, so the centers need to have a good heart team where they can analyze their results in such a way like the MIDA registry has done demonstrating a good durability of the repair. Dr Carolyn Lam:                And do you have anything to add to that Jean-Louis? Dr Jean-Louis Vanoverschelde:  No, I think basically Victoria very well summarized the basic features not only of the paper itself but also of the condition and what currently is in the guidelines. In fact, the guidelines have already said that we should be preferring mitral valve repair over replacement, but the data on which this was based were probably not as conclusive as the one that are provided by this analysis of our registry, so I think it's really reinforcing the idea that we should go ahead and try to perform repair as much as possible, now with a caveat of course that the surgeons need to be skilled enough to perform that. But with the type of differences that we see in survival between the two cohorts I think that if a surgeon does not feel comfortable with repairing the valve and would rather replace it, he might refer the patient to another surgeon that is capable of repairing the valve. The impact and outcome is such that I think this really supports the idea that the patient should be referred to high volume and skilled centers. Dr Carolyn Lam:                Could you give us an idea of what kind of impact you're talking about, what kind of numbers that you see? Dr Jean-Louis Vanoverschelde:  It's the same in all the analysis, whether it's in the overall population or in the matched cohorts by 20 years, we have something like 20 to 25% survival difference, absolute survival difference between the two groups. So it's a reduction of mortality approximately by half if you perform repair compared to replacement, and it is increasing with time, so it's not something that is only present in the first years but is increasing with time, so it's about 20 to 25% absolute difference between the two cohorts. Dr Carolyn Lam:                That truly is remarkable. Congratulations again on such a landmark paper like Victoria said. Now to either of you, question that's a bit left field maybe, but what do you think the role is now for percutaneous techniques of mitral valve repair or replacement then? Dr Jean-Louis Vanoverschelde:  That's an interesting question. I think that if you really look far away into the future probably everything at some point in time will be percutaneous. At this stage I'm not sure that the percutaneous technique able to mimic what we can do with surgery in terms of mitral valve repair. So, it's an alternative to surgery in patients who are inoperable. In those who can undergo a surgical mitral repair, my first choice will certainly be to go surgically rather than percutaneously, at least right now. Dr Carolyn Lam:                Victoria? Dr Victoria Delgado:        I also agree with those comments. I think that now we have a lot of possibilities to treat these patients but the most important thing is to have the entire clinical picture of the patient, to see the pros and cons of preparing the patient for surgery or for percutaneous valve. There should be also an integration of imaging to know which is the cause of the valve dysfunction and to see whether the anatomy could be easily repaired by surgery or instead if the patient has contraindication for surgery, if it could be repairable as well with transcatheter therapy. But then for that I think that is really important and this is what the editorial also highlights, the role of the heart team, where there are different specialist surgeons, clinical cardiologists, heart failure specialists, imaging specialists that can integrate the entire information of the patient in order to select the most appropriate therapy. But still for patients who do not have contraindications for surgery who have repairable valve and as you can see from this registry, the percentage of repairability is quite high, I would still refer the patient as well for surgical valve repair. Dr Carolyn Lam:                You heard it right here. Thank you so much for joining us today and please don't forget to tune in next week.  

Carolyn: 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 Centre and Duke National University of Singapore. Have you ever wondered what the clinical implications of very brief episodes of device-detected atrial tachyarrhythmias are? Well, we will be discussing this with novel data from the RATE registry in just a moment. First, here's your summary of this week's journal.     The first study provides the first evaluation of the Sweden nationwide abdominal aortic aneurysm screening program. Of almost 303,000 men invited for screening, 84% attended. The prevalence of screening detected abdominal aortic aneurysm was 1.5%. After a mean of 4.5 years, 29% of patients with aneurysms had been operated upon with a 30-day mortality rate of 0.9%. The introduction of screening was associated with a significant reduction in aneurysm-specific mortality. The number needed to screen to prevent 1 premature death was 667, while the number needed to operate on to prevent 1 premature death was 1.5.     Furthermore, the authors showed that their screening program was highly cost-effective in the contemporary setting in Sweden. These findings confirm results from earlier randomized controlled trials in a large population-based setting, and may be important for future healthcare decision-making. This and the diverse requirements for efficient population screening for abdominal aortic aneurysm, from program management to maintaining skills in open repair are discussed in an excellent accompanying editorial by Dr. Cole from Imperial College London.     The next study looks at thoracic epidural anesthesia and suggests that caution may be needed in patients with or at risk for right ventricular dysfunction. You see, thoracic epidural anesthesia involves blockade of cardiac sympathetic fibers, which may affect right ventricular function and interfere with the coupling between the right ventricle and right ventricular afterload. Dr. Wink and colleagues from the Leiden University Medical Center therefore used combined pressure volume conductance catheters to study the effects of thoracic epidural anesthesia on right ventricular function and ventricular pulmonary artery coupling in 10 patients scheduled for lung resection.     Thoracic epidural anesthesia resulted in a significant reduction in right ventricular contractility, stroke work, dP/dt max and ejection fraction. This was accompanied by a reduction in effective arterial elastance such that ventricular pulmonary coupling remain unchanged. Clamping of the pulmonary artery increased right ventricular contractility but decreased ventricular pulmonary coupling. These effects of increased afterload were the same before and after thoracic epidural anesthesia. In conclusion, therefore, thoracic epidural anesthesia impaired right ventricular contractility but did not inhibit the native positive ionotropic response of the right ventricle to increase afterload. These findings are clinically relevant for daily practice in cardiothoracic surgery because pulmonary hypertension is frequently encountered, and right ventricular function is an important determinant of early and late outcomes.     The next study suggests that the use of point of care hemostatic testing may have a place in the management of patients undergoing cardiac surgery. Dr. Karkouti and colleagues of the Toronto General Hospital hypothesized that point of care hemostatic testing within the context of an integrated transfusion algorithm would improve the management of coagulopathy in cardiac surgery, thereby reducing blood transfusion. They therefore conducted a pragmatic multi-center stepped-wedge cluster randomized controlled trial of a point of care based transfusion algorithm in 7,402 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass in 12 hospitals in Ontario, Canada. They found that the trial intervention reduced rate of red cell transfusion with an adjusted relative risk of 0.91 and a number needed to treat of 24.7.     The intervention also reduced rates of platelet transfusion and major bleeding but had no effect on other blood product transfusions or major complications. These findings that point of care testing improved management of coagulopathy in cardiac surgery support the consideration of their broader adoption in clinical practice.     The next study provides experimental evidence that brings us one step closer to therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis. In this study from first author Dr. Ortega-Gómez, corresponding author Dr. Soehnlein and colleagues from LMU Munich, authors focus on cathepsin G, which is stored in neutrophil and azurophil granules and discharged upon neutrophil activation. They studied site-specific myeloid cell behavior after high-fat diet feeding or TNF stimulation in the carotid artery, the jugular vein, and cremasteric arterioles and venules in APOE E and Cathepsin G-deficient mice.     Their studies revealed a crucial role for Cathepsin G in arterial leukocyte adhesion, an effect that was specific for the arteries and not found during venular adhesion. Consequently, Cathepsin G deficiency attenuated atherosclerosis but not acute lung inflammation. Mechanistically, Cathepsin G was immobilized on arterial endothelium, where it activated leukocytes to firmly adhere, engaging endocrine clustering, a process of crucial importance to achieve effective adherence under high-sheer flow.     Therapeutic neutralization of Cathepsin G specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of Cathepsin G-neutralizing antibodies really allowed the inhibition of atherogenesis in the mice. Taken together, these findings presented evidence of an arterial-specific recruitment pattern centered on Cathepsin G adhesion, thus representing a potential novel strategy and target for the treatment of arterial inflammation. Well, that wraps it up for the summary of this week's journal. Now, for our featured discussion.     Our feature paper for today discusses the clinical implications of brief device-detected atrial tachycardias and really novel findings from the RATE registry. I'm so happy to be here with the first and corresponding author, Dr. Steven Swiryn from Feinberg School of Medicine, Northwestern University. Hi, Steven.   Steven: Good morning.   Carolyn: We also have with us Dr. Mark Link, associate editor from UT Southwestern. We all know that prolonged episodes of atrial tachycardia or atrial fibrillation are associated with increased risk and that if we anticoagulate those with a high CHA2DS2–VASc score, we can lower the risk of stroke. Now, the European Society of Cardiology guidelines also say that recent data reinforced the assumption that even brief episodes of silent atrial fibrillation may convey an increased risk of stroke. We also know that prior studies have looked at device-detected atrial fibrillation. Steven, I'd really love if you could start by telling us what makes your study different. What was the main thing you were trying to look at?   Steven: Well, one reason it's attractive to use the device population, patients with pacemakers or defibrillators, to look at these issues is because devices have a very high likelihood of detecting episodes of atrial fibrillation whereas symptoms or single 12 EKGs miss a lot of atrial fibrillation, so the sensitivity is much higher, although not perfect. The problem is that very brief episodes of atrial fibrillation are very poorly detected by devices. The specificity of automatic detection is very low, such that all previous studies until the RATE registry have excluded any episode of atrial fibrillation detected by a device less than 5 minutes in duration because they're unreliable. A lot of them turn out to be false positive detections. Our study was designed to evaluate whether even very brief episodes of an atrial tachyarrhythmia might also be associated with risk of clinical events and might or might not warrant anti-coagulation.   Carolyn: Ah, that's interesting, so you really helped to answer how brief is "brief" when we need to talk about device-detected atrial fibrillation. Could you expand on how you actually defined "short episodes" here?   Steven: Right. A short episode for the purpose of the RATE registry was defined as an episode where the electrogram that we scrutinized had both the onset and the offset of the episode within the same electrogram tracing, so although we can't put a specific time duration on it because that wasn't part of the criterion, it's typically less than 20 seconds or so, although not always, whereas a long episode was defined as an electrogram where either the onset and/or the offset was not captured by the device memory and therefore we don't know the duration. Some of those may not have been very long, and some of those may have been extremely prolonged episodes. That allows us to actually scrutinize the electrogram. We looked at 37,530 individual electrograms using 8 teams of adjudicators, each with a physician and a field clinical engineer from the device company so that we could actually say definitively, "Yes, this was atrial fibrillation," or, "No, it wasn't."   Carolyn: This is the first study to really look under that 5-minute limit of atrial tachycardias. What did you find?   Steven: Well, we found that in contrast to prolonged episodes, short episodes of atrial tachyarrhythmias were not associated with an increased risk compared to those without atrial fibrillation of pre-defined clinical events, including death from any cause, heart failure, stroke, hospitalization for atrial fibrillation, and a few other smaller events.   Carolyn: This was over a 2-year follow-up period, is that right?   Steven: The median follow-up was slightly less than 2 years, that's right.   Carolyn: What I really was struck with was also the second finding, the propensity to develop longer episodes. Could you expand on that?   Steven: We reasoned that in the clinic, one might be faced with a short episode was we defined them, and then you don't know what's going to happen for the next 2 years to bring to bear the results of our study. We looked at if your first episode was short, what was your likelihood over the full follow-up of the study of progressing to longer episodes. About 50% of patients who had their first episode as only a short episode progressed to a longer episode over the full follow-up and therefore were in the long category for the rest of the results. Half of them never got a longer episode.     It was, as one might imagine, if you had your first short episode very early in the study and had a longer follow-up, you were more likely to end up in the long category, and if you had very frequent short episodes, you were also more likely to end up in the long category by the time the full follow-up was over with. Having an initial short episode is not a guarantee that you're never going to get a long episode and that you'll never acquire a consideration of anti-coagulation.   Carolyn: That was a very important message to me as well because it meant that although I can be secure or reassured by these data for very short episodes, I needed to look out for the development of longer episodes, at least that's what your registry showed over 2 years of follow-up. I'm curious, Mark, what were your take-home messages because that leaves us with a bit of a conundrum. What do we do about anti-coagulation in these patients?   Mark: I think this study is a big help to the practicing electrophysiologist and practicing cardiologists. It's a very ledger number of patients with a lot of episodes of afib. It's reassuring to me that the shorter episodes of afib as defined by the study, the individuals did not have a higher incidence of stroke compared to those with no episodes, so it's reassuring and very important clinically as I go through my practice.     I do look forward to more analyses and more data from this study because although now we know that episodes less than 20 seconds are in all likelihood not going to need anti-coagulation, we still don't know about those from 20 seconds to 5 minutes. Hopefully with more analysis of this study we'll get that answer also.   Carolyn: Steven, do you agree with that?   Steven: We would love to have that. At first glance, you would think that devices would give you all of the data you needed because after all, they're monitoring the patient 100% of the time, but there are difficulties with that because device memory is limited, and you don't get electrograms that go on until the termination of atrial fibrillation even if the device were accurate in determining when that termination was because depending on how the device was programmed and depending on whether it was a more modern device later in the trial or earlier and had more or less memory, it cuts off after a limited amount of time, and you don't see necessarily how long the duration is.     Now, you can use device-based data. The device gives you its estimate of how long the episode is, but those are not as reliable as adjudicating the electrograms and actually looking at them. Those data would be a little softer than the main results if we get there.   Mark: That was the data that was used for all of the other studies, was [transassert 00:14:51]. It would be comparable to those other studies. I still think it would be very important data that I'd love to see.   Steven: Okay, well, I agree. I think it would be very interesting to look at that and a number of other things. We have a number of other things we could do with this database. There are a number of substudies that are in progress. For example, one interesting one is there were some instances we found, because we actually looked at these electrograms, there's something that we termed "competitive atrial pacing," where the device will pace at times when we as clinicians would not want to pace. For example, pacemaker-mediated tachycardia would be an instance of that, but then you can pace in the atrium inappropriately. There's a rhythm called repetitive non-reentrant ventricular atrial systole, which, although it's exotic to all of us, actually turned out to be fairly common where there's pacing in the atrium that occurs for various reasons when we want it to.     We actually saw instances where the device itself induced atrial fibrillation. It wasn't that common, but we did see it. We have a substudy that we're working on about the subjective competitive atrial pacing to see how much of that there was and of what, if any, consequence that was. That's one of the things that's been done. Because we scrutinized these so carefully, we tracked morphology and atrial rate at least as a crude estimate, and we have those data, so we could actually evaluate whether if something looks very, very rapid and disorganized as opposed to more organized electrograms at a slower rate, did that make any difference. We don't have any results for those analyses yet. I agree with Mark that the intermediate durations would be interesting to look at.   Carolyn: I agree too, and I'm really grateful for you sharing those thoughts. Very grateful for both of you for your time today. I just have to congratulate you. I completely agree this paper fills an important knowledge gap, and congratulations once again.   Steven: Thank you very much.   Mark: Thank you.   Carolyn: Thank you for listening. You've been listening to Circulation on the Run. Please tune in next week.      

  Speaker 1: 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. Joining me in just a moment are Dr. James Gammie and Dr. Timothy Gardner to discuss our feature paper this week describing the first-in-human clinical experience with a novel transapical beating heart mitral valve repair.     First, here are the highlights of this week's journal. The first paper is from co-primary authors doctors Yoon, [Tsue 00:00:49], and [Cha 00:00:50] as well as corresponding authors Dr. [Che 00:00:55]  and Dr. Kim from the Seoul National University College of Medicine. These authors examine mechanisms underlying diabetes-induced microvasculopathy, testing the hypothesis that Notch signaling in endothelial cells may play an important role in this condition.     The authors tested this hypothesis by inducing diabetes in eight-week-old adult mice using intravenous streptozotocin. They then modulated endothelial Notch signaling using chemical inhibitors in both wild type and transgenic mice. Results showed that the Notch ligand called Jagged-1 was markedly increased in endothelial cells of diabetic mice. Using endothelial specific Jagged-1 knocked down mice, they found that blocking Jagged-1 prevented diabetic microvaculopathy. Furthermore, using the induceable endothelium-specific Jagged-1 knocked down mice, blocking Jagged-1 even at four weeks after the establishment of diabetic microvaculopathy could reverse the condition.     In summary, these findings show that diabetes induces Jagged-1 over expression and suppresses Notch signalling in endothelial cells leading to diabetic microvaculopathy in adult mice. The clinical implications are that dysregulated intercellular Notch signalling may therefore represent a novel molecular target in the treatment of diabetic retinopathy.     The next study by Dr. Smith and colleagues at the Leiden University Medical Center in the Netherlands evaluated the association between LDL cholesterol variability and four cognitive domains at 30 months in the 4428 participants of the prosper study.     Results showed that a higher LDL cholesterol variability was associated with lower cognitive test performance for intermediate and delayed memory-related tasks, selective attention, and processing speed. Higher LDL cholesterol variability was also associated with lower cerebral blood flow and greater white matter hyperintensity load in an MRI substudy of 535 patients.     In addition to being independent of the mean LDL cholesterol levels and of clinically overt cardiovascular diseases, these associations were present both in the placebo and pravastatin treatment [inaudible 00:03:43] of the prosper trial suggesting that the findings did not mearly reflect pleiotropic effects of statins or of nonadherence.     The study importantly provides the first observational evidence that lipid variability, not just absolute or mean values, but the variability, maybe of importance to neurocognitive function and thus contributes while understanding potential pathways of neurocogniticve decline.     The next study is by first author, Dr. [Huh 00:04:19], and corresponding author, Dr. Ralph, from the Menzies School of Health Research Charles Darwin University in Australia. These authors aimed to investigate the long term outcomes from acute rheumatic fever and rheumatic heart disease.     They achieved this aim by using linked data between the rheumatic heart disease register, hospital data, and death register for residents of the northern territory of Australia, and examined 1248 patients with rheumatic heart disease as well as 572 patients with acute rheumatic fever in the period 1997 to 2013.     The main findings were that in the first year after an acute rheumatic fever episode, the incidents of progression to rheumatic heart disease was 10 times higher than acute rheumatic fever recurrence; 10% of rheumatic heart disease patients had severe disease at diagnosis. The presence of comorbidities was associated with higher incidence of rheumatic heart disease complications and mortality. In particular, comorbid renal failure and hazardous alcohol use accounted for 28% of the access indigenous mortality.     These findings have global relevance for settings with high acute rheumatic fever, rheumatic heart disease rates and really emphasized the need for integrated chronic disease management strategies for these patients.     The final paper is by first author Dr Bettencourt, corresponding author Dr. Blankstein, and colleagues from Brigman and Women's Hospital in Boston, Massachusetts. These authors sought to answer the question what is the most appropriate score for evaluating the pretest probability of obstructive coronary artery disease?     To answer the question, the authors compared the Diamond-Forrester score with the two CAD consortium scores recently recommended by the European Society of Cardiology, and they did this in 2274 consecutive patients without prior CAD referred for coronary CT angiography. CT angiography findings were used to determine the presence or absence of obstructive CAD defined as 50% or more stenosis.     Here's a refresher of the different probability scores. The Diamond-Forrester score is calculated based on chest pain type such as non-anginal, atypical or typical angina, gender, and age. The first CAD consortium model score called CAD consortium basic is also based on these factors, but was developed using more advanced statistical modeling strategies which were not available when the Diamond-Forrester model was derived. Additionally, the population had a lower prevalence of disease than the original Diamond-Forrester derivation cohort.     The second CAD consortium score called CAD consortium clinical included the same characteristics as CAD basic, but also included the following clinical risk factors; diabetes, smoking status, hypertension, and dyslipidemia. Moreover, the presence of typical chest pain was weighted less in diabetics compared to nondiabetics in the CAD clinical score.  Results showed that among symptomatic individuals referred for coronary CT angiography, the CAD consortium clinical pretest probability score demonstrated improved calibration and discrimination for the prediction of obstructive CAD compared to the Diamond-Forrester classification.     Driving home the clinical implications of this, the authors applied these observed differences in pretest probability of obstructive CAD to guidelines-based patient management algorithms and projected that the use of the newest score could decrease the proportion of individuals in whom testing would be recommended and increase the yield of diagnosing obstructive CAD.     Those were the highlights of these weeks issue. Now, for our feature paper. Our feature paper today is about the first-in-human clinical experience with the transapical beating heart mitral valve repair using a expanded polytetrafluoroethylene chordal insertion device. We're really lucky today to have the first and corresponding author, Dr. James Gammie from the University of Maryland Medical Center as well as Dr. Timothy Gardner, associate editor from Christiana Care Health System to discuss this exciting paper. Welcome, both of you.   Tim: Thank you.   James: Thank you.   Speaker 1: James, may I start with you? What an exciting title, a first-in-human experience, and this is really sounding very reminiscent of our experience with TAVR and aortic stenosis valves. Could I ask you, with so many exciting things, what is it about the results that excited you most?   James: This is an exciting project in that we believe it affords a new treatment option for patients with degenerative mitral regurgitation. We believe that this is a less invasive way of achieving surgical grade reduction of mitral regurgitation. This is a project which has involved a great number of people on our team both within the university and then within Harpoon Medical, as well as our colleagues in Europe to bring this device from an idea which was asked more than a decade ago into a clinical experience.     It really rose out of our recognition in particularly my own practice that virtually, every patient with degenerative mitral regurgitation could be fixed with ePTFE or Gore-Tex neo-chords, and the question became how can we place neo chords on a prolapsed mitral leaflets without doing open heart surgery?     We begin working on that in the laboratory a number of years ago and went through a variety of prototypes, and ultimately, came up with this idea where we could use a 3 millimeter shafted instrument with a specially designed wrap of Gore-Tex on a 21-gauge needle such that we could land on the underside of the mitral leaflet, deploy device, and create a specially designed knot on the atrial surface of the leaflet, and that would anchor the ePTFE on the leaflet. We could repeat that a few times transapically and then adjust the length of those chords in real time using transesophageal echo guidance.     We got this to work in the laboratory and we had hoped that we would have some modest success in humans, but we've been quite pleasantly surprised that it has just worked and we've outlines this initial clinical experience in the manuscript.   Speaker 1: First of all, I'd just like to pick up on the point that this is degenerative mitral regurgitation, so this is limited to the primary mitral regurgitation, not secondary?   James: That's correct and we know that right now, at least in North America, that two-thirds of mitral valve operations are done for degenerative disease. That's correct.   Speaker 1: I think a lot of the audience out there is going to be wondering how this new technique compares to the MitraClip. Could you tell us a little bit more about that?   James: I do MitraClip as well, so I think I'm well positioned to comment on the differences. The Harpoon device right now is still in operation. It does require a small one or two-inch incision. We anticipate it's going to be a thoracoscopic approach in the very near future and then, beyond that, we would hope to extend it to a transcatheter approach. That's one difference.     The MitraClip now is certainly across the world. It's used predominantly for functional mitral regurgitation. In our own experience, it seems to work best for functional mitral regurgitation and as you know, there are anatomic limitations for MitraClip in degenerative disease. The MiraClip replicates the LCRA surgical approach and I think what we've learned from all the less invasive approaches to treat mitral valve disease is that we have to respect what we've learned from our surgical experience, and we know that the LCRA approach works best when it's combined with an annuplasty ring, and certainly, the MitraClip, again, is mostly this perfunctional MR.     Another point I'd bring up is that the experience with MitraClip has been that when you place a MitraClip, you get a fairly strong fibrous reaction and in most of the series, it's not been possible to then go back and surgical repair the valve, but you have to do a replacement because you've compromised the leaflets. Our own approach were simply putting Gore-Tex sutures in the leaflets and we believe that one advantage is that we're not burning any bridges, and that you can go back and do an open repair of you had to.     In our experience, you asked about our results, we had great results in 10 out of 11 of our patients. One patient did require a reoperation. Actually, one of the chords had come untied on the surface in that patient. We were able to go ahead and do a repair and we saw as we had anticipated it based on our animal experience, there was not much compromised to the leaflets.     One of the advantages of our approach is that we can titrate the length to the Gore-Tex chords to optimize the amount of coaptation and maximize the quality of the repair, and that's something that we can't do an open cardiac surgery, and one of the challenges of mitral valve repair is that you have to figure out how long to make those chords while the heart is arrested and placid, and that's one of the challenges in why mitral valve repair is certainly some degree of an art to doing that.     What we've found is that the imager is incredibly important, and so we've teamed up with our echocardiography colleagues, and they really provide essential input into the procedure, and it's done not looking directly at the valve, but looking up at the screens. I think as surgeons, with this procedure, we're moving more into almost becoming interventionalists.   Speaker 1: Thank you, James. That was so exciting. Tim, I have to bring you into this now. Now that James has said they're becoming like the interventionalist. Back to my original comment of TAVR and aortic stenosis, are we witnessing history in the making now? You invited an editorial by Dr. Michael Mack and his title was very provocative, Transcatheter Treatment of Mitral Valve Disease. Is it deja vu all over again? What are your thoughts?   Tim: I think this is an exciting report and I think that this is the wave of the future. I agree completely with Michael Mack that we are beginning to see interventions for mitral valve disease that are effective, less invasive, in some instances catheter based, but this is just the beginning. In fact, mitral valve disease is somewhat more complex even than aortic stenosis, but this type of experience and the ingenuity and the technical prowess, and the ability to do this minimally, invasively, and so on really portend a whole new era.     I agree with Jim. This is sort of the common ground between the interventional structural cardiologist and the surgeon, and we're becoming even more entwined, more collaborative, and more mutually supportive. We are in a new era and I think over those next decade or so, we're going to see this and similar, and even different procedures tried and proven to be useful for the variety of mitral valve disorders that we encounter. Perhaps the era of the full sternotomy for fairly straightforward, single, focused operations will become something of a thing of the past.   Speaker 1: That's beautifully put. James, with that comment, what are the next steps?   James: As we said in the manuscript, this isn't barely experience and we're continuing to learn as we move [inaudible 00:17:07] to the clinical arena. We are currently in the midst of a CE Mark trial in Europe. We rolled it out to eight separate centers. As we approve clinical experience, we will learn more about precisely which patients work best with this approach and we will accrue longer term data. We now have a number of patient out to a year with stable results and so, as the numbers go up, we'll do that, and then we anticipate a randomized trial in the United States in the early to mid portion of 2017 where we'll compare this approach to conventional open cardiac surgery.   Speaker 1: That's fantastic. Thank you so much to both of you, gentlemen, for joining me on our podcast today.   Tim: Thank you.   James: Thank you.   Speaker 1: You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week.  

Interview with Prof. Fred Falkenburg, Prof of Hematology, Leiden University Medical Center, Leiden, The Netherlands. Prof. Falkenburg discusses the topic 'Donor lymphocyte infusions, immunological and clinical aspects'. The interview is led by Shaun McCann, Chair of EHATol Unit, Member of EHA Education Committee.

Interview with Prof. Fred Falkenburg, Prof of Hematology, Leiden University Medical Center, Leiden, The Netherlands. Prof. Falkenburg discusses the topic 'Donor lymphocyte infusions, immunological and clinical aspects'. The interview is led by Shaun McCann, Chair of EHATol Unit, Member of EHA Education Committee.

Cornelis (Kees) J.M. Melief, M.D., Ph.D., Leiden University Medical Center, Leiden, The Netherlands

Cornelis (Kees) J.M. Melief, M.D., Ph.D., Leiden University Medical Center, Leiden, The Netherlands

Interview with Prof. Willem Fibbe, Professor of Haematology and Stem Cell Biology at Leiden University Medical Center. Prof. Fibbe discusses the topic 'Mesenchymal stem cell therapy'. The interview is led by Shaun McCann, Chair of EHATol Unit, Member of EHA Education Committee.

Interview with Prof. Willem Fibbe, Professor of Haematology and Stem Cell Biology at Leiden University Medical Center. Prof. Fibbe discusses the topic 'Mesenchymal stem cell therapy'. The interview is led by Shaun McCann, Chair of EHATol Unit, Member of EHA Education Committee.

Guest: Dr. Annemieke Aartsma-Rus, DMD Genetic Therapy Group, Dept. of Human Genetics, Leiden University Medical Center, The Netherlands Access an abstract of this Month's Featured Research Article: Progress in therapeutic antisense applications for neuromuscular disorders. Eur J Hum Genet. 2010 Feb;18(2):146-53.

Guest: Dr. Annemieke Aartsma-Rus, DMD Genetic Therapy Group, Dept. of Human Genetics, Leiden University Medical Center, The Netherlands Access an abstract of this Month's Featured Research Article: Progress in therapeutic antisense applications for neuromuscular disorders. Eur J Hum Genet. 2010 Feb;18(2):146-53.

Celiac Update. Celiac disease is an uncontrolled immune response to wheat gluten and similar proteins of rye and barley. In those who have celiac disease, gluten can damage the small intestine, inhibit nutritional uptake and lead to malnutrition. Among the symptoms are diarrhea, stomach pain, fatigue, weight loss and slow growth. One study estimated that 1 in 133 people in the U.S. population have celiac disease. Many people do not know they have it, sometimes because there are no symptoms. Because celiac disease has a genetic component, there can be a much higher prevalence of the disease within families.Three years ago, a group of Dutch researchers led by Frits Koning of the Leiden University Medical Center published a study on an enzyme that showed promise as a treatment for celiac disease. The enzyme, prolyl endoprotease, or PEP, could quickly break down gluten in the stomach before it ever reached the small intestine, where it causes damage. In this episode, we ask Frits Koning to update us on his research. (Begins at 2:45)Total Time:  11:20

Guest: Suzanne Cannegieter, MD Host: Gary Kohn, MD Dr. Suzanne Cannegieter, director of clinical epidemiology, and the lead international researcher for the Wright Project, from Leiden University Medical Center in the Netherlands, talks about the history of research on deep venous thrombosis and extensive air travel.