Podcasts about perlman school

Recent advances have provided new options for when and how best to treat patients with chronic lymphocytic leukemia (CLL). Trials of combination strategies have shown promise in providing patients the potential for unmaintained remissions. Marco Ruella, MD, an assistant professor of medicine in hematology-oncology at the Perlman School of Medicine at the University of Pennsylvania and scientific director of the lymphoma program, speaks with Robert Figlin, MD, the Steven Spielberg Family Chair in hematology-oncology at Cedars-Sinai Cancer Center in Los Angeles, about the current state of CLL care and what changes are likely in the near future. Although satisfied in many ways with recent progress, Dr. Ruella argues in favor of moving past simply “maintaining the disease at long-term” and, instead, pushing for a cure.   Dr. Ruella reports relationships with AbClon, BMS, Bayer, NanoString, and UPenn/Novartis.   Dr. Figlin has reported relationships with numerous companies.

Do we still need doctors? There are umpteen alternative sources of medical advice, including endless and heartfelt health tips from people without medical degrees. Frankly, self-diagnosis with a health app is easier and cheaper than a trip to a clinic. Since we're urged to be our own health advocate and seek second opinions, why not ask Alexa or consult with a celebrity about what ails us? Find out if you can trust these alternative medical advice platforms. Plus, lessons from an AIDS fighter about ignoring the findings of medical science.   And, if AI can diagnose better than an MD, will we stop listening to doctors altogether? It's our monthly look at critical thinking … but don't take our word for it! Guests: Katherine Foley – Science and health reporter at Quartz, and author of the article “Alexa is a Terrible Doctor” Paul Offit – Professor of pediatrics at the Children's Hospital of Philadelphia and the Perlman School of Medicine at the University of Pennsylvania, and author of “Bad Advice: Or Why Celebrities, Politicians, and Activists Aren't Your Best Source of Health Information” Richard Marlink – Director Rutgers Global Health Institute. Shinjini Kundu – Research Fellow, University of Pittsburgh Medical Center Stuart Schlisserman – Internist, Palo Alto, California   originally aired September 24, 2018 A special offer to Big Picture Science listeners: Receive 60% off the first month of a MEL Physics, MEL Chemistry or MEL STEM subscription. Just go to MELscience.com and use the promo code BPS or follow this link: https://melscience.com/sBI3/. Big Picture Science is part of the Airwave Media podcast network. Please contact sales@advertisecast.com to inquire about advertising on Big Picture Science. You can get early access to ad-free versions of every episode by joining us on Patreon. Thanks for your support!     Learn more about your ad choices. Visit megaphone.fm/adchoices

Do we still need doctors? There are umpteen alternative sources of medical advice, including endless and heartfelt health tips from people without medical degrees. Frankly, self-diagnosis with a health app is easier and cheaper than a trip to a clinic. Since we're urged to be our own health advocate and seek second opinions, why not ask Alexa or consult with a celebrity about what ails us? Find out if you can trust these alternative medical advice platforms. Plus, lessons from an AIDS fighter about ignoring the findings of medical science.   And, if AI can diagnose better than an MD, will we stop listening to doctors altogether? It's our monthly look at critical thinking … but don't take our word for it! Guests: Katherine Foley – Science and health reporter at Quartz, and author of the article “Alexa is a Terrible Doctor” Paul Offit – Professor of pediatrics at the Children's Hospital of Philadelphia and the Perlman School of Medicine at the University of Pennsylvania, and author of “Bad Advice: Or Why Celebrities, Politicians, and Activists Aren't Your Best Source of Health Information” Richard Marlink – Director Rutgers Global Health Institute. Shinjini Kundu – Research Fellow, University of Pittsburgh Medical Center Stuart Schlisserman – Internist, Palo Alto, California   originally aired September 24, 2018 A special offer to Big Picture Science listeners: Receive 60% off the first month of a MEL Physics, MEL Chemistry or MEL STEM subscription. Just go to MELscience.com and use the promo code BPS or follow this link: https://melscience.com/sBI3/. Big Picture Science is part of the Airwave Media podcast network. Please contact sales@advertisecast.com to inquire about advertising on Big Picture Science. You can get early access to ad-free versions of every episode by joining us on Patreon. Thanks for your support!     Learn more about your ad choices. Visit megaphone.fm/adchoices

This week is a Double Feature Circulation on the Run. Please join authors Alexander Benz and Lars Wallentin as they discuss their article "Biomarker-Based Risk Prediction With The ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation." Then, please join author Timothy McKinsey, editorialist Thomas Gillette and Associate Editor Sergio Lavandero as they discuss the article "HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling" and the editorial "HDAC Inhibition in the Heart: Erasing Hidden Fibrosis." TRANSCRIPT BELOW Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I cannot get enough of our double features, and this one's really nice because it's a clinical feature and a preclinical feature, and both are just phenomenally interesting. The first is about the ABC-AF scores. In case you don't recognize it, well, then you just have to listen. Very, very important information on biomarker-based risk prediction in patients with atrial fibrillation, not receiving oral anticoagulation. Then we've got a really interesting paper talking about HDAC inhibition and diastolic dysfunction. Interested? Well, listen up. Dr. Carolyn Lam: First, let's talk about some of the papers in today's issue, shall we? I want to start, Greg. You grab your coffee. I need to talk about this first one, which really provides the first extensive genetic and phenotypic landscape of a very important condition, peripartum cardiomyopathy. This is from Dr. Arany and colleagues from Perlman School of Medicine, University of Pennsylvania. What they did is studied 469 women with peripartum cardiomyopathy, who were identified from several US and international academic centers. They acquired clinical information and DNA samples. Next-generation sequencing was performed on 67 genes and evaluated for the burden of truncating and missense variance. Dr. Carolyn Lam: What they found was that women with peripartum cardiomyopathy bear a significantly high burden of loss of function variants in a number of genes, including familiar ones like TTN, FLNC, DSP, and BAG3. The identity and relative abundance of these variants were remarkably similar to that seen in idiopathic dilated cardiomyopathy, indicating that the genetic predisposition to peripartum cardiomyopathy and dilated cardiomyopathy may be one in the same. Now, while peripartum cardiomyopathy patients with the TTN truncating variants presented with lower ejection fraction. No significant differences in the rates of recovery were seen. Dr. Greg Hundley: Really interesting, Carolyn. Clinically, what are the implications today as we see these patients? Dr. Carolyn Lam: Well, I think the most important one is that genetic counseling and testing should, perhaps, be considered for women with peripartum cardiomyopathy, following the guidelines for dilated cardiomyopathy. What about you, Greg? Dr. Greg Hundley: Very nice, Carolyn. Well, my paper evaluates the role of inflammation and outcomes in patients that sustain out-of-hospital cardiac arrest. It comes to us from Dr. Martin Meyer from Rigshospitalet. Carolyn, out-of-hospital cardiac arrest patients who remain comatose after initial resuscitation are at high risk of morbidity and mortality due to the ensuing post-cardiac arrest syndrome. Now, systemic inflammation constitutes a major component of the post-cardiac arrest syndrome and interleukin 6 levels are associated with this severity. The IL-6 receptor antagonists tocilizumab could potentially dampen inflammation after post-cardiac arrest. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest, A presumed cardiac cause, and thereby potentially mitigate organ injury. Dr. Carolyn Lam: Oh, wow. Interesting, Greg. what did they find? Dr. Greg Hundley: Carolyn, they had 80 comatose out-of-hospital cardiac arrest patients and they were randomized 1:1 in a double-blind, placebo-controlled trial to a single infusion of tocilizumab or placebo, in addition to standard of care, including targeted temperature management. The primary endpoint of the study was reduction of CRP response. This was achieved by tocilizumab, as there was a significant treatment-by-time interaction. Systemic inflammation was reduced by treatment with tocilizumab, as both CRP and leukocyte levels were markedly reduced. Now, myocardial injury was also reduced, documented by reductions in CK-MB and troponin T. However, there were no differences, Carolyn, in survival or neurological outcome. So Carolyn, it looks like for those that survive an out-of-hospital cardiac arrest and do experience neurological recovery, there could be cardiac benefits. Dr. Carolyn Lam: Wow, very interesting. I cannot imagine how difficult it must've been to perform such a trial. Thanks, Greg. Well, the next paper demonstrates a new mechanism underlying diastolic dysfunction, and provides theoretical and experimental evidence to explain, perhaps, the ineffectiveness of conventional nitric oxide enhancement trials for HFpEF. And you know, that's my favorite topic. Dr. Greg Hundley: Wow, Carolyn, really interesting. Can you summarize it for us? Dr. Carolyn Lam: Sure. Well, first of all, this comes from Doctors Eom and Kook from Chonnam National University Biomedical Research Center in Korea. These authors used two animal models of diastolic dysfunction, the salty drinking water, unilateral nephrectomy with aldosterone, or SAUNA, model, and a mild transverse aortic constriction model. They also looked at human heart samples from patients with left ventricular hypertrophy. Dr. Carolyn Lam: Together, in very, very elegant experiments, they showed that neuronal nitric oxide synthase was upregulated in diastolic dysfunction, which increases S-nitrosylation and cardiomyocytes, and its pharmacologic inhibition, as well as genetic ablation, alleviated diastolic dysfunction. Now, specifically, protein S-nitrosylation of histone deacetylase 2, or HDAC2, played a critical role in the development of diastolic dysfunction and nitric oxide reduction and the following protein denitrosylation may provide a novel therapeutic strategy for HFpEF. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes from Dr. William Pu from Boston Children's Hospital and looks at reactive oxygen species-mediated CaM kinase 2 activation, and how that contributes to calcium handling abnormalities and impaired contraction in the Barth syndrome. Carolyn, mutations in tafazzin, a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome. Carolyn, remember that Barth syndrome occurs primarily in males, is associated with cardiomyopathy, a low white count, and recurrent infections, and also skeletal muscle myopathy and short stature. Cardiomyopathy and the risk of sudden cardiac death are prominent features of the Barth syndrome, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and these arrhythmias are poorly understood. Dr. Carolyn Lam: Oh, Greg, thanks so much for not quizzing me on that one. I was trying to remember what Barth syndrome is, and thanks for the review. Okay, so what did they find? Dr. Greg Hundley: Right, Carolyn. The investigators identified a molecular pathway that links tafazzin mutation to abnormal calcium handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat Barth syndrome, and potentially other diseases with elevated mitochondrial reactive oxygen species production. Dr. Carolyn Lam: Thanks, Greg. Nicely summarized. Well, let's go through what else there is in today's issue. There is a Perspective piece by Dr. Singh, entitled The Morbidly Obese Patients with Symptomatic Atrial Fibrillation: Why are we Holding Back on Bariatric Surgery? There's an On My Mind piece by Dr. Wenger on the incremental change versus disruptive transformation: COVID-19 and the cardiovascular community. There's also a research letter by Dr. Phillip on cardiovascular evaluation after COVID-19 in 137 collegiate athletes, and it's the results of an algorithm-guided screening. A very interesting piece. Dr. Greg Hundley: Very nice, Carolyn. Well, Carolyn, in the mailbag, I've got an exchange of letters regarding the article Anti-Inflammatory Actions of Soluble Ninjurin-1 and the Amelioration of Atherosclerosis with Dr. Zheng, Jianmin, and Oh. Then finally, Dr. Rob Califf has an On My Mind piece, entitled Avoiding the Coming Tsunami of Common Chronic Disease: What the Lessons of the COVID-19 Pandemic Can Teach Us. Well, Carolyn, I'm really excited. Another double feature Tuesday. How about we turn our attention and move toward those articles? Dr. Carolyn Lam: Yep. Something for everyone in this one. Let's go. Today's feature discussion will sound somewhat familiar if we're talking about the ABC scores. Now, remember that stands for age, biomarkers, clinical history scores, and they're the scores that we use in patients with atrial fibrillation receiving oral anticoagulation, or at least that's the data we have so far. But, what are the utilities of these ABC scores in patients not receiving oral anticoagulation? Dr. Carolyn Lam: Well, guess what? That's what today's feature paper is all about. I'm so pleased to have with us today, the first author, Dr. Alexander Benz, from Population Health Research Institute, McMaster University in Canada, as well as Dr. Lars Wallentin, he's a senior author from Uppsala University in Sweden. Welcome, gentlemen. Alex, if I could start with you, please. A very interesting question and not so easy to answer, could you please tell us a little bit about the background to your study, what you did, and what you found? Dr. Alexander Benz: Sure. Thanks for the opportunity to speak here. The ABC scores have now been shown to outperform clinical risk scores in the setting of patients with AFib receiving oral anticoagulant therapy. But so far, nobody has ever looked at the performance of these scores in patients who are not treated with oral anticoagulant therapy. So here we validated the ABC stroke, bleeding, and death scores in patients with AFib who were not receiving oral anticoagulant therapy. We chose the ACTIVE A and AVERROES trials, where patients were randomized to receive antiplatelet therapy, so aspirin or aspirin plus clopidogrel, for the validation study. We ended up studying the scores and over 4,300 patients who were receiving either aspirin, which were over 3,195 patients, or aspirin plus clopidogrel in about 1100 patients, in these studies. Dr. Alexander Benz: Now, we found that the ABC stroke score was superior to the CHA2DS2–VASc score, yielding a C-index of 0.7. The ABC bleeding score was also better than the currently recommended HAS-BLED score for the assessment of the risk of bleeding, yielding an overall C-index of 0.73. And finally, the ABC-AF death score yielded a C-index of 0.78, which I think is remarkable. Dr. Alexander Benz: Now, as these scores were derived from patients receiving oral anticoagulant therapy, we're not surprised to see that the ABC stroke score underestimated the risk of stroke in this population. And very similarly, the ABC bleeding score overestimated the risk of bleeding in these patients receiving antiplatelet therapy. So these scores, the ABC stroke and bleeding scores, were recalibrated for our prediction of absolute event rates in the absence of oral anticoagulant therapy. Dr. Carolyn Lam: Thanks, Alex. That was a beautiful summary. Now, Lars, if I could ask you, please, could you really highlight to all of us, what is the key thing about validating these scores in patients with atrial fibrillation, but not receiving oral anticoagulation? Dr. Lars Wallentin: I think what people like to have is an estimate of the risk of stroke and the risk of bleeding. If you start them on oral anticoagulation and that has been difficult, we only knew this based on the risk scores on patients that were on treatment. But if we now are using this score, which are also well-calibrated, we can really estimate the absolute risk of a stroke. Let's say, 3% without oral anticoagulation, then how much is it lowered by oral anticoagulation down to 1%? And we can do this on an individual level, because there is a variability between patients and we can identify the risk for an individual patient without treatment, and the risk on treatment, and that can be balanced then against the risk for bleeding on treatment and without the treatment. And thereby, you can get the precise estimate on the risk-benefit ratio for the individual patients. Dr. Lars Wallentin: This is a precision medicine approach, which we think will provide a better treatment with better outcomes for the patients than we have had before. Also, death can be, of course, involved at the final net benefit, with and without treatment. Therefore, we think this is a great step forward, and this cannot be implemented in the real life because we have used biomarkers that now can be available in the routine laboratories. These are NTproBNP and troponin, which are available in all hospitals, and a new marker, GDF-15, a marker that's related to the bleeding risk and that is currently launched by Roche Diagnostics as a new tool. So I think this is a realistic future to improve treatments. Dr. Carolyn Lam: Dr. Lars, I have to tell you, all us editors fully agreed as well, that this is a great contribution, filling an important gap in the literature so far in a very clinically important question when we face the patient who hasn't started anticoagulation. So really, again, thank you both for this study and for publishing with us. A couple of questions, though. It does require these extra biomarkers that come with some, what can I say, cost of needing to measure them if they're not already measured. Could you give us some idea of how much the scores add to what we're used to, the CHA2DS2–VASc and the HAS-BLED score? I don't know, maybe Alex? Dr. Alexander Benz: Sure. I think one downside of the widely-accepted and also often useD clinical scores is that they rely on Arbitrary categorization and dichotomization of clinical variables, and with biomarkers, we have the great advantage of having a continuous tool to assess the risk of outcomes here. And as Lars mentioned, these are mainly the cardiac biomarkers NTproBNP and cardiac troponin, as well as the GDF-15, or growth differentiation factor 15. We think that biomarkers reflect a powerful tool to also reflect underlying subclinical disease, which is very important, I think, in this stratification, and this is probably where much of the superiority of the biomarker-based tool stems from. Dr. Carolyn Lam: Right, thanks. Back to what Lars had said about more precision, which is exactly what the whole of cardiology is, I think, moving towards as well, but it was very, very clever to look for the studies ACTIVE and AVERROES. Hard to think of the population in which you tested this. But weren't the blood samples in these studies very old? Did you then have to remeasure those biomarkers? Were they reliable? Dr. Lars Wallentin: Yes. These were old samples that were taken at entry into the ACTIVE and AVERROES trial. The investigators in Canada were really very clever to save the sample, but the samples have been saved for a decade or more since then. But fortunately, these assays are very stable over time, so all of them, and therefore the results are reliable. The levels are very similar to the ones we get in the real-life setting for samples as the one we have in ARISTOTLE and RE-LY, where the scores were derived. So this seems to be, I think, also an advantage that this can be used for stored samples, and fresh samples. Dr. Carolyn Lam: Thank you for addressing that so nicely. We're running out of time sadly, but I would love to hear, maybe as final remarks, what you think are the overall clinical implications and perhaps the next steps for important studies that need to be done. Maybe I could ask Alex to start first and then Lars can finish? Dr. Alexander Benz: Well, I think the next steps in the ABC score program will depend on potential integration or a combination of scores, which then may guide physicians in whom to treat or even whom not to treat. Withholding anti-platelet therapy in certain very low-risk patients, that's what comes to mind. I know that Lars and his colleagues are performing a randomized controlled trial in Sweden where they're testing the ABC scores in clinical practice against the usual care with the clinical scores. Maybe, Lars, you want to elaborate on this. Dr. Lars Wallentin: Yeah, I think the final step is, of course, a prospective randomized trial showing which are the real benefits. We are randomizing 6,000 patients to conventional care versus precision medicine-based care using the ABC risk scores. Outcomes are death and stroke and bleeding. I hope that we will find usefulness of this also in a prospective trial, which will be the final piece of evidence, of course. Dr. Carolyn Lam: Wow, Lars, that is amazing. Thank you so much for sharing that with us. First time on Circulation on the Run. Well, audience, I'm sure you enjoyed that. Thank you so much, Lars and Alex. Now, hold on tight, we're going on to our next feature discussion. Dr. Carolyn Lam: Oh, I can't wait to get onto this feature discussion. You see, it's actually going to reveal a potential new way to target diastolic dysfunction. My absolute favorite topic. It's a basic science paper. It is incredible. You're going to hear all about its clinical translational potential and significance, and from none other than the corresponding author, Dr. Timothy McKinsey from University of Colorado School of Medicine, and editorialist of a beautiful accompanying editorial, Dr. Thomas Gillette from UT Southwestern, and Dr. Sergio Lavandero, our Associate Editor from University of Chile, San Diego. Thank you so much for being here. Tim, could I get you started off? Recognizing there are a lot of clinicians listening out there, this is an incredible paper. HDAC, I think for some, it will be the first time you've been hearing such a word. Please, please, could you break it down for us what you did and what you found? Dr. Timothy McKinsey: Sure. Thanks, Carolyn, and thanks for inviting me to do this. It's really a pleasure. HDAC, that stands for a class of enzymes called histone deacetylases, and those are also known as erasers of acetyl marks on chromatin. So they're really famous for the regulation of epigenetics or gene expression. But we found that HDACs do a lot of other things in the heart too, by deacetylating both histone and non-histone proteins, and we're just really interested in the therapeutic potential of inhibiting HDAC enzymes for the treatment of heart failure. And, in so doing, we assess their ability to reverse existing diastolic dysfunction in a mouse model of kidney disease and hypertension. Dr. Carolyn Lam: You know what, Tim, I really liked the way you very carefully said that. A mouse model of diastolic dysfunction with preserved ejection fraction, that I think, previously, a lot of people with just very loosely used the word HFpEF for such a model, but I really, really appreciate how carefully you worded that. Could you tell us a little bit about the model and what you found? Dr. Timothy McKinsey: Sure. Yeah, we've been really careful not to call it a model of HFpEF, because it isn't a model of heart failure. It really is a model of isolated diastolic dysfunction and preserved ejection fraction. It's a model that's been used in the literature in the past, where you perform a uninephrectomy in mice, so remove one kidney, and then implant something called DOCA, which is an aldosterone memetic. And over time, these animals develop systemic hypertension that results in cardiac hypertrophy and diastolic dysfunction. Dr. Timothy McKinsey: We were perplexed because we couldn't see any fibrosis in the model. But when we did a deep dive into fibrosis using more sensitive methods than are traditionally used, we did uncover what we're calling hidden fibrosis. We believe that HDAC inhibitors, our data suggests that HDAC inhibitors, can actually block the formation of hidden fibrosis that leads to diastolic dysfunction. Dr. Carolyn Lam: Very nice. If you could just give us a one-line on how will you find this hidden fibrosis? Dr. Timothy McKinsey: We got stuck on that for years, because we did all the traditional assays to measure cardiac fibrosis, mainly picrosirius red stain, and we didn't see anything. But we were fortunate to team up with some really talented collaborators, including Maggie Lam here at the University of Colorado, who is an expert at using mass spectrometry to study cardiac remodeling, and also Luisa Mestroni and Brisa Peña who use atomic force microscopy to look at tissue stiffness. When we teamed up with those investigators, first with Maggie we found that, sure enough, when we used her sensitive mass spec assay to look at extracellular matrix protein expression in the heart, there was really a profound increase in ECM protein expression in this mouse model, even though the staining for fibrosis was negative. That told us that there was this underlying hidden fibrosis. Dr. Carolyn Lam: Oh, that is really interesting. And so it is that form of fibrosis that was actually reversed, perhaps, by the HDAC inhibition, and that's what you showed. Would that be accurate to say? Dr. Timothy McKinsey: Yeah. So the HDAC inhibitor really had this profound ability to block that ECM remodeling, the hidden fibrosis, to the point where initially we thought it was an artifact. We thought maybe there was a mix-up of samples. It wasn't a mix up. It's just that the compound, this inhibitor of HDAC enzymatic activity, really has this amazing ability to block the formation of hidden fibrosis. Dr. Carolyn Lam: Oh, wow. Wow, Tom, I really, really loved your editorial where you put all of this in context and talked a little bit about the translational and clinical potential. Could you maybe share your thoughts here? I love the title by the way, Erasing Hidden Fibrosis. Dr. Thomas Gillette: Thanks. Thanks for that. Yeah, first of all, Tim, it was a really great piece of work, and it's actually really exciting because when we think of this diastolic dysfunction, and really it's the development of HFpEF, I think, that a lot of people are... It's the single most critical unmet need in cardiovascular medicine, is the treatment for HFpEF. That diastolic dysfunction, it's really that stiffness that Tim was measuring with his atomic force microscopy and those changes in ECM that really seemed to be critical, at least in that model. Dr. Thomas Gillette: And we know from other models as well that these underlying changes in fibrosis and stiffness, perhaps in the ECM, play a really important role, not only in the diastolic dysfunction, but also if you think about in strain as well, because I know in our models of HFpEF and this mouse model of HFpEF, we have the two-hit model published that Gabrielle, a Allie developed with Dr. Hale in Nature. It's that strain that we could measure that really seems to correlate well with the heart failure phenotype. And so it begs the question, has he caught a very early change in the ECM that's really critical to the development of this pathology? And is there a way that we could detect it early on in patients? Is there a way we could measure that in patients and really get a sense of who's progressing and how they're progressing? Dr. Thomas Gillette: Then there's a second point, and I mentioned a little bit in the editorial, I didn't go into it too deeply, and that is, it's really intriguing what this might mean for the development of the disease, because the matrix not only is involved in stiffness, but it's also a reservoir for growth factors, it helps recruit inflammatory cells, and inflammation plays a huge role in HFpEF. And so it begs the question, how many of those changes may proceed a lot of that pathology as well? Dr. Carolyn Lam: Wow, Tom, I really couldn't agree more. I made a big deal earlier about agreeing with Tim, calling this a diastolic dysfunction model rather than HFpEF, but I completely agree with you that the implications are for the development of HFpEF, and it needed the begs, the question of how many patients actually have this hidden fibrosis? And we know that in patients with HFpEF, there is a stage of advanced fibrosis where we feel patients don't respond to treatment as well. So have we caught an early phase that may be clinically applicable? I really loved the way you worded that. But finally, with Sergio, could you put it all together and what the editors thought of this paper? Why you invited Tom to write this editorial? And perhaps what next steps are? Dr. Sergio Lavandero: Okay, Tim, this is really a fascinating work. I have a long road, because in Italy, you develop the most important new concept. The new concept, the hidden fibrosis. The second important, originally, most of the HDAC inhibitors were developed for other diseases, originally for cancer. So now we have more data that, probably, this compound can apply to other diseases like cardiovascular disease. It was difficult to convince at the beginning some reviewers about the concept of hidden fibrosis, because it's not traditional. But finally, we asked to another expert to, "Okay, why don't you explain, please, this new technique?" For the future, Tim, what do you think? How can we evaluate hidden fibrosis in patients? Dr. Timothy McKinsey: Ideally, and you would have a non-invasive approach to assessing hidden fibrosis in patients. Obviously I know myocardial biopsies could be analyzed using the mass spec approach and atomic force microscopy, but not everyone is going to want to get a myocardial biopsy. So ultimately, we would like to correlate data that we obtain with biopsies, with circulating factors to see if there is a non-invasive surrogate circulating factor that correlates with the existence of hidden fibrosis. I think that would be very powerful clinically. Dr. Sergio Lavandero: What do you think the specificity of this research, because maybe it's too broad? What do you think? Dr. Timothy McKinsey: Yeah, that's a great point. There's a negative impression of general HDAC inhibition, because people just can't believe that you could inhibit a large number of HDAC enzymes throughout the body and not kill someone. But you can. And in our models you can use pretty low doses of these HDAC inhibitors and see efficacy. But obviously, the holy grail in this field would be to identify specific HDAC isoforms that regulate specific disease processes. So we have an active area of investigation where we're trying to tease apart the roles of different HDACs in the heart, with the ultimate goal of finding the HDAC or a subset of HDACs that regulate in fibrosis. Then you could selectively inhibit those and perhaps have a safer drug than a general HDAC inhibitor. Dr. Carolyn Lam: Thank you, once again. This is an amazing discussion and really, really an example of just the kind of papers we love publishing at Circulation. So novel and with such translational potential. Thank you, Tim, again, and Tom and Sergio. Thank you, audience, for joining us today. From Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

This week's episode features author Adnan Kastrati and Associate Editor Dharam Kumbhani as they discuss ticagrelor or prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. TRANSCRIPT BELOW: Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your 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 Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature Ticagrelor Prasmul in patients with ST segment elevation myocardial infarction undergoing primary PCI. More on that story later, though. How about we grab a cup of coffee and look at some of the other papers in the issue. Would you like to go first? Dr. Carolyn Lam: I would. And actually, I'm going to talk about two papers and they're all about BET, BET or promo domain, an extra terminal epigenetic reta proteins. And in particular, this one called BRD4. Now these proteins have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small molecular BET protein inhibitors, such as JQ1 have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet genetic studies elucidating the biology of BET proteins in the heart have not been conducted. Well, at least until this week's issue where we have not one, but two papers, both elegantly using mouse genetic studies. Dr. Carolyn Lam: In the first from Dr. Srivastava from Gladstone Institute of Cardiovascular Disease in San Francisco and Dr. Jain from Perlman School of Medicine in Philadelphia and their colleagues, they found that BRD4, that particular BET epigenetic reader protein, forms a transcriptional regulatory module with GATA4, a lineage determining transcription factor in cardiomyocytes. This BRD4 GATA4 module was a critical orchestrator of mitochondrial bioenergetics in the adult heart. Dr. Greg Hundley: Well Carolyn, that is a wonderful summary. What are the clinical implications? Dr. Carolyn Lam: Identification of this new BRD4 interaction partner, such as GATA4 could provide new insights into developing epigenetic based therapies for heart failure. And the second paper is from Dr. Joseph Hill and Thomas Gillette from University of Texas Southwestern Medical Center and their colleagues. And what they found was that BRD4 was essential to the maintenance of mitochondrial electron transport chain function via transcriptional regulation of a nuclear mitochondrial gene network. BRD4 heterozygous deletion resulted in delayed heart failure, whereas pharmacological BRD4 inhibition using JQ1 induced modest changes in mitochondrial genes suggesting potential cardiac toxicity in targeting BRD4 at baseline. Dr. Greg Hundley: So what does this mean for us clinically, Carolyn? Dr. Carolyn Lam: As more potent and specific inhibitors are developed targeting BRD4 for clinical settings in oncology and other diseases, we must carefully monitor bezel cardiac performance for functional and mitochondrial deterioration. Important clinical message there. Dr. Greg Hundley: Great job, Carolyn. Well, my first paper is entitled "An Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaques" And it comes to us from Dr. Tomas Neilan and his colleagues at the Mass General Hospital. The study was situated in a single academic medical center. And Carolyn in this paper, there are actually three studies described. First, there's a primary analysis that evaluated whether exposure to an immune checkpoint inhibitor during treatment for cancer was associated with atherosclerotic cardiovascular events among 2,842 patients versus 2,842 controls that were matched by age, a history of cardiovascular events and cancer type. Dr. Greg Hundley: In the second study, a case crossover analysis was performed with an at risk period defined as the two year period after, and the control period as the two year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events including myocardial infarction, coronary revascularization, and ischemic stroke. And secondary outcomes included the individual components of that primary outcome. Dr. Greg Hundley: Finally, in the third study in this paper, there's an imaging stub study of 40 individuals, and it looked at the rate of atherosclerotic plaque progression compared from before and after starting the immune checkpoint inhibitor. All study measures and outcomes were blindly adjudicated in this third study. Dr. Carolyn Lam: Wow, a three in one. That really sounds novel. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. In the matched cohort study, there was a three-fold higher risk for cardiovascular events after starting an immune checkpoint inhibitor. There was a similar increase in each of the individual components of the primary outcome. In the case crossover study, there was also an increase in cardiovascular events from 1.37 to 6.55 per hundred person years at the two year time point. Dr. Greg Hundley: And then lastly, Carolyn, in the imaging study, the rate of progression of total aortic plaque volume was three fold higher after immune checkpoint inhibitors from 2.1% per year to 6.7% per year after receiving these agents. The association between immune checkpoint inhibitor use and increased atherosclerotic plaque progression was attenuated with the concomitant use of statins or corticosteroids. Dr. Carolyn Lam: Wow, Greg. So I suppose what all this shows is that we need to be aware of the cardiovascular risk prior to, during and after treatment with immune checkpoint inhibitors and perhaps, you know, optimize these cardiovascular risk factors. Thank you, Greg. Dr. Greg Hundley: You bet. Well, Carolyn, my next paper is from Dr. George Vlachojannis from University Medical Center at Utrecht. These authors conducted a randomized control multi-center trial in the Netherlands enrolling STEMI patients planned to undergo primary PCI. Now patients were randomly allocated to receive in the ambulance before transfer a 60 milligram loading dose of Prasugrel, either being crushed or as integral tablets. The independent primary end points were thrombolysis in myocardial infarction, TIMI three flow in the infarct related artery at initial coronary angiography, and complete greater than they go to 70% ST segment resolution one hour post primary PCI. The safety end points were TIMI major and bleeding academic research consortium, or BARC, greater than three bleedings and secondary end points included platelet reactivity and ischemic outcomes. Dr. Carolyn Lam: Nice trial design. So what did they find? Dr. Greg Hundley: Well, Carolyn, a total of 727 patients were assigned to either crushed or integral tablets of Prasugrel. The median time from study treatment to wire crossing during primary PCI was 57 minutes, and the primary end point of TIMI three flow in the infarct related pre primary PCI artery occurred in 31% in the crushed group versus 32.7% in the integral group. No difference, P .064. Complete ST segment resolution one hour post primary PCI was present in 59.9% in the crush group and 57.3% in the integral group. Again, no difference, P equals .055. Platelet reactivity at the beginning of primary PCI measured as the P2Y12 reactivity unit, differed significantly between the groups. Crushed was 192 versus integral was 227 and the P value was less than 0.01. TIMI major and BARC greater than three bleeding occurred in 0% in the crushed group and 0.8% in the integral group and in 0.3% in the crushed group versus 1.1% in the integral group respectively. So there were no differences observed between groups regarding ischemic events at 30 days. Dr. Greg Hundley: So Carolyn, in conclusion, prehospital administration of crushed Prasugrel tablets does not improve TIMI three flow in the infarct related artery, pre primary PCI or complete SD segment resolution one hour post primary PCI in patients presenting with STEMI planned for primary PCI. Dr. Carolyn Lam: Interesting and interesting stuff with platelet reactivity and bleeding. Thank you, Greg. Well, there are other papers in today's issue. There's an in-depth paper by Dr. Katsanos on stroke prevention in atrial fibrillation, looking forward. There's a research letter by Dr. Berger on myocardial injury in adults hospitalized with COVID-19 and another by Dr. Hacker on again, immune checkpoint inhibitor therapy and how that induces inflammatory activity in large arteries. Dr. Greg Hundley: Well, Carolyn, I've got a couple other papers to talk about in this issue. There's a On My Mind piece from Dr. deFilippi entitled "Navigating Testing for COVID-19." There's a Perspective from Dr. Ridker entitled "Equipoise Trust and the Need for Cardiologists to Randomize Patients into Anticoagulation Trials in the Time of COVID." There's an ECG challenge from Dr. Arias entitled, "A Paced Tachycardia." And then finally, there's an exchange of letters from Drs. Liu regarding a prior publication entitled "Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets." Well, Carolyn, how about we get to the world of anti-platelet therapy, ticagrelor prasugrel in patients with ST segment elevation myocardial infarction, shall we? Dr. Carolyn Lam: Yes, let's go Greg. Dr. Greg Hundley: Well welcome, listeners, to our featured discussion today on this December 15, and we are going to learn and discuss a little more, a paper pertaining to ticagrelor versus prasugrel in patients with ST segment elevation myocardial infarction. And our lead author today is Adnan Kastrati from Deutsches Heart center in Munich. And we also have our own Associate Editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas. Welcome, gentlemen. Adnan, maybe I'll start with you. Could you tell us a little bit about the background related to this article and what was the hypothesis that you wanted to address? Dr. Adnan Kastrati: First of all, thank you very much for having me here to share with you some thoughts. Thank you, Dharam, for handling our paper in Circulation. We are very honored to have it published there. About these are the ISAR REACT-5 series of studies dedicated to optimizing the antiplatelet therapy in patients and anticoagulant therapy in patients with acute and chronic coronary syndromes, mostly who are undergoing a PCI procedure. We started to think about that study immediately after the publication of the platelet trial. We showed the superiority of prasugrel in patients with acute coronary syndromes. These were the two new ADP receptor antagonists at the time. And so as a physician, we are interested to know which of them was better because there was no direct comparison. And so that's why we decided to have an open-label trial randomized. Most of the centers were situated in Germany. Two centers were situated in Italy. The private end point was adopted to the private end point of the trials in this skill. Only one difference was there, instead of cardiovascular death, we put all cause death in the primary end point. Why? Because all cause death may also reflect the gradient end bleeding between the two drugs. We wanted to have a more integrative endpoint in this sense. So it was a combination of all cause death, myocardial infarction, and stroke. Dr. Adnan Kastrati: It was a one year followup study. The study had two groups of steady patients, which was about 40% of the patients, included in the multicentral trial. And what we found in this trial, it was the same results as it was found in the whole trial. The advantages seen for prasugrel was present here also. Although we lost the significance in the evaluation of the primary endpoint. It was a 31% increase or 24% decrease with prasugrel in that sense. But otherwise everything was in the same direction as in the whole trial. And if you look also in the components of the primary end point…, you have the chance to see that numerically, it was the same trend for all components. Although the trial was not powered for going to evaluate the component of the prime end point. This was the main result. Dr. Greg Hundley: It sounds like you had 1,653 patients with STEMI randomized to receive ticagrelor or prasugrel and 10% experienced the primary end point in the ticagrelor group, but only 7.9% in the prasugrel group. But the P value was only .10. We saw trends toward favoring prasugrel rather than sort of a definitive difference. Is that a correct summary? Dr. Adnan Kastrati: Yes, it is a correct summary. I would say this group of patients is the most interesting subgroup of patients in ISAR 5 trial. Why? Because the pretreatment strategy is the same. Because there have been a lot of discussions about non-S-segment segment elevation acute myocardial infarction due to the difference in pretreatment. Although it was intentional, some people felt it's different and they said you have two different strategies there. In the STEMI subgroup, the pretreatment strategy was the same, so it was a head to head comparison of two drugs, even according to the same strategy. This is one. Dr. Adnan Kastrati: Second, you have to look back at the trials in the same field…Both these trials, if you look closely to the results of for STEMI patients, both of these trials haven't shown a significant result for the STEMI subgroup. For plateau it was a P value of 007 and for tritan it was a P value of 0014 only. Why? Because in the tritan it was very specific. They included also patients after fever analyzes and the significance came only from the comparison of tritan in this group, not in the primary PCI group. In the plateau and ISAR-5 we excluded these patients. Dr. Greg Hundley: Dharam, we're going to turn to you now. Adnan's really framed this study nicely, but can you help us from your perspective, put this study in perspective with others that have been published in this space? Dr. Dharam Kumbhani: Yeah, thanks, Greg. And I want to congratulate Adnan and his group for providing the field with another really well conducted study in a very important field. The center has done some very, very landmark trials, and I think this is another one of those. It sort of helps us understand potentially the best treatment mechanism or protocol for patients undergoing primary PCI for STEMI in this case. As you nicely outlined sort of the background for this, the only other trial that I'm aware of in this space is directly comparing pasugrel and ticagrelor head to head was the Prague 18 trial, which was smaller. I think it was about under 1100 patients. So even the STEMI cohort here was larger than that trial. But that trial ended up being terribly underpowered and unfortunately, also discontinued prematurely. So there wasn't really any significant difference that was noted in that trial and there was also a high crossover to clopidogrel in that other trials. Dr. Dharam Kumbhani: So I think that trial, in fact, we had published a trial in circulation as well. And I think this study sort of helps to advance the field a little bit by providing a head to head comparison between the two drugs. If I may extend some of the discussion points that were brought up earlier, I think, again, there is a couple of things that jumped out to me. One is, as you mentioned, the semi cohort is very interesting and very important. The p-value for interaction between the STEMI and the non-STEMI population was not significant for the primary end point. So that is certainly important when considering these results. Dr. Dharam Kumbhani: And the second thing is the differences that were noted in the rates of reinfarction, both spontaneous as well as PCI related. And although that is very interesting, we certainly have to keep that first point in mind when considering that. I think it becomes more hypothesis generating that MI rates ended up being higher with ticagrelor compared with prasugrel, and then sort of trying to tease that out in terms of, was that just a play of chance? Do we end up seeing that, is there a real biological reason for that? All of the trials was extremely well done. There were about 29 patients that did not have one-year follow-up and there were about 67 or so MI events. I think it's very interesting, and I think for at least for me, when I review this trial, I think it brings up some very interesting hypotheses that I think we would need to test further. Those anyway, my sort of high-level thoughts on this excellent trial. Dr. Greg Hundley: Very good. Well, I'd like to ask you just in 20 seconds, each of you, what's the next study that needs to be performed in this field? Adnan, start with you. Dr. Adnan Kastrati: I don't expect trials doing the same thing that we have done in ISAR-X5. We are planning now that ISAR-X6 trial. They are finalizing the protocol, and it will be a large trial of 9,000 patients with acute coronary syndromes in which will test the need for aspirin after discharge. That means all the spaces will be with the potent P2I12 inhibitors. And one group, it will be a placebo controlled trial. One group will have aspirin after discharge, the other placebo. And this is now, for us, the most important thing in this area. Dr. Adnan Kastrati: If I have the chance to respond to Dharam about the mechanistic insights of this effect, I would say that we have shown aggressive cardiology, our data about platelet function. It is the biggest platelet function studies in this area, 600 patients. We have tested in patients after PCI. We tested ADP in used aggregation after ticagrelor and prasugrel. And prasugrel was associated with a 30% reduction in platelet aggregation in these patients. And I think that this offers the mechanistic basis also for our results. And the results will be published shortly. Dr. Greg Hundley: Very nice, and Dharam. Dr. Dharam: Thank you for that response, Adnan. And Greg, to your question, I agree. I think it would be hard, although the field would really benefit from having a head to head comparison between these two drugs again in a larger study. I do think a lot of the interest and excitement in the ACS field is on de-escalation strategies as the outline. And so I suppose that that's sort of where we'll see a lot more in terms of clinical trials. Dr. Greg Hundley: Very good. Well listeners, this has been a wonderful discussion and we appreciate the input from the primary author, Dr. Adnan Kastrati, from the Deutsches Heart Center in Munich and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern. Really reviewing prasugrel versus ticagrelor for primary PCI in patients with STEMI only, and showing really no difference in their primary endpoint of death, myocardial infarction, and stroke, with however an increased risk of reinfection in the patients receiving ticagrelor only. Dr. Greg Hundley: So on behalf of Carolyn and myself, we wish you a great week and look forward to catching you next week On the Run. This program is copyright the American Heart Association, 2020.  

Finding a cure for type 1 diabetes includes two essential goals: growing insulin-producing beta cells and introducing them into patients successfully. Those two achievements appear fast-approaching yet also seem elusive. This podcast takes a closer look at these goals, interviewing one researcher studying how beta cells grow and mature. Listen and learn Where current research stands regarding endocrine system physiology, pancreatic beta cells, and diabetes, What scientists understand about pancreatic beta cell development and pancreas function and what is still a mystery, and How current stem-cell derived pancreatic cells are made and how well they function. Diana Elena Stanescu is an assistant professor of pediatrics with the Department of Pediatrics at the Perlman School of Medicine with the University of Pennsylvania. She's a physician scientist, treating patients and researching how beta cells develop, grow, and mature. “As a pediatrician,” she says, “everything is about growing, developing, maturing: I keep that perspective across my work.” She adds that scientists think an initial cure for type 1 diabetes will center on cell replacement therapy: they're finding ways to make embryonic cells become beta cells that make insulin. By looking at how beta cells develop and mature, she hopes to advise stem cell biologists on making better beta cells. While scientists have been able to make these cells, they are still too inefficient. Her work aims to change that. Developmental biologists like her are therefore informing these stem cell biologists how these cells need to mimic what happens in normal development to a closer degree. They also need to produce an envelope in which to deliver these cells, protecting them from the body's immune system. “We are able to do this in the lab but the problem is taking it from the lab and scaling up to a lot of people,” she says. Furthermore, the cells don't make enough insulin to meet the body's demands. She's directing her research towards making higher quality cells, so that the few cells that they are able to include in this envelope are of the best possible quality and efficiency. This means researching how cells determine their glucose threshold before insulin secretion and other issues like hyperinsulin condition, when babies actually make too much insulin. This work will hopefully lead scientists closer to a cure. For more about her work, she welcomes getting in touch via email. See her information page at the University of Pennsylvania for more information. Available on Apple Podcasts: apple.co/2Os0myK

Movies discussed: Scare Package, Come to Daddy, The Invisible Man, Rebooted (short) This week we enjoy the re-imagining of The Invisible Man, are divided by Come to Daddy, and delight in hearing Charlie’s experiences working on Scare Package. Scare Package is a lot of fun in it’s own right too. Next weeks assignments: The Wretched Yummy Stay Out Stay Alive NSFW (short) Watch along with us if you like and we’ll see you next week. The post Episode 369 – The Ron Perlman School of Head Size appeared first on Horror Show Hot Dog.

People who experience weight discrimination are more likely to gain more weight over time than people with obesity who don't describe these kinds of experiences. Weight bias, stigma and discrimination have received more and more attention among researchers, but also in the public. Think, for example, of the term "fat shaming." Among the researchers doing pathbreaking work in this area is Dr. Rebecca Pearl at the Perlman School of Medicine. Her research focuses on weight bias and its associated outcomes in patients with obesity. About Rebecca Pearl Rebecca Pearl, PhD, is an Assistant Professor of Psychology in Psychiatry at the Perelman School of Medicine at the University of Pennsylvania. She received her BA from Duke University and her PhD in clinical psychology from Yale University. She completed her predoctoral psychology internship at McLean Hospital/Harvard Medical School and her postdoctoral fellowship at the Penn Center for Weight and Eating Disorders. Her research focuses on weight bias and its associated health outcomes in patients with obesity. She also investigates strategies for reducing weight bias and its internalization. Her work has been recognized with awards from The Obesity Society and the American Psychological Association and is currently supported by a K23 mentored patient-oriented research career development award from the National Heart, Lung and Blood Institute of the NIH. Interview Summary Rebecca, I'm very grateful that you could join us, and let me start with a fundamental question. What is weight bias? How do you define it? Well, Kelly, first, thank you so much for having me, and it's a real treat to speak with you about this topic considering that you are one of the first people to really draw attention to this issue, especially in the scientific context. So when we're talking about weight bias, we're thinking about negative attitudes toward people because of their weight, so people with overweight and obesity, and these negative attitudes are rooted in some common stereotypes, such as that people with obesity are lazy, they don't have any self control, they're unhealthy or don't care about their health. They're greedy, or might even be less intelligent than other people. And then there's also a strong sense of blame that's put on people because of their weight, due to this belief that weight should be entirely within an individual's control. So when people are perceived as not being able to control their weight, they're perceived as being a weak person, or having weak character, or having a failure of personal responsibility. So actually being perceived as an irresponsible person because they have a higher body weight, and these negative attitudes and stereotypes and this blame lead people with obesity to face societal stigma, experiences of weight-based teasing or bullying, discrimination or social rejection, or just generally being devalued by society. And these consequences can be pretty severe, can't they? Absolutely. From a socioeconomic level, when people are denied employment opportunities or denied promotions because of their weight, that can affect wages and socioeconomic advancement. There are also educational disparities that can be attributed to weight bias and weight-based discrimination, and then there are also a number of health disparities that might be in part explained by experiences of weight discrimination or stigmatization. So we'll come back to the health issues in just a minute, but I want to ask you about a particularly important area that you've worked on, weight bias internalization. You and others have documented the impact on people, but you've looked at this particular issue in great depth about internalization. Can you tell us what you mean by that? People can experience weight bias from other people, but they can also apply it to themselves. So weight bias internalization is sometimes called self-directed stigma, and this occurs when people with obesity are aware of the negative attitudes and stereotypes about people with a higher body weight. People with obesity might come to also believing that they are a weak person, or lazy, or a failure, or less worthy than other people, so it's really how stigma can get under the skin, if you will, when people are devaluing themselves because of their weight. And is there variability in how much people with obesity do internalize these negative messages? And what effects does that have when somebody does? Not everybody with obesity internalizes weight bias, but given how pervasive the societal messages are about weight, it's understandable when people do internalize these messages. There's certainly a significant minority of people who have high levels of internalized weight bias, and then many more people who internalize these messages, at least to some degree. A lot of the same health effects that we see from experiencing discrimination from other people, we're also seeing independently associated with this internalized weight bias, and some studies actually suggest that weight bias internalization, above and beyond the experiences of weight bias, might be a stronger predictor of some of the negative health outcomes. So let's loop back to that issue of weight bias and health. And one could imagine that if you internalize the bias and-or you're just subjected to all these things happening out there in society, and it affects your wages, your success in education and all these other kinds of things, that it could affect your health through things like depression and stress. Are there other ways that weight bias might affect health? So those are the big ones. We do know people have higher rates of depression when they're reporting experiences of weight discrimination. Also more anxiety disorders, which makes sense too if you think about when people are anticipating rejection or anticipating discrimination, that that is stressful and might also increase anxiety, especially in social interactions. We also know that substance use disorders are higher in people who have perceived weight discrimination. And then the stress issue is a big one that more and more researchers have been looking at. There's a physiological stress as well as a psychological distress that might affect health outcomes. So if we see changes in cortisol, blood pressure, other markers of inflammation, and those independently are risk factors for cardiovascular disease, but those can also affect people's appetite. So cortisol, for example, is a hormone in relation to stress that can increase appetite, so people might also have behavioral responses to these experiences or even just the internalization of weight bias that's in part driven by physiological responses of eating more food because their body is in a state of stress. So many of us eat as a way of coping with negative emotions, as a way of soothing ourselves or finding comfort. And so for a lot of people who experience weight bias, this is a common way of coping. People also might avoid engaging in physical activity when they are concerned about how others might be perceiving them because of their weight. Especially in public settings like in a gym, they might feel intimidated or just very self-conscious. The patients I've worked with have described negative comments that they've received in fitness type settings, so that would understandably lead them to want to avoid being in those settings. And so that combination of eating more food in response to these experiences as well as avoiding physical activity can actually lead to more weight gain over time. And the last aspect of health that is really important to highlight is how weight bias can play out in health care. So many patients describe having humiliating or disparaging experiences in health care settings, and this might not be intentional on the part of the physician. They might not even be aware of the bias. So for example, a patient coming in for a health concern that's completely unrelated to weight, and the physician solely focusing on the need to lose weight. That can be a very frustrating experience for a patient that might make them want to avoid even bothering to go to the doctor's office the next time they have any health concern. And so if patients are avoiding health care settings, then that's also setting up a higher risk for missing health problems early or for missing out on preventative healthcare services. And the quality of care, too, can also be influenced by weight bias. So Rebecca, what strategies do you think might be effective for reducing weight bias? There are some structural level interventions that have been showing promise. So these interventions include changing media portrayals to reduce the stereotypical or stigmatizing images, and news content in stories about obesity. Other interventions might include policies, for example, legislation to prohibit weight discrimination. In most cities and states in the United States, with the exception of a few cities and one state, the state of Michigan, it is entirely legal to discriminate against hiring or promoting someone because of their weight, so policies to address that could be very effective at reducing instances of discrimination, as well as anti-bullying laws that specifically incorporate weight as a reason that bullying is prohibited. And then other policies at institutional levels within workplaces or educational settings or healthcare settings to promote awareness of body size diversity and increase weight sensitivity by incorporating more education about obesity, especially in healthcare settings, might be helpful as well. Obesity is tied to biological factors, to environmental factors, and it's not a matter of personal weakness or a failure of personal responsibility. There are so many complex factors that influence a person's weight. Some of that kind of education might be helpful for increasing understanding and reducing bias. Another principle that's been looked at is the idea of social consensus as well. Weight is a very socially acceptable thing to tease people about or to stigmatize people for, and so if we could figure out ways, whether it would be through campaigns or just individual actions of making it clear that it is not acceptable to tease someone or make someone feel badly about themselves because of their weight, then that could also go a long way in shifting societal attitudes and behaviors. Well, thanks for those ideas. They're really very promising roads to go down. So let me ask one final question. Is there a way to reduce the internalization of these messages in people with obesity? That's a question I've been very interested in in the past few years, and I do want to emphasize that we need to be, first and foremost, trying to improve societal attitudes and behaviors to try to prevent experiences of weight bias or prevent people from internalizing these messages. And for the people who have already internalized these messages, I think it's really important to develop strategies to help them cope with this and to try to retrain their brains or undo some of this internalized weight bias. So some of the strategies that myself and my colleagues have been testing draw upon psychological principles and psychological treatments that have been used for things like depression and anxiety, and trying to adapt those strategies specifically for targeting internalized weight bias. So this might include cognitive and behavioral skills like examining myths and stereotypes about weight and really digging into, what is the evidence that would support a stereotype like people with obesity are lazy? And what are some of the points of evidence that might poke holes in that idea, or to really challenge the evidence against this idea? Other strategies might include learning how to speak up for oneself, so promoting assertiveness skills. If someone does make a comment to you about your weight, how do you respond? What do you say? How do you have a conversation with a loved one to ask them to stop making comments about what you're eating or what your weight is at the dinner table? And other skills like increasing self-compassion, improving body image, these are all strategies that we're looking at to see if they could have an effect on reducing weight bias internalization. And the last potential strategy might be engaging in advocacy as a way of feeling empowered to do something about this social injustice in the world, that that might help people feel better about themselves and also help to combat this bigger problematic issue in society  

Do we still need doctors? There are umpteen alternative sources of medical advice, including endless and heartfelt health tips from people without medical degrees. Frankly, self-diagnosis with a health app is easier and cheaper than a trip to a clinic.  Since we're urged to be our own health advocate and seek second opinions, why not ask Alexa or consult with a celebrity about what ails us? Find out if you can trust these alternative medical advice platforms. Plus, lessons from an AIDS fighter about ignoring the findings of medical science.   And, if AI can diagnose better than an MD, will we stop listening to doctors altogether? It's our monthly look at critical thinking … but don't take our word for it! Guests: Katherine Foley – Science and health reporter at Quartz, and author of the article “Alexa is a Terrible Doctor” Paul Offit – Professor of pediatrics at the Children's Hospital of Philadelphia and the Perlman School of Medicine at the University of Pennsylvania, and author of “Bad Advice: Or Why Celebrities, Politicians, and Activists Aren't Your Best Source of Health Information” Richard Marlink – Director Rutgers Global Health Institute. Shinjini Kundu – Research Fellow, University of Pittsburgh Medical Center Stuart Schlisserman – Internist, Palo Alto, California   originally aired September 24, 2018 Learn more about your ad choices. Visit megaphone.fm/adchoices

Do we still need doctors?  There are umpteen alternative sources of medical advice, including endless and heartfelt health tips from people without medical degrees. Frankly, self-diagnosis with a health app is easier and cheaper than a trip to a clinic.   Since we’re urged to be our own health advocate and seek second opinions, why not ask Alexa or consult with a celebrity about what ails us? Find out if you can trust these alternative medical advice platforms.  Plus, lessons from an AIDS fighter about ignoring the findings of medical science.   And, if AI can diagnose better than an MD, will we stop listening to doctors altogether? It’s our monthly look at critical thinking … but don’t take our word for it! Guests: Katherine Foley – Science and health reporter at Quartz, and author of the article “Alexa is a Terrible Doctor” Paul Offit – Professor of pediatrics at the Children’s Hospital of Philadelphia and the Perlman School of Medicine at the University of Pennsylvania, and author of “Bad Advice: Or Why Celebrities, Politicians, and Activists Aren’t Your Best Source of  Health Information” Richard Marlink – Director Rutgers Global Health Institute. Shinjini Kundu – Research Fellow, University of Pittsburgh Medical Center Stuart Schlisserman – Internist, Palo Alto, California   originally aired September 24, 2018

Many policies have been proposed and enacted to help improve public health by changing their diet and preventing obesity. Among the most prominent, our efforts to reduce consumption of sugary beverages, ranging from programs that educate consumers about risks to the most dramatic approach: taxing such beverages. Evaluating these other policies is critical and understanding how governments can best move ahead. Leading the charge was such evaluation as our guest today on the Leading Voices in Food Dr. Christina Roberto from the University of Pennsylvania. About Christina Roberto Christina Roberto joined the faculty at the Perlman School of Medicine at the University of Pennsylvania in 2015 having served previously on the faculty at the Harvard School of Public Health. She's a highly productive scholar, having done pioneering work on, for example, evaluating the impact of placing calories on restaurant menus in front of package labeling schemes and other policy interventions and has another entire body of research on eating disorders. Christina received joint Ph.D. Degrees in psychology and epidemiology from Yale University. Interview Summary You run the Psychology of Eating and Consumer Health (PEACH) Lab at Penn. Would you explain some of the work you're doing with your students and colleagues? Sure, so the mission of the PEACH Lab, as we call it, is to identify policies and interventions to promote healthy eating. And we work across six broad areas. We think a lot about the psychology of eating and along the lines of how do you design nutrition information so that it's really accessible to people. We do work on the economics of eating - so thinking about beverage tax policies and the influence they have some work around culture and eating. Issues like why does a country like Japan have a 4% obesity rate and other countries have 30%, and then some work around mental well being with a focus on eating disorders. And, we're moving more and more into questions around planetary health - so win/wins like reducing red meat consumption, it's good for people's health, but it's also good for the planet's health. So we really work across a broad range of areas. You received a large grant to study sugar-sweetened beverage intake Guatemala. So it's well known in the United States about the high risks of sugary beverage consumption and the high rates of consumption, but what's the picture in other countries and why would Guatemala be of particular importance? Guatemala is a really, it's an interesting country. So it's a classic example of the double burden of disease. So, on the one hand, you have 47% of kids have childhood stunting that's due to malnutrition. And then you've got 30% of kids increasingly struggling with overweight and obesity. And so Guatemala is a country where they're on this really worrisome upward trajectory where you get these rising rates of obesity, even in the context of malnutrition. And so people are really concerned and really starting to think about policy changes there to try to prevent them from continuing on this. And in terms of sugar-sweetened beverages, there's not a lot of data from Guatemala, but there is some survey research that suggests that about 80% of kids drink a sugar-sweetened beverage at least once per week. So it's obviously a prime target to want to change behavior around that on the sooner side. So what does your project involve? We've been working with a team in Guatemala, a terrific group led by Joachim Barnolia, and the project has two goals. So the first one is to do a field experiment where we would test a policy of placing warning labels on sugary drinks in school stores. So we would randomize different schools, two different kinds of labels and then try to understand how those labels would influence the types of drinks kids are purchasing at the school store. And we're testing labels like text-based warning labels that literally would say something like drinking beverages with added sugar, contributes to obesity, diabetes and tooth decay. And then we're using some graphic images. So what happens if you display the teaspoons or sugar cubes of sugar. And then we're going to test a symbol that's very similar to the symbol being used in Chile--sort of a stop sign like symbol that would just alert consumers to the high amounts of sugar. We'll be able to look at kids' purchases, and we'll also do some survey work with them to see if this is a policy that might really be able to move the needle on behavior. So there are a lot of things one could possibly do to reduce sugary-beverage consumption. You're talking about warning labels. One could also imagine broad education campaigns through the media. One could imagine taxes. Why have you chosen the warning labels as a place to start? So it was a combination of, um, something that we did think would be impactful but also feasible. If you ask me right now to list the number one policy you could pick to try to move the needle, I would tell you taxes. But I think working with local partners has been really critical and they felt like there might be an opportunity policy wise around labels and that we'd really need an evidence base. And I do think something like a warning label has different psychology to it than just a typical food label. We've learned that the word warning really comes with a sort of an extra, an impactful punch when you're trying to get a message out there. So I'm quite curious about these labels and think they could be pretty promising. So is there a certain segment of the population you think might be most responsive to labels? Would it be parents, older adults, younger adults, children? What do you think about that? The Devil's in the details with labels. There are definitely ways to design labels where they can have a broader reach across the whole population. It's pretty well established that when you're talking about a label, like the standard nutrition facts label we see in the US, that has lots of numbers and percentages and lots of information, you tend to get higher socioeconomic status folks using them and then lower socioeconomic status folks not using them. And so, the wave of new kinds of labels where you're talking about traffic lights or stop signs or these really intuitive symbols - the hope, we don't have very good on it yet, but the hope is that that's going to cut across a broader segment of the population and really resonate with most people. You mentioned some numbers about how frequently beverages, sugary-beverages are consumed by children. But why pick sugary beverages as the target for warning labels? Are there other parts of the food supply that would have been logical candidates as well? I think sugary beverages are really a special product and there's a special case to be made to focus on them specifically. So certainly in the US, we see that they're the largest source of added sugar in the diet. There are data to suggest that when you drink calories in liquid form, it doesn't keep you as full than if you eat the same number of calories in solid form. And so I think that makes them uniquely problematic. And they just have no nutritional value, right? So, it's pretty much all coming from sugar where you could imagine even some candy bars have nuts in them or sort of other redeeming qualities. So I think for all those reasons, plus the really strong scientific evidence base that links them in particular to weight gain suggests that it just makes a boatload of sense to focus on them. Has the industry in Guatemala, the beverage industry, started in the mobilize against these policies? It's interesting. I mean, these are multinational companies, and so they're obviously working across the globe in a variety of ways to try to, for all intents and purposes, undermine these policies. I think part of the reason you haven't seen much action in Guatemala is some worry about that. But I will say Latin America is a really interesting place right now for food policy because some of the most progressive, interesting work is happening on the policy front. And Chile is a good example of that where they've done food marketing restrictions and taxes and really aggressive labeling. So a lot's happening there, and we really need to pay attention to what they're doing and evaluate it. So a little closer to home, another major project you have underway is the evaluation of the soda tax in Philadelphia. In an earlier podcast, we had Dr. Thomas Farley, the health commissioner in Philadelphia, as a guest and he explained the rationale for the tax and answered some of the same questions you have on why soda for example. He outlined the structure of the tax and the industry response, which has been considerable. What are you learning about the impact that tax? We've been doing this fairly large evaluation that's funded by Bloomberg Philanthropies where we're able to study the tax from a bunch of different angles. And the first component is looking at what's happened to tax beverage sales and large chain retailers. So supermarkets, fast merchandisers, and pharmacies where beverages are being sold. And we have some really, I think important and exciting results. So there are two issues to think about with the tax. The way it's structured in Philadelphia is that the tax is on distributors. And so what that means is that a distributor and makes a decision of how much of tax to pass on to a store and then the store decides how much of that tax to pass onto the consumer. And the store could absorb all of the tax, or they could pass it all on, and there would be really considerable price increases. And so the first thing we've learned from our evaluation is that that the passthrough has differed based on the store types. So in supermarkets, about 43% of the tax has been passed on. It's 58% of mass merchandisers, and pharmacies have actually passed on 104% of the tax. So we're seeing the biggest price increases there. Now what we're really interested in is how that translates into volume sale reductions. And so what we're seeing in our data is that overall there's been a 51% reduction in the volume sales of tax beverages in Philly. And this is when you do a natural experiment. So we have a control site in Baltimore so we can be really confident in these results. Now there is one other piece to this story, which is something called cross-border shopping, right? So when you tax things, they're going to be some people who hopped the border and try to buy products over there. And we do see some of that. But only about a quarter of the taxes offset by that. So at the end of the day, we see reductions over the city of about 38% of tax beverages. And the last piece is you get some variability across store types. So the biggest effects are in supermarkets. It's a 59% drop there. It's 40% mass merchandisers, and then a little bit smaller, it's 13% in pharmacies. So that's counter-intuitive because the pharmacies passed along more tax than the other places. Why do you think that's happening? Yes, exactly. So when we dig into the data, what we see is that the real action here, and what's really changing, are the larger size beverages. So your 2-liters, your 12-packs or 24-packs--that's where, and it makes sense, their price increase is more salient. And so that's what's driving a lot of this effect. And pharmacies are selling many fewer of those types of large-sized beverages. You see that much more in supermarkets. And so we think that's what's explaining that difference. With the tobacco companies, as tobacco taxes have been raised a number of times, over the years, there have been occasions where the tobacco companies have actually passed along a higher increase in price than what the tax would dictate. Like the 104% you mentioned for pharmacies. Why don't you think the soda industry has done that? Do you think that deferring taxes across venues will even out over time because consumers will just learn where the soda is cheaper? We've got one year of data, and obviously, it's curious to see what happens beyond that. We're going to look at two-year results. We know the past through occurs pretty early on, sort of very soon after January 1st and starts then. And so at least our one-year long term data suggests they are holding pretty stable at these price increases. So I don't know if that would even out over time. And yes, you do sometimes see this over shifting in economic terms where some places capitalize on it, and they just raise prices even more. It is interesting on the ground in Philly because a lot of retailers have put signs up basically saying to consumers - 'Look don't blame us, this isn't our fault. Your soda is more expensive because of the tax.' And so I think part of the reason they didn't pass all of it on all of the tax is there was a real worry of losing customers, of losing revenue, and that they were a little hesitant to do that. I do think there's kind of a potentially interesting effect of the signage that it actually makes the tax more salient. And so I wonder if that might boost the behavioral impact of it. Something that some individuals had predicted would happen has come true, according to Tom Farley in that the soda industry has not been able to fight the taxes in the courts and in other ways. So they are now putting money into political campaigns so they can try to shift over the composition of the city council in hopes that they can vote down a tax. Do you have any sense of where that stands, how the public is reacting? Is it clear who the soda companies are supporting and not, and how's that playing out? I don't have a sense about how it's ultimately going to play out. So certainly, you know, that's happening, and there's a worry about it. I do think it's mixed. It really depends who you talk to, right? So there are store owners who really don't like the tax, but we do survey work with people, and oftentimes when they hear that their revenue is being used to expand Pre-K, that can really shift people's thinking on the tax. So their first reaction is, oh a tax, I don't like it. Oh wait, this is being used to really help some very low-income areas in Philadelphia and expand education opportunities? And people tend to get behind it for that reason. And so I think that's part of the reason it passed, that there is a lot of support and enthusiasm for that particular goal. And that might really help people running for city council to make that case for the importance of this tax sort of irrespective of this other public health effect that it likely has. So then there could be a strong political price to pay for anybody who wants to repeal the tax if the consumers and the citizens are valuing the use of the revenue. Yes, absolutely. I think that's right. As you think ahead to the future of policies to prevent obesity and to improve diet overall, what do you think are some of the ways things might go? If you could fast forward five years, what do you think the picture might look like? I think there's a lot of promise and a lot to be hopeful for because I think we're starting to see action. Particularly if you look at this in a global way. I think everyone who works in this space feels like there is no one policy that's going to solve this problem, and that we really need a suite of policies. And I think you have examples of certain countries which are now finally doing that. And so I think as you get some success stories like a country like Chile, as some of these beverage taxes have success, I think that kind of data could be very persuasive. And we'll start to see ripple effects of lots of places doing labeling, doing these kinds of tax policies. And also, not just the policy front but sitting down with industry and making plans around reformulation. We've got the national salt reduction program in this country. The UK has done some of this and engaging across sectors. I think we just hope that something like beverage taxes that has stalled out a little bit in the US, and so I hope that once some more evidence comes out that that'll pick up again. I think there's a lot to be excited about, you know, and, and happening in the next five years. You mentioned reformulation. Do you think if a food industry, for example, gradually reduced the salt across a number of products or within a category like soup, for example, do you think consumers can get used to having less salt, less fat, less sugar, and things? Oh, absolutely. I mean, I think it's pretty well documented that with sodium, in particular, consumers can get used to it. And then there are benefits to not necessarily advertising that it's happening. It was funny, I was talking to a colleague in the UK where they have lower sodium levels, and he says every time he comes over here, the food is just so salty and he can't stand it. I do think there are exciting ways to do this and there are folks also working on the sugar front to figure out can we do it with sugar as well. Do you think it's best to let consumers know these shifts are happening or not? I think the advice I would give a company is not to advertise it. Because you know, as someone who studies the psychology of eating, we do make all these sorts of inferences and can be influenced by marketing and things we think about a product. And so I think, the term is stealth health, that doing this in a way that doesn't overly advertise it probably benefits everyone.

Jaya Aysola, MD, MPH (http://bit.ly/2J65PYJ), joins Nick to talk about workplace inclusivity among genders. Dr. Aysola is an assistant professor of medicine and pediatrics at the Perlman School of Medicine. Her primary appointment in the Divisions of General Internal Medicine. In early August 2018, Dr. Aysola and her colleagues published a qualitative narrative analysis (http://bit.ly/2R1KmDo) regarding the perceptions of the factors associated with inclusive workplaces in healthcare.

Do we still need doctors? There are umpteen alternative sources of medical advice, including endless and heartfelt health tips from people without medical degrees. Frankly, self-diagnosis with a health app is easier and cheaper than a trip to a clinic.  Since we're urged to be our own health advocate and seek second opinions, why not ask Alexa or consult with a celebrity about what ails us? Find out if you can trust these alternative medical advice platforms. Plus, lessons from an AIDS fighter about ignoring the findings of medical science.   And, if AI can diagnose better than an MD, will we stop listening to doctors altogether? It's our monthly look at critical thinking … but don't take our word for it! Guests: Katherine Foley – Science and health reporter at Quartz, and author of the article “Alexa is a Terrible Doctor” Paul Offit – Professor of pediatrics at the Children's Hospital of Philadelphia and the Perlman School of Medicine at the University of Pennsylvania, and author of “Bad Advice: Or Why Celebrities, Politicians, and Activists Aren't Your Best Source of Health Information” Richard Marlink – Director Rutgers Global Health Institute. Shinjini Kundu – Research Fellow, University of Pittsburgh Medical Center Stuart Schlisserman – Internist, Palo Alto, California Learn more about your ad choices. Visit megaphone.fm/adchoices

Do we still need doctors?  There are umpteen alternative sources of medical advice, including endless and heartfelt health tips from people without medical degrees. Frankly, self-diagnosis with a health app is easier and cheaper than a trip to a clinic.   Since we’re urged to be our own health advocate and seek second opinions, why not ask Alexa or consult with a celebrity about what ails us? Find out if you can trust these alternative medical advice platforms.  Plus, lessons from an AIDS fighter about ignoring the findings of medical science.   And, if AI can diagnose better than an MD, will we stop listening to doctors altogether? It’s our monthly look at critical thinking … but don’t take our word for it! Guests: Katherine Foley – Science and health reporter at Quartz, and author of the article “Alexa is a Terrible Doctor” Paul Offit – Professor of pediatrics at the Children’s Hospital of Philadelphia and the Perlman School of Medicine at the University of Pennsylvania, and author of “Bad Advice: Or Why Celebrities, Politicians, and Activists Aren’t Your Best Source of  Health Information” Richard Marlink – Director Rutgers Global Health Institute. Shinjini Kundu – Research Fellow, University of Pittsburgh Medical Center Stuart Schlisserman – Internist, Palo Alto, California

Eat dark chocolate. Don't drink coffee. Go gluten-free. If you ask people for diet advice, you'll get a dozen different stories. Ideas about what's good for us sprout up faster than alfalfa plants (which are still healthy … we think). How can you tell if the latest is fact or fad? We'll help you decide, and show you how to think skeptically about popular trends. One example: a study showing that gluten-free diets didn't ease digestive problems in athletes. Also, medical researchers test whether wearable devices succeed in getting us off the couch and a nutritionist explains how things got so confusing.  Plus, why part of our confusion may be language. Find out why one cook says that no foods are “healthy,” not even kale. It's Skeptic Check … but don't take our word for it! Guests: Dana Lis - Sports dietician, PhD student, University of Tasmania Michael Ruhlman - Cook, author of many books about cooking as well as the recent trio of novellas, In Short Measures Beth Skwarecki - Freelance health and science writer, nutrition teacher Mitesh Patel - Assistant professor of medicine, Perlman School of Medicine, Assistant Professor of Health Care Management, The Wharton School, University of Pennsylvania Learn more about your ad choices. Visit megaphone.fm/adchoices

ENCORE  Eat dark chocolate.  Don’t drink coffee.  Go gluten-free.  If you ask people for diet advice, you’ll get a dozen different stories.  Ideas about what’s good for us sprout up faster than alfalfa plants (which are still healthy … we think).  How can you tell if the latest is fact or fad? We’ll help you decide, and show you how to think skeptically about popular trends.  One example: a study showing that gluten-free diets didn’t ease digestive problems in athletes.  Also, medical researchers test whether wearable devices succeed in getting us off the couch and a nutritionist explains how things got so confusing.  Plus, why part of our confusion may be language.  Find out why one cook says that no foods are “healthy,” not even kale. It’s Skeptic Check … but don’t take our word for it! Guests: Dana Lis - Sports dietician, PhD student, University of Tasmania Michael Ruhlman - Cook, author of many books about cooking as well as the recent trio of novellas, In Short Measures Beth Skwarecki - Freelance health and science writer, nutrition teacher Mitesh Patel - Assistant professor of medicine, Perlman School of Medicine, Assistant Professor of Health Care Management, The Wharton School, University of Pennsylvania