POPULARITY
2 episodes with brigham women's hospital
3 episodes with brigham women's hospital
2 episodes with brigham women's hospital
2 episodes with brigham women's hospital
Dr. Hayes interviews Dr. Bruce Chabner on his experience with cancer drug discovery and development, phase I trials and pharmacology. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of the shows, including this one, at podcast.ASCO.org. Today my guest on this podcast is Dr. Bruce Chabner. Dr. Chabner's is widely considered one, or frankly if not the father, of our understanding of the pharmacology principles of anti-neoplastic drugs. And probably more importantly, the translation of these principles to the intelligent application of the agents we use in clinic every day. Among the many accomplishments that Dr. Chabner has had working with his mentor, Dr. Joseph Bertino at Yale, who developed the concept of high dose methotrexate leucovorin rescue, that was completely based on their preclinical understandings of the mechanism of action, and more importantly, resistance to this agent. Dr. Chabner was also instrumental in the development of paclitaxel when he was at the National Cancer Institute, and he was intimately involved in many of the early studies that led to better understanding of AIDS and the ways to treat it. Dr. Chabner was raised in Shelbyville, Illinois, and I'm going to digress for a moment, because I've always had a very special soft spot in my own heart for Bruce Chabner. A, because of his science, but more importantly, because I was raised in Shelbyville, Indiana. Both of these towns were named after Colonel Isaac Shelby, who was a hero in both the Revolutionary War and the War of 1812. By the way, Dr. Chabner, I know you were a big student of history when you were in college, so I thought you'd like this. Dr. Shelby became the first and then the fifth governor of Kentucky, and as a citizen he was a land surveyor. There were actually nine counties and 11 cities and towns spread around the Eastern and Midwest regions that are named after Colonel Shelby. And I don't know about you, Bruce, but I had this drilled into my brain in eighth grade history class. I had to learn all about Colonel Shelby. Anyway, so he and I are brothers in Shelbyville. Dr. Chabner received his undergraduate degree of Yale, where again, he spent a lot of his time in the history department but also in the biology department. And then he got his medical degree at Harvard, where he stayed to complete his residency in internal medicine at the Peter Bent Brigham Hospital before it became the Brigham Women's Hospital. In 1967, Dr. Chabner became a clinical associate in medical oncology at the National Cancer Institute, where he was, in succession, a senior investigator in the laboratory of clinical pharmacology, chief of the clinical branch of the clinical oncology program, associate director of the clinical oncology program, and then he succeeded Dr. Ben [? Stabida, ?] someone I have previously interviewed for this series, as director of the division of cancer therapy. In 1995, after 25 years at the NCI, he moved to Boston as the chief of the division of hematology oncology and the clinical director of the Massachusetts General Hospital Center, where he is now the clinical director emeritus. Dr. Chabner has authored, I counted, over 500 peer reviewed papers. I think even more than that. By the way, his first was in 1969, a case report of shaking chills related to occult lymphoma, authored with Drs. DeVita and the [INAUDIBLE] of the [INAUDIBLE] syndrome. Bruce, that really shows how old you are. He's been the editor of all five editions of the Principles and Practice of Cancer Chemotherapy and Biologic Response Modifiers, which I consider the bible of cancer pharmacology. And I'm looking at my fifth edition on my bookshelf right now. He's trained too many Fellows for me to name, but numerous of them have gone on to be cancer center directors, chiefs of division, department chairs, and other leaders of oncology in the world. He's won way too many awards me to go through, but he received a Karnofsky award from ASCO, and he served on the ASCO board of directors. Dr. Chabner, welcome to our program. Nice, that's a lot of history. It speaks to my name. Well, that's the problem of interviewing all of you folks. It takes a long time to get through all the things you've done. It's a good problem to have, though. First, I want to start out, I understand you carry the flag rank of rear admiral. And I want to know, have you ever even been on a ship? And more importantly, did you and Dr. Shelby actually serve together in the Revolutionary War? I couldn't figure that out. You know, I never bumped into him when I was on the battleship Shelbyville, but who knows. He seemed to be what I call a name dropper. He left his name on so many different things, and I think there's a Shelby County, Tennessee, which is Memphis. Plus I think the smallest thing that he ever created was Shelbyville, Illinois, which was even smaller than your hometown. Yep, that's true. All right, that's the last joke I'm going to tell in this interview, but I like that connection. Anyway, so how did a guy from Shelbyville, Illinois get to Yale and then Harvard and NCI? And more importantly, what made you decide to be an oncologist? I know your father was a general practitioner, but at that time the field barely existed. What was your motivation? Well, OK, I'll tell you a bit of a story. My mother came from Chicago and she had a brother who was pretty smart. And he went to Harvard. And he used to come down to Shelbyville because he liked the pies that she made. And we were 200 miles south, so it was a trip for a pie, but anyway we used to play chess together. And when he was a college student and I was like in fourth grade, I beat him in chess and he said, Jesus, you ought to go to an Ivy League school. So that put the idea in my mind. And then my parents were not really happy with that. They wanted me to go to Washington University or University of Illinois, but I wanted to get away from home. It was a little bit confining to be around my parents for the rest of my life. So I applied to Yale, Harvard, and Princeton, and the deal was I could go to school if I got a scholarship. So I got a scholarship to Yale, so I went there. I was happy with that choice. I really-- it was sort of, you know, life changing, actually. Stayed on the east coast. But I still have many good friends from my Shelbyville days. We all get together once a year to play golf and poker and tell life stories. So I have to interject. My father told me I could go to any college in the United States as long as the tuition was the same as in-state tuition of Indiana University, which at the time was $400 a year. So I ended up going to Indiana University. So how did you-- That was such a great deal. Yeah, that was my-- How did you get into oncology? Well, when I was at the Brigham, I got interested in cancer. There was not much going on there, but one of my residents was a guy named Jack [? Moxley, ?] who had been a part of the initial study with DeVita and others, George [? Kinellas, ?] of the mop treatment for Hodgkin's disease. And I got really interested in that. And actually during my internship my sister got an immediate stromal tumor during her pregnancy, and it turned out to be a thymoma. But cancer really intrigued me at that point. And we all had to apply for positions at NIH as a way to get out of the draft, and I wanted to do research, so that really appealed to me. And I actually applied for cardiology and cancer, and I was interviewed by Gene Brown for cardiology, and he didn't seem very impressed. But the cancer people did like me, particularly George and Vince, who had come back there. And they were young and energetic and they had interesting ideas about combination therapy, so I ended up in oncology. Yeah, I talked with some of the other people I've interviewed about the so-called era of the yellow berets and how that really transformed medicine, in my opinion. Because so many smart people went to the NIH to stay out of Vietnam. It's probably the only good thing that came out the Vietnamese war, as far as I can see, and especially the NCI. So when you went to the NCI, [? Harlan ?] and Frye and [? Freirach, ?] I believe, were gone. So you've already started to say, it sounds like Dr. DeVita and Dr. [? Kinellas ?] were the movers and shakers at the time. Is that fair, or? Yeah, well they were really young. I mean, it was like working for, you know, contemporaries. There were no old people there. And Frye and [? Freirach ?] weren't that old at that time. They were in their 40s with Vince and George, who were in their mid 30s. And I was 28 years old, I guess, when I went down there. I loved it. We had laboratory opportunities, we had patients, we had people that believed that they could change the way cancer was treated. George and Vince, particularly Vince, were so energetic and so committed to the idea of changing therapy, and particularly combination therapy. And then the other thing that made it such a great experience were the colleagues that I had in my first group of clinical Fellows. Bob Young was part of it, and I became very close friends with Bob Young. And in the same group, David Livingston was my next door neighbor, and we had interned together and been arrested together. So we had just constant stimulation from a lot of different people, all of them energetic and interested in research. Who else was in your class besides Dr. Livingston and Young, then? Phil Shine, who made a name for himself in toxicology and then in industry. And let's see-- He was director at the cancer center at Georgetown for a while. Georgetown, right. Subsequently, there was just a long list of wonderful Fellows. When I came back, I actually spent two years at Yale between my NCI time and then coming back to NCI. And I had a wonderful time with Joe Bertino. He was, I think, very important to me, because he was really a great scientist. And I learned a lot about biochemistry enzyme purification and working in the lab. And so when I came back to NCI I had sort of converted to being an anti-folate person from being interested in alkylating agents. And so I was always interested, I guess, in anti-metabolites. But that was a great anti-folate experience with Joe, high dose methotrexate. It was really his idea, not mine. But the thing I worked on was the clinical pharmacology and trying to figure out why it was so toxic to kidneys. So we actually did some really interesting experiments. We gave high dose methotrexate to monkeys, and then when they died, we took the kidneys out and looked at them. And we were doing it because we thought we would see interesting pathology. What we saw were a bunch of yellow gravel in their tubules. And it turned out it was methotrexate, and it became obvious what was happening. The drug was precipitating in the acid urine environment. But that was sort of the beginning of the methotrexate studies. And personally, I don't think we teach pharmacology very well anymore. What made you want to go to high dose methotrexate? Well, interestingly, I was particularly interested in-- Joe was trying head and neck cancer. There was almost simultaneously an article from Frye and Isaac [? Jurassi ?] about adjuvant therapy of osteogenic sarcoma. And there were several interesting things about that. One is that it turned out that 12 patients weren't all patients with osteogenic sarcoma. But prognosis of those patients wasn't apparently obvious. But there seemed to be some success with it, and there was a lot of toxicity that they didn't really know how to deal with. And so I started doing pharmacokinetic monitoring in patients that we had that were on the treatment. And then when they went into renal failure, they just didn't clear the drug. The drug was hanging around for many days and they were getting this horrible toxicity. So we got into this business of why the renal toxicity and the need for hydration and alkylization, particularly. And so first of all, I have to tell you I blamed you for much of my first year as a Fellow, because we had to draw the blood. So there were no study coordinators. Dr. Frye would just run around at all times of day and night drawing blood on patients for getting high dose methotrexate. And I still mumble under my breath when I hear your name. Well, you don't have to do all of that now, but you know, in those days we were trying to get a more complete profile, so we did. There was a woman there at the Farber that was doing similar work. I can't remember her name. Sue Pittman I think, right? Yeah, Sue Pittman. That's right, that's right, that's right. But that was certainly the introduction to the anti-folate. And then I got into a very interesting area of polyglutamation and how it changed the potency of the drug and led to retention, and it was an important determinant of response. That was quite an interesting area of research. Were you the first to report amplification of DHFR? No, that happened in 1978. I was working on MTX at the time and we had noticed that you could select highly resistant cells in culture. But then we were interested in knowing why, and Joe and Joe Bertino had described the fact that increased dihydrofolate reductase activity was found in this circumstance. But the actual demonstration of amplification in mammalian cells was done by Bob [? Shimke ?] when Joe was on a sabbatical with him. And they had a medical student working in the lab on that on that paper, and that was Dan [? Haber ?] actually. Who came back to-- Who is now the cancer center director [INAUDIBLE], right? Yeah, he wrote a key paper. So we had, at the time when that came out, we got interested in that. And we stuck radiolabeled methotrexate in the culture with some tumor cells and found these odd migrating entities that turned out to be polyglutamate. So that led to the whole issue of what were polyglutamates and how did they change the biochemistry? And that was quite interesting, and then actually at the same time we saw a patient. It was a young man who came to NIH with non-Hodgkin's lymphoma and was treated with high dose methotrexate. I can't remember. I think he had CNS involvement or something like this. We found evidence of gene amplification in this patient. So it was actually the first demonstration that gene amplification occurs in people on the drug. There are a lot of interesting things that were happening at that time. How was translational medicine before it was called translational medicine? That was the nice part of NIH, you know? The emphasis was on the labs working with the clinics, and particularly with physician scientists. So, you know, we were one of the few places where our Fellows were expected to work in labs in their second and third years, and they did, and we had a wonderful group of Fellows that came through. The first guy that worked on polyglutamation of MTX was Rich [? Shilske. ?] Who is now the chief medical officer of ASCO, and many, many other accomplishments after that. Right. But many-- Actually, I'd like to change gears for a minute, because I know you had a lot to do with the development of paclitaxel. And I always found that story interesting that, you know, it was in the bark of the Japanese yew tree, which had to do with ultimate supplies. But also the first phase one trials, which some of that was done at the Dana Farber when I was there. Can you just walk through the history of paclitaxel? I think our listeners would love to hear this. Well, it was an accident of history. Believe me. The thing started in 1964, when a group at the research triangle, a chemist, isolated this compound from the yew tree. And they didn't actually know what it was, but it was cytotoxic. And it was an anti-mitotic, and it took him seven years to figure out the structure. So finally in 1971 a guy named Ronnie from that group published the structure. It was a ridiculously complicated structure, And nobody could synthesize it, at least at that point. It hung around in the lab and nobody was interested in developing it, because it was such an odd molecule. It was insoluble. Nobody can put it in solution. So it really wasn't an attractive pharmaceutical. And the thing that happened was, in 1978 or 1979, we had a very hot drug that was called maitansine. And we were very eager to put this into the clinic. And it was an anti-mitotic also, and very, very potent drug. And so Dr. DeVita asked me to personally shepherd this thing and he told me that he didn't want it to fail. And so I put it into patients and it was terrible. And I kept telling him, this is not going to work. He said, it's got to work. He was pretty persistent. Well, it didn't, and he was very disappointed. So was I. And the fact is, we had nothing else to put in the clinic at that time except for paclitaxel. So we said, oh, well, we'll try it. And we put it in a lipid emulsion. It was like putting it in engine oil or something, but it went into the clinic in several places. Peter [? Wernick ?] did it. Einstein. I guess you guys did it at the Farber. And it was causing all sorts of hypersensitivity responses. It looked impossible. And it took about, I don't know, four or five years to get it into a regimen that was tolerable. And there had been responses. The first response was in melanoma, so we were all excited about that. That was the usual circumstance in those days that, when you took a drug into the clinic, melanoma would be the first response. And no one else from melanoma. Everywhere was-- and so but then Peter began noticing responses in ovarian cancer. And a regimen was worked out with antihistamines so it was reasonably tolerable. And finally in 1991, which was eight years after it went into the clinic, we finally decided, well, it was time to license it to industry. There was no patent, but we did it under a co-operative research and development agreement. And the only company that was interested in the US was Bristol-Myers. Everybody else said, this is ridiculous. Nobody wants this drug. And it was too hard to make it. You had to make it from the bark of plants and it was insoluble and it caused hypersensitivity. So they took it. And about a month afterward there was a report from M.D. Anderson saying that it was active in breast cancer. And at that point it just took off like a rocket. And, you know, tried in all sorts of different diseases. Was active in lung and bladder and-- I can't remember all the other things. Head and neck. Anyway, it became the first billion dollar drug in the cancer drug industry. And I think, you know, there are two things that really set off industry to be interested in cancer. One was that, the fact that you could actually make money on it. And the second was the notion of targeted therapies, which was growing at that time. So to my knowledge, this is the only time somebody at the NCI had to work with the US Forest Service and the Bureau of Land Management regarding a new drug. Can you tell that story? Well, yes. The only place where you get the raw material for the drug was from the US Forest Service. And so Texas plants were being sort of cut and burned because they were considered scrub and not worth anything as lumber. So they were cooperating. And finally when we licensed it, Senator Ron Wyden, who's still in the Senate from Oregon, got interested in this whole thing. He said, why isn't the government making money on this license? Why did you license it to Bristol-Myers and you didn't you didn't ask for anything back? And we said, well, you know, that's not the function of NIH. We didn't have a patent. I guess we could have asked for a slice of the pie, but we didn't because no one else wanted it. We really were trying to give it away. And he was giving us a really hard time at this hearing. And then the key thing that happened was a woman who was a forest ranger with ovarian cancer, we found this woman, and she testified to how much good it did for her. And that sort of stopped all the fuss about the license. And we actually, it was the first drug where as part of the licensing agreement we had the chance to fix the price or agree to the price that Bristol-Myers fixed. And the government never has done that since that time. Of course, this was a circumstance where we sort of owned the information, so they had to listen to it. But they set the price at $2,000 a course. And we consider that pretty high, but it was sort of equivalent to what other drugs were costing at the time, so we let that go by. But ever since then, the price of drugs has just escalated remarkably. I hope there are some young people listening, because this story, in my opinion, the story of trastuzumab again, I think people think that these things just happen because the system makes them. And my experience is they happen because the drug or the treatment gets a hero, gets a champion. Ultimately the science has to prove it works, but I'm sure lots of people wanted to walk from Taxol. You know, everybody thought it was a dog. Because it was, you know, caused hypersensitivity, it wasn't all that active in the initial testing, and it was really hard to make the stuff. Well, the same thing is true with platinum I did my residency at UT Southwestern with Donald Sullivan, who's the chair of medicine. He was a renal guy, and a patient with metastatic-- and I had gone to Indiana. So Dr. [? Einhardt ?] taught me how to give it. So I had a patient come in with widespread testicular cancer, I wanted to give him cisplatin, and Dr. Sullivan wouldn't let me do it because it would hurt his kidneys. I said, Dr. Sullivan, he's going to die if we don't do this. And he said, he'll die anyway. And so I did it behind Dr. Sullivan's back and I got a complete response. Fortunately in those days the residents didn't have a lot of oversight so I could do what I wanted to do. There were a lot of people that thought these drugs should be shut down, and it took the courage that you guys had back at the NCI and other places to push them out. Don Sullivan was very anti cancer chemotherapy for the rest of his life. And it was odd for me, because I actually had a relative who was on his faculty and I went down there a couple times to talk. And I always felt very uncomfortable telling him that we were accomplishing something. Because his concept of success in science was getting an RO1 in your lab. Yeah. He finally came to terms because [? Shelfke, ?] myself, Fred [? Lemaitre, ?] and a number of us went into oncology and had been reasonably successful. And I think he decided that it was worthwhile after all. But it wasn't easy for him. We lost him a year ago. I still miss him. Yeah, he was an amazing guy, but he really did have a hard time believing in cancer. So the other question, I wanted to change gears a little bit, because I know just about the time you became the director of the DCT was when the AIDS epidemic was exploding in the early 1980s. That must have been a very confusing situation about who should be in charge of this at the NIH, which institute, and how you approach it. Can you give us some background on that? Again, it was really a crazy time. Because I remember one of the first patients that was identified as having AIDS was a person admitted to the immunology branch at the NCI. Not the medicine branch or the clinical branches. It was a patient who had disseminated tuberculosis and it had no CD4 cells. And, you know, everybody said, oh my god, what is this? This is really a weird, weird circumstance. And then other people began reporting this from San Francisco and New York. So we actually, DCT, the reason we got involved was because of Bob Gallo. Bob Gallo had discovered the HTLV1 virus, which was causing this lymphoma in T cells. And we suspected that this might be a syndrome caused by a T cell virus. So in 1981, really quite early, we convened I think the first meeting about the biology of what was called HTLV2, I think, at the time, or three. I can't remember which one it was. But at any rate, there were a cadre of people at NIH that felt that it was caused by inhaling gases or, I don't know, their various weird theories about it. But this theory that made sense to us was that it was caused by a virus. So Sam [? Brodeur ?] was collecting samples from patients and brought them over to Gallo's lab. And of course Gallo mixed those samples with the French sample and found virus and then made a test kit for the virus, which was really a key event in beginning to control the epidemic. And because of all that work going on at NCI at the time, we were asked-- we had the only drug development system at NIH. We were asked to, well, look, can you set up a drug development system for this? And Sam [? Brodeur ?] set up assays in infected T cells and showed that certain nucleocyte analogs could stop the virus from replicating. The first one was ADT. And his first study was, I think, was 16 patients with AIDS in which he showed that the T cell counts recovered and people didn't die. And from that point on, we were getting significant funding for doing research on treatment development. And it was it was done in conjunction with NIAID and Tony Fauci. What Tony did is he delegated a fellow to work with us and sort of be the liaison. And the first fellow that did that was Margaret Hamburger, who became [INAUDIBLE] FDA subsequently. And, you know, subsequently, four other people from our division-- well, actually one from NGH, became directors of FDA. Ned Sharpless most recently, and then Steve Hahn, who was a Fellow in the medical oncology group at NCI. Yeah, he's just been named. It was, you know, an unusual breeding ground for people interested in therapeutics. That's interesting. You know, I was a third year resident at UT Southwestern. I was at the VA in March and a young man was admitted to our service. He had been a Vietnam veteran and he had red splotches all over him, so I called a dermatologist who biopsied it. And I got a page from the pathologist and I called him back and he said, you have mislabeled the samples. And I said, what do you mean? He said, well, this says it's a 37-year-old man. This is something I've never seen before, but I looked it up and it's called Kaposi sarcoma, and that only happens in old men or people from Africa. And I said, I don't think we mislabeled things. And I think he was probably the first man in Dallas to be diagnosed with this. Because just as the MWR and the new journal paper came out a few months after that. So again, for the young folks listening to this, and we've already hit this a couple of times, it's one or two patients that pique your interest that often change the world in terms of, gee, I wonder why that happened. Yeah, absolutely. I mean, you know, a lot of this is an outcome of the fact that you have research people as physicians who are working with patients, and then they ask questions. Yeah. One of the things I've carried forward, Dr. Frye used to always say, think like a scientist. Think like a doctor. And ask yourself, so what? And I know you do that, because again, you've already told us today and I've seen you do that in other places. You know, so what? Why did this happen to this patient? Why did that happen, yeah. What in my lab actually will change that? And you guys did that in spades, I think, 40, 50 years ago. It's pretty amazing. Yeah. Well, I [INAUDIBLE]. [INAUDIBLE]. Go ahead. Go ahead. No, it's really happening a lot now, you know, in terms of recognizing subsets of diseases. We used to think that non-small cell lung cancer was just one disease. Now it's 20 diseases. It's amazing, you know? It's amazing, you know, as science progresses, you begin to understand the complexity of cancer. And then therapies become meaningful. Yes, I agree. It's so nice. And so I wish, you know, we were curing people. But we are making a difference, and least we're understanding it a little. I agree. Anyone who has not heard or read Bruce Johnston's ASCO presidential address should do so. Because he did point out exactly what you just said. He had a pie chart, and 10 years ago the entire pie chart was chemotherapy for metastatic non-small cell lung cancer with little or no success. And now the pie chart is well over half the patients getting some kind of targeted or immunotherapy. Yeah, it's pretty amazing. It is quite [INAUDIBLE] for young people that are listening to this, is that there are enormous opportunities for doing even better than we did. So we just made a start in this whole thing. OK. With that inspiring message, which I'm glad you said it, we've run out of time. Actually we come at the end of our time. But Dr. Chabner, I want to thank you on behalf of all of us who trained after you, who've learned so much from what you've done, and more importantly, the patients who have benefited from the stuff that you've contributed to the field. It's pretty remarkable and inspiring. I don't use that word too often, but it is. So thank you, and thank you for taking time today. I hope folks listen to this and say, I'm going to go back and make a difference here. Thank you, Dan. I have enjoyed it. It's been a wonderful time in this career. Yeah. Well, my pleasure. Until next time, thank you for listening to this JCO's Cancer Story, the Art of Oncology Podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.ASCO.org.
Last chance for LIVE Strengthening Intuition course http://jjflizanes.com/intuition Dr. Eben Alexander, author of Proof of Heaven and Living in a Mindful Universe, spent over 25 years as an academic neurosurgeon, including 15 years at the Brigham & Women's Hospital, the Children’s Hospital and Harvard Medical School in Boston. Since Proof of Heaven was released in 2012, he has been a guest on The Dr. Oz Show, Super Soul Sunday with Oprah Winfrey, ABC-TV’s 20-20 and Good Morning America, FOX-TV’s FOX & Friends, and his story has been featured on the Discovery Channel and the Biography Channel. He has been interviewed for over 400 national and international radio and internet programs and podcasts. His books are available in over 40 countries worldwide, and have been translated into over 30 languages. Since his NDE, Dr. Alexander has dedicated himself to sharing information about near-death experiences and other spiritually-transformative experiences, and what they teach us about consciousness and the nature of reality. He continues to promote further research on the unifying elements of science and spirituality, and encourages people to be inspired by the power of unconditional love in their daily lives and in their work in their communities. For more information: http://ebenalexander.com http://unitedinhopeandhealing.com http://sacredacoustics.com Inner Circle Membership http://jjflizanes.com/innercircle JJ Flizanes is an Empowerment Strategist and the host of several podcasts including People’s Choice Awards nominee Spirit, Purpose & Energy. She is the Director of Invisible Fitness, a best-selling author of Fit 2 Love: How to Get Physically, Emotionally, and Spiritually Fit to Attract the Love of Your Life and The Invisible Fitness Formula: 5 Secrets to Release Weight and End Body Shame. Named Best Personal Trainer in Los Angeles for 2007 by Elite Traveler Magazine, JJ has been featured in many national magazines, including Shape, Fitness, and Women’s Health as well as appeared on NBC, CBS, Fox, the CW and KTLA. Grab a free copy of the Invisible Fitness Formula at http://jjflizanes.com/book
Last chance for LIVE Strengthening Intuition course http://jjflizanes.com/intuition Dr. Eben Alexander, author of Proof of Heaven and Living in a Mindful Universe, spent over 25 years as an academic neurosurgeon, including 15 years at the Brigham & Women's Hospital, the Children’s Hospital and Harvard Medical School in Boston. Since Proof of Heaven was released in 2012, he has been a guest on The Dr. Oz Show, Super Soul Sunday with Oprah Winfrey, ABC-TV’s 20-20 and Good Morning America, FOX-TV’s FOX & Friends, and his story has been featured on the Discovery Channel and the Biography Channel. He has been interviewed for over 400 national and international radio and internet programs and podcasts. His books are available in over 40 countries worldwide, and have been translated into over 30 languages. Since his NDE, Dr. Alexander has dedicated himself to sharing information about near-death experiences and other spiritually-transformative experiences, and what they teach us about consciousness and the nature of reality. He continues to promote further research on the unifying elements of science and spirituality, and encourages people to be inspired by the power of unconditional love in their daily lives and in their work in their communities. For more information: http://ebenalexander.com http://unitedinhopeandhealing.com http://sacredacoustics.com Inner Circle Membership http://jjflizanes.com/innercircle JJ Flizanes is an Empowerment Strategist and the host of several podcasts including People’s Choice Awards nominee Spirit, Purpose & Energy. She is the Director of Invisible Fitness, a best-selling author of Fit 2 Love: How to Get Physically, Emotionally, and Spiritually Fit to Attract the Love of Your Life and The Invisible Fitness Formula: 5 Secrets to Release Weight and End Body Shame. Named Best Personal Trainer in Los Angeles for 2007 by Elite Traveler Magazine, JJ has been featured in many national magazines, including Shape, Fitness, and Women’s Health as well as appeared on NBC, CBS, Fox, the CW and KTLA. Grab a free copy of the Invisible Fitness Formula at http://jjflizanes.com/book
Last chance for LIVE Strengthening Intuition course http://jjflizanes.com/intuition Dr. Eben Alexander, author of Proof of Heaven and Living in a Mindful Universe, spent over 25 years as an academic neurosurgeon, including 15 years at the Brigham & Women's Hospital, the Children’s Hospital and Harvard Medical School in Boston. Since Proof of Heaven was released in 2012, he has been a guest on The Dr. Oz Show, Super Soul Sunday with Oprah Winfrey, ABC-TV’s 20-20 and Good Morning America, FOX-TV’s FOX & Friends, and his story has been featured on the Discovery Channel and the Biography Channel. He has been interviewed for over 400 national and international radio and internet programs and podcasts. His books are available in over 40 countries worldwide, and have been translated into over 30 languages. Since his NDE, Dr. Alexander has dedicated himself to sharing information about near-death experiences and other spiritually-transformative experiences, and what they teach us about consciousness and the nature of reality. He continues to promote further research on the unifying elements of science and spirituality, and encourages people to be inspired by the power of unconditional love in their daily lives and in their work in their communities. For more information: http://ebenalexander.com http://unitedinhopeandhealing.com http://sacredacoustics.com Inner Circle Membership http://jjflizanes.com/innercircle JJ Flizanes is an Empowerment Strategist and the host of several podcasts including People’s Choice Awards nominee Spirit, Purpose & Energy. She is the Director of Invisible Fitness, a best-selling author of Fit 2 Love: How to Get Physically, Emotionally, and Spiritually Fit to Attract the Love of Your Life and The Invisible Fitness Formula: 5 Secrets to Release Weight and End Body Shame. Named Best Personal Trainer in Los Angeles for 2007 by Elite Traveler Magazine, JJ has been featured in many national magazines, including Shape, Fitness, and Women’s Health as well as appeared on NBC, CBS, Fox, the CW and KTLA. Grab a free copy of the Invisible Fitness Formula at http://jjflizanes.com/book
Upstatement officially opened its doors in 2008 but was born during late nights at the Syracuse University student newspaper. That's where founders Mike, Jared, and Tito met before graduating to the newsrooms of The New York Times and Boston Globe. But they don't come from a typical agency background, and Upstatement doesn't look like your typical studio. Their team is filled with curious, versatile designers and engineers who all do a little bit of everything: Designers develop. Engineers sketch. Everyone contributes to creative concepts (because the best work comes from diverse teams). That's why nothing they do is cookie cutter. It's much more about daring to dream big, looking for fresh challenges, and push themselves. Here in 2020, the company provides design leadership for a diverse client list: publishers, products, non-profits, and the world's most remarkable brands. All unified by strong stories and the desire to make a positive impact. Tito Bottitta joins me on Tech Talks Daily to talk about how Upstatement is connecting with doctors on the front lines of the coronavirus pandemic to build the COVID Protocols product. Tito shares how they are helping the team of over 50 Brigham and Women's Hospital physicians, respiratory therapists, pharmacists, and nurses from multiple different divisions, organize the vast amounts of incoming info, and decide next how best to share it. From a technology perspective, I learn how Upstatement is building something useful around obstacles like hospital firewalls, etc. We also discuss what it's like designing quality work under extreme pressure (time & safety). The latest iteration, viewable at covidprotocols.org, came together thanks to Dr. Lee and Boston-based digital design and engineering studio, Upstatement. Through the partnership, Upstatement rapidly worked to find user base value in the tool while keeping it as a Google Doc by rebuilding potential caching problems that sending tens of thousands of people into a file at once could pose - making them a major key player in the project's success. The tool also had to be something useful built around obstacles like hospital firewalls, etc. Tito shares their inspirational work across three projects that are leveraging technology to create a unique approach to making a difference against the global pandemic. COVID Protocols - Captures emergent medical conventions that help doctors make life-saving decisions on the front lines. In association with Brigham & Women's Hospital. Read more about it on Medium. COVID Safe Paths - A privacy-first contact tracing app that could help us flatten the curve and return to normal. In association with MIT, Path Check Inc., and others. Read more about it on Medium. Project Z - Think of it as Yelp for COVID safety. Find the local businesses that are doing the most to keep you safe. When you have to go out, do it with confidence. In association with a group of silicon valley founders & V.C.s.
-030- Join me as I interview Sara Manjikian, working as a nurse for COVID-19 patients in the ICU at Brigham Women's Hospital in Boston, MA. We discuss protocols, testing, personal protective equipment, working overtime, and more. For show notes visit:www.livingwithscanxiety.orgPlease note Sara is in her internship and graduates in May 2021 as a Registered Nurse.
In Part 2, I sit down with nephrologist Ali Mehdi, MD, and neurologist Ghulam Abbas Kharal, MD, MPH, to discuss their different specialty perspectives on working up patients with suspected cryoglobulinemic vasculitis. Brought to you by GSK. Considering a treatment change for patients with active SLE? Learn about a treatment option for your patients at treatfortodayandtomorrow.com. Intro :20 Introduction of Ali Mehdi, MD :45 Interview with Dr. Mehdi 2:02 Brought to you by GSK. Consider the long-term impact of disease activity, flares and corticosteroid use on patients with active SLE. Learn more now at treatfortodayandtomorrow.com Introduction of Ghulam Abbas Kharal, MD, MPH 25:01 Interview with Dr. Kharal 26:37 To hear more of my interview with Abbas, keep listening 44:47 Thank you, Dr. Kharal 53:07 Ghulam Abbas Kharal, MD, MPH, is a Partners Neurology Resident at Massachusetts General Hospital, Brigham & Women's Hospital, Harvard School of Medicine. Ghulam Abbas Kharal, MD, MPH, is a staff neurologist at Cleveland Clinic. Kharal did his training in a combined program at Massachusetts General Hospital and Brigham & Women's Hospital, Harvard School of Medicine. Ali Mehdi, MD, is a Nephrology Fellow at the Cleveland Clinic. Mehdi did his Internal medicine residency and chief year at the Cleveland Clinic. We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum
From the Show http://noedic.org Search Spontaneous Remission https://www.galileocommission.org/ Sacred Acoustics- JJ’s free special http://jjflizanes.com/sacredaudio Dr. Eben Alexander spent over 25 years as an academic neurosurgeon, including 15 years at the Brigham & Women's Hospital, the Children’s Hospital and Harvard Medical School in Boston. Over those years he personally dealt with hundreds of patients suffering from severe alterations in their level of consciousness. Many of those patients were rendered comatose by trauma, brain tumors, ruptured aneurysms, infections, or stroke. He thought he had a very good idea of how the brain generates consciousness, mind and spirit. In the predawn hours of November 10, 2008, he was driven into coma by a rare and mysterious bacterial meningo-encephalitis of unknown cause. He spent a week in coma on a ventilator, his prospects for survival diminishing rapidly. On the seventh day, to the surprise of everyone, he started to awaken. Memories of his life had been completely deleted inside of the coma, yet he awoke with memories of a fantastic odyssey deep into another realm – more real than this earthly one! His older son advised him to write down everything he could remember about his journey, before he read anything about near-death experiences, physics or cosmology. Six weeks later, he completed his initial recording of his remarkable journey, totaling over 20,000 words in length. Then he started reading, and was astonished by the commonalities between his journey and so many others reported throughout all cultures, continents and millennia. His journey brought key insights to the mind-body discussion and to our human understanding of the fundamental nature of reality. His experience clearly revealed that we are conscious in spite of our brain – that, in fact, consciousness is at the root of all existence. His story offers a crucial key to the understanding of reality and human consciousness. It will have a major effect on how we view spirituality, soul and the non-material realm. In analyzing his experience, including the scientific possibilities and grand implications, he envisions a more complete reconciliation of modern science and spirituality as a natural product. He has been blessed with a complete recovery and shares his most powerful, life-changing story in his book, Proof of Heaven: A Neurosurgeon’s Journey into the Afterlife (2012), which debuted at #1 on the New York Times Bestseller list and remained in the top ten for over a year. His second book, The Map of Heaven: How Science, Religion and Ordinary People are Proving the Afterlife (2014), explores humankind's spiritual history and the progression of modern science from its birth in the seventeenth century, showing how we forgot, and are now at last remembering, who we really are and what our destiny truly is. His third book, co-authored with Karen Newell, was released in 2017. Living in a Mindful Universe: A Neurosurgeon’s Journey into the Heart of Consciousness, explains his journey and insights since his NDE, with suggested practices for individuals to use in order to reap the benefits of an awakening in their own personal lives. His story was featured in a series of peer-reviewed medical articles about near-death experiences (NDEs) in Missouri Medicine (2015), now published as the book The Science of Near-Death Experiences (edited by John C. Hagan III, 2017). It concludes with his chapter, “Near-Death Experiences, The Mind-Body Debate, and The Nature of Reality.” A graduate of the University of North Carolina at Chapel Hill, Dr. Alexander received his medical degree from Duke University School of Medicine in 1980. He taught neurosurgery at Harvard Medical School in Boston for fifteen years, and has performed over 4,000 neurosurgical operations. During his academic career he authored or co-authored over 150 chapters and papers in peer reviewed journals, authored or edited five books on radiosurgery and neurosurgery, and made over 230 presentations at conferences and medical centers around the world. Since Proof of Heaven was released in 2012, he has been a guest on The Dr. Oz Show, Super Soul Sunday with Oprah Winfrey, ABC-TV’s 20-20 and Good Morning America, FOX-TV’s FOX & Friends, and his story has been featured on the Discovery Channel and the Biography Channel. He has been interviewed for over 400 national and international radio and internet programs and podcasts. His books are available in over 40 countries worldwide, and have been translated into over 30 languages. Since his NDE, Dr. Alexander has dedicated himself to sharing information about near-death experiences and other spiritually-transformative experiences, and what they teach us about consciousness and the nature of reality. He continues to promote further research on the unifying elements of science and spirituality, and encourages people to be inspired by the power of unconditional love in their daily lives and in their work in their communities. For more information: www.ebenalexander.com Claim Your Free Gifts! http://healthandwealthgifts.com Free 30 Day Manifestation Challenge: http://jjflizanes.com/30day Inner Circle Membership http://jjflizanes.com/innercircle JJ Flizanes is an Empowerment Strategist and the host of several podcast including People’s Choice Awards nominee Spirit, Purpose & Energy. She is the Director of Invisible Fitness, a best-selling author of Fit 2 Love: How to Get Physically, Emotionally, and Spiritually Fit to Attract the Love of Your Life and The Invisible Fitness Formula: 5 Secrets to Release Weight and End Body Shame. Named Best Personal Trainer in Los Angeles for 2007 by Elite Traveler Magazine, JJ has been featured in many national magazines, including Shape, Fitness, and Women’s Health as well as appeared on NBC, CBS, Fox, the CW and KTLA. Grab a free copy of the Invisible Fitness Formula at http://jjflizanes.com/book
AS SEEN ON OPRAH's SUPER SOUL SUNDAY AND DR. OZ SHOW!!! Dr. Eben Alexander spent over 25 years as an academic neurosurgeon, including 15 years at the Brigham & Women's Hospital, the Children’s Hospital and Harvard Medical School in Boston. Over those years he personally dealt with hundreds of patients suffering from severe alterations in their level of consciousness. Many of those patients were rendered comatose by trauma, brain tumors, ruptured aneurysms, infections, or stroke. He thought he had a very good idea of how the brain generates consciousness, mind and spirit. In the predawn hours of November 10, 2008, he was driven into coma by a rare and mysterious bacterial meningo-encephalitis of unknown cause. He spent a week in coma on a ventilator, his prospects for survival diminishing rapidly. On the seventh day, to the surprise of everyone, he started to awaken. Memories of his life had been completely deleted inside of the coma, yet he awoke with memories of a fantastic odyssey deep into another realm – more real than this earthly one! His older son advised him to write down everything he could remember about his journey, before he read anything about near-death experiences, physics or cosmology. Six weeks later, he completed his initial recording of his remarkable journey, totaling over 20,000 words in length. Then he started reading, and was astonished by the commonalities between his journey and so many others reported throughout all cultures, continents and millennia. His journey brought key insights to the mind-body discussion and to our human understanding of the fundamental nature of reality. His experience clearly revealed that we are conscious in spite of our brain – that, in fact, consciousness is at the root of all existence. His story offers a crucial key to the understanding of reality and human consciousness. It will have a major effect on how we view spirituality, soul and the non-material realm. In analyzing his experience, including the scientific possibilities and grand implications, he envisions a more complete reconciliation of modern science and spirituality as a natural product. He has been blessed with a complete recovery and shares his most powerful, life-changing story in his book, Proof of Heaven: A Neurosurgeon’s Journey into the Afterlife (2012), which debuted at #1 on the New York Times Bestseller list and remained in the top ten for over a year. His second book, The Map of Heaven: How Science, Religion and Ordinary People are Proving the Afterlife (2014), explores humankind's spiritual history and the progression of modern science from its birth in the seventeenth century, showing how we forgot, and are now at last remembering, who we really are and what our destiny truly is. His third book, co-authored with Karen Newell, is Living in a Mindful Universe: A Neurosurgeon’s Journey into the Heart of Consciousness (2017). It explains his journey and insights since his NDE, with suggested practices for individuals to use in order to reap the benefits of an awakening in their own personal lives. His story was featured in a series of peerreviewed medical articles about near-death experiences (NDEs) in Missouri Medicine (2015), now published as the book The Science of Near-Death Experiences (edited by John C. Hagan III, 2017). It concludes with his chapter, “Near-Death Experiences, The Mind-Body Debate, and The Nature of Reality.” A graduate of the University of North Carolina at Chapel Hill, Dr. Alexander received his medical degree from Duke University School of Medicine in 1980. He taught neurosurgery at Harvard Medical School in Boston for fifteen years, and has performed over 4,000 neurosurgical operations. During his academic career he authored or co-authored over 150 chapters and papers in peer reviewed journals, authored or edited five books on radiosurgery and neurosurgery, and made over 230 presentations at conferences and medical centers around the world. Since Proof of Heaven was released in 2012, he has been a guest on The Dr. Oz Show, Super Soul Sunday with Oprah Winfrey, ABC-TV’s 20-20 and Good Morning America, FOX-TV’s FOX & Friends, Larry King NOW, and his story has been featured on the Discovery Channel and the Biography Channel. He has been interviewed for over 400 national and international radio and internet programs and podcasts. His books are available in over 40 countries worldwide, and have been translated into over 30 languages. Since his NDE, Dr. Alexander has dedicated himself to sharing information about near-death experiences and other spiritually-transformative experiences, and what they teach us about consciousness and the nature of reality. He continues to promote further research on the unifying elements of science and spirituality, and encourages people to be inspired by the power of unconditional love in their daily lives and in their work in their communities. For more information: www.ebenalexander.com Peeling Back the Layers of Your Life® Podcast Creator, Host, and Producer: Loronda C. Giddens www.lorondacgiddens.com
From the Show http://noedic.org Search Spontaneous Remission https://www.galileocommission.org/ Sacred Acoustics- JJ’s free special http://jjflizanes.com/sacredaudio Dr. Eben Alexander spent over 25 years as an academic neurosurgeon, including 15 years at the Brigham & Women's Hospital, the Children’s Hospital and Harvard Medical School in Boston. Over those years he personally dealt with hundreds of patients suffering from severe alterations in their level of consciousness. Many of those patients were rendered comatose by trauma, brain tumors, ruptured aneurysms, infections, or stroke. He thought he had a very good idea of how the brain generates consciousness, mind and spirit. In the predawn hours of November 10, 2008, he was driven into coma by a rare and mysterious bacterial meningo-encephalitis of unknown cause. He spent a week in coma on a ventilator, his prospects for survival diminishing rapidly. On the seventh day, to the surprise of everyone, he started to awaken. Memories of his life had been completely deleted inside of the coma, yet he awoke with memories of a fantastic odyssey deep into another realm – more real than this earthly one! His older son advised him to write down everything he could remember about his journey, before he read anything about near-death experiences, physics or cosmology. Six weeks later, he completed his initial recording of his remarkable journey, totaling over 20,000 words in length. Then he started reading, and was astonished by the commonalities between his journey and so many others reported throughout all cultures, continents and millennia. His journey brought key insights to the mind-body discussion and to our human understanding of the fundamental nature of reality. His experience clearly revealed that we are conscious in spite of our brain – that, in fact, consciousness is at the root of all existence. His story offers a crucial key to the understanding of reality and human consciousness. It will have a major effect on how we view spirituality, soul and the non-material realm. In analyzing his experience, including the scientific possibilities and grand implications, he envisions a more complete reconciliation of modern science and spirituality as a natural product. He has been blessed with a complete recovery and shares his most powerful, life-changing story in his book, Proof of Heaven: A Neurosurgeon’s Journey into the Afterlife (2012), which debuted at #1 on the New York Times Bestseller list and remained in the top ten for over a year. His second book, The Map of Heaven: How Science, Religion and Ordinary People are Proving the Afterlife (2014), 2 explores humankind's spiritual history and the progression of modern science from its birth in the seventeenth century, showing how we forgot, and are now at last remembering, who we really are and what our destiny truly is. His third book, co-authored with Karen Newell, was released in 2017. Living in a Mindful Universe: A Neurosurgeon’s Journey into the Heart of Consciousness, explains his journey and insights since his NDE, with suggested practices for individuals to use in order to reap the benefits of an awakening in their own personal lives. His story was featured in a series of peer-reviewed medical articles about near-death experiences (NDEs) in Missouri Medicine (2015), now published as the book The Science of Near-Death Experiences (edited by John C. Hagan III, 2017). It concludes with his chapter, “Near-Death Experiences, The Mind-Body Debate, and The Nature of Reality.” A graduate of the University of North Carolina at Chapel Hill, Dr. Alexander received his medical degree from Duke University School of Medicine in 1980. He taught neurosurgery at Harvard Medical School in Boston for fifteen years, and has performed over 4,000 neurosurgical operations. During his academic career he authored or co-authored over 150 chapters and papers in peer reviewed journals, authored or edited five books on radiosurgery and neurosurgery, and made over 230 presentations at conferences and medical centers around the world. Since Proof of Heaven was released in 2012, he has been a guest on The Dr. Oz Show, Super Soul Sunday with Oprah Winfrey, ABC-TV’s 20-20 and Good Morning America, FOX-TV’s FOX & Friends, and his story has been featured on the Discovery Channel and the Biography Channel. He has been interviewed for over 400 national and international radio and internet programs and podcasts. His books are available in over 40 countries worldwide, and have been translated into over 30 languages. Since his NDE, Dr. Alexander has dedicated himself to sharing information about near-death experiences and other spiritually-transformative experiences, and what they teach us about consciousness and the nature of reality. He continues to promote further research on the unifying elements of science and spirituality, and encourages people to be inspired by the power of unconditional love in their daily lives and in their work in their communities. For more information: www.ebenalexander.com Claim Your Free Gifts! http://healthandwealthgifts.com Free 30 Day Manifestation Challenge: http://jjflizanes.com/30day Inner Circle Membership http://jjflizanes.com/innercircle JJ Flizanes is an Empowerment Strategist and the host of several podcast including People’s Choice Awards nominee Spirit, Purpose & Energy. She is the Director of Invisible Fitness, a best-selling author of Fit 2 Love: How to Get Physically, Emotionally, and Spiritually Fit to Attract the Love of Your Life and The Invisible Fitness Formula: 5 Secrets to Release Weight and End Body Shame. Named Best Personal Trainer in Los Angeles for 2007 by Elite Traveler Magazine, JJ has been featured in many national magazines, including Shape, Fitness, and Women’s Health as well as appeared on NBC, CBS, Fox, the CW and KTLA. Grab a free copy of the Invisible Fitness Formula at http://jjflizanes.com/book
From the Show http://noedic.org Search Spontaneous Remission https://www.galileocommission.org/ Sacred Acoustics- JJ’s free special http://jjflizanes.com/sacredaudio Dr. Eben Alexander spent over 25 years as an academic neurosurgeon, including 15 years at the Brigham & Women's Hospital, the Children’s Hospital and Harvard Medical School in Boston. Over those years he personally dealt with hundreds of patients suffering from severe alterations in their level of consciousness. Many of those patients were rendered comatose by trauma, brain tumors, ruptured aneurysms, infections, or stroke. He thought he had a very good idea of how the brain generates consciousness, mind and spirit. In the predawn hours of November 10, 2008, he was driven into coma by a rare and mysterious bacterial meningo-encephalitis of unknown cause. He spent a week in coma on a ventilator, his prospects for survival diminishing rapidly. On the seventh day, to the surprise of everyone, he started to awaken. Memories of his life had been completely deleted inside of the coma, yet he awoke with memories of a fantastic odyssey deep into another realm – more real than this earthly one! His older son advised him to write down everything he could remember about his journey, before he read anything about near-death experiences, physics or cosmology. Six weeks later, he completed his initial recording of his remarkable journey, totaling over 20,000 words in length. Then he started reading, and was astonished by the commonalities between his journey and so many others reported throughout all cultures, continents and millennia. His journey brought key insights to the mind-body discussion and to our human understanding of the fundamental nature of reality. His experience clearly revealed that we are conscious in spite of our brain – that, in fact, consciousness is at the root of all existence. His story offers a crucial key to the understanding of reality and human consciousness. It will have a major effect on how we view spirituality, soul and the non-material realm. In analyzing his experience, including the scientific possibilities and grand implications, he envisions a more complete reconciliation of modern science and spirituality as a natural product. He has been blessed with a complete recovery and shares his most powerful, life-changing story in his book, Proof of Heaven: A Neurosurgeon’s Journey into the Afterlife (2012), which debuted at #1 on the New York Times Bestseller list and remained in the top ten for over a year. His second book, The Map of Heaven: How Science, Religion and Ordinary People are Proving the Afterlife (2014), explores humankind's spiritual history and the progression of modern science from its birth in the seventeenth century, showing how we forgot, and are now at last remembering, who we really are and what our destiny truly is. His third book, co-authored with Karen Newell, was released in 2017. Living in a Mindful Universe: A Neurosurgeon’s Journey into the Heart of Consciousness, explains his journey and insights since his NDE, with suggested practices for individuals to use in order to reap the benefits of an awakening in their own personal lives. His story was featured in a series of peer-reviewed medical articles about near-death experiences (NDEs) in Missouri Medicine (2015), now published as the book The Science of Near-Death Experiences (edited by John C. Hagan III, 2017). It concludes with his chapter, “Near-Death Experiences, The Mind-Body Debate, and The Nature of Reality.” A graduate of the University of North Carolina at Chapel Hill, Dr. Alexander received his medical degree from Duke University School of Medicine in 1980. He taught neurosurgery at Harvard Medical School in Boston for fifteen years, and has performed over 4,000 neurosurgical operations. During his academic career he authored or co-authored over 150 chapters and papers in peer reviewed journals, authored or edited five books on radiosurgery and neurosurgery, and made over 230 presentations at conferences and medical centers around the world. Since Proof of Heaven was released in 2012, he has been a guest on The Dr. Oz Show, Super Soul Sunday with Oprah Winfrey, ABC-TV’s 20-20 and Good Morning America, FOX-TV’s FOX & Friends, and his story has been featured on the Discovery Channel and the Biography Channel. He has been interviewed for over 400 national and international radio and internet programs and podcasts. His books are available in over 40 countries worldwide, and have been translated into over 30 languages. Since his NDE, Dr. Alexander has dedicated himself to sharing information about near-death experiences and other spiritually-transformative experiences, and what they teach us about consciousness and the nature of reality. He continues to promote further research on the unifying elements of science and spirituality, and encourages people to be inspired by the power of unconditional love in their daily lives and in their work in their communities. For more information: www.ebenalexander.com Claim Your Free Gifts! http://healthandwealthgifts.com Free 30 Day Manifestation Challenge: http://jjflizanes.com/30day Inner Circle Membership http://jjflizanes.com/innercircle JJ Flizanes is an Empowerment Strategist and the host of several podcast including People’s Choice Awards nominee Spirit, Purpose & Energy. She is the Director of Invisible Fitness, a best-selling author of Fit 2 Love: How to Get Physically, Emotionally, and Spiritually Fit to Attract the Love of Your Life and The Invisible Fitness Formula: 5 Secrets to Release Weight and End Body Shame. Named Best Personal Trainer in Los Angeles for 2007 by Elite Traveler Magazine, JJ has been featured in many national magazines, including Shape, Fitness, and Women’s Health as well as appeared on NBC, CBS, Fox, the CW and KTLA. Grab a free copy of the Invisible Fitness Formula at http://jjflizanes.com/book
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia, from VCU Health. Dr Carolyn Lam: You know what, Greg, I may have a hoarse voice today and I'm a little bit scratchy, but my goodness, I couldn't be more excited about this issue. It's the TCT issue. Dr Greg Hundley: Well Carolyn, I cannot wait to discuss with our listeners the feature article that compares Apixaban and a P2Y12 inhibitor without Aspirin, versus regimens with Aspirin in patients with AFib who have ACS, whether managed medically or with PCI, or also those undergoing elective PCI that experience regimens that include vitamin K antagonists, aspirin, or both, but more to come later. Carolyn, should I start with my first discussion article and we grab a cup of coffee? Dr Carolyn Lam: You bet, Greg. Dr Greg Hundley: So my first article is from Seung-Jung Park from the Asan Medical Center at the University of Ulsan College of Medicine. So Carolyn, here's our first quiz question. In terms of Ticagrelor, have studies been performed in those from Asia evaluating bleeding risk? Dr Carolyn Lam: You know, I have to admit, Greg, I'm not totally familiar with the literature, but I do know that it's a very important question for us practicing in Asia. We have a perception that the bleeding risk, especially intracranial bleeding, may be higher in Asians. Dr Greg Hundley: Absolutely. Well, in this multicenter trial, 800 Korean patients hospitalized for acute coronary syndromes with or without ST elevation, and intended for invasive management, were randomly assigned to receive in a one to one ratio, Ticagrelor with a 180 milligram loading dose, and then 90 milligrams twice daily, or Clopidogrel with a 600 milligram loading dose and 75 milligrams daily thereafter, and the primary safety outcome was clinically significant bleeding, which was a composite of major bleeding or minor bleeding according to the PLATO outcomes criteria at 12 months. Dr Carolyn Lam: Oh, so what did they find? Dr Greg Hundley: Well Carolyn, at 12 months, the incidence of clinically significant bleeding was higher in the Ticagrelor group than in the Clopidogrel group. So it was 11.7% versus 5.3, and that included major bleeding and fatal bleeding. They were also higher in the Ticagrelor group. The incidents of death from cardiovascular causes, myocardial infarction or stroke, was not significantly different between the Ticagrelor group and the Clopidogrel group, although there was a strong trend toward a higher incidence in the Ticagrelor group with a P value of 0.07. So consequently, Carolyn, these results identified safety concerns regarding bleeding complications of standard dose Ticagrelor in East Asian, Korean patients with acute coronary syndromes, and therefore large adequately powered randomized trials are needed to determine the optimal antithrombotic regimen in this patient population. Dr Carolyn Lam: Very important data for our patients, as is this next paper, which really examines the cost effectiveness of transcatheter mitral valve repair versus medical therapy in patients with heart failure and secondary mitral regurgitation. Now, these are results from the COAPT trial. As a reminder, the COAPT trial demonstrated that edge-to-edge transcatheter mitral valve repair using the MitraClip resulted in reduced mortality and heart failure hospitalizations and improved quality of life when compared with maximally tolerated guideline directed medical therapy in patients with heart failure and three to four plus secondary mitral regurgitation. In the current paper, first author Dr Baron from Lahey Hospital and Medical Center in Burlington, Massachusetts and St. Luke’s Mid America Heart Institute in Kansas City, as well as corresponding author Dr Cohen from University of Missouri, Kansas City, and their colleagues used data from the COAPT trial to perform a formal patient level economic analysis of the COAPT from the perspective of the US healthcare system, and they found that although the follow up costs were lower with the MitraClip compared with guideline directed medical therapy, and lower by more than $11,000 per patient. However, the cumulative two year costs remain higher by about $35,000 per patient with the transcatheter mitral valve repair, and this is all due to the upfront costs of the index procedure. Now when in trial survival, health, utilities, and costs were modeled over a lifetime horizon, transcatheter mitral valve repair was projected to increase life expectancy by 1.13 years, and quality adjusted life years, or QALYs, by 0.82 years at a cost of $45,648, yielding a lifetime incremental cost effectiveness ratio, or ICER, of $40,361 per life year gained, and $55,600 per QALY gained. Dr Greg Hundley: Very interesting. So how do we interpret these results for clinical practice? Dr Carolyn Lam: Ah, good question. So in order to place this in context, perhaps the most comparable case is the use of transcatheter aortic valve replacement, or TAVR. So based on the partner 1B trial, the ICER for TAVR, compared to medical therapy, was $61,889 per QALY gains. So this is very similar to what you just heard as the ICER for the transcatheter mitral valve repair. The cost effectiveness is also comparable for other commonly used treatments such as the implantable cardiac defibrillators for biventricular pacing, and was interestingly substantially more than the cost effectiveness of continuous flow LVADs, for example, and this is really discussed in a beautiful editorial by Dr Bonow, Mark, and O'Gara, and in this editorial, I think it's really important that they say the cost effectiveness projections really need to be placed in the context of continuing uncertainties regarding the interpretation of COAPT compared to that of the MITRA-FR trial, which reported no benefit of transcatheter mitral valve replacement compared to medical therapy, and so they warn that the current cost effectiveness analysis is not a carte blanche for interventional cardiologists to dramatically escalate their use of MitraClip procedure, and the data do support the thoughtful and deliberate use of this potentially life lengthening procedure in carefully selected patients and under very careful circumstances. You've got to read their editorial. Dr Greg Hundley: That sounds excellent, Carolyn. I really like that, putting that editorial that puts that data in perspective. Well, my next study really emanates from the ABSORB III trial, and it's from Dr Dean Kereiakes at the Christ Hospital Heart and Vascular Center. The manuscript addresses the long-term cardiovascular event rates among bioresorbable vascular scaffolds and drug eluting metallic stents. Dr Carolyn Lam: Greg, remind me, what were the results of the original ABSORB trial? Dr Greg Hundley: Right, Carolyn. So the ABSORB III trial demonstrated non-inferior rates of target lesion failure, cardiac death, target vessel myocardial infarction, or ischemia driven target lesion revascularization at one year with the bioresorbable vascular scaffolds compared with cobalt chromium everolimus-eluting stents, but between one year and three years, and therefore the cumulative to 3 year time point, the adverse event rates, particularly for target vessel myocardial infarction and scaffold thrombosis, were increased with this bioresorbable vascular scaffold. Dr Carolyn Lam: Ah, I see. Okay, so this current study evaluated the outcomes from three to five years beyond the implantation? Dr Greg Hundley: Exactly. So what this study did is they looked at an interval of time between three and five years out, and they found reductions in the relative hazards for the bioresorbable vascular scaffolds compared to the common coated stents, and that particularly occurred for target lesion failure, either cardiac death or target vessel MI or ischemia driven target revascularization when compared to the earlier zero to three year time period. So therefore Carolyn, the authors conclude that improved scaffold design and development techniques to mitigate that zero to three year bio resorbable vascular scaffold risk may enhance the late benefits that one sees in this three to five year time point, because of the complete bioresorption. Dr Carolyn Lam: So that's interesting Greg. Well, my next paper is kind of related. It is the first report of a randomized comparison between magnesium based bioresorbable scaffold and sirolimus-eluting stent in this clinical setting of STEMI with one year clinical and angiographic follow-up. So this study is from the Spanish group, Dr Sabaté and colleagues from the Interventional Cardiology Department and Cardiovascular Institute in Barcelona in Spain, and they found that at one year when compared to the sirolimus-eluting stent, the magnesium based bioresorbable scaffold demonstrated a higher capacity of vasal motor response to pharmacological agents, either endothelium, independent or dependent, at one year. However, the magnesium based bioresorbable scaffolds were also associated with a lower angiographic efficacy, a higher rate of target lesion revascularization, but without thrombotic safety concerns. Dr Greg Hundley: Wow, Carolyn, very interesting, and Dr Lorenz Räber and Yasushi Ueki wrote a very nice editorial on this whole topic of bioresorbable scaffolds, and they wonder about some of the unfulfilled prophecies. Great for our readers to put these two articles together. Now, how about in that mailbox, Carolyn? What have you got in there? Dr Carolyn Lam: First there's a research letter by Dr Kimura entitled Very Short Dual Antiplatelet Therapy After Drug-eluting Stent Implantation in Patients with High Bleeding Risk, and that's insights from the STOPDAPT-2 trial. There's another research letter by Dr Lopes entitled The Hospitalization Among Patients with Atrial Fibrillation and a Recent Acute Coronary Syndrome, or PCI, Treated with Apixaban or Aspirin, and that's insights from the AUGUSTUS trial. A very interesting perspective piece by Dr Rob Califf entitled The Balanced Dysfunction in the Health Care Ecosystem Harms Patients, a really, really interesting read, especially those working in the U.S. healthcare system. An ECG challenge deals with fast and slow, long and shorter. I would love to give you a clue to what it is. It's got to do with the atrial ventricular nodes, but I'll let you take a look and test yourself. There’re highlights from the TCT by Drs Giustino, Leon, and Greg Stone, and finally there's Highlights from the Circulation Family of Journals by Sara O'Brien. Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a couple reviews. Richard Whitlock in a primer provides a nice historical review of anticoagulation for mechanical valves. How do we get here in anticoagulating this particular patient population? Next, Dr Mark Brzezinski from Brigham Women's Hospital in the Harvard Medical School in an on my mind piece provides very elegant figures, beautiful figures, demonstrating inadequate angiogenesis within the fibrous cap of atherosclerotic plaques, and indicates this could be a source or thought of as a contributing factor toward plaque rupture. What an issue, and I can't wait to get onto that featured discussion. Dr Carolyn Lam: For our featured discussion today, it is a super-hot topic, and a question that comes up again and again in clinical practice. What is the right antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome, not just those treated with PCI, but also in those treated medically? Well guess what? We're going to have answers right here. I'm so pleased to have with us Dr Renato Lopes, who's a corresponding author from Duke Clinical Research Institute and our associate editor, Dr Stefan James from Uppsala University in Sweden. Wow. Very, very important question here. Renato, could you just start by outlining what is the AUGUSTUS trial? Dr Renato Lopes: The AUGUSTUS trial was basically one of the four trials trying to give an answer, or help answering about the antithrombotic therapy in patients with anti fibrillation and/or NACS and/or PCI. So in other words, this combination of patients undergoing PCI who require antiplatelet therapy and also patients with AFib who requires anticoagulation therapy, and in summary, what the AUGUSTUS trial did was randomize patients to Apixaban versus VKA, or aspirin placebo in a double blind fashion, and this was a two by two factorial design. So these were basically the two questions that we wanted to answer. Is Apixaban better than VKA, and is it safe to drop aspirin from this treatment strategy? Remembering that everybody received a P2Y12 inhibitor for at least eight months. So this was basically the design of the AUGUSTUS trial, trying to answer two questions in the same study, a two by two factorial design. Dr Greg Hundley: Very, very nice. And Renato, if I could, I mean I said it in the intro, but may I make sure I got it right. This is the only trial in the field that included patients with ACS that was managed medically. So that's a very important group of patients that we still don't know what the best regimen is, is that right? Dr Renato Lopes: That is correct. The other trials, the PIONEER, the RE-DUAL PCI and the VPCI, they only included patients undergoing PCI, and when we designed the trial, we thought that it would be important to also include the whole spectrum of ACS, including not only the PCI treated patients, but also the medically managed patients. Dr Greg Hundley: Well, super. So could you tell us now what were the results? Dr Renato Lopes: So first, in terms of the breakdown, we found that the breakdown of the PCI, ACS versus elective PCI, was really nice. We had about 60% of the trial being ACS patients, and about 39%-40% elective PCI, and then within the PCI, I think that our results pretty much reflect practice in a lot of parts of the world, which was about 39% medically managed and about 61% PCI treated patients. So to begin with, I think a very nice breakdown that gives us power to look at these three separate groups: ACS medically managed, ACS PCI treated, and also elective PCI, which allows us to understand the whole spectrum of coronary disease in patients also with AFib, and in summary, what we showed for the primary endpoint, which was clinical major or relevant non-major bleeding. Let's start with the Apixaban versus VKA comparison, and we show that Apixaban was safer than VKA in all three groups, in the ACS medically managed, in the PCI treated patients, and also in the elective PCI patients. There was no significant direction for those three subgroups, although it was borderline 0.052, just showing maybe a little bit less pronounced results in the elective PCI group, but nonetheless, I would say that in general, very consistent, and in terms of Aspirin for the primary endpoint, also no difference, no interaction among those three groups. In other words, as we increase substantially the risk of bleeding about two folds in all the three groups, ACS medically managed, PCI treated patients, and elective PCI patients, with about again, two fold increase in bleeding compared to placebo. If we go to ischemic events, again, that's our hospitalization and other that are ischemic events. In terms of Apixaban versus VKA, the results were very consistent with the overall trial among these three groups, and in terms of as ACS versus placebo, the results also for the ischemic events were also similar among the three groups. So again, reassuring that the main results of the trial were very consistent, regardless how patients were managed in terms of the ACS, medically or through PCI, and also included in the elect PCI group. Dr Carolyn Lam: Thank you for explaining that so well. Stephan, I would love for you to take us under the hood. What were the editors thinking when we saw this paper, why we're highlighting it now, and what do you think are the implications? Dr Stefan James: The AUGUSTUS trial was unique in many aspects. I think Renato highlighted a few of them. As he told, there have been several similar trials without the other DOAX, factor 10A inhibitors and the dabigatran, but the AUGUSTUS trial was larger. It includes, as you mentioned previously, patients with ACS and medical management, and it also was designed as a two by two factorial design. So it actually asks two different questions and made two different randomizations, both anticoagulation with the two different agents, Warfarin versus Apixaban, but also Aspirin versus placebo, and so it's possible from this trial to understand more of the different aspects of treating patients, these complex patients with atrial fibrillation, NACS or PCI, and gave the study group and us an opportunity to better understand all these complexities. So with that, I'd like to turn to Renato and try to, with that background that I just outlaid, and you just try to make us understand what are the clinical implications of these aspects of the trial and the treatment of Apixaban and Aspirin in these patients? Dr Renato Lopes: I think we were in the area that we desperately needed randomized data, because basically until five years ago, the standard of care of treating these patients was the classic triple therapy with Aspirin, Clopidogrel, and Warfarin, and this was based on no randomized trials and all observational data, and we know how problematic this is, and this field has evolved tremendously almost year after year since the PIONEER trial, since the RE-DUAL trial, and this year, we had AUGUSTUS and ENTRUST and I think now, as Mike Gibson used to say, that we have about 2.8 million different combination of antithrombotic strategies to treat these patients because we have different anticoagulants, different anti-platelets, different doses, different durations, different types of stents, which makes it really impossible for physicians or for any guidelines to contemplate all these options. So we really needed a few trials to at least try to give a few options that are evidence based and not just based on low quality of data, and I think now, if you look at the Augustus results, and the totality of the data from all these trials, which now is about almost 11,000 patients all together, actually almost 12,000 patients all together. I think that what we know today is that yes, the initial period in hospital for some time it's important to use Aspirin. I think this is an important point to highlight, Stephan, that Aspirin still needs to be used for the acute treatment, and I would say at least for the first few initial days while patients are still in the hospital, but then by the time of discharge, which sometimes might be five days, six days, seven days, I think that now the totality of data show that it's reasonable to drop Aspirin for most patients. So based on the AUGUSTUS results, what we show is that if you're going to use anticoagulation as Apixaban at the dose that is approved for stroke preventions in atrial fibrillation, combined with a P2Y12 inhibitor without Aspirin after the initial period, you have the best outcomes in terms of lower rates of bleeding, lower rates of hospitalizations, and we don't have to pay a cost in terms of ischemic events when we actually drop Aspirin and keep only the NOAC, in this case was Apixaban, plus a P2Y12 inhibitor, which most of the time was Clopidogrel, and here with AUGUSTUS, we basically show that this is true for patients with AFib and ACS, irrespective of the management with medical managing, with medical therapy, or with PCI. So I think that's an additional piece that that is true irrespective of how we're going to treat your ACS patient, or if the patient basically underwent elective PCI, and I think we learned today that the classic treatment therapy of VKA plus Aspirin plus P2Y12 inhibitor, so in other words, the triple classic triple therapy should generally be avoided. Dr Stefan James: Thank you Renato. I think that that was a very complete answer in this complex arena. I'd like just to mention that of course the AUGUSTUS, as well as the other trials, have their limitations, as all trials. Although it was large, it was powered for safety, for bleeding events, and it was not powered for ischemic events. Having said that, we still want to look at ischemic events and clinical outcomes, and to what degree do you think we can do that? What conclusions can we draw from an ischemic point of view because of the fact that the trial was underpowered for that interpretation? Dr Renato Lopes: That is a great question, Stephan, and in fact, if we look at events like stent thrombosis, they are very rare, and if you really want to attack a significant difference between Aspirin versus placebo in patients having stent thrombosis, we're really going to need a trial with about 30-40,000 people, which would be not feasible and not doable. So we need to be cautious when we analyze those events in the power trial for ischemic events. Nonetheless, there was a signal, if you look at all trials, and even in the meta-analysis that we published recently, that dropping Aspirin probably increased the risk of ischemic events, not in a statistically significant fashion, but nonetheless, this trend exists. The signal exists. So probably keeping Aspirin, add some protection for ischemic events, primarily stent thrombosis and myocardial infarction. The problem is a tradeoff. The problem is that the cost of adding aspirin is too high. So now the question to us, Stephan, is to look further into our data and in the combined data sets that we're trying to work with the other authors and try to identify, okay, Aspirin really increased the risk of bleeding, but is there a group of patients who might benefit from a little bit longer Aspirin? So that's the first question. Who are those patients? May be complex PCI, maybe bifurcation lesions, maybe multiple lesions, multiple stents, and second, if we decide to give Aspirin longer, how much longer should we give? Because again, the cost is very high in terms of bad bleeds. So we are trying now to identify what is the trade off, and who most benefit from keeping Aspirin longer, and for how long in a way the cost might be worth it to pay in exchange of potentially save some ischemic events? And with that, we can further refine the treatment that I think I highlighted before. For most patients, I think what I said before is probably reasonable. We can drop Aspirin by the time of discharge after a few days, but for a few patients, for some patients, it might be wise to keep Aspirin a little bit longer, and we are trying now to identify first, who those patients are and second, form how much longer should we keep Aspirin, since the 40,000 patient trial is very unlikely to happen. Dr Stefan James: I like his interpretation, Renato, although I wanted to highlight that there are limitations, I think this trial is extremely informant for clinicians. We learned a lot how to treat these very complex patients with complex treatments. Dr Carolyn Lam: No, I couldn't have agreed more. I mean quoting Mike Gibson, 2.8 million combinations. Well, at least we've talked about some of them here and had a very clear take home message, although with the caveats that we were discussing. Thank you so much, Stefan and Renato. This was really a great discussion, and thank you audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2019.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. What are the long-term effects of oxygen therapy in patients with suspected acute myocardial infarction? Well, to find out, stay tuned for our discussion of our feature paper this week, coming right up after these summaries. The first two original papers demonstrate that, similar to neonatal mice, one day old and two-day old neonatal pigs are capable of mounting a cardiac regenerative response following myocardial infarction, which is characterized by restoration of contractile function, cardiomyocyte replenishment, and minimal fibrosis. Now, interestingly, this regenerative capacity is lost after the first two days of life. The first paper is from co-corresponding authors, Drs Yeh and Cook from National Heart Research Institute of Singapore and National Heart Center, Singapore, and the second from co-corresponding, authors Drs Zhang and Zhu from the University of Alabama at Birmingham. These authors report collectively that proliferation of preexisting cardiomyocytes appear to be the primary source of cardiomyocyte replenishment in neonatal pigs with markers of cardiomyocyte mitosis, sarcomere disassembly, and cytokinesis elevated following injury in the one day and two-day old hearts, but not at later time points. Furthermore, cardiomyocyte DNA synthesis was increased following neonatal pig myocardial infarction. Cardiomyocyte proliferation significantly decreased after this two-day window, which was associated with a marked reduction in telomerase activity. Heart failure with preserved ejection fraction may look different in the young compared to that in the elderly. First author, Dr Jasper Tromp, corresponding author, myself, Carolyn Lam from the National Heart Center, Singapore and Duke National University of Singapore, and our colleagues from the Asian Heart Failure Registry studied more than 1,200 patients with HEF PEF from 11 Asian regions and found that 37% of our Asian HEF PEF population was under 65 years of age. Younger age was associated with male preponderance, a higher prevalence of obesity, and less renal impairment, atrial fibrillation, and hypertension. Left ventricular filling pressures and the prevalence of left ventricular hypertrophy was similar in the very young of less than 55 years and elderly HEF PEF of more than 75 years of age. Compared to age matched controls from the community without heart failure, the very young HEF PEF patients had a three-fold higher death rate and twice the prevalence of left ventricular hypertrophy. Thus, young and very young patients with HEF PEF display similar adverse cardiac remodeling as their older counterparts, but very poor outcomes compared to controls without heart failure. Obesity may be a major driver of HEF PEF in a high proportion of HEF PEF in the young and very young. How important is hospitalization for heart failure as a complication of diabetes? In the next paper from first and corresponding author, Dr McAllister from University of Glasgow, the authors examined the incidents and case fatality of heart failure hospitalizations in the entire population age 30 years and older resident in Scotland during 2004 to 2013. Over the 10-year period of study, among 3.25 million people, the coot incidence rates of heart failure hospitalization were 2.4 per thousand-person years for those without diabetes, 12.4 for those with type two diabetes, and 5.6 for those with type one diabetes. Heart failure incidents had fallen over time for people with and without diabetes, but remained around two times higher in people with diabetes than those without diabetes. Heart failure case fatality was higher in people with type one diabetes. Duration of diabetes and glycated hemoglobin was associated with increased risk of heart failure in type one and type two diabetes. Thus, clinicians should be aware of the importance of heart failure and diabetes, especially in type one diabetes where this is under appreciated. What are epigenetic mechanisms contributing to ischemia reperfusion injury? Co-first authors Dr Yu, Yang, and Zhang, co-corresponding authors, Dr Xu from Nanjing Medical University, Dr Sun from Fudan University, and Dr Ge from Fudan University, and their colleagues evaluated the potential role of megakaryocytic leukemia one, or MKL 1, as a bridge linking epigenetic activation of NAD pH oxidases, or NOX, to reactive oxygen species production and cardiac ischemia reperfusion injury in mice. They found that genetic deletion of pharmaceutical inhibition of MKL 1 attenuated cardiac ischemia reperfusion injury in mice. MKL 1 levels were elevated in macrophages, but not in cardiomyocytes in vivo, following cardiac ischemia reperfusion injury. MKL 1 recruited the histone acetyltransferase, MOF, to activate NOX transcription in macrophages. Pharmaceutical inhibition of MOF attenuated cardiac ischemia reperfusion injury in mice, and pharmaceutical inhibition of NOX one or four attenuated cardiac ischemia reperfusion injury as well. These findings provide a novel link between MKL 1-mediated epigenetic regulation of gene expression in macrophages and ischemic heart disease. This opens the door to small molecule compounds targeting the MKL 1 MOF NOX access as a novel therapeutic strategy against ischemic heart disease. Is the time from last hospitalization for heart failure to placement of a primary prevention ICD associated with patient outcomes? First and corresponding author Dr Ambrosy from the Permanente Medical Group in San Francisco performed a post hoc analysis of Medicare beneficiaries enrolled in the national Cardiovascular Data Registries implantable cardioverter defibrillator, or ICD registry, all with a known diagnosis of heart failure and an ejection fraction of less than 35%, undergoing a new ICD placement for primary prevention. They found that older patients, currently or recently hospitalized for heart failure, undergoing initial ICD placement for primary prevention, experienced a higher rate of periprocedural complications and were at increased risk of death compared to those receiving an ICD without recent heart failure hospitalization. Additional prospective real world pragmatic comparative effectiveness studies should be conducted to define the optimal timing of ICD placement. The final original paper presents result of the VERDICT trial, a large scale randomized controlled trial evaluating the value of very early invasive strategy conducted within 12 hours of diagnosis on long term clinical outcomes in patients with non-SD elevation acute coronary syndrome. First and corresponding author Dr Kofoed from University of Copenhagen and colleagues studied 2,147 patients who were randomized and found that an invasive strategy performed within 4.7 hours after diagnosis was not associated with improved outcomes, compared to an invasive strategy conducted within two to three days. However, in the pre-specified subgroup of patients with a GRACE risk score of more than 140, a very early invasive treatment strategy did appear to improve outcomes, compared to a standard invasive treatment strategy. And that wraps it up for our summaries. Now, for our feature discussion. For our feature discussion today, we are talking about oxygen therapy for patients with suspected acute myocardial infarction. Something that seems so benign, something we've taken for granted, and yet now we now question since the Detox AMI trial. Well, for today's feature paper, we have a follow-up of this trial, and I'm so pleased to have actually our associate editor, but also author of this paper, Dr Stefan James from Uppsala Clinical Research Center, and the guest editor for this paper, Dr David Morrow, who's from Brigham Women's Hospital and Harvard Medical School. So, thank you both for being here. Stefan, could I just ask you to start by taking us back. How was Detox AMI first conceived? What made you even question oxygen therapy? And then, perhaps then, tell us about what this new paper adds. Dr Stefan James: I think that's so interesting because I think we all learned in medical school that for myocardial infarction, you should always deliver oxygen. That's sort of the first choice. And the other sort of first choice that we learned was morphine. Some of the other important things that we learned was to give not only oxygen but morphine, and nitroglycerin, and perhaps aspirin. And by those four, only aspirin is really the agent that has been proven beneficial to patients. But we thought for many years actually about this oxygen hypothesis, or we were interested in trying to understand, is it really helpful to give patients oxygen? Or are we in fact harming patients? Because there is, as you may know, there is a metanalysis performed long ago with small trials on the fibrinolysis era that showed actually a threefold increased risk of dying in those patients who had received oxygen in randomized various small trials, and their animal experience actually suggesting that oxygen is also hazardous. You don't think about that so often, but it's really an agent that constricts arteries, and so as the arteries close by a clot in myocardial infarction, there is no way the oxygen that you breathe in your nose can reach the suffering myocardium. It actually contracts the arteries, and may make the infarct larger than it would be otherwise. Dr Carolyn Lam: I love that explanation. Alright, so what did you find in the current analysis of longer term results? Dr Stefan James: So, we performed this, the main oxygen trial that we call Detox. We built it upon our national registries, and so we decided to include not only MI patients, but patients who were suspected of MI, in order to be able to enroll patients before the diagnosis was clear. We didn't want to wait for troponins, so we enrolled patients in the ambulances, in the emergency departments, in the cath labs, or in the wards, patients who had suspected myocardial infarction. Most of them, eventually, did have myocardial infarction, but a proportion did not have myocardial infarction. They had other diseases that resembles MI and have breathing problems. And we selected the cut point of 90%. We said if they are below 90%, they're hypoxic, and it would be unethical to withdraw oxygen, if you were hypoxic. So, we sort of arbitrarily selected the cut point of 90%. And then, we randomized patients to receive oxygen or do not receive oxygen. We considered to do double blind, but in order to do a double blind, you need to provide air on a mask. And air is not available in ambulances or in the emergency department. We cannot put a mask without anything in it because then it will feel more difficult to breathe. So, we had actually oxygen versus nothing, and we enrolled all patients coming to the cath labs, and emergency departments, and ambulances in Sweden. And thanks to the infrastructure that we have built on the national registries, we were able to enroll these to conduct this large trial, larger than any other trial, 6,600 patients. In the main study, we found no benefit, and fortunately, no harm of providing oxygen for our primary end point, which was all caused death. But we realized that we were little bit underpowered actually to really clearly rule out that there was any benefit on the primary endpoints. And so, we said, we probably need a longer follow-up, and we probably also need other important measures such as heart failure. Because we thought that oxygen may, if it works, it may reduce the infarct size and may result in a lower risk of heart failure in the long-term. We don't believe that we will reduce the risk of re-MI because we're not interfering with atherosclerosis or plaque ruptures, but we may interfere with the development of heart failure. So, in this particular paper, we said, longer follow up in order for patients to possibly develop heart failure and increase their risk of heart failure hospitalizations. So, in this paper, we used as a primary endpoint of this analysis, death or hospitalization for heart failure, post MI. And with this way of calculating events, we are more sure that we are not underpowered for this evaluation. Dr Carolyn Lam: Right. And the results? Dr Stefan James: The results were completely neutral. There was no benefit at all in any sub group. It doesn't matter if you were ST elevation MI, or no ST elevation MI, or no MI, or high risk prior MI, prior heart failure, respiratory disease, there is no benefits and no harm, which is good. And those results are supported by our findings on troponin levels. So, we checked troponins repeatedly. I shouldn't say top troponin, but the highest measured, we did not find any difference between the two groups in Troponin elevations. And we did not find any difference in LVEF and in Echo performed during the initial hospitalization. So, I think both of those results support the primary endpoint of death and repeat hospitalization for heart failure. Dr Carolyn Lam: So David, you've thought a lot about this, and also framed it so nicely when we were just talking a little bit earlier. What do you think is the real significance of this paper on so many levels? Dr David Morrow: Yeah, I think there are many levels. I think it's such important work because it takes something that we are still doing in many hospitals every day for patients and is difficult to study because it's become part of standard of care, as Dr James pointed out, and so the authors are to be congratulated for being able to study this intervention. And I think in additionally because it is a therapy that's not associated with high cost, has been part of our care for so long, it's not one where there is the support for a large type of randomized trials. So, the ability to perform this with relatively low costs by nesting it in a registry is important, not only for this particular test, but also as a model for future research of so many interventions that we make right now where they started in a time where our threshold for a need for data was much less. Dr Carolyn Lam: Yeah. Indeed. That's wonderfully put. I am also really struck. It's the importance of the message, but also especially about how you do a pragmatic registry-based randomized trial. The ability of Sweden to do this, it's just rock the world, right? Because we really need solutions like that for our clinical trial world, which has to be sustainable somehow. Could you maybe take us behind the scenes a little bit? I mean you did already in your description. I didn't realize there were so many considerations when you're planning this, but how easy or difficult is it to do a trial like this? Dr Stefan James: We call the entity RRCT. We call it registry based randomized trial, but being aware that there is no strict definition of what is a registry based randomized trial. So, sometimes for some simple interventions like strategies, we can use only the registry for collection of baseline variables, procedure variables, and also outcomes. The registry can really do everything. The only thing we need to add is a randomization, so then we just program into the registry, which is used live in front of the patients. So, when I enter a patient in the registry, the personal identification number collects me to the population registry that supports directly back to me name and gender of the patient, and then I enter all the baseline characteristics anyway in the registry. And then, there is a question that comes up that screens my patients. So, the system proposes to me to randomize patients who are eligible because I programmed the inclusion/exclusion criteria. So, it proposes to every doctor in the country, this is a patient that is eligible potentially for this trial and just click randomize, and that's the trial. Everything is completed by that. No extra tests, no visits, no follow up, no telephone calls. That's the basic, very simple format that can only be used for a strategy, like a device or a strategy. But many of the questions we have in medicine are really regarding strategies. How long should you treat? How often do you need to come back? Sort of strategies. Then, when we've tried to expand this to pharmaceutical agents, and oxygen was the first pharmaceutical agent that we wanted to try. You may not consider oxygen as a pharmaceutical agent, but it is in fact. But it's not manufactured by any companies, and we are still, in this trial, wanted to keep all-cause mortality as the primary end point because that's very reliable. That's indisputable, and in our country it's absolutely 100% correct. If they registered dead, they are dead. There's no question. The next level we did in the validate was a true pharmaceutical agent manufactured by a company, [byobatterin seprin 00:18:31]. A little bit more complex because you need to be careful about making sure that the patients are receiving the pharmaceutical agent in the right manner, in the right time point. We need to be a little bit careful about collection of side effects, and complications, and so on, but it also worked very well in that trial. If they validated, we did actually adjudicate events because in the primary end point we had it where it was more complex primary endpoint, including myocardial infarction. If you include myocardial infarction or bleeding events, that needs to be defined in a certain way according to protocol. You need to adjudicate. If you really need to rely on the outcome assessment. We're not trying to take this type of study to the next level, to use it for typical oral pharmaceutical agents. Our largest trial now running is the spirit HFPF lactone versus no treatment in patients with HFPF. And again, this is a pharmaceutical agent that is a very inexpensive. There's no company that would sponsor such a trial, but we think it's a really important question. There's so many patients that suffer from HFPF, and in order to do that trial, it has to be simple and inexpensive. So, that's running. We hope to be successful. There are, of course, many challenges. Like any other trial, it's difficult to write a protocol. You have to be very dedicated and detailed for any trial. So backstage, this is not easier than any other trial, but for the investigator, it is much easier. That's the reason we have succeeded to reach out to every hospital in the country, and every physician seeing these patients are investigators. And many of them have never done any trials before. They have no experience with research, but still they should be able to randomize and do the trials because it seems to be so easy for them and for the patients. That's the whole idea. Dr Carolyn Lam: Yeah. I'm just enamored by the whole concept, and of course, a lot of people I think are wishing that we could institute that in all countries as well. Trust me, a lot of conversation has occurred about that in Singapore, for example, where population based capture is possible. But, as you said, it's not that easy. It's got to be well thought out. Protocols still have to well thought out. Investigators still need to be trained, and so on. Dr Stefan James: We want the investigators to feel that it's easy, that it's attractive to participate. Not for money, just because it's so easy and so interesting to be part of such an experiment. Dr David Morrow: I think testing some of those therapies that are commonplace that they're used to, and our nature of practice is this is the perfect type of setting than more complicated interventions where you may need to train the investigators more in order how to implement to them, and apply the therapy correctly. That's the new trend, is ... I think the key issue is that in order to reliably test things where mortality is not the acceptable outcome that you could power adequately for, it's really the endpoint collection in the safety collection, and because of the robust medical record systems you have, you're able to do that. And we're so far from being able to do that reliably in the United States right now that it's not possible to do that. Unless we have specific well-constructed registries, which we do in some areas. I think we're learning, and hopefully we'll get there, but we're far behind [crosstalk 00:21:55]. Dr Stefan James: [crosstalk 00:21:55] Yeah, but even- Dr David Morrow: [crosstalk 00:21:57] Nationals- Dr Stefan James: Even if you're not able to do a registry based, I think we all should consider in all trials to do it as easy as possible and really try to ask ourselves, what is the most important reason we're doing this trial? Sometimes we need to collect a lot of extra information because we need to understand the mechanisms or the side effects. If that's the case, I don't think at this trial methodology is not suitable. You shouldn't perform it that way. It needs to be the more traditional, more conservative, more expensive and burdensome way, but for many therapies, a more simple approach, more pragmatic approach is preferable. Dr Carolyn Lam: Well, thanks again for diving into that because it gives us a real, to me at least, even greater appreciation for this paper when you understand the amount of work that's gone into it. But may I just end by saying, what do you think is the take home message for clinicians now? David, for example, you started by saying everyone's still doing it? I fully agree. Dr David Morrow: Yeah. I think it's a very simple message, and that we know that oxygen is not effective in patients who have an oxygen saturation above 90%. And there's really no rationale to use it. Dr Carolyn Lam: Perfect. Has this been put in practice in Sweden already? Dr Stefan James: It has been. One of the virtues of running these registries is that we can also check the adherence to the results, so we can check that this is not used anymore. Dr David Morrow: And since the investigators are your entire country, they all learned actually from participation in these trials. Dr Stefan James: Exactly. Exactly. Dr David Morrow: There's more of an investment in it already. Dr Carolyn Lam: That's amazing. So, thank you again for sharing. Thank you for publishing this in circulation and for helping us to do that. You've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright the American Heart Association in 2018.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Can proteomic biomarkers distinguish between subtypes of aortic stenosis even years before surgery? Well, to find out more, stay tuned. That's coming right up after these summaries. The first original paper this week adds to the evidence that smoke-free policies are associated with a lower risk of cardiovascular disease. First and corresponding author, Dr Mayne from Northwestern University Feinberg School of Medicine, and her colleagues linked smoke-free policies to participants of the Coronary Artery Risk Development in Young Adults, or CARDIA study, which has a follow-up of up to 20 years. They found that smoke-free policies in workplaces were associated with significantly lower risk of incident cardiovascular disease after controlling for a wide range of covariants. Results were weaker for bar and restaurant bans, but in the same direction. Preventive fractions range from an impressive 24 to 46%. Thus, smoke-free policies may improve cardiovascular health through reducing population exposure to tobacco smoke. However, we should remember that much of the US population remains unprotected by smoke-free policies. Thus, taken together with prior ecological work, these results support the continued expansion of smoke-free policies in indoor public places. Most phase-3 randomized control trials feature time-to-first event end points for their primary analysis. In chronic diseases, however, a clinical event can occur more than once and recurrent event methods have been proposed to more fully capture the disease burden, as well as to improve statistical precision and power. However, is this really the case? This question was examined by first author, Dr Brian Claggett, corresponding author, Dr Scott Solomon, from Brigham Women's Hospital in Boston, Massachusetts, and their colleagues, who sought to better characterize factors that influence the statistical properties of recurrent events and time-to-first event methods in the evaluation of randomized therapy. They performed repeated simulated trials with 1:1 randomization of 4000 patients to active versus control therapy. Through simulation, they varied the degree of between-patient heterogeneity of risk as well as the extent of treatment discontinuation. They then compared their findings with those from the actual randomized control trials. The authors found that the statistical power of both recurrent events and time-t- first event methods were reduced by increasing heterogeneity of patient risk, a parameter that's not usually included in conventional power and sample size formulae. Furthermore, data from real clinical trials were consistent with the simulation studies, confirming that the greatest statistical gains from the use of recurrent events methods occurred in the presence of high patient heterogeneity and low rates of study drug discontinuation. The next paper uncovers a novel biomarker and therapeutic target of pulmonary arterial hypertension, and that is selenoprotein P. First author Dr Kikuchi, corresponding author, Dr Shimokawa, from Takaoka University Graduate School of Medicine in Japan and their colleagues performed micro-array analyses using pulmonary arterial hypertension, pulmonary artery smooth muscle cells, and found a 32-fold up regulation of selenoprotein P compared with controls. Selenoprotein P promotes cell proliferation and apoptosis through increased oxidative stress and mitochondrial dysfunction. Using five strains of genetically modified mice, the authors demonstrated a pathogenic role of selenoprotein P in the development of hypoxia-induced pulmonary hypertension. Furthermore, sanguinarine, which is an orally active small molecule identified by throughput screening reduced selenoprotein P expression and pulmonary arterial smooth muscle cell proliferation and ameliorated pulmonary hypertension. In summary, this study shows that selenoprotein P plays a crucial role in the pathogenesis of pulmonary arterial hypertension and may be a useful and novel biomarker and therapeutic target in this disorder. Familial hypercholesterolemia is known to be associated with a high risk of ischemic heart disease, including myocardial infraction, but what about the risk of ischemic stroke? Well, first author, Dr Beheshti, corresponding author, Dr Nordestgaard, from Copenhagen University Hospital and their colleagues examined the associations of familial hypercholesterolemia and high LDL cholesterol with ischemic stroke in both causal, genetic, and observational analyses using more than 106000 individuals from the Copenhagen General Population Study, and more than 10000 individuals from the Copenhagen City Heart Study. They used a Mendelian randomization design to test whether high LDL per se had a causal effect on ischemic stroke risk using a combination of the familial hypercholesterolemia causative mutations and common genetic variants associated with high LDL. The authors found that there was no association between familial hypercholesterolemia mutations and ischemic stroke risk. In the Mendelian randomization analysis, also including common genetic variants, there was also no causal effect of high LDL on the risk of ischemic stroke. These findings imply that the predominant goal of targeting LDL lowering in those with and without familiar hypercholesterolemia is likely to reduce myocardial infractions, rather than ischemic stroke. Well, that wraps it up for our summaries. Now for our feature discussion. Circulation publishes numerous papers regarding circulating biomarkers. We talk about biomarkers in the diagnostic, prognostic sense, but what about in a pathophysiologic sense, and especially in a disease as important as aortic stenosis? Well, that's what our featured paper this week is all about and I'm so excited to have with us corresponding author, Dr Stefan Söderberg, from Umeå University in Sweden, as well as our associate editor, Dr Peipei Ping from UCLA. We will be discussing the paper entitled “Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement.” Stefan, could you tell us a bit about what made you look at this very interesting question, and perhaps the unique resources you had in Sweden to look at this? Dr Stefan Söderberg: I'm a practicing cardiologist, and I have been working a lot with aortic stenosis over the years. It's frustrating that we can't do anything to stop the process. In many cases, the patients are old and frail, and if you could find the means to stop the process long before they need surgery, it will be of great benefit for the human and for the society. Also, knowing that the interventions on the statins, for example, have been unsuccessful, we thought that there must be better ways or other biomarkers. Furthermore, that many of these studies, the phenotype of aortic stenosis has been very poorly described and there is probably much more behind just aortic stenosis than just, for example, calcium deposits in an X-ray, et cetera, et cetera. Dr Carolyn Lam: You used some very unique resources in Sweden to therefore look at the proteomic signatures of aortic stenosis. Could you describe that and simplify perhaps the results so we can understand it? Dr Stefan Söderberg: First of all, I got this idea from other studies done up in northern Sweden. If you have an absolutely unique setting, the combination of huge population-based studies in 30 years back, we have a huge biobank with examples of extraordinary good quality from each of these participants. For example, for each participant, the blood has been spun and put into freezer, deep freezer, within one hour for 30 years, and they are now, as I said, about 100000. Furthermore, I'm working as a cardiologist at a university, and up here, you do all of the aortic surgery for the whole northern Sweden. That is, we can combine the names of the person undergoing surgery together with these population-based surveys and we can get details from all those who have participated in the surveys long before they did the surgery, and they can go and retrieve samples from cases and match controls from the freezers. It's a unique setup. Then, when we were designing the study, we got the chance to get these analyses done by our friends at the university to get the proteomic analysis via a unique data technique. Dr Carolyn Lam: Wow. Could you describe your results? Dr Stefan Söderberg: The results that we found in the first set of 334 patients who underwent surgery is 10 years after their first sampling, we found six proteins. Then, we got the question back from Circulation to establish a validation cohort, and we were able to do so to include all those new cases in the last 2 years, and there we could replicate five of these proteins. The interesting thing that the pattern is completely different between those having coronary artery disease from those without. That kind of phenotyping has not been done throughout other aortic stenosis studies. Therefore, this study is unique. We have had two papers in the last year in the Journal of American Heart Association from the cohort, as well, showing the thing that happened. For example, lipoprotein little A is only associated with future aortic stenosis valve replacement only in those with concomitant coronary artery disease. There are many unique things, the prospective design, and the phenotype differentiating those with and without coronary artery disease. Dr Carolyn Lam: Yeah, and if I may just reiterate that the population base that you work with is just enviable and just so that the audience realizes, these are biomarkers that were collected 11 years before the aortic stenosis surgery, isn't it? You really had a long follow-up. Also, just to let everyone know, it was a proximity extension assay that you used for the discovery, and the six proteins were growth differentiating factor 15, or GDF15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and PCSK9, so very interesting. Peipei, you have a way of putting things into context so beautifully. Could you tell us your thoughts when you saw this paper? Dr Peipei Ping: I thought this is a very high-quality study that actually benefited from the long-term established, well-controlled cohort in northern Sweden, as Dr Söderberg just shared with us. On the other end, it married a technology platform that's very well-established and -validated, and this situation targeted proteomics platforms using multi-proximity extension assays with carefully controlled markers and screened 92 cardiovascular candidate markers. This is the kind of approach that provides semi-quantitative as well as quantitative outputs and is capable to offer validated screens on large population clinical subsets. A study of such with a high value cohort combined with a validated and well-controlled technology platform offered results that clearly have clinical significance, as well as setting up examples for other studies to follow. The enthusiasm from the editorial boards, as well as the reviewers, have been substantially high and supportive. Dr Stefan Söderberg: Fantastic. I'm very glad to hear this. Dr Carolyn Lam: Stefan, you also mentioned that a very unique element was the separation of aortic stenosis with and within coronary artery disease, or at least established or visible coronary artery disease. Could you explain how that provided pathophysiologic insights? Dr Stefan Söderberg: First, I should say we were very, very strict. Our routine is that everyone was 100% undergoing, aortic valve replacement, they undergo a coronary angiogram before. If we saw any sign of atheromatosis, it was not enough that they had the significant stenosis, but any signs, they were put into the group of coronary artery disease. Those without, we couldn't see anything there. Radiograph here reported absolutely clean coronary arteries. Of course, we cannot exclude if there were aortic changes within them all, of course. We believe that this is a very important message that in order to further study aortic stenosis, we should be very careful in phenotyping the disease. We hope the growing cohort will be able to do this further. For example, cuspid versus tricuspid valves, women versus men, et cetera. My answer in short is phenotype. Let me take one example which I found very, very exciting. That is the finding of PCSK9, which is closely related not only to cholesterol symptoms, but also to lipoprotein little A emphasis. As you know, the first strong finding in aortic stenosis was the LP little A. This is related to that genetic finding, and that was in the huge study from Canada. They did not have the same phenotyping, so we had information to his important findings. That's one example. Another example is the transferring receptor, where data has shown that bleeding acutely in the valvular tissue causes damage, and this relates iron metabolism to the formation of the aortic valve. Obviously, it seems that the process in the aortic valve is very much similar to the vessel arteriosclerosis. It seems to be different. This is the indication that when we formulate new studies or new drugs on aortic stenosis, we must be very careful to use the right drug for the right type of valvular disease. Dr Carolyn Lam: Those are great points. Peipei, do you think that's the main clinical take-home message, beyond that great comment you made earlier that this paper's just a great example of the use of tools, modern tools, that we have in proteomic characterization like the proximity extension assay to provide pathophysiologic insights when you have a really well-phenotyped cohort? What's the critical take-home message, though? Is there one now? Dr Peipei Ping: The take-home message is marriage of amazing high value cohort's data sets with that of the well-controlled clinical study using target proteomics approaches. In this particular study, one main critical innovation is the study is capable of providing insights regarding molecular signatures that have predicted values. As stated in the manuscript, the circulating proteins that found critically important, their alterations took place years before the surgery were associated with aortic stenosis. That is of value, clinical value, to many other clinical studies to follow. Dr Carolyn Lam: Wow. That's wonderful. Thank you so much for putting these findings in context for us. Thank you, listeners, for joining us today. Don't forget to tune in again next week.
Jane Ferguson: Hi everyone. Welcome to episode seven of Getting Personal, -Omics of the Heart. I'm Jane Ferguson, an assistant professor of medicine at Vanderbilt University Medical Center and the chair of the Publications and Professional Education Committee of the Functional Genomics and Translational Biology Council of the American Heart Association. This month I'm particularly excited to announce a new venture. We have teamed up with the journal, Circulation: Cardiovascular Genetics to bring you this and future podcasts. CircGen publishes a lot of the most compelling research in cardiovascular genetics and genomics and precision medicine in cardiometabolic disease. We've already featured a lot of the research in previous episodes of the podcast. With this new collaboration, you can look forward to even more in-depth features of the newest research published in Circulation: Cardiovascular Genetics. This month, Anwar Chahal, a cardiology fellow at the Mayo Clinic, talked to Calum MacRae, the Chief of Cardiology at the Brigham Women's Hospital in Boston. The interview covered a variety of topics and we couldn't fit everything into this half-hour podcast. What you will hear in this episode is a discussion related to a recent publication by Dr. MacRae and colleague Aaron Aday in Circulation published in July 2017 entitled Genomic Medicine in Cardiovascular Fellowship Training. Dr. MacRae expands on the topic, How to Train Clinicians to Deal with Advances in Genomic Medicine and What we Can Do to Improve Implementation of Knowledge from Genetics and Genomics to Helping Patients with Cardiovascular Diseases. If you'd like to hear more from the interview, including discussion of Dr. MacRae's bold One Brave Idea project, and to hear more pearls of wisdom and career advice from Dr. MacRae, you can download the full interview in the special hour-long podcast. First, I do want to highlight one recent paper from the Functional Genomics and Translational Biology Council which was published in the June 2017 issue of Circulation: Cardiovascular Genetics. This clinical genomics paper was published by Laura Zahavich, Sarah Bowdin and Seema Mital, all from the Hospital for Sick Children in Toronto. The paper is entitled Use of Clinical Exome Sequencing in Isolated Congenital Heart Disease and describes the case of an infant with congenital heart disease where a pathogenic mutation in the notch one gene was identified through whole exome sequencing. The paper highlights the utility of whole exome sequencing when candidate gene panels are negative, allowing for increased understanding of causality and the ability to make risk predictions for future offspring. At the same time, this approach reinforces the importance of well-trained clinical personnel including genetic counseling, to appropriately interpret and disseminate findings from whole exome sequencing. A little aside, in case you are not aware of this, Circulation: Cardiovascular Genetics has a really nice feature on their website where you can apply filters to see specific types of publications. From the toolbar along the top of the homepage, you can go to Browse Features and then you can select Options from the dropdown menu, so if you click on Clinical Genomics Cases, for example, you will see all of the genomic case reports, which may be of particular interest to this audience. Dr Anwar Chahal: My name's Dr. Anwar Chahal. I am a cardiology fellow in training from London, UK, and I am doing my research fellowship here at the Mayo Clinic. I'm very honored and delighted to have our guest, Dr. Calum MacRae, so you are the Chief of Cardiovascular Medicine. You are a MD PhD by training and you are associate professor at Harvard Medical School and your expertise amongst many other things, internal medicine, cardiovascular diseases, but in particular inherited cardiovascular conditions. Is there anything else that you would add to that? Dr Calum MacRae: I'm a big fan of generalism and I'm quite interested in cardiovascular involvement in systemic disease as well, largely as a means of keeping myself abreast with the biological mechanisms in every system that seems to be relevant to cardiovascular disease. Dr Anwar Chahal: I think training across the world has increasingly recognized the importance of genetics and genomics, but I just want to share one little anecdote. My wife's a primary care physician and I was visiting the GP practice where she works and she'd mentioned that I had an interest in genetics and genomics and one of the partners came out with one of these reports that a patient had sent their sample to a private company, got this analyzed, brought it into the clinic appointment, and asked for an interpretation. The GP partner said to me, "I've absolutely no idea what any of these numbers, values, et cetera mean. I actually am looking forward to my retirement because I really don't want to have to cover all of this. Can you help me with it?" I sort of remember hearing Dr. [inaudible 00:05:48] talk here at Mayo Clinic, who's really pushed forward pharmacogenomics and he's been arguing for quite some time, as I've heard you say as well, that genomics and genetics is just going to be a part of the medical record in the same way that hemoglobin or a chest x-ray is and people better catch on because it's here, it's available, commercially people can send their samples directly without their doctor's involvement and then it's trying to make sense of all of that. I think as a community research and clinical we have to take this very seriously and I'd be grateful for your insights on that and then if you could then tell us what would be the best way for the up and coming generation and for programs to incorporate that into their training. Dr Calum MacRae: I think you're right, there is a general tendency in the public domain to test a variety of different genotypes, and in many instances I think the key elements are how do we as a profession conceive of these tests? I think one of the things that we forget perhaps at our peril is that many of these things are problems that we've encountered before. There's a natural cycle of different tests in medicine where they start off in the academic medical centers, they propagate into the periphery, and then eventually they're assimilated as part of internal medicine. I think the scale of genomics is obviously somewhat broader than many individuals have seen in the types of data that they deal with on a day-to-day basis, but I think that's something that's happening in everybody's life, and every aspect of your life, you have many more channels to deal with, you have many more choices in the supermarket to deal with. I don't see this as a sort of existential challenge to medicine; quite the opposite. In my experience, the core things that we need to remember is that DNA is no different from any other assay, except for the fact that it's relatively straightforward to do DNA diagnostics. It's technically not as sensitive a set of biochemical issues as are many other assays that we use in day-to-day clinical practice. The other thing that I think is perhaps a key element is that I said a few minutes ago, it's a [inaudible 00:08:35] dataset and it's stable for your whole life. You only need to have it tested once. It's sort of invert to the typical diagnostic paradigm, so instead of a primary test being interpreted in the context of an ongoing clinical event, the test may have been present for four decades and the results will evolve over time in light of the changing phenotype or some new information in respect to that genotype. What I've actually looked on genomics as is almost an organizing principle for the way that you build care. In fact, I see quite frequently, we probably now have an average one or two new patients a month in my clinic who bring their entire full genome with them, either an exome or a whole genome. We've begun to really get to know quite well how to manage patients. Obviously they're a select group of patients but one of the things that I find is that patients are really quite astute in understanding that genotype and phenotype are not deterministic relationships. What you have to do is always interpret these things in context of a probabilistic understanding. Most patients I think when they're told this understand that we're going to learn much more about genomics going forward than we will ever imagine that we could know at the present. That will involve lots of different things. It will involve new ways of displaying data, new ways of thinking about the data in the clinical context. I actually think one of the most interesting things about genomics and to be honest any assay is that they rarely reach any form of maturity until they are used in the clinic, until they are actually used in implementation. For example, many genetic tests at the moment don't change therapy and they don't change outcomes, but partly that's because they've never been studied in that context, and one of the things that I think [inaudible 00:10:45] has to be really congratulated for is his focus on pharmacogenomics as being one of the early areas in which this will really move forward. I believe that by immersing ourselves in it, by actually trying it within the clinic where we're going to learn much more, and part of that gets back to the original topic that we spoke about, which is phenotype. The only way to really begin to understand collection of phenotype is if you do it in the context of existing genotype I think. As we move into new phenotypic areas, we're not going to be able to test everything and everybody. I think there the genome will end up being an important framework, lifelong framework for the management of a patient's diagnosis, prognostication and then therapy, potentially in that order. I think you need a whole different set of skills, you need a whole different set of technologies, but most importantly you need information that you can interpret in the context of the person in front of you. Until you can make mechanistically important insights with one person, it's going to be very difficult for genomics to really change medical care. That's something I think we should be focusing on. I think we've tended to have an associate of strategy for genetics. We haven't driven it into the clinic. As we drive tests into the clinic, whether it's troponin T or whatever, you begin to understand much better how to use them, although sometimes that can also go in quite extreme directions that you may not necessarily anticipate. I mean, troponin originally was a stratification tool for acute coronary symptoms, and now it's virtually a diagnosis in its own right. I think you'll see that tendency revert over time as people begin to understand the biology of troponin, of isoform switching in peripheral tissues of the way in which troponin may represent very different disease biologies. At the moment, it seems like it's a very simple and straightforward yes/no type of test. There's no such thing in medicine, and I think that's what we're learning about genomics and so instead of conceiving it as a series of 10 to the nine yes/no tests, we're going to end up with a very different vision and view of how it can be implemented to clinical practice. That can only come from having clinicians and geneticists work together on this. In fact, one of the things that we've been doing in the partners environment with some of our colleagues, and I have NIH funding to do this with Heidi [Ream 00:13:31], with Sandy [Aronson 00:13:34] and with Sean Murphy is to think about how we display data, but also how we collect information in light of that genomic data that helps in an iterative way in the learning fashion inform genotype phenotype relationships in a much more probabilistic manner than we have done to date. There are lots of efforts and that's great, that just happens to be one that I'm involved in, but I think it's a generalizable approach that you're going to see moving into the clinic in the next few years. From the standpoint of training, I think what you want to do is get exposure to all types of genetic information so you understand common [alleles 00:14:15], rare alleles, genomics and individual panels and I think the best way of doing that is to have it be part of training programs. In fact, with one of my junior colleagues, Dr. Aaron Aday, we recently wrote a short piece highlighting how important it will be for all of us to come together to think about how do we start to introduce the concepts of genomics into standard clinical training programs, and that's something we're working on fairly avidly at the Brigham and I'm sure there are, I know there are efforts at many other institutions to do similar things. Dr Anwar Chahal: That article is published in Circulation in July of this year if anybody wants to download that. I think if we talked to clinical trainees and asked them what are their concerns about training, as you know training can be very long in cardiology, which is a procedurally based specialty whether or not you become an invasive proceduralist at the end of it, there is that component at the beginning, and do you think a standard, in the US, a standard three-year program with two years of clinical and one year of research can incorporate that at a sound enough level to allow somebody to practice or do you think we're going to look at increasingly a one-year or a six-month sort of add-on fellowship for those interested more on the inherited side or more on the genomic side? I, like yourself, trained in London and the training programs are longer in the UK. It was probably six years when you were there. It shortened to five, and now increasingly it's going to become six and maybe even more with a general fellowship for five years and then a super advanced fellowship and inherited cardiovascular conditions certainly there has become a module that is encouraged for people to take and then become somewhat certified in inherited cardiovascular conditions. What do you think there in terms of incorporating all of that as well as learning basics of eco and device therapy and catheterization? What are your thoughts there? Dr Calum MacRae: Again, I look at this as a spectrum. I think there's a trajectory for all of these types of innovation and knowledge and it starts off being super specialized, it goes into a more general location, and then eventually it's an integral part of everybody's clinical practice. I do think that what you're going to see is rather than, and this is already I think the case in many elements of medicine, medicine has already exceeded the knowledge base even when I was training by probably a long order in terms of the complexity and extent of content, not that I trained that long ago. One of the core elements I think that we're seeing is that we need to move medicine from what I believe has become somewhat de-professionalized, say, to one where you're focusing on, not on the actual core knowledge that you bring with you to the table, but actually the way in which you integrate knowledge. I think the focus of training is going to change somewhat. It has had to change in other fields. Medicine I think for a long time favored that sort of single, comprehensive approach in one mind. Medicine is going to become more of a team sport and it's also going to become more of a knowledge integrator profession than it has been for some time. It's interesting, when medicine started there was so little knowledge that you really had to have almost every physician be an experimentalist using [inaudible 00:18:37] experiments in front of them. I think the way that I see medicine evolving is that as the knowledge base and the rigor of that knowledge base improves, many of the things that we think of as professional activity today will actually devolve to primary care, and to be honest into the community. There are many things where the rigor of the underlying data are such that there's no reason for a provider to be involved, for a licensed provider to be involved. We allow our patients to install their own wireless networks without a technician. I'm sure most of them can look after their own lipids pretty effectively if they were given the right information. A lot of stuff will begin to move in that direction. As that happens, I think the way in which information is displayed, the way in which data are collected and the workflow around integrating information will change. That doesn't get past the point that you brought up, which is that that will probably take a couple decades and in the interim, I think people are going to end up training in modules of sub-specialties, but I think one of the things that I sometimes like to ask myself is, "What's the end game? Where is this going to end up? Can we build systems that train directly for that end game rather than going through these intermediate steps?" I think that's something where I think we tried in the short piece that we wrote in Circulation to argue that everybody should have some exposure and that that exposure can change over time. We should be equipping people not to know genomics but to be able to learn how genomics is impacting their patients for the next 50 years. That model of professional training is actually the one that really was the dominant model until maybe a hundred years ago, and then the reasons for it don't quite seem obvious to me, at least at the moment. We sort of tended to slowly move to more of a learned knowledge base that was then applied. Physicians sort of steadily got to the point where we're now data entry clerks. The actual amount of professional and intellectual engagement has I think slowly diminished in many medical sub-specialties and medical specialties. The opportunity that genomics and other advancements in technology in medicine bring is the chance to I think re-professionalize ourselves to move from just simply defining ourselves in terms of the knowledge base that we each bring to the table, but defining ourselves rather in terms of how we put the knowledge together around individual problems and individual patients, a very much more patient-centered, biological approach than perhaps we've had over the last couple of decades. I think these are, I'm obviously stating a lot of this in somewhat in extremes, but I think these are general trends that you see in medicine. They've happened in other fields as well and people have overcome them. It's usually a function of changing the workflow itself, of changing the way in which the information ends up in the professional's hands and how you collect the data that you use then to interpret the existing knowledge. That I believe we haven't really reworked probably since Osler's time. It is amazing that we still have workflow, I mean it's amazing in lots of ways. It's an amazing tradition. It is quite interesting that we still have workflow that's probably largely dependent on what Osler liked to do when he was growing up, in terms of the times of day that he got up and his workflow. That's sort of instantiated in many ways in everything that we do. Nothing entirely wrong with it, but there's a lot happened since then that we haven't really changed. Medicine is not yet in many instances a 24/7 profession, and yet most other things that have much less in the way of impact in society are already 24/7 professions in many settings. I think you're going to see a lot of demographic changes in medicine come from the advent of technology in other industries. I think those will all transform the way that we imagine training in medicine. Along the same sort of timeline as some of the traditional approaches that you described, building out a training module and then having a subgroup of people do six months or a year of extra training. I see that as a short-term solution. I think ultimately longer term solutions are changing the whole workflow of medicine. Dr Anwar Chahal: What have you done in your own program at the Brigham to introduce genomic medicine training for fellows? Dr Calum MacRae: We are building out, obviously we have a fairly large cardiovascular genetics clinic, I think probably the largest in the world. We have now seven, soon to be eight providers working only and wholly in cardiovascular genetics. We therefore have the ability to have our fellows rotate through our genetics clinic. We have in-patient and out-patient genetic services and we also obviously involve our fellows in a lot of the academic pursuits going on in both our genetics and genomics programs in the cardiovascular clinics, as we do our colleagues who are no longer in training. We have regular, in our clinical conference slot we have several times a year, we have a genetics component, and then what we have also is an integrated training program with clinicians and pathologists that is really bringing the individuals who are understanding the technical aspects of the genetic testing with the individual sort of learning and understanding the clinical aspects of that testing. We imagine over time that this will evolve into potentially the type of specialist module that you described but also into a fixture that goes all the way through our two-year clinical training program. We've sort of taken the point of view that we probably need to do a bit of both. We need to, given what I said in the last few minutes, that we need to take a thread that recognizes a short-term and intermediate term need for specialization but also recognizes that we have to equip every one of our trainees and every one of our physicians with the ability to begin to learn the underlying science of genomics and the underlying approaches to using genomics in every aspect of clinical cardiology. We're doing both of those things and have active efforts in both. Dr Anwar Chahal: You mentioned integration with pathologists but for our colleagues who are not clinicians, what about the research angle and the scientists when they're in training, is that integrated so that we are getting this meeting of minds that is essential? Dr Calum MacRae: Absolutely, in fact we, thanks to a variety of efforts at Brigham Women's we have now at least three separate venues in which this occurs. I mentioned cardiovascular genetic clinic. We also have a genomic medicine clinic, which I'm one of the clinical codirectors for, where we actually have cases of [inaudible 00:26:45] through routine clinical care that seems as if they would benefit from whole genome or whole exome sequencing, and then we have a weekly conference that's actually led by Dick [Mass 00:26:58] and Shamil [Sonaya 00:27:01], two of our genetics colleagues and takes in specialists from all throughout medicine as well as scientists from the entire Harvard Medical School environment, and so we bring everybody together around mechanistically solving individual clinical cases. The third venue is one that's part of a national network, the undiagnosed diseases network. We're one of the sites on the national, the NIH-funded UDN network. There again one of the themes is identifying individuals or families who would benefit from both rigorous genomic analyses as well as much deeper phenotyping. That's been a program that I think has been very exciting and one that we again have learned a huge amount from in terms of how do you begin to build the infrastructure that brings not just the first clinician to see the patient, but somebody who, a whole team of people who understand and can evaluate all the biological aspects that are relevant in that patient. Then also brings to bear the scientific expertise that you might need in order to make a mechanistic connection between genotype and phenotype in that one individual, and some of that involves animal modeling. In cancer for example there's a concept that has emerged over the last two to three years of what's called co-clinical modeling that once you've identified some of the genomic features it allows you to begin to model in an animal in parallel with the trajectory of a patient- Dr Anwar Chahal: [inaudible 00:28:40] as some people call them. Dr Calum MacRae: Exactly. Creating an avatar. In many instances that's an avatar that includes multiple different disease models. We've begun to do that in the cardiovascular space. I think obviously it's early days yet, but I think there are lessons to be learned about how you build the types of infrastructure that allow people to move beyond this state where a patient's outcome is dependent on him seeing the right doctor on the right day at the right time. There are actually systems that funnel the patients into the right venue based on objective criteria at every stage. I think that's the type of re-organization, re-imagination of the medical system that we need. We sort of duplicate things in lots of different areas and you're still dependent on hitting the right specialist at the right day at the right time, or not seeing a specialist, seeing a generalist on the right day at the right time, who's able to put everything together, or even hitting somebody who has the time to listen to your story in a way that helps you identify the exposure or the genetic basis of your condition. If we recreate the professional environment that I talked about earlier, I think, in ways that are both traditional and novel at the same time, I think we'll do ourselves a great service and build a platform that lets all of the technologies, including genomics that we've talked about today, begin to impact patients in a real way on a regular basis. Dr Anwar Chahal: Thank you for that Dr. Calum MacRae for giving up your precious time and sharing your thoughts and insights and experience. Dr Calum MacRae: Thank you for your time and I've enjoyed talking to you. Dr Anwar Chahal: Thank you Dr. MacRae.
Startup Grind Columbus hosts monthly startup events to teach, inspire, and connect entrepreneurs, and meet new hires and investors in Columbus or our 200 other startup communities around the world. In this episode we feature Jeff Harper, CEO and Co-Founder of Duet Health. Duet Health has created a next generation software platform delivering a powerful suite of tools for Patients, Members, & Health Consumers. Duet empowers health providers, plans, and educators with education, communication, and engagement for enterprise delivery to patient populations. The Platform has a robust Patient Intelligence Center that monitors every click, transaction, and data entry for a more meaningful relationship and learning about educational effectiveness. Duet tools are technology agnostic, and while they are recognized experts in mobile communication, the Duet team is experienced in every phase of the solution process. Duet has solutions on all the smartphone platforms (iPhone, iPad, Android phones and Tablets, and Windows Mobile phones and tablets) as well as through traditional web browsers, kiosks, and television applications. Duet has doubled in size every year and was awarded Computer World's 21st Century Award in 2012. Duet clients and strategic partners include: the CDC, the FDA, Wolters Kluwer, the Harvard Medical School, Boston Children’s Hospital, Cardinal Health, Brigham & Women's Hospital, OhioHealth, Nationwide Children’s Hospital, The Ohio State University, and the list just keeps growing. This is the audio recording from the live event on 5/9/2017. www.duethealth.com www.startupgrind.com/columbus www.awh.net www.rev1ventures.com
Dr. Eben Alexander spent over 25 years as an academic neurosurgeon, including 15 years at the Brigham & Women's Hospital, the Children’s Hospital and Harvard Medical School in Boston. Over those years he has personally dealt with hundreds of patients suffering from severe alterations in their level of consciousness. Many of those patients were rendered comatose by trauma, brain tumors, ruptured aneurysms, infections, or stroke. In his academic career he has authored or co- authored over 150 chapters and papers in peer reviewed journals, and made over 200 presentations at conferences and medical centers around the world. He thought he had a very good idea of how the brain generates consciousness, mind and spirit. In the predawn hours of November 10, 2008, he was driven into coma by a rare and mysterious bacterial meningitis-encephalitis of unknown cause. He spent a week in coma on a ventilator, his prospects for survival diminishing rapidly. On the seventh day, to the surprise of everyone, he started to awaken. Memories of his life had been completely deleted inside of the coma, yet he awoke with memories of a fantastic odyssey deep into another realm – more real than this earthly one! His older son advised him to write down everything he could remember about his journey, before he read anything about near-death experiences, physics or cosmology. Six weeks later, he completed his initial recording of his remarkable journey, totaling over 20,000 words in length. Then he started reading, and was astonished by the insights his journey brought to the world’s literature on near-death experiences, and to all phenomena of extended consciousness. His experience clearly revealed that we are conscious in spite of our brain – that, in fact, consciousness is at the root of all existence. His story offers a crucial key to the understanding of reality and human consciousness. It will have a major effect on how we view spirituality, soul and the non-material realm. In analyzing his experience, including the scientific possibilities and grand implications, he envisions a more complete reconciliation of modern science and spirituality as a natural product. He has been blessed with a complete recovery and shares his most powerful, life-changing story in his book, Proof of Heaven: A Neurosurgeon’s Journey into the Afterlife, which debuted at #1 on the New York Times Bestseller list and has remained in the top ten for over a year. His second book, Map of Heaven: How Science, Religion and Ordinary People are Proving the Afterlife, explores humankind's spiritual history and the progression of modern science from its birth in the seventeenth century, showing how we forgot, and are now at last remembering, who we really are and what our destiny truly is. Dr. Alexander has dedicated himself to sharing this information, promoting further research on the unifying elements of science and spirituality, and encouraging people to be inspired by the power of unconditional love in their daily lives and in their work in their communities. For more information: www.ebenalexander.com ____________________________________________ About Path 11 Productions: You can find DVDs of our films on our website at thepathseries.com or by streaming on vimeo.com, gaia.com & itunes find us on facebook and follow us on twitter, @thepathseries
Host: Shira Johnson, MD Guest: Meryl S. LeBoff, MD Osteoporosis is a major public health threat for an estimated 54 million Americans 50 years of age and older. In the U.S. today, 10.2 million individuals are estimated to already have the disease and 43.4 million more are estimated to have low bone mass, placing them at increased risk for osteoporosis and fractures. Because bone density tends to decline with age, the problem of osteoporosis has reached epidemic proportions with the rapidly aging population. It is estimated that by 2020 over 61 million Americans will have osteoporosis or low bone mass. Join host Dr. Shira Johnson welcomes Dr. Meryl LeBoff, Endocrinologist; Chief of the Calcium and Bone Section at Brigham Women's Hospital in Boston, Massachusetts; and, trustee of the National Osteoporosis Foundation. About NOF & Fracture Liaison Service (FLS) NOF has adopted the 20/20 Vision of the National Bone Health Alliance (NBHA), of which NOF is a founding member. The goal is to reduce bone breaks by 20% by the year 2020. Approximately 2 million fractures are caused by osteoporosis each year. Compliance around osteoporosis and post-fracture quality measures is not consistent despite the existence of several NCQA and CMS healthcare provider quality measures. The solution to resolving the 75 ...
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