Podcasts about mass general

Webinar from the National Celiac Assocaition: Gut-Brain Health and Celiac Disease: Caring for Your Second “Brain"Jun 6, 2025 01:00 PM in Eastern TimeJoin the National Celiac Association for their Spring 2025 webinar in the “From the Experts” series. Speakers will present on selected topics for 60 minutes, followed by 15 minutes for Q&A, on Friday, June 6, 2025 from 1-2:15 pm ET.Dr Alessio Fasano, MD, Director of the Mucosal Immunology and Biology Research Center at Mass General for Children; Professor of Pediatrics at Harvard Medical School; and Professor of Nutrition at T.H. Chan School of Public Health, will speak about the “crosstalk” between the gut microbiome and the brain, focusing on developmental disorders and mental health issues in the context of gluten-related disorders. Deanna Kelly, PharmD, BCPP, the Dr. William and Carol Carpenter Professor in Psychiatry for Mental Illness at the University of Maryland School of Medicine and Director and Chief of the Treatment Research Program at the Maryland Psychiatric Research Center, will share her research on schizophrenia, anxiety, and depression, which are often diagnosed as part of the impressive range of celiac disease symptoms.Register here: https://partners.zoom.us/webinar/register/WN_NtbsSjn7TqCVOEUxY2t_cQ?mc_cid=6f22c46ae9#/registrationI would love to hear from you! Leave your messages for Andrea at contact@baltimoreglutenfree.com and check out www.baltimoreglutenfree.comInstagramFacebookGluten Free College 101Website: www.glutenfreecollege.comFacebook: http://www.Facebook.com/Glutenfreecollege Hosted on Acast. See acast.com/privacy for more information.

Kim, who is a nurse at Mass General, called in to suggest that fasting at night (not eating after 6pm) could be an option for Kendra...

Listen to ASCO's JCO Oncology Practice, Art of Oncology Practice article, "An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last” by Dr. David Johnson, who is a clinical oncologist at University of Texas Southwestern Medical School. The article is followed by an interview with Johnson and host Dr. Mikkael Sekeres. Through humor and irony, Johnson critiques how overspecialization and poor presentation practices have eroded what was once internal medicine's premier educational forum. Transcript Narrator: An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last, by David H. Johnson, MD, MACP, FASCO   Over the past five decades, I have attended hundreds of medical conferences—some insightful and illuminating, others tedious and forgettable. Among these countless gatherings, Medical Grand Rounds (MGRs) has always held a special place. Originally conceived as a forum for discussing complex clinical cases, emerging research, and best practices in patient care, MGRs served as a unifying platform for clinicians across all specialties, along with medical students, residents, and other health care professionals. Expert speakers—whether esteemed faculty or distinguished guests—would discuss challenging cases, using them as a springboard to explore the latest advances in diagnosis and treatment. During my early years as a medical student, resident, and junior faculty member, Grand Rounds consistently attracted large, engaged audiences. However, as medicine became increasingly subspecialized, attendance began to wane. Lectures grew more technically intricate, often straying from broad clinical relevance. The patient-centered discussions that once brought together diverse medical professionals gradually gave way to hyperspecialized presentations. Subspecialists, once eager to share their insights with the wider medical community, increasingly withdrew to their own specialty-specific conferences, further fragmenting the exchange of knowledge across disciplines. As a former Chair of Internal Medicine and a veteran of numerous MGRs, I observed firsthand how these sessions shifted from dynamic educational exchanges to highly specialized, often impenetrable discussions. One of the most striking trends in recent years has been the decline in presentation quality at MGR—even among local and visiting world-renowned experts. While these speakers are often brilliant clinicians and investigators, they can also be remarkably poor lecturers, delivering some of the most uninspiring talks I have encountered. Their presentations are so consistently lackluster that one might suspect an underlying strategy at play—an unspoken method to ensure that they are never invited back. Having observed this pattern repeatedly, I am convinced that these speakers must be adhering to a set of unwritten rules to avoid future MGR presentations. To assist those unfamiliar with this apparent strategy, I have distilled the key principles that, when followed correctly, all but guarantee that a presenter will not be asked to give another MGR lecture—thus sparing them the burden of preparing one in the future. Drawing on my experience as an oncologist, I illustrate these principles using an oncology-based example although I suspect similar rules apply across other subspecialties. It will be up to my colleagues in cardiology, endocrinology, rheumatology, and beyond to identify and document their own versions—tasks for which I claim no expertise. What follows are the seven “Rules for Presenting a Bad Medical Oncology Medical Grand Rounds.” 1.  Microscopic Mayhem: Always begin with an excruciatingly detailed breakdown of the tumor's histology and molecular markers, emphasizing how these have evolved over the years (eg, PAP v prostate-specific antigen)—except, of course, when they have not (eg, estrogen receptor, progesterone receptor, etc). These nuances, while of limited relevance to general internists or most subspecialists (aside from oncologists), are guaranteed to induce eye-glazing boredom and quiet despair among your audience. 2. TNM Torture: Next, cover every nuance of the newest staging system … this is always a real crowd pleaser. For illustrative purposes, show a TNM chart in the smallest possible font. It is particularly helpful if you provide a lengthy review of previous versions of the staging system and painstakingly cover each and every change in the system. Importantly, this activity will allow you to disavow the relevance of all previous literature studies to which you will subsequently refer during the course of your presentation … to wit—“these data are based on the OLD staging system and therefore may not pertain …” This phrase is pure gold—use it often if you can. NB: You will know you have “captured” your audience if you observe audience members “shifting in their seats” … it occurs almost every time … but if you have failed to “move” the audience … by all means, continue reading … there is more! 3. Mechanism of Action Meltdown: Discuss in detail every drug ever used to treat the cancer under discussion; this works best if you also give a detailed description of each drug's mechanism of action (MOA). General internists and subspecialists just LOVE hearing a detailed discussion of the drug's MOA … especially if it is not at all relevant to the objectives of your talk. At this point, if you observe a wave of slack-jawed faces slowly slumping toward their desktops, you will know you are on your way to successfully crushing your audience's collective spirit. Keep going—you are almost there. 4. Dosage Deadlock: One must discuss “dose response” … there is absolutely nothing like a dose response presentation to a group of internists to induce cries of anguish. A wonderful example of how one might weave this into a lecture to generalists or a mixed audience of subspecialists is to discuss details that ONLY an oncologist would care about—such as the need to dose escalate imatinib in GIST patients with exon 9 mutations as compared with those with exon 11 mutations. This is a definite winner! 5. Criteria Catatonia: Do not forget to discuss the newest computed tomography or positron emission tomography criteria for determining response … especially if you plan to discuss an obscure malignancy that even oncologists rarely encounter (eg, esthesioneuroblastoma). Should you plan to discuss a common disease you can ensure ennui only if you will spend extra time discussing RECIST criteria. Now if you do this well, some audience members may begin fashioning their breakfast burritos into projectiles—each one aimed squarely at YOU. Be brave … soldier on! 6. Kaplan-Meier Killer: Make sure to discuss the arcane details of multiple negative phase II and III trials pertaining to the cancer under discussion. It is best to show several inconsequential and hard-to-read Kaplan-Meier plots. To make sure that you do a bad job, divide this portion of your presentation into two sections … one focused on adjuvant treatment; the second part should consist of a long boring soliloquy on the management of metastatic disease. Provide detailed information of little interest even to the most ardent fan of the disease you are discussing. This alone will almost certainly ensure that you will never, ever be asked to give Medicine Grand Rounds again. 7. Lymph Node Lobotomy: For the coup de grâce, be sure to include an exhaustive discussion of the latest surgical techniques, down to the precise number of lymph nodes required for an “adequate dissection.” To be fair, such details can be invaluable in specialized settings like a tumor board, where they send subspecialists into rapturous delight. But in the context of MGR—where the audience spans multiple disciplines—it will almost certainly induce a stultifying torpor. If dullness were an art, this would be its masterpiece—capable of lulling even the most caffeinated minds into a stupor. If you have carefully followed the above set of rules, at this point, some members of the audience should be banging their heads against the nearest hard surface. If you then hear a loud THUD … and you're still standing … you will know you have succeeded in giving the world's worst Medical Grand Rounds!   Final Thoughts I hope that these rules shed light on what makes for a truly dreadful oncology MGR presentation—which, by inverse reasoning, might just serve as a blueprint for an excellent one. At its best, an outstanding lecture defies expectations. One of the most memorable MGRs I have attended, for instance, was on prostaglandin function—not a subject typically associated with edge-of-your-seat suspense. Given by a biochemist and physician from another subspecialty, it could have easily devolved into a labyrinth of enzymatic pathways and chemical structures. Instead, the speaker took a different approach: rather than focusing on biochemical minutiae, he illustrated how prostaglandins influence nearly every major physiologic system—modulating inflammation, regulating cardiovascular function, protecting the gut, aiding reproduction, supporting renal function, and even influencing the nervous system—without a single slide depicting the prostaglandin structure. The result? A room full of clinicians—not biochemists—walked away with a far richer understanding of how prostaglandins affect their daily practice. What is even more remarkable is that the talk's clarity did not just inform—it sparked new collaborations that shaped years of NIH-funded research. Now that was an MGR masterpiece. At its core, effective scientific communication boils down to three deceptively simple principles: understanding your audience, focusing on relevance, and making complex information accessible.2 The best MGRs do not drown the audience in details, but rather illuminate why those details matter. A great lecture is not about showing how much you know, but about ensuring your audience leaves knowing something they didn't before. For those who prefer the structured wisdom of a written guide over the ramblings of a curmudgeon, an excellent review of these principles—complete with a handy checklist—is available.2 But fair warning: if you follow these principles, you may find yourself invited back to present another stellar MGRs. Perish the thought! Dr. Mikkael SekeresHello and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the oncology field. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami.  What a pleasure it is today to be joined by Dr. David Johnson, clinical oncologist at the University of Texas Southwestern Medical School. In this episode, we will be discussing his Art of Oncology Practice article, "An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last."  Our guest's disclosures will be linked in the transcript.  David, welcome to our podcast and thanks so much for joining us. Dr. David JohnsonGreat to be here, Mikkael. Thanks for inviting me. Dr. Mikkael SekeresI was wondering if we could start with just- give us a sense about you. Can you tell us about yourself? Where are you from? And walk us through your career. Dr. David JohnsonSure. I grew up in a small rural community in Northwest Georgia about 30 miles south of Chattanooga, Tennessee, in the Appalachian Mountains. I met my wife in kindergarten. Dr. Mikkael SekeresOh my. Dr. David JohnsonThere are laws in Georgia. We didn't get married till the third grade. But we dated in high school and got married after college. And so we've literally been with one another my entire life, our entire lives. Dr. Mikkael SekeresMy word. Dr. David JohnsonI went to medical school in Georgia. I did my training in multiple sites, including my oncology training at Vanderbilt, where I completed my training. I spent the next 30 years there, where I had a wonderful career. Got an opportunity to be a Division Chief and a Deputy Director of, and the founder of, a cancer center there. And in 2010, I was recruited to UT Southwestern as the Chairman of Medicine. Not a position I had particularly aspired to, but I was interested in taking on that challenge, and it proved to be quite a challenge for me. I had to relearn internal medicine, and really all the subspecialties of medicine really became quite challenging to me. So my career has spanned sort of the entire spectrum, I suppose, as a clinical investigator, as an administrator, and now as a near end-of-my-career guy who writes ridiculous articles about grand rounds. Dr. Mikkael SekeresNot ridiculous at all. It was terrific. What was that like, having to retool? And this is a theme you cover a little bit in your essay, also, from something that's super specialized. I mean, you have had this storied career with the focus on lung cancer, and then having to expand not only to all of hematology oncology, but all of medicine. Dr. David JohnsonIt was a challenge, but it was also incredibly fun. My first few days in the chair's office, I met with a number of individuals, but perhaps the most important individuals I met with were the incoming chief residents who were, and are, brilliant men and women. And we made a pact. I promised to teach them as much as I could about oncology if they would teach me as much as they could about internal medicine. And so I spent that first year literally trying to relearn medicine. And I had great teachers. Several of those chiefs are now on the faculty here or elsewhere. And that continued on for the next several years. Every group of chief residents imparted their wisdom to me, and I gave them what little bit I could provide back to them in the oncology world. It was a lot of fun. And I have to say, I don't necessarily recommend everybody go into administration. It's not necessarily the most fun thing in the world to do. But the opportunity to deal one-on-one closely with really brilliant men and women like the chief residents was probably the highlight of my time as Chair of Medicine. Dr. Mikkael SekeresThat sounds incredible. I can imagine, just reflecting over the two decades that I've been in hematology oncology and thinking about the changes in how we diagnose and care for people over that time period, I can only imagine what the changes had been in internal medicine since I was last immersed in that, which would be my residency. Dr. David JohnsonWell, I trained in the 70s in internal medicine, and what transpired in the 70s was kind of ‘monkey see, monkey do'. We didn't really have a lot of understanding of pathophysiology except at the most basic level. Things have changed enormously, as you well know, certainly in the field of oncology and hematology, but in all the other fields as well. And so I came in with what I thought was a pretty good foundation of knowledge, and I realized it was completely worthless, what I had learned as an intern and resident. And when I say I had to relearn medicine, I mean, I had to relearn medicine. It was like being an intern. Actually, it was like being a medical student all over again. Dr. Mikkael SekeresOh, wow. Dr. David JohnsonSo it's quite challenging.  Dr. Mikkael SekeresWell, and it's just so interesting. You're so deliberate in your writing and thinking through something like grand rounds. It's not a surprise, David, that you were also deliberate in how you were going to approach relearning medicine. So I wonder if we could pivot to talking about grand rounds, because part of being a Chair of Medicine, of course, is having Department of Medicine grand rounds. And whether those are in a cancer center or a department of medicine, it's an honor to be invited to give a grand rounds talk. How do you think grand rounds have changed over the past few decades? Can you give an example of what grand rounds looked like in the 1990s compared to what they look like now? Dr. David JohnsonWell, I should all go back to the 70s and and talk about grand rounds in the 70s. And I referenced an article in my essay written by Dr. Ingelfinger, who many people remember Dr. Ingelfinger as the Ingelfinger Rule, which the New England Journal used to apply. You couldn't publish in the New England Journal if you had published or publicly presented your data prior to its presentation in the New England Journal. Anyway, Dr. Ingelfinger wrote an article which, as I say, I referenced in my essay, about the graying of grand rounds, when he talked about what grand rounds used to be like. It was a very almost sacred event where patients were presented, and then experts in the field would discuss the case and impart to the audience their wisdom and knowledge garnered over years of caring for patients with that particular problem, might- a disease like AML, or lung cancer, or adrenal insufficiency, and talk about it not just from a pathophysiologic standpoint, but from a clinician standpoint. How do these patients present? What do you do? How do you go about diagnosing and what can you do to take care of those kinds of patients? It was very patient-centric. And often times the patient, him or herself, was presented at the grand rounds. And then experts sitting in the front row would often query the speaker and put him or her under a lot of stress to answer very specific questions about the case or about the disease itself.  Over time, that evolved, and some would say devolved, but evolved into more specialized and nuanced presentations, generally without a patient present, or maybe even not even referred to, but very specifically about the molecular biology of disease, which is marvelous and wonderful to talk about, but not necessarily in a grand round setting where you've got cardiologists sitting next to endocrinologists, seated next to nephrologists, seated next to primary care physicians and, you know, an MS1 and an MS2 and et cetera. So it was very evident to me that what I had witnessed in my early years in medicine had really become more and more subspecialized. As a result, grand rounds, which used to be packed and standing room only, became echo chambers. It was like a C-SPAN presentation, you know, where local representative got up and gave a talk and the chambers were completely empty. And so we had to go to do things like force people to attend grand rounds like a Soviet Union-style rally or something, you know. You have to pay them to go. But it was really that observation that got me to thinking about it.  And by the way, I love oncology and I'm, I think there's so much exciting progress that's being made that I want the presentations to be exciting to everybody, not just to the oncologist or the hematologist, for example. And what I was witnessing was kind of a formula that, almost like a pancake formula, that everybody followed the same rules. You know, “This disease is the third most common cancer and it presents in this way and that way.” And it was very, very formulaic. It wasn't energizing and exciting as it had been when we were discussing individual patients. So, you know, it just is what it is. I mean, progress is progress and you can't stop it. And I'm not trying to make America great again, you know, by going back to the 70s, but I do think sometimes we overthink what medical grand rounds ought to be as compared to a presentation at ASH or ASCO where you're talking to subspecialists who understand the nuances and you don't have to explain the abbreviations, you know, that type of thing. Dr. Mikkael SekeresSo I wonder, you talk about the echo chamber of the grand rounds nowadays, right? It's not as well attended. It used to be a packed event, and it used to be almost a who's who of, of who's in the department. You'd see some very famous people who would attend every grand rounds and some up-and-comers, and it was a chance for the chief residents to shine as well. How do you think COVID and the use of Zoom has changed the personality and energy of grand rounds? Is it better because, frankly, more people attend—they just attend virtually. Last time I attended, I mean, I attend our Department of Medicine grand rounds weekly, and I'll often see 150, 200 people on the Zoom. Or is it worse because the interaction's limited? Dr. David JohnsonYeah, I don't want to be one of those old curmudgeons that says, you know, the way it used to be is always better. But there's no question that the convenience of Zoom or similar media, virtual events, is remarkable. I do like being able to sit in my office where I am right now and watch a conference across campus that I don't have to walk 30 minutes to get to. I like that, although I need the exercise. But at the same time, I think one of the most important aspects of coming together is lost with virtual meetings, and that's the casual conversation that takes place. I mentioned in my essay an example of the grand rounds that I attended given by someone in a different specialty who was both a physician and a PhD in biochemistry, and he was talking about prostaglandin metabolism. And talk about a yawner of a title; you almost have to prop your eyelids open with toothpicks. But it turned out to be one of the most fascinating, engaging conversations I've ever encountered. And moreover, it completely opened my eyes to an area of research that I had not been exposed to at all. And it became immediately obvious to me that it was relevant to the area of my interest, which was lung cancer. This individual happened to be just studying colon cancer. He's not an oncologist, but he was studying colon cancer. But it was really interesting what he was talking about. And he made it very relevant to every subspecialist and generalist in the audience because he talked about how prostaglandin has made a difference in various aspects of human physiology.  The other grand rounds which always sticks in my mind was presented by a long standing program director at my former institution of Vanderbilt. He's passed away many years ago, but he gave a fascinating grand rounds where he presented the case of a homeless person. I can't remember the title of his grand rounds exactly, but I think it was “Care of the Homeless” or something like that. So again, not something that necessarily had people rushing to the audience. What he did is he presented this case as a mysterious case, you know, “what is it?” And he slowly built up the presentation of this individual who repeatedly came to the emergency department for various and sundry complaints. And to make a long story short, he presented a case that turned out to be lead poisoning. Everybody was on the edge of their seat trying to figure out what it was. And he was challenging members of the audience and senior members of the audience, including the Cair, and saying, “What do you think?” And it turned out that the patient became intoxicated not by eating paint chips or drinking lead infused liquids. He was burning car batteries to stay alive and inhaling lead fumes, which itself was fascinating, you know, so it was a fabulous grand rounds. And I mean, everybody learned something about the disease that they might otherwise have ignored, you know, if it'd been a title “Lead Poisoning”, I'm not sure a lot of people would have shown up. Dr. Mikkael Sekeres That story, David, reminds me of Tracy Kidder, who's a master of the nonfiction narrative, will choose a subject and kind of just go into great depth about it, and that subject could be a person. And he wrote a book called Rough Sleepers about Jim O'Connell - and Jim O'Connell was one of my attendings when I did my residency at Mass General - and about his life and what he learned about the homeless. And it's this same kind of engaging, “Wow, I never thought about that.” And it takes you in a different direction.  And you know, in your essay, you make a really interesting comment. You reflect that subspecialists, once eager to share their insight with the wider medical community, increasingly withdraw to their own specialty specific conferences, further fragmenting the exchange of knowledge across disciplines. How do you think this affects their ability to gain new insights into their research when they hear from a broader audience and get questions that they usually don't face, as opposed to being sucked into the groupthink of other subspecialists who are similarly isolated? Dr. David Johnson That's one of the reasons I chose to illustrate that prostaglandin presentation, because again, that was not something that I specifically knew much about. And as I said, I went to the grand rounds more out of a sense of obligation than a sense of engagement. Moreover, our Chair at that institution forced us to go, so I was there, not by choice, but I'm so glad I was, because like you say, I got insight into an area that I had not really thought about and that cross pollination and fertilization is really a critical aspect. I think that you can gain at a broad conference like Medical Grand Rounds as opposed to a niche conference where you're talking about APL. You know, everybody's an APL expert, but they never thought about diabetes and how that might impact on their research. So it's not like there's an ‘aha' moment at every Grand Rounds, but I do think that those kinds of broad based audiences can sometimes bring a different perspective that even the speaker, him or herself had not thought of. Dr. Mikkael SekeresI think that's a great place to end and to thank David Johnson, who's a clinical oncologist at the University of Texas Southwestern Medical School and just penned the essay in JCO Art of Oncology Practice entitled "An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last."  Until next time, thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all of ASCO's shows at asco.org/podcasts.  David, once again, I want to thank you for joining me today. Dr. David JohnsonThank you very much for having me. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Show notes: Like, share and subscribe so you never miss an episode and leave a rating or review.  Guest Bio: Dr David Johnson is a clinical oncologist at the University of Texas Southwestern Medical School.

Frontline Connections: Strengthening Our ResilienceIn honor of May's National Nurses Week, EMS Week, Hospital Week, and more, Transmission Interrupted celebrates the frontline professionals who stand at the crossroads of care, safety, and preparedness.In this special episode, host Jill Morgan is joined by a panel of experts from across the country: Tristan Twohig, an emergency department nurse from Spokane, Washington; Caroline Persson, who co-leads the NETEC IPC and BCU leadership workgroups and joins from Denver Health; and Stefanie Lane, co-leader of the NETEC Regional Coordination workgroup from Mass General in Boston.Together, they unpack the real-world challenges facing frontline healthcare providers—the moments when communication breaks down between EMS and hospital teams, the risks of missed or unclear handoffs, and the persistent gaps in infection prevention. The panel shares stories from the field, discusses the importance of the “identify, isolate, inform” model, and explores strategies for strengthening resilience and teamwork across emergency settings.Whether you're a healthcare worker, a leader, or simply curious about how our health systems come together in high-risk scenarios, this episode amplifies the voices of those who make healthcare resilient from the ground up.Questions or comments for NETEC? Contact us at info@netec.org.Visit Transmission Interrupted on the web at netec.org/podcast.GuestsStefanie Lane, MS, MPH, NREMT Biothreats Program Manager, Center for Disaster Medicine Massachusetts General HospitalStefanie Lane serves as a Biothreats Program Manager within the MGH Center for Disaster Medicine. In this role, she ensures operational readiness of the special pathogens program, spearheads the development of novel educational modalities (including XR/VR) for high-risk low frequency events, and serves as a SME/liaison between the EMS and healthcare facilities. Stefanie has an extensive background in education and has designed and facilitated a wide variety of training courses. She has eighteen years of experience as an Emergency Medical Technician, where she has served as a training coordinator and board member for ambulance services in Vermont. Stefanie completed her undergraduate degree in Biology at the University of Vermont, and holds Masters degrees in Environmental Science & Policy from Johns Hopkins University and Public Health from Harvard University. Caroline Croyle Persson, MPH, MPA, CIC , PMP, FAPIC Program Director, Denver Health  Caroline Croyle Persson is the Program Director for Disaster Health at Denver Health & Hospital Authority. Her work focuses on healthcare emergency management, coordination and collaboration, and capacity building to enhance healthcare preparedness and response efforts. Ms. Persson also serves as an agency representative (AREP) for NDMS IMT. Prior to her current role, Mrs. Persson worked in infection prevention and control with a focus on influenza, emergency management, high risk pathogens, program and policy management, hand hygiene, and regulatory compliance. She has worked on various public health projects prior to arriving at Denver Health spanning malaria prevention, community health worker sustainment, emergency management, and HIV/AIDs mobile health application acceptance. Mrs. Persson has an MPH from Columbia University with a certificate in Infectious Disease Epidemiology, an MPA from the University of Colorado Denver, and is a Fellow of the Association for Professionals in Infection Control and Epidemiology. Tristan...

In our divided world we face or avoid conflicts on a frequent basis. I turned to Bob Bordone and Joel Salinas to find out the best strategies to deal with these, including having them take on a mock conflict between each other on the merits of Covid research.Audio fileYou can also find this on Spotify and Apple podcasts with Ground Truths.The video is also posted on YouTubeTranscript with Audio LinksEric Topol (00:06):Well, hello. It's Eric Topol with Ground Truths, and we're going to get into a new book called Conflict Resilience: Negotiating Disagreement Without Giving Up or Giving In, and we're lucky to have its two authors, Bob Bordone, who is a Senior Fellow at Harvard Law School, and Joel Salinas, who is a physician, neurologist, a clinician scientist at NYU. So welcome both Bob and Joel.Bob Bordone and Joel Salinas (00:34):Thank you for having us. Yeah, looking forward to the conversation.Eric Topol (00:37):Yeah. So first, how did you guys get together? This is a pretty diverse, you got law and medicine, usually they don't talk to each other very much.Bob Bordone (00:46):Well, we were very fortunate. I mean, we basically were friends, but part of that friendship, I think emerged from work that I do around conflict issues in the Mass General system and then just the larger, bigger Mass General, Harvard community. Yeah, so this began really as a friendship where we were each swimming in very different waters, but then as we would start to talk, we realized there was a lot of connection and maybe the possibility to bring two different disciplines together in a way that might be practically useful and make an impact. And even when we started writing this, which was during Covid, what seemed to be some pretty polarizing times that were unlikely to resolve by the time the book would come out.Eric Topol (01:44):Yeah, well you sure hit it with the divisiveness and the polarized world that we live in is perhaps worse than ever, certainly in all my years, and probably long before then as well. So this topic of resilience, it's a very interesting concept because some people might think of resilience as just being tough. So go into a conflict and just go heavy tough. That obviously is not what you're writing about. And I guess maybe we can start off, what was the goal here? Obviously, there's other books that have addressed this topic, I'm sure, but yours is somewhat unique in many respects because it brings in the science of it and many strategies perhaps that have never been developed. But when you got together, what was the mission that you set out to do?Joel Salinas (02:38):Yeah, well maybe I can start out and then you can add on. So my research has been all around understanding how social relationships influenced brain health, and one of the things that I was seeing was social isolation and loneliness had been steadily increasing. Want to figure out what kind of interventions or what are the factors that are involved here? And I think one of the things that has stood out is just the difficulty with being able to navigate conflict in different contexts. And so, the idea around conflict resilience is really, even though there's been lots of books on what to say and what specific tactics to use, I think that there was this skillset around just being able to sit with the discomfort of that disagreement, which will ultimately help make it much more useful to take on those tactics. One way to think about it, if it's like all these tactics are like learning how to cook with a set of recipes in the kitchen, what we're really proposing here is that you also need to be able to stand the heat of the kitchen to even be able to cook.Eric Topol (03:47):Okay. Go ahead, Bob.Bob Bordone (03:49):Yeah, and I would say I was starting to write about my first kind of piece on this topic where I use the word conflict resilience was in 2018, and it really came from an observed dynamic that I was seeing in my teaching of Harvard Law School students. I was on the admissions committee, I'd been on the admissions committee for many years. I knew that we worked very hard and were quite successful in fact, at bringing together a very diverse student body, including politically. And people sometimes maybe think of elite law schools as being very progressive. But Harvard Law School, the biggest student organization is actually the Federalists, which is the conservative students. And despite that effort, what I noticed in the classroom was a reduction in conversation, diversity of viewpoint across the board, interesting classrooms became boring. And even though I was teaching around conflict and negotiation and difficult conversations, I would read in students' journals things like, I want to avoid conflict or I don't want to get into it.Bob Bordone (04:59):And so, it occurred to me that quite a part, as Joel said, from any skills, if we don't develop this capacity to sit with disagreement, then we will never get to problem solving. I'm in favor of problem solving. But this paper on conflict resilience, its original title was called Against Problem Solving. Mostly because I thought that if we had opened the possibility of problem solving as a precondition for entering the room, then we might never enter the room, particularly if we've told the demonized and dehumanized story about them. And so, that somehow we had to make the case that sitting with the discomfort of the disagreement, even if it didn't mean problem solving, although we hope for that, even if we didn't mean that it was worthwhile and it was important. And so, part of what was really attractive to me about joining up with Joel is that he just brought all of this brain science aspect to it that I had this kind of teaching and kind of academic in the negotiation and dispute resolution research experience, but couldn't bring to bear the kind of brain science parts of, well, what is going on in our brain when we do want to run or when we get into that really unproductive battle.Eric Topol (06:27):Yeah, I agree that the unique part here is that whole scaffolding with the neuroscience, the behavioral science, and those five Fs that you mentioned. You alluded to fight, flight, freeze, fawn, or fester. Yeah, so avoidance of conflict has kind of been the default for many people now because we have political divides, we have anti-science versus pro-science divides and on and on. There's a quote in the book that I thought we'd start off with because it really lays the groundwork from you both. “The biggest hidden barrier to being conflict resilient stems from the inability or unwillingness to face and sit with our own internal conflicts - the negotiations between our divided and sometimes contradictory “selves.” Even more surprising is that although there are dozens of self-help books on negotiation and conflict resolution, almost none of them spend any meaningful time on this critical intrapersonal barrier to handing conflict.” So maybe Joel, maybe start you off here. I guess you were bullied as a kid, and maybe that gives you a little background here. Joel, tell us about that if you would.Bob Bordone (07:46):Hey, Eric. On our bad days sometimes I probably inadvertently bully Joel still today, but he's pretty resilient now.Joel Salinas (07:53):Yeah, I'm a Teflon. So I think I am generally conflict of what an individual, and I think a lot of listeners and viewers can relate with that experience. And I think that also kind of speaks to some of the neuroscience that comes into this, which is that our brain has really evolved to be a fortune telling machine. It takes all of our past experiences, turns them into memories, and then makes projections about what's going to happen. And this projection or prediction of what's going to happen might as well be reality for our brain's sake. And so, if we had really negative experiences with conflict in the past growing up, whether through our families or the schoolyard or others, there'll be likely a very negative charge of negative emotional charge that comes with that. And what that does is that it increases the chances that you'll trigger this system for salience and arousal, which then sets off the alarms essentially in your body that then creates these fight or flight type responses where you're more likely to fall back on these really reflexive behaviors to make the bad thing less bad.Joel Salinas (09:08):And when you do that, whether it's through avoiding or to blowing through conflict like a battering ram that then trains your brain to assign some kind of a reward using the orbital frontal cortex, a system that kind of keeps tabs over how much reward you get for a behavior, it makes it much more likely that you'll do it again. And so, we from a very young age, develop a propensity to either avoid conflict or tackle it. And it varies depending on the context and how you're feeling, but it just makes it much, much harder to be able to bring on a much more thoughtful and deliberative approach to conflict.Eric Topol (09:49):Yeah, I mean, I think one of the salient points is that avoiding the conflict can make things worse. And as you described that it's not, I would've thought that there are some people who are just innately gifted to being diplomatic and artful about having to deal with the conflict issue and others, there's just no hope. But in fact, it can be acquired. And you alluded to this kind of neuroplasticity, the brain and you advocate for chair work. Can you tell us about chair work, because that's something I wouldn't have thought would help in this manner.Bob Bordone (10:30):Sure. I mean, I'll say a little bit work about that. A big part of this chair work idea, frankly, is influenced by work in internal family systems. And I was very fortunate early in my career, even though I was at teaching at law school to start partnering with some folks who did IFS work, they call it peace work often. But the chair work is really identifying some of these conflicted sides of ourself, right? The side of ourself that maybe feels like it's important and okay to raise this issue because it's something that matters to me and maybe the side of ourself that feels like it's pointless and it will hurt the relationship and maybe the side of ourself that's fearful and to name each of them. And then to actually give each in preparation a physical chair where we sit in that chair and give voice to each of those sides.Bob Bordone (11:32):And I'm imagining that at least some people listening to this will say, this sounds very hokey, and does he really mean going to the chairs? And the answer is, yes, I do mean that because there is something about the physicality of it that forces you to give voice to something that is true and real in you. And the chair work is very helpful to set up what an opening might be into a hard conversation, meaning that all of the chairs are real and authentic and okay, they're worthy of getting some voice. So as someone who teaches in a law school, it's all about advocacy. And you would find students who would be very good at advocating on behalf of a client would be incredibly poor at advocating on behalf of themself. And so, separating out the side that maybe has a little bit of feeling, it's selfish, but actually giving it a legitimate voice, help them when they get to the table to be able to say, I'm worried about this, or I realize I may be wrong about this, or it might be upsetting. And also, it's important and deserves to be heard because one of the things around avoidance is we often do avoidance in service of preserving the relationship or not disrupting. And we do maybe preserve the relationship for the time being of the person across the table, except we go home and there's still the side of us that is not feeling good about it, and the person we're not preserving the relationship with is that side, then we just get to have a sleepless night. And so, that's really the kind of idea behind the chair work.Eric Topol (13:22):That's helpful, Bob. I guess managing conflict, of course, I think we know you don't get emotional. Okay, sure. But yeah, there's three parts of that, three components, self-awareness. We've been talking about that deep listening, which of course when you're engaging in a discussion that's potentially leading to escalation of a conflict or the amplification that is really important. And then effective assertion. Now, that's where it seems to me things fall apart. If you're making effective assertion, then everything kind of blows up. So tell us about how you can be assertive and still, you're not trying to win the argument. I get that, but how can you be assertive and still come out in a positive way?Joel Salinas (14:16):Maybe I can start, Bob.Joel Salinas (14:19):I think one of the things that really is a good predictor of how effective you'll be at effective assertion is how good you were at the deep listening part. So the more genuine you are and curious you are about the perspective of the other person, really understanding what are the set of facts, experiences, beliefs that eventually lead up to that headline of what their position is or what their interests are. The better you'll be able articulate your own perspective while still engaging in the conversation. And the other thing that's really important here is that in that listening piece, it's really essential to be able to bring in tenets of really great listening that includes eliminating distractions, both external and internal. It involves having a nonjudgmental position toward the other person and being able to reflect an understanding of what the other person is saying. But all of that does not mean that you are endorsing their point of view. And I think that's really essential. It's really about getting as clear as you can about where the other person is coming from. So that way when you have an opportunity to share your perspective, you're able to really speak to the concerns of the other person and your own.Eric Topol (15:46):Yeah. Well, in reading the book, it took me, interestingly to an evening discussion I had with a very close friend.Eric Topol (15:56):And he was saying, we do need a randomized trial of the measles vaccine, MMR for autism. And I said, what? And I started thinking about, well, I'm going to hear him out because there's so much evidence now that you would think this has been totally debunked. And his view is, well, it can't hurt. And I'm thinking, well, so in that discussion, a lot of these points that you've been raising help me to come not to a point where basically I was trying to put a bow on it, as you said, or trying to externalize or abstract it. But to have a happy ending with him about this saying, okay, well it's never going to get done, but if you want to get it, I'm supportive of that. We don't do enough of this. I had to listen to what he had to say. I had to deal with my own confirmation biases and not get emotional and all that stuff, right. Now, I'd like the two of you to role play on something like that if you would. And let me just give you an example. Maybe you can run with it. Let's go to Covid, okay?Eric Topol (17:14):So one of you will take the side that we shouldn't do any more Covid research because the pandemic is over and we need to be efficient and not use these funds for other things. Covid is over, Long Covid is a hoax, and the other person will take the side that, no, this is a really big deal because Covid has not gone away and there's still a endemic of the virus, Long Covid in millions of people. Who wants to take away the funds? Would that be you, Bob?Bob Bordone (17:52):As a lawyer, I am happy to take any side.Eric Topol (17:55):Okay. You are the one to be on that side. Okay. And Joel, you are going to be the pro science side, if you will. Can you start that argument?Bob Bordone (18:05):Eric, can I make a suggestion? Yeah, but I'm happy to. It might be fun if one of us tries to be a person who hasn't read the book and the other person maybe tries to actually model the skills. What do you think about that?Eric Topol (18:18):Sure. Yeah, that's fine.Joel Salinas (18:19):Bob, I'll take on the unskilled position.Bob Bordone (18:22):Okay, fine.Joel Salinas (18:25):All right. So Bob, you know what? I keep hearing about people wanting to cut Covid funding and just really, I just can't believe it. It just makes me want to throw up because there's such an important need to do this research. It's just critical to understand the long-term effects of it, and Covid even gone yet. So I just can't believe that people would even want to cut this research at all.Bob Bordone (18:50):Well, first of all, it sounds like you're stunned and surprised by this. Am I right about that?Joel Salinas (18:56):Yeah, I'm beyond stunned. I'm revolted by it.Bob Bordone (19:01):So you're pretty angry about it. And I'm curious if I can ask you, you said that the disease is still going on, and of course Covid still exists. I am curious from your perspective, what do you think the benefits of spending lots and lots of money on the diseases at this point, since it's not at that level where it's killing a lot of people?Joel Salinas (19:30):Well, I think that it is killing a lot of people. Still, the disease hasn't gone away and it has a huge impact on health. I think we're still feeling the impacts on that. So I think that being able to understand what the impact does require funding to be able to do the research. And if we don't do that research, then we don't understand what interventions there can be.Bob Bordone (19:51):And what are the impacts? I mean, clearly there's impacts of the pandemic broadly in our society, but what are the kinds of health impacts from your perspective that research would be helpful to from a medical perspective?Joel Salinas (20:05):Well, for sure it impacts cognition. We have people talking about brain fog and Long Covid, and that has a real societal impact on productivity and people's ability to engage in life. It affects people's mood. And then you've got the people who have respiratory symptoms from Covid that have continued to gone on, and that decreases their ability to do their day-to-day things. It's a real societal impact.Bob Bordone (20:28):And how would you think about balancing whatever impact Covid has from all of the other funding choices that need to be made given a shrinking research pool for funds?Joel Salinas (20:44):I don't know. I mean, I think it's an important priority, and I know that there's a lot of other priorities. I think it needs to be weighed against a lot of other big programs that are out there. I just want to make sure that it doesn't go away because it needs to happen.Bob Bordone (20:56):Yeah. No, it's helpful to hear that. And if we had more time, I'd ask you some more questions. I mean, one thing that, as I think about this is given just the number of priorities out there, I worry that because Covid was in the press so much and is so politicized that we overweight the importance of money in that direction. And I would say that there's probably other things if we have a fixed set of money that kills a lot more people and has a lot more health impact. And so, I'd rather see the funds get placed there than just satisfy some kind of highly salient political issue.Joel Salinas (21:40):And I just want to make sure that the funding happens. I mean, it should be to a level that it makes sense to continue the funding so that we get good results from it, that it can be applied. But yeah, I guess you're right that it needs to be weighed against other research priorities. I mean, that's a whole other topic that gets me upset, but I think I just want to make sure that this funding doesn't go away.Bob Bordone (22:03):Yeah. So it sounds like for you, the concern is less about reduction and more about moving it to zero?Joel Salinas (22:12):I think so, yeah.Bob Bordone (22:13):And if it did move to zero, what is the thing you'd be most worried about?Joel Salinas (22:18):I think we would lose out on this really unique opportunity after all these people had been affected by this condition to understand the long-term effects. So that way, if there's another resurgence, we'll understand what can we do about it to mitigate those effects. I mean, we're still trying to figure out what the effects of a lockdown were on people. I think that's something that needs to be better understood.Bob Bordone (22:40):So for you, the research is very forward looking about future pandemics that might come up.Joel Salinas (22:46):Absolutely.Bob Bordone (22:47):And that might be something that I'd be more interested in than how can we prevent future pandemics than I would worrying about. I mean, it's very regrettable what has happened to this set of people who have Long Covid, of course. I just think that that has happened, and I would almost rather see the funds move in the direction of how do we prevent another pandemic than how do we worry about a relatively small set of people, although it's tragic on them, a relatively small set of people who may still suffer those benefits.Joel Salinas (23:26):Yeah, I think we do want to focus on the prevention, definitely. I still just don't want to lose sight of making sure that we're getting the research done that needs to happen.Bob Bordone (23:38):Should we cut?Eric Topol (23:39):That's helpful. These are two experts in conflict resilience here. I mean, the only thing I'd add is that Long Covid is affecting millions of Americans, perhaps as many as 60 million people around the world, and we have no treatment for it. So it's a big deal.Bob Bordone (23:56):I just want to say for the record, I was just being an actor there.Eric Topol (24:03):Yeah, that's okay.Bob Bordone (24:04):I don't even know if my arguments on the other side were making sense, but I was trying.Eric Topol (24:08):I think you did a good job. I think both of you did a good job. I think the point here is that you were able to have a civil discussion, make your points, I forced you into it. You couldn't avoid it. You're in touch, obviously with your own innate issues. You kind of really emphasize that throughout the book, which is you got to be in touch with yourself, not just about your priors, but also your current, what you're feeling, your posture, your heart rate, all these other physical things. So you really got us queued into what's important when you're having a discussion that could lead to, it could exacerbate the conflict rather than help come to a happy mid stance or where both people feel that they've expressed themselves adequately. I really love the Frederick Douglass quote in your book, “if there is no struggle, there is no progress. Those who profess to favor freedom and yet depreciate agitation…want crops without plowing up the ground. They want rain without thunder and lightning. They want the ocean without the awful roar of its many waters.” I think that is so rich. And before we wrap up, I just want to get your overall thoughts. What haven't we touched on in our brief conversation about the topic, about the book that we should before we close today? Maybe start with you, Bob.Bob Bordone (25:53):Yeah, I mean, in some sense, I think it connects to exactly that quote, which is that without conflict, we are not going to get the kind of changes and dynamism we would want in our organizations, whether it's a medical center, a country, a family, but also without the conflict, we don't get the deeper connection that is possible because it's not until the first, no, that all of the yeses actually have the meaning that they should. And so, even though it seems scary to go into conflict, what I would say is it offers opportunities maybe for agreement, but if not for agreement, for a deeper kind of more authentic and real relationship. And I would just say for me, part of this is inviting people to reframe the way they think about what conflict can do in their lives.Joel Salinas (26:58):Yeah. I think if there's one thing that listeners or viewers take from this is awareness is more than half the battle. So just really taking the time to become more aware of how you react to different disagreements with different conflicts, how you're responding to it physically and mentally, and what specific patterns might emerge in terms of whether it's with colleagues, with people with authority, with family members. And I think that alone begins to get you to pay more attention about how you can be more deliberate in your responses. And ideally, you can try out some of the skills from the book with those disagreements that are a little less stressful for you. Just like when you go to the gym, you don't start out by lifting the heaviest weights. You start out by getting the reps down with the good form, and then you build that muscle. And similar with building the brain programming wiring around it is to start low and build up from there.Eric Topol (27:57):Yeah. Well, I think what you have put forth in the book will go down anchoring such an important problem. It's magnified now than more than ever. People are socially isolated, not just in the pandemic, but post pandemic and the divisiveness is profound. So hopefully the tips that you've provided, the science behind it, the practical ways to navigate and deal with this will help people as we go forward. So thank you both for the work you did in putting together the book, and hopefully some of our listeners or viewers will use these tools in the future and will have much better exchanges with others who have different views, different what might be considered adversarial perspective, whatever. So thank you very much for joining today.Joel Salinas (28:58):Well, thank you.Bob Bordone (28:59):Thank you for having us. It's been a delight.********************************As you can imagine, I'm excited to get my new book out on May 6th. It's about extended our healthspan, and I introduce 2 of my patients (one below, Mrs. L.R.) as exemplars to learn from. My op-ed preview of the book was published in The NY Times last week. Here's a gift link. I did a podcast with Mel Robbins on the book here. Here's my publisher ‘s (Simon and Schuster) site for the book. If you're interested in the audio book, I am the reader (first time I have done this, quite an experience!)Here's the back cover to give you an idea of what some people had to say about it.Thanks for reading and subscribing to Ground Truths.If you found this interesting please share it!That makes the work involved in putting these together especially worthwhile.All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don't hesitate to post comments and give me feedback. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. Get full access to Ground Truths at erictopol.substack.com/subscribe

Gluten has become one of the most misunderstood aspects of modern nutrition. Let's set the record straight. In this episode, we untangle the medical, neurological, and cultural narratives surrounding gluten, from celiac disease and non-celiac gluten sensitivity to real (and rare) cases of gluten-induced brain dysfunction. We discuss: • The differences between celiac disease, gluten sensitivity, and wheat allergy • How gluten affects the gut, and what ‘leaky gut' really means • Whether gluten can trigger neurological symptoms like ataxia and brain fog • Why cutting out gluten without a diagnosis may do more harm than good • How wheat contributes to a healthy microbiome (and why fiber matters) • What role zonulin plays in gut permeability and immune activation • Why brain fog isn't yet well understood (and the theories behind it) To help us decode the science (and bust the myths) of gluten, nutrition, and the brain, we're joined by two world-renowned experts: DR. ALESSIO FASANO: pediatric gastroenterologist, research scientist, and chief of Pediatric Gastroenterology and Nutrition at Mass General for Children (MGfC), and director of the Center for Celiac Research. DR. FRANK CUSIMANO: gastroenterologist, physician-scientist, and gut-brain health communicator with a PhD in Nutritional and Metabolic Biology from Columbia University Institute of Human Nutrition. This is... Your Brain On Gluten. ‘Your Brain On' is hosted by neurologists, scientists and public health advocates Ayesha and Dean Sherzai. ‘Your Brain On... Gluten' • SEASON 5 • EPISODE 2 ——— Your Brain On... is supported by the FREE monthly Brain Box, available in our NEURO World community: http://thebraindocs.com/brainbox

There were two flashes of white light at my feet, like quick fireworks, and then everything went black.  My brain knew that my right leg was beyond repair.  -Roseann Sdoia Materia April 15, 2013: That's the day the bombs went off at the Boston Marathon finish line.  This is the story of an innocent bystander who lost her right leg when the second bomb went off in front of the Forum Restaurant. Roseann Sdoia Materia's life would be saved that day by three people who stepped into the smoke and mayhem to save her life:  college student Shores Salter, Boston police officer Shana Cottone, and Boston firefighter Mike Matteria risked their lives to help her, and their story is told in Roseann's memoir:  Perfect Strangers:  Friendship, Strength and Recovery After Boston's Worst Day.  Originally released as part of this series in 2018, the interview brings the listener into the events of that day, when brothers Tamerlan and Dzhokhar Tsarnaev unleashed a terror attack using homemade pressure cooker bombs planted near the Boston Marathon finish line, killing three people and injuring 264.  Days later, the brothers would also kill MIT police officer Sean Collier. Treated by trauma surgeon Daniel King, MD at Mass General, Roseann explains how fortunate she was to have a doctor who had experienced treating soldiers wounded by IEDs during his deployments to Iraq and Afghanistan.  Beyond the details of what happened on that fateful day, Roseann's story is a profile in courage as she struggled to accept the loss of her leg and a new reality as an amputee.  Says Roseann, “Courage is getting up every day and facing the world. Some days you have it and some days, you don't. “  The founder of robostrong.com, she is an in-demand public speaker, an advocate for amputees everywhere, and a supporter of the many charities that have been born out of the bombings.  The friendships Roseann forged with those who rescued her remain strong. In fact, Roseann married firefighter Mike Materia!  For 23 minutes of strength, courage, community, and the resiliency of the human spirit, just hit that download button.  #bostonmarathonbombings #bostonmarathon #bostonstrong #massgeneralhospital#spauldingrehab 

Description: Co-hosts Ryan Piansky, a graduate student and patient advocate living with eosinophilic esophagitis (EoE) and eosinophilic asthma, and Holly Knotowicz, a speech-language pathologist living with EoE who serves on APFED's Health Sciences Advisory Council, interview Dr. John Accarino, an allergist and immunologist at Massachusetts General Hospital and Mass General for Children, on the topic of immunology support for eosinophilic esophagitis (EoE). Dr. Accarino shares his experiences as a person living with food allergies, allergic asthma, peanut allergy, and eosinophilic esophagitis. He tells how his experiences help him in his work with patients. Dr. Accarino shares some education on a variety of allergy mechanisms and the treatments that mitigate them. Disclaimer: The information provided in this podcast is designed to support, not replace the relationship that exists between listeners and their healthcare providers. Opinions, information, and recommendations shared in this podcast are not a substitute for medical advice. Decisions related to medical care should be made with your healthcare provider. Opinions and views of guests and co-hosts are their own.   Key Takeaways: [:49] Co-host Ryan Piansky introduces the episode, brought to you thanks to the support of Education Partners Bristol Myers Squibb, GSK, Sanofi, and Regeneron. Ryan introduces co-host Holly Knotowicz.   [1:14] Holly introduces today's topic, immunology support for eosinophilic esophagitis (EoE), and introduces today's guest, Dr. John Accarino, an allergist and immunologist at Massachusetts General Hospital. Holly welcomes Dr. Accarino to Real Talk.   [1:49] Holly notes that Dr. Accarino is her allergist and immunologist.   [2:03] Dr. Accarino works at Massachusetts General Hospital and Mass General for Children. Allergy and Immunology is a field where he can see pediatrics and adults. Originally trained in pediatrics, now Dr. Accarino sees patients of all ages.   [2:23] Dr. Accarino grew up with allergies. He has experienced food allergies since he was young, along with allergic asthma, and some eczema, which he grew out of. Later in life, he was diagnosed with eosinophilic esophagitis. He talks with his patients about his experiences.   [2:47] Dr. Accarino also does research on drug allergies in the context of certain drug interactions that involve eosinophils.    [3:06] When Holly was referred to Dr. Accarino, it was for multiple sclerosis (MS). He told her, “It looks like you have EoE. I have EoE.” It was a huge relief to Holly not to have to explain EoE to her doctor.   [3:41] Some patients start to explain their EoE to Dr. Accarino, and he assures them he understands where they're coming from. Sometimes, he has to be careful not to think everyone has his symptoms, as there is a large spectrum of presentations.   [4:26] Dr. Accarino wasn't diagnosed with EoE until he was in his allergy fellowship, after he suspected it when he had a food impaction at a steakhouse at a graduation party from his pediatric residency. He tried to manage the EoE with lifestyle changes.   [5:39] Dr. Accarino didn't often go to see a doctor during residency, but he realized it was probably a good time to get an endoscopy.   [5:52] Holly shares how she was also diagnosed as a clinical fellow. She was subbing for someone on the GEDP team at Children's Hospital in Colorado. Listening to all the patients, she realized, “This sounds a little bit like me … What is going on?”   [6:23] Even with his medical background, it took Dr. Accarino some time to decide to get the endoscopy and biopsies. You or your doctor have to have a high level of suspicion to realize this isn't just reflux. Food doesn't get stuck in every person's throat.   [7:01] Thinking back, Dr. Accarino remembers an instance as a child when a dry muffin got stuck in his throat. He stayed calm and waited for it to pass. He thought it was normal.   [7:39] He drank a lot of water and chewed his food a lot. Those are markers of potential esophageal inflammation.   [8:20] Different groups have different management strategies for EoE. Dietary management, topical steroids, biologics. A subgroup of people with EoE are responsive to proton pump inhibitors (PPIs). Finding the best management strategy is a work in progress.   [8:53] With pediatric patients, the parents control the diet, and the children eat what is prepared. He notes that with adult patients, sometimes they let foods slip through.   [9:10] If you want to do a single-food elimination diet with dairy, there's a lot of dairy in the American diet. Dr. Accarino tried eliminating dairy and wheat, but he still had persistent eosinophils with dietary elimination.   [9:24] Dr. Accarino then tried PPIs. To know if you have PPI-responsive EoE, you might do twice-daily omeprazole at a significant dose. Have the endoscopy after a few weeks pass and see if the eosinophils are still present in the biopsy.   [9:59] Dr. Accarino did that recently and still has the eosinophils. He plans to talk to his gastroenterologist about considering dupilumab, but he feels that he can mitigate his subjective day-to-day experience of symptoms with dietary elimination and PPIs.    [10:24] If you still have the presence of eosinophils on biopsy, there's still inflammation happening. In the long term, you still have to worry about fibrosis and narrowing.    [10:34] The last treatment Dr. Accarino tried was as a research participant in a study for dissolvable fluticasone. He received either the medication or a placebo; he doesn't know which.   [11:01] To stay in the study, he had to journal and report his symptoms regularly. He didn't have enough symptoms to stay in the study. They were looking for a baseline to see how it changed with either the placebo or the medication.   [11:20] In research, you have to have a baseline to start, and then you want to see improvement, plus or minus. With EoE, it's difficult. You have the biopsy and eosinophils, but there's a large spectrum of symptoms that people may experience.   [12:40] Holly appreciates Dr. Accarino's unique perspective as a doctor with EoE who has experienced various treatments and diets. He understands the concerns of his patients.   [12:43] Dr. Accarino says even taking a twice-daily PPI or other medication is difficult for a lot of people, and that's the most simple of these therapies.   [13:06] Dr. Accarino wants to validate everyone's experience in terms of how difficult it is to treat this disorder, how it may present in different ways, and how there may be a delay in diagnosis.   [13:16] This isn't IgE-mediated immediate food allergy, where you eat a food and may have swelling within minutes; you may have flushing or hives. That's very clear. With EoE, it's a different mechanism; in many cases, there is a delay.   [14:37] Allergy, in general, is under the purview of clinical immunology. Dr. Accarino is allergic to peanuts and has an  IgE-mediated immediate reaction to them. If he eats a peanut, he has symptoms within minutes. He could have anaphylaxis. As a result, he carries an epinephrine auto-injector.   [15:01] If Dr. Accarino has a skin test, it will be positive for peanut. He has IgE antibodies to peanuts. He also has oral allergy syndrome where the body mistakes certain fruits, vegetables, or nuts with certain tree pollens or grass pollens.   [15:23] Oral allergy syndrome is usually a lower-risk condition where it's a less-stable protein that once cooked might not produce any symptoms. If it's raw when you consume it, you may have oral itching, a bit of throat discomfort, or tongue itching. [15:54] Your stomach acid breaks it down so it doesn't get into your bloodstream and you shouldn't have a systemic reaction.   [16:01] If Dr. Accarino eats a peanut, his stomach acid doesn't break down the high-risk, stable peanut protein, it gets into his bloodstream, and he can have a systemic anaphylactic reaction.   [16:20] Chronic EoE symptoms can present with something like a food impaction, or bad reflux or belly pain, and nausea. The reaction may not be immediate. It may be progressive over days or weeks.   [16:38] FIRE is an interesting condition that takes some time to narrow down. It's an immediate response of the esophagus, but we don't think it's histamine-mediated.   [16:56] We don't know, exactly, the mechanism but it's in people with eosinophilic esophagitis. They feel differently, and there would be different specific food triggers.   [17:11]  It took some time to figure out what was going on. Dr. Accarino felt like he had a lump in his throat, then a lump in his chest, nausea, and belly pain. It felt like a slow progression of EoE symptoms, and it was from specific food triggers, in his case.   [17:30] In some of the FIRE literature, they looked at banana and avocado. For Dr. Accarino, it took a couple of exposures to protein bars and milk protein whey isolate, specific to protein bars he had multiple times, until he figured out that was the trigger.   [17:50] Another protein whey isolate that Dr. Accarino scooped as a powder and made into a shake also led to FIRE.   [17:55] It took that event for Dr. Accarino to figure out it wasn't just a flareup of EoE or reflux but some trigger that caused this response that wasn't anaphylaxis but may be due to the recruitment of eosinophils or some immediate process not well understood.   [18:18] FIRE is going to be very hard to research. How would we figure this out? Would we bring someone in and do an endoscopy immediately and see what happens? There's a lot of descriptive data and case series.   [18:32] Dr. Accarino has had experiences when he knew it wasn't an immediate anaphylactic reaction, oral allergy, or reflux. He asked what else it could be in the context of EoE. When he looked at different case series, that's the presentation he had.   [19:17] Dr. Accarino acknowledges that having personal experience with FIRE, oral allergies, and IgE-mediated allergies, on top of EoE, has influenced his work as a medical professional. He can share anecdotes with patients as he explains the available testing.   [19:39] Dr. Accarino says a lot of immunology and allergy is explaining the diagnostic tools and management strategies we have and what we think is going on.   [19:50] The immune system is infinitely complex, and a lot of the practice is making a digestible analogy, not just in the context of allergic conditions but also everything with the immune system. There are so many cells doing so many different things.   [20:04] Dr. Accarino explains false positives in testing. He has positive scratch tests for peanuts, cashews, and almonds, which shows he has IgE for each of them. He is allergic to peanuts, but he can eat cashews and almonds. Those are false positives.    [20:56] When a scratch test is negative for immediate food allergy, it's a powerful predictive tool. But you may get false positives. How positive is it? There might be room for more discussion.   [21:10] There may be more hesitation for people who do large panels of food testing without any history of reacting to any foods.   [21:31] Some people have EoE triggered by milk or wheat but have negative skin tests. That doesn't mean they aren't triggered by these foods. The skin test is an IgE histamine mast cell mechanism, not for eosinophils, which are other immune cells.   [21:58] We go down these steps of thinking about diagnostic triggers and eventually treatment for those immediate symptoms mentioned for EoE.   [22:09] Dr. Accarino doesn't expect FIRE to be responsive to epinephrine. He doesn't have to stabilize the mast cells. It's a chronic disease that's flaring up. You treat it with a chronic type of treatment.   [24:10] Dr. Accarino says that for a doctor, immunology is rewarding, interesting, and complex, but it's intimidating until you get your foothold and see patients and clinical experiences.   [25:14] A lot of medical students and residents are a little fearful of immunology. They might not think about it too much. Dr. Accarino loves to talk about it and think about it. He can't think of anything more complex in terms of systems within our body.   [25:37] Ryan comments on his experiences with IgE-mediated food allergies, some environmental allergies that he has no idea how they work, and EoE, which he believes he has a good grasp on.   [25:55] Ryan imagines that having a physician with a good understanding of the immune system and also personal experience would be helpful for a patient with multiple allergic conditions.   [26:13] Dr. Accarino sees a large overlap of seasonal or year-round environmental allergies and EoE. There are some studies that show that endoscopies on patients with EoE may change at different times of the year if they have underlying seasonal allergies.   [26:33] Some people who have food allergies also have EoE or other eosinophilic disorders. Some discussions with them may be about blood tests that detect eosinophils in the bloodstream versus biopsies of the esophagus, stomach, or colon.   [27:15] It's thinking about what tests are available, what they tell us, and how to use them to predict the next steps, things like dietary changes or for immediate food allergy, considering challenges versus full avoidance. Each test has its pluses and minuses.   [27:35] People like a clear test, and they like an easy fix, but sometimes there's a lot of nuanced conversation of shared decision-making and trying things in a supervised setting.   [27:57] Holly speaks as a patient of the investigative testing Dr. Acarino is doing with her immune system trying to figure it out along with her MS and EoE.   [28:14] Dr. Accarino says the words immune system, immunity, and inflammation are used a lot in talking about foods. Dr. Accarino uses the framework of the immune system trying to help you.   [28:42] Sometimes, instead of making helpful antibodies to things like vaccines or viruses, that give you protection, the immune system makes antibodies that attack a certain organ or your joints.   [29:02] Dr. Accarino thinks of treatments that suppress the immune system in certain ways. Some treatments cool down the populations of many different immune cells. Oral steroids and prednisone are used for many conditions for autoimmune flares.    [29:29] Oral steroids, in the long term, may lead to weight gain, bone density changes, and diabetes. The big push for many diseases is toward non-steroidal biologics to target specific cells that cause disease.   [29:59] For Crohn's disease, a specific monoclonal antibody is used to target TNF-alpha molecules and blocks that inflammation pathway.   [30:14] For EoE, dupilumab, a specifically designed antibody, blocks a specific receptor in a specific pathway so the immune system doesn't have to be shut down and the patient doesn't have the side effects of steroids. It's a targeted therapy.   [30:32] What you see in commercials for injectable medications are large, designed antibodies that, if you took them in a pill form, your stomach acid would break down and digest. So they are injections and infusions that go directly into the bloodstream.   [31:22] Medications that end in -mab are monoclonal antibodies. They are very large molecules that would not be stable in stomach acid.   [32:09] Dr. Accarino talks of eosinophil normal function and aberrant function. IgE-mediated reactions are usually related to mast cells, a type of immune cell that shouldn't be in the bloodstream.   [32:54] Dr. Accarino can do a CBC with differential to see the number of white blood cells and the number of red blood cells. The differential of white blood cells will include neutrophils, lymphocytes, and eosinophils. It shouldn't show mast cells.   [33:19] If you have mast cells in your bloodstream, that's mastocytosis, a different problem. Mast cells live in your skin, in your gut, and around your blood vessels. They're full of granules like histamine and tryptase.   [33:38] Dr. Accarino explains how mast cells release their contents and how he would treat the resulting swelling or itch with an antihistamine or epinephrine. Epinephrine treats systemic reactions and stabilizes the mast cells.   [34:16] Mast cells have many receptors and may be triggered by many things other than IgE. This is a conversation Dr. Accarino has with patients who have chronic hives unrelated to any foods.   [34:29] Some people get hives from non-steroidal anti-inflammatory drugs NSAIDs. Some get hives from vancomycin. Some get hives when the temperature changes, from tight clothing, or from IV contrast. It's not an IgE-mediated mechanism, but it's still mast cells being degranulated.   [35:45] Dr. Accarino says people see hives and they think allergy. But, like EoE, it doesn't involve histamine. There can be hives that aren't related to allergies. This can be idiopathic urticaria or spontaneous urticaria.   [36:04] Sometimes, when switching from a day shift to a night shift, hormonal changes will trigger hives. Sometimes, the stress of having a family member in the hospital will cause hives. An accumulation of triggers can lead to mast cell degranulation.   [36:38] There are many ways that allergy can have different mechanisms and treatments, with different cells involved. There are different molecules that cause symptoms and manifestations.   [36:50] Navigating that and understanding what might be going on can give people a sense of reassurance. The biggest fear is a life-threatening allergic reaction. People will read about fatal anaphylaxis and wonder if it will happen to them with their condition.   [37:16] Sometimes, thinking of the cells involved and the pathways may give a level of reassurance that this may not be the same thing that they read about.   [37:28] Ryan thanks Dr. Accarino for joining us today.   [37:37] Dr. Accarino says it was nice to reflect on things and to go through different scenarios and experiences he has gone through. It was nice to have the opportunity to share them with Ryan, Holly, and all the listeners.   [37:57] For our listeners who would like to learn more about eosinophilic disorders, including EoE, please visit APFED.org and check out the links in the show notes.   [38:06] If you're looking to find a specialist who treats eosinophilic disorders, we encourage you to use APFED's Specialist Finder at APFED.org/specialist.   [38:15] If you'd like to connect with others impacted by eosinophilic diseases, please join APFED's online community on the Inspire Network at APFED.org/connections.   [38:25] Ryan thanks Dr. Accarino for joining us today for this fun conversation. Holly also thanks APFED's Education Partners Bristol Myers Squibb, GSK, Sanofi, and Regeneron for supporting this episode.   Mentioned in This Episode: Dr. John Accarino, MD, Allergist and Immunologist at Massachusetts General Hospital and Mass General for Children Episode 034: Food-Induced Response and Eosinophilic Esophagitis   APFED on YouTube, Twitter, Facebook, Pinterest, Instagram Real Talk: Eosinophilic Diseases Podcast apfed.org/specialist apfed.org/connections   Education Partners: This episode of APFED's podcast is brought to you thanks to the support of Bristol Myers Squibb, GSK, Sanofi, and Regeneron.   Tweetables:   “Allergy and immunology is a field where I can see pediatrics and adults. I was originally trained in pediatrics, but now I see all ages, from infants up until older adults.” — Dr. John Accarino   “Part of the conversation sometimes is trying not to overly bias myself, where I say, ‘Oh, this is my experience.' … Like many diseases, there's a large spectrum of presentations, … different symptoms that people have.” — Dr. John Accarino   “We don't think [Food-Induced Response in Eosinophilic Esophagitis is] histamine-mediated. We don't know exactly the mechanism, but it's in people with eosinophilic esophagitis. They feel differently, and there would be different specific food triggers. It took some time to figure out that was going on.” — Dr. John Accarino   “When a scratch test is negative for immediate food allergy, it's a very powerful predictive tool. But there are times that you may get false positives. How positive is it? There might be room for more discussion.” — Dr. John Accarino   “There are a lot of ways that allergy can have different mechanisms and different treatments, with different cells involved.” — Dr. John Accarino

Funding for the NIH and US biomedical research is imperiled at a momentous time of progress. Exemplifying this is the work of Dr. Anna Greka, a leading physician-scientist at the Broad Institute who is devoted to unlocking the mysteries of rare diseases— that cumulatively affect 30 million Americans— and finding cures, science supported by the NIH.A clip from our conversationThe audio is available on iTunes and Spotify. The full video is linked here, at the top, and also can be found on YouTube.Transcript with audio and external linksEric Topol (00:06):Well, hello. This is Eric Topol from Ground Truths, and I am really delighted to welcome today, Anna Greka. Anna is the president of the American Society for Clinical Investigation (ASCI) this year, a very prestigious organization, but she's also at Mass General Brigham, a nephrologist, a cell biologist, a physician-scientist, a Core Institute Member of the Broad Institute of MIT and Harvard, and serves as a member of the institute's Executive Leadership Team. So we got a lot to talk about of all these different things you do. You must be pretty darn unique, Anna, because I don't know any cell biologists, nephrologists, physician-scientist like you.Anna Greka (00:48):Oh, thank you. It's a great honor to be here and glad to chat with you, Eric.Eric Topol (00:54):Yeah. Well, I had the real pleasure to hear you speak at a November conference, the AI for Science Forum, which we'll link to your panel. Where I was in a different panel, but you spoke about your extraordinary work and it became clear that we need to get you on Ground Truths, so you can tell your story to everybody. So I thought rather than kind of going back from the past where you were in Greece and somehow migrated to Boston and all that. We're going to get to that, but you gave an amazing TED Talk and it really encapsulated one of the many phenomenal stories of your work as a molecular sleuth. So maybe if you could give us a synopsis, and of course we'll link to that so people could watch the whole talk. But I think that Mucin-1 or MUC1, as you call it, discovery is really important to kind of ground our discussion.A Mysterious Kidney Disease Unraveled Anna Greka (01:59):Oh, absolutely. Yeah, it's an interesting story. In some ways, in my TED Talk, I highlight one of the important families of this story, a family from Utah, but there's also other important families that are also part of the story. And this is also what I spoke about in London when we were together, and this is really sort of a medical mystery that initially started on the Mediterranean island of Cyprus, where it was found that there were many families in which in every generation, several members suffered and ultimately died from what at the time was a mysterious kidney disease. This was more than 30 years ago, and it was clear that there was something genetic going on, but it was impossible to identify the gene. And then even with the advent of Next-Gen sequencing, this is what's so interesting about this story, it was still hard to find the gene, which is a little surprising.Anna Greka (02:51):After we were able to sequence families and identify monogenic mutations pretty readily, this was still very resistant. And then it actually took the firepower of the Broad Institute, and it's actually from a scientific perspective, an interesting story because they had to dust off the old-fashioned Sanger sequencing in order to get this done. But they were ultimately able to identify this mutation in a VNTR region of the MUC1 gene. The Mucin-1 gene, which I call a dark corner of the human genome, it was really, it's highly repetitive, very GC-rich. So it becomes very difficult to sequence through there with Next-Gen sequencing. And so, ultimately the mutation of course was found and it's a single cytosine insertion in a stretch of cytosines that sort of causes this frameshift mutation and an early stop codon that essentially results in a neoprotein like a toxic, what I call a mangled protein that sort of accumulates inside the kidney cells.Anna Greka (03:55):And that's where my sort of adventure began. It was Eric Lander's group, who is the founding director of the Broad who discovered the mutation. And then through a conversation we had here in Boston, we sort of discovered that there was an opportunity to collaborate and so that's how I came to the Broad, and that's the beginnings of this story. I think what's fascinating about this story though, that starts in a remote Mediterranean island and then turns out to be a disease that you can find in every continent all over the world. There are probably millions of patients with kidney disease in whom we haven't recognized the existence of this mutation. What's really interesting about it though is that what we discovered is that the mangled protein that's a result of this misspelling of this mutation is ultimately captured by a family of cargo receptors, they're called the TMED cargo receptors and they end up sort of grabbing these misfolded proteins and holding onto them so tight that it's impossible for the cell to get rid of them.Anna Greka (04:55):And they become this growing heap of molecular trash, if you will, that becomes really hard to manage, and the cells ultimately die. So in the process of doing this molecular sleuthing, as I call it, we actually also identified a small molecule that actually disrupts these cargo receptors. And as I described in my TED Talk, it's a little bit like having these cargo trucks that ultimately need to go into the lysosome, the cells recycling facility. And this is exactly what this small molecule can do. And so, it was just like a remarkable story of discovery. And then I think the most exciting of all is that these cargo receptors turn out to be not only relevant to this one mangled misshapen protein, but they actually handle a completely different misshapen protein caused by a different genetic mutation in the eye, causing retinitis pigmentosa, a form of blindness, familial blindness. We're now studying familial Alzheimer's disease that's also involving these cargo receptors, and there are other mangled misshapen proteins in the liver, in the lung that we're now studying. So this becomes what I call a node, like a nodal mechanism that can be targeted for the benefit of many more patients than we had previously thought possible, which has been I think, the most satisfying part about this story of molecular sleuthing.Eric Topol (06:20):Yeah, and it's pretty extraordinary. We'll put the figure from your classic Cell paper in 2019, where you have a small molecule that targets the cargo receptor called TMED9.Anna Greka (06:34):Correct.Expanding the MissionEric Topol (06:34):And what's amazing about this, of course, is the potential to reverse this toxic protein disease. And as you say, it may have applicability well beyond this MUC1 kidney story, but rather eye disease with retinitis pigmentosa and the familial Alzheimer's and who knows what else. And what's also fascinating about this is how, as you said, there were these limited number of families with the kidney disease and then you found another one, uromodulin. So there's now, as you say, thousands of families, and that gets me to part of your sleuth work is not just hardcore science. You started an entity called the Ladders to Cures (L2C) Scientific Accelerator.Eric Topol (07:27):Maybe you can tell us about that because this is really pulling together all the forces, which includes the patient advocacy groups, and how are we going to move forward like this?Anna Greka (07:39):Absolutely. I think the goal of the Ladders to Cures Accelerator, which is a new initiative that we started at the Broad, but it really encompasses many colleagues across Boston. And now increasingly it's becoming sort of a national, we even have some international collaborations, and it's only two years that it's been in existence, so we're certainly in a growth mode. But the inspiration was really some of this molecular sleuthing work where I basically thought, well, for starters, it cannot be that there's only one molecular node, these TMED cargo receptors that we discovered there's got to be more, right? And so, there's a need to systematically go and find more nodes because obviously as anyone who works in rare genetic diseases will tell you, the problem for all of us is that we do what I call hand to hand combat. We start with the disease with one mutation, and we try to uncover the mechanism and then try to develop therapies, and that's wonderful.Anna Greka (08:33):But of course, it's slow, right? And if we consider the fact that there are 30 million patients in the United States in every state, everywhere in the country who suffer from a rare genetic disease, most of them, more than half of them are children, then we can appreciate the magnitude of the problem. Out of more than 8,000 genes that are involved in rare genetic diseases, we barely have something that looks like a therapy for maybe 500 of them. So there's a huge mismatch in the unmet need and magnitude of the problem. So the Ladders to Cures Accelerator is here to address this and to do this with the most modern tools available. And to your point, Eric, to bring patients along, not just as the recipients of whatever we discover, but also as partners in the research enterprise because it's really important to bring their perspectives and of course their partnerships in things like developing appropriate biomarkers, for example, for what we do down the road.Anna Greka (09:35):But from a fundamental scientific perspective, this is basically a project that aims to identify every opportunity for nodes, underlying all rare genetic diseases as quickly as possible. And this was one of the reasons I was there at the AI for Science Forum, because of course when one undertakes a project in which you're basically, this is what we're trying to do in the Ladders to Cures Accelerator, introduce dozens of thousands of missense and nonsense human mutations that cause genetic diseases, simultaneously introduce them into multiple human cells and then use modern scalable technology tools. Things like CRISPR screens, massively parallel CRISPR screens to try to interrogate all of these diseases in parallel, identify the nodes, and then develop of course therapeutic programs based on the discovery of these nodes. This is a massive data generation project that is much needed and in addition to the fact that it will help hopefully accelerate our approach to all rare diseases, genetic diseases. It is also a highly controlled cell perturbation dataset that will require the most modern tools in AI, not only to extract the data and understand the data of this dataset, but also because this, again, an extremely controlled, well controlled cell perturbation dataset can be used to train models, train AI models, so that in the future, and I hope this doesn't sound too futuristic, but I think that we're all aiming for that cell biologists for sure dream of this moment, I think when we can actually have in silico the opportunity to make predictions about what cell behaviors are going to look like based on a new perturbation that was not in the training set. So an experiment that hasn't yet been done on a cell, a perturbation that has not been made on a human cell, what if like a new drug, for example, or a new kind of perturbation, a new chemical perturbation, how would it affect the behavior of the cell? Can we make a predictive model for that? This doesn't exist today, but I think this is something, the cell prediction model is a big question for biology for the future. And so, I'm very energized by the opportunity to both address this problem of rare monogenic diseases that remains an unmet need and help as many patients as possible while at the same time advancing biology as much as we possibly can. So it's kind of like a win-win lifting all boats type of enterprise, hopefully.Eric Topol (12:11):Yeah. Well, there's many things to get to unpack what you've just been reviewing. So one thing for sure is that of these 8,000 monogenic diseases, they have relevance to the polygenic common diseases, of course. And then also the fact that the patient family advocates, they are great at scouring the world internet, finding more people, bringing together communities for each of these, as you point out aptly, these rare diseases cumulatively are high, very high proportion, 10% of Americans or more. So they're not so rare when you think about the overall.Anna Greka (12:52):Collectively.Help From the Virtual Cell?Eric Topol (12:53):Yeah. Now, and of course is this toxic proteinopathies, there's at least 50 of these and the point that people have been thinking until now that, oh, we found a mangled protein, but what you've zeroed in on is that, hey, you know what, it's not just a mangled protein, it's how it gets stuck in the cell and that it can't get to the lysosome to get rid of it, there's no waste system. And so, this is such fundamental work. Now that gets me to the virtual cell story, kind of what you're getting into. I just had a conversation with Charlotte Bunne and Steve Quake who published a paper in December on the virtual cell, and of course that's many years off, but of course it's a big, bold, ambitious project to be able to say, as you just summarized, if you had cells in silico and you could do perturbations in silico, and of course they were validated by actual experiments or bidirectionally the experiments, the real ones helped to validate the virtual cell, but then you could get a true acceleration of your understanding of cell biology, your field of course.Anna Greka (14:09):Exactly.Eric Topol (14:12):So what you described, is it the same as a virtual cell? Is it kind of a precursor to it? How do you conceive this because this is such a complex, I mean it's a fundamental unit of life, but it's also so much more complex than a protein or an RNA because not only all the things inside the cell, inside all these organelles and nucleus, but then there's all the outside interactions. So this is a bold challenge, right?Anna Greka (14:41):Oh my god, it's absolutely from a biologist perspective, it's the challenge of a generation for sure. We think taking humans to Mars, I mean that's an aspirational sort of big ambitious goal. I think this is the, if you will, the Mars shot for biology, being able to, whether the terminology, whether you call it a virtual cell. I like the idea of saying that to state it as a problem, the way that people who think about it from a mathematics perspective for example, would think about it. I think stating it as the cell prediction problem appeals to me because it actually forces us biologists to think about setting up the way that we would do these cell perturbation data sets, the way we would generate them to set them up to serve predictions. So for example, the way that I would think about this would be can I in the future have so much information about how cell perturbations work that I can train a model so that it can predict when I show it a picture of another cell under different conditions that it hasn't seen before, that it can still tell me, ah, this is a neuron in which you perturbed the mitochondria, for example, and now this is sort of the outcome that you would expect to see.Anna Greka (16:08):And so, to be able to have this ability to have a model that can have the ability to predict in silico what cells would look like after perturbation, I think that's sort of the way that I think about this problem. It is very far away from anything that exists today. But I think that the beginning starts, and this is one of the unique things about my institute, if I can say, we have a place where cell biologists, geneticists, mathematicians, machine learning experts, we all come together in the same place to really think and grapple with these problems. And of course we're very outward facing, interacting with scientists all across the world as well. But there's this sort of idea of bringing people into one institute where we can just think creatively about these big aspirational problems that we want to solve. I think this is one of the unique things about the ecosystem at the Broad Institute, which I'm proud to be a part of, and it is this kind of out of the box thinking that will hopefully get us to generate the kinds of data sets that will serve the needs of building these kinds of models with predictive capabilities down the road.Anna Greka (17:19):But as you astutely said, AlphaFold of course was based on the protein database existing, right? And that was a wealth of available information in which one could train models that would ultimately be predictive, as we have seen this miracle that Demi Hassabis and John Jumper have given to humanity, if you will.Anna Greka (17:42):But as Demis and John would also say, I believe is as I have discussed with them, in fact, the cell prediction problem is really a bigger problem because we do not have a protein data bank to go to right now, but we need to create it to generate these data. And so, my Ladders to Cures Accelerator is here to basically provide some part of the answer to that problem, create this kind of well-controlled database that we need for cell perturbations, while at the same time maximizing our learnings about these fully penetrant coding mutations and what their downstream sequelae would be in many different human cells. And so, in this way, I think we can both advance our knowledge about these monogenic diseases, build models, hopefully with predictive capabilities. And to your point, a lot of what we will learn about this biology, if we think that it involves 8,000 or more out of the 20,000 genes in our genome, it will of course serve our understanding of polygenic diseases ultimately as well as we go deeper into this biology and we look at the combinatorial aspects of what different mutations do to human cells. And so, it's a huge aspirational problem for a whole generation, but it's a good one to work on, I would say.Learning the Language of Life with A.I. Eric Topol (19:01):Oh, absolutely. Now I think you already mentioned something that's quite, well, two things from what you just touched on. One of course, how vital it is to have this inner or transdisciplinary capability because you do need expertise across these vital areas. But the convergence, I mean, I love your term nodal biology and the fact that there's all these diseases like you were talking about, they do converge and nodal is a good term to highlight that, but it's not. Of course, as you mentioned, we have genome editing which allows to look at lots of different genome perturbations, like the single letter change that you found in MUC1 pathogenic critical mutation. There's also the AI world which is blossoming like I've never seen. In fact, I had in Science this week about learning the language of life with AI and how there's been like 15 new foundation models, DNA, proteins, RNA, ligands, all their interactions and the beginning of the cell story too with the human cell.Eric Topol (20:14):So this is exploding. As you said, the expertise in computer science and then this whole idea that you could take these powerful tools and do as you said, which is the need to accelerate, we just can't sit around here when there's so much discovery work to be done with the scalability, even though it might take years to get to this artificial intelligence virtual cell, which I have to agree, everyone in biology would say that's the holy grail. And as you remember at our conference in London, Demi Hassabis said that's what we'd like to do now. So it has the attention of leaders in AI around the world, obviously in the science and the biomedical community like you and many others. So it is an extraordinary time where we just can't sit still with these tools that we have, right?Anna Greka (21:15):Absolutely. And I think this is going to be, you mentioned the ASCI presidency in the beginning of our call. This is going to be the president gets to give an address at the annual meeting in Chicago. This is going to be one of the points I make, no matter what field in biomedicine we're in, we live in, I believe, a golden era and we have so many tools available to us that we can really accelerate our ability to help more patients. And of course, this is our mandate, the most important stakeholders for everything that we do as physician-scientists are our patients ultimately. So I feel very hopeful for the future and our ability to use these tools and to really make good on the promise of research is a public good. And I really hope that we can advance our knowledge for the benefit of all. And this is really an exciting time, I think, to be in this field and hopefully for the younger colleagues a time to really get excited about getting in there and getting involved and asking the big questions.Career ReflectionsEric Topol (22:21):Well, you are the prototype for this and an inspiration to everyone really, I'm sure to your lab group, which you highlighted in the TED Talk and many other things that you do. Now I want to spend a little bit of time about your career. I think it's fascinating that you grew up in Greece and your father's a nephrologist and your mother's a pathologist. So you had two physicians to model, but I guess you decided to go after nephrology, which is an area in medicine that I kind of liken it to Rodney Dangerfield, he doesn't get any respect. You don't see many people that go into nephrology. But before we get to your decision to do that somehow or other you came from Greece to Harvard for your undergrad. How did you make that connect to start your college education? And then subsequently you of course you stayed in Boston, you've never left Boston, I think.Anna Greka (23:24):I never left. Yeah, this is coming into 31 years now in Boston.Anna Greka (23:29):Yeah, I started as a Harvard undergraduate and I'm now a full professor. It's kind of a long, but wonderful road. Well, actually I would credit my parents. You mentioned that my father, they're both physician-scientists. My father is now both retired, but my father is a nephrologist, and my mother is a pathologist, actually, they were both academics. And so, when we were very young, we lived in England when my parents were doing postdoctoral work. That was actually a wonderful gift that they gave me because I became bilingual. It was a very young age, and so that allowed me to have this advantage of being fluent in English. And then when we moved back to Greece where I grew up, I went to an American school. And from that time, this is actually an interesting story in itself. I'm very proud of this school.Anna Greka (24:22):It's called Anatolia, and it was founded by American missionaries from Williams College a long time ago, 150 and more years ago. But it is in Thessaloniki, Greece, which is my hometown, and it's a wonderful institution, which gave me a lot of gifts as well, preparing me for coming to college in the United States. And of course, I was a good student in high school, but what really was catalytic was that I was lucky enough to get a scholarship to go to Harvard. And that was really, you could say the catalyst that propelled me from a teenager who was dreaming about a career as a physician-scientist because I certainly was for as far back as I remember in fact. But then to make that a reality, I found myself on the Harvard campus initially for college, and then I was in the combined Harvard-MIT program for my MD PhD. And then I trained in Boston at Mass General in Brigham, and then sort of started my academic career. And that sort of brings us to today, but it is an unlikely story and one that I feel still very lucky and blessed to have had these opportunities. So for sure, it's been wonderful.Eric Topol (25:35):We're the ones lucky that you came here and set up shop and you did your productivity and discovery work and sleuthing has been incredible. But I do think it's interesting too, because when you did your PhD, it was in neuroscience.Anna Greka (25:52):Ah, yes. That's another.Eric Topol (25:54):And then you switch gears. So tell us about that?Anna Greka (25:57):This is interesting, and actually I encourage more colleagues to think about it this way. So I have always been driven by the science, and I think that it seems a little backward to some people, but I did my PhD in neuroscience because I was interested in understanding something about these ion channels that were newly discovered at the time, and they were most highly expressed in the brain. So here I was doing work in the brain in the neuroscience program at Harvard, but then once I completed my PhD and I was in the middle of my residency training actually at Mass General, I distinctly remember that there was a paper that came out that implicated the same family of ion channels that I had spent my time understanding in the brain. It turned out to be a channelopathy that causes kidney disease.Anna Greka (26:43):So that was the light bulb, and it made me realize that maybe what I really wanted to do is just follow this thread. And my scientific curiosity basically led me into studying the kidney and then it seemed practical therefore to get done with my clinical training as efficiently as possible. So I finished residency, I did nephrology training, and then there I was in the lab trying to understand the biology around this channelopathy. And that sort of led us into the early projects in my young lab. And in fact, it's interesting we didn't talk about that work, but that work in itself actually has made it all the way to phase II trials in patients. This was a paper we published in Science in 2017 and follow onto that work, there was an opportunity to build this into a real drug targeting one of these ion channels that has made it into phase II trials. And we'll see what happens next. But it's this idea of following your scientific curiosity, which I also talked about in my TED Talk, because you don't know to what wonderful places it will lead you. And quite interestingly now my lab is back into studying familial Alzheimer's and retinitis pigmentosa in the eye in brain. So I tell people, do not limit yourself to whatever someone says your field is or should be. Just follow your scientific curiosity and usually that takes you to a lot more interesting places. And so, that's certainly been a theme from my career, I would say.Eric Topol (28:14):No, I think that's perfect. Curiosity driven science is not the term. You often hear hypothesis driven or now with AI you hear more AI exploratory science. But no, that's great. Now I want to get a little back to the AI story because it's so fascinating. You use lots of different types of AI such as cellular imaging would be fusion models and drug discovery. I mean, you've had drug discovery for different pathways. You mentioned of course the ion channel and then also as we touched on with your Cell paper, the whole idea of targeting the cargo receptor with a small molecule and then things in between. You discussed this of course at the London panel, but maybe you just give us the skinny on the different ways that you incorporate AI in the state-of-the-art science that you're doing?Anna Greka (29:17):Sure, yeah, thank you. I think there are many ways in which even for quite a long time before AI became such a well-known kind of household term, if you will, the concept of machine learning in terms of image processing is something that has been around for some time. And so, this is actually a form of AI that we use in order to process millions of images. My lab has by produced probably more than 20 million images over the last few years, maybe five to six years. And so, if you can imagine it's impossible for any human to process this many images and make sense of them. So of course, we've been using machine learning that is becoming increasingly more and more sophisticated and advanced in terms of being able to do analysis of images, which is a lot of what we cell biologists do, of course.Anna Greka (30:06):And so, there's multiple different kinds of perturbations that we do to cells, whether we're using CRISPR or base editing to make, for example, genome wide or genome scale perturbations or small molecules as we have done as well in the past. These are all ways in which we are then using machine learning to read out the effects in images of cells that we're looking at. So that's one way in which machine learning is used in our daily work, of course, because we study misshape and mangled proteins and how they are recognized by these cargo receptors. We also use AlphaFold pretty much every day in my lab. And this has been catalytic for us as a tool because we really are able to accelerate our discoveries in ways that were even just three or four years ago, completely impossible. So it's been incredible to see how the young people in my lab are just so excited to use these tools and they're becoming extremely savvy in using these tools.Anna Greka (31:06):Of course, this is a new generation of scientists, and so we use AlphaFold all the time. And this also has a lot of implications of course for some of the interventions that we might think about. So where in this cargo receptor complex that we study for example, might we be able to fit a drug that would disrupt the complex and lead the cargo tracks into the lysosome for degradation, for example. So there's many ways in which AI can be used for all of these functions. So I would say that if we were to organize our thinking around it, one way to think about the use of machine learning AI is around what I would call understanding biology in cells and what in sort of more kind of drug discovery terms you would call target identification, trying to understand the things that we might want to intervene on in order to have a benefit for disease.Anna Greka (31:59):So target ID is one area in which I think machine learning and AI will have a catalytic effect as they already are. The other of course, is in the actual development of the appropriate drugs in a rational way. So rational drug design is incredibly enabled by AlphaFold and all these advances in terms of understanding protein structures and how to fit drugs into them of all different modalities and kinds. And I think an area that we are not yet harnessing in my group, but I think the Ladders to Cures Accelerator hopes to build on is really patient data. I think that there's a lot of opportunity for AI to be used to make sense of medical records for example and how we extract information that would tell us that this cohort of patients is a better cohort to enroll in your trial versus another. There are many ways in which we can make use of these tools. Not all of them are there yet, but I think it's an exciting time for being involved in this kind of work.Eric Topol (32:58):Oh, no question. Now it must be tough when you know the mechanism of these families disease and you even have a drug candidate, but that it takes so long to go from that to helping these families. And what are your thoughts about that, I mean, are you thinking also about genome editing for some of these diseases or are you thinking to go through the route of here's a small molecule, here's the tox data in animal models and here's phase I and on and on. Where do you think because when you know so much and then these people are suffering, how do you bridge that gap?Anna Greka (33:39):Yeah, I think that's an excellent question. Of course, having patients as our partners in our research is incredible as a way for us to understand the disease, to build biomarkers, but it is also exactly creating this kind of emotional conflict, if you will, because of course, to me, honesty is the best policy, if you will. And so, I'm always very honest with patients and their families. I welcome them to the lab so they can see just how long it takes to get some of these things done. Even today with all the tools that we have, of course there are certain things that are still quite slow to do. And even if you have a perfect drug that looks like it fits into the right pocket, there may still be some toxicity, there may be other setbacks. And so, I try to be very honest with patients about the road that we're on. The small molecule path for the toxic proteinopathies is on its way now.Anna Greka (34:34):It's partnered with a pharmaceutical company, so it's on its way hopefully to patients. Of course, again, this is an unpredictable road. Things can happen as you very well know, but I'm at least glad that it's sort of making its way there. But to your point, and I'm in an institute where CRISPR was discovered, and base editing and prime editing were discovered by my colleagues here. So we are in fact looking at every other modality that could help with these diseases. We have several hurdles to overcome because in contrast to the liver and the brain, the kidney for example, is not an organ in which you can easily deliver nucleic acid therapies, but we're making progress. I have a whole subgroup within the bigger group who's focusing on this. It's actually organized in a way where they're running kind of independently from the cell biology group that I run.Anna Greka (35:31):And it's headed by a person who came from industry so that she has the opportunity to really drive the project the way that it would be run milestone driven, if you will, in a way that it would be run as a therapeutics program. And we're really trying to go after all kinds of different nucleic acid therapies that would target the mutations themselves rather than the cargo receptors. And so, there's ASO and siRNA technologies and then also actual gene editing technologies that we are investigating. But I would say that some of them are closer than others. And again, to your question about patients, I tell them honestly when a project looks to be more promising, and I also tell them when a project looks to have hurdles and that it will take long and that sometimes I just don't know how long it will take before we can get there. The only thing that I can promise patients in any of our projects, whether it's Alzheimer's, blindness, kidney disease, all I can promise is that we're working the hardest we possibly can on the problem.Anna Greka (36:34):And I think that is often reassuring I have found to patients, and it's best to be honest about the fact that these things take a long time, but I do think that they find it reassuring that someone is on it essentially, and that there will be some progress as we move forward. And we've made progress in the very first discovery that came out of my lab. As I mentioned to you, we've made it all the way to phase II trials. So I have seen the trajectory be realized, and I'm eager to make it happen again and again as many times as I can within my career to help as many people as possible.The Paucity of Physician-ScientistsEric Topol (37:13):I have no doubts that you'll be doing this many times in your career. No, there's no question about it. It's extraordinary actually. There's a couple of things there I want to pick up on. Physician-scientists, as you know, are a rarefied species. And you have actually so nicely told the story about when you have a physician-scientist, you're caring for the patients that you're researching, which is, most of the time we have scientists. Nothing wrong with them of course, but you have this hinge point, which is really important because you're really hearing the stories and experiencing the patients and as you say, communicating about the likelihood of being able to come up with a treatment or the progress. What are we going to do to get more physician-scientists? Because this is a huge problem, it has been for decades, but the numbers just keep going lower and lower.Anna Greka (38:15):I think you're absolutely right. And this is again, something that in my leadership of the ASCI I have made sort of a cornerstone of our efforts. I think that it has been well-documented as a problem. I think that the pressures of modern clinical care are really antithetical to the needs of research, protected time to really be able to think and be creative and even have the funding available to be able to pursue one's program. I think those pressures are becoming so heavy for investigators that many of them kind of choose one or the other route most often the clinical route because that tends to be, of course where they can support their families better. And so, this has been kind of the conundrum in some ways that we take our best and brightest medical students who are interested in investigation, we train them and invest in them in becoming physician-scientists, but then we sort of drop them at the most vulnerable time, which is usually after one completes their clinical and scientific training.Anna Greka (39:24):And they're embarking on early phases of one's careers. It has been found to be a very vulnerable point when a lot of people are now in their mid-thirties or even late thirties perhaps with some family to take care of other burdens of adulthood, if you will. And I think what it becomes very difficult to sustain a career where one salary is very limited due to the research component. And so, I think we have to invest in our youngest people, and it is a real issue that there's no good mechanism to do that at the present time. So I was actually really hoping that there would be an opportunity with leadership at the NIH to really think about this. It's also been discussed at the level of the National Academy of Medicine where I had some role in discussing the recent report that they put out on the biomedical enterprise in the United States. And it's kind of interesting to see that there is a note made there about this issue and the fact that there needs to be, I think, more generous investment in the careers of a few select physician-scientists that we can support. So if you look at the numbers, currently out of the entire physician workforce, a physician-scientist comprised of less than 1%.Anna Greka (40:45):It's probably closer to 0.8% at this point.Eric Topol (40:46):No, it's incredible.Anna Greka (40:48):So that's really not enough, I think, to maintain the enterprise and if you will, this incredible innovation economy that the United States has had this miracle engine, if you will, in biomedicine that has been fueled in large part by physician investigators. Of course, our colleagues who are non-physician investigators are equally important partners in this journey. But we do need a few of the physician-scientists investigators I think as well, if you really think about the fact that I think 70% of people who run R&D programs in all the big pharmaceutical companies are physician-scientists. And so, we need people like us to be able to work on these big problems. And so, more investment, I think that the government, the NIH has a role to play there of course. And this is important from both an economic perspective, a competition perspective with other nations around the world who are actually heavily investing in the physician-scientist workforce.Anna Greka (41:51):And I think it's also important to do so through our smaller scale efforts at the ASCI. So one of the things that I have been involved in as a council member and now as president is the creation of an awards program for those early career investigators. So we call them the Emerging-Generation Awards, and we also have the Young Physician-Scientist Awards. And these are really to recognize people who are making that transition from being kind of a trainee and a postdoc and have finished their clinical training into becoming an independent assistant professor. And so, those are small awards, but they're kind of a symbolic tap on the shoulder, if you will, that the ASCI sees you, you're talented, stay the course. We want you to become a future member. Don't give up and please keep on fighting. I think that can take us only so far.Anna Greka (42:45):I mean, unless there's a real investment, of course still it will be hard to maintain people in the pipeline. But this is just one way in which we have tried to, these programs that the ASCI offers have been very successful over the last few years. We create a cohort of investigators who are clearly recognized by members of the ASCI is being promising young colleagues. And we give them longitudinal training as part of a cohort where they learn about how to write a grant, how to write a paper, leadership skills, how to run a lab. And they're sort of like a buddy system as well. So they know that they're in it together rather than feeling isolated and struggling to get their careers going. And so, we've seen a lot of success. One way that we measure that is conversion into an ASCI membership. And so, we're encouraged by that, and we hope that the program can continue. And of course, as president, I'm going to be fundraising for that as well, it's part of the role. But it is a really worthy cause because to your point, we have to somehow make sure that our younger colleagues stay the course that we can at least maintain, if not bolster our numbers within the scientific workforce.Eric Topol (43:57):Well, you outlined some really nice strategies and plans. It's a formidable challenge, of course. And we'd like to see billions of dollars to support this. And maybe someday we will because as you say, if we could relieve the financial concerns of people who have curiosity driven ideas.Anna Greka (44:18):Exactly.Eric Topol (44:19):We could do a lot to replenish and build a big physician-scientist workforce. Now, the last thing I want to get to, is you have great communication skills. Obviously, anybody who is listening or watching this.Eric Topol (44:36):Which is another really important part of being a scientist, no less a physician or the hybrid of the two. But I wanted to just go to the backstory because your TED Talk, which has been watched by hundreds of thousands of people, and I'm sure there's hundreds of thousands more that will watch it, but the TED organization is famous for making people come to the place a week ahead. This is Vancouver used to be in LA or Los Angeles area and making them rehearse the talk, rehearse, rehearse, rehearse, which seems crazy. You could train the people there, how to give a talk. Did you have to go through that?Anna Greka (45:21):Not really. I did rehearse once on stage before I actually delivered the talk live. And I was very encouraged by the fact that the TED folks who are of course very well calibrated, said just like that. It's great, just like that.Eric Topol (45:37):That says a lot because a lot of people that do these talks, they have to do it 10 times. So that kind of was another metric. But what I don't like about that is it just because these people almost have to memorize their talks from giving it so much and all this coaching, it comes across kind of stilted and unnatural, and you're just a natural great communicator added to all your other things.Anna Greka (46:03):I think it's interesting. Actually, I would say, if I may, that I credit, of course, I actually think that it's important, for us physician-scientists, again, science and research is a public good, and being able to communicate to the public what it is that we do, I think is kind of an obligation for the fact that we are funded by the public to do this kind of work. And so, I think that's important. And I always wanted to cultivate those communication skills for the benefit of communicating simply and clearly what it is that we do in our labs. But also, I would say as part of my story, I mentioned that I had the opportunity to attend a special school growing up in Greece, Anatolia, which was an American school. One of the interesting things about that is that there was an oratory competition.Anna Greka (46:50):I got very early exposure entering that competition. And if you won the first prize, it was in the kind of ancient Rome way, first among equals, right? And so, that was the prize. And I was lucky to have this early exposure. This is when I was 14, 15, 16 years old, that I was training to give these oratory speeches in front of an audience and sort of compete with other kids who were doing the same. I think these are just wonderful gifts that a school can give a student that have stayed with me for life. And I think that that's a wonderful, yeah, I credit that experience for a lot of my subsequent capabilities in this area.Eric Topol (47:40):Oh, that's fantastic. Well, this has been such an enjoyable conversation, Anna. Did I miss anything that we need to bring up, or do you think we have it covered?Anna Greka (47:50):Not at all. No, this was wonderful, and I thoroughly enjoyed it as well. I'm very honored seeing how many other incredible colleagues you've had on the show. It's just a great honor to be a part of this. So thank you for having me.Eric Topol (48:05):Well, you really are such a great inspiration to all of us in the biomedical community, and we'll be cheering for your continued success and thanks so much for joining today, and I look forward to the next time we get a chance to visit.Anna Greka (48:20):Absolutely. Thank you, Eric.**************************************Thanks for listening, watching or reading Ground Truths. Your subscription is greatly appreciated.If you found this podcast interesting please share it!That makes the work involved in putting these together especially worthwhile.All content on Ground Truths—newsletters, analyses, and podcasts—is free, open-access.Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. And such support is becoming more vital In light of current changes of funding and support for biomedical research at NIH and other US governmental agencies.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research. Get full access to Ground Truths at erictopol.substack.com/subscribe

Description: Co-hosts Ryan Piansky, a graduate student and patient advocate living with eosinophilic esophagitis (EoE) and eosinophilic asthma, and Holly Knotowicz, a speech-language pathologist living with EoE who serves on APFED's Health Sciences Advisory Council, interview Dr. Wayne Shreffler, Chief of Pediatric Allergy and Immunology and Co-Director of The Food Allergy Center at Massachusetts General Hospital. Dr. Shreffler is also an investigator at The Center for Immunology and Inflammatory Disease and The Food Allergy Science Initiative. His research is focused on understanding how adaptive immunity to dietary antigens is both naturally regulated and modulated by therapy in the context of food allergy. This interview covers the results of a research paper on The Intersection of Food Allergy and Eosinophilic Esophagitis, co-authored by Dr. Shreffler. Disclaimer: The information provided in this podcast is designed to support, not replace the relationship that exists between listeners and their healthcare providers. Opinions, information, and recommendations shared in this podcast are not a substitute for medical advice. Decisions related to medical care should be made with your healthcare provider. Opinions and views of guests and co-hosts are their own.   Key Takeaways: [:50] Co-host Ryan Piansky introduces the episode, brought to you thanks to the support of Education Partners Bristol Myers Squibb, GSK, Sanofi, and Regeneron. Ryan introduces co-host, Holly Knotowicz.   [1:15] Holly introduces today's topic, the intersection of food allergy and eosinophilic esophagitis.   [1:26] Holly introduces today's guest, Dr. Wayne Shreffler, Chief of Pediatric Allergy and Immunology and Co-Director of The Food Allergy Center at Massachusetts General Hospital and an investigator at The Center for Immunology and Inflammatory Disease and The Food Allergy Science Initiative.   [1:43] Dr. Shreffler's research is focused on understanding how adaptive immunity to dietary antigens is both naturally regulated and modulated by therapy in the context of food allergy.   [1:54] Holly welcomes Dr. Shreffler to Real Talk. When Holly moved to Maine, she sent her patients to Dr. Shreffler at Mass General.   [2:25] Dr. Shreffler trained in New York on a Ph.D. track. He was interested in parasitic diseases and the Th2 immune response. Jane Curtis, a program director at Albert Einstein College of Medicine, encouraged him to consider MD/PhD programs. He did.   [3:31] Jane Curtis connected him to Hugh Sampson, who was working with others to help understand the clinical prevalence of food allergy and allergens.   [3:51] As a pediatric resident, Dr. Shreffler had seen the burden of allergic disease, caring for kids in the Bronx with asthma. His interest in Th2 immunity, the clear and compelling unmet clinical need, and the problem of food allergy guided his career.   [4:31] Dr. Shreffler's wife has food allergies and they were concerned for their children. Fortunately, neither of them developed food allergies.   [5:21] Dr. Shreffler thinks the food allergy field has a lot of people who gravitate toward it for personal reasons.   [5:53] Food allergy is an adverse response to food that is immune-mediated. There is still uncertainty about this but Dr. Shreffler believes that a large percentage of patients with EoE have some triggers that are food antigens.   [6:27] The broad definition of food allergy would include things like food protein-induced enterocolitis syndrome (FPIES).   [6:47] The way we use the term food allergy in the clinic, there are two forms: IgE-mediated allergies and non-IgE-mediated allergies, including EoE.   [7:40] Some patients have food-triggered eczema, some have FPIES.   [8:04] In 2024, Dr. Shreffler and Dr. Caitlin Burk released a paper that looked at the triggers of EoE, particularly the intersection of IgE-mediated food allergy and EoE.   [8:41] Dr. Caitlin Burk joined the group as they were publishing papers on IG food allergy and EoE. It was a moment where things unexpectedly came together.   [9:17] Adaptive immunity to food proteins comes from antibodies that cause milk allergy, egg allergy, peanut allergy, or multiple allergies. The IgE has specificity.   [9:40] T cells also are specific to proteins. They express a host of receptors that recognize almost anything the immune system might encounter. They have a long memory like B-cells.   [10:09] The overlap in these two threads of research was regarding a population of T cells that are important for mediating chronic inflammation at epithelial sites, including the gut.   [10:36] These T cells have been described in the airways in asthma, in the skin in eczema, and the GI tract. Researchers years ago had also described them as being associated with IgE food allergy. People with IgE food allergies avoid allergens.   [11:13] T cells, being associated with chronic allergic inflammation, now being associated with food allergies which are not having chronic exposures to the allergen, was interesting and surprising.   [11:30] Dr. Shreffler and his group found the T cell subset in patients who don't do well with Oral Immunotherapy (OIT) and patients who have EoE with immediate symptoms.   [12:01] Dr. Shreffler notes differences. There are immediate symptoms of IgE food allergy. There is a subset of patients with EoE who have immediate symptoms that are not fully understood. Maybe IgE plays a role there.   [12:28] There are different mechanisms for how symptoms are caused and so different ways of making a diagnosis. A food allergy with an IgE antibody can be measured through skin tests and blood tests. This can help identify which foods are the trigger.   [12:57] This common T cell subset that we see in EoE and food allergy, helps to explain why IgE alone is not always a very specific marker for identifying people who will have immediate reactions when they're exposed to the food.   [13:17] For patients who react at low levels, it's not just that they have more or better IgE but they also have an expansion of these T cells that are common between EoE and other chronic forms of allergy and IgE food allergy.   [13:41] There's a lot to learn that might be relevant for patients about this T cell subset.   [14:23] These T cells are a specific subset of the group of Th2 T cells, which are a subset of all CD4 T cells. Some CD4 T cells are important for responding to viruses and tumors. Others are important for responding to outside allergens.   [15:01] In an allergy or a parasite infection, Th2 T cells are important. There is a subset of T cells that is driven by repetitive and chronic exposure to the triggering protein, antigen, or allergen.   [15:47] Most antigens are proteins that trigger an immune response. An antigen that elicits an allergic response is an allergen. [16:30] A food trigger is a protein antigen that is an allergen. In IgE, food allergies, milk, and eggs are prevalent triggers early in life. For reasons not well understood, a lot of people outgrow them. In older patients, peanut and tree nut allergies are prevalent.   [17:01] In EoE, milk is one of the most common dietary triggers into adulthood. Some patients with IgE allergy to milk can tolerate it if it's well cooked. Patients with EoE are less likely to be able to get away with regular and ongoing exposure to milk protein.   [17:54] Milk, eggs, and nuts are common triggers in both conditions. There can also be rare food allergy triggers. That's part of the early evidence that the adaptive immune response was likely to be involved. It can be so specific for some people to rare things.   [18:20] Hallmarks of something being immune-mediated are that it is reproducibly demonstrable as a trigger. It's going to be long-lived. It's going to be generally relatively small amounts. The immune system is good at detecting small exposures.   [19:07] EoE is tricky because there's not that clear and easy temporal association between an offending allergen exposure for most people and their symptoms. People don't associate the symptoms with the triggers.   [20:14] A history of having blood in the stools can be milk-allergen-driven and was associated with a diagnosis of EoE in those kids when they're older.   [20:26] There are a lot of commonalities in the allergens but it's not always obvious clinically.   [22:40] A challenge in diagnosing EoE is that providers have to be on guard against their biases. They have to give a patient good advice. In EoE there is no test to identify triggers, except rigorous introduction, elimination, reintroduction, and endoscopies.   [24:18] For some of Dr, Shreffler's patients, it becomes less important to know their dietary triggers. They gravitate toward an approved form of treatment that may, if successful, allow them to have a more normal diet because of effective medication.   [24:50] Dr. Shreffler thinks there are other triggers, including pollens. There is evidence of seasonality of active EoE in patients shown to have allergic sensitization to pollens. That's indirect evidence. If the body is making IgE, it's likely making other responses.   [25:32] There are questions about how large the population of patients is who have EoE that may be more intrinsically than extrinsically driven because of genetic variations.   [25:54] Dr. Shreffler believes that EoE in some patients is allergen-driven and in some patients EoE is food-driven. Food is a trigger for the majority of pediatric patients and a large percentage of adult patients but not necessarily the exclusive trigger.   [27:04] If a patient is motivated to learn what dietary triggers may be at play, Dr. Shreffler often makes assessments outside of pollen season for allergens to which the patient has demonstrated positivity.   [28:09] Looking at the epidemiology, both EoE and food allergy are atopic disorders. You see an increased prevalence of asthma, hay fever, eczema, and even allergic proctocolitis in infancy. You see an enrichment of one disorder to another.   [28:29] The overlap of food allergy to EoE is stronger than you might expect. About 30 to 40% of patients with EoE will also have IgE food allergy. A higher rate will have IgE positivity, whether or not that food is a trigger of immediate symptoms.   [28:48] Patients with food allergies are about four times more likely to have EoE than the general population. That's a stronger association than the risk of eczema or other atopic conditions to EoE.   [30:09] There are differences between IgE food allergy and EoE. The presence of IgE gives a useful tool for identifying the food trigger in food allergy, but not in EoE. Identifying rare triggers in EoE patients is done by clinical observation.   [31:46] Epinephrine and antihistamines are not useful in treating EoE. Blocking IgE with Omalizumab has not been effective in trials in treating EoE. PPIs, topical steroids, and dupilumab are helpful for many EoE patients.   [32:38] Dupilumab has been evaluated a bit in food allergy in combination with OIT, and there was no statistically significant benefit from dupilumab in food allergy.   [33:25] A group in Pennsylvania has been evaluating epicutaneous immunotherapy as a modality to treat EoE. It's also being evaluated for IgE food allergy. Dr. Shreffler thinks it's something to keep an eye on.   [33:40] The oral route for immunotherapy can drive EoE for patients. As they become less sensitive from an immediate reactivity viewpoint, a significant percentage of patients develop GI symptoms. This has also been observed with sublingual therapy.   [34:14] Iatrogenic EoE, caused by the treatment, may resolve on the cessation of the immunotherapy treatment.   [36:25] Dr. Shreffler says in some cases, the shared decision is a decision where he has a strong evidence-based opinion. In some cases, there's a lot more room for a range of clinical decisions that could be equally supported by what we know right now.   [36:57] We've said that EoE is a contraindication for OIT. There is a shift happening. Dr. Shreffler sits with families and has a conversation about restricting diet or trying chronic therapy and keeping an ad-lib diet.   [37:38] What about doing the same thing by treating the immediate-type food allergy with chronic allergen exposure and then ameliorating the effects of EoE if it emerges, with another therapy? A hundred providers would have a diversity of responses.   [38:19] When there is a history of EoE in a family, Dr. Shreffler advocates for getting a baseline scope. It becomes an important “ground zero.”   [38:28] The goal is to have less invasive ways to monitor these conditions.   [39:32] Chronic inflammation, which is the hallmark of EoE, is well-targeted by therapies like PPIs and steroids. Steroids don't help with IgE-related food allergies. They're not effective at blocking the IgE-driven immediate response.   [41:13] Until recently, IgE food allergy has only been managed with avoidance. We have some other tools now. Xolair is not effective in EoE but is effective in two-thirds to three-quarters of patients with immediate-type food allergies for preventing anaphylaxis.   [41:45] Dr. Shreffler refers to an upcoming study on the effectiveness of Xolair in treating people with food allergies. Those who were able to tolerate a minimum amount were allowed to begin consuming allergen. We'll get insight into how those patients did.   [43:08] Food-induced immediate response of the esophagus (FIRE) is immediate discomfort with exposure to some allergens. Dr. Shreffler explains it. Data supports that these patients are experiencing an IgE-mediated but local response to those triggers.   [44:59] If FIRE is IgE-mediated, it may be that Xolair would help suppress it in these patients. It's worth looking at Xolair for this subset of EoE patients.   [45:20] Ryan invites any listeners who want to learn more about FIRE to check out episode #34 with Dr. Nirmala Gonsalvez.   [45:37] In the paper, Dr. Shreffler wrote about what he hopes will be the practical usefulness of the finding, the intersection between IgE food allergy and EoE.   [45:56] A subset of Th2 T cells express a protein called GPR15. It appears to be a marker for the subset of cells that are playing a role in the EoE.   [46:36] Caitlin Burk's work now is looking at their activation status in active disease and post-diet elimination and remission. She is developing a data set that is leading us toward the possibility of focusing on that cell subset and techniques to adopt in clinics.   [47:12] She is also working out more advanced techniques to look at the receptors. Dr. David Hill at CHOP is working on similar research. This research has the potential to lead to the development of better tests for EoE.   [47:44] Holly tells Dr. Shreffler this has been such an informative episode with so many tidbits of things to help patients advocate for themselves. Holly thanks him for sharing all of that.   [48:12] Dr. Shreffler is trying to see what can be utilized from their research to make non-invasive tests to identify food allergen triggers for patients so they don't have to go through so many endoscopies. He sees it as a huge unmet need.   [48:31] Ryan thanks Dr. Shreffler for joining us. For our listeners who would like to learn more about eosinophilic disorders, including EoE, please visit APFED.org and check out the links in the show notes.   [48:41] If you're looking to find a specialist who treats eosinophilic disorders, we encourage you to use APFED's Specialist Finder at APFED.org/specialist.   [48:50] If you'd like to connect with others impacted by eosinophilic diseases, please join APFED's online community on the Inspire Network at APFED.org/connections.   [49:00] Ryan thanks Dr. Shreffler for joining us today for this interesting conversation. Holly also thanks APFED's Education Partners Bristol Myers Squibb, GSK, Sanofi, and Regeneron for supporting this episode.   Mentioned in This Episode: Dr. Wayne Shreffler, MD, Ph.D., Chief of Pediatric Allergy and Immunology and Co-Director of The Food Allergy Center at Massachusetts General Hospital “Triggers for eosinophilic esophagitis (EoE): The intersection of food allergy and EoE” Dr. Caitlin Burk Dr. David A. Hill   APFED on YouTube, Twitter, Facebook, Pinterest, Instagram Real Talk: Eosinophilic Diseases Podcast apfed.org/specialist apfed.org/connections   Education Partners: This episode of APFED's podcast is brought to you thanks to the support of Bristol Myers Squibb, GSK, Sanofi, and Regeneron.   Tweetables:   “This fascinating problem of food allergy: why does the immune system do that for some people — recognize what should be nutritive and innocuous sources of energy as an immunological trigger? ” — Dr. Wayne Shreffler   “A food allergy; because there is this IgE antibody, we can do skin tests. We can measure that in the blood. It's a useful marker for helping to identify which foods are the trigger.” — Dr. Wayne Shreffler   “EoE is tricky because there's not that clear and easy temporal association between an offending allergen exposure for most people and their symptoms. People don't associate the symptoms with the triggers.” — Dr. Wayne Shreffler   “Everything is shared decision-making. In some cases, it's a shared decision where I have a strong evidence-based opinion. In some cases, there's a lot more room for a range of clinical decisions that could be equally justified.” — Dr. Wayne Shreffler   “Steroids don't help with IgE-related food allergy. They're not effective at blocking that IgE-driven immediate response.” — Dr. Wayne Shreffler   “I'm trying to see what we can utilize from our research to make non-invasive tests to identify food allergen triggers for patients so they don't have to go through so many endoscopies. I think that's a huge unmet need.” — Dr. Wayne Shreffler  

About Dr. Brian Anderson:Dr. Brian Anderson is a leading voice in health AI as CEO and Co-Founder of the Coalition for Health AI (CHAI), guiding the development of national standards for safe and effective AI in healthcare. Formerly Chief Digital Health Physician at MITRE, he spearheaded crucial research initiatives, including advancements in clinical trials and oncology. An internationally recognized expert, Dr. Anderson speaks frequently on digital health, AI assurance, and interoperability. A Harvard Medical School graduate with an MD (honors) and a BA (cum laude), Dr. Anderson trained at Mass General, practiced at Greater Lawrence Family Health Center, and lives in Boston with his family.Things You'll Learn:A significant gap exists in the lack of independent labs to evaluate health AI, as these are already standard practice in other sectors with regulated technologies. The proposed national network of certified labs will fill this gap by providing independent assessments of AI models, promoting trust in their use.AI model cards are crucial for transparency because they detail the training methodologies and ingredients of AI models. This information helps users, such as physicians, make informed decisions about the tool's appropriateness for their patients.Clinicians need upskilling to critically evaluate AI tools and make informed decisions about their use in patient care.Generative AI applications like ambient scribes have the potential to greatly mitigate physician burnout by streamlining administrative tasks. This can give them more time to focus on their patients and improve their work-life balance.The creation of quality assurance labs will be a critical first step in AI regulation, helping to bridge the gap between rapidly evolving technology and established safety standards.Resources:Connect with and follow Dr. Brian Anderson on LinkedIn.Discover more about Coalition for Health AI (CHAI) on their LinkedIn and website.

In this episode, Scott Becker highlights six major healthcare stories, including Mass General's layoffs amid a $250M budget gap, Massachusetts hospitals' financial and access struggles, a surge in flu cases, and the growing crisis of healthcare access.

Surveys show that more and more Americans put down the bottle this January to try out drinking less. For some people, the goal was sobriety, and for others, moderation. Researchers are finding that alcohol consumption is going down in general across the population after spiking during the pandemic. Helping the cause are some stark recommendations from top health officials saying alcohol can cause cancer. Shirley takes a trip to a non-alcoholic bottle shop in Boston to try some mocktails, and later talks to Dr. Scott Hadland, who is a substance use specialist at Mass General for Children. Email us at saymore@globe.com. See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

In this episode of BioTalk with Rich Bendis, Dr. Kolaleh Eskandanian, Vice President and Chief Innovation Officer at Children's National Hospital, discusses her work driving pediatric healthcare innovation. Dr. Eskandanian introduces the BARDA SPARK Accelerator, a groundbreaking initiative focused on advancing medical countermeasures for children, and explains how it aligns with Children's National's mission to lead in pediatric healthcare innovation. She also highlights the unique challenges in developing pediatric medical countermeasures and the importance of partnerships with organizations like Rainbow Babies, Mass General, and others. Additionally, Dr. Eskandanian shares insights into the hospital's role in fostering innovation through the National Capital Consortium for Pediatric Device Innovation (NCC-PDI) and the Children's National Research and Innovation Campus. Join us for an engaging conversation about the future of pediatric healthcare, the opportunities for innovation, and how the SPARK Accelerator is paving the way for advancements that will improve the lives of children worldwide. Editing and post-production work for this episode was provided by The Podcast Consultant. Kolaleh Eskandanian, Ph.D., M.B.A., P.M.P. is Vice President and Chief Innovation Officer at Children's National Hospital, reporting to hospital's Executive Vice President, Physician-In-Chief and Chief Academic Officer. In this capacity, she oversees the Office of Innovation Ventures, the Sheikh Zayed Institute's R&D operations, and has a leadership role in the development of the Children's National Research and Innovation Campus (opening 2020). She is also the executive director of the FDA-funded National Capital Consortium for Pediatric Device Innovation (NCC-PDI), focused on accelerating the path to market for pediatric devices. Eskandanian works with a large network of small and large businesses, nonprofits and government agencies –addressing the unmet medical needs of children. She is the producer of an annual innovation competition that supports small businesses who demonstrate the ability to address a significant medical need in the pediatric space. Eskandanian's expertise includes the full spectrum of product development activities, having held management positions at Accenture, a global management consulting firm, where she directed major product launches for clients. Eskandanian is the co-PI on the FDA-funded Global Pediatric Clinical Trials Network grant and the CTSI-CN lead of the Orphan Product Accelerator.  Eskandanian's own innovations are in the market space, used by millions. She is the lead inventor of the first-ever adverse event reporting system, initially deployed in a research academic environment. This technology and its derivatives have now been in the market for over 10 years. She has had leadership roles in the development of the first web-based trouble entry management system for a Fortune 100 company in the telecommunications sector. She has been a key contributor in securing over $40 million in government funding for two large research enterprises. Prior to joining Children's National, Kolaleh held positions with Intelsat, Accenture and Georgetown University. Her background is in mechanical engineering with a PhD in operations science and an MBA from American University Kogod School of Business.

Chime In, Send Us a Text Message!In this episode, we explore the critical role of social determinants of health (SDOH) in stroke prevention and recovery with an incredible panel of experts from the Bugher Collaborative. Our guests include:Dr. Nirupama Yechoor, Principal Investigator at Mass General Hospital and leader of the Bugher Collaborative.Dr. Devanshi Choksi, neurologist and colleague of Dr. Yechoor at Mass General.Rachel Kitagawa and Sofia Constantinescu, neurology postgraduates from Yale University.We dive into:The Bugher Collaborative: Its mission, the partnership between Mass General, Yale, and UCSF, and how it addresses equity in stroke care.Research Highlights: Insights into how socioeconomic status, access to care, and community support affect stroke outcomes.Yale's Findings: Key demographic differences uncovered through their research and what they reveal about health equity.The Road Ahead: Next steps for the collaborative and their vision for improving stroke care.Magic Wand Wishes: What each guest would change to improve stroke prevention and recovery if they had unlimited resources.This conversation builds on our discussion of the 2024 ASA Stroke Prevention Guidelines, offering a deeper dive into the intersection of health equity and stroke care.Resources and Links:Learn more about the Bugher CollaborativeDr. Nirupama Yechoor's BioDr. Devanshi Choksi's BioRachel Kitagawa's BioSofia Constantinescu's BioSupport Our Show! Thank you for helping us to continue to make great content. We appreciate your generosity! Support the showShow credits:Music intro credit to Jake Dansereau. Our intro welcome is the voice of Caroline Goggin, a stroke survivor and our first podcast guest! Please listen to her inspiring story on Episode 2 of the podcast.Connect with Us and Share our Show on Social:Website | Linkedin | Twitter | YouTube | FacebookKnow Stroke Podcast Disclaimer: Our podcast and media advertising services are for informational purposes only and do not constitute the practice of medical advice, diagnosis or treatment.

Diagnosing IBS-C can be a complex process, often leaving patients and healthcare providers searching for clarity. In this episode, we're joined by Dr. Kyle Staller, Gastroenterologist and Neurogastroenterologist at Mass General, to explore the intricacies of diagnosing IBS-C. Dr. Staller sheds light on the challenges and misconceptions surrounding this condition, the vital role of the brain-gut connection, and how it influences patient care. We'll also dive into the latest diagnostic criteria, tools, and research available to help healthcare providers deliver effective symptom relief to their patients. Tune in for expert insights and practical strategies to support your IBS-C patients. This episode is brought to you with support from Ardelyx.  

Nutrition is key to a child's development, but for some children with Down syndrome, feeding challenges make it difficult to get the nutrition they need. That's where tube feeding comes in. Today, we're chatting with Dr. Lauren Fiechtner, Director of Nutrition at Mass General for Children, to talk about the different types of feeding tubes, why they are sometimes necessary, and the unique feeding challenges that children with Down syndrome may face. We're chatting about when tube feeding is typically used, the emotional and physical challenges parents may experience, and how feeding therapies and supportive resources can make a difference. We hope Dr. Fiechtner's compassionate advice helps families feel empowered and reassured as they navigate tube feeding and nutrition. - - - - - SHOW NOTES Learn more about Feeding Matters Learn more about The Oley Foundation JOIN THE MOVEMENT Join us in celebrating and supporting The Lucky Few Podcast! For just $0.99, $4.99, or $9.99 a month, you can help us continue shouting worth and shifting narratives for people with Down syndrome. Your support makes a difference in our ability to create meaningful content, enable us to cover production costs, and explore additional opportunities to expand our resources. Become an essential part of The Lucky Few movement today!  DISCOUNT CODE Friends, grab your narrative shifting gear over on The Lucky Few Merch Shop and use code PODCAST for 10% off! HELP US SHIFT THE NARRATIVE Interested in partnering with The Lucky Few Podcast as a sponsor? Email hello@theluckyfewpodcast.com for more information! THANK YOU TO OUR SPONSORS: Thank you, National Down Syndrome Society for sponsoring this episode! Check out episode 174 on The Down Syndrome Learning Profile Check out episode 181 with NDSS team member Dana Sciullo and her brother Anthony! Check out episode 262 with NDSS President Kandi Pickard celebrating their 45 years of advocacy! Thank you, Enable SNP for sponsoring this episode! 47. Planning for the Future w/Phillip Clark from Enable SNP 191. Future Planning for the WHOLE Family - ft. Phillip Clark, Enable SNP LET'S CHAT Email hello@theluckyfewpodcast.com with your questions and Good News for future episodes. --- Support this podcast: https://podcasters.spotify.com/pod/show/theluckyfewpod/support

"The vascular surgeons had felt like, 'The patients are going to you before they come to us and ... why don't we just take you on?' And there was sort of an interest in trying to get me to join up with them, but I told them 'I'm not trained ..." So if I had wanted, I could have ended up in the department of surgery as a nonsurgeon surgeon."—Arthur Waltman, MD, FSIRIn this episode, part of the ongoing celebration of the Society of Interventional Radiology (SIR) 50th anniversary, host Warren Krackov, MD, FSIR, speaks with one of his early mentors, interventional radiology pioneer Arthur Waltman, MD, FSIR, and his wife Carol Watson about the very days of interventional radiology at Mass General, his work with Stanley Baum, MD, FSIR, and others, how the specialty and SIR have grown over the decades, and more. Related resources:SIR 50th Anniversary homepageContact us with your ideas and questions, or read more about about interventional radiology in IR Quarterly magazine or SIR's Patient Center.(c) Society of Interventional Radiology.Support the show

Host: Peter Buch, MD, FACG, AGAF, FACP Guest: Kyle Staller, MD, MPH Join Dr. Peter Buch as he speaks with Dr. Kyle Staller, Director of the Gastrointestinal Motility Laboratory at Mass General and Assistant Professor of Medicine at Harvard Medical School, about uncovering the cause of a patient's bloating and determining how to manage it.

Today we have Dr. Rudolph E. Tanzi, who is perhaps best known for co-discovering all three familial early-onset Alzheimer's disease genes. In addition, Rudy's lab was the first to use human stem cells to create three-dimensional human brain organoids and three-dimensional neural-glial culture models of Alzheimer's disease, which became known as “Alzheimer's-in-a-Dish.” These models were the first to recapitulate all three of the key pathological hallmarks of Alzheimer's disease and have made drug screenings faster and cheaper. Rudy is the director of the Genetics and Aging Research Unit as well as the director of the Henry and Allison McCance Center for Brain Health. Rudy is also co-Director of the Massachusetts General Institute for Neurodegenerative Disease at Massachusetts General Hospital and serves as the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Rudy has published more than 700 research papers and is one of the top 50 most cited neuroscientists in the world. He is author of “Decoding Darkness,” and a co-author of two books with Deepak Chopra, “Super Brain” and “The Healing Self.” Show notes: [00:03:18] Ken opens the interview mentioning that Rudy began playing the accordion when he was just seven years old. Ken goes on to ask Rudy about the time his father gave him a Jimmy Smith album and some advice. [00:05:51] Ken mentions that, in addition to Rudy's musical talents, he was also interested in science growing up. Ken asks about Rudy's participation in the Westinghouse Science Talent Search and what that experience was like. [00:07:09] Ken asks Rudy about growing up in Cranston, Road Island. [00:08:39] Rudy talks about how he ended up at the University of Rochester after high school. [00:09:51] Ken mentions that both Rudy's grandfather and father passed away at the age of 45. Ken asks Rudy if this played a role in his pursuit of a career in genetics research. [00:10:57] Rudy explains how he chose Harvard Medical School for his Ph.D. [00:12:47] Ken pivots to ask Rudy about his time working with Jim Gusella in the early 80's at Mass General, where they were the first to ever find a disease gene. Family studies at the time had shown that the Huntington's disease gene was linked to a polymorphic DNA marker. Rudy talks about this discovery and how the chromosomal localization of the Huntington's disease gene was the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder. [00:16:07] Ken asks Rudy about his work in 1987, when he discovered the first Alzheimer's gene, recombinant DNA technology, which causes the production of amyloid. Ken goes on to explain that mutations in the APP gene can cause a rare form of early onset Alzheimer's. Rudy talks about the paper that came out in “Science” that detailed this discovery. [00:18:38] Rudy discusses his personal philosophy and approach to research. [00:19:43] Ken mentions that in Rudy's book, Decoding Darkness, he writes that few nightmares on Earth can compare to Alzheimer's disease. Ken asks Rudy to talk more about this book. [00:21:50] Ken explains that in the same way our physical capabilities will suffer some form of decline with age, it is also expected that we have some decline in memory and cognitive ability as we age as well. However, Ken goes on to say that when people begin to experience age-related memory lapses, it can lead to a lot of anxiety about their genetic predisposition to Alzheimer's. Ken asks Rudy to talk about the lifestyle factors that play into whether someone predisposed to develop Alzheimer's can stave off or avoid disease development. [00:26:09] Ken explains that aging appears to intensify when people stop challenging themselves with new things. Given this, Ken asks Rudy what his thoughts are on challenging our brains as they age to protect our cognitive abilities. [00:29:08] Ken asks Rudy about the principal advances in...

Welcome to a very special episode of The Sports Docs Podcast. In celebration of our 101st episode, we are honoring Dr. Mark Price who passed away on August 16, 2024 following his battle with leiomyosarcoma. We wanted to pay tribute to Dr. Price, who mentored us both through our residency at Harvard. His death is an immeasurable loss to his family and the community. Dr. Price was the Head Team Physician and Medical Director of the New England Patriots since 2016 and a team physician for the Boston Red Sox since 2009. He was a Captain in the U.S. Navy Reserves and served in combat operations in Afghanistan, where he was awarded the Bronze Star Medal. Most importantly, he was a bright example of a physician who cared deeply for his friends and family, including his wife Stephanie and their children, Henry, Julia and Sarah. The words shared by family and friends at his memorial service in Wellesley last month demonstrated a life rooted in purpose and accomplishments aligned with his values.Mark was one of our first guests, coming onto the show for Episode #3 and #4 in March of 2021. Consistent with who he was, he was willing to take the time out of his busy schedule to help two of his mentees build something new. So, with that, we thank Mark Price for all that he taught us and the mentorship he provided to not only us, but our community.--On today's episode we're continuing our discussion on shoulder instability with Dr. Mark Price, Orthopaedic Surgeon at Massachusetts General Hospital and Head Team Physician for the New England Patriots. We have 5 great articles which we discuss over two episodes that really contribute well this conversation on how to best manage shoulder instability in athletes both in-season and post-season. We're very honored to have Dr. Mark Price join our discussion today. Dr. Price specializes in sports medicine, knee and shoulder surgery. He is an attending surgeon at Massachusetts General Hospital and Assistant Professor of Orthopaedic Surgery at Harvard Medical School. Dr. Price earned his MD from Harvard Medical School and PhD in Medical Physics from MIT. He completed the Harvard Combined Orthopaedic Residency Program, where Catherine and I both attended as well, and then went on to complete a fellowship in sports medicine and shoulder reconstructive surgery at Mass General. Dr. Price is Head Team Physician and Medical Director for the New England Patriots and a Team Physician for the Boston Red Sox. He is a Captain in the US Navy Reserves and has served in combat operations in Afghanistan, where he was awarded the Bronze Star Medal for meritorious service. We begin with Dr. Hettrich of Brigham and Women's Hospital who recently investigated the question “Are there racial differences between patients undergoing surgery for shoulder instability?” We'll dive further into this topic and chat about how this impacts resident and fellow education. We will follow these articles up with a discussion on the surgical management of shoulder instability by reviewing two articles from the March issue of Arthroscopy. The first is a prospective randomized controlled trial titled Arthroscopic Bankart Repair With and Without Curettage of the Glenoid Edge. Desai and his team concluded that curettage of the glenoid edge reduced the incidence of postoperative recurrence of instability likely relating to improved healing of the capsulolabrum repair. Avramidis and colleagues contributed their cases on the management of recurrent anterior shoulder instability by All-Arthroscopic Modified Eden-Hybinette Procedure Using Iliac Crest Autograft and Double-Pair Button Fixation System. 

Welcome to a very special episode of The Sports Docs Podcast. In celebration of our 100th episode, we are honoring Dr. Mark Price who passed away on August 16, 2024 following his battle with leiomyosarcoma. We wanted to pay tribute to Dr. Price, who mentored us both through our residency at Harvard. His death is an immeasurable loss to his family and the community. Dr. Price was the Head Team Physician and Medical Director of the New England Patriots since 2016 and a team physician for the Boston Red Sox since 2009. He was a Captain in the U.S. Navy Reserves and served in combat operations in Afghanistan, where he was awarded the Bronze Star Medal. Most importantly, he was a bright example of a physician who cared deeply for his friends and family, including his wife Stephanie and their children, Henry, Julia and Sarah. The words shared by family and friends at his memorial service in Wellesley last month demonstrated a life rooted in purpose and accomplishments aligned with his values.Mark was one of our first guests, coming onto the show for Episode #3 and #4 in March of 2021. Consistent with who he was, he was willing to take the time out of his busy schedule to help two of his mentees build something new. So, with that, we thank Mark Price for all that he taught us and the mentorship he provided to not only us, but our community.--We have 5 great articles which we discuss over two episodes that really contribute well this conversation on how to best manage shoulder instability in athletes both in-season and post-season. We're very honored to have Dr. Mark Price join our discussion today. Dr. Price specializes in sports medicine, knee and shoulder surgery. He is an attending surgeon at Massachusetts General Hospital and Assistant Professor of Orthopaedic Surgery at Harvard Medical School. Dr. Price earned his MD from Harvard Medical School and PhD in Medical Physics from MIT. He completed the Harvard Combined Orthopaedic Residency Program, where Catherine and I both attended as well, and then went on to complete a fellowship in sports medicine and shoulder reconstructive surgery at Mass General. Dr. Price is Head Team Physician and Medical Director for the New England Patriots and a Team Physician for the Boston Red Sox. He is a Captain in the US Navy Reserves and has served in combat operations in Afghanistan, where he was awarded the Bronze Star Medal for meritorious service. The first paper is from the February issue of AJSM, titled Incidence of Posterior Shoulder Instability in the United States Military. It is a descriptive epidemiology study by Brett Owen and his team which found the incidence is higher than previously reported. Then, from the January issue of Sports Health, we feature the publication Does Functional Bracing of the Unstable Shoulder Improve Return to Play in Scholastic Athletes? Tokish and colleagues found functional bracing did not result in increased success rates when compared to no bracing in adolescent athletes.

In this episode, Daniel Arnold sits down with Dr. Vidur Mahajan   Dr. Vidur Mahajan is the Chief Executive Officer of CARPL.ai, the world's first end-to-end platform for testing, deployment, and monitoring of medical imaging AI solutions. With a background as a physician and an MBA from the Wharton School of Business, he has significantly contributed to healthcare technology adoption.   They discuss the company's two-step AI deployment framework (Dev-D), which helps institutions discover, test, and integrate AI applications. Key clients include academic centers like Mass General and Yale, and the Singapore government, using the platform for AI benchmarking and deployment.   The conversation highlights the significant investment radiologists, especially in India, make in upskilling with AI technology. Dr. Mahajan compares the current state of radiology AI to the early days of MRI, noting that while AI's capabilities are proven, its practical usefulness is still being established. They observe new AI companies emerging from regions like Eastern Europe and Southeast Asia.   A critical lesson shared involves the importance of proper client qualification in sales, avoiding pushing products onto uninterested clients. The guest emphasizes the need for a neutral platform to evaluate AI solutions transparently, ensuring healthcare providers can choose the best tools without bias. The episode concludes with insights on the future of radiology AI and reflections on the entrepreneurial journey in this field.   Learn more at https://medality.com/the-radiology-report-podcast   Like this episode? We'd love it if you could leave us a five-star review! And make sure to subscribe, so you never miss an opportunity to hear from the leaders in radiology.

Pradeep is a brilliant geneticist and Director of Preventive Cardiology, holds the Paul & Phyllis Fireman Endowed Chair in Vascular Medicine at Mass General Hospital and on faculty at Harvard Medical School and the Broad Institute. His prolific research has been illuminating for the field of improving our approach to reduce the risk of heart disease. That's especially important because heart disease is the global (and US) #1 killer and is on the increase. We didn't get into lifestyle factors here since there was so much ground to cover on new tests. drugs, and strategies.A video snippet of our conversation on ApoB. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to key publications and audioEric Topol (00:06):Well, welcome to Ground Truths. I'm Eric Topol and with me is Pradeep Natarajan from Harvard. He's Director of Preventative Cardiology at the Mass General Brigham Health System and he has been lighting it up on the field of cardiovascular. We're going to get to lots of different parts of that story and so, Pradeep welcome.Pradeep Natarajan (00:31):Thanks Eric, really delighted and honored to be with you and have this discussion.Eric Topol (00:36):Well, for years I've been admiring your work and it's just accelerating and so there's so many things to get to. I thought maybe what we'd start off with is you recently wrote a New England Journal piece about two trials, two different drugs that could change the landscape of cardiovascular prevention in the future. I mean, that's one of the themes we're going to get to today is all these different markers and drugs that will change cardiology as we know it now. So maybe you could just give us a skinny on that New England Journal piece.Two New Lipid Targets With RNA DrugsPradeep Natarajan (01:16):Yeah, yeah, so these two agents, the trials were published at the same time. These phase two clinical trials for plozasiran, which is an siRNA against APOC3 and zodasiran, which is an siRNA against ANGPTL3. The reason why we have medicines against those targets are based on human genetics observations, that individuals with loss of function mutations and either of those genes have reduced lipids. For APOC3, it's reduced triglycerides for ANGPTL3 reduced LDL cholesterol and reduced triglycerides and also individuals that have those loss of function mutations also have lower risk for coronary artery disease. Now that's a very similar parallel to PCSK9. We have successful medicines that treat that target because people have found that carriers of loss of function mutations in PCSK9 lead to lower LDL cholesterol and lower coronary artery disease.(02:11):Now that suggests that therapeutic manipulation without significant side effects from the agents themselves for APOC3 and ANGPTL3 would be anticipated to also lower coronary artery disease risk potentially in complementary pathways to PCSK9. The interesting thing with those observations is that they all came from rare loss of function mutations that are enriched in populations of individuals. However, at least for PCSK9, has been demonstrated to have efficacy in large groups of individuals across different communities. So the theme of that piece was really just the need to study diverse populations because those insights are not always predictable about which communities are going to have those loss of function mutations and when you find them, they often have profound insights across much larger groups of individuals.Eric Topol (03:02):Well, there's a lot there that we can unpack a bit of it. One of them is the use of small interfering RNAs (siRNA) as drugs. We saw in the field of PCSK9, as you mentioned. First there were monoclonal antibodies directed against this target and then more recently, there's inclisiran which isn't an RNA play if you will, where you only have to take it twice a year and supposedly it's less expensive and I'm still having trouble in my practice getting patients covered on their insurance even though it's cheaper and much more convenient. But nonetheless, now we're seeing these RNA drugs and maybe you could comment about that part and then also the surprise that perhaps is unexplained is the glucose elevation.Pradeep Natarajan (03:53):Yeah, so for medicines and targets that have been discovered through human genetics, those I think are attractive for genetic-based therapies and longer interval dosing for the therapies, which is what siRNAs allow you to do because the individuals that have these perturbations, basically the naturally occurring loss of function mutations, they have these lifelong, so basically have had a one-time therapy and have lived, and so far, at least for these targets, have not had untoward side effects or untoward phenotypic consequences and only reduce lipids and reduce coronary artery disease. And so, instead of taking a pill daily, if we have conviction that that long amount of suppression may be beneficial, then longer interval dosing and not worrying about the pill burden is very attractive specifically for those specific therapeutics. And as you know, people continue to innovate on further prolonging as it relates to PCSK9.(04:57):Separately, some folks are also developing pills because many people do feel that there's still a market and comfort for daily pills. Now interestingly for the siRNA for zodasiran at the highest dose, actually for both of them at the highest doses, but particularly for zodasiran, there was an increase in insulin resistance parameters actually as it relates to hyperglycemia and less so as it relates to insulin resistance, that is not predicted based on the human genetics. Individuals with loss of function mutations do not have increased risks in hyperglycemia or type 2 diabetes, so that isolates it related to that specific platform or that specific technology. Now inclisiran, as you'd mentioned, Eric is out there. That's an siRNA against PCSK9 that's made by a different manufacturer. So far, the clinical trials have not shown hyperglycemia or type 2 diabetes as it relates inclisiran, so it may be related to the specific siRNAs that are used for those targets. That does merit further consideration. Now, the doses that the manufacturers do plan to use in the phase three clinical trials are at lower doses where there was not an increase in hyperglycemia, but that does merit further investigation to really understand why that's the case. Is that an expected generalized effect for siRNAs? Is it related to siRNAs for this specific target or is it just related to the platform used for these two agents which are made by the same manufacturer?Eric Topol (06:27):Right, and I think the fact that it's a mystery is intriguing at the least, and it may not come up at the doses that are used in the trials, but the fact that it did crop up at high doses is unexpected. Now that is part of a much bigger story is that up until now our armamentarium has been statins and ezetimibe to treat lipids, but it's rapidly expanding Lp(a), which for decades as a cardiologist we had nothing to offer. There may even be drugs to be able to lower people who are at high risk with high Lp(a). Maybe you could discuss that.What About Lp(a)?Pradeep Natarajan (07:13):Yeah, I mean, Eric, as you know, Lp(a) has been described as a cardiovascular disease risk factors for quite so many years and there are assays to detect lipoprotein(a) elevation and have been in widespread clinical practice increasing widespread clinical practice, but we don't yet have approved therapies. However, there is an abundance of literature preclinical data that suggests that it likely is a causal factor, meaning that if you lower lipoprotein(a) when elevated, you would reduce the risk related to lipoprotein(a). And a lot of this comes from similar human genetic studies. The major challenge of just relating a biomarker to an outcome is there are many different reasons why a biomarker might be elevated, and so if you detect a signal that correlates a biomarker, a concentration to a clinical outcome, it could be related to that biomarker, but it could be to the other reasons that the biomarker is elevated and sometimes it relates to the outcome itself.(08:10):Now human genetics is very attractive because if you find alleles that strongly relate to that exposure, you can test those alleles themselves with the clinical outcome. Now the allele assignment is established at birth. No other factor is going to change that assignment after conception, and so that provides a robust, strong causal test for that potential exposure in clinical outcome. Now, lipoprotein(a) is unique in that it is highly heritable and so there are lots of different alleles that relate to lipoprotein(a) and so in a well powered analysis can actually test the lipoprotein(a) SNPs with the clinical outcomes and similar to how there is a biomarker association with incident myocardial infarction and incident stroke, the SNPs related to lipoprotein(a) show the same. That is among the evidence that strongly supports that this might be causal. Now, fast forward to many years later, we have at least three phase three randomized clinical trials testing agents that have been shown to be very potent at lowering lipoprotein(a) that in the coming years we will know if that hypothesis is true. Importantly, we will have to understand what are the potential side effects of these medicines. There are antisense oligonucleotides and siRNAs that are primarily in investigation. Again, this is an example where there's a strong genetic observation, and so these genetic based longer interval dosing therapies may be attractive, but side effects will be a key thing as well too. Those things hard to anticipate really can anticipate based on the human genetics for off target effects, for example.(09:52):It's clearly a risk signal and hopefully in the near future we're going to have specific therapies.Eric Topol (09:57):Yeah, you did a great job of explaining Mendelian randomization and the fact the power of genetics, which we're going to get into deeper shortly, but the other point is that do you expect now that there's these multiple drugs that lower Lp(a) efficiently, would that be enough to get approval or will it have to be trials to demonstrate improved cardiovascular outcomes?Pradeep Natarajan (10:24):There is a great regulatory path at FDA for approval just for LDL cholesterol lowering and inclisiran is on the market and the phase three outcomes data has not yet been reported because there is a wide appreciation that LDL cholesterol lowering is a pretty good surrogate for cardiovascular disease risk lowering. The label will be restricted to LDL cholesterol lowering and then if demonstrated to have clinical outcomes, the label could be expanded. For other biomarkers including lipoprotein(a), even though we have strong conviction that it is likely a causal factor there hasn't met the bar yet to get approval just based on lipoprotein(a) lowering, and so we would need to see the outcomes effects and then we would also need to understand side effects. There is a body of literature of side effects for other therapies that have targeted using antisense oligonucleotides. We talked about potential side effects from some siRNA platforms and sometimes those effects could overtake potential benefits, so that really needs to be assessed and there is a literature and other examples.(11:31):The other thing I do want to note related to lipoprotein(a) is that the human genetics are modeled based on lifelong perturbations, really hard to understand what the effects are, how great of an effect there might be in different contexts, particularly when introduced in middle age. There's a lot of discussion about how high lipoprotein(a) should be to deliver these therapies because the conventional teaching is that one in five individuals has high lipoprotein(a), and that's basically greater than 75 nanomoles per liter. However, some studies some human genetic studies to say if you want to get an effect that is similar to the LDL cholesterol lowering medicines on the market, you need to start with actually higher lipoprotein(a) because you need larger amounts of lipoprotein(a) lowering. Those are studies and approaches that haven't been well validated. We don't know if that's a valid approach because that's modeling based on this sort of lifelong effect. So I'm very curious to see what the overall effect will be because to get approval, I think you need to demonstrate safety and efficacy, but most importantly, these manufacturers and we as clinicians are trying to find viable therapies in the market that it won't be hard for us to get approval because hopefully the clinical trial will have said this is the context where it works. It works really well and it works really well on top of the existing therapies, so there are multiple hurdles to actually getting it directly to our patients.How Low Do You Go with LDL Cholesterol?Eric Topol (13:02):Yeah, no question about that. I'm glad you've emphasized that. Just as you've emphasized the incredible lessons from the genetics of people that have helped guide this renaissance to better drugs to prevent cardiovascular disease. LDL, which is perhaps the most impressive surrogate in medicine, a lab test that you already touched on, one of the biggest questions is how low do you go? That is Eugene Braunwald, who we all know and love. They're in Boston. The last time I got together with him, he was getting his LDL down to close to zero with various tactics that might be extreme. But before we leave these markers, you're running preventive cardiology at man's greatest hospital. Could you tell us what is your recipe for how aggressive do you go with LDL?Pradeep Natarajan (14:04):Yeah, so when I talk to patients where we're newly getting lipid lowering therapies on, especially because many people don't have a readout of abnormal LDL cholesterol when we're prescribing these medicines, it's just giving them a sense of what we think an optimal LDL cholesterol might be. And a lot of this is based on just empirical observations. So one, the average LDL cholesterol in the modern human is about 100 to 110 mg/dL. However, if you look at contemporary hunter gatherers and non-human primates, their average LDL is about 40 to 50 and newborn babies have an LDL cholesterol of about 30. And the reason why people keep making LDL cholesterol lowering medicines because as you stack on therapies, cardiovascular disease events continue to reduce including down to these very low LDL cholesterol values. So the population mean for LDL cholesterol is high and everybody likely has hypercholesterolemia, and that's because over the last 10,000 years how we live our lives is so dramatically different and there has not been substantial evolution over that time to change many of these features related to metabolism.(15:16):And so, to achieve those really low LDL cholesterol values in today's society is almost impossible without pharmacotherapies. You could say, okay, maybe everybody should be on pharmacotherapies, and I think if you did that, you probably would reduce a lot of events. You'll also be treating a lot of individuals who likely would not get events. Cardiovascular disease is the leading killer, but there are many things that people suffer from and most of the times it still is not cardiovascular disease. So our practice is still rooted in better identifying the individuals who are at risk for cardiovascular disease. And so, far we target our therapies primarily in those who have already developed cardiovascular disease. Maybe we'll talk about better identifying those at risk, but for those individuals it makes lots of sense to get it as low as possible. And the field has continued to move to lower targets.(16:07):One, because we've all recognized, at least based on these empirical observations that lower is better. But now increasingly we have a lot of therapies to actually get there, and my hope is that with more and more options and the market forces that influence that the cost perspective will make sense as we continue to develop more. As an aside, related aside is if you look at the last cholesterol guidelines, this is 2018 in the US this is the first time PCSK9 inhibitors were introduced in the guidelines and all throughout that there was discussions of cost. There are a lot of concerns from the field that PCSK9 inhibitors would bankrupt the system because so many people were on statins. And you look at the prior one that was in 2013 and cost was mentioned once it's just the cost effectiveness of statins. So I think the field has that overall concern.(17:01):However, over time we've gotten comfortable with lower targets, there are more medicines and I think some of this competition hopefully will drive down some of the costs, but also the overall appreciation of the science related to LDL. So long-winded way of saying this is kind of the things that we discussed just to give reassurance that we can go to low LDL cholesterol values and that it's safe and then we think also very effective. Nobody knows what the lower limit is, whether zero is appropriate or not. We know that glucose can get too low. We know that blood pressure can be too low. We don't know yet that limit for LDL cholesterol. I mean increasingly with these trials we'll see it going down really low and then we'll better appreciate and understand, so we'll see 40 is probably the right range.Eric Topol (17:49):40, you said? Yeah, okay, I'll buy that. Of course, the other thing that we do know is that if you push to the highest dose statins to get there, you might in some people start to see the hyperglycemia issue, which is still not fully understood and whether that is, I mean it's not desirable, but whether or not it is an issue, I guess it's still out there dangling. Now the other thing that since we're on LDL, we covered Lp(a), PCSK9, the siRNA, is ApoB. Do you measure ApoB in all your patients? Should that be the norm?Measuring ApoBPradeep Natarajan (18:32):Yeah, so ApoB is another blood test. In the standard lipid panel, you get four things. What's measured is cholesterol and triglycerides, they're the lipids insoluble in blood to get to the different tissues that get packaged in lipoprotein molecules which will have the cholesterol, triglycerides and some other lipids and proteins. And so, they all have different names as you know, right? Low density lipoprotein, high density lipoprotein and some others. But also in the lipid panel you get the HDL cholesterol, the amount of cholesterol in an HDL particle, and then most labs will calculate LDL cholesterol and LDL cholesterol has a nice relationship with cardiovascular disease. You lower it with statins and others. Lower risk for cardiovascular disease, turns out a unifying feature of all of these atherogenic lipoproteins, all these lipoproteins that are measured and unmeasured that relate to cardiovascular disease, including lipoprotein(a), they all have an additional protein called ApoB. And ApoB, at least as it relates to LDL is a pretty good surrogate of the number of LDL particles.(19:37):Turns out that that is a bit better at the population level at predicting cardiovascular disease beyond LDL cholesterol itself. And where it can be particularly helpful is that there are some patients out there that have an unexpected ratio between ApoB and LDL. In general, the ratio between LDL cholesterol and ApoB is about 1.1 and most people will have that rough ratio. I verify that that is the expected, and then if that is the expected, then really there is no role to follow ApoB. However, primarily the patients that have features related to insulin resistance have obesity. They may often have adequate looking LDL cholesterols, but their ApoB is higher. They have more circulating LDL particles relative to the total amount of LDL cholesterol, so smaller particles themselves. However, the total number of particles may actually be too high for them.(20:34):And so, even if the LDL cholesterol is at target, if the ApoB is higher, then you need to reduce. So usually the times that I just kind of verify that I'm at appropriate target is I check the LDL cholesterol, if that looks good, verify with the ApoB because of this ratio, the ApoB target should be about 10% lower. So if we're aiming for about 40, that's like 36, so relatively similar, and if it's there, I'm good. If it's not and it's higher, then obviously increase the LDL cholesterol lowering medicines because lower the ApoB and then follow the ApoB with the lipids going forward. The European Society of Cardiology has more emphasis on measuring ApoB, that is not as strong in the US guidelines, but there are many folks in the field, preventive cardiologists and others that are advocating for the increasing use of ApoB because I think there are many folks that are not getting to the appropriate targets because we are not measuring ApoB.Why Aren't We Measuring and Treating Inflammation?Eric Topol (21:37):Yeah, I think you reviewed it so well. The problem here is it could be part of the standard lipid panel, it would make this easy, but what you've done is a prudent way of selecting out people who it becomes more important to measure and moderate subsequently. Now this gets us to the fact that we're lipid centric and we don't pay homage to inflammation. So I wrote a recent Substack on the big miss on inflammation, and here you get into things like the monoclonal antibody to interleukin-6, the trial that CANTOS that showed significant reduction in cardiovascular events and fatal cancers by the way. And then you get into these colchicine trials two pretty good size randomized trials, and here the entry was coronary disease with a high C-reactive protein. Now somehow or other we abandon measuring CRP or other inflammatory markers, and both of us have had patients who have low LDLs but have heart attacks or significant coronary disease. So why don't we embrace inflammation? Why don't we measure it? Why don't we have better markers? Why is this just sitting there where we could do so much better? Even agents that are basically cost pennies like colchicine at low doses, not having to use a proprietary version could be helpful. What are your thoughts about us upgrading our prevention with inflammation markers?Pradeep Natarajan (23:22):Yeah, I mean, Eric, there is an urgent need to address these other pathways. I say urgent need because heart disease has the dubious distinction of being the leading killer in the US and then over the last 20 years, the leading killer in the world as it takes over non-communicable diseases. And really since the early 1900s, there has been a focus on developing pharmacotherapies and approaches to address the traditional modifiable cardiovascular disease risk factors. That has done tremendous good, but still the curves are largely flattening out. But in the US and in many parts of the world, the deaths attributable to cardiovascular disease are starting to tick up, and that means there are many additional pathways, many of them that we have well recognized including inflammation. More recently, Lp(a) that are likely important for cardiovascular disease, for inflammation, as you have highlighted, has been validated in randomized controlled trials.(24:18):Really the key trial that has been more most specific is one on Canakinumab in the CANTOS trial IL-1β monoclonal antibody secondary prevention, so cardiovascular disease plus high C-reactive protein, about a 15% reduction in cardiovascular disease and also improvement in cancer related outcomes. Major issues, a couple of issues. One was increased risk for severe infections, and the other one is almost pragmatic or practical is that that medicine was on the market at a very high price point for rare autoinflammatory conditions. It still is. And so, to have for a broader indication like cardiovascular disease prevention would not make sense at that price point. And the manufacturer tried to go to the FDA and focus on the group that only had C-reactive protein lowering, but that's obviously like a backwards endpoint. How would you know that before you release the medicine? So that never made it to a broader indication.(25:14):However, that stuck a flag in the broader validation of that specific pathway in cardiovascular disease. That pathway has direct relevance to C-reactive protein. C-reactive protein is kind of a readout of that pathway that starts from the NLRP3 inflammasome, which then activates IL-1β and IL-6. C-reactive protein we think is just a non causal readout, but is a reliable test of many of these features and that's debatable. There may be other things like measuring IL-6, for example. So given that there is actually substantial ongoing drug development in that pathway, there are a handful of companies with NLRP3 inflammasome inhibitors, but small molecules that you can take as pills. There is a monoclonal antibody against IL-6 that's in development ziltivekimab that's directed at patients with chronic kidney disease who have lots of cardiovascular disease events despite addressing modifiable risk factors where inflammatory markers are through the roof.(26:16):But then you would also highlighted one anti-inflammatory that's out there that's pennies on the dollar, that's colchicine. Colchicine is believed to influence cardiovascular disease by inhibiting NLRP3, I say believed to. It does a lot of things. It is an old medicine, but empirically has been shown in at least two randomized controlled trials patients with coronary artery disease, actually they didn't measure C-reactive protein in the inclusion for these, but in those populations we did reduce major adverse cardiovascular disease events. The one thing that does give me pause with colchicine is that there is this odd signal for increased non-cardiovascular death. Nobody understands if that's real, if that's a fluke. The FDA just approved last year low dose colchicine, colchicine at 0.5 milligrams for secondary prevention given the overwhelming efficacy. Hasn't yet made it into prevention guidelines, but I think that's one part that does give me a little bit pause. I do really think about it particularly for patients who have had recurrent events. The people who market the medicine and do research do remind us that C-reactive protein was not required in the inclusion, but nobody has done that secondary assessment to see if measuring C-reactive protein would be helpful in identifying the beneficial patients. But I think there still could be more work done on better identifying who would benefit from colchicine because it's an available and cheap medicine. But I'm excited that there is a lot of development in this inflammation area.Eric Topol (27:48):Yeah, well, the development sounds great. It's probably some years away. Do you use colchicine in your practice?Pradeep Natarajan (27:56):I do. Again, for those folks who have had recurrent events, even though C-reactive protein isn't there, it does make me feel like I'm treating inflammation. If C-reactive protein is elevated and then I use it for those patients, if it's not elevated, it's a much harder sell from my standpoint, from the patient standpoint. At the lower dose for colchicine, people generally are okay as far as side effects. The manufacturer has it at 0.5 milligrams, which is technically not pennies on the dollar. That's not generic. The 0.6 milligrams is generic and they claim that there is less side effects at the 0.5 milligrams. So technically 0.6 milligrams is off label. So it is what it is.CHIP and Defining High Risk People for CV DiseaseEric Topol (28:40):It's a lot more practical, that's for sure. Now, before I leave that, I just want to mention when I reviewed the IL-1β trial, you mentioned the CANTOS trial and also the colchicine data. The numbers of absolute increases for infection with the antibody or the cancers with the colchicine are really small. So I mean the benefit was overriding, but I certainly agree with your concern that there's some things we don't understand there that need to be probed more. Now, one of the other themes, well before one other marker that before we get to polygenic risk scores, which is center stage here, defining high risk people. We've talked a lot about the conventional things and some of the newer ways, but you've been one of the leaders of study of clonal hematopoiesis of indeterminate potential known as CHIP. CHIP, not the chips set in your computer, but CHIP. And basically this is stem cell mutations that increase in people as we age and become exceptionally common with different mutations that account in these clones. So maybe you can tell us about CHIP and what I don't understand is that it has tremendous correlation association with cardiovascular outcomes adverse as well as other system outcomes, and we don't measure it and we could measure it. So please take us through what the hell is wrong there.Pradeep Natarajan (30:14):Yeah, I mean this is really exciting. I mean I'm a little bit biased, but this is observations that have been made only really over the last decade, but accelerating research. And this has been enabled by advances in genomic technologies. So about 10 years or plus ago, really getting into the early days of population-based next generation sequencing, primarily whole exome sequencing. And most of the DNA that we collect to do these population-based analyses come from the blood, red blood cells are anucleate, so they're coming from white blood cells. And so, at that time, primarily interrogating what is the germline genetic basis for coronary artery disease and early onset myocardial infarction. At the same time, colleagues at the Broad Institute were noticing that there are many additional features that you can get from the blood-based DNA that was being processed by the whole exome data. And there were actually three different groups that converged on that all in Boston that converged on the same observation that many well-established cancer causing mutations.(31:19):So mutations that are observed in cancers that have been described to drive the cancers themselves were being observed in these large population-based data sets that we were all generating to understand the relationship between loss of function mutations in cardiovascular disease. That's basically the intention of those data sets for being generated for other things. Strong correlation with age, but it was very common among individuals greater than 70; 10% of them would have these mutations and is very common because blood cancer is extremely, it's still pretty rare in the population. So to say 10% of people had cancer causing driver mutations but didn't have cancer, was much higher than anyone would've otherwise expected. In 2014, there were basically three main papers that described that, and they also observed that there is a greater risk of death. You'd say, okay, this is a precancerous lesion, so they're probably dying of cancer.(32:17):But as I said, the absolute incidence rate for blood cancer is really low and there's a relative increase for about tenfold, but pretty small as it relates to what could be related to death. And in one of the studies we did some exploratory analysis that suggested maybe it's actually the most common cause of death and that was cardiovascular disease. And so, a few years later we published a study that really in depth really looked at a bunch of different data sets that were ascertained to really understand the relationship between these mutations, these cancer causing mutations in cardiovascular disease, so observed it in enrichment and older individuals that had these mutations, CHIP mutations, younger individuals who had early onset MI as well too, and then also look prospectively and showed that it related to incident coronary artery disease. Now the major challenge for this kind of analysis as it relates to the germline genetic analysis is prevalence changes over time.(33:15):There are many things that could influence the presence of clonal hematopoiesis. Age is a key enriching factor and age is the best predictor for cardiovascular disease. So really important. So then we modeled it in mice. It was actually a parallel effort at Boston University (BU) that was doing the same thing really based on the 2014 studies. And so, at the same time we also observed when you modeled this in mice, you basically perturb introduce loss of function mutations in the bone marrow for these mice to recapitulate these driver mutations and those mice also have a greater burden of atherosclerosis. And Eric, you highlighted inflammation because basically the phenotype of these cells are hyper inflamed cells. Interestingly, C-reactive protein is only modestly elevated. So C-reactive protein is not fully capturing this, but many of the cytokines IL-1β, IL-6, they're all upregulated in mice and in humans when measured as well.(34:11):Now there've been a few key studies that have been really exciting about using anti-inflammatories in this pathway to address CHIP associated cardiovascular disease. So one that effort that I said in BU because they saw these cytokines increased, we already know that these cytokines have relationship with atherosclerosis. So they gave an NLRP3 inflammasome inhibitor to the mice and they showed that the mice with or without CHIP had a reduction in atherosclerosis, but there was a substantial delta among the mice that are modeled as having CHIP. Now, the investigators in CANTOS, the manufacturers, they actually went back and they survey where they had DNA in the CANTOS trial. They measured CHIP and particularly TET2 CHIP, which is the one that has the strongest signal for atherosclerosis. As I said, overall about 15% reduction in the primary outcome in CANTOS. Among the individuals who had TET2 CHIP, it was a 64% reduction in event.(35:08):I mean you don't see those in atherosclerosis related trials. Now this has the caveat of it being secondary post hoc exploratory, the two levels of evidence. And so, then we took a Mendelian randomization approach. Serendipitously, just so happens there is a coding mutation in the IL-6 receptor, a missense mutation that in 2012 was described that if you had this mutation, about 40% of people have it, you have a 5%, but statistically significant reduction in coronary artery disease. So we very simply said, if the pathway of this NLRP3 inflammasome, which includes IL-6, if you have decreased signaling in that pathway, might you have an even greater benefit from having that mutation if you had CHIP versus those who didn't have CHIP. So we looked in the UK Biobank, those who didn't have CHIP 5% reduction, who had that IL-6 receptor mutation, and then those who did have CHIP, if they had that mutation, it was about a 60% reduction in cardiovascular disease.(36:12):Again, three different lines of evidence that really show that this pathway has relevance in the general population, but the people who actually might benefit the most are those with CHIP. And I think as we get more and more data sets, we find that not all of the CHIP mutations are the same as it relates to cardiovascular disease risk. It does hone in on these key subsets like TET2 and JAK2, but this is pretty cool as a preventive cardiologist, new potential modifiable risk factor, but now it's almost like an oncologic paradigm that is being applied to coronary artery disease where we have specific driver mutations and then we're tailoring our therapies to those specific biological drivers for coronary artery disease. Hopefully, I did that justice. There's a lot there.Why Don't We Measure CHIP?Eric Topol (36:57):Well, actually, it's phenomenal how you've explained that, but I do want to review for our listeners or readers that prior to this point in our conversation, we were talking about germline mutations, the ones you're born with. With CHIP, we're talking about acquired somatic mutations, and these are our blood stem cells. And what is befuddling to me is that with all the data that you and others, you especially have been publishing and how easy it would be to measure this. I mean, we've seen that you can get it from sequencing no less other means. Why we don't measure this? I mean, why are we turning a blind eye to CHIP? I just don't get it. And we keep calling it of indeterminate potential, not indeterminate. It's definite potential.Pradeep Natarajan (37:51):Yeah, no, I think these are just overly cautious terms from the scientists. Lots of people have CHIP, a lot of people don't have clinical outcomes. And so, I think from the lens of a practicing hematologists that provide some reassurance on the spectrum for acquired mutation all the way over to leukemia, that is where it comes from. I don't love the acronym as well because every subfield in biomedicine has its own CHIP, so there's obviously lots of confusion there. CH or clinical hematopoiesis is often what I go, but I think continuing to be specific on these mutations. Now the question is why measure? Why aren't we measuring it? So there are some clinical assays out there. Now when patients get evaluated for cytopenias [low cell counts], there are next generation sequencing tests that look for these mutations in the process for evaluation. Now, technically by definition, CHIP means the presence of these driver mutations that have expanded because it's detectable by these assays, not a one-off cell because it can only be detected if it's in a number of cells.(38:55):So there has been some expansion, but there are no CBC abnormalities. Now, if there's a CBC abnormality and you see a CHIP mutation that's technically considered CCUS or clonal cytopenia of unknown significance, sometimes what is detected is myelodysplastic syndrome. In those scenarios still there is a cardiovascular disease signal, and so many of our patients who are seen in the cancer center who are being evaluated for these CBC abnormalities will be detected to have these mutations. They will have undergone some risk stratification to see what the malignancy potential is. Still pretty low for many of those individuals. And so, the major driver of health outcomes for this finding may be cardiovascular. So those patients then get referred to our program. Dana-Farber also has a similar program, and then my colleague Peter Libby at the Brigham often sees those patients as well. Now for prospective screening, so far, an insurance basically is who's going to pay for it.(39:51):So an insurance provider is not deemed that appropriate yet. You do need the prospective clinical trials because the medicines that we're talking about may have side effects as well too. And what is the yield? What is the diagnostic yield? Will there actually be a large effect estimate? But there has been more and more innovation, at least on the assay and the cost part of the assay because these initial studies, we've been using whole exome sequencing, which is continuing to come down, but is not a widely routine clinical test yet. And also because as you highlighted, these are acquired mutations. A single test is not necessarily one and done. This may be something that does require surveillance for particular high risk individuals. And we've described some risk factors for the prevalence of CHIP. So surveillance may be required, but because there are about 10 genes that are primarily implicated in CHIP, that can substantially decrease the cost of it. The cost for DNA extraction is going down, and so there are research tests that are kind of in the $10 to $20 range right now for CHIP. And if flipped over to the clinical side will also be reasonably low cost. And so, for the paradigm for clinical implementation, that cost part is necessary.Eric Topol (41:10):I don't know the $10 or $20 ones. Are there any I could order on patients that I'm worried about?Pradeep Natarajan (41:17):Not yet clinical. However, there is a company that makes the reagents for at least the cores that are developing this. They are commercializing that test so that many other cores, research cores can develop it. I think it's in short order that clinical labs will adopt it as well too.Eric Topol (41:36):That's great.Pradeep Natarajan (41:37):I will keep you apprised.What About Polygenic Risk Scores?Eric Topol (41:39):I think that's really good news because like I said, we're so darn lipid centric and we have to start to respect the body of data, the knowledge that you and others have built about CHIP. Now speaking of another one that drives me nuts is polygenic risk score (PRS) for about a decade, I've been saying we have coronary disease for most people is a polygenic trait. It's not just a familial hypercholesterolemia. And we progressively have gotten better and better of the hundreds of single variants that collectively without a parental history will be and independently predict who is at double, triple or whatever risk of getting heart disease, whereby you could then guide your statins at higher aggressive or pick a statin, use one or even go beyond that as we've been talking about. But we don't use that in practice, which is just incredible because it's can be done cheap.(42:45):You can get it through whether it's 23andMe or now many other entities. We have an app, MyGeneRank where we can process that Scripss does for free. And only recently, Mass General was the first to implement that in your patient population, and I'm sure you were a driver of that. What is the reluctance about using this as an orthogonal, if you will, separate way to assess a person's risk for heart disease? And we know validated very solidly about being aggressive about lipid lowering when you know this person's in the highest 5% polygenic risk score. Are we just deadheads in this field or what?Pradeep Natarajan (43:30):Yeah, I mean Eric, as you know, lots of inertia in medicine, but this one I think has a potential to make a large impact. Like CHIP mutations, I said news is about 10% in individuals greater than 70. The prospect here is to identify the risk much earlier in life because I think there is a very good argument that we're undertreating high risk individuals early on because we don't know how to identify them. As you highlighted, Dr. Braunwald about LDL cholesterol. The other part of that paradigm is LDL cholesterol lowering and the duration. And as we said, everybody would benefit from really low LDL cholesterol, but again, you might overtreat that if you just give that to everybody. But if you can better identify the folks very early in life, there is a low cost, low risk therapy, at least related to statins that you could have a profound benefit from the ones who have a greater conviction will have future risk for cardiovascular disease.(44:21):You highlighted the family history, and the family history has given the field of clues that genetics play a role. But as the genome-wide association studies have gotten larger, the polygenic risk scores have gotten better. We know that family history is imperfect. There are many reasons why a family member who is at risk may or may not have developed cardiovascular disease. A polygenic risk score will give a single number that will estimate the contribution of genetics to cardiovascular disease. And the thing that is really fascinating to me, which is I think some of a clinical implementation challenge is that the alleles for an individual are fixed. The genotyping is very cheap. That continues to be extremely cheap to do this test. But the weights and the interpretation of what the effects should be for each of the SNPs are continually being refined over time.(45:18):And so, given the exact same SNPs in the population, the ability to better predict cardiovascular diseases getting better. And so, you have things that get reported in the literature, but literally three years later that gets outdated and those hypotheses need to be reassessed. Today, I'll say we have a great relative to other things, but we have a great polygenic risk score was just reported last year that if you compare it to familial hypercholesterolemia, which has a diagnostic yield of about 1 in 300 individuals, but readily detectable by severe hypercholesterolemia that has about threefold risk for cardiovascular disease. By polygenic risk score, you can find 1 in 5 individuals with that same risk. Obviously you go higher than that, it'll be even higher risk related to that. And that is noble information very early in life. And most people develop risk factors later in life. It is happening earlier, but generally not in the 30s, 40s where there's an opportunity to make a substantial impact on the curve related to cardiovascular disease.(46:25):But there is a lot of momentum there. Lots of interest from NIH and others. The major challenge is though the US healthcare system is really not well set up to prevention, as you know, we practice healthcare after patient's developed disease and prevent the complications related to progression. The stakeholder incentives beyond the patient themselves are less well aligned. We've talked a lot here today about payers, but we don't have a single payer healthcare system. And patients at different times of their lives will have different insurers. They'll start early in life with their parents, their first employer, they'll move on to the next job and then ultimately Medicare. There's no entity beyond yourself that really cares about your longevity basically from the beginning and your overall wellness. That tension has been a major challenge in just driving the incentives and the push towards polygenic risk scores. But there are some innovative approaches like MassMutual Life Insurance actually did a pilot on polygenic risk scoring.(47:33):They're in the business of better understanding longevity. They get that this is important data. Major challenges, there are federal protections against non-discrimination in the workplace, health insurance, not necessarily life insurance. So I think that there are lots of things that have to be worked out. Everybody recognizes that this is important, but we really have to have all the incentives aligned for this to happen at a system-wide level in the US. So there's actually lots of investment in countries that have more nationalized healthcare systems, lots of development in clinical trials in the UK, for example. So it's possible that we in the US will not be the lead in that kind of evidence generation, but maybe we'll get there.The GLP-1 DrugsEric Topol (48:16):Yeah, it's frustrating though, Pradeep, because this has been incubating for some time and now we have multi ancestry, polygenic risk scores, particularly for heart disease and we're not using it, and it's not in my view, in the patient's best interest just because of these obstacles that you're mentioning, particularly here in the US. Well, the other thing I want to just get at with you today is the drugs that we were using for diabetes now blossoming for lots of other indications, particularly the glucagon-like peptide 1 (GLP-1) drugs. This has come onto the scene in recent years, not just obviously for obesity, but it's anti-inflammatory effects as we're learning, mediated not just through the brain but also T cells and having extraordinary impact in heart disease for people with obesity and also with those who have heart failure, about half of heart failure for preserved ejection fraction. So recently you and your colleagues recently published a paper with this signal of optic neuropathy. It was almost seven eightfold increase in a population. First, I wanted to get your sense about GLP-1. We're also going to get into the SGLT2 for a moment as well, but how do you use GLP-1? What's your prognosis for this drug class going forward?Pradeep Natarajan (49:55):As it relates to the paper, I can't claim credit as one of my former students who is now Mass Eye and Ear resident who participated, but we can talk about that. There's obviously some challenges for mining real world data, but this was related to anecdotes that they were observing at Mass Eye and Ear and then studied and observed an enrichment. In general though, I feel like every week I'm reading a new clinical trial about a new clinical outcome benefit as it relates to GLP-1 receptor agonists. This is kind of one thing that stands out that could be interrogated in these other clinical trials. So I would have that caveat before being cautious about ocular complications. But the data has been overwhelmingly beneficial, I think, because at minimum, obesity and inflammation are relayed to myriad of consequences, and I'm really excited that we have therapies that can address obesity that are safe.(50:52):There's a legacy of unsafe medicines for obesity, especially related to cardiovascular disease. So the fact that we have medicines that are safe and effective for lowering weight that also have real strong effects on clinical outcomes is tremendous. We in cardiology are increasingly using a range of diabetes medicines, including GLP-1 receptor agonists and SGLT2 inhibitors. I think that is also the secular changes of what influences cardiovascular disease over time. I talked about over the last 10 years or so with this increase in deaths attributable to cardiovascular disease. If you look at the influences of traditional clinical risk factors today, many of them have decreased in importance because when abnormal, we recognize them, in general we modify them when recognized. And so, many of the things that are unaddressed, especially the features related to insulin resistance, obesity, they start rising in importance. And so, there is a dramatic potential for these kinds of therapies in reducing the residual risks that we see related to cardiovascular disease. So I'm enthusiastic and excited. I think a lot more biology that needs to be understood of how much of this is being influenced specifically through this pathway versus a very effective weight loss medicine. But also interesting to see the insights on how the effect centrally on appetite suppression has profound influences on weight loss as well too. And hopefully that will lead to more innovations in weight management.The SGLT-2 DrugsEric Topol (52:25):And likewise, perhaps not getting near as much play, but when it came on the cardiovascular scene that an anti-diabetic drug SGLT2 was improving survival, that was big, and we still don't know why. I mean, there's some ideas that it might be a senolytic drug unknowingly, but this has become a big part of practice of cardiology in patients with diabetes or with preserved ejection fraction heart failure. Is that a fair summary for that drug?Pradeep Natarajan (53:00):Yeah, I totally agree. I mean, as there has been increased recognition for heart failure preserved ejection fraction, it has been almost disheartening over the last several years that we have not had very specific effective therapies to treat that condition. Now, it is a tremendous boon that we do have medicines interestingly focused on metabolism that are very helpful in that condition for heart failure with preserved ejection fraction. But there is still much more to be understood as far as that condition. I mean, the major challenge with heart failure, as you know, especially with heart failure preserved ejection fraction, it likely is a mix of a wide variety of different etiologies. So in parallel with developing effective therapies that get at some aspect is really understanding what are the individual drivers and then targeting those specific individual drivers. That requires a lot of unbiased discovery work and further profiling to be done. So lot more innovation, but relative to heart failure itself, it is not had widespread recognition as heart failure reduced ejection fraction. So much more to innovate on, for sure.Eric Topol (54:07):Right, right. Yeah, I am stunned by the recent progress in cardiovascular medicine. You have been center stage with a lot of it, and we've had a chance to review so much. And speaking of genetics, I wanted to just get a little insight because I recently came across the fact that your mother here at the City of Hope in Southern California is another famous researcher. And is that, I don't know what chromosome that is on regarding parental transmission of leading research. Maybe you can tell me about that.Pradeep Natarajan (54:41):Yeah, I mean, I guess it is a heritable trait when a parent has one profession that there is a higher likelihood that the offspring will have something similar. So both of my parents are PhDs, nonphysicians. There is a diabetes department at the City of Hope, so she's the chair of that department. So very active. We do overlap in some circles because she does investigate both vascular complications and renal complications. And then sometimes will ask my advice on some visualization. But she herself has just had a science translational medicine paper, for example, just a couple of months ago. So it's fun to talk about these things. To be honest, because my parents are researchers, I was not totally sure that I would be a researcher and kind of wanted to do something different in medicine. But many of my early observations and just how common cardiovascular disease is around me and in my community and wanting to do something useful is what got me specifically into cardiology.(55:45):But obviously there are numerous outstanding, important questions. And as I went through my career, really focused on more basic investigations of atherosclerosis and lipids. What got me excited sort of after my clinical training was the ability to ask many of these questions now in human populations with many new biological data sets, at least first centered on genetics. And the capabilities continue to expand, so now I teach first year Harvard medical students in their genetics curriculum. And when I talk to them just about my career arc, I do remind them they're all doing millions of things and they're exploring lots of things, but when they get to my shoes, the capabilities will be tremendously different. And so, I really advise them to take the different experiences, mainly in an exercise for asking questions, thoughtfully addressing questions, connecting it back to important clinical problems. And then once they start to understand that with a few different approaches, then they'll totally take off with what the opportunities are down the road.Eric Topol (56:51):No, it's great. I mean, how lucky somebody could be in the first year of med school with you as their teacher and model. Wow. Pradeep, we've really gone deep on this and it's been fun. I mean, if there's one person I'm going to talk to you about cardiovascular risk factors and the things that we've been into today, you would be the one. So thank you for taking the time and running through a lot of material here today, and all your work with great interest.Pradeep Natarajan (57:24):Thanks, Eric. I really appreciate it. It's tremendous honor. I'm a big fan, so I would be glad to talk about any of these things and more anytime.***************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informative!Voluntary paid subscriptions all go to support Scripps Research. 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Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Thank you for reading Ground Truths. This post is public so feel free to share it.Transcript with audio and external linksEric Topol (00:05):Hello, it's Eric Topol with Ground Truths, and I am really thrilled to have with me Professor Faisal Mahmood, who is lighting it up in the field of pathology with AI. He is on the faculty at Harvard Medical School, also a pathologist at Mass General Brigham and with the Broad Institute, and he has been publishing at a pace that I just can't believe we're going to review that in chronological order. So welcome, Faisal.Faisal Mahmood (00:37):Thanks so much for having me, Eric. I do want to mention I'm not a pathologist. My background is in biomedical imaging and computer science. But yeah, I work very closely with pathologists, both at Mass General and at the Brigham.Eric Topol (00:51):Okay. Well, you know so much about pathology. I just assume that you were actually, but you are taking computational biology to new levels and you're in the pathology department at Harvard, I take it, right?Faisal Mahmood (01:08):Yeah, I'm at the pathology department at Mass General Brigham. So the two hospitals are now integrated, so I'm at the joint department.Eric Topol (01:19):Good. Okay. Well, I'm glad to clarify that because as far as I knew you were hardcore pathologist, so you're changing the field in a way that is quite unique, I should say, because a number of years ago, deep learning was starting to get applied to pathology just like it was and radiology and ophthalmology. And we saw some early studies with deep learning whereby you could find so much more on a slide that otherwise would be not even looked at or considered or even that humans wouldn't be able to see. So maybe you could just take us back first to the deep learning phase before these foundation models that you've been building, just to give us a flavor for what was the warmup in this field?Faisal Mahmood (02:13):Yeah, so I think around 2016 and 2017, it was very clear to the computer vision community that deep learning was really the state of the art where you could have abstract feature representations that were rich enough to solve some of these fundamental classification problems in conventional vision. And that's around the time when deep learning started to be applied to everything in medicine, including pathology. So we saw some earlier cities in 2016 and 2017, mostly in machine learning conferences, applying this to very basic patch level pathology dataset. So then in 2018 and 2019, there were some studies in major journals including in Nature Medicine, showing that you could take large amounts of pathology data and classify what's known to us and including predicting what's now commonly referred to as non-human identifiable features where you could take a label and this could come from molecular data, other kinds of data like treatment response and so forth, and use that label to classify these images as responders versus non-responders or having a certain kind of mutation or not.(03:34):And what that does is that if there is a morphologic signal within the image, it would pick up on that morphologic signal even though humans may not have picked up on it. So it was a very exciting time of developing all of these supervised, supervised foundation models. And then I started working in this area around 2019, and one of the first studies we did was to try to see if we can make this a little bit more data efficient. And that's the CLAM method that we published in 2021. And then we took that method and applied it to the problem of cancers of unknown primary, that was also in 2021.Eric Topol (04:17):So just to review, in the phase of deep learning, which was largely we're talking about supervised with ground truth images, there already was a sign that you could pick up things like the driver mutation, the prognosis of the patient from the slide, you could structural variations, the origin of the tumor, things that would never have been conceived as a pathologist. Now with that, I guess the question is, was all this confined to whole slide imaging or could you somehow take an H&E slide conventional slide and be able to do these things without having to have a whole slide image?Faisal Mahmood (05:05):So at the time, most of the work was done on slides that were fully digital. So taking a slide and then digitizing the image and creating a whole slide image. But we did show in 2021 that you could put the slide under a microscope and then just capture it with a camera or just with a cell phone coupled to a camera, and then still make those predictions. So these models were quite robust to that kind of domain adaptation. And still I think that even today the slide digitization rate in the US remains at around 4%, and the standard of care is just looking at a glass light under a microscope. So it's very important to see how we can further democratize these models by just using the microscope, because most microscopes that pathologists use do have a camera attached to them. So can we somehow leverage that camera to just use a model that might be trained on a whole slide image, still work with the slide under a microscope?Eric Topol (06:12):Well, what you just said is actually a profound point that is only 4% of the slides are being reviewed digitally, and that means that we're still an old pathology era without the enlightenment of machine eyes. I mean these digital eyes that can be trained even without supervised learning as we'll get to see things that we'll never see. And to make, and I know we'll be recalling back in 2022, you and I wrote a Lancet piece about the work that you had done, which is very exciting with cardiac biopsies to detect whether a heart transplant was a rejection. This is a matter of life or death because you have to give more immunosuppression drugs if it's a rejection. But if you do that and it's not a rejection or you miss it, and there's lots of disagreement among pathologists, cardiac pathologists, regarding whether there's a transplant. So you had done some early work back then, and because much of what we're going to talk about, I think relates more to cancer, but it's across the board in pathology. Can you talk about the inner observer variability of pathologists when they look at regular slides?Faisal Mahmood (07:36):Yeah. So when I first started working in this field, my kind of thinking was that the slide digitization rate is very low. So how do we get people to embrace and adapt digital pathology and machine learning models that are trained on digital data if the data is not routinely digitized? So one of my kind of line of thinking was that if we focus on problems that are inherently so difficult that there isn't a good solution for them currently, and machine learning provides, or deep learning provides a tangible solution, people will be kind of forced to use these models. So along those lines, we started focusing on the cancers of unknown primary problem and the myocardial biopsy problem. So we know that the Cohen's kappa or the intra-observer variability that also takes into account agreement by chance is around 0.22. So it's very, very low for endomyocardial biopsies. So that just means that there are a large number of patients who have a diagnosis that other pathologists might not agree with, and the downstream treatment regimen that's given is entirely based on that diagnosis. The same patient being diagnosed by a different cardiac pathologist could be receiving a very different regimen and could have a very, very different outcome.(09:14):So the goal for that study is published in Nature of Medicine in 2022, was to see if we could use deep learning to standardize that and have it act as an assistive tool for cardiac pathologists and whether they give more standardized responses when they're given a machine learning based response. So that's what we showed, and it was a pleasure to write that corresponding piece with you in the Lancet.Eric Topol (09:43):Yeah, no, I mean I think that was two years ago and so much has happened since then. So now I want to get into this. You've been on a tear every month publishing major papers and leading journals, and I want to just go back to March and we'll talk about April, May, and June. So back in March, you published two foundation models, UNI and CONCH, I believe, both of these and back-to-back papers in Nature Medicine. And so, maybe first if you could explain the foundation model, the principle, how that's different than the deep learning network in terms of transformers and also what these two different, these were mega models that you built, how they contributed to help advance the field.Faisal Mahmood (10:37):So a lot of the early work that we did relied on extracting features from a resonant trained on real world images. So by having these features extracted, we didn't need to train these models end to end and allowed us to train a lot of models and investigate a lot of different aspects. But those features that we used were still based on real world images. What foundation models led us do is they leveraged self supervised learning and large amounts of data that would be essentially unlabeled to extract rich feature representations from pathology images that can then be used for a variety of different downstream tasks. So we basically collected as much data as we could from the Brigham and MGH and some public sources while trying to keep it as diverse as possible. So the goal was to include infectious, inflammatory, neoplastic all everything across the pathology department while still being as diverse as possible, including normal tissue, everything.(11:52):And the hypothesis there, and that's been just recently confirmed that the hypothesis was that diversity would matter much more than the quantity of data. So if you have lots and lots of screening biopsies and you use all of them to train the foundation model, there isn't enough diversity there that it would begin to learn those fundamental feature representations that you would want it to learn. So we used all of this data and then trained the UNI model and then together with it was an image text model where it starts with UNI and then reinforces the feature representations using images and texts. And that sort of mimics how humans learn about pathology. So a new resident, new trainee learning pathology has a lot of knowledge of the world, but it's perhaps looking at a pathology image for the first time. But besides looking at the image, they're also being reinforced by all these language cues from, whether it's from text or from audio signals. So the hope there was that text would kind of reinforce that and generate better feature representation. So the two studies were made available together. They were published in Nature Medicine back in March, and with that we made both those models public. So at the time we obviously had no idea that they would generate so much interest in this field, downloaded 350,000 times on Hugging Face and used for all kinds of different applications that I would've never thought of. So that's been very exciting to see.Eric Topol (13:29):Can you give some examples of some of the things you wouldn't have thought of? Because it seems like you think of everything.Faisal Mahmood (13:35):Yeah, people have used it to when there was a challenge for detecting tuberculosis, I think in a very, very different kind of a dataset. It was from the Nightingale Foundation and they have large data sets. So that was very interesting to see. People have used it to create newer data sets that can then be used for training additional foundation models. It's being used to extract rich feature representations from pathology images, corresponding spatial transcriptomic data, trying to predict spatial transcriptomics directly from histology. And there's a number of other options.Eric Topol (14:27):Well, yeah, that was March. Before we get to April, you slipped in the spatial omics thing, which is a big deal that is ability to look at tissue, human tissue over time and space. I mean the spatial temporal, it will tell us so much whether an evolution of a cancer process or so many things. Can you just comment because this is one of the major parts of this new era of applying AI to biology?Faisal Mahmood (15:05):So I think there are a number of things we can do if we have spatial data spatially resolved omic data with histology images. So the first thing that comes to my mind as a computer scientist would be that can we train a joint foundation model where we would use the spatially resolved transcriptomics to further enforce the pathology signal as a ground truth in a contrastive manner, similar to what we do with text, and can we use that to extract even richer feature representation? So we're doing that. In fact, we made a data set of about a thousand pathology images with corresponding spatial transcriptomic information, both curated from public resources as well as some internal data publicly available so people could investigate that question further. We're entrusted in other aspects of this because there is some indication including a study from James Zou's group at Stanford showing that we can predict histology, predict the spatial transcriptomic signal directly from histology. So there's early indications that we might also be able to do that in three dimensions. So yeah, it's definitely very interesting. More and more of that data is becoming available and how machine learning can sort of augment that is very exciting.Eric Topol (16:37):Yeah, I mean, most of the spatial omics has been a product of single cell sequencing, whether it's single nuclei and different omics, not just DNA, of course, RNA and even methylation, whatnot. So the fact that you could try to impute that from the histologies is pretty striking. Now, that was March and then in April you published to me an extraordinary paper about demographic bias and how generative AI, we're in the generative AI year now since as we discussed with foundation models, here again that gen AI could actually reduce biases and enhance fairness, which of course is so counterintuitive to everything that's been written to date. So maybe you can take us through how we can get a reduction in bias in pathology.Faisal Mahmood (17:34):Yeah, so in the study, the study was about, this had been investigated in other fields, but what we try to show is that a model trained on large, diverse, publicly available data. When that's applied internally and we stratify it based on demographic differences, race and so forth, we see these very clear disparities and biases. And we investigated a lot of different solutions that were out there to equalize the distribution of the data to balance the distribution using or sampling and some of these simple techniques. And none of them worked quite well. And then we observed that using foundation models or just having richer feature representations eliminates some of those biases. In parallel, there was another study from Google where they use generative AI to synthesize additional images from those underrepresented groups and then use those images to enhance the training signal. And then they also showed that you could reduce those biases.(18:49):So I think the common denominator there is that richer feature representations contribute to reduced biases. So the biases not because there is some inherent signal tied to these subgroups, but the bias is essentially there because the feature representations are not strong enough. Another general observation is that there's some kind of a confounder often there that leads to the bias. And one example would be that patients with socioeconomic disparities might just be diagnosed late and there might not be enough advanced cases in the training dataset. So quite often when you go in and look at what your training distribution looks like and how it varies from your test distribution and what that dataset shift is, you're able to figure out where the bias inherently comes from. But as a general principle, if you use the richest possible feature representation or focus on making your feature representations richer by using better foundation models and so forth, you are able to reduce a lot of the bias.Eric Topol (19:58):Yeah, that's really another key point here is about the richer features and the ability counterintuitively to actually reduce bias. And what is important in interrogating data inputs, as you said before, you wind up with a problem with bias. Now, then it comes May since we're just March and April, in May you published TriPath, which is now bringing in the 3D world of pathology. So maybe you can give us a little skinny on that one.Faisal Mahmood (20:36):Yeah. So just looking at the spectrum of where pathology is today, I think that we all agree in the community that pathologists often look at extremely sampled tissue. So human tissue is inherently three-dimensional, and by the time it gets to a pathologist, it's been sampled and cut so many times that it often would lack that signal. And there are a number of studies that have shown that if you subsequently cut sections, you get to a different outcome. If you look at multiple slides for a prostate biopsy, you get to a different Gleason score. There are all of these studies that have shown that 3D pathology is important. And with that, there's been a growing effort to build tools, microscopes, imaging tools that can image tissue in 3D. And there are about 10 startups who've built all these different technologies, open-top light-sheet microscopy, microCT and so forth that can image tissue really well in three dimensions, but none of them have had clinical adoption.(21:39):And we think that a key reason is that there isn't a good way for a pathologist to examine such a large volume of tissue. If they spend so much time examining this large volume of tissue, they would never be able to get through all the, so the goal here really was to develop a computational tool that would look through the large volume and highlight key regions that a pathologist can then examine. And the secondary goal was that does using three dimensional tissue actually improve patient stratification and does using, essentially using three 3D deep learning, having 3D convolutions extract richer features from the three dimensions that can then be used to separate patients into distinct risk groups. So that's what we did in this particular case. The study relied on a lot of data from Jonathan Liu's group at University of Washington, and also data that we collected at Harvard from tissue that came from the Brigham and Women's Hospital. So it was very exciting to show that what the value of 3D pathology can be and how it can actually translate into the clinic using some of these computational tools.Eric Topol (22:58):Do you think ultimately someday that will be the standard that you'll have a 3D assessment of a biopsy sample?Faisal Mahmood (23:06):Yeah, I'm really convinced that ultimately 3D would become the standard because the technology to image these tissue is becoming better and better every year, and it's getting closer to a point where the imaging can be fast enough to get to clinical deployment. And then on the computational end, we're increasingly making a lot of progress.Eric Topol (23:32):And it seems, again, it's something that human eyes couldn't do because you'd have to look at hundreds of slides to try to get some loose sense of what's going on in a 3D piece of tissue. Whereas here you're again taking advantage, exploiting the digital eyes. Now this culminates to your June big paper PathChat in Nature, and this was a culmination of a lot of work you've been doing. I don't know if you do any sleep or your team, but then you published a really landmark paper. Can you take us through that?Faisal Mahmood (24:12):Yeah, so I think that with the foundation models, we could extract very rich feature representation. So to us, the obvious next step was to take those feature representations and link them with language. So a human would start to communicate with a generative AI model where we could ask questions about what's going on in a pathology image, it would be capable of making a diagnosis, it would be capable of writing a report, all of those things. And the reason we thought that this was really possible is because pathology knowledge is a subset of the world's knowledge. And companies like OpenAI are trying to build singular, multimodal, large language models that would harbor the world's information, the world knowledge and pathology is much, much more finite. And if we have the right kind of training data, we should be able to build a multimodal large language model that given any pathology image, it can interpret what's going on in the image, it can make a diagnosis, it can run through grading, prognosis, everything that's currently done, but also be an assistant for research, analyzing lots of images to see if there's anything common across them, cohorts of responders versus non-responders and so forth.(25:35):So we started by collecting a lot of instruction data. So we started with the foundation models. We had strong pathology image foundation models, and then we collected a lot of instruction data where we have images, questions, corresponding answers. And we really leveraged a lot of the data that we had here at Brigham and MGH. We're obviously teaching hospitals. We have questions, we have existing teaching training materials and work closely with pathologists at multiple institutions to collect that data. And then finally trained a multimodal large language model where we could give it a whole slide image, start asking questions, what was in the image, and then it started generating all these entrusting morphologic descriptions. But then the challenge of course is that how do you validate this? So then we created validation data sets, validated on what multiple choice questions on free flowing questions where multiple pathologists, we had a panel of seven pathologists look through every response from our model as well as more generic models like the OpenAI, GPT-4 and BiomedCLIP and other models that are publicly available, and then compare how well this pathology specific model does in comparison to some of those other models.(26:58):And we found that it was very good at morphologic description.Eric Topol (27:05):It's striking though to think now that you have this large language model where you're basically interacting with the slide, and this is rich, but in another way, just to ask you, we talk about multimodal, but what about if you have electronic health record, the person's genome, gut microbiome, the immune status and social demographic factors, and all these layers of data, environmental exposures, and the pathology. Are we going to get to that point eventually?Faisal Mahmood (27:45):Yeah, absolutely. So that's what we're trying to do now. So I think that it's obviously one step at a time. There are some data types that we can very easily integrate, and we're trying to integrate those and really have PathChat as being a binder to all of that data. And pathology is a very good binder because pathology is medicine's ground truth, a lot of the fundamental decisions around diagnosis and prognosis and treatment trajectory is all sort of made in pathology. So having everything else bind around the pathology is a very good idea and indication. So for some of these data types that you just mentioned, like electronic medical records and radiology, we could very easily go that next step and build integrative models, both in terms of building the foundation model and then linking with language and getting it to generate responses and so forth. And for other data types, we might need to do some more specific training data types that we don't have enough data to build foundation models and so forth. So we're trying to expand out to other data types and see how pathology can act as a binder.Eric Topol (28:57):Well if anybody's going to build it, I'm betting on you and your team there, Faisal. Now what this gets us to is the point that, was it 96% or 95% of pathologists in this country are basically in an old era, we're not eking out so much information from slides that they could, and here you're kind of in another orbit, you're in another world here whereby you're coming up with information. I mean things I never thought really the prognosis of a patient over extended period of time, the sensitivity of drugs to the tumor from the slide, no less the driver mutations to be able to, so you wouldn't even have to necessarily send for mutations of the cancer because you get it from the slide. There's so much there that isn't being used. It's just to me unfathomable. Can you help me understand why the pathology community, now that I know you're not actually a pathologist, but you're actually trying to bring them along, what is the reason for this resistance? Because there's just so much information here.Faisal Mahmood (30:16):So there are a number of different reasons. I mean, if you go into details for why digital pathology is not actively happening. Digitizing an entire department is expensive, retaining large amounts of slides is expensive. And then the value proposition in terms of patient care is definitely there. But the financial incentives, reimbursement around AI is not quite there yet. It's slowly getting there, but it's not quite there yet. In the meantime, I think what we can really focus on, and what my group is thinking a lot about is that how can we democratize these models by using what the pathologists already have and they all have a microscope and most of them have a microscope with a camera attached to it. Can we train these models on whole slide images like we have them and adapt them to just a camera coupled to a microscope? And that's what we have done for PathChat2.(31:23):I think one of the demos that we showed after the article came out was that you could use PathChat on your computer with the whole slide image, but you can also use it with a microscope just coupled to a camera and you put a glass light underneath. And in an extreme lower source setting, you can also use it with just a cell phone coupled to a microscope. We're also building a lighter weight version of it that wouldn't require internet, so it would just be completely locally deployed. And then it could be active in lower source settings where sometimes sending a consult can take a really, really long time, and quite often it's not very easy for hospitals in lower source settings to track down a patient again once they've actually left because they might've traveled a long distance to get to the clinic and so forth. So the value of having PathChat deployed in a lower source setting where it can run locally without internet is just huge because it can accelerate the diagnosis so much. In particular for very simple things, which it's very, very good at making a diagnosis for those cases.Eric Topol (32:33):Oh, sure. And it can help bridge inequities, I mean, all sorts of things that could be an outgrowth of that. But what I still having a problem with from the work that you've done and some of the other people that well that are working assiduously in this field, if I had a biopsy, I want all the information. I don't want to just have the old, I would assume you feel the same way. We're not helping patients by not providing the information that's there just with a little help from AI. If it's going to take years for this transformation to occur, a lot of patients are going to miss out because their pathologists are not coming along.Faisal Mahmood (33:28):I think that one way to of course solve this would be to have it congressionally mandated like we had for electronic medical records. And there are other arguments to be made. It's been the case for a number of different hospitals have been sued for losing slides. So if you digitize all your slides and you're not going to lose them, but I think it will take time. So a lot of hospitals are making these large investments, including here at the Brigham and MGH, but it will take time for all the scanners, all the storage solutions, everything to be in place, and then it will also take time for pathologists to adapt. So a lot of pathologists are very excited about the new technology, but there are also a lot of pathologists who feel that their entire career has been diagnosing cases or using a microscope and slide. So it's too big of a transition for them. So I think there'll obviously be some transition period where both would coexist and that's happening at a lot of different institutions.Eric Topol (34:44):Yeah, I get what you're saying, Faisal, but when I wrote Deep Medicine and I was studying what was the pathology uptake then of deep learning, it was about 2% and now it's five years later and it's 4% or 5% or whatever. This is a glacial type evolution. This is not keeping up with how the progress that's been made. Now, the other thing I just want to ask you before finishing up, there are some AI pathology companies like PathAI. I think you have a startup model Modella AI, but what can the companies do when there's just so much reluctance to go into the digital era of pathology?Faisal Mahmood (35:31):So I think that this has been a big barrier for most pathology startups because around seven to eight years ago when most of these companies started, the hope was that digital pathology would happen much faster than it actually has. So I think one thing that we're doing at Modella is that we understand that the adoption of digital pathology is slow. So everything that we are building, we're trying to enable it to work with the current solutions that exist. So a pathologist can capture images from a pathology slide right in their office with a camera with a microscope and PathChat, for example, works with that. And then the next series of tools that we're developing around generative AI would also be developed in a manner that it would be possible to use just a camera coupled to a microscope. So I think that I do feel that all of these pathology AI companies would have been doing much, much better if everything was digital, because adopting the tools that they developed would very straightforward. Right now, the barrier is that even if you want to deploy an AI driven solution, if your hospital is not entirely digital, it's not possible to do that. So it requires this huge upfront investment.Eric Topol (37:06):Yeah, no, it's extraordinary to me. This is such an exciting time and it's just not getting actualized like it could. Now, if somebody who's listening to our conversation has a relative or even a patient or whatever that has a biopsy and would like to get an enlightened interpretation with all the things that could be found that are not being detected, is there a way to send that to a center that is facile with this? Or if that's a no go right now?Faisal Mahmood (37:51):So I think at the moment it's not possible. And the reason is that a lot of the generic AI tools are not ready for this. The models are very, very specific for specific purposes. The generalist models are just getting started, but I think that in the years to come, this would be a competitive edge for institutions who do adopt AI. They would definitely have a competitive edge over those who do not. We do from time to time, receive requests from patients who want us to run their slides on the cancers of unknown primary tool that we built. And it depends on whether we are allowed to do so or not, because it has to go through a regular diagnostic first and how much information can we get from the patient? But it's on a case by case basis.Eric Topol (38:52):Well, I hope that's going to change soon because you have been, your team there has just been working so hard to eke out all that we can learn from a path slide, and it's extraordinary. And it made me think about what we knew five years ago, which already was exciting, and you've taken that to the fifth power now or whatever. So anyway, just to congratulate you for your efforts, I just hope that it will get translated Faisal. I'm very frustrated to learn how little this is being adopted here in this country, a rich country, which is ignoring the benefits that it could provide for patients.Faisal Mahmood (39:40):Yeah. That's our goal over the next five years. So the hope really is to take everything that we have developed so far and then get it in aligned with where the technology currently is, and then eventually deploy it both at our institution and then across the country. So we're working hard to do that.Eric Topol (40:03):Well, maybe patients and consumers can get active about this and demand their medical centers to go digital instead of living in an analog glass slide world, right? Yeah, maybe that's the route. Anyway, thank you so much for reviewing at this pace of your publications. It's pretty much unparalleled, not just in pathology AI, but in many parts of life science. So kudos to you, Richard Chen, and your group and so many others that have been working so hard to enlighten us. So thanks. I'll be checking in with you again on whatever the next model that you build, because I know it will be another really important contribution.Faisal Mahmood (40:49):Thank you so much, Eric. Thanks.**************************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. 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In neurocritical care, the initial evaluation is often fast paced, and assessment and management go hand in hand. History, clinical examination, and workup should be obtained while considering therapeutic implications and the need for lifesaving interventions. In this episode, Aaron Berkowitz, MD, PhD FAAN, speaks with Sarah Wahlster, MD, an author of the article “The Neurocritical Care Examination and Workup,” in the Continuum June 2024 Neurocritical Care issue. Dr. Berkowitz is a Continuum® Audio interviewer and professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California. Dr. Wahlster is an associate professor of neurology in the departments of neurology, neurological surgery, and anesthesiology and pain medicine at Harborview Medical Center, University of Washington in Seattle, Washington. Additional Resources Read the article: The Neurocritical Care Examination and Workup Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @SWahlster Full Episode Transcript Sarah Wahlster, MD   Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by clicking on the link in the Show Notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the Show Notes. AAN members: stay tuned after the episode to hear how you can get CME for listening.  Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Sarah Wahlster about her article on examination and workup of the neurocritical care patient, which is part of the June 2024 Continuum issue on neurocritical care. Welcome to the podcast, Dr Wahlster. Can you please introduce yourself to the audience? Dr Wahlster: Thank you very much, Aaron. I'm Sarah Wahlster. I'm a neurologist and neurontensivist at Harborview Medical Center at the University of Washington. Dr Berkowitz: Well, Sarah and I know each other for many, many years. Sarah was my senior resident at Mass General and Brigham and Women's Hospital. Actually, Sarah was at my interview dinner for that program, and I remember meeting her and thinking, “If such brilliant, kind, talented people are in this program, I should try to see if I can find my way here so I can learn from them.” So, I learned a lot from Sarah as a resident, I learned a lot from this article, and excited for all of us to learn from Sarah, today, talking about this important topic. So, to start off, let's take a common scenario that we see often. We're called to the emergency room because a patient is found down, unresponsive, and neurology is called to see the patient. So, what's running through your mind? And then, walk us through your approach as you're getting to the bedside and as you're at the bedside. Dr Wahlster: Yeah, absolutely. This was a fun topic to write about because I think this initial kind of mystery of a patient and the initial approach is something that is one of the puzzles in neurology. And I think, especially if you're thinking about an emergency, the tricky part is that the evaluation and management go hand in hand. The thinking I've adapted as a neurointensivist is really thinking about “column A” (what is likely?) and “column B” (what are must-not-miss things?). It's actually something I learned from Steve Greenberg, who was a mutual mentor of us - but he always talked me through that. There's always things at the back of your head that you just want to rule out. I do think you evaluate the patient having in mind, “What are time-sensitive, critical interventions that this patient might need?” And so, I think that is usually my approach. Those things are usually anything with elevated intracranial pressure: Is the patient at risk of herniating imminently and would need a neurosurgical intervention, such as an EVD or decompression? Is there a neurovascular emergency, such as an acute ischemic stroke, a large-vessel occlusion, a subarachnoid hemorrhage that needs emergent intervention? And then other things you think about are seizures, convulsive/nonconvulsive status, CNS infection, spinal cord compression. But I think, just thinking about these pathologies somewhere and then really approaching the patient by just, very quickly, trying to gather as much possible information through a combination of exam and history. Dr Berkowitz: Great. So, you're thinking about all these not-to-miss diagnoses that would be life-threatening for the patient and you're getting to the bedside. So, how do you approach the exam? Often, this is a different scenario than usual, where the patient's not going to be able to give us a history or maybe necessarily even participate in the exam, and yet, as you said, the stakes are high to determine if there are neurologic conditions playing into this patient's status. So, how do you approach a patient at the bedside? Dr Wahlster: So, I think first step in an ICU setting (especially if the patient has a breathing tube) is you think about any confounders (especially sedation or metabolic confounders) - you want to remove as soon as possible, if able. I think as you do the exam, you try to kind of incorporate snippets of the history and really try to see - you know, localize the problem. And also kind of see, you know, what is the time course of the deterioration, what is the time course of the presentation. And that is something I actually learned from you. I know you've always had this framework of “what is it, where is it?” But I think in terms of just a clinical exam, I would look at localizing signs. I think, in the absence of being able to do the full head-to-toe neuro exam and interact with the patient, you really try to look at the brainstem findings. I always look at the eyes right away and look at, I think, just things like, you know, the gaze (how is it aligned? is there deviation? is there a skew? what do the pupils look like? [pupillary reactivity]). I think that's usually often a first step - that I just look at the patient's eyes. I think other objective findings, such as brainstem reflexes and motor responses, are also helpful. And then you just look whether there's any kind of focality in terms of - you know, is there any difference in size? But I think those are kind of the imminent things I look at quickly. Dr Berkowitz: Fantastic. Most of the time, this evaluation is happening kind of en route to the CT scanner or maybe a CT has already happened. So, let's say you're seeing a patient who's found down, the CT has either happened or you asked for it to happen somewhat quickly after you've done your exam, and let's say it's not particularly revealing early on. What are the sort things on your exam that would then push you to think about an MRI, a lumbar puncture, an EEG? You and I both spend time in large community hospitals, right, where “found down” is one of the most common chief concerns. In many cases, there isn't something to see on the CT or something obvious in the initial labs, and the question always comes up, “Who gets an MRI? Who gets an LP? Who gets an EEG?” - and I'm not sure I have a great framework for this. Obviously, you see focality on your exam, you know you need to look further. But, any factors in the history or exam that, even with a normal CT, raise your suspicion that you need to go further? Dr Wahlster: It's always a challenge, especially at a community hospital, because some of these patients come in at 1 AM where the EEG is not imminently available. But I think - let's say the CT scan is absolutely normal and doesn't give me a cause, but as an acute concerning deterioration, I think both EEG and LP would cross my mind. MRI I kind of see a little bit as a second-day test. I think there's very rare situation where an acute MRI would inform my imminent management. It's very informative, right, because you can see very small-vessel strokes. We had this patient that actually had this really bad vasculitis and we were able to see the small strokes everywhere on the MRI the day later, or sometimes helps you visualize acute brainstem pathology. But I think, even that - if you rule out a large-vessel occlusion on your CTA, there's brainstem pathology that is not imminently visible on the CT - it's nothing you need to go after. So, I do think the CT is a critical part of that initial eval, and whereas I always admire the neurological subspecialties, such as movements, where you just – like, your exam is everything. I think, to determine these acute time-sensitive interventions, the CT is key. And also, seeing a normal CT makes me a little less worried. You always look at these “four H” (they're big hypodensity, hyperdensity, any shift; is there hydrocephalus or herniation). I think if I don't have an explanation, my mind would imminently jump to seizure or CNS infection, or sometimes both. And I think then I would really kind of - to guide those decisions and whether I want to call in the EEG tech at 2 AM - I would, you know, again, look at the history and exam, see if there's any gaze deviation, tongue biting, incontinence - anything leading up towards seizure. I think, though, even if I didn't have any of those, those would strengthen my suspicion. If I really, absolutely don't have an explanation and the patient off sedation is just absolutely altered, I would still advocate for an EEG and maybe, in the meantime, do a small treatment trial. And I think with CNS infection - obviously, there are patients that are high risk for it - I would try to go back and get history about prodromes and, you know, look at things like the white count, fevers, and all of that. But again, I think if there's such a profound alteration in neurologic exam, there's nothing in the CT, and there's no other explanation, I would tend to do these things up front because, again, you don't want to miss them. Dr Berkowitz: Yeah, perfect. So many pearls in there, but one I just want to highlight because I'm not sure I've heard the mnemonic - can you tell us the four Hs again of sort of neurologic emergencies on CT? Dr Wahlster: Yeah. So, it's funny; for ages - I'm actually not sure where that's coming from, and I learned it from one of my fellows, one of our neurocritical care fellows - he's a fantastic teacher and he would teach our EM and anesthesia residents about it and his approach to CT. But yeah, the four H - he was always kind of like, “Look at the CT. Do you see any acute hypodensities, any hyperdensities?” And hypodensities would be involving infarct or edema; hyperdensities would be, most likely, hemorrhage (sometimes calcification or other things). Then, “Do you see hydrocephalus?” (because that needs an intervention). And, “Look at the midline structures and the ventricles.” And then, “Do you see any signs of herniation?” And he would go through the different types of herniation. But I thought that's a very good framework for looking at the “noncon” and just identifying critical pathology that needs some intervention. Dr Berkowitz: Yeah – so, hypodensity, hyperdensity, herniation, hydrocephalus. That's a good one – the four Hs; fantastic. Okay. So, a point that comes up a few times in your article - which I thought was very helpful to walk through and I'd love to pick your brain about a little bit – is, which patients need to be intubated for a neurologic indication? So, often we do consultations in medical, surgical ICUs; patients are intubated for medical respiratory reasons, but sometimes patients are intubated for neurologic reasons. So, can you walk us through your thinking on how to decide who needs to be intubated for the concern of depressed level of consciousness? Dr. Wahlster: It's an excellent question, and I think I would bet there's a lot of variation in practice and difference in opinion. There was actually the 2020 ESICM guidelines kind of commented on it, and those are great guidelines in terms of just intubation, mechanical ventilation of patients, and just acknowledging how there is a lack of really strong evidence. I would say the typical mantra (“GCS 8, intubate”) has been proposed in the trauma literature. And at some point, I actually dug into this to look behind the evidence, and there's actually not as much evidence as it's been put forth in guidelines and that kind of surprised me - that was just recently. I was like, “Actually, let me look this up.” I would say I didn't find a ton of strong evidence for it. I would say, as neurologist – you know, I'm amazed because GCS, I think is a - in some ways, a good tool to track things because it's so widely used across the board. But I would say, as neurologists, we all know that it sometimes doesn't account for some sort of nuances; you know, if a patient is aphasic, if a patient has an eyelid-opening apraxia - it can always be a little confounded. I'm amazed that GCS is still so widely used, to be frank. But I would say there is some literature - some school of thought - that maybe just blindly going by that mantra could be harmful or could not be ideal. I would say – I mean, I look at the two kind of functional things: oxygenation and ventilation. I think, in a neuro patient, you always think about airway protection or the decreased level of consciousness being a major issue (What is truly airway protection? Probably a mix of things). Then there's the issue of respiratory centers and respiratory drive - I think those are two issues you think about. But ultimately, if it leads to insufficient oxygenation - hypoxia early on is bad and that's been shown in several neurologic acute brain injuries. I think you also want to think about ventilation, especially if the mental status is poor to the point that the PCO2 elevates, that could also augment an ICP or exacerbate an ICP crisis. Or sometimes, I think there's just dysregulation of ventilation and there's hyperventilation to the point that the PCO2 is so low that I worry about cerebral vasoconstriction. So, I worry about these markers. I think, the oxygenation, I usually just kind of initially track on the sats. Sometimes, if the patient is profoundly altered, I do look at an arterial blood gas. And then there are things like breathing sounds (stridor, stertor [the work of breathing]). And I think something that also makes me have a lower threshold to intubate is if I'm worried and I want to scan, and I'm worried that the patient can't tolerate it - I want an imminent scan to just see why the patient is altered, or seizing, or presenting a certain way. Dr Berkowitz: All great pearls for how to think through this. Yeah - it's hard to think of hard and fast rules, and you can get to eight on the GCS in many different ways, as you said, some of which may not involve the respiratory mechanics at all. So, that's a helpful way of thinking about it that involves both the mental state, kind of the tracheal apparatus and how it's being managed by the neurologic system, and also the oxygen and carbon dioxide (sort of, respiratory parameters) – so, linking all those together; that's very helpful. And, related question – so, that's sort of for that patient with central nervous system pathology, who we're thinking about whether they need to be intubated for a primary neurologic indication. What about from the acute neuromuscular perspective (so, patients with Guillain-Barré syndrome or myasthenic crisis); how do you think about when to intubate those patients? Dr Wahlster: Yeah, absolutely - I think that's a really important one. And I think especially in a patient that is rapidly progressing, you always kind of think about that, and you want them in a supervised setting, either the ER or the ICU. I mean, there's some scores - I think there's the EGRIS score; there's some kind of models that predict it. I would say, the factors within that model, and based on my experience, often the pace of progression of reflex motor syndrome. I often see things like, kind of, changes in voice. You know, myasthenia, you look at things like head extension, flexion - those are the kind of factors. I would say there's this “20/30/40 rule” about various measures of, like, NIF and vital capacities, which is great. I would say in practice, I sometimes see that sometimes the participation in how the NIF is obtained is a little bit funky, so I wouldn't always blindly go by these numbers but sometimes it's helpful to track them. If you get a reliable kind of sixty and suddenly it drops to twenty, that makes me very concerned. But I would say, in general, it's really a little bit the work of breathing - looking at how the patient looks like. There's also (at some point) ABG abnormalities, but we always say, once those happen, you're kind of later in the game, so you should really - I think anyone that is in respiratory distress, you should think about it and have a low threshold to do it, and, at a minimum, monitor very closely. Dr Berkowitz: Yeah, we have those numbers, but so often, our patients who are weak, from a neuromuscular perspective, often have facial and other bulbar weakness and can't make a seal on the device that is used to check these numbers, and it can look very concerning when the patient may not, or can be a little bit difficult to interpret. So, I appreciate you giving us sort of the protocol and then the pearls of the caveats of how to interpret them and going sort of back to basics. So, just looking at the patient at the bedside and how hard they are working to breathe, or how difficult it is for them to clear their secretions from bulbar weakness. Moving on to another topic, you have a really wonderful section in your article on detecting clinical deterioration in patients in the neuro ICU. Many patients in the neuro ICU - for example, due to head trauma or large ischemic stroke or intracerebral hemorrhage, subarachnoid hemorrhage, or status epilepticus - they can't communicate with us to tell us something is getting worse, and they can't (in many cases) participate in the examination. They may be intubated, as you said, sedated or maybe even not sedated, and there's not necessarily much to follow on the exam to begin with if the GCS is very low. So, I'd love to hear your thoughts and your pearls, as someone who rounds in the neuro-ICU almost every day. What are you looking for at the bedside to try to detect sort of covert deterioration, if you will, in patients who already have major neurologic deficits, major neurologic injury or disease that we're aware of? I'm trying to see if there is some type of difference at the bedside that would lead you to be concerned for some underlying change and go back to the scanner or repeat EEG, LP, et cetera. Dr Wahlster: Yeah. I think that's an excellent question because that's a lot of what we do in the neuro ICU, right? And when you read your Clans, your residency, like, “Ah, QNR neuro checks, [IG1]  ” right? We often do that in many patients. But I think in the right patient, it can really be life or death a matter, and it is the exam that really then drives a whole cascade of changes in management and detects the need for lifesaving procedure. I would say it depends very much on the process and what you anticipate, right? If you have, for example, someone with a large ischemic stroke, large MCA stroke, especially, right, then there's sometimes conversations about doing a surgical procedure before they herniate. But let's say, kind of watch them and are worried that they will, you do worry about uncal herniation, and you pay attention to the pupil, because often, if the inferior division is infarcted, you know, you can see that kind of temporal tickling the uncus already. And so, I think those are patients that I torture with those NPi checks and checking the pupil very vigilantly. I would say, if it's a cerebellar stroke, for example, right, then you think about, you know, hydrocephalus. And often patients with cerebellar stroke - you know, the beauty of it is that if you detect it early, those patients can do so well, but they can die, and will die if they develop hydrocephalus start swelling. But I think, often something I always like to teach trainees is looking at the eye movements in upgaze and downgaze because, often, as the aqueduct, the third ventricle gets compressed and there's pressure on the colliculi – you kind of see vertical gaze get worse. But I would say I think it's always good to know what the process is and then what deterioration would look like. For example, in subarachnoid hemorrhage, where you talk about vasospasm - it's funny - I think a really good, experienced nurse is actually the best tool in this, but they will sometimes come to you and say, “I see this flavor,” and it's actually a constellation of symptoms, especially in the anterior ACA (ACom) aneurysms. You sometimes see patients suddenly, like, making funky jokes or saying really weird things. And then you see that in combination with, sometimes, a sodium drop, a little bit of subfebrile temperature; blood pressure shoot up sometimes, and that is a way the brain is sometimes regulating. But it's often a constellation of things, and I think it depends a little on the process that you're worried about. Dr Berkowitz: Yeah, that's very helpful. You just gave us some pearls for detecting deterioration related to vasospasm and subarachnoid hemorrhage; some pearls for detecting malignant edema in an MCA stroke or fourth ventricular compression in a large cerebellar stroke. Patients I find often very challenging to get a sense of what's going on and often get scanned over and over and back on EEG, not necessarily find something: patients with large intracerebral hemorrhage (particularly, in my experience, if the thalamus is involved) just can fluctuate a lot, and it's not clear to me actually what the fluctuation is. But you're looking for whether they're developing hydrocephalus from third ventricular compression with a thalamic hemorrhage (probably shouldn't be seizing from the thalamus, but if it's a large hemorrhage and cortical networks are disrupted and it's beyond sort of the subcortical gray matter, or has the hemorrhage expanded or ruptured it into the ventricular system?) And yet, you scan these patients over and over, sometimes, and just see it's the same thalamic hemorrhage and there's some, probably, just fluctuation level of arousal from the thalamic lesion. How do you, as someone who sees a lot of these patients, decide which patients with intracerebral hemorrhage - what are you looking for as far as deterioration? How do you decide who to keep scanning when you're seeing the same fluctuations? I find it so challenging - I'm curious to hear your perspective. Dr Wahlster: Yeah, no - that is a very tricky one. I mean, unfortunately, in patients with deeper hemorrhages or deeper lesions - you know, thalamic or then affecting brainstem - I think those are the ones that ultimately don't have good, consistent airway protection and do end up needing a trach, just because there's so much fluctuation. But I agree - it's so tricky, and I don't think I can give a perfect answer. I would say, a little bit I lean on the imaging. And for example - let's say there's a thalamic hemorrhage. We recently actually had a patient - I was on service last week - we had a thalamic hemorrhage with a fair amount of edema on it that was also kind of pressing on the aqueduct and didn't have a lot of IVH, right? But it was, like, from the outside pushing on it and where we ended up getting more scans. And I have to say, that patient actually just did fine and actually got the drain out and didn't need a shunt or anything, and actually never drained. We put an EVD and actually drained very little. So, I think we're still bad at gauging those. But I think, in general, my index of suspicion or threshold to scan would be lower if there was something, like, you know, a lot of IVH associated, if, you know, just kind of push on the aqueduct. It's very hard to say, I think. Sometimes, as you get to know your patients, you can get a little bit of a flavor of what is within normal fluctuation. I think it's probably true for every patient, right? - that there's always some fluctuation within the realm of like, “that's what he does,” and then there's something more profound. Yeah, sorry - I wish I could give a better answer, but I would say it's very tricky and requires experience and, ideally, you really taking the time to examine the patient yourself (ideally, several times). Sometimes, we see the patient - we get really worried. Or the typical thing we see the ICU is that the neurosurgeons walk around at 5 AM and say, like, “She's altered, she's different, she's changed.” And then the nurse will tell you at 8 AM, like, “No, they woke up and they ate their breakfast.” So, I think really working with your nurse and examining the patient yourself and just getting a flavor for what the realm of fluctuation is. Dr Berkowitz: Yeah - that's helpful to hear how challenging it is, even for a neurocritical care expert. I'm often taking care of these patients when they come out of the ICU and I'm thinking, “Am I scanning these patients too much?” Because I just don't sort of see the initial stage, and then, you know, you realize, “If I'm concerned and this is not fitting, then I should get a CT scan,” and sometimes you can't sort it out of the bedside. So, far from apologizing for your answer, it's reassuring, right, that sometimes you really can't tell at the bedside, as much as we value our exam. And the stakes are quite high if this patient's developed intraventricular hemorrhage or hydrocephalus, and these would change the management. Sometimes you have these patients the first few days in the ICU (for us, when they come out of the ICU) are getting scanned more often than you would like to. But then you get a sense of, “Oh, yeah - these times of day, they're hard to arouse,” or, “They're hard to arouse, but they are arousable this way,” and then, “When they are aroused, this is what they can do, and that's kind of what we saw yesterday.” And yet, as you said, if anyone on the team (the resident, the nurse, the student, our neurosurgery colleague) says, “I don't think this is how they were yesterday,” then, very low threshold to just go back and get a CT and make sure we're not missing something. Dr. Wahlster: Exactly. Yeah. I would say the other thing is also certain time intervals, right? If I'm seeing a patient that may be in vasospasm kind of around the days seven to ten, for the first fourteen day, I would be a little bit more nervous. Or with swelling - acute ischemic stroke says that could peak swelling, when knowing which [IG2]  , I would just be more anxious or have a lower threshold to scan. Yeah. Dr Berkowitz: Yeah - very helpful. Well, thank you so much for joining me today on Continuum Audio. Dr Wahlster: Thank you very much, Aaron. Dr Berkowitz: Again, today we've been interviewing Dr Sarah Wahlster, whose article, “Examination and Workup of the Neurocritical Care Patient” appears in the most recent issue of Continuum, on neurocritical care. Be sure to check out Continuum Audio episodes from this and other issues. And thank you so much to our listeners for joining us today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practice. And right now, during our Spring Special, all subscriptions are 15% off. Go to Continpub.com/Spring2024 or use the link in the episode notes to learn more and take advantage of this great discount. This offer ends June 30, 2024. AAN members: go to the link in the episode notes and complete the evaluation to get CME. Thank you for listening to Continuum Audio.

Denise Octavia Smith, Executive Director of the National Association of Community Health Workers, discusses the need for sustained funding for Community Health Workers; and Dr. Scott Hadland, Chief of Adolescent Medicine at Mass General for Children, discusses a survey that reveals most pediatricians don't feel equipped to help teenage patients struggling with drug addiction. National Association of Community Health Workers Webpage American Academy of Pediatrics Webpage: Perceptions, Preparedness & Practices Treating Adolescent Opioid Use in Primary Care KFF Health News Article: More Kids Are Dying of Drug Overdoses. Could Pediatricians Do More to Help?  

Indomethacin-responsive headache disorders are rare conditions whose hallmark is an absolute response to the medicine and include paroxysmal hemicrania and hemicrania continua. In this episode, Gordon Smith, MD, FAAN, speaks with Peter Goadsby, MD, PhD, FRS, author of the article “Indomethacin-Responsive Headache Disorders,” in the Continuum® April 2024 Headache issue. Dr. Smith is a Continuum® Audio interviewer and professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia. Dr. Goadsby is a professor of neurology at King's College London in London, United Kingdom and professor emeritus of neurology at the University of California, Los Angeles in Los Angeles, California. Additional Resources Read the article: Indomethacin-Responsive Headache Disorders Subscribe to Continuum: continpub.com/Spring2024 Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @gordonsmithMD Guest: @petergoadsby Transcript Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the Show Notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the Show Notes. AAN members: Stay tuned after the episode to hear how you can get CME for listening. Dr Smith: This is Dr Gordon Smith. Today, I've got the great pleasure of interviewing Dr Peter Goadsby on indomethacin-responsive headache disorders, which is part of the April 2024 Continuum issue on headache. Dr. Goadsby is a Professor of Neurology at King's College London, in London, United Kingdom and a Professor Emeritus of Neurology at the University of California, Los Angeles, which is located in Los Angeles, California. Dr Goadsby, welcome to the podcast. Well Peter, I'm super excited to have the opportunity to talk to you. And I think, before we begin, we probably ought to expand on your introduction. I think there may be three or four neurologists who don't know who you are, and I think they should know who you are because you've got a really amazing story. These are exciting times in headache, right? And a lot of that's because of your work and you've been widely acknowledged for that; you received the appropriately named “Brain Prize,” which (if I'm correct) is the largest neuroscience award in the world; got to meet Danish royalty; you're - more recently, the ABF Scientific Breakthrough Award, which is super excited. So, particularly interested in hearing about your Continuum article. But before we get there, I think it would be really great to hear your story. How did you get into this in the beginning, and what's inspired you along the way to the many achievements you've had? Dr Goadsby: Why, it's a very kind introduction. People have been nice to me. It has to be said, Danish royalty were very nice, I have to say, and the very jolly chap, the Prince of Denmark. I got into neurology - I guess it's all about mentoring for me. I got into neurology because I got into medical school pretty much by accident. I really wasn't that interested and heard a lecture by James Lance, who was Professor of Neurology, University of New South Wales, at the time. He was talking about a nondominant parietal lobe. I'd seen the case as a medical student; it sort of just seemed weird to me and I wasn't that interested. But he set out this way of thinking about things to try and understand why a clinical presentation is what it is - what he described as a physiological approach to clinical neurology. He described a number of things, but he described that in this lecture and then gave a reference to some work that Mountcastle did on nondominant parietal recordings from awake behaving monkeys in the Journal of Neurophysiology. And I thought to myself, “Wow, this is really interesting - you could really get to the bottom of something,” and had that sort of “puzzle-y” thing going on. And I thought Lance was just wonderful, so I became interested in that. And then eventually I asked him about research - actually, I asked him about research after a lecture he gave on migraine, and the explanation of the time was some circulating substance - probably just as silly now. I went up to him afterwards and said to him, I thought the explanation he was giving was wrong. Like, here was a global person - he described Lance-Adams syndrome; this was someone who trained at Mass General, trained at Queen Square; was the first professor of neurology in Australia. I was just – like, it was a stupid thing to do. But I couldn't resist myself - I told him I thought it was wrong. And he's very polite, and he said, “Well, perhaps you could come and help us by doing some research.” And I thought, “Okay, that's a very nice response.” Interestingly, his daughter described him as unfailingly polite at his funeral. Of the many things you'd say about him, he was a kind person. Whether it's science or just the way you practice - that word (kind) - you can know as much about a subject as you like, but if you're not kind to patients, you're probably in the wrong game. He taught me to be curious about a problem and got me interested in headache, and to be kind in clinical practice - just kind – and I think they were very important lessons. So, I got into it because of excellent mentoring, and I'd like to think I've helped some others along the way. Dr Smith: Well, you certainly have helped a lot of people, Peter, and what a great story. I'm reflecting - I think the first vignette in The Man Who Mistook His Wife for a Hat was a right parietal syndrome - wasn't it? You've read that book? Dr Goadsby: Yes, I have. And I've met Sacks. When Sacks came to Australia, he wanted to see Lance, and Lance said, “Fine, but you have to meet me between the morning round and the afternoon clinical meeting.” And he got him to come and have lunch with him in the hospital cafeteria at the Prince Henry Hospital and invited me to this lunch. And I sat there and watched them chat. But it was a measure of Lance and how people were interested in him that Oliver Sacks had to get in a taxi and come out to a hospital cafeteria to have lunch if you wanted to have a chat. Because it was - it was a privilege to train with the person. You know, I've done okay, but I only do okay if you've got – you know, you can work with patients, you've got great collaborators, and you've got someone you can get advice from (a great mentor). Dr Smith: Yeah, that's actually really great words of wisdom for the residents and fellows and junior faculty listening to this. Maybe we should actually talk about your article, which was really great. Your article was on indomethacin-responsive headaches - and we can maybe talk about some specific questions - but what's the main take-home point? If our listeners needed to take or were to take home one point from your article, what would it be, other than it's indomethacin-responsive (that's in the title)? Dr Goadsby: Yeah, it's what it says on the jar. Well, I think the one thing to take home is that there are forms of headache that seem relatively pedestrian, like one-sided headache that feels like it ought to be migraine that's strictly one-sided, and a small percentage of them respond almost like switching a light off to indomethacin. So, I think you have to have a high index of suspicion. And I'm sure I give indomethacin to ten, twenty times as many people - or thirty - who end up (or even more, probably) who end up having a response. But we do it for a short period of time. For those who get the response - I can tell you, when they come back, they're crying, their partners crying, or the other day I saw one, their child's crying, because all of a sudden, you've basically fixed the problem up. So, the message would be, if you've heard about something and it feels a bit “maybe, could be” - you've heard this indomethacin thing - just do it for a couple of weeks. The worst thing that can happen is nothing (nothing happens). For a couple of weeks, they're not going to have a problem with the tummy (and I'm not advocating taking people with a active gastric ulcer, trying to bump them off). But you cover them properly, you give them a short trial, and occasionally in your practice, you will be so rewarded by that - you will dance home. Dr Smith: Well, this is going to be my next question. There are very specific criteria, right, for defining cluster, SUNCT, SUNA (and there was a really great Continuum Audio conversation I had with Mark Burish I'll refer our listeners to about cluster, SUNCT, and SUNA), but the indomethacin-responsive headaches - and even migraine - that sounds to me, as someone who's not a headache person, like, that could be challenging to sort out. If you see someone who has consistent, unilateral headache, do you just do an indomethacin trial, or do you select based on other criteria from the classification system? Dr Goadsby: I'd like to think I was aware of the criteria, and I am. But the longer I practice, the more I'm inclined simply to give the indomethacin and get the question off the table because I don't think there's a sine qua non; there's nothing that will - apart from the indomethacin effect - there's nothing that will convince me 100% to be able to not do it. I've seen enough people who haven't clearly read the classification in detail (patients, I mean) and took indomethacin, and got a response where you wouldn't have predicted it, and they're very happy and the story ends well. So, I would advise people not to worry too much about whether it ought to or not respond, but find out if it does. Dr Smith: So, the obvious next question is, how does this work? It's pretty unusual in medicine, certainly in neurology, to have something that's so dramatically effective. What's the mechanism? Dr Goadsby: Well, that's the easiest question - we don't understand it. It is particular to indomethacin - it's weird. Some patients will say, “We'll give you a little bit of a hint by telling you (maybe) that ibuprofen was useful,” but most don't give you that much of a hint (some will even say aspirin is useful). But we haven't really gotten to the bottom of it. What are the current thoughts? It must be something that's not simply cyclo-oxygenase because other cyclo-oxygenase inhibitors don't do that – so, that's helpful. The other broad things people think about are whether there's a nitrergic aspect to it. We've got some basic science work that can show that nitrergically induced changes in experimental animal model of these trigeminal autonomic cephalalgias can be modified by indomethacin in one part of the model, where naproxen (for example) can't. So, we think there may be a nitrergic component to it. The other thing is the structure of the molecule makes you think about melatonin, if you put the two up – it's a work in progress. Of the things I would like to do in my life, I'd really like to get to the bottom of it, I have to tell you, because if we could work out what it is that's great about indomethacin and then get rid of the GI thing . . . Then, if you talk about cure - because when people get a response to this (you know, the oldest reported case with a response took it for thirty-seven years; they died of something else) - and continue to respond. It's one of the sort of upsides and downsides when you diagnose it - you can tell a person that they're going to continue to respond (take a breath) until they die basically, because unfortunately, the problem doesn't tend to settle down - at least the treatment stays consistent. If we could get rid of the tummy problem, that would be real progress. Dr Smith: So, what do you do with the patient who has the tummy problem? Is there another approach? Dr Goadsby: Well, there's a range of things you try and do; you use PPIs (proton pump inhibitors) and H2 blockers pretty liberally; you try to get the lowest dose, and that's usually best done by the patient. I give them the ordinary-release indomethacin; it's an impression that I have, over the years, that the slow-release indomethacin is not as efficient (just as a recommendation). I let patients - they take it three times a day, or twice - I let them work out what the littlest amount is that they need, having given them a regime to iron it out, because they can work it out for themselves. It's a partnership. It'll be very individual. If someone wants to take two in the morning and one at night and feels happy, have at it. If they want to take one three times a day, if they want to take one at lunchtime - whatever they - let them work out the minimal amount. And the other thing that we found useful - small percentage (maybe one in five) will find the coxibs useful (like celecoxib), but that's not universal at all; it generally takes the edge off. A palpable percentage will find adding melatonin in can be indomethacin sparing. Then the other (probably most important) thing is that the noninvasive vagal nerve stimulator can be very useful in reducing indomethacin dosing or even getting patients entirely off indomethacin dosing. How that works, of course, is as mysterious in the sense of these problems as is indomethacin. But that's something really worth thinking about - can be very, very useful in getting the doses down. Dr Smith: You've been doing this for a while, right? And you've seen a lot of – Dr Goadsby: Let's not emphasize that “for a while” side, right, okay? Dr Smith: For a while – just a little while, Peter. Dr Goadsby: A little while. Dr Smith: I'm just thinking - and I'm a neuromuscular guy, so give me a little latitude - but when I was a resident, our concept of headache was pretty simple; it was migraine, classic or common, and we knew a little bit about cluster. And no one talked about SUNCT or SUNA or all these other things, and wow, what an amazing several decades it's been. What's the future look like? And - maybe think big – so, is a cure for migraine in the foreseeable future? What's coming next? Dr Goadsby: If you think really big (and I'll think really big), if “cure” means that we could control it sufficiently that you wouldn't notice it, I think that's very much - it's almost here, for some. Now, I think of it like cholesterol - someone's got high cholesterol; they take a statin, and if they don't get any problems, the cholesterol normalizes. I'm simplifying things (I'm not a cardiologist), but you take your cholesterol tablet - you take it once a day; everything's fine and dandy. You never get “cured,” as such, but the effect is an effective cure from manifestations of the problem - and I am simplifying things a little bit. If I look at it like that, then I think we're getting to a place where some patients, we can treat them so well, and the problem is so suppressed, and they have so few problems with side effects (and some have none), that we're really getting there. We saw a study of the promontory phase of migraine using a gepant (ubrogepant), and we saw the ability (if you recognize the attack early enough) to treat and never have pain. Never have pain. Well, that's pretty close. It might sound crazy to think about it as a cure because someone will say, “Well, they've still got their genes,” and so on. Fine. But migraine is about disability, and if you can stop the disability and give a person full function in their life, well, you're pretty much there. And we're getting there, as we understand the disease. Dr Smith: Really amazing. I have another question that I've actually been really dying to ask you. I'm a peripheral nerve guy, and you may not be aware of this, but those of us who are interested in therapeutic development in peripheral neuropathy, or advocacy, or recognition of neuropathy as a substantive, meaningful entity, are inspired by the work of you and your colleagues in headache. Examples might be advocacy for federal funding or having CDMRP funding - things like this. But an area where - I'm just curious - we spent a lot of effort (and it seems like it's been really transformational for you guys) is having taxonomy, which isn't a particularly sexy topic. But maybe you can talk about the power of having a taxonomic classification and getting towards a cure. Because looking through this Continuum issue - it's really remarkable – it's just all sorts of things that I never would have thought of twenty years ago, and each of them is treated a bit differently. Dr Goadsby: Yes. As with all things in medicine, if you don't get the diagnosis, you can't get to the base - you've got to be able to get a diagnosis. And our taxonomy, the International Classification of Headache Disorders, has gone through three editions. We're working on the fourth. I have the privilege of being the chairman for the fourth edition (the first three were chaired by Jes Olesen). I do think it's one of the absolute achievements of our field (and Olesen needs to be really feted for doing this) that we have a definition system - it's operational; it's reasonably straightforward; it's been translated into, like, forty languages; that every government on the planet that I know of - and I'm talking about (I think I'd better mention no governments) but every big government you can think of, without exception, has adopted (‘cause I'll just get in trouble with the ones I've mentioned) have all adopted this classification; all the health technology assessments (the FDA, for example; the European Medicine, for another example), the Chinese government (People's Republic), Taiwan. Just, all over the world, people use one thing. So, if we do a randomized control trial - there's one recently came out; it doesn't really matter which gepant it is - but you look at the results in North America, and then you look at the results that were done by the Chinese and the South Koreans in a study, and the placebo rates and the active rates are more or less identical. Because what we've been able to do is homogenize who gets into clinical trials and understand what's happening. So, if I get up and talk about whatever we're going to talk about now, like, in rural India, people will know what we're talking about; all the neurologists will be on the same page and so we can make progress. And when we make progress, it's global progress because we sing from the same hymn sheets. I think the taxonomy has been really important for this. And, of course, if you get the diagnosis right, then you can start to begin to get the treatments right and you can bring all the knowledge from randomized controlled trials. There's no point having a whole lot of data if you can't apply it, and what's great about our taxonomy is we can apply it everywhere in the world. Dr Smith: Wow, what a cool answer. So, I have a follow up question for you, Peter, which has to do with reproducibility. This is a huge issue, right? In reproducibility and clinical trial evidence and in many fields, this has been a big issue - in psychiatry and other areas of neurology, where trials are nonreproducible. To what extent do you think this problem in other fields is a taxonomic problem, or a internal validity problem, in terms of the populations being recruited? I'm really impressed to hear that you don't have that problem in headache. Dr Goadsby: I do think one of the advantages that the International Classification of Headache Disorders has given us (International Headache Society being the proponent of that) is that there's clinical homogeneity, relatively speaking, in our clinical trial populations. This comes back to the clinic; good clinical trials are as much about the clinicians who are involved and the care they take in recruiting patients, and so on. Which is not to say that psychiatrists are not careful - not at all. But I do think that if you want to just test a question, everyone in the laboratory will tell you that you need to have - say you're doing work with rodents, for example; you want about the same weight, you want the same strain, they're eating about the same, they're up and down at night - everything is about the same. If you want to do good clinical trial work, you have to tidy up as much as you can so the only thing that's really impacting upon the question is the medicine, or the placebo, or whatever that you're testing. So, I think you're right. I think sometimes the pain people struggle with this because, as you say, a painful neuropathy can come from a lot of places. Well, if you just take all of those etiologies, you throw them into one study, and you test it against something, it doesn't surprise me that that's not so useful, compared to taking an individual thing that's really well defined - where you've understood the clinical side, you've understood the pathophysiology as much as you could - and just test that, one at a time. I think that's been a good lesson for us. And that's why there's nothing that's ever failed in a migraine clinical trial (a properly designed one) that ever was useful, and nothing that was ever successful that didn't continue to be successful. Now, some things were successful, and they produced, like, liver enzyme problems - so, that's “no win-no foul” situation. But the homogeneity's been quite important, I think. And it comes back to good clinical practice. Dr Smith: Well, thank you for the roadmap - that's really, really interesting. I'd like to finish up with another shift in gears, and to talk about workforce. Obviously, we have a national shortage of neurologists in the United States. We're never going to be able to train enough headache neurologists to take care of all headache patients, and we need to think about systems of care, which I guess we could talk about. But my question for you is, what would you say - a lot of residents listen to Continuum Audio, and hopefully, more medical students in the future and now - what do you say to them about a career in headache? Listening to this, I kind of feel like I want to go do a headache fellowship - it's pretty exciting. What's your pitch to them? Dr Goadsby: I'll tell you one small thing first before I say that; I did do twelve months in clinical neurophysiology, doing nerve conduction, muscle biopsies, evoked potentials. I actually did over ninety muscle biopsies (needle muscle biopsies) when I was training, so I understand your feeling. But I just got the feeling many years earlier than you've had it. What do I say to residents? Well, headache is an area where you can make a diagnosis, you can manage the patient, and you can make them better. I'd say to the resident, “Ask - just look in the mirror and ask yourself, why did you get into medicine?” You got into medicine to help people, and headache is an area where you can really help them. Plus, there's tens of millions of people with the problem, so you will always be in demand. And one of the great things about headache (I think it's probably true of neuromuscular) is it's also a very good lifestyle choice because our problems are generally with primary headache disorders - are not emergent (people don't tend to ring you up at night), and it's not really an on-call issue. You can have a proper balanced existence (work-life balance), and you can do it in a way that's really enjoyable. And then there's an extra bonus: there's all the wonderful neuroscience and neuropharmacology that's going on in headache. I just think if a resident looks in the mirror and says, “Why am I doing this?” most of them are going to look back at themselves and say, “Because I want to do good.” And they also want to do good in a way that they can have a proper life themselves. And if they're the two answers you got back when you look in the mirror (“I want to do good” and “I want to have some life myself”) - headache - that's the place to go, because there's plenty of room and you can do both. Dr Smith: Well Peter, that's great - sign me up. And I think people know where to find you to call for a recommendation. What a great conversation and a really great article. And again, I'll refer our listeners to Mark Burish's article on cluster, which is a really great companion to your article ‘cause it gives you the full spectrum of trigeminal autonomic cephalgias (which is pretty cool), and the rest of the issue is equally amazing. Peter, you don't disappoint. The next time you see the Danish Crown Prince, say “Hi” from me (I love Denmark - it's a lovely place to be). And thanks again for doing this. Dr Goadsby: Well, thank you, and thanks for the Academy for organizing. And the other thing about residents - if you want to stay in touch with neurology, stay in touch with the Academy; they're a pretty good bunch. Dr Smith: Couldn't agree more, couldn't agree more. Again, today we've been interviewing Dr. Peter Goadsby. His article on indomethacin-responsive headache disorders appears in the most recent issue of Continuum, on headache. Be sure to check out our Continuum Audio podcasts from this and other issues. And listeners, thank you very much for joining us today.   Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practice. Right now, during our Spring Special, all subscriptions are 15% off. Go to Continpub.com/Spring2024, or use the link in the episode notes to learn more and take advantage of this great discount. This offer ends June 30, 2024. AAN members: go to the link in the episode notes and complete the evaluation to get CME. Thank you for listening to Continuum Audio.

Allison Bryant, MD, MPH, Associate Chief Health Equity Officer, Mass General Brigham (MGB), joins Eric to discuss how the health system ensures its innovations are accessible to everyone, particularly those from marginalized communities. Allison elaborates on MGB's unique approach, viewing its mission as providing healthcare and as a catalyst for improving equity of outcomes for patients and the communities it serves.   Topics covered include: Community health Bridging the digital divide Equity in maternal health United Against Racism (MGB's Diversity, Equity and Inclusion statement)   About Allison In her role at MGB, Allison works to eliminate longstanding inequities in patient care and outcomes. She is a maternal-fetal medicine subspecialist, an associate professor of obstetrics, gynecology and reproductive sciences at Harvard Medical School and is the Frederic D. Frigoletto, MD Endowed Chair in the Department of Obstetrics and Gynecology at Massachusetts General Hospital. She received degrees in biology, public health and medicine from Harvard University, where she also completed residency training in obstetrics and gynecology and fellowships in maternal/fetal medicine and the Commonwealth Fund/Harvard University Fellowship in Minority Health Policy. She previously served as the vice chair for quality, equity and safety for the Department of Obstetrics and Gynecology at Mass General.   About Mass General Brigham Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation's leading biomedical research organizations with several Harvard Medical School teaching hospitals. Mass General Brigham https://www.massgeneralbrigham.org/   United Against Racism: https://www.massgeneralbrigham.org/en/about/diversity-equity-and-inclusion/united-against-racism

- Sage Steele explains how the fix was in on her Biden interview. - Joe Biden's latest lie about Donald Trump. - Ashley Biden's diary isn't Russian disinformation. - A bearded "lady" dominates basketball in Lynn, MA. - Mass General won't report if babies have drugs in their system, it's racist. - Paul Pierce has thoughts on Caitlin Clark. Today's podcast is sponsored by: Hillsdale College: Select from several completely FREE online college history courses at http://hillsdale.edu/Gerry Ladder: One thing in life that you really cannot afford to wait on is setting up term coverage life insurance. Get instantly approved at http://LadderLife.com/Gerry Listen to Newsmax LIVE and see our entire podcast lineup at http://Newsmax.com/Listen Make the switch to NEWSMAX today! Get your 15 day free trial of NEWSMAX+ at http://NewsmaxPlus.com Looking for NEWSMAX caps, tees, mugs & more? Check out the Newsmax merchandise shop at : http://nws.mx/shop Follow NEWSMAX on Social Media:  • Facebook: http://nws.mx/FB  • Twitter: http://nws.mx/twitter • Instagram: http://nws.mx/IG • YouTube: https://youtube.com/NewsmaxTV • Threads: http://threads.net/@NEWSMAX  • Telegram: http://t.me/newsmax  • TRUTH Social: https://truthsocial.com/@NEWSMAX  • GETTR: https://gettr.com/user/newsmax Learn more about your ad choices. Visit megaphone.fm/adchoices

Regardless of the underlying cause of spinal cord disease, we have many tools at our disposal to improve symptoms and function in these patients. Even better, technology in this area is advancing rapidly. In this episode, Lyell Jones, MD, FAAN, speaks with Kathy Chuang, MD, author of the article “Symptomatic Treatment of Myelopathy,” in the Continuum February 2024 Spinal Cord Disorders issue. Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Dr. Chuang is an instructor in neurology at Harvard Medical School and assistant in neurology co-director at Paralysis Center, Massachusetts General Hospital and Spaulding Rehabilitation Hospital in Boston, Massachusetts. Additional Resources Read the article: Symptomatic Treatment of Myelopathy Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @LyellJ Transcript  Full transcript available on Libsyn   Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum Lifelong Learning in Neurology. Today, I'm interviewing Dr Kathy Chuang, who has recently authored an article on symptomatic management of myelopathy in the latest issue of Continuum, on spinal cord disorders. Dr. Chuang is a neurologist and physical medicine and rehabilitation specialist at Mass General, where she serves as Co-Director of the MGH Paralysis Program and Chief of the Neuromuscular Rehabilitation Program. Dr Chuang, welcome, and thank you for joining us today. Would you introduce yourself to our listeners? Dr Chuang: Hi, my name is Kathy Chuang. As you said, I'm a neurologist at Mass General Hospital specializing in neuromuscular medicine, also physiatry, physical medicine, and rehab. And I'm glad to be here. Dr Jones: Thank you for joining us. Basically, if we want to know more about managing spinal cord disorders, we have come to the right person, right? Dr Chuang: I try to do my best with all patients - yep. Dr Jones: For our listeners who are new to Continuum, Continuum is a journal dedicated to helping clinicians deliver the highest quality neurologic care to their patients, and we do this with high-quality and current clinical reviews. For our long-time Continuum Audio listeners, you'll notice a few different things with our latest issue and series of author interviews. For many years, Continuum Audio has been a great way to learn about our Continuum articles. Starting with our issue on spinal cord disorders (this issue), I'm happy to announce that our Continuum Audio interviews will now be available to all on your favorite open podcast platform, with some exciting new content in our interviews. Dr. Chuang, your article is absolutely full of extremely helpful and clinically relevant recommendations for the treatment of myelopathy, regardless of the cause. If there were one single most important practice-changing recommendation that you'd like our listeners to take away, what would that be? Dr Chuang: I think the most important thing to take away is that spinal cord injury of any type spans so many organ systems, it is good to get people - or multidisciplinary care - involved early on. There's eighteen model systems for spinal cord injuries scattered across the US. Those can be great avenues of resources for patients and for practitioners, for people around. Physical medicine and rehab specialists (our physiatrists or spinal cord injury specialists) can be very useful. And then, also for each individual organ system, there are specialists involved. And so, having that multidisciplinary care is probably the most important thing for a patient that's suffering from myelopathy because every patient is different and coordinating that care is so important to them. Dr Jones: So, teamwork is probably the most important thing, and I think most of our listeners who have taken care of patients with spinal cord disorders realize that that's really key. Your article - it leads off with such a great review of one of the big problems with myelopathy, which is spasticity management. From a medication perspective, I think many of us struggle with the balance between controlling the spasticity and some of the side effects of those medications, like sedation. How do you walk that fine line, Dr. Chuang? Dr Chuang: Spasticity management, like everything else, is patient directed. It depends on what the patient is most complaining of. If a patient has spasticity but they're not actually having any complaints from it, we don't need to treat, because of fear of side effects. I tend to try to use focal procedures (like botulinum toxin injections) earlier on, in order to try and spare side effects of antispasticity medications. Use of other conservative therapies, like bracing, stretching, is very essential. Another thing to consider is that dantrolene doesn't usually have side effects - cognitive side effects, at least - and actually can be monitored pretty closely for hepatotoxicity, which is its major side effect. Other possibilities are the baclofen pumps, which can be very useful in patients with spinal cord injury because their spasticity is often more in their lower limbs than in their upper limbs. By using multimodality approaches, we can definitely limit the amount of cognitive side effects of medications. Dr Jones: That's fantastic. Do you start with that multimodal at the beginning, or do you step into it with one, then the other, then the other? Dr Chuang: I usually start off with a low-dose baclofen because they usually have generalized tone - first, in order to see if they have cognitive side effects with it and if so, at what dose. Also, so that insurers have a trial of some medication before we proceed to something as expensive as botulinum toxin injection. But yes, if there's significant focal spasticity, especially, I try to bring in botulinum toxin injections as early as possible, just because of the possibility of minimizing the effect. Dr Jones: That's a great point - that you can start these from multiple angles and start them early. And great point about dantrolene - I think the hepatotoxicity makes many of us nervous. But it's a key point there - that it can spare some of the cognitive side effects. Dr Chuang: Yes, and actually, it can be monitored pretty closely. As long as a patient has access to labs, we can check liver function tests weekly or every two weeks until you're on a stable dose, and after that, only at intervals. And it can be weaned off just as quickly. Dr Jones: Fantastic. Another issue that you cover really nicely in the article, that I think is an underrecognized complication of spinal cord diseases - neuropathic pain. What's your approach to that problem, Dr. Chuang? Dr Chuang: Neuropathic pain is very, very tough to treat a lot of times. I usually give the chance of gabapentin, pregabalin, and duloxetine early, just to see if we can start managing their pain early and to try to prevent potentiation of pain. But I also tend to try to get pain management specialists on early, and also keep in mind that there can be other causes of pain other than just the actual spinal cord injury itself. Because of deafferentation and reafferentation, patients may think of neuropathic pain, and it could be something as simple as appendicitis. If there's a change in pain, there always needs to be a workup for acute causes. Again, multidisciplinary treatment, especially with pain specialists, can be really helpful. Dr Jones: Great point about thinking of other causes, including appendicitis or the musculoskeletal things that I'm sure can be pain generators in this pain population, right? Dr Chuang: Yeah, it's very common. Patients can often fracture themselves just with a simple transfer and that can cause a huge flare-up of pain. So, not all pain should be just dismissed as being neuropathic or just from the spinal cord injury itself. Dr Jones: Great point - thank you. Another topic that you cover - that I think is mystifying to many of us - is the neurogenic bladder problems that occur in patients with myelopathy. You talk about the different types - how do you tell them apart? Dr Chuang: It's hard to tell them apart from a patient perspective because a patient will just say that they have difficulty with urination. With a spastic bladder or detrusor sphincter dyssynergia, oftentimes, patients will complain of a short stream and having to force things out. And with an atonic bladder or flaccid bladder, they have difficulty initiating a stream. What can be useful are postvoid residuals - where, if a patient is in the hospital, or if you have access to an ultrasound, or if they see a urologist - after they void, you measure the amount of urine left in their bladder. You can see whether it's a smaller amount, which is suggestive of a spastic bladder, versus a large amount, or an atonic or flaccid bladder. The standard procedure that's done to measure these are also urodynamic studies that are done, oftentimes, by urologists, where they can actually measure pressure volumes and oftentimes get EMG recordings of the actual bladder - the sphincters. Dr Jones: Perfect. When you do those postvoid residuals (easiest done with ultrasound), what's the general cutoff you use to say - that's a small amount that might be suggestive of a spastic bladder? Dr Chuang: I would say, probably less than a hundred. And then, if it was flaccid, more than five hundred. If there's in between, it may fall into either category. Dr Jones: Got it. When you think about neurogenic bladder, what are the treatment options? How do they vary between the different types that patients may have? Dr Chuang: If you have an atonic or flaccid bladder, the main possibilities for patients just are, oftentimes, Credé maneuvers (or pressure on the bladder) in order to try and help with the bladder to squeeze urine out. But a lot of times they need clean intermittent catheterization or maybe placement of a suprapubic catheter long term. For patients who have a spastic bladder or detrusor sphincter dyssynergia, we can use anticholinergic medications, like bethanechol, tolterodine - those medications - in order to try to relax the sphincter a little bit and then allow the urine to pass through. You can also have BOTOX injections to these sphincters of the bladder as well, which can be useful to relax them so that they can allow the urine to pass through. But a lot of times, a mainstay of treatment is intermittent catheterization, also for patients with severe detrusor sphincter dyssynergia, so that we can maintain small bladder volumes and not develop hydronephrosis, urinary tract infections, and complications of holding urine in the bladder. Dr Jones: Thanks for that, Dr. Chuang. Another part of your article that I thought was really fascinating, and probably will cover some new ground for our readers and listeners, is the use of nerve transfers or surgical treatment of weakness, basically. Tell us about that and how it's used in patients with myelopathy. Dr Chuang: For patients with myelopathy, it's used often in the upper extremities. If a patient has voluntary control of either elbow flexion or elbow extension (usually, elbow flexion), you can oftentimes have the ability to transfer nerves into the finger flexors and allow voluntary hand closure. If there's supination or wrist extension, you can oftentimes allow transfers of branches of the nerve - for example, from the supinator, or from the branch to the extensor carpi radialis brevis, into the finger extensor - so that, over a period of nine to twelve months, we'll be able to slowly regrow the nerve back in and allow the denervated muscle to become reinnervated with a voluntary controlled muscle and then restore voluntary finger extension, which can be extremely beneficial - just being able to voluntarily open and close their hands. Dr Jones: Right. And it sounds like the goal is really that functional use of grip and use of the upper limb. Not really so much for transfers, I imagine - is that not so much the goal? Dr Chuang: If there's less than antigravity strength of elbow extension and reasonable external rotation strength, you may be able to get elbow extension strong enough antigravity, and at that point a patient may be able to transfer independently - with a lot of training. Dr Jones: Wow, that's fantastic - thank you. There's lots of therapeutic options, really, for many of these complications, which I think is an important point for our readers and our listeners to take home. When you look into the future, Dr. Chuang, what do you see on the horizon as the next generation of care for patients with spinal cord disorders? Dr Chuang: I see a huge, expanding field, both of therapeutics - there are stem cell trials all over the world; there are neurorestorative hormones that are being tried. I'm very excited about the advent of robotics, with motors being basically shrunk down to the size of millimeters, and exoskeletons becoming lighter and lighter. I suspect that, long term, we'll be able to have robotic exoskeletons to be able to help patients walk and move their limbs normally. I know there are clinical trials right now involving orthoses that are controlled with brain interfaces that will hopefully help restore function in patients who need it. Dr Jones: It sounds like science fiction, but a lot of that technology exists now, right? Dr Chuang: Yes, it does. We definitely have prototypes of multigear hands with multiple directions. Now, the problem is trying to find the way to control these motors and to control these robotic hands and legs. Dr Jones: Caring for patients with myelopathy I imagine can be challenging, but I imagine it can also be quite rewarding. Tell us, Dr. Chuang, what drew you to this work specifically, and what do you find most exciting about it? Dr Chuang: I want to help people move better. I'm a physiatrist by training, and our job as physiatrist is to try to get people back to their activities of daily living as soon as possible; to try to remove any barriers to becoming active, independent people in their society. And so, I think that spinal patients that suffer from myelopathies or other spinal cord injuries have a lot of potential in the amount of activities that they can do and the way that they can contribute. I've seen patients who have been paralyzed and unable to move their hands at all develop tenodesis scripts, initially in order to just pick up things and then later obtain voluntary control of opening and closing their fingers. And it's huge in terms of what they can do in their everyday lives. Just being able to see that is just really rewarding. And even being able to help patients navigate society around them is just a hugely rewarding experience. Dr Jones: I imagine that must be really fantastic to see folks regain those milestones. Dr Chuang: Yes. Dr Jones: It's pretty unusual for someone to have done a neurology and a physiatry residency. So, between me and you and all of our listeners, which residency was better? Dr Chuang: Wouldn't trade one without the other. Probably wouldn't have done the one without the other, either! Dr Jones: What a great, diplomatic answer. Okay, good. Dr Chuang: It's true. Dr Jones: Yeah. You avoided offending all the neurologists and physiatrists out there. And really fascinating discussion, Dr. Chuang. It's an outstanding article. I think it's a must-read for anyone who takes care of patients with spinal cord disorders. I want to thank you Dr. Wang for joining us and for such a thoughtful, fascinating discussion on symptomatic management of spinal cord disorders. Dr Chuang: Thank you, Dr. Jones for having me today. Dr Jones: Again, we've been speaking with Dr. Kathy Chuang, author of an article on symptomatic treatment of myelopathy in Continuum's most recent issue on spinal cord disease - please check it out. And thank you to our listeners for joining today. Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members, go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

Doctors say the patient, a 62-year-old-man is recovering well from the surgery. It is seen as a milestone and a potential solution to the worldwide shortage of human organs for patients who need transplants.

Welcome to the MassDevice Fast Five medtech news podcast, the show that keeps you up-to-date on the latest breakthroughs in medical technology. Here's what you need to know for today, March 13, 2024. Check out the show notes for links to the stories we discussed today at MassDevice.com/podcast. GE HealthCare and Mass General are bringing artificial intelligence to imaging. Fast Five hosts Sean Whooley and Danielle Kirsh discuss the partnership and how it can transform healthcare. Ascensia and Senseonics have announced new CGM cost savings. Hear more about some of the cost saving initiatives and the devices that are included in the initiatives. SS Innovations has used its surgical robot in mitral valve replacement procedures. Whooley talks about what the robot does and what people think about its performance.  3M CEO Mike Roman is stepping down as CEO and a successor has been named. Learn who is taking over the corner office and the optimism they bring to the role. A recent recall of Abbott's HeartMate communications system is Class I, according to the FDA. The Fast Five hosts talk about the reason behind the recall and if there have been any adverse reports.

    Meet Beth Allan Kellam, a seasoned medical research expert with over 20 years of experience collaborating with renowned hospitals such as Memorial Sloan Kettering, John's Hopkins, and Mass General. More recently, Beth launched an organization that aims to revolutionize the way we address urinary tract infections (UTIs) by providing a new natural supplement […]

Today's guest is Dr. Dan Elton, a Data Scientist at the Mass General Brigham Data Science Office. He's also a fellow at the Foresight Institute and previously served as a staff scientist at the National Institutes of Health. He joins Emerj Senior Editor Matthew DeMello on today's show to talk about promising AI use cases in healthcare, including use cases in radiology, compliance, and medical record generation, search, and summarization. Later, the two discuss how foundational models will transform how AI is used in radiology. To discover more AI use cases, best practice guides, white papers, frameworks, and more, join Emerj Plus at emerj.com/p1.

In an effort to protect us from getting killed by something we've ingested, our brain's vomit control center processes a lot of information from several different places … and sometimes is a little overly cautious.   LEARN MORE To learn more about this topic, start your googling with these keywords:  Emesis: The act of vomiting Vomiting: The oral eviction of gastrointestinal contents due to contractions in the gut and stomach. Nausea: A diffuse sensation of uneasiness and discomfort often felt as the need to vomit. Vomiting Center: An area in the brain's medulla oblongata that initiates and controls emesis. Chemoreceptor Trigger Zone: An area in the area postrema of the medulla oblongata that is sensitive to certain toxic chemicals in the blood.  Nucleus Tractus Solitarius: A region in the medulla oblongata that receives input from the cardiovascular, respiratory and GI systems.  Vagus Nerve: A cranial nerve that regulates internal organ functions, including vomiting.  Vestibular System: A Sensory system that provides our brain with information about motion, head position, and spatial positioning for balance. SUPPORT MINUTEEARTH If you like what we do, you can help us!: Become our patron:   Share this video with your friends and family Leave us a comment (we read them!)   CREDITS David Goldenberg | Script Writer, Narrator and Director Arcadi Garcia i Rius | Illustration, Video Editing and Animation  Nathaniel Schroeder | Music MinuteEarth is produced by Neptune Studios LLC      OUR STAFF Lizah van der Aart • Sarah Berman • Arcadi Garcia i Rius David Goldenberg • Melissa Hayes • Alex Reich  Henry Reich • Peter Reich • Ever Salazar Alexander Vidal • Leonardo Souza • Kate Yoshida   OUR LINKS Youtube | TikTok |   Twitter |   Instagram |   Facebook |   Website |   Apple Podcasts |    REFERENCES Singh P, Yoon SS, Kuo B. Nausea: a review of pathophysiology and therapeutics. Therap Adv Gastroenterol. 2016;9(1):98-112. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699282/ Hasler, W. (2013). Pathology of emesis: its autonomic basis. Handbook of Clinical Neurology, Vol. 117 (3rd series) Autonomic Nervous System. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/24095137/ Zhong W, Shahbaz O, Teskey G, Beever A, Kachour N, Venketaraman V, Darmani NA. Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems. Int J Mol Sci. 2021 May 28;22(11):5797. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/34071460/ Kowalski A, Rapps N, Enck P. Functional cortical imaging of nausea and vomiting: a possible approach. Auton Neurosci. 2006 Oct 30;129(1-2):28-35. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/16945593/ Hornby, PJ. Central neurocircuitry associated with emesis. Am J Med. 2001 Dec 3;111 Suppl 8A:106S-112S. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/11749934/ Kuo, Braden. (2022). Personal Communication. Director of the Center for Neurointestinal Health at Mass General. https://www.massgeneral.org/doctors/17189/brad-kuo

TW: suicide   Dr. Uma Naidoo is a Nutritional Psychiatrist at Harvard Medical School, best-selling author, professional chef, and more. She joins your hosts today to discuss how the gut and brain are connected, the importance of what food you eat, and the link between mental and metabolic health. She shares what drew her to this field of medicine, how our diet is linked to our brain, and offers quick and easy recipes that can make a big difference for shift workers. She touches on foods that support your mental health, foods to support people going through fertility treatments, and discusses her new project: the first CME program in nutritional psychiatry with Mass General.     Be sure to follow Dr. Uma Naidoo @drumanaidoo. To get a copy of her book and sign up for her newsletter visit umanaidoomd.com    Thanks to our amazing sponsors for making this episode possible:  Caraway — Visit Carawayhome.com/WOMED to take advantage of this limited-time offer for 10% off your next purchase. This deal is exclusive for our listeners, so visit Carawayhome.com/WOMED or use code WOMED at checkout. Caraway: Non-Toxic cookware made modern.   Hello Fresh — Go to HelloFresh.com/womedfree and use code womedfree for FREE breakfast for life!   Osea — Give the gift of glow this holiday season with clean, vegan skincare from OSEA. Right now we have a special discount just for our listeners. Get 10% off your first order sitewide with code WOMED at OSEAMalibu.com     Quince — Go to Quince.com/WOMED for free shipping on your order and 365-day returns.   If you haven't already, please follow, rate, and review the podcast, follow us on Instagram @TheWoMed and check out womedpodcast.com. Plus, give us a follow on TikTok @thewomedpodcast. Be sure to follow your hosts personally @dmmaltby and @jackiethefnp and be sure to check out @riothealers!   WoMed Cover Art — Makeup: Annelise Carey, MUA/LME @annelisemua & Photography: Brooke Boling @honorcreative    Learn more about your ad choices. Visit megaphone.fm/adchoices

In this episode, Jules and Erica talk about Valentine's Day, including gluten-free Valentine's Day finds at Target and gluten-free Valentine's Day recipes. They also talk about facial misbranding of spices and a new FDA recall, plus the most recent findings from the CDGEMM study on celiac disease from Mass General. RESOURCESGluten-Free Valentine's Day Candy ListGluten-Free Valentine's Day Recipe Round-upYum Earth Valentine's Day CandiesLesser Evil Valentine's Day Popcorn Sweetheart PopEnjoy Life Foods Vegan White Chocolate ChipsPascha Vegan ChocolateEndangered Species Chocolate Oat Milk Chocolate ChipsTrupo Treats Earth GemsgfJules heart-shaped cookie cakegfJules gluten-free hand piesgfJules sugar cookie recipegfJules Gluten Free Cut Out Sugar Cookie MixMass General CDGEMM StudyDesigner Shit DocumentarygfJules Instagram Post about spice mislabelingContact/Follow Jules & Erica Tweet us @THEgfJules & @CeliacBeast Find us on IG @CeliacandTheBeast & @gfJules Follow us on FB @gfJules & @CeliacandTheBeast Email us at support@gfJules.com Find more articles, recipes & info at gfJules.com & celiacandthebeast.com Thanks for listening! Be sure to subscribe!**some links may be affiliate links; purchasing through these links will not cost you more, but will help to fund the podcast you ❤️

Can we prevent our kids from getting addicted to substances? Is there a more common personality "type" of kid that gets addicted to drugs? What drugs are we worried about in tweens and tweens? It's these questions and more that we ask Dr. Scott Hadland, Addiction Doctor and Chief of Adolescent Medicine at Mass General and Harvard Medical School. It's an episode you don't want to miss because we think this kind of information is necessary for parents with kids of any age. To follow Dr. Scott and learn more about his wealth of knowledge in this space you can find him @drscotthadland on Instagram and Twitter. Want our podcasts sent straight to your phone? Text us the word "Podcast" to +1 (917) 540-8715 and we'll text you the new episodes when they're released!Tune in for new Cat & Nat Unfiltered episodes every Monday, Tuesday, Thursday and Friday!Follow @catandnatunfiltered on Instagram: https://instagram.com/catandnatunfilteredOur new book "Mom Secrets" is now available! Head to www.catandnat.ca/book to grab your autographed copy! Come see us LIVE on tour!! To see a full list of cities and dates, go to https://catandnattour.com.Follow our parenting platform - The Common Parent - over on Instagram: https://instagram.com/thecommonparentBecome a Member of The Common Parent, our ultimate parenting toolkit for parents of teens and tweens for just $74.99/year: https://thecommonparent.comGet a FREE “Thoughts Between Us” Journal with The Common Parent Annual Membership: Click Here!Make sure you subscribe to our YouTube channel for our new cooking show and our #momtruth videos: https://bitly.com/catnatyoutubeCheck out our Amazon Lives here: https://bitly.com/catnatamazonliveOrder TAYLIVI here: https://taylivi.comGet personalized videos from us on Cameo: https://cameo.com/catandnatCome hang with us over on https://instagram.com/catandnat all day long.And follow us on https://tiktok.com/@catandnatofficial! Hosted on Acast. See acast.com/privacy for more information.

Today, I am blessed to have here with me Alastair Bostwick. He is a New York City Journalist with a multifaceted career that spans various media outlets and industries. With a passion for video production, Alastair has made a significant mark in the world of journalism, capturing attention with his engaging and insightful content. In this episode, Alastair dives into the intricate interplay between UV light and opioid receptors. Alastair takes us through the nuanced connections between light exposure and mood disorders, shedding light on the intriguing parallels between sunlight and opioid experiences. We address opioid addiction and the dualities surrounding tanning beds, challenging conventional approaches with the potential of UV light as a substitute. Lastly, we cover the controversy surrounding sunblocks, navigating discussions involving dermatologists, and emphasizing a balanced perspective on skin cancer prevention and vitamin D synthesis. Free Detox Masterclass. Reserve Your Spot Here: http://www.toxinsmasterclass.com / / E P I S O D E   S P ON S O R S  Wild Pastures: $20 OFF per Box for Life + Free Shipping for Life + $15 OFF your 1st Box! https://wildpastures.com/promos/save-20-for-life-lf?oid=6&affid=132&source_id=podcast&sub1=ad BonCharge: Blue light Blocking Glasses, Red Light Therapy, Sauna Blankets & More. Visit https://boncharge.com/pages/ketokamp and use the coupon code KETOKAMP for 15% off your order. Beam Minerals: BEAM Minerals products are the perfect support for the keto/carnivore/fasting way of living as they won't break your fast, PLUS they taste just like water and will help you keep carb cravings at bay as you move into a fat-adapted state. Give BEAM Minerals a try today for an enhanced keto experience. Head to http://www.beamminerals.com and use the coupon code AZADI for a sweet discount!  [06:15] Exploring the Impact of UV Light on Opioid Receptors -       Alastair based his hypothesis on research papers he uncovered, particularly focusing on UV light's effects on opioid receptors in the brain. -       He spoke to a doctor at Mass General who was conducting research on this topic, primarily with mice. The hypothesis suggested that UV light could affect opioid receptors in human brains. -       Alastair took a proactive approach to test his hypothesis by exposing himself aggressively to UV light. Living in New York City, he deliberately spent two hours in the sun every day during the summer, in addition to using a tanning bed vigorously. The goal was to maximize exposure to UV light. -       Alastair was strategic about the timing of UV exposure, going out between 11 a.m. and 1 p.m., which is considered the highest UV index. He aimed to expose himself during the peak hours of UV intensity to enhance the effectiveness of the experiment. [08:30] Narcan's Swift Action and Alastair's UV Light Experiment -       Narcan rapidly detaches substances that bind to opioid receptors in the brain. It acts quickly, causing not only a reversal of the respiratory effects but also inducing withdrawal symptoms if the person is not breathing. This mechanism serves as the basis for Alastair's experiment. -       Alastair hypothesized that if there is a correlation between UV light and the opioid effect in the brain, Narcan, known to work on normal opioid usage, should have a similar effect in the presence of UV light. This led him to experiment by exposing himself to UV light and then taking Narcan, resulting in a full withdrawal experience. -       According to him, the consistent results indicated that UV light does indeed affect opioid receptors in the brain. -       Alastair's experience lends support to the notion that UV light has a significant and consistent impact on opioid receptors in the brain. [12:30] An Exploration of Light, Mood, and the Subtle Opioid Influence of UV Rays -       Alastair decided to dig deeper into the connection between light exposure, particularly visible light, and mood disorders like SAD. -       He discovered that, separate from the positive effects of visible light seen in SAD treatment, there's another aspect involving UV light, which is not visible to the human eye. -       UV light, distinct from visible light, has effects on the body, including replenishing vitamin D levels and influencing opioid receptors. -       Alastair explained that UV light, over time, subtly affects human opioid receptors, similar to substances like heroin, morphine, fentanyl, and Vicodin. -       While the response is not as strong, prolonged exposure to sunlight can lead to feelings of tiredness or reinvigoration, akin to experiencing a mild opioid stimulation. This sheds light on why people may enjoy spending a day at the beach or using tanning beds to achieve a subtle opioid effect. [19:20] Addressing Opioid Addiction and Tanning Bed Dualities -       Alastair suggests that one approach to address opioid addiction is to ensure individuals receive enough sunlight and vitamin D throughout their lives. By maintaining adequate levels of vitamin D, the brain may be less likely to respond to prescription painkillers in an addictive manner, potentially preventing addiction from the outset. -       Researchers are exploring an alternative approach for individuals already abusing or dependent on opioids. Instead of traditional methods like methadone clinics, where individuals are gradually tapered off opioids, there is evidence suggesting that ultraviolet (UV) light could serve as a substitute. -       Alastair discusses the dual nature of tanning beds. While he initially doubted the concept of tanning bed addiction, he acknowledges that there is compelling evidence from esteemed researchers suggesting that tanning beds, with their potent UVA light, can be as addictive as synthetic opioids like Vicodin or Oxycodone. -       However, he also highlights the potential use of tanning beds as a tool to help individuals transition off synthetic opioids. [23:45] Sunblock Controversies: Balancing Skin Cancer Prevention and Vitamin D Synthesis -       The use of sunblock is a controversial subject, particularly in discussions involving dermatologists who often focus on skin cancer prevention. -       Overexposure to ultraviolet radiation, especially from the sun, is known to cause skin cancer. While some doctors recommend avoiding UV light and using vitamin D supplements, Alastair suggests a more relaxed approach, emphasizing the benefits of an active lifestyle and time spent outdoors. -       Some doctors advocate for sunblock as a means to prevent skin cancer, while others, like Alastair, express concerns about its potential negative impact on vitamin D synthesis. -       Alastair expresses skepticism about the marketing behind sunblocks, suggesting that it may not always be honest. [48:00] A Journey through Mood Changes and Tanning Bed Seeking Behavior -       As the seasons changed, Alastair noticed a shift in his mood and described feeling a compulsion in the back of his mind. This compulsion led to what he referred to as "tanning bed seeking behavior." -       He experienced a sense of low-level gloom and a compulsion to seek out tanning, akin to textbook drug-seeking behavior. -       Alastair was mindful of the behavioral changes he observed in himself, characterized by a compulsion to seek out tanning beds. -       He noted that the compulsion to seek out tanning eventually went away. While he initially felt the urge to address the low mood through tanning, with time, the compulsion subsided. AND MUCH MORE! Resources from this episode: ●      Website: https://www.bostwiki.com/ ●      Watch the Opiod Documentary: here: https://www.youtube.com/watch?v=GHh3qU5XYsw&t ●      Follow Alastair Bostwick ●      X: https://twitter.com/BostWiki ●      YouTube: https://www.youtube.com/bostwiki ●      LinkedIn: https://www.linkedin.com/in/alastairbostwick/ ●      Instagram: https://www.instagram.com/bostwiki/ Free Detox Masterclass. Reserve Your Spot Here: http://www.toxinsmasterclass.com / / E P I S O D E   S P ON S O R S  Wild Pastures: $20 OFF per Box for Life + Free Shipping for Life + $15 OFF your 1st Box! https://wildpastures.com/promos/save-20-for-life-lf?oid=6&affid=132&source_id=podcast&sub1=ad BonCharge: Blue light Blocking Glasses, Red Light Therapy, Sauna Blankets & More. Visit https://boncharge.com/pages/ketokamp and use the coupon code KETOKAMP for 15% off your order. Beam Minerals: BEAM Minerals products are the perfect support for the keto/carnivore/fasting way of living as they won't break your fast, PLUS they taste just like water and will help you keep carb cravings at bay as you move into a fat-adapted state. Give BEAM Minerals a try today for an enhanced keto experience. Head to http://www.beamminerals.com and use the coupon code AZADI for a sweet discount!  Text me the words "Podcast" +1 (786) 364-5002 to be added to my contacts list.  *Some Links Are Affiliates* // F O L L O W ▸ instagram | @thebenazadi | http://bit.ly/2B1NXKW ▸ facebook | /thebenazadi | http://bit.ly/2BVvvW6 ▸ twitter | @thebenazadi http://bit.ly/2USE0so ▸clubhouse | @thebenazadi Disclaimer: This podcast is for information purposes only. Statements and views expressed on this podcast are not medical advice. This podcast including Ben Azadi disclaim responsibility from any possible adverse effects from the use of information contained herein. Opinions of guests are their own, and this podcast does not accept responsibility of statements made by guests. This podcast does not make any representations or warranties about guests qualifications or credibility. Individuals on this podcast may have a direct or non-direct interest in products or services referred to herein. If you think you have a medical problem, consult a licensed physician.

Happy New Year! Thank you for being a part of our journey this year. We are looking forward to sharing more medical misadventures with you in 2024.  Today Sara and Ashley discuss the deadliest fire in Boston's history and how its aftermath influenced the way hospitals treat burn victims and respond to mass casualties. If you are enjoying Don't Look Under the Med, please help us out and leave a five-star review! And make sure you follow the podcast on your favorite platform so you never miss an episode. Books: Pletcher, L. (2017). Massachusetts Disasters: True Stories of Tragedy and Survival. Globe Pequot. Articles: Bench Press- How the Cocoanut Grove Fire Changed Burn Care at Mass General and Beyond, by Andrew Glyman Academic Articles: Saffle JR. The 1942 fire at Boston's Cocoanut Grove nightclub. Am J Surg. 1993 Dec;166(6):581-91. doi: 10.1016/s0002-9610(05)80661-0. PMID: 8273835. Podcast Art By: Irit Mogilevsky --- Support this podcast: https://podcasters.spotify.com/pod/show/dontlookunderthemed/support

This episode features Dr. Paul Anderson, MD, PhD, Chief Academic Officer at Mass General Brigham. Here, he discusses healthcare research and teaching. He offers a glimpse into the future of Mass General's research, shares what he is currently excited about, details the heart of medical innovation, and envisions a healthcare landscape in 5-10 years.

In this insightful episode of the Incubator Podcast, join Daphna and Ben as they delve into the world of NICU follow-up care. Featuring guests Melissa Woythaler, Molly Warren, and Kristen Sullivan, the discussion explores the comprehensive approach to post-NICU care, including the innovative Transition to Home program established at Mass General Brigham and the challenges of establishing a medical home for former NICU patients. Discover the intricacies of managing various NICU follow-up programs, the vital role of neonatologists, and the significant impact these programs have on families. This episode is a deep dive into the importance of continuous care from NICU to home, underscoring the dedication and collaboration needed to support vulnerable infants and their families. As always, feel free to send us questions, comments, or suggestions to our email: nicupodcast@gmail.com. You can also contact the show through Instagram or Twitter, @nicupodcast. Or contact Ben and Daphna directly via their Twitter profiles: @drnicu and @doctordaphnamd. The papers discussed in today's episode are listed and timestamped on the webpage linked below. Enjoy!

Is this the tipping point or just another deal?

One in four Americans are aware of the sober curious movement, and 34% said they were trying to drink less in 2023. To chat about this, I called on Dr. Sarah Wakeman, an addiction medicine specialist at Mass General and a national thought leader in treatment for substance use disorders. In this episode, we define sober curiosity, learn about alcohol use disorder, and how to decide whether a sober-curious lifestyle is right for you. Plus: How to talk to friends and family about your alcohol choices, whether there's truth to the "red wine is good for you" line we've been hearing for years, how many drinks are acceptable under the U.S. Dietary Guidelines, and how alcohol really impacts on the body. SOCIAL ⁠@drsarahwakeman ⁠@emilyabbate⁠ ⁠@hurdlepodcast⁠ OFFERS AG1 | Had to drinkag1.com/hurdle to get five free travel packs and a year's supply of vitamin D with your purchase. JOIN: ⁠⁠THE *Secret* FACEBOOK GROUP⁠⁠ SIGN UP: ⁠⁠Weekly Hurdle Newsletter⁠⁠ ASK ME A QUESTION: ⁠⁠Leave me a voice message, ask me a question, and it could be featured in an upcoming episode! --- Send in a voice message: https://podcasters.spotify.com/pod/show/hurdle/message

Host David Mandell chats with Dr. Jordan Romano in Episode 4.4 of the podcast. Jordan talks about his career, how he became involved in working as a medical expert witness, grew the work into a business, and now advises other physicians who are interested in this potential “side hustle.” Jordan begins with the story of how he ended up in medicine and at Harvard and Mass General, as well as the non-traditional steps he took along the way. He relates why business was in his blood, given his family background in banking and finance. Jordan covers how and why he first jumped into the field of medical expert witnessing, what he liked about it initially and what it took to turn it into a real business. He also shares what he sees as the most significant challenges to growing the business. Jordan then discusses his current work in advising and coaching physicians looking to get into this space, what doctors typically can earn in the field, and common mistakes he sees physicians make when starting out. Jordan wraps up the episode with his big picture advice for physicians considering this type of work. Learn more and listent to this and past episodes by visiting www.physicianswealthpodcast.com.

Dr. Steven J. Spear (DBA MS MS)Principal, HVE LLCSr. Lecturer, MIT Sloan SchoolSr. Fellow, Institute for Healthcare ImprovementCreator, See to Solve Gemba and Real Time Alert SystemsSSpear@MIT.edu www.SeeToSolve.com Steve@HVELLC.comKnowing how to get smarter about what you do and better at doing it, faster than anyone else, is critical, a bona fide source of sustainable competitive advantage.How so? All organizations share a challenge. They're trying to coordinate people—sometimes a few, sometimes many thousands—towards shared purpose, somewhere on the spectrum from upstream conceptualization and discovery, through development, design, and ultimately delivery. The problem is, particularly at the startof any undertaking, no one really knows what to do, how to do it, nor can they do it well. All that has to be invented, created, discovered…figured out. So, those who solve problems faster, win more. After all, if your team and mine chase similar goals (or we face off as adversaries), you succeed (or win) because you come to your moments of test better prepared than I do. Since knowhow and skills are not innate, you won because you solved your problems, better and faster than I didmine, gaining edges in relevance, reliability, resilience, and agility.Spear's work focuses on the theme of leading complex collaborative situations, imbuing them with powerful problem solving dynamics. The High Velocity Edge earned the Crosby Medal from ASQ. “Fixing Healthcare from the Inside” won a Harvard Business Review McKinsey Award, and five of Spear's articles won Shingo Prizes. “Decoding the DNA of the Toyota Production System” is a leading HBR reprint and part of the “lean” canon. He's written for medical professionals and educators in Annals of Internal Medicine, Academic Medicine, and Health Services Research, for public school superintendents in Academic Administrator, and for the general public in the New York Times, the Boston Globe, Fortune, and USA Today. High velocity learning concepts have been tested in practice, helping building internal capability for accelerated improvement and innovation at Alcoa—which generated recurring savings in the $100s of millions, Beth Israel Deaconess, a pharma company—with compressions by half in a key drug development phase, Intel, Intuit, Pittsburgh hospitals, Memorial Sloan Kettering, Mass General, Novartis, Pratt and Whitney—which won the F-35 engine contract with its pilot, DTE Energy, US Synthetic, and the US Army's Rapid Equipping Force. The Chief of Naval Operations made high velocity learning a service wide initiative, and Spear was one of a few outside advisors to the Navy's internal review of 2017's Pacific collisions. He was also an advisor to Newport News Shipbuilding bout introducing innovative systems on the Gerald Ford, the first in a new generation of aircraft carriers. The See to Solve suite of apps has been developed to support introducing and sustaining high velocity learning behaviors.At MIT, Spear teaches Leaders for Global Operations and Executive Education students, has advised dozens of theses, and is principal investigator for research titled “Making Critical Decisions with Hostile Data.” Spear's work history includes Prudential-Bache Capital Funding, the US Congress Office of Technology Assessment, the LongTerm Credit Bank of Japan, and the University of Tokyo. His doctorate is from Harvard, his masters in mechanicalengineering and in management are from MIT, and he majored in economics, at Princeton, to earn his bachelors.Spear lives in Brookline with his wife Miriam, an architect, and their three children, where he is on the board of the Maimonides School.Link to claim CME credit:

Madelaine Claire Weiss is a licensed psychotherapist and mindset expert who helps clients control their thoughts for a happier, more successful life. With a robust educational background from Harvard, she holds an MBA and is a Board-Certified Executive, Career, and Life Coach. She co-authored the “Handbook of Stressful Transitions Across the Lifespan” and authored “Getting to G.R.E.A.T: 5-Step Strategy for Work and Life…Based on Science and Stories.” Throughout her career, Madelaine has had a diverse career, overseeing mental health practices and holding the role of a chief organizational development officer in the corporate world. Her journey led her to an associate director role at Harvard Medical School's Anatomical Gift Program. As a corporate trainer, Madelaine delivered programs to diverse organizations, including law firms, Harvard Medical School, Legal Services Corporation, and more. She's been a guest on numerous TV programs and podcasts, spreading her wisdom and contributing to various publications. Madelaine Weiss is a beacon of guidance for those striving to make the most of their lives. Listen & Subscribe on: iTunes / Stitcher / Podbean / Overcast / Spotify Contact Info Website: https://www.MadelaineWeis.com Book: Getting To G.R.E.A.T.: A 5-Step Strategy For Work and Life; Based on Science and Stories by Madelaine Weiss Most Influential Person Ellen Langer, Author Jon Kabat Zinn Effect on Emotions You know, I am so even now that it scares me sometimes. So if I cry at a movie, it's like, oh, thank God I can still cry. You know, because, it's (my emotions) evened out so much. I'm also old. And I heard that that happens when you're old too. So I don't know how much of it is mindfulness, but I know that Sarah Lazar at Mass General has done studies on this kind of thickening in the brain that happens through meditation, which is kind of like a buffer. So it doesn't mean that you don't know how you feel. It's just that it doesn't break through in a way that overwhelms you.To your question, I like to think that mindfulness helps, and it's not just that I'm old, but I'm not sure. Thoughts on Breathing I think that the 30-second mindset reset called polyvagal breathing, diaphragmatic breathing, power breathing, call it what you want, is just everybody's best friend forever. When I talk about how we get primitive under stress. When it's extreme, and I think it feels extreme to a lot of people right now, understandably, we go into fight-flight freeze and that's in the sympathetic nervous system. So, just these 3 breaths that are taken in a very specific way. Suggested Resources Book: The Mindful Body: Thinking Our Way to Chronic Health by Ellen Langer Book: How People Change by Allen Wheelis App: n/a Bullying Story I used to believe that I was the one being bullied, without going into too much detail. The bullying came from different sources, which made it hard to understand. But a few years ago, when I met up with some high school friends for lunch, something surprising happened. One of them pulled out a song I had written during my high school sorority days. They told me I had to write a mean song about someone, and when I saw it, I was horrified. I wanted to believe it was made up, but it wasn't. I had written that song. I couldn't reconcile this unkind act with the kind person I considered myself to be. It made me wonder how mindfulness could have helped. Children today are guided more than we were back then, and I hope such behavior would be recognized as wrong. I wrote a blog post about rudeness this week, as it seems to be on the rise. While it's not a new problem, it's essential to encourage kindness and civility, as even ancient civilizations struggled with these issues. Related Episodes Lessen Your Stress Using This Super Achiever Habit; Amy Novotny Adjust Your Sails With Joel Brookman Steven Shalowitz Uses Mindfulness to Embrace Cultural Differences Are you experiencing anxiety & stress? I'm Bruce Langford, a practicing coach and hypnotist helping fast-track people just like you to shed their inner bully and move forward with confidence. Book a Free Coaching Session to get you on the road to a more satisfying life, feeling grounded and focused. Send me an email at bruce@mindfulnessmode.com with ‘Time Is Right' in the subject line. We'll set up a call to discuss how you can move forward to a better life.

Emma Foley joins the show to discuss the woke calendar MGH sent to their donor list. Columbus Day has been scratched completely, and several other Leftist additions have been made. Then, John Fetterman is at it again. This time, he's talking about red pandas. As always, tune in for the Chump Line to start off the hour.

Thank you for tuning in to Episode 258 of the Down Cellar Studio Podcast. This week's segments included:   Off the Needles, Hook or Bobbins On the Needles, Hook or Bobbins From the Armchair In my Travels KAL News Events Life in Focus On a Happy Note Quote of the Week Off the Needles, Hook or Bobbins Summer Rainbow Socks   Pattern: OMG Heel Socks by Megan Williams ($5 knitting pattern available on Ravelry ) Yarn:  Desert Vista Dyeworks Viso base in the Summer Rainbow Colorway Needles: US 1.5 (2.5 mm) Ravelry Project Page 253.8 meters for Stash Dash Hattie's Water Bottle Holder   Pattern: Freedom Water Bottle Holder by Wendy Serrao (free crochet pattern available on Ravelry & on Wendy's website) Yarn: Lion Brand Re-Up Hook: G (4.25 mm) Ravelry Project Page About the project: Hattie (age 5) saw a water bottle holder at the local refill store and asked for one. Her Mom, Megg texted asking if I could please make one for Hattie. The pattern is designed for an adult/larger sized water bottle so I knew I wanted to make mine smaller than called for in the pattern. I started in blue and increased up to about 38 sts around. Instead of double crochets, I worked half double crochets instead. 6 rows hdc, followed by 3 rows of (ch1, dc around) in purple. Then I repeated that in pink. I had planned to do the strap half pink and half purple, but when I had Hattie try it on, it was too long (even though I had been accounting for a serious amount of stretch). She said it needed attention regardless because there wasn't any blue in the strap. Noted. Thankfully, I'd anticipated my picky client and brought all three colors with me to the pool. I ripped back, adjusted the length, added some blue to the second half of the strap and voila! 80.2 meters for Stash Dash Seeing Spirals Washcloth   Pattern: Seeing Spirals Washcloth by Lindsey Dale (free crochet pattern available on Ravelry or on Lindsey's website) Yarn: Lion Brand Re-Up Hook: G (4.25 mm) Ravelry Project Page 14 meters for Stash Dash Musselburgh Hat   Pattern: Musselburgh by Ysolda Teague ($7.77 US/ 6 GBP knitting pattern available on Ravelry or on Ysolda's website) Yarn: YarnBaker Fingering in the Blazer Colorway & On The Round Nimble Sock (unsure of colorway) Needles: US 2 (2.75) circular- 32 in (magic loop for beginning & end of project & US 2 (also called US 2.5) 3.0 mm 16-inch circular for the body of the hat Ravelry Project Page Size: Adult Medium About the project: Half light blue, half darker denim blue, about 8.5 inches tall. You can still fold up the brim if you really want to. 384.7 meters for Stash Dash Chevron Scrap Blanket   Pattern: Chevron Scrap Blanket by Maria's Blue Crayon (free crochet pattern) available on Ravelry & the Maria's Blue Crayon Website. This pattern presumes you already know the c2c crochet technique. Yarn: Knit Picks Brava Worsted in White & Tranquil (light green), Lion Brand Pound of Love in Pastel Pink and Loops & Threads Snuggly Wuggly Big! in colorway Soft Lilac Hook: J (6.0 mm) Ravelry Project Page (I crocheted one of these in summer 2020- click here for that Ravelry Project Page) For help learning the Corner to Corner Crochet method you could check out this free Ravelry Download from Lauri Bolland or this video tutorial from Lion Brand on https://youtu.be/mQPVlaRE4Gw Each section is 11 squares tall. Green, white, pink, white, purple, white. I used mattress stitch to seam  all 6 strips together. I used white to do a dc border round, then a hdc round. From there I did a crochet pom pom border using 2 puff stitches that you fold over to make bobbles. I first used this border on a Cozy Clusters Blanket last summer (Ravelry project page here). I learned about this edge technique on this website. 3,024 meters for Stash Dash On the Needles, Hook or Bobbins Mini Skein Hexagon Blanket   Pattern: Basic Crochet Hexagon Pattern & Tips from Make Do and Crew Website & https://youtu.be/X4hgFCAKHkg?list=PLsrz34yAA5TqZ9zDYjyLp4A1tx_2x0Ub6 Hook: F (3.75 mm) Yarn: Mini skeins from 2022 agirlandherwool Advent Calendar, 24 Days of Cheer Swap minis + other scraps/swap yarn Ravelry Project Page I've been closing the end of each hexagon with this join- link to Instagram post 4 rounds per hexagon. 3.75 inches each. Likely need over 300 Twin sized blanket is 60×80 inches. 17×22 hexis- 374. Learned double magic circle from this YouTube video. The trick is to know how to pull both loops to tighten the loop. Progress: I started seaming! 3 Christmas Stockings   Pattern: Christmas Stockings to Knit and Crochet from Family Circle Magazine. Available in this web archive link. I've also saved it to my podcast Gmail Google Drive in case it disappears! web.archive.org-Christmas Stockings to Knit and Crochet from Our Archives.pdf Yarn: Red Heart Super Saver in Cherry Red, Hunter Green and White Hook: G (4.0 mm) Ravelry Project Page Progress: I have 3 of the 4 front/back panels I need for the frist 2 done. The forth is onto the leg. I am going to crochet up 2 more and then iron them, and start seaming them. LFA Helical Socks   Pattern: OMG Heel Socks by Megan Williams ($5 knitting pattern available on Ravelry ) Yarn: Legacy Fiber Artz Steel Toes in the Portal Colorway + 50g skein in a mystery colorway Needles: US 1.5 (2.5 mm) Ravelry Project Page About the colorways: both have a pink base. The mystery skein leans more to blues and purples. Portal has some brighter sky blues and bits of green and maroon. Together they just look like one beautiful colorway.  Progress: a few inches from the heel on the first sock Zebra Stripes Socks   Pattern: OMG Heel Socks by Megan Williams ($5 knitting pattern available on Ravelry ) Yarn: Patons Kroy in the Zebra Stripes Colorway Needles: US 1.5 (2.5 mm) Ravelry Project Page About the colorway- approximately 3 round stripes of black and cream Progress: Finished first sock. Turned the heel on the second sock. Woolens and Nosh Socks   Yarn: Woolens & Nosh Targee Socks- 2022 Advent Calendar Pattern: OMG Heel by Megan Williams ($5 Knitting Pattern available on Ravelry) Needles: US 1.5 (2.5 mm) Ravelry Project Page 1 stripe a day. So manageable– then I got to Vegas and realized I was using US 2 instead of US 1.5. Thought the gauge looked strange. Ripped back to cuff. I got off track after that. 20g mini in dark purple; used for cuff and will use for the heel. Progress: I finished the first sock (did not use the mini for the toe). Cast on the second sock, using the mini for the cuff. From the Armchair Watching: Shrinking (on Apple TV+)I finished reading: Beach Read by Emily Henry. Bookshop Affiliate Link. Amazon Affiliate Link. Note: Some links are listed as Amazon Affiliate Links. If you click those, please know that I am an Amazon Associate and I earn money from qualifying purchases.   In My Travels While in Phoenix with Mom, she, Merry & I took a day trip tour to Sedona through Detours. Nicki was our guide. First stop: Montezuma Castle. where the Sinagua people built dwellings into the side of the rock face. It was a 20 room, multi-story structure access via sets of wooden ladders. Bell Rock trailhead/ vista.  Chapel of the Holy Cross – beautiful setting with nearly 360 views of the red rocks all around, beautiful face of windows on one end with a large statue of Jesus over the altar. Uptown Sedona. Lunch. Coffee. Shopping. Ice cream! KAL News Splash Pad Party 23: May 26-July 31, 2023   Sign up using this Google Form. To confirm you're signed up, check the Stats/Registration Spreadsheet here. Splash Pad '23 Sponsors  with all the links you need to their websites & social media. Many of our Sponsors are offering coupon codes. Find them here- Google Doc or Ravelry Thread. Tune in to hear if you are one of our Participation Winners Events Stash Dash, hosted by Leslie & Laura of the Knit Girllls Video Podcast starts May 26th and runs through August 31, 2023. Check out details in the knit girllls discord My total as of this episode: 5,630 meters You can check out my Stash Dash 2023 Progress on this Google Sheet. Legacy Fiber Artz Knit Your Stash MAL- check out the details on the Treehouse Fiber Arts website Runs May 29- September 4, 2023 #legacyfiberartzknityourstashMal and #flashyourstash Crafty Bingo- Craft Cook Read Repeat Podcast May 26-September 4, 2023 Grab the Bingo card over on their Instagram feed The Grocery Girls are hosting Hot Granny Square Summer MAL. Check out details in their Ravelry Group & in Episode 183 on their YouTube Channel. Summer Sock Camp hosted in the Crazy Sock Lady Ravelry Group 5/26- 8/31/2023 Vermont Sheep & Wool: Sept 30 & Oct 1 at the Tunbridge Fairgrounds Check out some West Coast (US) Events on the Seattle Knitters Guild site (thanks Kristen- kips206) Life in Focus I shared in the last episode that my mother-in-law, Marilyn, passed away shortly before I left for Phoenix. When I returned home, we finished the of the plans and held her funeral mass that Thursday morning. Dan's younger sister Kathy (and her husband Tony) came in from Florida and stayed with us as did my friend Laura (from NYC). We all met up for dinner on Wednesday night with Dan & Matt's aunt who came in from Maine and 2 of her daughters and their families. The services and lunch afterwards were beautiful. Readings and music were all specially chosen and read/performed by people she loved. Its was a beautiful send off. We had a small gathering after at my friend Megg's house. She, Laura and I walked down to the beach just before sunset. On a Happy Note While Laura was in town we went for a late lunch with Kris and Megg at the Salt Society and then Laura, Kris and I got ice cream at Hornstra and Laura and I went on to see No Hard Feelings at the movies. Saturday July 8th we had a big pool party for our friend Trish's birthday. Fun day with all the kiddos before they head off to their various camps. On Sunday, Dan's friends came for a visit and brought us a delicious homemade strawberry rhubarb pie. Monday night we did a double date night with Megg and Tom to The Snug, an Irish pub, for live music to catch up before they head to Ireland for summer visits. Thursday I celebrated 20 years at Mass General with the annual Ether Day Dinner (normally held in October but ours was postponed) where they celebrate staff with milestones in 5 year increments from 20-60 years of service. Cocktail hour with live music followed by a delicious dinner for over 600 people! It was made especially fun because my dear friend Waveney and her husband Atticus were there- and Dan ran into a friend from work whose wife was also celebrating 20 years. On October 16, 1846, the first successful public demonstration of the use of ether for surgical anesthesia was performed, making pain-free surgery possible. Friday pool night. Meagan and Gayle, up from NH, brought resin/acrylic crafts and the fam decorated cutting boards and trays. I missed it but Dan and the others who learned are going to teach me. Quote of the Week We can take a wonderful vacation in spirit, even though we are obliged to stay at home, if we will only drop our burdens from our minds for a while. –Laura Ingalls Wilder Thank you for tuning in!Contact Information:   Check out the Down Cellar Studio Patreon! Ravelry: BostonJen & Down Cellar Studio Podcast Ravelry Group Instagram: BostonJen1 YouTube: Down Cellar Studio Facebook: https://www.facebook.com/downcellarstudio Sign up for my email newsletter to get the latest on everything happening in the Down Cellar Studio Check out my Down Cellar Studio YouTube Channel Knit Picks Affiliate Link Bookshop Affiliate Link Yarnable Subscription Box Affiliate Link Music -“Soft Orange Glow” by Josh Woodward. Free download: http://joshwoodward.com/ Note: Some links are listed as Amazon Affiliate Links. If you click those, please know that I am an Amazon Associate and I earn money from qualifying purchases.