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The most enthralling conversation I've ever had with anyone on cancer. It's with Charlie Swanton who is a senior group leader at the Francis Crick Institute, the Royal Society Napier Professor in Cancer and medical oncologist at University College London, co-director of Cancer Research UK.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with audio links and many external linksEric Topol (00:07):Well, hello, this is Eric Topol with Ground Truths, and I am really fortunate today to connect us with Charlie Swanton, who is if not the most prolific researcher in the space of oncology and medicine, and he's right up there. Charlie is a physician scientist who is an oncologist at Francis Crick and he heads up the lung cancer area there. So Charlie, welcome.Charles Swanton (00:40):Thank you, Eric. Nice to meet you.Learning from a FailureEric Topol (00:43):Well, it really is a treat because I've been reading your papers and they're diverse. They're not just on cancer. Could be connecting things like air pollution, it could be Covid, it could be AI, all sorts of things. And it's really quite extraordinary. So I thought I'd start out with a really interesting short paper you wrote towards the end of last year to give a sense about you. It was called Turning a failing PhD around. And that's good because it's kind of historical anchoring. Before we get into some of your latest contributions, maybe can you tell us about that story about what you went through with your PhD?Charles Swanton (01:26):Yeah, well thank you, Eric. I got into research quite early. I did what you in the US would call the MD PhD program. So in my twenties I started a PhD in a molecular biology lab at what was then called the Imperial Cancer Research Fund, which was the sort of the mecca for DNA tumor viruses, if you like. It was really the place to go if you wanted to study how DNA tumor viruses worked, and many of the components of the cell cycle were discovered there in the 80s and 90s. Of course, Paul Nurse was the director of the institute at the time who discovered cdc2, the archetypal regulator of the cell cycle that led to his Nobel Prize. So it was a very exciting place to work, but my PhD wasn't going terribly well. And sort of 18, 19 months into my PhD, I was summoned for my midterm reports and it was not materializing rapidly enough.(02:25):And I sat down with my graduate student supervisors who were very kind, very generous, but basically said, Charlie, this isn't going well, is it? You've got two choices. You can either go back to medical school or change PhD projects. What do you want to do? And I said, well, I can't go back to medical school because I'm now two years behind. So instead I think what I'll do is I'll change PhD projects. And they asked me what I'd like to do. And back then we didn't know how p21, the CDK inhibitor bound to cyclin D, and I said, that's what I want to understand how these proteins interact biochemically. And they said, how are you going to do that? And I said, I'm not too sure, but maybe we'll try yeast two-hybrid screen and a mutagenesis screen. And that didn't work either. And in the end, something remarkable happened.(03:14):My PhD boss, Nic Jones, who's a great guy, still is, retired though now, but a phenomenal scientist. He put me in touch with a colleague who actually works next door to me now at the Francis Crick Institute called Neil McDonald, a structural biologist. And they had just solved, well, the community had just solved the structure. Pavletich just solved the structure of cyclin A CDK2. And so, Neil could show me this beautiful image of the crystal structure in 3D of cyclin A, and we could mirror cyclin D onto it and find the surface residue. So I spent the whole of my summer holiday mutating every surface exposed acid on cyclin D to an alanine until I found one that failed to interact with p21, but could still bind the CDK. And that little breakthrough, very little breakthrough led to this discovery that I had where the viral cyclins encoded by Kaposi sarcoma herpes virus, very similar to cyclin D, except in this one region that I had found interactive with a CDK inhibitor protein p21.(04:17):And so, I asked my boss, what do you think about the possibility this cyclin could have evolved from cyclin D but now mutated its surface residues in a specific area so that it can't be inhibited by any of the control proteins in the mammalian cell cycle? He said, it's a great idea, Charlie, give it a shot. And it worked. And then six months later, we got a Nature paper. And that for me was like, I cannot tell you how exciting, not the Nature paper so much as the discovery that you were the first person in the world to ever see this beautiful aspect of evolutionary biology at play and how this cyclin had adapted to just drive the cell cycle without being inhibited. For me, just, I mean, it was like a dream come true, and I never experienced anything like it before, and I guess it's sizes the equivalent to me of a class A drug. You get such a buzz out of it and over the years you sort of long for that to happen again. And occasionally it does, and it's just a wonderful profession.Eric Topol (05:20):Well, I thought that it was such a great story because here you were about to fail. I mean literally fail, and you really were able to turn it around and it should give hope to everybody working in science out there that they could just be right around the corner from a significant discovery.Charles Swanton (05:36):I think what doesn't break you makes you stronger. You just got to plow on if you love it enough, you'll find a way forward eventually, I hope.Tracing the Evolution of Cancer (TRACERx)Eric Topol (05:44):Yeah, no question about that. Now, some of your recent contributions, I mean, it's just amazing to me. I just try to keep up with the literature just keeping up with you.Charles Swanton (05:58):Eric, it's sweet of you. The first thing to say is it's not just me. This is a big community of lung cancer researchers we have thanks to Cancer Research UK funded around TRACERx and the lung cancer center. Every one of my papers has three corresponding authors, multiple co-first authors that all contribute in this multidisciplinary team to the sort of series of small incremental discoveries. And it's absolutely not just me. I've got an amazing team of scientists who I work with and learn from, so it's sweet to give me the credit.Eric Topol (06:30):I think what you're saying is really important. It is a team, but I think what I see through it all is that you're an inspiration to the team. You pull people together from all over the world on these projects and it's pretty extraordinary, so that's what I would say.Charles Swanton (06:49):The lung community, Eric, the lung cancer community is just unbelievably conducive to collaboration and advancing understanding of the disease together. It's just such a privilege to be working in this field. I know that sounds terribly corny, but it is true. I don't think I recall a single email to anybody where I've asked if we can collaborate where they've said, no, everybody wants to help. Everybody wants to work together on this challenge. It's just such an amazing field to be working in.Eric Topol (07:19):Yeah. Well I was going to ask you about that. And of course you could have restricted your efforts or focused on different cancers. What made you land in lung cancer? Not that that's only part of what you're working on, but that being the main thing, what drew you to that area?Charles Swanton (07:39):So I think the answer to your question is back in 2008 when I was looking for a niche, back then it was lung cancer was just on the brink of becoming an exciting place to work, but back then nobody wanted to work in that field. So there was a chair position in thoracic oncology and precision medicine open at University College London Hospital that had been open, as I understand it for two years. And I don't think anybody had applied. So I applied and because I was the only one, I got it and the rest is history.(08:16):And of course that was right at the time when the IPASS draft from Tony Mok was published and was just a bit after when the poster child of EGFR TKIs and EGFR mutant lung cancer had finally proven that if you segregate that population of patients with EGFR activating mutation, they do incredibly well on an EGFR inhibitor. And that was sort of the solid tumor poster child along with Herceptin of precision medicine, I think. And you saw the data at ASCO this week of Lorlatinib in re-arranged lung cancer. Patients are living way beyond five years now, and people are actually talking about this disease being more like CML. I mean, it's extraordinary the progress that's been made in the last two decades in my short career.Eric Topol (09:02):Actually, I do want to have you put that in perspective because it's really important what you just mentioned. I was going to ask you about this ASCO study with the AKT subgroup. So the cancer landscape of the lung has changed so much from what used to be a disease of cigarette smoking to now one of, I guess adenocarcinoma, non-small cell carcinoma, not related to cigarettes. We're going to talk about air pollution in a minute. This group that had, as you say, 60 month, five year plus survival versus what the standard therapy was a year plus is so extraordinary. But is that just a small subgroup within small cell lung cancer?Charles Swanton (09:48):Yes, it is, unfortunately. It's just a small subgroup. In our practice, probably less than 1% of all presentations often in never smokers, often in female, never smokers. So it is still in the UK at least a minority subset of adenocarcinomas, but it's still, as you rightly say, a minority of patients that we can make a big difference to with a drug that's pretty well tolerated, crosses the blood-brain barrier and prevents central nervous system relapse and progression. It really is an extraordinary breakthrough, I think. But that said, we're also seeing advances in smoking associated lung cancer with a high mutational burden with checkpoint inhibitor therapy, particularly in the neoadjuvant setting now prior to surgery. That's really, really impressive indeed. And adjuvant checkpoint inhibitor therapies as well as in the metastatic setting are absolutely improving survival times and outcomes now in a way that we couldn't have dreamt of 15 years ago. We've got much more than just platinum-based chemo is basically the bottom line now.Revving Up ImmunotherapyEric Topol (10:56):Right, right. Well that actually gets a natural question about immunotherapy also is one of the moving parts actually just amazing to me how that's really, it's almost like we're just scratching the surface of immunotherapy now with checkpoint inhibitors because the more we get the immune system revved up, the more we're seeing results, whether it's with vaccines or CAR-T, I mean it seems like we're just at the early stages of getting the immune system where it needs to be to tackle the cancer. What's your thought about that?Charles Swanton (11:32):I think you're absolutely right. We are, we're at the beginning of a very long journey thanks to Jim Allison and Honjo. We've got CTLA4 and PD-1/PDL-1 axis to target that's made a dramatic difference across multiple solid tumor types including melanoma and lung cancer. But undoubtedly, there are other targets we've seen LAG-3 and melanoma and then we're seeing new ways, as you rightly put it to mobilize the immune system to target cancers. And that can be done through vaccine based approaches where you stimulate the immune system against the patient's specific mutations in their cancer or adoptive T-cell therapies where you take the T-cells out of the tumor, you prime them against the mutations found in the tumor, you expand them and then give them back to the patient. And colleagues in the US, Steve Rosenberg and John Haanen in the Netherlands have done a remarkable job there in the context of melanoma, we're not a million miles away from European approvals and academic initiated manufacturing of T-cells for patients in national health systems like in the Netherlands.(12:50):John Haanen's work is remarkable in that regard. And then there are really spectacular ways of altering T-cells to be able to either migrate to the tumor or to target specific tumor antigens. You mentioned CAR-T cell therapies in the context of acute leukemia, really extraordinary developments there. And myeloma and diffuse large B-cell lymphoma as well as even in solid tumors are showing efficacy. And I really am very excited about the future of what we call biological therapies, be it vaccines, an antibody drug conjugates and T-cell therapies. I think cancer is a constantly adapting evolutionary force to be reckoned with what better system to combat it than our evolving immune system. It strikes me as being a future solution to many of these refractory cancers we still find difficult to treat.Eric Topol (13:48):Yeah, your point is an interesting parallel how the SARS-CoV-2 virus is constantly mutating and becoming more evasive as is the tumor in a person and the fact that we can try to amp up the immune system with these various means that you just were reviewing. You mentioned the other category that's very hot right now, which is the antibody drug conjugates. Could you explain a bit about how they work and why you think this is an important part of the future for cancer?Antibody-Drug ConjugatesCharles Swanton (14:26):That's a great question. So one of the challenges with chemotherapy, as you know, is the normal tissue toxicity. So for instance, neutropenia, hair loss, bowel dysfunction, diarrhea, epithelial damage, essentially as you know, cytotoxics affect rapidly dividing tissues, so bone marrow, epithelial tissues. And because until relatively recently we had no way of targeting chemotherapy patients experienced side effects associated with them. So over the last decade or so, pioneers in this field have brought together this idea of biological therapies linked with chemotherapy through a biological linker. And so one poster chart of that would be the drug T-DXd, which is essentially Herceptin linked to a chemotherapy drug. And this is just the most extraordinary drug that obviously binds the HER2 receptor, but brings the chemotherapy and proximity of the tumor. The idea being the more drug you can get into the tumor and the less you're releasing into normal tissue, the more on tumor cytotoxicity you'll have and the less off tumor on target normal tissue side effects you'll have. And to a large extent, that's being shown to be the case. That doesn't mean they're completely toxicity free, they're not. And one of the side effects associated with these drugs is pneumonitis.(16:03):But that said, the efficacy is simply extraordinary. And for example, we're having to rewrite the rule books if you like, I think. I mean I'm not a breast cancer physician, I used to be a long time ago, but back in the past in the early 2000s, there was HER2 positive breast cancer and that's it. Now they're talking about HER2 low, HER2 ultra-low, all of which seem to in their own way be sensitive to T-DXd, albeit to a lower extent than HER2 positive disease. But the point is that there doesn't seem to be HER2 completely zero tumor group in breast cancer. And even the HER2-0 seem to benefit from T-DXd to an extent. And the question is why? And I think what people are thinking now is it's a combination of very low cell service expression of HER2 that's undetectable by conventional methods like immunohistochemistry, but also something exquisitely specific about the way in which HER2 is mobilized on the membrane and taken back into the cell. That seems to be specific to the breast cancer cell but not normal tissue. So in other words, the antibody drug conjugate binds the tumor cell, it's thought the whole receptor's internalized into the endosome, and that's where the toxicity then happens. And it's something to do with the endosomal trafficking with the low level expression and internalization of the receptor. That may well be the reason why these HER2 low tumors are so sensitive to this beautiful technology.Eric Topol (17:38):Now I mean it is an amazing technology in all these years where we just were basically indiscriminately trying to kill cells and hoping that the cancer would succumb. And now you're finding whether you want to call it a carry or vector or Trojan horse, whatever you want to call it, but do you see that analogy of the HER2 receptor that's going to be seen across the board in other cancers?Charles Swanton (18:02):That's the big question, Eric. I think, and have we just lucked out with T-DXd, will we find other T-DXd like ADCs targeting other proteins? I mean there are a lot of ADCs being developed against a lot of different cell surface proteins, and I think the jury's still out. I'm confident we will, but we have to bear in mind that biology is a fickle friend and there may be something here related to the internalization of the receptor in breast cancer that makes this disease so exquisitely sensitive. So I think we just don't know yet. I'm reasonably confident that we will find other targets that are as profoundly sensitive as HER2 positive breast cancer, but time will tell.Cancer, A Systemic DiseaseEric Topol (18:49):Right. Now along these lines, well the recent paper that you had in Cell, called embracing cancer complexity, which we've talking about a bit, in fact it's kind of those two words go together awfully well, but hallmarks of systemic disease, this was a masterful review, as you say with the team that you led. But can you tell us about what's your main perspective about this systemic disease? I mean obviously there's been the cancer is like cardiovascular and cancers like this or that, but here you really brought it together with systemic illness. What can you say about that?Charles Swanton (19:42):Well, thanks for the question first of all, Eric. So a lot of this comes from some of my medical experience of treating cancer and thinking to myself over the years, molecular biology has had a major footprint on advances in treating the disease undoubtedly. But there are still aspects of medicine where molecular biology has had very little impact, and often that is in areas of suffering in patients with advanced disease and cancer related to things like cancer cachexia, thrombophilia. What is the reason why patients die blood clots? What is the reason patients die of cancer at all? Even a simple question like that, we don't always know the answer to, on death certificates, we write metastatic disease as a cause of cancer death, but we have patients who die with often limited disease burden and no obvious proximal cause of death sometimes. And that's very perplexing, and we need to understand that process better.(20:41):And we need to understand aspects like cancer pain, for example, circadian rhythms affect biological sensitivity of cancer cells to drugs and what have you. Thinking about cancer rather than just sort of a single group of chaotically proliferating cells to a vision of cancer interacting both locally within a microenvironment but more distantly across organs and how organs communicate with the cancer through neuronal networks, for example, I think is going to be the next big challenge by setting the field over the next decade or two. And I think then thinking about more broadly what I mean by embracing complexity, I think some of that relates to the limitations of the model systems we use, trying to understand inter-organ crosstalk, some of the things you cover in your beautiful Twitter reviews. (←Ground Truths link) I remember recently you highlighted four publications that looked at central nervous system, immune cell crosstalk or central nervous system microbiome crosstalk. It's this sort of long range interaction between organs, between the central nervous system and the immune system and the cancer that I'm hugely interested in because I really think there are vital clues there that will unlock new targets that will enable us to control cancers more effectively if we just understood these complex networks better and had more sophisticated animal model systems to be able to interpret these interactions.Eric Topol (22:11):No, it's so important what you're bringing out, the mysteries that still we have to deal with cancer, why patients have all these issues or dying without really knowing what's happened no less, as you say, these new connects that are being discovered at a remarkable pace, as you mentioned, that ground truths. And also, for example, when I spoke with Michelle Monje, she's amazing on the cancer, where hijacking the brain cells and just pretty extraordinary things. Now that gets me to another line of work of yours. I mean there are many, but the issue of evolution of the tumor, and if you could put that in context, a hot area that's helping us elucidate these mechanisms is known as spatial omics or spatial biology. This whole idea of being able to get the spatial temporal progression through single cell sequencing and single cell nuclei, all the single cell omics. So if you could kind of take us through what have we learned with this technique and spatial omics that now has changed or illuminated our understanding of how cancer evolves?Charles Swanton (23:37):Yeah, great question. Well, I mean I think it helps us sort of rewind a bit and think about evolution in general. Genetic selection brought about by diverse environments and environmental pressures that force evolution, genetic evolution, and speciation down certain evolutionary roots. And I think one can think about cancers in a similar way. They start from a single cell and we can trace the evolutionary paths of cancers by single cell analysis as well as bulk sequencing of spatially separated tumor regions to be able to reconstruct their subclones. And that's taught us to some extent, what are the early events in tumor evolution? What are the biological mechanisms driving branched evolution? How does genome instability begin in tumors? And we found through TRACERx work, whole genome doubling is a major route through to driving chromosome instability along with mutagenic enzymes like APOBEC that drive both mutations and chromosomal instability.(24:44):And then that leads to a sort of adaptive radiation in a sense, not dissimilar to I guess the Cambrian explosion of evolutionary opportunity upon which natural selection can act. And that's when you start to see the hallmarks of immune evasion like loss of HLA, the immune recognition molecules that bind the neoantigens or even loss of the neoantigens altogether or mutation of beta 2 microglobulin that allow the tumor cells to now evolve below the radar, so to speak. But you allude to the sort of spatial technologies that allow us to start to interpret the microenvironments as well. And that then tells us what the evolutionary pressures are upon the tumor. And we're learning from those spatial technologies that these environments are incredibly diverse, actually interestingly seem to be converging on one important aspect I'd like to talk to you a little bit more about, which is the myeloid axis, which is these neutrophils, macrophages, et cetera, that seem to be associated with poor outcome and that will perhaps talk about pollution in a minute.(25:51):But I think they're creating a sort of chronic inflammatory response that allows these early nascent tumor cells to start to initiate into frankly tumor invasive cells and start to grow. And so, what we're seeing from these spatial technologies in lung cancer is that T-cells, predatory T-cells, force tumors to lose their HLA molecules and what have you to evade the immune system. But for reasons we don't understand, high neutrophil infiltration seems to be associated with poor outcome, poor metastasis free survival. And actually, those same neutrophils we've recently found actually even tracked to the metastasis sites of metastasis. So it's almost like this sort of symbiosis between the myeloid cells and the tumor cells in their biology and growth and progression of the tumor cells.Eric Topol (26:46):Yeah, I mean this white cell story, this seems to be getting legs and is relatively new, was this cracked because of the ability to do this type of work to in the past everything was, oh, it's cancer's heterogeneous and now we're getting pinpoint definition of what's going on.Charles Swanton (27:04):I think it's certainly contributed, but it's like everything in science, Eric, when you look back, there's evidence in the literature for pretty much everything we've ever discovered. You just need to put the pieces together. And I mean one example would be the neutrophil lymphocyte ratio in the blood as a hallmark of outcome in cancers and to checkpoint inhibitor blockade, maybe this begins to explain it, high neutrophils, immune suppressive environment, high neutrophils, high macrophages, high immune suppression, less benefit from checkpoint inhibitor therapy, whereas you want lymphocyte. So I think there are biomedical medical insights that help inform the biology we do in the lab that have been known for decades or more. And certainly the myeloid M2 axis in macrophages and what have you was known about way before these spatial technologies really came to fruition, I think.The Impact of Air PollutionEric Topol (28:01):Yeah. Well you touched on this about air pollution and that's another dimension of the work that you and your team have done. As you well know, there was a recent global burden of disease paper in the Lancet, which has now said that air pollution with particulate matter 2.5 less is the leading cause of the burden of disease in the world now.Charles Swanton (28:32):What did you think of that, Eric?Eric Topol (28:34):I mean, I was blown away. Totally blown away. And this is an era you've really worked on. So can you put it in perspective?Charles Swanton (28:42):Yeah. So we got into this because patients of mine, and many of my colleagues would ask the same question, I've never smoked doctor, I'm healthy. I'm in my mid 50s though they're often female and I've got lung cancer. Why is that doctor? I've had a good diet, I exercise, et cetera. And we didn't really have a very good answer for that, and I don't want to pretend for a minute we solved the whole problem. I think hopefully we've contributed to a little bit of understanding of why this may happen. But that aside, we knew that there were risk factors associated with lung cancer that included air pollution, radon exposure, of course, germline genetics, we mustn't forget very important germline variation. And I think there is evidence that all of them are associated with lung cancer risk in different ways. But we wanted to look at air pollution, particularly because there was an awful lot of evidence, several meta-analysis of over half a million individuals showing very convincingly with highly significant results that increasing PM 2.5 micron particulate levels were associated with increased risk of lung cancer.(29:59):To put that into perspective, where you are on the west coast of the US, it's relatively unpolluted. You would be talking about maybe five micrograms per meter cubed of PM2.5 in a place like San Diego or Western California, assuming there aren't any forest fires of course. And we estimate that that would translate to about, we think it's about one extra case of never smoking lung cancer per hundred thousand of the population per year per one microgram per meter cube rise in the pollution levels. So if you go to Beijing for example, on a bad day, the air pollution levels could be upwards of a hundred micrograms per meter cubed because there are so many coal fired power stations in China partly. And there I think the risk is considerably higher. And that's certainly what we've seen in the meta-analyses in our limited and relatively crude epidemiological analyses to be the case.(30:59):So I think the association was pretty certain, we were very confident from people's prior publications  this was important. But of course, association is not causation. So we took a number of animal models and showed that you could promote lung cancer formation in four different oncogene driven lung cancer models. And then the question is how, does air pollution stimulate mutations, which is what I initially thought it would do or something else. It turns out we don't see a significant increase in exogenous like C to A carcinogenic mutations. So that made us put our thinking caps on. And I said to you earlier, often all these discoveries have been made before. Well, Berenblum in 1947, first postulated that actually tumors are initiated through a two-step process, which we now know involves a sort of pre initiated cell with a mutation in that in itself is not sufficient to cause cancer.(31:58):But on top of that you need an inflammatory stimulus. So the question was then, well, okay, is inflammation working here? And we found that there was an interleukin-1 beta axis. And what happens is that the macrophages come into the lung on pollution exposure, engulf phagocytose the air pollutants, and we think what's happening is the air pollutants are puncturing membranes in the lung. That's what we think is happening. And interleukin-1 beta preformed IL-1 beta is being released into the extracellular matrix and then stimulating pre-initiated cells stem cells like the AT2 cells with an activating EGFR mutation to form a tumor. But the EGFR mutation alone is not sufficient to form tumors. It's only when you have the interleukin-1 beta and the activated mutation that a tumor can start.(32:49):And we found that if we sequence normal lung tissue in a healthy adult 60-year-old adult, we will find about half of biopsies will have an activating KRAS mutation in normal tissue, and about 15% will have an activating mutation in EGFR in histologically normal tissue with nerve and of cancer. In fact, my friend and colleague who's a co-author on the paper, James DeGregori, who you should speak to in Colorado, fascinating evolutionary cancer biologists estimates that in a healthy 60-year-old, there are a hundred billion cells in your body that harbor an oncogenic mutation. So that tells you that at the cellular level, cancer is an incredibly rare event and almost never happens. I mean, our lifetime risk of cancer is perhaps one in two. You covered that beautiful pancreas paper recently where they estimated that there may be 80 to 100 KRAS mutations in a normal adult pancreas, and yet our lifetime risk of pancreas cancer is one in 70. So this tells you that oncogenic mutations are rarely sufficient to drive cancer, so something else must be happening. And in the context of air pollution associated lung cancer, we think that's inflammation driven by these white cells, these myeloid cells, the macrophages.Cancer BiomarkersEric Topol (34:06):No, it makes a lot of sense. And this, you mentioned the pancreas paper and also what's going in the lung, and it seems like we have this burden of all you need is a tipping point and air pollution seems to qualify, and you seem to be really in the process of icing the mechanism. And like I would've thought it was just mutagenic and it's not so simple, right? But that gets me to this is such an important aspect of cancer, the fact that we harbor these kind of preconditions. And would you think that cancer takes decades to actually manifest most cancers, or do we really have an opportunity here to be able to track whether it's through blood or other biomarkers? Another area you've worked on a lot whereby let's say you could define people at risk for polygenic risk scores or various cancers or genome sequencing for predisposition genes, whatever, and you could monitor in the future over the course of those high-risk people, whether they were starting to manifest microscopic malignancy. Do you have any thoughts about how long it takes for the average person to actually manifest a typical cancer?Charles Swanton (35:28):That's a cracking question, and the answer is we've got some clues in various cancers. Peter Campbell would be a good person to speak to. He estimates that some of the earliest steps in renal cancer can occur in adolescence. We've had patients who gave up smoking 30 or so years ago where we can still see the clonal smoking mutations in the trunk of the tumor's evolutionary tree. So the initial footprints of the cancer are made 30 years before the cancer presents. That driver mutation itself may also be a KRAS mutation in a smoking cigarette context, G12C mutation. And those mutations can precede the diagnosis of the disease by decades. So the earliest steps in cancer evolution can occur, we think can precede diagnoses by a long time. So to your point, your question which is, is there an opportunity to intervene? I'm hugely optimistic about this actually, this idea of molecular cancer prevention.An Anti-Inflammatory Drug Reduces Fatal Cancer and Lung Cancer(36:41):How can we use data coming out of various studies in the pancreas, mesothelioma, lung, et cetera to understand the inflammatory responses? I don't think we can do very much about the mutations. The mutations unfortunately are a natural consequence of aging. You and I just sitting here talking for an hour will have accumulated multiple mutations in our bodies over that period, I'm afraid and there's no escaping it. And right now there's not much we can do to eradicate those mutant clones. So if we take that as almost an intractable problem, measuring them is hard enough, eradicating them is even harder. And then we go back to Berenblum in 1947 who said, you need an inflammatory stimulus. Well, could we do something about the inflammation and dampen down the inflammation? And of course, this is why we got so excited about IL-1 beta because of the CANTOS trial, which you may remember in 2017 from Ridker and colleagues showed that anti IL-1 beta used as a mechanism of preventing cardiovascular events was associated with a really impressive dose dependent reduction in new lung cancer primaries.(37:49):Really a beautiful example of cancer prevention in action. And that data weren't just a coincidence. The FDA mandated Novartis to collect the solid tumor data and the P-values are 0.001. I mean it's very highly significant dose dependent reduction in lung cancer incidents associated with anti IL-1 beta. So I think that's really the first clue in my mind that something can be done about this problem. And actually they had five years of follow-up, Eric. So that's something about that intervening period where you can treat and then over time see a reduction in new lung cancers forming. So I definitely think there's a window of opportunity here.Eric Topol (38:31):Well, what you're bringing up is fascinating here because this trial, which was a cardiology trial to try to reduce heart attacks, finds a reduction in cancer, and it's been lost. It's been buried. I mean, no one's using this therapy to prevent cancer between ratcheting up the immune system or decreasing inflammation. We have opportunities that we're not even attempting. Are there any trials that are trying to do this sort of thing?Charles Swanton (39:02):So this is the fundamental problem. Nobody wants to invest in prevention because essentially you are dealing with well individuals. It's like the vaccine challenge all over again. And the problem is you never know who you are benefiting. There's no economic model for it. So pharma just won't touch prevention with a barge pole right now. And that's the problem. There's no economic model for it. And yet the community, all my academic colleagues are crying out saying, this has got to be possible. This has got to be possible. So CRUK are putting together a group of like-minded individuals to see if we can do something here and we're gradually making progress, but it is tough.Eric Topol (39:43):And it's interesting that you bring that up because for GRAIL, one of the multicenter cancer early detection companies, they raised billions of dollars. And in fact, their largest trial is ongoing in the UK, but they haven't really focused on high-risk people. They just took anybody over age 50 or that sort of thing. But that's the only foray to try to reboot how we or make an early microscopic diagnosis of cancer and track people differently. And there's an opportunity there. You've written quite a bit on you and colleagues of the blood markers being able to find a cancer where well before, in fact, I was going to ask you about that is, do you think there's people that are not just having all these mutations every minute, every hour, but that are starting to have the early seeds of cancer, but because their immune system then subsequently kicks in that they basically kind of quash it for that period of time?Charles Swanton (40:47):Yeah, I do think that, I mean, the very fact that we see these sort of footprints in the tumor genome of immune evasion tells you that the immune system's having a very profound predatory effect on evolving tumors. So I do think it's very likely that there are tumors occurring that are suppressed by the immune system. There is a clear signature, a signal of negative selection in tumors where clones have been purified during their evolution by the immune system. So I think there's pretty strong evidence for that now. Obviously, it's very difficult to prove something existed when it doesn't now exist, but there absolutely is evidence for that. I think it raises the interesting question of immune system recognizes mutations and our bodies are replete with mutations as we were just discussing. Why is it that we're not just a sort of epithelial lining of autoimmunity with T-cells and immune cells everywhere? And I think what the clever thing about the immune system is it's evolved to target antigens only when they get above a certain burden. Otherwise, I think our epithelial lining, our skin, our guts, all of our tissues will be just full of T-cells eating away our normal clones.(42:09):These have to get to a certain size for antigen to be presented at a certain level for the immune system to recognize it. And it's only then that you get the immune predation occurring.Forever Chemicals and Microplastics Eric Topol (42:20):Yeah, well, I mean this is opportunities galore here. I also wanted to extend the air pollution story a bit. Obviously, we talked about particulate matter and there's ozone and nitric NO2, and there's all sorts of other air pollutants, but then there's also in the air and water these forever chemicals PFAS for abbreviation, and they seem to be incriminated like air pollution. Can you comment about that?Charles Swanton (42:55):Well, I can comment only insofar as to say I'm worried about the situation. Indeed, I'm worried about microplastics actually, and you actually cover that story as well in the New England Journal, the association of microplastics with plaque rupture and atheroma. And indeed, just as in parenthesis, I wanted to just quickly say we currently think the same mechanisms that are driving lung cancer are probably responsible for atheroma and possibly even neurodegenerative disease. And essentially it all comes down to the macrophages and the microglia becoming clogged up with these pollutants or environmental particulars and releasing chronic inflammatory mediators that ultimately lead to disease. And IL-1 beta being one of those in atheroma and probably IL-6 and TNF in neurodegenerative disease and what have you. But I think this issue that you rightly bring up of what is in our environment and how does it cause pathology is really something that epidemiologists have spent a lot of time focusing on.(43:56):But actually in terms of trying to move from association to causation, we've been, I would argue a little bit slow biologically in trying to understand these issues. And I think that is a concern. I mean, to give you an example, Allan Balmain, who works at UCSF quite close to you, published a paper in 2020 showing that 17 out of 20 environmental carcinogens IARC carcinogens class one carcinogens cause tumors in rodent models without driving mutations. So if you take that to a logical conclusion, in my mind, what worries me is that many of the sort of carcinogen assays are based on driving mutagenesis genome instability. But if many carcinogen aren't driving DNA mutagenesis but are still driving cancer, how are they doing it? And do we actually have the right assays to interpret safety of new chemical matter that's being introduced into our environment, these long-lived particles that we're breathing in plastics, pollutants, you name it, until we have the right biological assays, deeming something to be safe I think is tricky.Eric Topol (45:11):Absolutely. And I share your concerns on the nanoplastic microplastic story, as you well know, not only have they been seen in arteries that are inflamed and in blood clots and in various tissues, have they been seen so far or even looked for within tumor tissue?Charles Swanton (45:33):Good question. I'm not sure they have. I need to check. What I can tell you is we've been doing some experiments in the lab with fluorescent microplastics, 2.5 micron microplastics given inhaled microplastics. We find them in every mouse organ a week after. And these pollutants even get through into the brain through the olfactory bulb we think.Charles Swanton (45:57):Permeate every tissue, Eric.Eric Topol (45:59):Yeah, no, this is scary because here we are, we have these potentially ingenious ways to prevent cancer in the future, but we're chasing our tails by not doing anything to deal with our environment.Charles Swanton (46:11):I think that's right. I totally agree. Yeah.Eric Topol (46:15):So I mean, I can talk to you for the rest of the day, but I do want to end up with a topic that we have mutual interest in, which is AI. And also along with that, when you mentioned about aging, I'd like to get your views on these two, how do you see AI fitting into the future of cancer? And then the more general topic is, can we actually at some point modulate the biologic aging process with or without help with from AI? So those are two very dense questions, but maybe you can take us through them.Charles Swanton (46:57):How long have we got?Eric Topol (46:59):Just however long you have.A.I. and CancerCharles Swanton (47:02):AI and cancer. Well, AI and medicine actually in general, whether it's biomedical research or medical care, has just infinite potential. And I'm very, very excited about it. I think what excites me about AI is it's almost the infinite possibilities to work across scale. Some of the challenges we raised in the Cell review that you mentioned, tackling, embracing complexity are perfectly suited for an AI problem. Nonlinear data working, for instance in our fields with CT imaging, MRI imaging, clinical outcome data, blood parameters, genomics, transcriptomes and proteomes and trying to relate this all into something that's understandable that relates to risk of disease or potential identification of a new drug target, for example. There are numerous publications that you and others have covered that allude to the incredible possibilities there that are leading to, for instance, the new identification of drug targets. I mean, Eli Van Allen's published some beautiful work here and in the context of prostate cancer with MDM4 and FGF receptor molecules being intimately related to disease biology.(48:18):But then it's not just that, not just drug target identification, it's also going all the way through to the clinic through drug discovery. It's how you get these small molecules to interact with oncogenic proteins and to inhibit them. And there are some really spectacular developments going on in, for instance, time resolved cryo-electron microscopy, where in combination with modeling and quantum computing and what have you, you can start to find pockets emerging in mutant proteins, but not the wild type ones that are druggable. And then you can use sort of synthetic AI driven libraries to find small molecules that will be predicted to bind these transiently emerging pockets. So it's almost like AI is primed to help at every stage in scientific investigation from the bench all the way through to the bedside. And there are examples all the way through there in the literature that you and others have covered in the last few years. So I could not be more excited about that.Eric Topol (49:29):I couldn't agree with you more. And I think when we get to multimodal AI at the individual level across all their risks for conditions in their future, I hope someday will fulfill that fantasy of primary prevention. And that is getting me to this point that I touched on because I do think they interact to some degree AI and then will we ever be able to have an impact on aging? Most people conflate this because what we've been talking about throughout the hour has been age-related diseases, that is cancer, for example, and cardiovascular and neurodegenerative, which is different than changing aging per se, body wide aging. Do you think we'll ever changed body wide aging?Charles Swanton (50:18):Wow, what a question. Well, if you'd asked me 10 years ago, 15 years ago, do you think we'll ever cure melanoma in my lifetime, I'd have said definitely not. And now look where we are. Half of patients with melanoma, advanced melanoma, even with brain metastasis curd with combination checkpoint therapy. So I never say never in biology anymore. It always comes back to bite you and prove you wrong. So I think it's perfectly possible.Charles Swanton (50:49):We have ways to slow down the aging process. I guess the question is what will be the consequences of that?Eric Topol (50:55):That's what I was going to ask you, because all these things like epigenetic reprogramming and senolytic drugs, and they seem to at least pose some risk for cancer.Charles Swanton (51:09):That's the problem. This is an evolutionary phenomenon. It's a sort of biological response to the onslaught of these malignant cells that are potentially occurring every day in our normal tissue. And so, by tackling one problem, do we create another? And I think that's going to be the big challenge over the next 50 years.Eric Topol (51:31):Yeah, and I think your point about the multi-decade challenge, because if you can promote healthy aging without any risk of cancer, that would be great. But if the tradeoff is close, it's not going to be very favorable. That seems to be the main liability of modulation aging through many of the, there's many shots on goal here, of course, as you well know. But they do seem to pose that risk in general.Charles Swanton (51:58):I think that's right. I think the other thing is, I still find, I don't know if you agree with me, but it is an immense conundrum. What is the underlying molecular basis for somatic aging, for aging of normal tissues? And it may be multifactorial, it may not be just one answer to that question. And different tissues may age in different ways. I don't know. It's a fascinating area of biology, but I think it really needs to be studied more because as you say, it underpins all of these diseases we've been talking about today, cardiovascular, neurodegeneration, cancer, you name it. We absolutely have to understand this. And actually, the more I work in cancer, the more I feel like actually what I'm working on is aging.(52:48):And this is something that James DeGregori and I have discussed a lot. There's an observation that in medicine around patients with alpha-1 antitrypsin deficiency who are at higher risk of lung cancer, but they're also at high risk of COPD, and we know the associations of chronic obstructive pulmonary disease with lung cancer risk. And one of the theories that James had, and I think this is a beautiful idea, actually, is as our tissues age, and COPD is a reflection of aging, to some extent gone wrong. And as our tissues age, they become less good at controlling the expansion of these premalignant clones, harboring, harboring oncogenic mutations in normal tissue. And as those premalignant clones expand, the substrate for evolution also expands. So there's more likely to be a second and third hit genetically. So it may be by disrupting the extracellular matrices through inflammation that triggers COPD through alpha-1 antitrypsin deficiency or smoking, et cetera, you are less effectively controlling these emergent clones that just expand with age, which I think is a fascinating idea actually.Eric Topol (54:01):It really is. Well, I want to tell you, Charlie, this has been the most fascinating, exhilarating discussion I've ever had on cancer. I mean, really, I am indebted to you because not just all the work you've done, but your ability to really express it, articulate it in a way that hopefully everyone can understand who's listening or reading the transcript. So we'll keep following what you're doing because you're doing a lot of stuff. I can't thank you enough for joining me today, and you've given me lots of things to think about. I hope the people that are listening or reading feel the same way. I mean, this has been so mind bending in many respects. We're indebted to you.Charles Swanton (54:49):Well, we all love reading your Twitter feeds. Keep them coming. It helps us keep a broader view of medicine and biological research, not just cancer, which is why I love it so much.******************************************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. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff tor audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

ReferencesJC mentioned that the diagnostic accuracy of 24 hour urine collection increases with more collections! Metabolic evaluation of patients with recurrent idiopathic calcium nephrolithiasisWe didn't refer to a particular study on sodium intake and the 24 hour urine but this meta-analysis Comparison of 24‐hour urine and 24‐hour diet recall for estimating dietary sodium intake in populations: A systematic review and meta‐analysis - PMC 24‐hour diet recall underestimated population mean sodium intake.Anna looking up ace i and urinary sodium Effects of ACE inhibition on proximal tubule sodium transport | American Journal of Physiology-Renal PhysiologyThe original FENa paper by Espinel: The FeNa Test: Use in the Differential Diagnosis of Acute Renal Failure | JAMA | JAMA NetworkSchreir's replication and expansion of Espinel's data: Urinary diagnostic indices in acute renal failure: a prospective studyHere's a report from our own JC on the Diagnostic Utility of Serial Microscopic Examination of the Urinary Sediment in Acute Kidney Injury | American Society of NephrologyJC shared his journey regarding FENa and refers to his recent paper Concomitant Identification of Muddy Brown Granular Casts and Low Fractional Excretion of Urinary Sodium in AKIAnd Melanie's accompanying editorial Mind the Cast: FENa versus Microscopy in AKI : Kidney360 (with a great image from Samir Parikh)JC referenced this study from Schrier on FENa with a larger series: Urinary diagnostic indices in acute renal failure: a prospective study​​Nonoliguric Acute Renal Failure Associated with a Low Fractional Excretion of Sodium | Annals of Internal MedicineUrine sodium concentration to predict fluid responsiveness in oliguric ICU patients: a prospective multicenter observational study | Critical Care | Full TextA classic favorite: Acute renal success. The unexpected logic of oliguria in acute renal failure Marathon runners had granular casts in their urine without renal failure. Kidney Injury and Repair Biomarkers in Marathon RunnersCute piece from Rick Sterns on urine electrolytes! Managing electrolyte disorders: order a basic urine metabolic panelThe Urine Anion Gap: Common Misconceptions | American Society of NephrologyThe urine anion gap in context CJASNExcellent review from Halperin on urine chemistries (including some consideration of the TTKG): Use of Urine Electrolytes and Urine Osmolality in the Clinical Diagnosis of Fluid, Electrolytes, and Acid-Base Disorders - Kidney International ReportsRenal tubular acidosis (RTA): Recognize The Ammonium defect and pHorget the urine pH | SpringerLinkOutlineChapter 13- New part: Part 3, Physiologic approach to acid-base and electrolyte disorders - Do you remember the previous two parts? - Renal physiology - Regulation of water and electrolyte balance- Chapter 13: Meaning and application of urine chemistries - Measurement of urinary electrolyte concentrations, osmolality and pH helps diagnose some conditions - There are no fixed normal values - Kidney varies rate of excretion to match intake and endogenous production - Example: urine Na of 125/day can be normal if patient euvolemic on a normal diet, and wildly inappropriate in a patient who is volume depleted. - Urine chemistries are: - Useful - Simple - Widely available - Usually a random sample is adequate - 24-hour samples give additional context - Gives example of urinary potassium, with extra renal loss of K, urine K should be < 25, but if the patient has concurrent volume deficiency and urine output is only 500 mL, then urine K concentration can appropriately be as high as 40 mEq/L - Table 13-1 - Seems incomplete, see my notes on page 406 - What is Gravity ARF?- Sodium Excretion - Kidney varies Na to maintain effective circulating volume (I'd say volume homeostasis) - Urine Na affected by RAAS and ANP - Na concentration can be used to determine volume status - Urine Na < 20 is hypovolemia - Says it is especially helpful in determining the etiology of hyponatremia - Calls out SIADH and volume depletion - Used 40 mEq/L for SIADH - Also useful in AKI - Where differential is pre-renal vs ATN - In addition to urine Na (and FENa) look at urine osmolality - Again uses 40 mEq/l - Mentions FENa and urine osmolality - Urine Na can estimate dietary sodium intake - Suggests doing this during treatment of hypertension to assure dietary compliance - 24 hour urine Na is accurate with diuretics as long as the dose is stable and the drugs are chronic - Diuretics increase Na resorption in other segments of the tubule that are not affected by the diuretic - Points to increased AT2 induced proximal Na resorption and aldosterone induced DCT resoprtion - In HTN shoot for less than 100 mEq/Day - Urine Na useful in stones - Urine uric acid and urine Ca can cause stones and their handling is dependent on sodium - Low sodium diet can mask elevated excretion of these stone forming metabolites - 24-hour Na > 75 and should be enough sodium to avoid this pitfall - Pitfalls - Low urine sodium in bilateral renal artery stenosis or acute GN - High urine sodium with diuretics, aldo deficiency, advanced CKD - Altered water handling can also disrupt this - DI with 10 liters of urine and urine sodium excretion of 100 mEq is 10 mEq/L but in this case there is no volume deficiency - Opposite also important, a lot of water resorption can mask volume deficiency by jacking up the urine sodium - Advises you to use the FENa - THE FENA - < 1% dry - >2-3% ATN - It will fail with chronic effective volume depletion - Heart failure, cirrhosis, and burns - Suggests that tubular function will be preserved in those situations - Also with contrast, rhabdo, pigment nephropathy - Limitations - Dependent on the amount of Na filtered - Goes through the math of a normal person with GFR of 125/min and Na of 150 has filtered sodium of 27,000/day so if they eat 125-250 mEq their FENa will be 600-800 - Urine osm < plasma osm in face of hypernatremia indicates renal water loss due to lack of or resistance to ADH - In ATN urine OSM < 400 - In pre-renal disease it could be over 500 - Specific but not sensitive due to people with CKD who are unable to concentrate urine- Specific gravity - Plasma is 8-10% igher than plasma so specific gravity is 1.008 to 1.010 - Every 30-35 mOsm/L raises urine Osm of 0.001 - so 1.010 is 300-350 mOsm/L H2O - Glucose raises urine specific gravity more than osmolality - Same with contrast - Carbenicillin- pH - Normally varies with systemic acid-base status - PH should fall before 5.3 (usually below 5.0) with systemic metabolic acidosis - Above 5.3 in adults and 5.6 in children indicate RTA - PH goal 6.0-6.5 - Separate individual RTAs through FR of HCO3 at various serum HCO3 levels - Also can monitor urine pH to look for success in treating metabolic alkalosis - Look for pH > 7 - In treatment of uric acid stone disease - Want to shift eq: H + urate – uric acid to the left because urate is more soluble - PH goal 6.0-6.5

Although data for hypertension after COVID vaccination is mixed, overall there does seem to be an increase. This is also the case after acute COVID infection. Let's review these data points. DrBeen: Medical Education Onlinehttps://www.drbeen.com/ FLCCC | Front Line COVID-19 Critical Care Alliancehttps://covid19criticalcare.com/ URL List (Aug. 31, 2023) The relationship between COVID-19 vaccines and increased blood pressure: A word of caution - PMChttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9986138/ Hypertension and Covid-19 vaccines: are there any differences between the different vaccines? A safety signal | SpringerLinkhttps://link.springer.com/article/10.1007/s00228-021-03197-8 Blood Pressure Increase following COVID-19 Vaccination: A Systematic Overview and Meta-Analysis - PMChttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9147472/ Understanding Blood Pressure Readings | American Heart Associationhttps://www.heart.org/en/health-topics/high-blood-pressure/understanding-blood-pressure-readings COVID-19 and ACE -inhibitors and angiotensin receptor blockers-: The need to differentiate between early infection and acute lung injury | Revista Colombiana de Cardiologíahttps://www.elsevier.es/es-revista-revista-colombiana-cardiologia-203-articulo-covid-19-ace-inhibitors-angiotensin-receptor-S0120563320300772 AT2 receptor interacting protein 1 (ATIP1) mediates COX-2 induction by an AT2 receptor agonist in endothelial cells - PMChttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767795/#:~:text=It%20is%20known%20that%20both,pathways%20%5B1%2C5%5D. Idiot's Guide to Odds Ratios – JournalFeedhttps://journalfeed.org/article-a-day/2018/idiots-guide-to-odds-ratios/ Disclaimer:This video is not intended to provide assessment, diagnosis, treatment, or medical advice; it also does not constitute provision of healthcare services. The content provided in this video is for informational and educational purposes only.Please consult with a physician or healthcare professional regarding any medical or mental health related diagnosis or treatment. No information in this video should ever be considered as a substitute for advice from a healthcare professional.

Chris and Jeremy look at some Pew research results about what adults say is important to them when it comes to shared beliefs between themselves and their kids. Links from today's episode: Pew Research Article: https://l.facebook.com/l.php?u=https%3A%2F%2Fwww.pewresearch.org%2Fsocial-trends%2F2023%2F01%2F24%2Fparenting-in-america-today%2F%3Ffbclid%3DIwAR2V1_Lt1fERrAI7PRdz7W-SBo9VcbVP9BOITDDTVJ2LCZmqPSOaeKOTjI0&h=AT2Rrkg2n9u5L8KiuHnMh-POX7Z_8Fyg7UWKfpQAGT6cIBOjUMpUZe18Z3_GvbsvwgSJenIPNO8qsAfgx8K2mGoYi5k9h3rFvAmuhSo943HGb328b7itswYwZ_aJNdYTTUAlamA&__tn__=R]-R&c[0]=AT28gVC0jSurjpijoCqKFKqGYgz6uUhFxT2btpwNz7PUnkOcIl0KYEmZ9W6G3bD9sDgXZrnZNVwUSt5HayOsnHv5ZBdcrnF49ufykHMYWK-QWaVllVwhtmSL4SnNMc_KmqokZNHWOI2wUKJhm-6HG4Stg5FKuLJaq7oSpm8S9Zhk1AwwICc_4VJzr891f3cvJuMWdnh9VjLon8NmPUKaDEQr Unitded Methodist Vows: https://l.facebook.com/l.php?u=https%3A%2F%2Fwww.umc.org%2Fen%2Fcontent%2Four-united-methodist-vows%3Ffbclid%3DIwAR2D8Yr5l9xswvVWO_JJUXWBw0okfV7kmvNspY0YZlOTv1HHCzG9K-DdNqc&h=AT3puMR0X3CorZVbkrfelvj7vTRO6AUoKa2NUGvpfhq4baH98FFt1ULaGvLuiBZDZvH8IngflgklTota2P7ResywLctVfGJx69twwrrXgfcjzDhFUsG5kTKoYtY0RdKhUSU13oU&__tn__=R]-R&c[0]=AT28gVC0jSurjpijoCqKFKqGYgz6uUhFxT2btpwNz7PUnkOcIl0KYEmZ9W6G3bD9sDgXZrnZNVwUSt5HayOsnHv5ZBdcrnF49ufykHMYWK-QWaVllVwhtmSL4SnNMc_KmqokZNHWOI2wUKJhm-6HG4Stg5FKuLJaq7oSpm8S9Zhk1AwwICc_4VJzr891f3cvJuMWdnh9VjLon8NmPUKaDEQr United Methodist Baptismal Covenant: https://l.facebook.com/l.php?u=https%3A%2F%2Fwww.umcdiscipleship.org%2Fbook-of-worship%2Fthe-baptismal-covenant-i%3Ffbclid%3DIwAR34ho2cr2Y4f9v1PaBr9PwLwf7Fp3_Z9RXctDXhBxzBRFZYFuZpbpWrMPg&h=AT3wrwSfxsx0lpmYSd8qUg7ravUfGi4FKftZohB8o0U6u8sjK5DcQP9M5Nc7aSasrcCayytZ-um-ya89oCYb0b2nuVlVBGosqDqX_XVdv6UNjc2ibfC-3rFXcxEG0yw3wdtgCbI&__tn__=R]-R&c[0]=AT28gVC0jSurjpijoCqKFKqGYgz6uUhFxT2btpwNz7PUnkOcIl0KYEmZ9W6G3bD9sDgXZrnZNVwUSt5HayOsnHv5ZBdcrnF49ufykHMYWK-QWaVllVwhtmSL4SnNMc_KmqokZNHWOI2wUKJhm-6HG4Stg5FKuLJaq7oSpm8S9Zhk1AwwICc_4VJzr891f3cvJuMWdnh9VjLon8NmPUKaDEQr United Methodist Social Principles: https://l.facebook.com/l.php?u=https%3A%2F%2Fwww.umc.org%2Fen%2Fwho-we-are%2Fwhat-we-believe%2Four-social-positions%3Ffbclid%3DIwAR223znRKvCtzox3ETw1669YJLB0ZTAzb1jywrBzDWO4GTSwAC0LQwiqM1E&h=AT2-jbq6yah_YoV_EsfrSJYgOf7gY5c-xsNw1PyAGnLx-oILy7wjtCPWhSPqiJ9EjnDChgbni85g_CmDFglhtKticnj-HQ-fMvouSGLy1L9rHGrpYuAm7It0bij-8NIzYbRUL4g&__tn__=R]-R&c[0]=AT28gVC0jSurjpijoCqKFKqGYgz6uUhFxT2btpwNz7PUnkOcIl0KYEmZ9W6G3bD9sDgXZrnZNVwUSt5HayOsnHv5ZBdcrnF49ufykHMYWK-QWaVllVwhtmSL4SnNMc_KmqokZNHWOI2wUKJhm-6HG4Stg5FKuLJaq7oSpm8S9Zhk1AwwICc_4VJzr891f3cvJuMWdnh9VjLon8NmPUKaDEQr

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.22.545997v1?rss=1 Authors: DiGiovanni, G. T., Han, W., Sherrill, T., Taylor, C. J., Nichols, D. S., Geis, N. M., Singha, U. K., Calvi, C. L., McCall, A. S., Dixon, M. M., Lui, Y., Jang, J.-H., Gutor, S. S., Polosukhin, V. V., Blackwell, T. S., Kropski, J. A., Gokey, J. J. Abstract: A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ have been implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrate that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings establish that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

  The Transforming Spousal Love of God & Atonement – Atonement: Soundings in Biblical, Trinitarian, and Spiritual Theology Discerning Hearts presents a series of conversations between Dr. Margaret Turek and Evan Collins about her book, “Atonement: Soundings in Biblical, Trinitarian, and Spiritual Theology.” You can pick up a copy of the book here: An excerpt ... Read more The post AT2 – The Transforming Spousal Love of God & Atonement – Atonement with Dr. Margaret Turek and Evan Collins – Discerning Hearts Catholic Podcasts appeared first on Discerning Hearts Catholic Podcasts.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.27.530122v1?rss=1 Authors: Lv, Z., Liu, Z., Liu, K., Pu, W., Li, Y., Zhao, H., Xi, Y., Vaughan, A., Gillich, A., Zhou, B. Abstract: Lung injury activates epithelial stem or progenitor cells for alveolar repair and regeneration. However, the origin and fate of injury-induced progenitors are poorly defined. Here, we report that p63-expressing progenitors emerge upon bleomycin-induced lung injury. These p63+ progenitors proliferate rapidly and differentiate into alveolar type 1 (AT1) and type 2 (AT2) cells through distinct trajectories. Dual recombinase-mediated sequential genetic lineage tracing reveals that p63+ progenitors originate from airway secretory cells and subsequently generate alveolar cells. Functionally, p63 activation is required for efficient alveolar regeneration from secretory cells. Our study identifies a secretory cell-derived p63+ progenitor that contributes to alveolar repair, indicating a potential therapeutic avenue for lung regeneration after injury. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.27.530149v1?rss=1 Authors: Yao, Y., Miethe, S., Kattler, K., Walter, J., Schneider-Daum, N., Herr, C., Garn, H., Ritzmann, F., Bals, R., Beisswenger, C. Abstract: Alveolar type 2 (AT2) and club cells are part of the stem cell niche of the lung and their differentiation is required for pulmonary homeostasis and tissue regeneration. A disturbed crosstalk between fibroblasts and epithelial cells contributes to the loss of lung structure in chronic lung diseases. Therefore, it is important to understand how fibroblasts and lung epithelial cells interact during regeneration. Here we analyzed the interaction of fibroblasts and the alveolar epithelium modelled in air-liquid interface cultures. Single-cell transcriptomics showed that co-cultivation with fibroblasts leads to increased expression of type 2 markers in pneumocytes, activation of regulons associated with maintenance of alveolar type 2 cells, and trans-differentiation of club cells towards pneumocytes. This was accompanied by an intensified transepithelial barrier. Vice versa, activation of NF{kappa}B pathways and the CEBPB regulon as well as the expression of IL-6 and other differentiation factors (e.g. FGFs) were increased in fibroblasts co-cultured with epithelial cells. Recombinant IL-6 enhanced epithelial barrier formation. Therefore, in our co-culture model, regulatory loops were identified by which lung epithelial cells mediate regeneration and differentiation of the alveolar epithelium in a cooperative manner with the mesenchymal compartment. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.19.524655v1?rss=1 Authors: Burgess, C. L., Huang, J., Bawa, P., Alysandratos, K.-D., Minakin, K., Morley, M. P., Babu, A., Villacorta-Martin, C., Hinds, A., Thapa, B. R., Wang, F., Matschulat, A. M., Morrisey, E. E., Varelas, X., Kotton, D. N. Abstract: In the distal lung, alveolar epithelial type I cells (AT1s) comprise the vast majority of alveolar surface area and are uniquely flattened to allow the diffusion of oxygen into the capillaries. This structure along with a quiescent, terminally differentiated phenotype has made AT1s particularly challenging to isolate or maintain in cell culture. As a result, there is a lack of established models for the study of human AT1 biology, and in contrast to alveolar epithelial type II cells (AT2s), little is known about the mechanisms regulating their differentiation. Here we engineer a human in vitro AT1 model system through the directed differentiation of induced pluripotent stem cells (iPSC). We first define the global transcriptomes of primary adult human AT1s, suggesting gene-set benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, that are enriched in these cells. Next, we generate iPSC-derived AT2s (iAT2s) and find that activating nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier which produces characteristic extracellular matrix molecules and secreted ligands. Our results indicate a role for Hippo-LATS-YAP signaling in the differentiation of human AT1s and demonstrate the generation of viable AT1-like cells from iAT2s, providing an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s that until now have been challenging to viably obtain from patients. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Intro: Sometimes the little guy just doesn't cut it.Let Me Run This By You: Time's a wastin' - giddyup, beggars and choosers.Interview: We talk to star of Parks and Recreation, Easter Sunday, and Barry - Rodney To about Chicago, Marquette University, Lane Tech,  getting discovered while pursuing a Chemistry degree, The Blues Brothers, Dürrenmatt's The Physicists, playing children well into adulthood, interning at Milwaukee Rep, Lifeline Theatre, Steppenwolf, doing live industrials for Arthur Anderson, Asian American actors and their representation in the media, IAMA Theatre Company, Kate Burton, and faking a Singaporean accent.FULL TRANSCRIPT (UNEDITED):1 (8s):I'm Jen Bosworth RAMIREZ2 (10s):And I'm Gina Pulice.1 (11s):We went to theater school together. We survived it, but we didn't quite understand2 (15s):It. 20 years later, we're digging deep talking to our guests about their experiences and trying to make sense of it all.1 (21s):We survived theater school and you will too. Are we famous yet?2 (30s):How's your, how's your eighties decor going for your1 (35s):New house? Okay, well we closed yesterday. Well,2 (39s):Congratulations.1 (40s):Thank you. House buying is so weird. Like we close, we funded yesterday, but we can't record till today because my lender like totally dropped the ball. So like, here's the thing. Sometimes when you wanna support like a small, I mean small, I don't know, like a small bank, like I really liked the guy who is the mortgage guy and he has his own bank and all these things. I don't even, how know how this shit works. It's like, but anyway, they were so like, it was a real debacle. It was a real, real Shannon situation about how they, anyway, my money was in the bank in escrow on Friday.1 (1m 20s):Their money that they're lending us, which we're paying in fucking fuck load of interest on is they couldn't get it together. And I was like, Oh no.2 (1m 29s):They're like, We have to look through the couch cushions,1 (1m 31s):Right? That's what it felt like, Gina. It felt like these motherfuckers were like, Oh shit, we didn't actually think this was gonna happen or something. And so I talked to escrow, my friend Fran and escrow, you know, I make friends with the, with the older ladies and, and she was like, I don't wanna talk bad about your lender, but like, whoa. And I was like, Fran, Fran, I had to really lay down the law yesterday and I needed my office mate, Eileen to be witness to when I did because I didn't really wanna get too crazy, but I also needed to get a little crazy. And I was like, Listen, what you're asking for, and it was true, does not exist. They needed one. It was, it was like being in the, in the show severance mixed with the show succession, mixed with, it was like all the shows where you're just like, No, no, what you're asking for doesn't exist and you wanna document to look a certain way.1 (2m 25s):And Chase Bank doesn't do a document that way. And she's like, Well she said, I don't CH bank at Chase, so I don't know. And I said, Listen, I don't care where you bank ma'am, I don't care. But this is Chase Bank. It happens to be a very popular bank. So I'm assuming other people have checking accounts that you deal with at Chase. What I'm telling, she wanted me to get up and go to Chase Bank in person and get a printout of a certain statement period with an http on the bottom. She didn't know what she was talking about. She didn't know what she was talking about. And she was like, 18, 18. And I said, Oh ma'am, if you could get this loan funded in the next, cuz we have to do it by 11, that would be really, really dope.1 (3m 6s):I'm gonna hang up now before I say something very bad. And then I hung up.2 (3m 10s):Right, Right. Yeah. Oh my God, I know. It's the worst kind of help. And regarding like wanting to support smaller businesses, I what, that is such a horrible sadness. There's, there's no sadness. Like the sadness of really investing in the little guy and having it. That was my experience. My big experience with that was going, having a midwife, you know, with my first child. And I really, I was in that whole thing of that, that time was like, oh, birth is too medicalized. And you know, even though my husband was a doctor, like fuck the fuck the medical establishment we're just, but but didn't wanna, like, I didn't wanna go, as my daughter would say, I didn't wanna be one of those people who, what did she say?2 (3m 52s):You know, one of those people who carry rocks to make them feel better.1 (3m 57s):That's amazing. Super.2 (4m 0s):So I didn't wanna go so far as to be one of those rock carrying people to have the birth at my house, but at the same time I really wanted to have this midwife and then there was a problem and she wasn't equipped to deal with it. And it was,1 (4m 11s):I was there,2 (4m 13s):Fyi. Yes, you were1 (4m 15s):The first one, right? For your first one.2 (4m 16s):The first one.1 (4m 18s):Here's the thing you're talking about this, I don't even remember her ass. What I, she, I don't remember nothing about her. If you had told me you didn't have one, I'd be like, Yeah, you didn't have one. I remember the problem and I remember them having to get the big, the big doctor and I remember a lot of blood and I remember thinking, Oh thank God there's this doctor they got from down the hall to come or wherever the hell they were and take care of this problem because this gene is gonna bleed out right here. And none of us know what to do.2 (4m 50s):Yes. I will never forget the look on your face. You and Erin looking at each other trying to do that thing where you're like, It's fine, it's fine. But you're such a bad liar that, that I could, I just took one look at you. I'm like, Oh my God, I'm gonna fucking bleed out right here. And Aaron's going, No, no, no, it's cool, it's cool, it's cool. And then of course he was born on July 25th and all residents start their residency on July 1st. So you know, you really don't wanna have a baby or have surgery in July cuz you're getting at a teaching hospital cuz you're getting a lot of residents. And this woman comes in as I'm bleeding and everything is going crazy and I haven't even had a chance to hold my baby yet. And she comes up to me and she says, Oh cuz the, the midwife ran out of lidocaine. There was no lidocaine.2 (5m 30s):That's right. They were trying to sew me up without lidocaine. And so this nurse comes in, she puts her hand on my shoulder, she says, Hi, I'm Dr. Woo and I'm, and I said, Dr. W do you have any lidocaine? I need some lidocaine stat right up in there. Gimme some lidocaine baby. And she had to call her boss. You know who I could tell when he came in, of course he was a man and I could tell when he came in, he looks at my midwife and is like, Oh, this is what you did here. I see we have to come in and clean up. But sometimes that's the case. Sometimes it's really just true that, you know, it's that the, that the bigger kind of like more corporate option is better cuz it just works better.1 (6m 8s):Well, and they've done this before, like there is, they've done the job before in a way, and they've seen the problems. They know how to troubleshoot in a way because they just have the fucking experience. Now you could say that getting that experience is like super fucked up and patriarchal and, and all the isms, it's, and you'd be right, but when you are bleeding to death or when you know you are in a big financial negotiation that could go south at any moment and lead to not having a ho like a all feeling lost. You want someone who knows how to fucking troubleshoot, dude. Like, come on. And I, you know, and it is sad, it's heartbreaking when you like, fuck man.1 (6m 50s):I really wanted this, like Dr. Altman always said, and I have an update on Dr. Altman, my favorite psychiatrist mentor of mine. But he always said like, well when I was going through med titration, when they put this dingling at Highland Park Hospital, who tried her best but put me on lithium thinking I was bipolar and then I was and all the meds, right? All the meds. And he's like, well they could've worked2 (7m 15s):It could've worked it1 (7m 17s):All's. And I was like, you are right. So like, it could've worked, it could've gone differently, but it just didn't. So it's like, yeah, it's better to look at it like that because, or else it's just infuriating that it didn't work in the first place, Right? Like, you're like, well fucker, Well they tried.2 (7m 35s):Yeah. I use that all the time that it could have worked. Things that I got through you from Dr. Altman, you know, my husband is having like some major, you know, growth moments. Like come like those moments where all the puzzle pieces become clear and you go, Okay, my childhood isn't what I thought it was and this person has got this and this person has got that. Yes. You know? And, and whenever he's doing the thing that we all do, which is like lamenting the life, the family he wish he had had, I always say like, well, as Dr. Almond says, it could have worked. Yes, these parents could have been just fine for you if you were a different person, but you're you.2 (8m 16s):And so, and they're them and it wasn't a good match. And like that happens sometimes.1 (8m 21s):And I think it's really good with kids maybe too. Cause it's like, listen, like, like I say to my niece, like it could, this could have been whatever it is the thing or my nephew too that worked and like that you loved volleyball or that you loved this. Like you are just looking, and I think it's all about titration, right? Like it's all about figuring out where we fit in, where we belong, where we don't. And it's a fucking process, which is what he was saying and like, and that you don't, we don't get it right the first time. Even in medicine, even in it's maybe especially in medicine, maybe in especially in relationships, like, so it, it also opens the door for like, possibility, right? That like, it's an experiment and like, we don't know, even doctors don't know, Hey, run this by you, Miles did of course.1 (9m 14s):And done. What about you? What about you?2 (9m 17s):I'm gonna do it after this, after we're done recording today, I'm gonna go over and I always like to take one of my kids so they, you know, see that this is the process and you have to do it and it's everybody's responsibilities to do it. That doesn't mean that I didn't get all angry at my own party this week. You know, my mom has a great expression. I think it's her expression. She says it. In any case, all politics is local, right? Like where it really, where the really meets the road is what's happening in your backyard. And like, I have a lot of problems with my town,1 (9m 52s):So Right.2 (9m 53s):They don't wanna have, you know, they voted down this measure to put a a, like a sober living place, wanted to take up residence here. Couldn't think of a greater idea. Nobody wanted it. You know, it's a lot of nis not in my backyarders over here. And it really drives me crazy. And in the, in the paper this week, there was a big scandal because there's this particular like committee in our town, Okay. That was in charge of, there was gonna be this, what is it, like a prize maybe or an honor or not a scholarship Okay. But something where they were gonna have to name it.2 (10m 33s):Okay. And they were, you know, really looking around for names. They were trying to think up what names would be appropriate. And somebody put forward the name of this person who is already kind of a named figure in our town. Like, we had this beautiful fountain, it's named after him. He was, he was a somewhat of a big guy, you know, he was an architect, whatever. Sure. So this name gets put forward in this woman who's on this committee says, I don't think this is a great time to name something after an old white man. Now, to me couldn't be a more reasonable thing in the world to say everybody's calling for her resignation. And these, you know, the thing that I hate the most about, not just conservatives, but it seems like it's especially conservatives.2 (11m 20s):I hate this saying. And I remember, I think I've said this before on the podcast, I remember hearing some black activists saying a lot of white, you know, a lot of racism perpetrated by white people is like founded on pretending. Pretending like you don't see color pretending like, you know, saying things like, Oh, well why would you have had that experience, you know, walking down our street at night? Like, or why would you have had that difficulty getting that job? I don't understand. And pretending like they don't know that this person just got1 (11m 51s):That job because of2 (11m 52s):The color biscuit and that kind kind of a thing. So of course the way that people are coming down on this woman is to say, Well, I don't know about you, but I was taught that we have to look beyond race and we have to recognize the person before the color of their skin. And if you can't be, you know, representing the needs of white men, then I just don't really think that you, there's a place on this council. And of course, you know, somebody who I know and have in the past really respected was quoted in this article as saying, Oh, somebody who considers himself like a staunch liberal. Yeah. I mean, I just really can't think of any people of note from our town who weren't white men.2 (12m 34s):Sure. And this motherfucker let himself be quoted in our newspaper as saying this. Now maybe he feels fine about it. Maybe he doesn't think there's anything wrong with it. But I I I think it's completely, completely disgusting. Of course. So then I went and I just did this research of like all the people who have lived in our town historically, they're not just white men. We, there's other people to choose from. Needless1 (12m 58s):To say. Yeah. Well also, like, it's so interesting. I mean, it's just that that quote just is so problematic on so many levels. It like goes so deep. But like the other thing is like, maybe they miss, the only thing I can think of is that dude, did they miss the second half of your quote? Which was, and that's a problem. Like, like if, if you can't, if you can't finish that quote with, you know, I can't really think of like anyone of note in our being or anyone being recognized in our town in this way that wasn't a white dude and that's really crazy. We should really reevaluate how we're doing things here.1 (13m 39s):Period. You're so2 (13m 41s):To offer, you're so, you're so sweet to offer him this benefit of the doubt. Of course I don't offer that to him because this is a person who, you know, there's been a few people in my life who I've had the opportunity to, you know, know what they say privately and then know what they say publicly. Right? And I, and I know this, you know, I know this person personally. And no, it doesn't surprise me at all that, that that would've been the entirety of the quote. It would've been taken out of context. Now it might have been, and I don't know, and I'm not, I'm not gonna call him up to ask him, but you know, at a minimum you go on the local Facebook page and say, I was misquoting.1 (14m 20s):No, no, yeah. Chances are that this, this person just said this. And actually the true crime is not realizing if, if, if that's the case, that they, that that statement is problematic. So that's really fucked up. And also, like, think of all the native people that were on that land, on our land. Like, you're gonna tell me that just because you haven't done, they haven't done the research. They don't think that a native person from the northeast did something of greatness. Shut up, man. Excellent. Before it was rich.2 (14m 56s):Excellent point, Excellent point. Maybe when I write to my letter to the editor, maybe I'll quote you on that because Yeah, yeah. It's like, it's so, it's just, and I'm, by the way, I'm, I have been, I'm sure I'm still am guilty of the same thing too, of just being the laziness of like, well, I don't know, we'd love to, you know, hire a person of color, but none have applied. I mean, I have definitely said things like that and I just understand differently now I understand. No, no, no, they're not gonna be at the top of the pile of resumes that you're gonna get because historically these people haven't felt like there's a place for them at your table. So what you have to do is go above and beyond and say, we are specifically recruiting people of color for this position. I understand.1 (15m 35s):And how about even like, do some research online and find out who those people are and try to like, hire them away from wherever they are to and make them a great offer. You know what I mean? Like all those things. Well,2 (15m 48s):This experience did cause me to go on my little Wikipedia and look up, you know, people who have lived here and I was really like, surprised to learn how many people have known. Now it's true to say that, you know, when, when you're just looking up a list of famous people, it is gonna mostly be white men because that's who mostly, you know, sort of, she made, made history, made the news, whatever. But yeah, one of the very first things that come up, comes up when you look it up my town on Wikipedia, is that the fact that this was the Ramapo tribe that lived here. You know, this is who we took the land away from. I was also surprised to that.1 (16m 29s):I've never,2 (16m 30s):Yeah, Yeah. It was also interesting to learn, supposedly according to this, how many people of live here currently, including people like Harvey Firestein, who I have, I've never seen around town, but God I would really love to. And like some other, you know, sort of famous people. But anyway, That's1 (16m 50s):So cool.2 (16m 51s):Yeah. So, so I will be voting after this and I really, I don't have a great feeling about the election, but I'm, you know, I'm just like, what can you do? You can just sort of go forward and, you know, stick to your values. Yeah. I mean,1 (17m 7s):The thing is, stick to your values, move forward. And like my aunt, happy birthday, Tia, it's her birthday today, and she is like super depressed that, you know, she, she said, what she says is like, fascism is really, today is the day that we really something about fascism, it's like really dire and like really, Okay. So my, it's so interesting that I think boomers feel really bad because they had it so good, even though it wasn't really good, there was an illusion of goodness. Right? So I, I am depressed. But here's the thing, and I was, I was gonna bring this up to you.1 (17m 47s):It's like I, I had an experience last night where I went to this theater and saw the small theater, which I really wanna do my solo show in which is this famous theater called The Hayworth, which is, they show silent movies and all, but there's now it's like an improv sort of venue and, and it's really cute and throwbacky. But anyway, I went there and I just was thinking like, as I was watching these performers, like, oh, it is not even that, Like, it's literally that I spent 45 years thinking that I was worse than everybody else, right? And so now that I don't really think that, I actually don't have that much time left to accomplish what I would like to accomplish. So I, I spent all this time feeling like I couldn't do what she's doing.1 (18m 29s):I can't do what he's doing, can't do what theirs doing. They're, they are doing because I'm not good enough. Like literally. And now I'm like, Oh my God, I'm good enough. I have things to say. I really wanna leave a legacy. And literally the clock is ticking. Now, I'm not saying I'm running around like a nut, but what I'm saying is like, I, I, I do feel that I literally don't have the time left to participate in half-assed measures of art or whatever we're gonna do. We gotta make it purposeful because I w i, I spent all this time getting ready 45 years to not hate myself. And now the clock is ticking, I donate myself and there are things to do.1 (19m 13s):That's literally how I feel. So then when I see art or something where I'm like, Why are you using your platform this way? What are you talking about? What are you saying? Oh no, I can't, I even now I know why people leave movies early, plays early if it is, and some, for me anyway, like some people probably just assholes and like the, the person on stage doesn't look cute and they're out or whatever, but, or they're having panic attacks like I used to and I have to leave. But like, mostly I understand where it's like this is wasting my, my time, time I could be using to sort of plant seeds that may do something to be of service.1 (19m 53s):So I'm gonna jet and good luck to you. But yeah, it's the first, I just really feel like time is of the essence. And I always thought that was such a stupid thing that old people said, which was, you know, time is our most precious commodity. And I was always like, that is the dumbest thing I've ever heard. And now I'm like, oh shit. Yeah, it's really true Dude.2 (20m 15s):Yeah. Yeah. I actually had an experience some that I relate to with that, which is that, you know, I, I volunteered to be part of this festival of one act and you know, the thing we were supposed to do is read all of the submissions and then pick our top three. And then they were gonna do this rank order thing where they're attempting to put each director with one of their top three choices. Well, I read, it was like 10 plays I read them and I, I didn't have three, three ch choices. There was only one play that I felt frankly was worth my time.2 (20m 56s):And I felt really uncomfortable about having that feeling. And I was doing all of the like, who do you think you are? And you know, it's, you haven't directed something in three years and beggars can't be choosers in the whole thing. And I just thought, you know, I know what I'm gonna do if I don't stand up for whatever it is I think I can do here is I'm gonna resent the thing that I get, you know, pitted with and then I'm gonna do something self-destructive or I'm gonna kind of like blow up the relationship and I don't wanna do that. So I spend a lot of time thinking about how I was gonna write this email back saying basically like, I don't have three choices. I only have one choice. And I understand if you don't want to give that to me that this, I might not be a good fit for you.2 (21m 37s):You know? But I really, I really kind of sweated over it because when you don't, you know, when you're a very, if I was an extremely established theater director, you know, I wouldn't have thought twice about it. But I'm not, I'm trying to be established here and I, you know, so my, my, my go-to has always been well having opinions and choices and stuff like that is for people who, you know, have more than you do or have more to offer than you do. And it doesn't always work out that when you kind of say, This is me and take me or leave me. It doesn't always work out. But in this case it doesn't. They gave me my first choice. And so I'm, I'm happy about that, but there's a lot.2 (22m 18s):Thank you. Thank you. Yeah, there's a lot that just goes into the, it's all just work I have to do on myself. Like, I have this, a way of thinking about things is like, I have to do this work with this other person or I have to convince them why it has nothing to do with that. It's just that I have to do this.1 (22m 34s):Well that's what I'm realizing, like Gina, Absolutely. And good for you for like, coming at it from a place of like, okay, like this might not work, but I have to do it to see and put it out there and it may not work and they may say, go fuck yourself. But the alternative one is resentment, but also is like, hmm, not doing anybody else any favors either. If you aren't saying like, I actually don't have three choices here, I'm not gonna do justice. And I also, it brings me to my other thing, which I thought was so full of shit, which is so true. It's like most things are just not, it's about not being a right fit. It's not about you're bad and I'm good, I'm good and you're bad.1 (23m 15s):It's like, this is not a good match. And I, I think it just takes what it takes to learn that it is a not, it's about a matching situation. So like you knew that like those other two wouldn't be good matches and you wouldn't do a service to them or yourself. And it's not, And also like this thing about beggars can't be choosers. I fucking think it's so dumb because like most of us are beggars all the time and, and we, we settle for garbage. And it doesn't, like, I feel like we can, like beggars should be more choosy. And I also feel like, I'm not saying not be humble, but like, fuck you if you take away our choices, like we have to have choices.1 (23m 57s):That's the thing. It's like beggars have choices, whatever you call a beggar, we still have choices. Like how we're gonna interact and how and how we're gonna send emails and shit. I'm just like,2 (24m 9s):Yeah. Plus that whole phrase is so like, in a way rooted in this kind of like terrible supremacy structure that we're trying to fight against, which is like, we wanna tell, of course we wanna tell beggars that they can't be choosers cuz we just, we don't wanna think about them as people who have the same agency in life as we do.1 (24m 25s):Sure. And now I've started saying to people when I have this conversation about like, about unhoused, people like having tent encampments and I get it, like, you're going to school, you're walking your kid to Montessori and there's a fucking tent encampment in your front yard. You did not pay for that. You did not sign up for that. You are, I get it. And also my question is, what are we gonna do when the tents outnumber the people in homes? Because then it's a real fucking problem. So like, how are we gonna do that? You think it's uncomfortable? I think it's uncomfortable to walk by a tent encampment as I'm on my way to a coffee date with someone or whatever.1 (25m 8s):That's uncomfortable. But what are we gonna do when, like in India, the, the quote slums or whatever people, you know, whatever people choose to call it, outnumber the goddamn people in the towers. Then we, then it's gonna be a different problem.2 (25m 35s):Today on the podcast, we were talking to Rodney Toe. Rodney is an actor, you know him from Parks and Recreation, Barry good girls Rosewood. He was in a film this summer called Easter Sunday. Anyway, he's a delight. He's also a professor of theater at USC and he's charming and wonderful and we know you are going to love listening to him as much as we loved talking to him. So please enjoy our conversation with Rodney Toe.3 (26m 8s):Can you hear me? Can you hear me okay?2 (26m 11s):Yes, you sound great. You sound1 (26m 13s):Happy. No echo. You have beautiful art behind you. We can't ask for a2 (26m 17s):Better Easter Sunday. We were just talking about Easter Sunday, so we're gonna have to ask you Oh sure about it, Beth. But first I have to say congratulations, Rodney tell you survive theater school.3 (26m 28s):Oh, thank you. Yes, I did. I sure did. Was2 (26m 31s):It usc? Did you go to3 (26m 32s):Usc? No, I, I'm a professor. I'm currently a professor at usc. So1 (26m 36s):We just assumed you went there, but where did you go3 (26m 38s):To No, no, no, no, no. I, that, that came about like in a roundabout way, but no, I, I totally, I went, went to Marquette University. Oh, in Milwaukee?1 (26m 46s):In Milwaukee. Oh my gosh. Yeah. So3 (26m 48s):Everybody's reaction, everybody's reactions like, well1 (26m 53s):I actually love Mil, I'm from Chicago and Evanston you do and then you are,3 (26m 58s):Yeah, born and raised north side. My family's still there. What1 (27m 1s):The hell? How did I not know this? Yeah, I'm from Evanston, but lived in Rogers Park and went to, we went to DePaul.3 (27m 7s):Well I hear the park. Yes, yes. Born and raised. My family's still there. I am a Chicago, I'm an undying Chicago and through and through. Yeah.1 (27m 15s):Wait a minute. So, so, okay, okay, okay. So you grew up on the north, you grew up in, on the north side.3 (27m 20s):Yeah, I grew up in, I, I grew up and I went to Lane Tech. Oh1 (27m 24s):My gosh, that's where my niece goes right this very minute. She goes, Yeah,3 (27m 28s):It's1 (27m 28s):Quite the school. I dunno how it was when you went, but it went through a hard time and now it's like one of these3 (27m 34s):Go, I mean when I went it was, it was still considered a magnet school. And I I, you know, I think like in like it went maybe through a period of like, sort of like shifting, but then it's like now it's an incredible school. I'm September 17th is apparently Rodney to day at Lane 10. No, Yeah, it just happened. I mean it's, it's silly. It's Easter significance. No, cause of Easter Sunday they did like a bunch of, you know, I do a lot of advocacy for the Asian American for Asian-American representation. So sort like all together1 (28m 4s):That movie had broke so many, broke so many barriers and was, I mean it was a phenomenal, and also I just feel like it's so obviously so needed. Duh. When people say like, more representation is needed, I'm like, okay, no shit Sherlock. But it's true. It bears repeat again. Cause it still is true that we need more representation. But I am fascinated. Ok, so you went to Lane Tech and were you like, I'm gonna be a famous actor, comedian? No, what,3 (28m 34s):What anything about it? Didn't I, you know, it's called Lane Tech for a reason, right? It's a technical school. Correct. So like we didn't, you know, it didn't, I mean there were arts, but I, it never really, you know, it was one of those things that were like, you know, I guess like when you were a kid, it's all like, hey, you wanna learn how to like macrame. But there were theater arts in my, in my high school, but it wasn't like,1 (28m 54s):In fact, my mother did macrame. And let me tell you something, it has come back in style. And the shit she made, we could be selling for $199 at Urban Outfitters right now. I'm just,3 (29m 4s):Oh yeah, it's trendy now. Yeah. It's like, yeah, it's in style.1 (29m 7s):Anyway, side note, side note. Okay, so you were like, I'm not doing, there was no performing at Lane Tech. There was no like out there, there,3 (29m 13s):There was, and there was, but it wasn't, again, you know, in terms of representation, there was nothing that like, I mean there was nothing that that showed me any kind of like longevity in, in, you know, it didn't even really occur to me that this was a business that people sort of like, you know, pursued for themselves. So it wasn't until I went to Marquette that I discovered theater. And so it was one of those things that like, I was like, oh, there's something here. So it wasn't like, it wasn't fostered since I was a kid.1 (29m 43s):This,2 (29m 44s):And this is my favorite type of origin story because it means, you know, like there are people who grow up in LA or their, their parents are in the industry. And then, so it's always a question like, am I gonna go into this industry? But, but people like you and like me and like Boz, who, there's no artist in our family, you know,3 (30m 4s):You2 (30m 4s):Just have to come to it on your own. So I would love to hear this story about finding it at Marquette.3 (30m 10s):So like the, this, I, I've told this story several times, but the short version of it is, so I went to college for chemistry. And so again, because I came from, you know, that that was just sort of the path that, that particularly, you know, an Asian American follows. It's a very sort of stem, regimented sort of culture. And when I went to Marquette, my first, my sort of my first like quarter there, it was overwhelming, you know, I mean, college was, was a big transition for me. I was away from home and I, I was overwhelmed with all of the STEM courses that I was taking, the GE courses. And I, I went to my advisor and at the time, you know, this is pre-internet, like he, we sat down, I sat down with him and he pulled out the catalog.3 (30m 52s):Oh yeah, the catalog, right? I1 (30m 54s):Remember the catalog. Oh yeah.3 (30m 56s):And so he was like, let's take a class that has nothing to do with your major. Oh,1 (30m 60s):I love this. I love this advisor. I love this advisor. Do you know, can he you say his name3 (31m 7s):At the, was it Daniel? Dr. Daniel t Hayworth. I mean, it's been a while I went to college with Dahmer was arrested. So that's been a1 (31m 15s):While. Okay. Yeah's, same with us. Same with me. Yeah.3 (31m 18s):Yeah. So like, I think it was Daniel Daniel Hayworth. Yeah. Cuz he was a, he was a chemistry professor as well. So he opened up, he opened up the, the thing in the, the catalog and it said acting for non-majors. And I remember thinking, that sounds easy, let's do that. And then I went to the class, I got in and he, he, he was able to squeeze me in because already it was already in the earl middle of the semester. And so I, the, the, the, the teacher for that class was a Jesuit priest. His name is Father Gerald Walling. And you know, God rest his soul. And he, his claim to fame was he had like two or three lines on Blues Brothers, the movie.1 (31m 59s):Amazing. I mean like great to fame to have Yes. Get shot in Chicago. Yeah. And if you're a Jesuit priest that's not an actor by trade, like that is like huge. Like most people would like die to have two to three lines on Blues Brothers that are working anyway. So, Okay, so you're, so he, so how was that class?3 (32m 19s):So I took the class and he, after like the first week he asked me, Hey is, and it was at 8:00 AM like typical, like one of those like classes that I was like, Oh my gosh, I'm gonna go in here miserable. Yeah. But he said to me early on, he said, Do you have any interest in doing this professionally? And I said, no. And he's like, and he, he said, and he said, I was like, You're hilarious. You know,1 (32m 43s):You're a hilarious Jesuit.3 (32m 45s):Yeah. I'm like, Good luck with God. He, he then he was directing, he was directing the university production of, and he asked me to audition for it. And I was, I don't even know what an audition was. That's amazing. So like, it was one of those things that I didn't really know how to do it. I didn't know much about it. And so he's like, Can you come in and audition for it? And I did and I got it and it was, it was Monts the physicist,1 (33m 12s):What the fuck is that?3 (33m 14s):Oh man, I love that play. It's Amont, it's the same, you know, it's the same. He's, you know, Exactly. It's really, it's one of those like sort of rarely done plays and it's about fictitious Albert Einstein, the real, lemme see if I, it's been so long since I recall this play. The real, So Isaac Newton and what was the other Mobius? A fictitious, So the real, I'm sorry, The real Albert Einstein, The real, the real Albert Einstein, the real Isaac Isaac New and a fake, a fictitious play scientist named Mobius.3 (33m 55s):And they were, they were all in, in a mental institution. And I1 (33m 60s):Think that I have this play and my shelves and I just have never read it before. Okay, so3 (34m 4s):Who did you play? It's extraordinary. Extraordinary. And so I played, I played a child like I did up until my mid thirties. I played a child who had like one line, and I remember it took, it took place in Germany, I believe. And I remember he's like, Do you have a German accent? I was like, No. You're1 (34m 20s):Like, I I literally am doing chemistry 90.3 (34m 23s):Yeah. I was all like, you're hilarious. Yeah. Only children do accents, You know what I mean? Like, it was totally, I was like, whatever's happening, I don't even know what's happening. And, and then I made up a European accent. I mean, I, I, I pulled it on my ass. I was like, sure, don't even remember it. But I was like, one of,1 (34m 39s):I love when people, like, recently Gina showed me a video of her in college with an accent. Let me tell you something, anytime anyone does an accent, I'm like, go for it. I think that it's so3 (34m 51s):Great. Yeah. I've got stories about, about, I mean, I'm Asian, right? So like, I mean it's been one of those things that all my life I've had to sort of navigate people being like, Hey, try this on for Verizon. I was like, Oh gosh. And you know, anyway, I can go on forever. But I did that, I had a line and then somebody saw me in the production with one line and said, Hey, this is at the Milwaukee Repertory Theater, somebody from the Milwaukee Repertory Theater. It's huge1 (35m 18s):Theater. Fyi. Right,3 (35m 20s):Right. Again, it's, it's to this day. And so they asked if I would intern, if I would be considered interning while I was in school. And I said, I didn't even know what that was. So I met with them. And when I walked into that theater, it was one of those, it's one of the biggest, most extraordinary music theaters in the wor in the country. Right. Won the regional, Tony and I, again, I had no frame of reverence for it. So walking in, it was like this magical place. And so I started, I started interning right, right off the bat. And it was one of those like life changing experiences. I, I mean, to this day, the best acting I think I've ever seen, you know, face to face has been on that stage. It's, you know, many of those actors are still, I'm still in touch with to this day.3 (36m 3s):Some of them have passed away. However, it was the best training, right? I mean, I got thrown into the deep end. It was like working with some of the greats who never, no one ever knew. Right. So it really, it was really a wonderful experience. And that's when I sort of, you know, that's when I was like, Oh, I actually can do this for a living. So it was,1 (36m 21s):Oh yeah, Milwaukee rep. I've seen some amazing stuff there. And also what would've been great is, yeah, we like, I mean there's so many things that would've been great at DePaul at the theater school, but one of them would've been, Hey, there's all these regional theaters, like if you wanna make some dough, it was either like, you are gonna be doing storefront and Die of Hunger, or you're gonna be a star. Hilarious was no like, what about Milwaukee Rep? What about the Guthrie? Like all the things3 (36m 50s):Gut, Yeah. Never1 (36m 51s):Told at least. Or I didn't listen or I was like in a blackout drunk state. But like, I just feel like hilarious. I just feel like that is so amazing that you got to do that. So then, Wait, did you change3 (37m 2s):Your It wasn't, I did. I eventually did. Yes. So I have both. And so now it was one of those, like, it was, it was harrowing, but eventually, I mean, I did nothing with my chemistry degree. Nothing. Like literally nothing. That's,2 (37m 16s):Most people do nothing with their theater degree. So, so it all evens out. Wait, I have a question. Now. This is a question that would be difficult for me to answer. So I wouldn't fault to you if it's difficult for you. What do you think it was in you that this person saw and said, have you ever considered doing this professionally? I mean, just trying to be really objective about the, the asce the essence of you that you bring to the table. Always. How, what did that person identify, do you think, if you3 (37m 44s):Had to guess? You know, I'd like to say it was talent. I'd love to be that person and be like, you know, they recognized in me in one line that ordinary artist was going to emerge into the universe and play children into his thirties. I, I wish I could. It was that, I mean, honestly, I looked different than everybody else on that's a white school and Milwaukee rep, you know, God, forgive me for saying this, but it was a sensibly all white institution.1 (38m 12s):Super white. Super white. Yeah.3 (38m 14s):So in comes this little Asian guy who like they thought might have had potential and also is Asian. And I checked off a lot of boxes for them. And you know what I could easily say, like I, I could easily sort of, when, if you asked me like 20 years ago, I was like, Oh, I was talented, but now I'm like, no, I made my way in because of, because I, I checked boxes for people and, and1 (38m 37s):Talented,3 (38m 38s):You couldn't,1 (38m 39s):You3 (38m 39s):Couldn't have done it if you didn't have talent to thank you. And I can, I can, you know, whatever, I can own that now. But the, but the reality is like, I made it in and that's how I got in. And I'm okay with that. And I'm not saying that it's not taking anything away from talent, but the reality is it's like you gotta get in on the inside to work your way out. And if I didn't have that exposure early on, I certainly wouldn't have had the regional career that I did for a little while. You know? So like that credit, like you, like you said Jen, it's like, it's a, it's a huge credit. So like I would not have made it in any other way. Right. And I certainly,1 (39m 12s):Yeah, I just am like noticing also like my reaction to, Yeah, it's interesting too as other humans in this industry or any industry, it's like, it's like we have had to, especially those of us that are, you know, I'm 47 and like those of us who have made it in or sort of in for, in my, I'm just speaking for myself. Like I, I sort of, right, It could have been fucked up reasons or weird reasons that we got in the door or even filling someone's need or fantasy. But then it's like what we do with it once we're in the room, that really, really matters. And I think that yeah, regardless of how you ended up in Milwaukee rep, like I think it's smart and like I really like the idea of saying okay, like that's probably why I was there.1 (39m 58s):I checked, I've checked boxes, but Okay. But that's why a lot of people are a lot of places. And so like, let's, let's, let's, you could stop there and be like, that is some fucked up shit. Fuck them. Or you could say, Wait a second, I'm gonna still have a fucking career and be a dope actor. Okay, so you're there, you're, you're still, you graduate from Marquette with a double major, I'm assuming, right? Chemistry and, and was it theater, straight up theater or what was your degree?3 (40m 23s):It's, well, no, no, it's called, it's, it's, it's the, at the time it's called, they didn't have a theater degree. Right. It was called the, you graduated with a degree in Communications. Communications,1 (40m 32s):Right? Yes. Okay, okay. Yeah. My, my niece likes to say Tia, all the people in communications at UCLA are the dumbest people. I'm like, No, no, no, no, no. That would've been me. And she's like, Well, anyway, so okay, so, so you graduate and what happens? What happens to you?3 (40m 54s):So, you know, I, I went from there. I went to, I got my equity card pretty ear pretty early cuz I went for my, I think it was my final between my, the summer, my junior year and my senior year I went to, because of the Milwaukee rep, I got asked to do summer stock at, at ppa, which is the Pacific Conservatory, the performing Arts, which is kind of like an Urda contract out in the West Co on the west coast. And so I was able to get credits there, which got me my equity card very quickly after, during that time I didn't get it at the institution, but I got like enough, you know, whatever credit that I was able to get my equity card. And again, at the time I was like, eh, what are the equity? I didn't even know know what that was really.3 (41m 34s):I don't know if anybody truly knows it when they're, when they're younger. So I had it and I went, right, I had my card and I went right to Chicago because family's there. So I was in Chicago. I did a couple of shows, I did one at at Lifeline at the time. I did one at North. Yeah. So it was nice to sort of go back and, and, and, and then I, you know, right then I, it's my favorite story, one of my favorite stories. I, I got my, my my SAG card and my after card in Chicago that summer, because at the time the union was separate. That's how old I am. And I got my SAG card doing a Tenax commercial, and I got my after card doing, I'm not sure if they're still there.3 (42m 18s):I think they are actually. It is a company called Break Breakthrough Services and they did it live industrial. Oh yeah.1 (42m 24s):They, I think they still wait live. How does that work? Yeah,3 (42m 29s):Exactly. So it's a lot of like those training, you know, you see it a lot, like the people do it, like corporate training stuff. Right. So they used, at the time it was really new. So like they used a lot of actors and they paid well.1 (42m 42s):Well, I did an Arthur Anderson one that like paid my rent3 (42m 45s):Long time. Yeah, yeah, yeah. So exactly when Arthur Anderson was still a, I think I did one too. So like, they,1 (42m 53s):Rodney,3 (42m 55s):Were you in St. Charles, Illinois?1 (42m 57s):I don't know. I had to take the Amtrak. It could have been,3 (42m 59s):Yeah. In St. Charles. Right? That's where they were centered. Yes. Yeah.1 (43m 2s):Okay, go ahead. Go ahead. So you, okay, so you got your, I know our world. Do you live, Where do you live?3 (43m 8s):I'm in, I'm in LA right now. This is my home. Yeah.1 (43m 11s):Okay. Well I'm coming to your home. Okay, great. I'm in Pasadena right now. Okay. Anyway, go ahead. Oh yeah.3 (43m 17s):Okay. So we, yeah, I went to Chicago, got my cards, and then was there for, you know, a hot minute and then I moved to New York. Okay.1 (43m 25s):Wait, wait, wait. Moved. Did you have, what years were you working in Chicago? Like were we still, were Gina and I in school? What, what, what years were that were you were like, Tampa, a man Chicago.3 (43m 35s):I did God bless that commercial. Yeah, it was so good. I did, let's see here, I grad, I was there in 90, let's see, 97,1 (43m 47s):We were there. Well, Gina was graduating and I, I was, yeah. Anyway, we were there.3 (43m 52s):And then I moved to New York in 98 and then I moved to New in 98. So1 (43m 55s):You were only in Chicago a hot minute? Yeah, yeah, yeah.3 (43m 57s):Okay. Yeah. But then I came back, I came back in 2004 five to do a show at Victory Gardens. Oh. And then I did a show at Victory Gardens, and then I did a workshop at Stepin Wolf. So it was nice. Look at1 (44m 12s):Victory Gardens. Victory Gardens. That was a whole,3 (44m 15s):I'm sorry, what was that?1 (44m 16s):R i p, Victory Gardens.3 (44m 17s):Oh, yeah. I mean, well I was there pre-K. Yeah. And so, but it was, yeah, r i p I mean, r i it was truly one of the most magnificent, magnificent shows that I've been part, but I mean,1 (44m 30s):Okay, so wait, wait, wait. Okay, so why New York? Why weren't you like, I'm gonna bust out and go to LA and be a superstar on,3 (44m 38s):It's all about representation. I mean, I didn't see at the time, and you know, if you think about it, like there were people on television, but, you know, in terms of like the, the, the, it wasn't pervasive. It was like sort of every once in a while I'll turn on my TV and I'll see like Dante Bosco or I'll see like, you know what I mean? But it wasn't like I saw like, you know, I wasn't flooded with the image of an Asian American making it. However, at the time, you know, it was already Asian Americans were starting to sort of like flood the theater world, right? So I started, you know, through James c and, and Lisa Taro in Chicago, and like, people who are like, who are still friends of mine to this day, Asian American actors, they were doing theater. And so I was like, you know what, I'm gonna do theater. And so I, it was just one of those, like, I went to, and I already had these credits.3 (45m 19s):I had my equity card, I had some credits. My natural proclivity was then to go to, to, to first theater in New York. So it wasn't, I didn't even think about LA it wasn't like, oh, let me, let me like think about doing television and film. So I went1 (45m 32s):To York. I just feel like in LA it's so interesting. As an actor, writing is a little different, but as an actor, it, most of us, if we plan to go to LA as actors, we're gonna fail. I just feel like you have to end up here as an actor by accident because you do something else that you love and that people like, and then they're like, I just, it's not the most welcoming. Right. Medium film and tv. So like, it's so hard. So I think by accident is really sort of the only way, or if you're just already famous for something else, but like, anyway, So you're in New York. Did you, did you love it? Wait, can I,2 (46m 9s):Can I hang on Buzz, Can I do a timeout? Because I've been wanting to ask this just a little bit back to, you know, your undergrad experience. Did you wanna be, did you love chemistry or did you just do that because Oh, you did, Okay. So it wasn't, it wasn't like, oh, finally I found something that I, like you liked chemistry.3 (46m 29s):Yeah. To this day, to this day, I still like, it's still very much like, you know, the, the, the values of a stem field is still very much in how I teach, unfortunately. Right? Like, I'm very empirical. I, I, I need to know an, I need to have answers. Like, you know, it tends to, sometimes it tends to be a lot of it, like, you know, you know, sort of heady and I'm like, and now I need, I need, I'm pragmatic that way. I need to understand like why, Right? That2 (46m 53s):Doesn't seem unfortunate to me. That seems actually really fortunate because A, you're not the only artist who likes to think. I mean, you know, what about DaVinci? Like, a lot of people like to think about art in a, in a, I mean it's really, they're, they're, they're really kind of married art and science.3 (47m 8s):Yeah. They really are people. I, I think people would, It's so funny. Like people don't see it as such, but you're absolutely right. I agree. It's so more, Yeah. There's so much more in common.1 (47m 18s):The other thing that I'm glad Gina brought that up is cuz I'm questioning like, okay, so like, I don't know about at Marquette, but like at DePaul we had like, we had, like, we had these systems of, you got warnings if you, you weren't doing great and I bet like you probably didn't have the cut system cause that just is okay, good. But okay.3 (47m 36s):Well we were, we remember we were, we weren't a conservatory, right? So we were very much a, a liberal programming.1 (47m 42s):Yeah, I love it. Oh God, how I longed for that later, right? But anyway, so what would've helped is if someone with an empirical, like someone with more a stem mind sat down with me and said, okay, like, here are the things that aren't working in a practical way for you, and here are the things that you can do to fix it. Instead, it was literally this nebulous thing where my warning said, You're not living up to your star power now that's not actually a note. So that, that, that Rick Murphy gave me, and I don't, to this day, I'm like, that is actually, so I would love if I had someone like you, not that you'd be in that system, but like this to say like, okay, like here's the reasons why.1 (48m 25s):Like there was no why we were doing anything. It was like, you just do this in order to make it. And I said, Okay, I'll do it. But I was like, what the hell? Why are we doing this? That's,3 (48m 35s):That's like going to a doctor and a doctor being like, you're sick. You know what I mean? And you're like, but can, that's why I'm here is for you to help me get to the root of it and figure it out. Right. Being like, you're,1 (48m 46s):I think they didn't know, Here's the thing, I don't think it, it3 (48m 50s):Was because they're in.1 (48m 51s):Yeah. I I don't think it was because they were, I mean, they could have been rude in all the things. I literally, now that I'm 47, looking back on that experience, I'm like, Oh, these teachers didn't fucking know what they were, how to talk. And3 (49m 3s):This is how I came. Yeah, yeah. Which is how I came back to usc. So like that's,1 (49m 7s):Anyway, continue your New York adventure. I just wanted to know.3 (49m 11s):No, no, no. New York is was great. New York is New York was wonderful. I love it. I still love it. I I literally just got back with it. That's why, remember I was texting you, emailing you guys. I I just got back, Yes. The night before. Some amazing things. My husband would move back in a heartbeat if I, if I like texted him right now. And I was like, Hey, like let's move back. The house would be packed and we'd, he'd be ready to go. He loves, we both love it. You know, Am I in love with New York? I, that, that remains to be seen. I mean, you know, as I get older that life is, it's a hard life and I, I love it when there's no responsibilities when you can like, skip around and have tea and you know, walk around Central Park and like see shows.3 (49m 53s):But you know, that's obviously not the real, the reality of the day to day in New York. So I miss it. I love it. I've been back for work many times, but I, I I don't know that the life is there for me anymore. Right. I mean, you know, six fuller walkups. Oh no. Oh no. I just, yeah, I1 (50m 11s):Just like constantly sweating in Manhattan. Like I can't navigate, It's like a lot of rock walking really fast and3 (50m 20s):Yeah. And no one's wearing masks right now. I just, I just came back and I saw six shows when I was there. No one's wearing masks. It's like unnerving. And again, like, you know, you know, not throwing politics in it. I was like, you guys, like, how are you okay with it? I'm just like, how are you not unnerved by the fact that we're cramped in worse than an airplane? And everyone's like coughing around you and we're sitting here for three hours watching Death of a Salesman. I mean, like, how was that1 (50m 43s):Of an2 (50m 45s):Yeah know?3 (50m 46s):I mean,2 (50m 47s):So what about the, so at some point you, you pretty much, I mean, you don't do theater anymore, right? You transition to doing3 (50m 55s):Oh, I know, I do. Very much so, very much. I'm also the associate, Yeah. I'm the associate artistic director of, I am a theater company, so like I'm, I'm very much theater's. I will never let go. It's, it's just one of those things I will never as, as wonderful as television and film has been. It's, it's also like theater's, you know? It's the, it's my own, it's my first child. Yeah.2 (51m 19s):Yeah.1 (51m 20s):We have guests like Tina Parker was like that, right? Wasn't,2 (51m 23s):Yeah. Well a lot of, a lot of people. It's also Tina Wong said the same thing.3 (51m 26s):He and I are different. She's part, we're in the same theater company. So Yeah. Tina's.2 (51m 30s):That's right. That's right. That's right. Okay, now I'm remembering what that connection was. So I have a question too about like, when I love it, like I said, when people have no idea anything related to performing arts, and then they get kind of thrust into it. So was there any moment in sort of discovering all this where you were able to make sense of, or flesh out like the person that you were before you came to this? Like a lot of people have the experience of, of doing a first drama class in high school and saying, Oh my God, these are my people. And never knowing that their people existed. Right. Did you have anything like that where you felt like coming into this performing sphere validated or brought some to fullness?2 (52m 14s):Something about you that previously you hadn't been able to explore?3 (52m 18s):Yeah. I mean, coming out, you know what I mean? Like, it was the first time that people talk, you know? Of course, you know, you know, I was born to, you know, like was God, I said I was born this way. But that being said, like again, in the world in which I grew up in, in Chicago and Lane Tech, it's, and, and the, you know, the technical high school and, and just the, the, the, I grew up in a community of immigrants. It's not like it was laid out on the table for one to talk about all the time. Right. It wasn't, and even though I may have thought that in my head again, it wasn't like, it was like something that was in the universe and in the, in the air that I breathed. So I would say that like when I got to the theater, it was the first time, you know, the theater, you guys we're, we're theater kids, right?3 (53m 2s):We know like every, everything's dramatic. Everything's laid, you know, out to, you know, for everyone. Everyone's dramas laid out for everyone. A the, and you know, part of it was like sexuality and talking about it and being like, and having just like, just being like talking about somebody's like ethnic background. And so it was the first time that I learned how to talk about it. Even to even just like how you even des you know, you know how you even describe somebody, right? And how somebody like, cuz that again, it's not, it wasn't like, it wasn't language that I had for myself. So I developed the language and how to speak about people. So that's my first thing about theater that I was like, oh, thank God.3 (53m 43s):You know? And then, you know, even talking about, you know, like queer, like queer was such a crazy insult back when I was a kid. And then now all of a sudden queer is now this embraced sort of like, badge of honor, Right? And so like, it was just like that and understanding like Asian and Asian American breaking that down, right? And being Filipino very specifically breaking that down, that all came about from me being in theater. And so like, I, I'm, I owe my, my life to it if you, and, and because I've, yeah, I didn't, you know, it's so funny how the title of this is I Survived Theater School for me. It's, Yes, Yes.3 (54m 23s):And I also, it also allowed theater also gave, allowed me to survive. Yes.2 (54m 31s):Theater helped you survive. Yes. That's beautiful. So in this, in the, in this spectrum or the arc, whatever you wanna call it, of representation and adequate representation and you know, in all of our lifetimes, we're probably never gonna achieve what we think is sort of like a perfect representation in media. But like in the long arc of things, how, how do you feel Hollywood and theater are doing now in terms of representation of, of specifically maybe Filipino, but Asian American people. How, how do you think we're doing?3 (55m 3s):I think we, you know, I think that there's, there's certainly a shift. You know, obviously it, we'd like it to be quicker than faster than, than it has been. But that being said, there's certainly a shift. Look, I'm being, I'll be the first person to say there are many more opportunities that are available that weren't there when I started in this, in this business, people are starting to like diversify casts. And you know, I saw Haiti's Town, it was extraordinary, by the way. I saw six shows in New York in the span of six days out of, and this was not conscious of me. This is not something I was doing consciously. Out of the six shows, I saw every single show had 90% people of color.3 (55m 43s):And it wasn't, and I wasn't conscientious of it. I wasn't like, I'm going to go see the shows that like, it just happened that all I saw Hamilton, I saw K-pop, I saw, you know, a death of a Salesman I saw. And they all were people of color and it was beautiful. So there's definitely a shift. That said, I, for me, it's never, this may sound strange, it's not the people in front of the camera or on stage that I have a problem with. Like, that to me is a bandaid. And this is me speaking like an old person, right? I need, it needs to change from the top down. And for me, that's what where the shift needs to happen for me. Like all the people at top, the, the, the people who run the thing that needs to change. And until that changes, then I can expect to starter from1 (56m 25s):The low. It's so interesting cuz like, I, I, I feel like that is, that is, we're at a point where we'd love to like the bandaid thing. Like really people really think that's gonna work. It never holds. Like that's the thing about a bandaid. The longer the shit is on, it'll fall off eventually. And then you still have the fucking wound. So like, I, I, I, and what I'm also seeing, and I don't know if you guys are seeing it, but what I'm seeing is that like, so people got scared and they fucking started to promote execs within the company of color and othered folks and then didn't train them. And now are like, Oh, well we gave you a shot and you failed, so let's get the white kid back in that live, you know, my uncle's kid back in to, to be the assistant.1 (57m 6s):And I'm3 (57m 7s):Like, no people up for success is a huge thing. Yeah. They need to set people up for success. Yes, yes, for sure.2 (57m 12s):Yeah. So it's, it's performative right now. We're still in the performative phase of1 (57m 16s):Our, you3 (57m 17s):Know, I would say it feels, it, it can feel performative. I I'm, I'm definitely have been. I've experienced people who do get it, you know what I mean? It's just, Sunday's a perfect example of somebody who does get it. But that being said, like again, it needs to, we need more of those people who get it with a capital I like, you know, up at the top. Cause again, otherwise it's just performative, like you said. So it's,1 (57m 38s):Does it make you wanna be an exec and be at the top and making choices? Yeah,3 (57m 42s):You know, I've always, people have asked me, you know, people have asked me what is the next thing for me. I'd love to show run. I've, I just, again, this is the, this is the stem part of me, right? Like, of us, like is I'm great at putting out fires, I just have been that person. I'm good with people, I'm, I'm, you know, and I've, I, you know, it's, it's, it's just one of those things that like I, I see is a, is a natural fit. But until that happens, you know, I'm, I'm, I'm also, you know, a professor is very much a version of show learning. So I've been doing that every day.1 (58m 14s):We talk about how, cause you've mentioned it several times about playing children into your thirties. So a lot, we have never had anyone on the show that I'm aware of that has had that sort of thing or talked about that thing. They may have had it. Mostly it's the opposite of like, those of us who like, I'll speak for myself, like in college, were playing old people at age, you know, 16 because I was a plus size Latina lady. And like that's what what went down. So tell me what, what that's what that journey has been like for you. I'm just really curious mostly, cuz you mentioned it a couple times, so it must be something that is part of your psyche. Like what's that about? Like what the, I mean obviously you look quote young, but there's other stuff that goes into that.1 (58m 57s):So how has that been for you and to not be, It sounds like you're coming out of that.3 (59m 1s):Yeah, I mean, look, all my life I've always been, you know, I mean I'm, I'm 5, 5 6 on a good day and I've always just been, I've always just looked young. Like, I mean, I mean, and I don't mean that like, oh I look young. Like I don't mean that in any sort of self-aggrandizing way. I literally just am one of those and you're built, like me, my one of my dear friends Ko, God rest his soul, he was always like, Rodney, you're like a little man look, looks, you're like a man that looks like a boy. And I was like that, that's hilarious. Like, and look, I for growing up little in, in high school and, and it, it was one of those things that I was always like, you know, like I was always chummy with people, but I was never sort of like, like there's a look, let's face it.3 (59m 45s):Like we're, we're a a a body conscious society and when you're, whatever it is, you can't help. There's implicit bias, right? Implicit bias, right. Supremacy at it's most insidious. And so I am not all my life, I was like always trying to, you know, the Napoleon complex of always trying to sort of be like, prove that I was older than I was.1 (1h 0m 6s):How did you do it? How did you do, how were you, what kind of techniques did you use? For3 (1h 0m 10s):Me, it wasn't even my technique. It was about doing everything and anything I possibly could. I mean, I was like president or vice president, I a gajillion different clubs. So it1 (1h 0m 18s):Was doing, it was doing, it was not like appearance. Okay, okay. So you3 (1h 0m 23s):Was actually yeah, I couldn't do anything about this. Yeah.1 (1h 0m 25s):Right. So yeah, but like people try, you know, like people will do all kinds of things to their body to try to, But for you, it sounds like your way to combat that was to be a doer, like a super3 (1h 0m 36s):Duer. And I certainly, I certainly like worked out by the time I got to college I was like working out hardcore to try and masculinize like, or you know, this. And, and eventually I did a gig that sort of shifted that mentality for me. But that being said, I think the thing that really, that the thing that, that for me was the big sort of change in all of this was just honestly just maturity. At some point I was like, you know what? I can't do anything about my age. I can't do anything about my height, nor do I want to. And when that shifted for me, like it just ironically, that's when like the maturity set in, right? That's when people started to recognize me as an adult.3 (1h 1m 17s):It's when I got got rid of all of that, that this, this notion of what it is I need to do in order for people to give me some sort of authority or gimme some sort of like, to l

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.11.516088v1?rss=1 Authors: Kortekaas, R. K., Geillinger-Kaestle, K. E., Borghuis, T., Belharch, K., Webster, M., Timens, W., Burgess, J. K., Gosens, R. Abstract: IL-11 is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL-11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung. The alveolar architecture is disrupted in IPF, yet the effect of IL-11 on dysregulated alveolar repair associated with IPF remains to be elucidated. We hypothesized that epithelial-fibroblast communication associated with lung repair is disrupted by IL-11. Thus, we studied whether IL-11 affects the repair responses of alveolar lung epithelium using mouse lung organoids and precision cut lung slices (PCLS). Additionally, we assessed the anatomical distribution of IL-11 and IL-11 receptor in human control and IPF lungs using immunohistochemistry. IL-11 protein was observed in human control lungs in airway epithelium, macrophages and in IPF lungs, in areas of AT2 cell hyperplasia. IL-11R staining was predominantly present in smooth muscle and macrophages. In mouse organoid co-cultures of epithelial cells with lung fibroblasts, IL-11 decreased organoid number and reduced the fraction of pro-SPC expressing organoids, indicating dysfunctional regeneration initiated by epithelial progenitors. In mouse PCLS alveolar marker gene expression declined, whereas airway markers were increased. The response of primary human fibroblasts to IL-11 on gene expression level was minimal, though bulk RNA-sequencing revealed IL-11 modulated a number of processes which may play a role in IPF, including unfolded protein response, glycolysis and Notch signaling. In conclusion, IL-11 disrupts alveolar epithelial regeneration by inhibiting progenitor activation and suppressing the formation of mature alveolar epithelial cells. The contribution of dysregulated fibroblast - epithelial communication to this process appears to be limited. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.28.514255v1?rss=1 Authors: Chioccioli, M., Magruder, S., McDonough, J. E., Nouws, J., Gonzalez, D., Borriello, L., Traub, B., Ye, X., Hendry, C. E., Entenberg, D., Kaminski, N., Krishnaswamy, S., Sauler, M. Abstract: Tissue repair requires a highly coordinated cellular response to ensure the correct balance of replacement cells to lost cells. In the lung, alveolar type 2 (AT2) cells act as stem cells and can replace both themselves and alveolar type 1 cells (AT1); however, the complex orchestration of AT2 stem cell activity following lung injury is poorly understood owing to the inability to track individual stem cells and their dynamic behavior over time. Here, we apply live time lapse imaging to ex vivo mouse precision cut lung slice (PCLS) culture and in vivo mouse lung to track individual GFP-labeled AT2 cells for 72h following intra-tracheal administration of bleomycin. We observe highly dynamic movement of AT2 cells, including migration within and between alveoli, as well as the emergence of at least three distinct morphokinetic AT2 cell states. Small molecule-based inhibition of Rho-associated protein kinase (ROCK) pathway significantly reduced motility of AT2 stem cells following injury and reduced expression of Krt8, a known marker of intermediate progenitor cells. Together, our results uncover motility of alveolar stem cells as a new injury response mechanism in the lung and uncover properties of stem cell motility at high cellular resolution. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Valsartan, also known as Diovan, is an angiotensin II receptor blocker (ARB). It is used for treating NYHA class II to IV heart failure along with both treating and managing hypertension. Another common indication is for both STEMI and NSTEMI patients. Typical initiation dosing for heart failure, STEMI and NSTEMI is 20 mg twice daily with titrations up to 160 mg twice daily. When initiating treatment for hypertension the range begins at 80-160 mg po every day up to a max dose of 320 mg per day. Valsartan works by blocking AT2 from the AT1 receptor and is considered to be more efficient than ACEs along with having less side effects such a cough. Some common side effects are orthostatic hypotension, dizziness, and lightheadedness. Common monitoring parameters for valsartan are blood pressure, blood pressure urea, pregnancy, and electrolytes. Patients should avoid salt substitutes containing potassium. There is a black box warning for fetal toxicity because drugs that affect the renin-angiotensin system can cause injury/death to the fetus. Go to DrugCardsDaily.com for my episode show notes which will contain a drug summary, quiz, and a link to FREE drug card sheets. SUBSCRIBE on Spotify or Apple Podcasts or search for us on your favorite place to listen to podcasts. I will go over the Top 100-200 Drugs as well as throwing in some recently released drugs that peak my interest. Also, if you'd like to say hello, suggest a drug, or leave any constructive feedback on the show I'd really appreciate it! Leave a voice message at anchor.fm/drugcardsdaily or message us through twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

Chapter Three: How the proximal tubule is like Elizabeth Warren and other truths my friends from Boston taught me References for Chapter 3: Faisy C, Meziani F, PLanquette B et al. Effect of Acetazolamide vs. Placebo on Duration of Invasive Mechanical Ventilation among patients with chronic obstructive pulmonary disease: a randomized clinical trial. JAMA 2016 https://pubmed.ncbi.nlm.nih.gov/26836730/This randomized controlled double blinded multi-center study of acetazolamide to shorten the duration of mechanical ventilation (known as DIABLO) there was no statistically significant difference (though it may have been underpowered to do so).Salazar H, Swanson J, Mozo K, White AC, Cabda MM Acute Mountain sickness impact among travelers to Cusco, Peru J Travel Med 2012 https://pubmed.ncbi.nlm.nih.gov/22776382/ Investigators found that altitude sickness is common and alters travel plans for 1 in 5 travelers but was prescribed infrequently.Buzas GM and Supuran CT. Journal of enzyme inhibition and medicinal chemistry 2015 https://www.tandfonline.com/doi/full/10.3109/14756366.2015.1051042This review describes the use of acetazolamide to treat peptic ulcers and how it was later learned that H. pylori have carbonic anhydrase NORDIC idiopathic intracranial Hypertension Study Writing Committee. The effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA 2014 https://pubmed.ncbi.nlm.nih.gov/24756514/In this multi-centered trial, acetazolamide and low sodium weight reduction diet improved mild visual loss more than diet alone. Mullens W et al. Rationale and design of the ADVOR (acetazolamide in decompensated heart failure with volume overload trial) Eur J Heart Failure 2018 https://pubmed.ncbi.nlm.nih.gov/30238574/This reference explains the rationale for this ongoing trial.Gordon CE, Vantzelfde S and Francis JM. Acetazolamide in Lithium-induced nephrogenic diabetes insipidus NEJM 2016 https://www.nejm.org/doi/full/10.1056/NEJMc1609483A case report of efficacy of acetazolamide in a patient with severe polyuria.Zehnder D et al. Expression of 25-hydroxyvitamin D-1alpha hydroxylase in the human kidney. JASN 1999 This report explores the activity in the enzyme in nephron segments and suggests that the distal nephron may play an important part in the formation of 1,25 vitamin D https://jasn.asnjournals.org/content/10/12/2465Outline: Chapter 3 - This is chapter three, kind of the first real chapter of the book- Proximal Tubule- Reabsorbs 55-60% of the filtrate - Active sodium resorption - 65% of the sodium - 55% of the chloride - 90% of HCO3 - 100% glucose and amino acids - Passive water resorption - Water resorption is isosmotic - Secretion of - Hydrogen - Organic anions - Organic cations - Anatomy - S1, S2, S3 can be differentiated by peptidases - S1 more sodium resorption and hydrogen secretion, high capacity - S2 more organic ion secretion - Cell model - Basolateral membrane - Na-K-ATPase powers all the resorption - Luminal membrane - 100 liters a day crosses the proximal tubule cells - Microvilli to increase surface area - Microvilli has brush border which has carrier proteins as well as carbonic anhydrase - Water permeable, so sodium resorption leads to water resorption - Aquaporin-1 (sounds like this transporter is unique to the proximal tubule and RBC) - HCO3 is reabsorbed early, along with Na, resulting in increased chloride concentration which passively reabsorbed via paracellular route. - Tight junction has only one strand (on freeze fracture) as opposed to 8 in distal nephron - The Na-K-ATPase - Lower activity than in the LOH and distal nephron - Maintained intracellular Na at effective concentration of 30 mmol/L - Interior of the cell is negative due to 3 sodium out and 2 K in, then K leaks back out. - 3 Na out for 2 K in - An ATP sensitive K outflow channel on the basolateral membrane - Increased ATP slows potassium eflux - The idea is if Na-K slows, ATP will accumulate and this will slow K leaving, because there is less potassium entering. - K channel is ATP sensitive, ATP antagonizes K leak. - Highly favorable ELECTROCHEMICAL gradient for sodium to flow into the cell through the luminal membrane - Must be via a channel or carrier - Cotransporters - Amino acids - Phosphate - Glucose - Called secondary active transport - Countertransporters - Only example is H excretion - Basolateral membrane - Na-3HCO3 transporter - Powered by the negative charge in the cell- Chloride resorption - Formate chloride exchanger - Formate combines with hydrogen in the lumen, becomes neutral formic acid, and is reabsorbed where the higher pH causes it to dissociate and recycle again. - Dependent on continued H+ secretion - Chloride moves across basolateral membrane thanks to Cl and KCl transporters, taking advantage of negative intracellular charge- Passive mechanisms of proximal tubule transport - Accounts for one third of fluid resorption - Mechanism - Early proximal tubule resorts most of the bicarb and less of the chloride - Tubular fluid gets a high chloride concentration - Chloride flows through the tight junction down its concentration gradient - Sodium and water follow passively behind - Water moves osmotically into intercellular space from tubular fluid even though the osmolalities are equal since chloride is an ineffective osmole, so tonicity is not the same. ****** - Argues that bicarb is primarily important solute for passive resorbtion - Acetazolamide blocks Na and chloride resorption - Similar thing happens with metabolic acidosis where less bicarb is available to drive passive resorbtion of Na and Cl - Summary - Other than Na-K-ATPase Na-H antiporter main determinant of proximal Na and water resorption - 1. Direct bicarb resorption - Preferential bicarb resorbtion proximally drives passive chloride resorption - Drives active the formate exchanger for chloride resorption- Neurohormonal influence - AT2 drives a lot of Na resorption, primarily in S1 segment - Does not have a net effect on H-CO3 movement - Dopamine antagonizes sodium resorption - Blocks both Na-K-ATPase and - Na H antiporter- Capillary uptake - Starlings. Again - Low hydraulic pressure due to glomerular arteriole - High plasma on oncotic pressure from loss of the filtrate - The two together promote resorption - There maybe movement from interstitial back into tubular fluid (back diffusion) conflicting data- Glomerular tubular balance - The fractional tubular reabsorption remains constant despite changes in GFR (tubular load) - It is essential the GFR is matched by resorption - The rise in capillary osmotic pressure with increased GFR via increased filtration fraction is one mechanism of GT balance - Glomerular tubular balance os one of three mechanisms that prevents fluid delivery from exceeding the resorptive capacity of the tubules - GT balance - TG feedback - Autoregulation - GT balance can be altered if patients are volume overloaded or depleted - Closes this section with a story of a kid born without a brush border - Primacy of sodium in proximal tubule activity - Discusses bicarb resorbtion - There is no Tm for Bicarb as long as volume overload is prevented, in rats can rise over 60! - If you give NaHCO3 you get volume overload and the Tm I about 60 - Glucose - S1 and S2 have high capacity, low affinity glucose resorption - S3 has high affinity 2 Na fo every glucose - Tm glucose is 375 mg/min - For a GFR of 125t that comes out to 300mg/dL - 125 ml/min * 3mg/ml (300 mg/dL) = 375 mg/min - Functionally this is 200 mg/dL due to splay - Urea - Only 50-60 of filtered urea is excreted - Calcium Loop and distal tubule - Phosphate - 3Na-Phosphate high affinity transporters late in proximal tubule - three types of Na-Phos transporters, type 2 are the most important - regulated by PTH and plasma phosphate - PTH suppresses Phos resorption -Metabolic acidosis also reduces phosphate resorption (good to have phosphate in the tubule to soak up H+ - Decreased tubular pH converts HPO42- to H2PO4- which has lower affinity for phosphate binding site - Mg Loop and distal tubule - Uric AcidWhy do I love acetazolamide?- I love the proximal tubule- Many uses- Often forgottenMOA- Inhibit carbonic anhydraseMain effects- Renal: less bicarb reabsorption (ie less H secretion) à more distal Na/bicarb delivery à hypokalemic metabolic acidosis- Brain: reduce CSF production, reduce ICP/IOP, aqueous humor- Pulm: COPDNotes- Tolerance develops in 2-3 days- Sulfonamide derivative- Highly protein bound, eliminated by kidneys Source: Buzas and upuran, JEIMC, 2016S Data:1968 - High altitudeHigh altitude usually results in respiratory alkalosisAcetazolamide – lessens symptoms of altitude sickness (insomnia, headache) which occur because of periodic breathing/apnea1979- NEJM study took 9 mountaineers asleep at 5360 meters à improvement in sleep, improved SaO2 from 72 to 78.7 mmHg, reduce periodic breathing, increased alveolar ventilation (pCO2 change from 37 mmHg to 30.8mm Hg)1950s - Seizures/migrainesCAI reduces pH (more H intracellularly), K movement extracellularly à hyperpolarization and increase in seizure thresholdWeak CAI (Topamax, zonisamide) but not though to be important mechanism of antiseizure effect (topamax enhances inhibitory effect of GABA, block voltage dependent Na and Ca channels)Pulmonary/COPDThought to help with the metabolic alkalosis and as a respiratory stimulant to increase RR, TV, reduce ventilator timeIn 2001 Cochrane review – no difference in clinical outcomes, but did reduce pH and bicarb minimallyDIABLO study (RCT) on ventilated COPD patients – no difference in median duration of mechanical ventilation despite correction of metabolic alkalosisHigh altitude erythropoiesis (Monge disease)First described in 1925 via Dr. Carlos Monge Medrano (Peruvian doctor), seen in people living > 2500-3000 meters (more common in South America than other high altitude areas)Usually chronic altitude sickness with HgB > 21 g/dL + chronic hypoxemia, pHTNAcetazolamide – reduces polycythemia because induces a met acidosis à increases ventilation and arterial PPO2 and SaO2 à blunts erythropoiesis and reduces HCT and improves pulmonary vascular resistanceGI ulcersWhen H2 and PPI available, less useHistory: 1932 – observed alkaline tide, presumed existence of gastric CA (demonstrated in 1939)Acetazolamide was used to inhibit acid secretion in 1960s, ulcer symptoms, with reversible metabolic acidosis, BUT lots of SE (electrolyte losses, used Na/K/Mg salts to help, renal colic, headache, fatigue, etc)Later found H. Pylori encodes for two different CasHelps to acclimatize to acidic environmentBasically, the Ca changes CO2 into H+ and HCO3They also have a urease which produces NH3The NH3 binds with H+, leaving an alkaline environment for them to live inInhibition of CA with acetazolamide is lethal for pathogen in vitro1940sFound there was CA in pancreasThought acetazolamide to reduce volume of secretions from NGT (output from exocrine pancreas) Source: Human Anatomy at Colby Blog Diuretic resistanceIf develop hyperchloremic metabolic alkalosis, short course of acetazolamide + spironolactone (b/c need distal Na blockage) à can helpMay help with urine alkalization (ie uric acid stone) but increases risk of calcium phosphate stonesADVOR trial acetazolamide in HF exacerbation in Belgiumuse may help to prevent new episode, lower total diuretic doseCSF reduction (pseudotumor cerebri)Reduces CSF by as much as 48% when > 99.5% of CA in choroid plexus is inhibitedNORDIC trial (acetazolamide v. placebo) – improvement in visual symptoms especially if advanced papilledema, and reduced opening pressure)Side note also used off label to help with increased ICP and CSF leaks, as alternative to VP shunts, repeat LPs, etc Source: Eftekari et al, Fluid Barriers CNS, 2019.

Market regulator Sebi has asked mutual fund houses to restrict the exposure to additional Tier I and II (AT1 and AT2) bonds. This directive comes after write-offs in such bonds issued by two banks in the past year had hit investors. The Department of Financial Services had written to Sebi to withdraw the guidelines related to the change in valuation norms. While industry body Association of Mutual Funds in India (AMFI) had said that it is in discussion with Sebi to further smoothen the process of implementation of the circular. So, what exactly are these AT1 or perpetual bonds? Why are they risky? And why are there conflicting views about such bonds? To understand everything about the Sebi norm and possible consequences, Mint's Nasrin Sultana is in conversation with Piyush Gupta, Director, Crisil Funds Research.

Back by popular demand…all two of you…the second chapter of The Clinical Physiology of Acid Base and Electrolyte Disorders. Chapter Outline- Renal Circulation and GFR - RBF is 20% of cardiac output - In terms of mL per 100 g organ weight it is 4x the liver and exercising muscle and 8x coronary blood flow! - After the glomeruli the efferent arteriole have two fates - Peritubular capillaries in the cortex - Peritubular capillaries are not necessarily associated with their parent glomeruli. Weird. - Vasa recta from juxtamedullary glomeruli in the medullaJoel Says: This seems wrong. Solute balance can be maintained down to a very low GFR. The R^2 here would be very low. Prove me wrong. - States that GFR is an important determinant of solute and water excretion. - Glomerular anatomy and function - Structure Four editions of the Bud Bible up top and a copy of Bud Light on the bottom. - Glomerulus is a tuft of capillaries - Enclosed in a capsule of epithelial cells, called Bowman's capsule - The epithelial cells of Bowman's capsule are continuous with the epithelial cells of the proximal tubule Looking at scanning EMs of the glomerulus is one of life's simple pleasures—Josh. Josh says: Look at the review in Nature Reviews Nephrology from Rachel Lennon's groupComplexities of the glomerular basement membrane - Filtration barrier - Epithelial cell (podocyte) - Epithelial cells adhere to the basement membrane via foot processes and the foot processes have slit diaphragms - Basement membrane New Super-resolution structure of the GBM: https://elifesciences.org/articles/01149 Hi res microscopy is really hi-res. Technique is call ed STORM. Melanie talks about conduits through the glomeruli. Here is a cool review: Why until just now? Undiscovered uniqueness of the human glomerulus! by L. Gabriel Navar, Owen RichfieldAm J Physiol Renal Physiol. 2018 Nov 1; 315(5): F1345–F1346. Published online 2018 Aug 15. doi: 10.1152/ajprenal.00369.2018 PMCID: PMC6293291 - Produced by both the endothelial cells and podocytes - Formed from type IV collagen - Abnormalities of type 4 collagen cause Alport - The gene coding for the alpha 5 chain is the culprit - COL4A5 - Abnormal Alpha 3 and 4 chains can also cause hereditary nephritis - Has other substances - Laminin - Nidogen - Heparin sulfate proteoglycans - Provides the negative charge - Enthothelial cell (fenestrated) - Protein excretion - Glomerular function: allow filtration of small solutes (Na and urea) while preventing filtration of larger molecules - Insulin MW 5,200 is freely filtered (upper range of freely filtered) - Preventing loss of protein prevents - Negative nitrogen balance - Development of hypoalbuminemia - Infection from loss of immunoglobulin - Size and charge selectivity of the GBM - pores are between cords of type 4 collagen - The epithelial cells and slit diaphragms matter - Macromolecules that pass through GBM can accumulate underneath the epithelial layer - Isolated GBM in invitro studies is much more permeable to than intact glomerulus - There is increased protein filtration in areas where the epithelial cells have detached from the GBM Josh really likes this figure from another Nature Reviews Nephrology paper. This one by Moeller and Chia-Gil. - Mutations in nephrin, localized to the slit diaphragm causes congenital nephrotic syndrome - Charge selectivity is important - Neutral and cationic particle are more likely to be filtered - Albumin (negative charge) is filtered 5% as well as same size neutral dextrans - In glomerular disease, while there is increased filtration of proteins there is decreased filtration of small solutes due to loss of glomerular surface areaJC says: Take a look at this research on the serving coefficient in glomerular disease. Some surprising results.Glomerular dysfunction in nephrotic humans with minimal changes or focal glomerulosclerosis - Why do people in remission have what appears to be spilling more high molecular radius particles than normal and why do patients with active MCD have lower clearance across all molecular diameters? - Other glomerular functionsJosh says: Take a look at this interesting paper by Butt et alA molecular mechanism explaining albuminuria in kidney disease - Synthetic - Epithelial cells produce GBM - Phagocytic - Remove circulating macromolecules that pass through GBM and get trapped in subepithelial spaceJosh says: The sFLT1 (soluble VEGF receptor) relationship to preeclampsia is just so cool. And here's the paper:Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsiaAnd in the NEJM: VEGF Inhibition and Renal Thrombotic Microangiopathy - Endocrine - Enthothelial cells regulate vascular tone by releasing - Prostacyclin - Endothelin - Nitric oxideJC says: Do yourself a favor and spend some time learning about extraglomerular mesangial cells with Stuart Shankland Extraglomerular origin of the mesangial cell after injury. A new role of the juxtaglomerular apparatusJoel adds, if you ever get a chance to party with Dr. Shankland, don't skip out. - Mesangial cells, two types - Intrinsic Mesangial cell - Microfilaments similar to smooth muscle - Responds to Ang2 - Regulates glomerular hemodynamics - Can release cytokines - Can respond to cytokines by proliferation - Circulating macrophages and monocytes - Phagocytic function - Clear molecules that get through the endothelial wall but cant get through the GBMJosh says, “Topf, get it right. Its Ree-nin not renin. Classic letter to JAMA. - Renin-Angiotensin System - Afferent arteriole contain specialized cells called juxtaglomerular cells - Produce prorenin which cleaved into renin - Stimuli for renin release - Hypotension - Volume depletion - Increased sympathetic activity - Renin catalyze the production of ang1 from angiotensinogen - Ang1 is catalyze to Ang2 by ACE located in the - Lung - Endothelial cells - Glomeruli itself pic.twitter.com/DaDfS7u8se— Roger Rodby (@NephRodby) February 22, 2021 - Discussion of local renin and Aniotensinogen - Explains why ACEi are useful even with low systemic renin levels and Ang2 - Actions of Ang2 - Sodium and water retention - By direct Na reabsorption in the early PT (and in the proximal tubule, water is permeable to the epithelium so every sodium reabsobed, brings a water molecule along for the osmotic ride. - Stimulates the Na-H antiporter - 40-50% of Na reabsorption in the S1 segment of the PT is due to Ang2 - By stimulation of aldosterone - Ang2 that stimulates Aldo comes from the kidney and from the adrenal gland itself - VasoconstrictionJosh talks angiotensin:Tenses the angios--love this Melanie!1961 paper from del Greco (who's endowed chair Dan Batlle has now) trying AT2 in "hopeless" patients and dialysis patients:https://jamanetwork.com/journals/jama/article-abstract/332265Great EM-crit/pulmcrit discussion here:https://emcrit.org/emcrit/deeper-vasopressors-athos-3/and caveats here:https://emcrit.org/pulmcrit/angiotensin-ii/ - Arteriolar vasoconstriction - Ang2 important for raising BP in RAS - Ang2 important in maintaining BP with volume depletion or in CHF, liver disease - Giving ACEi to cirrhosis can cause BP to dump 25 points - Regulation of GFR - Affects constriction at afferent arteriole and efferent arteriole - Mediated via thromboxane JC talks about the ATHOS trial and how there is a signal for improved outcomes especially in patients requiring renal replacement therapy.Angiotensin II for the Treatment of Vasodilatory ShockOutcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II - Afferent arteriole starts bigger so reductions have less of an effect than constriction does on the narrower efferent arteriole. - This results in a fall of RBF due to increased resistance but maintaining GFR by increasing inrtaglomerular pressure. - Also stimulates prostaglandins which are vasodilator, modulating this affectJoel says: You haven't heard of the Trolly Problem? Oh you need to take 5 minutes and read this. - It can stimulate contraction of the mesangium reducing surface area of the glom reducing filtration. - It sensitizes the afferent arteriole to TG feedback so it can reduce glomerular flow in response to increased chloride detection in the TLoH. - Control of renin secretionEver wanted to know about intrarenal renin concentrations? Yeah, me neither. But JC's got you covered: Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. - Primarily sodium intake, increased intake results in less renin - Mediated by baroreceptors - Baroreceptors in afferent vessel wall - Cardiac and arterial baroreceptors which activate the sympathetic nervous system and catecholamines which then stimulates reninRoger says: Do your self a favor and read about Yanomamo IndiansBlood pressure and electrolyte excretion in the Yanomamo Indians, an isolated population - Cells of the macula densa in the early distal tubule which detect decreased chloride delivery - This allows loop diuretics to be particularly effective at increasing renin as they block chloride resorption - Suppression of renin in response to chloride is mediated by adenosine - Stimulation of renin in response to decreased chloride is mediated by PGE - The PGE cause local vasodilation so the kidney maintained a rich blood flow while using renin and Ang2 to cause systemic vasoconstrictionAnna's notes for the deep dive in glomerular barrierOur understanding is based on technology available at the time. Even in 1920s, there was thought that tubular reuptake of protein may be important, but studies never demonstrated this til 2007 and even then are debated. 2007 Russo, et al (and BM at IU!) showed that The normal kidney filters nephrotic levels of albumin and that failure of retrieval by proximal tubule cells is what separates proteinuria from nonproteinuria. This was countered by a study in 2009 demonstrating much lower GSC and suggesting that the high GSC in the 2007 could be the result of nonphysiologic states.Check out this 2008 debate in JASN regarding the validity of the charge model and “normal” albumin in the glomerular filtrate. Hotly debated with too many studies to cite. 2017: Lawrence et al publish their findings that the GBM and podocyte processes are sufficient and the slit diaphragm likely does not exist. They used labeled proteins and confocal microscopy to determine migration of particles through the enodthelium and GBM. They also injected NaSCN oligoclusters from the size of albumin (66kDa)up to the size of IgG dimers (300 kDa) into mice, then fixed. The size-sensitive permeation into the lamina densa of the GBM and the podocyte glycocalyx of albumin and uptake of any “escaping” albumin by the proximal tubule was also observed. This countered the common prior conception that the slit diaphragms pores are the site of albumin “capture.” For your reading pleasure the review of Clinical Physiology of Acid-Base and Electrolyte Disorders Fourth Edition in Annals of Internal Medicine

In this episode the guys are jooined by a friend of Chico's Mr. AT2. You might of heard of AT2 name on the podcast before. Chico has guest spotted on his podcast "Talk the real deal with AT2". The guys jump right into it this week with the recnt interview with Will Smith and Jada Pinkett Smith. Chico calls Jada a predator and taking advantage of August Alsina. Next the guys move onto their homework on if they could replace Mount Rushmore or build a second one who would you put on it? Each of the guys read off their list which is really interesting. Moving on the guys talk about Martha McSally and her thoughts on women getting pregnant to dodge a deployment. Ken breaks it down on why this is bad for any unit. Finally the guys wrap it up with the couple being charged of a hate crime for painting over the Black Lives Matter in the street. Is this really a hate crime? Join the conversation!

Ahmaud Arbery was shot by two men while jogging in his neighborhood in Brunswick, Georgia. I am joined by AT2, Bread Montgomery and Brunswick resident Tonya Armstrong to discuss the issue. Thank you as always for listening and supporting. Don't forget to send topics you would like me to cover. Love ya! #withthatbeingced --- Send in a voice message: https://anchor.fm/withthatbeingced/message

Today's episode is just a short recap of Superbowl and all the events surrounding it. I discuss the game, commercials, The Carters, and more. This is a solo episode that features just me, AT2! Were you going for the Niners or the Chiefs.

It's our anniversary!!! #TTRD turns 1 while AT2 turns "Dirty 1." We get acquainted with a few new guest and reintroduced with some of your favorites!

Part 2: It's our anniversary!!! #TTRD turns 1 while AT2 turns "Dirty 1." We get acquainted with a few new guest and reintroduced with some of your favorites!

Me & Bread Montgomery talk about his start in stand-up and the need to be supportive of each other. The links for Bread and other names mentioned during the episode are listed below.  Thank you for your continued support and feedback.    Bread Montgomery: IG- @bread_montgomery SC:Bat_e202 Katrina: IG- katrinathatsit &IG- themeasurepod Goldie: IG-everything_goldiie & IG: goldengurltalk DBWhit- dbwhits_hot AT2- IG-at2_4real I'm pulling an AT2 on y'all this time because the episode ran a bit long so I split it up in two parts.  --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app --- Send in a voice message: https://anchor.fm/withthatbeingced/message

So much craziness has happened in the month of September. AT2 is here to talk about it all. Let me know if there is any topic I discussed that you would like to speak about on a future episode.

This is AT2's review of night 1 and night 2 of the democratic debates. I try to stay very neutral when it comes to politics but I decided to come out of my shell. I hear so many of my friends say " I don't know who to vote for," "I'm not voting," or "Trump is going to win again." That's why you have to do your research. Now I'm not telling you who to vote for. I'm just hear to guide you along.

I comment on listener questions about Racism, why it isn’t ok to say “White Pride” and we check the voicemail inbox. Be sure to send me something for the Father’s Day Shout outs Check out katrina on “Tha Slay List” —-> https://podcasts.apple.com/us/podcast/tha-slaylist-show/id1379919557 Check out AT2 ——> https://podcasts.apple.com/us/podcast/talk-the-real-deal-w-at2/id1451653148 --- Send in a voice message: https://anchor.fm/withthatbeingced/message

In this episode I conclude the 2019 Texas 70.3 series. I talk with another athlete who was unable to finish the race. Tiffany is such a humble and gracious person overall. We talk about how she trained and raced, but also how the weather turned and how this impacted her emotionally as well. She was on the bike when the storm hit, and this alone is enough to scare most people. This storm was large enough to actually cancel the race and not allow nearly 85% of the field to finish. Family is very important to Tiffany and her husband and the way that she looks forward it is very evident that she has the mental strength to face nearly anything put in front of her. Thank you Tiffany for coming on the show, I enjoyed talking with you!Weather that day: 50-70ishWater: WSL-Age Group: F35-39Height: 4’11.5”Weight: 125Calories per hour: 200PSI for this course: 110Depth of Wheels: StockBike Elevation Gain: 328ftRun Elevation Gain: 220ftSwim: 58:28T1: 7:35Bike: n/aT2: n/aRun: n/aTotal Race Time: DNF-Follow Coach Terry:Instagram: @PerfectRacePodcastFacebook: www.facebook.com/CoachTerryWilsonWebsite: www.CoachTerryWilson.com

In this episode I conclude the 2019 Texas 70.3 series. I talk with another athlete who was unable to finish the race. Tiffany is such a humble and gracious person overall. We talk about how she trained and raced, but also how the weather turned and how this impacted her emotionally as well. She was on the bike when the storm hit, and this alone is enough to scare most people. This storm was large enough to actually cancel the race and not allow nearly 85% of the field to finish. Family is very important to Tiffany and her husband and the way that she looks forward it is very evident that she has the mental strength to face nearly anything put in front of her. Thank you Tiffany for coming on the show, I enjoyed talking with you!Weather that day: 50-70ishWater: WSL-Age Group: F35-39Height: 4’11.5”Weight: 125Calories per hour: 200PSI for this course: 110Depth of Wheels: StockBike Elevation Gain: 328ftRun Elevation Gain: 220ftSwim: 58:28T1: 7:35Bike: n/aT2: n/aRun: n/aTotal Race Time: DNF-Follow Coach Terry:Instagram: @PerfectRacePodcastFacebook: www.facebook.com/CoachTerryWilsonWebsite: www.CoachTerryWilson.com

Today's episode features @iamkatrinac_ (Twitter, IG, SC) from @thaslaylistshow (IG). Katrina and I discuss the latest in celebrity gossip. We also give advice to women as well. This episode is dedicated to all the strong women in our lives. Happy Women's History Month from AT2!

Ced talks to the host of “Talk the Real Deal with AT2” the man himself AT2 about podcasting, blind dates, first time sex and more. Check out https://anchor.fm/AT2 *email the podcast at WTBCed23@gmail.com * #podcast #sex #dating #family #friends #comedy --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app --- Send in a voice message: https://anchor.fm/withthatbeingced/message

Check out “Talk the Real Deal with AT2” https://anchor.fm/AT2 *check me out on Instagram @withthatbeingced *email WTBCed2@gmail.com --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app --- Send in a voice message: https://anchor.fm/withthatbeingced/message

Introduction to Talk The Real Deal w/ AT2

Disclaimer: This is the unedited transcript of the podcast. Please excuse any typos. Jeff:  Welcome back to Emplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta. This month, we’ll be talking Updates and Controversies in the Early Management of Sepsis and Septic Shock. We have a special  episode for you this month… We’ve brought Dr. Jeremy Rose, one of the peer reviewers, and a sepsis expert, on with us to talk through the content this month. Jeremy: Dr. Jeremy Rose here. Thanks for having me in on this conversation.  I’m always happy to talk about this topic because it’s clearly important.  There’s a great deal of confusion around sepsis and I hope that in the next couple minutes we can clarify things in a way that really help your average front line doc trying to get it right. Nachi: So Dr. Rose, before we get started, tell us a bit about your background and your interest in sepsis… Jeremy: I’m the Assistant Medical Director and Sepsis Chair at Mount Sinai Beth Israel in Manhattan.  For those listening, my hospital probably looks a little bit like yours.  We’re busy, interesting, and just a little rough around the edges.  We like it that way.  More importantly, though, we mirror the national averages regarding sepsis.  Roughly half of in-hospital mortality is associated with septic  in some fashion.  Pretty incredible when you think about it.  Half. Jeff:  Sepsis chair... clearly this is an important topic if it warrants it’s own chair at a major hospital in NYC. But getting back to the article this month. This month’s issue was authored by Faheem Guirgis, Laurent Page Black, and Elizabeth DeVos of the University of Florida, Department of Emergency Medicine. Nachi: And it was peer reviewed by Michael Allison, Assistant Director of the Adult ICU at Saint Agnes Hospital, and Jeremy Rose and Eric Steinberg of Mount Sinai Beth Israel. Jeff: So as well all know Sepsis is bread and butter emergency medicine, but, what is sepsis?  It seems that every month or so we have a new guideline, bundle, definition, or whatever… I think it’s best to start with the basics -  At its core, sepsis is a dysregulated response to infection that can be life-threatening. Nachi: Right and it’s the combined inflammatory with immunosuppressive features of sepsis that lead to the devastating organ dysfunction and even death. Optimal management of septic patients has been a source of intense research, stemming from the landmark study by Rivers in 2001. Jeremy, can you give us a little historical context there? Jeremy: Rivers was a real pioneer.  He found a 16% mortality reduction with randomization to an early aggressive care bundle.  Amazing work.  That being said, many components of that bundle have since been disregarded.  For example, Manny Rivers would measure CVP in all of his patients, something we rarely do. Nachi: Not to cut you off and steal your thunder there, but we’ll get to the most recent updates in management shortly. Let’s first talk definitions and terminology, and specifically, diagnosis, which is definitely a big elephant in the room. As Jeff mentioned a few minutes ago, diagnostic criteria have undergone so so so many changes. Jeff: Yes it has! 1991 marked the first standardized definition.  Then in 2001, sepsis-2 was introduced.  In 2014, the Society of Critical Care Medicine and the European Society of Intensive Care Medicine started a task force, and by 2016, updated definitions were out again! Sepsis-3!! A lot of this came after the realization that SIRS was just too broad and was overly sensitive and non-specific. Jeremy, why don’t you take us through Sepsis 3. Jeremy: So just to back up a little and frame this: Here’s the fundamental problem:  As we likes to say, “there’s no troponin for sepsis.”  And if you look at our patients, we tend not to miss the hypotensive, tachycardic, febrile patient.  We know they’re septic.  But how do we find the ones who don’t look as sick.  Frequently elderly, possibly with normal-ish vitals and no fever.  Those can be a lot harder to spot, but they may indeed be septic.  Also, for research purposes we have to have a common definition, so Sepsis 3 came up with something called the SOFA score. The problem with the SOFA score is that its difficult to perform in the ED.  It has parameters like bilirubin that often aren’t available when we want to screen out very sick patients.  Fortunately there is the abridged version qSOFA, which identifies non-icu patients who are at high risk of inpatient mortality. So here it is, and if you get one thing from this episode, this is it: There are ONLY 3 criteria to the qSOFA.  3 Criteria. RR > 22; AMS; SBP 2. So quite a few changes! Jeff: And Jeremy, sticky topic coming up here. Center for Medicare and Medicaid Services (or CMS) quality measures - They haven’t really caught on to and adapted to Sepsis-3 yet, have they? Jeremy:  The CMS mandate is based on the presence of SIRS criteria. Sepsis 3 is based on SOFA.  This is definitely confusing.  Part of the challenge in discussing this topic is separating out the QI guidelines from what is actually relevant to patient care based on the latest evidence-based medicine. Nachi: That seems fair.  We’re really going to put you in an uncomfortable spot for a second and push you here Jeremy. Do you have any insight into why CMS isn’t interested in following the mountains of research that have led to sepsis-3? Is there a reason they are sticking to their current criteria? Jeremy:  I think some of it is the slow pace of bureaucracy and the time that it takes to develop a consensus on management.  Even if we can agree on who is septic, it’s really hard, if not impossible to link the care to a pay-for-performance metric which is what CMS ultimately would like to see.  That’s not how Sepsis-3, or for that matter, SIRS, was designed to be used.  You’re trying to take a tool which was originally designed for research and mold them into a tool used for pay for performance. Nachi: What a struggle. The CMS metrics are slightly different from the 2001 sepsis guidelines also. Take a look at Table 2 of the article for a quick comparison of sepsis-3, 2001 sepsis, and cms side-by-side. And for those on twitter, we’ll be sure to tweet this table out too for your review. Jeff: With so many different scores and definitions, I think that adequately sets the stage for the challenge this month’s authors faced coming up with real evidenced based guidelines. Nachi: Oh absolutely.  And to make matters worse - this is a HUGE problem. We’re talking up to 850,000 ED visits annually in the US, and 19 million cases worldwide. Compounding this, sepsis results in death in approximately 1 out of 4 cases. Not only is it lethal, it is also very costly -- 17 billion dollars per year in the US alone! Jeff: And don’t forget importantly the 30-day hospital readmission rate. Sepsis is coming in at a higher readmission rate and cost per admission than acute MI, CHF, COPD, and PNA. Nachi: Let’s speak briefly on the etiology and pathophysiology of sepsis: we all know that sepsis is due to local infections that then become systemic. Previously, it was believed that the bacterial infection itself was the cause of the clinical syndrome of sepsis. However, we now know now that the syndrome of sepsis is due to the inflammatory and immunosuppressive mediators that were triggered by the infection. Normal immune regulatory safeguards fail and this leads to the syndrome. And interestingly, several studies have shown that critically ill septic patients experience reactivations of specific viruses that were previously limited to patients with severe immunosuppression. Jeff: Definitely something to look out for in your critically ill septic patients.  We should talk  briefly about the most common inciting infections that lead to sepsis. In order, these are: pneumonia, intra-abdominal infections, and urinary tract infections. No surprises there! Nachi: Yeah, that basically parallels my own experience, so that’s reassuring!  That takes us to our next potentially controversial topic - blood cultures.  Jeremy - we’re going to punt this one back to you Jeremy: This is another interesting topic that has received plenty of attention.   CMS loves blood cultures.  It’s an easy metric to track.  That doesn’t mean they’re always helpful.  We looked at our patients with lactates between 2.1 and 4.0 which had “severe sepsis.”  These patients were normotensive though, In other words, the ones that aren’t that sick.  We found that blood cultures are useful about 20% of the time.  That’s not bad.  So what do we do? We draw cultures before pushing antibiotics.  Is that helpful? Sometimes yes, does it waste money?  Debatable.  Does it help us meet our metrics, yes. Jeff: And I think that gets at the crux of the problem here: we don’t want to delay antibiotics on anybody, but we must balance this with the potential harm of further increasing the drug resistant bacterial population via sound antibiotic stewardship.  Remember also that there is a broad differential for sepsis, with several “sepsis mimics”. To name a few, we have PE, MI, CHF, acute pulmonary edema, DKA, thyroid storm, GI bleeds, drug intoxications, and withdrawal syndromes, just to name a few.  In case that wasn’t enough check out Table 3 of the article. Nachi:  And we already mentioned the leading causes of sepsis, that’s pneumonia, intra abdominal infections, and uti’s. But remember the source can be anywhere. Be sure to also think of pyelonephritis, central line associated bloodstream infections, prosthetics, endocarditis, necrotizing fasciitis, and meningitis. Jeff:  I don’t think we need to dwell on this much longer - basically the differential is huge.  Let’s move on to my favorite section - prehospital care. Jeremy: 20 pages of evidenced based recommendations and your favorite is the prehospital section, what’s up with that? Jeff: I’m an EMS fellow, what can I say… Anyway, on to my favorite section -- prehospital care.  This is always a hot topic because the prehospital period is a special opportunity to get early interventions in for septic patients  as 40 - 70% of all severe sepsis hospitalizations arrive via EMS. Nachi: And in one study taking place in a large metropolitan area, prehospital care time was over 45 minutes, and less than  37% arrived with IV access. Of course, these numbers would vary significantly based on where you practice. Jeff: So get this -- one study showed that out-of-hospital shock index and respiratory rate were highly predictive of ICU admission. So clearly early recognition and therapy may play a role here. Another study, however, showed knowledge gaps by advanced EMS providers in diagnosis and management of sepsis. And yet another study showed that only 18 to 21% of confirmed septic patients were suspected of having sepsis by EMS. Out of hospital fluids were started in only half of patients with severe sepsis. In essence, there is likely a strong role here for pre hospital protocols for identifying and treating sepsis. Nachi: In terms of pre hospital treatments though, prehospital IV fluids haven’t been shown to improve mortality, but have been associated with shorter hospital stays. Prehospital sepsis protocols have been described, but in general more research is needed in this area. Jeff: While prehospital care hasn’t yet been shown to improve the prognosis of septic patients, those presenting via EMS do have shorter delays to initiation of antibiotics, IV fluids, and early care bundles. EMS should focus primarily on stabilizing vital signs and providing efficient transport. If it’s possible to establish an IV and initiate fluids without delaying transport, EMS should do that as well. Nachi: And of course, oxygen for the hypoxic patients! Moving on to history and physical for your presumed septic patient. Jeremy, what are the big hitting things here that you always ask and check for, and that you make sure your residents are doing? Jeremy:  After ABC’s and glucose, AMS is really important, it’s in the QSOFA SCORE.  Unfortunately, this can be hard in many septic patients where they’re baseline mental status is less than perfect.  The other thing is to try and find the source.  Finding the source lets you make wise choices about therapy. Jeff:  Great point about the mental status - so many of our older population have an altered baseline, but recognizing changes from that baseline is key. Nachi:  Absolutely, with that in mind, let’s talk diagnostic studies, especially lactate.  Where I trained, basically everybody was getting a lactate, even tired looking residents seemed to be having their lactates checked, and trust me, they weren’t looking that good... Jeremy:  Brace yourself: lactate is really important in septic patients.  That being said, not every cause of elevated lactate is sepsis.  There is this animal called Type B lactic acidosis can come from numerous drugs like albuterol. Just because you see elevated lactate doesn’t mean you can forget about the other causes.  That being said, we know that patients with sepsis do better when they clear lactate. Jeff: Seems like the evidence is definitely in favor of serial lactate testing… Jeremy: For sure.  At least until you have a reasonable trend towards improvement.  We know lactate clearers do better.  We’ve looked at our own lactate numbers.  Interestingly, the takeoff point for sepsis seems to be around 2.5.  Meaning that patients with altered vitals and lactates above 2.5 tend to do worse.  But, there is a broad ddx to elevated lactate.   What is true, though, is that lactate is a marker for badness.  If your patient’s lactate is rising, yours should be too. Nachi: I bet I’m a “lactate clearer”. I may add “lactate clearer to my CV,” sounds impressive.  But I digress…  Next up we have Procalcitonin.   Since procalcitonin becomes elevated in those with bacterial infections, intuitively, this should be a valuable marker to assess in potentially septic patients.  Unfortunately procalcitonin lacks negative predictive value so most literature supports its use in diagnosing pulmonary infections and for antibiotic de-escalation. Jeff: Good to know, I’ve seen it being used a lot more recently and wondered how evidence based this test was. Jeremy:  Honestly, I don’t see Procalcitonin changing ED management at the moment.  If you’re   waiting for Procalcitonin to start antibiotics or fluids, you’re waiting too long. Nachi: Moving on, let’s talk imaging.  Based on current studies, the authors recommend focused imaging only.  In addition, they also note that our good friend, the point of care ultrasound, likely plays a role, as in one study, POCUS demonstrated a 25% improvement in sensitivity from clinical impression alone. Jeremy:  I think there are two ways POCUS comes in.  One, lung ultrasound can be really useful to find that occult pneumonia or differentiating pneumonia from CHF.   Two, your ultrasound is your best tool for assessing volume status.  I try to look at the IVC of all my septic patients and echo them when possible. Nachi: Right.  So now we’ve examined, drawn labs and cultures, checked a lactate, may be obtained imaging… next up we should probably start treating the patient. Whether you like it or not, we have to discuss CMS. Jeremy: Just to clarify before we start.  CMS defines “severe sepsis” as SIRS + infection with a lactate of 2.1-4.0. Septic shock is SIRS + infection with hypotension or a lactate > 4.0. That’s where we’re at. Jeff:  Good point.  Back to treatment: within the first 3 hours, for any patient with sepsis and septic shock, you must measure a lactate, obtain 2 sets of blood cultures, administer antibiotics, and give an isotonic fluid challenge with 30 cc/kg to patients with hypotension or a lactate greater than 4.   Then, within the first 6 hours, you must apply vasopressors to achieve a MAP of at least 65, re-assess volume status and perfusion, and remeasure a lactate. Nachi: This begs the question - are these recommendations evidenced based? Jeremy…. Jeremy: I’m so glad you asked that . Let’s start with fluids. Patient’s need adequate fluid resuscitation.  Interestingly there are 3 large RCT’s, PROMISE, PROCESS and ARISE,  that compared a Rivers type bundle to usual care.  Surprisingly, they showed no difference.  But when your drill down into these 3 trials, you see that “the usual care,” now generally includes at least 2 liters of fluid. Jeff: Ok, so it seems that there is some pretty good data to support a rapid fluid challenge of at least 30 cc/kg.  But how do we determine who needs more fluids and how much more they need.  There must be an endpoint to all of this? Jeremy: Another million dollar question. 30cc/kg is probably a good place to start.  How much is too much?  I think we need to be smart about our fluids.  Some patients will need less and some will need much more.  So, I remind my resident’s to be smart about fluids.  Sono an IVC, trend a lactate, follow a urine output, do a passive leg raise, even check JVP.  I mean just because you haven’t seen a unicorn doesns’t mean they’re not real.  Do something to monitor volume status. Nachi: Very important. Put your ultrasound skills to work here. They’ll only improve as you practice more.  Jeff, let’s get started on the ever important topic of antibiotics. Jeff: Sounds good.  Current guidelines recommend that broad spectrum antibiotics be administered within the first hour of presentation for those with sepsis or septic shock, ideally with blood cultures being drawn beforehand. In one study, every hour of delayed abx administration was associated with an 8% increase in mortality.  Since this 2006 study, other studies have had mixed results - with studies showing increased odds of death with delays in abx administration and others showing only a benefit in those with septic shock with or without hypotension with no benefit to those without shock. Nachi:  In terms of antibiotic coverage - you need to consider the site of infection, local resistance patterns, the presence of immunosuppression, and the patient’s age and comorbidities.  Table 5 of the article is very thorough and should be kept as a quick reference. Jeremy do you have any specific recommendations for our listeners on how we should approach antibiotic usage in the septic patient? Jeremy: I like to think about antibiotics a little more simply than referencing a table.  I ask a couple questions.  Does my patient need MRSA coverage ?  Does my patient need Pseudomonal coverage?  If the answer is no and no, then narrow your coverage.  You don’t necessarily have to use a bunch of Vanco, or a big gun antipseudomonal like Pip/tazo.  Also, have a look at your local antibiogram.  I can’t tell you how many times this changes prescribing habits for even things like simple UTIs.  I’m going to stray into some controversial territory here. The benefits of sepsis protocols are measured one patient at a time, but the harms are only measured in the aggregate.  What does that mean?  CMS metrics have caused us to  use to use more broad spectrum antibiotics.  As a result, we’re seeing more resistance.  My resident’s tell me to make it easy, give em VZ (that’s vanco/zosyn) and it kills me.   Every time you put a Z-pack into the world a pneumococcus gets it’s wings. So think more about your antibiotics, and know your local biograms. Jeff: That’s a great way to think about it, I fear I’ve given a lot of pneumococci wings during my training…  Next we’re on to vasopressors.  The data is pretty clear on this one - norepinephrine is the recommended first line vasopressor for septic shock.  In numerous trials comparing Norepi to dopamine, NE was far superior, with dopamine increasing arrhythmias in one trial and associated with an increased risk of death as compared to NE in another trial. Jeremy:  So here’s a question I get all the time: How can I give Norepi without a central line.  Let’s use Dopamine, its safe peripherally.  Ok, so follow that through.  We’re going to give a drug to increase blood pressure by constricting blood vessels, but don’t worry, it’s safe peripherally.  What does that mean?  It means it doesn’t work!!  It doesn’t give much blood pressaure.  Dopamine is a lousy pressor.  It causes a lot of tachycardia, which is not what you want in failing septic hearts.  So what do we do if we don’t have a central line?   We start norepi peripherally into a large bore IV for the time it takes us to get a central line.  That’s where the evidence is.  There’s a mortality benefit to NE over dopaine in septic shock. Jeff:  Right, this month’s authors note peripheral pressors may be safe for brief periods in settings with close monitoring.  While this is commonplace in some hospitals, others haven’t yet jumped on that bandwagon. I think it’s important to mention that this is becoming more and more commonplace, even in the prehospital realm.  With the service I fly for, we routinely start peripheral vasopressors without hesitation.  But this isn’t limited to the air.  Many ground 911 services have also adopted peripheral vasopressors in a variety of settings. Nachi: I’m sure there are many trials to come in the future documenting their safety profile, but moving on to the next pressor to discuss... vasopressin. This should be your second line vasopressor for septic shock.  In the VASST trial, low-dose vasopressin was found to be noninferior to NE.  In other trials, vasopressin also appeared to show a potential benefit in those with AKI and sepsis, although the subsequent VANISH trial (perhaps the best name for a clinical trial so far) failed to demonstrate a benefit to vasopressin titration with regard to renal outcomes in septic shock. Vasopressin has also been shown to reduce NE dosing when administered at a fixed dose of 0.03-0.04 units/min. Jeff: Next we have epinephrine.  In one study epinephrine and NE were equivalent in achieving MAP goals in ICU patients with shock, however several of those receiving epi developed marked tachycardia, lactic acidosis, or an increased insulin requirement.  The increasing lactic acidosis could confound the trending of lactates, so in those requiring inotropy in addition to some peripheral squeeze - the authors recommend adding dobutamine to norepinephrine instead of starting epinephrine. Although, keep in mind, this can lead to some hypotension so remember to start at low doses. Nachi: Phenylephrine, a pure alpha adrenergic agent, is next and should be considered neither first nor second line, but it may have a role as a push dose agent while preparing other vasoactive agents. Jeff: And lastly, we have angiotensin 2.  One recent 2017 study examining the role of angiotensin 2 in those with septic shock already on 0.2 mcg/kg/min of NE found that those receiving AT2 had significant improvements in MAPs as well as cardiovascular SOFA score at 48h with no difference in mortality.  Unfortunately, these benefits do not come without risk as AT2 may increase risk of arterial and venous thrombosis and potentially thromboembolism.  Clearly, one study isn’t enough to change practice, but it’s certainly food for thought. Nachi: So that wraps up vasopressors. Jeremy, we’re on to corticosteroids -- another hotly debated topic. When do you give steroids in sepsis? Jeremy:  Hmmm steroids, this is an age old question.  No study has clearly supported the blanket use of steroids in septic shock. Several like CORTICUS and ADRENAL showed no difference.  I will use hydrocortisone for pressor refractory shock. Meaning, you’ve tried everything else, so you might as well try.  Also, I do tend to avoid Etomidate, given the possibility of adrenal suppression and that there are several other induction agents, notably Ketamine  that don’t have this problem. Jeff: Those trials are certainly important, thanks for bringing them up - Especially with all the FOAM content out there, it’s incredibly important to look back at the data to understand where certain recommendations are coming from.   Anyway… one quick note on blood transfusions before we move on to special populations - Although part of the original early goal directed therapy, thanks to data from the TRISS trial which showed no difference in outcomes with a transfusion goal of 7 vs 9, transfusions are reserved for those with a hbg of less than 7. Jeremy:  One population we should make sure to mention and be careful with is end stage liver disease.  In the ER, we tend to miss SBP alot.  Mostly because these patients have lots of reasons to be sick and they already have elevated lactate because of their deceased clearance.  My practice is to give a dose of Ceftriaxone and sent a diagnostic tap to patients who are sick and have ascites. Nachi: Alright Jeremy, let’s talk controversies in sepsis. We’re giving you all the big questions this month! Jeremy:  We’ve already talked about fluids and how much to give.  Just a reminder that a history of CHF doesn’t preclude proper fluid resuscitation.  I think broad spectrum antibiotics for relatively well patients is a big controversy.  Our national rates of antibiotic resistance are terrible, and yet we’re using more antibiotics all the time.  There are very few if any antibiotics coming down the pharma pipeline and we’re going to have to face the music eventually.  Finally, we need national metrics that mirror clinical evidnece.  Protocols should be a tool and not a crutch.  You know what’s best for the patient in front of you, so don’t let metrics or protocols make you do things you think are not in your patient’s best interest. Nachi: So how do you escape the hospital protocols and CMS and do what’s best for your patient without “getting in trouble”? Jeremy: Here’s how I deal with it as the one who reads and QI’s all of our sepsis charts. I tell my colleagues to do what’s right, and if you need to deviate from the protocol tell me why.  As long as you can explain your decision, I’ll support it.  Explaining your thinking is good clinical practice and is good medico-legal practice. CMS has been unable to link these metric  to payment, simply because no hospital can meet them with any regularity.  It’s important that we advocate for our patients or nothing will change. Make them respect you for the highly educated professional that you are, and your patients will ultimately benefit. Jeff: Preach!! And before we close out with disposition, there are a few new therapies and trials on the horizon to keep a lookout for. The RACE trail examined the role of L-carinitine.  The VICTAS trial is looking at vitamin C, thiamine, and steroids in sepsis.  The CLOVERS trial is looking at early vasopressors vs a crystalloid liberal strategy.  And lastly, IL-7 is also being investigated.  All really cool stuff that could change how we manage sepsis in the future.. Nachi  A few quick notes on disposition before we close this episode out.  Certainly not all patients meeting SIRS require admission, but many do.  Those with qSOFA of 2 or higher represent a sick population and an ICU admission should be considered.   Even for those with a qSOFA of 1 but a lacate over 2 -- they have a mortality approaching that of patients with a qSOFA of 2.  Be careful just sending a patient who is on the fence to the floor because several studies have demonstrated that patients who are later upgraded have worse outcomes. Jeff: That’s in line with the general themes we’ve laid out today - definitely better to start early with aggressive care rather than play catch up later.  Jeremy - in 30 seconds or less, what are the most salient points in the management of sepsis that you would like our listeners to take with them from this episode. Jeremy:  Here are my take aways: qSOFA, RR, AMS SBP < 100 Norepi, not Dopamine - it doesn’t work! Be smart about fluids!! Be smarter about antibiotic use! You are the best advocate for your patient, despite what anyone else says! Jeff: Excellent, so that wraps up the October 2018 episode of Emplify. A big thanks to Jeremy Rose for joining us. Jeremy: Thank you for having me!!! It was great talking with you. Nachi: For our listeners -- additional materials are available on our website for Emergency Medicine Practice subscribers. If you’re not a subscriber, consider joining today. You can find out more at www.ebmedicine.net/subscribe. Subscribers get in-depth articles on hundreds of emergency medicine topics, concise summaries of the articles, calculators and risk scores, and CME credits. You’ll also get enhanced access to the podcast, including the images and tables mentioned. You can find everything you need to know at ebmedicine.net/subscribe. Jeff: And the address for this month’s credit is ebmedicine.net/E1018, so head over there to get your CME credit.  As always, the ding sound  you heard throughout the episode corresponds to the answers to the CME questions. Nachi: Lastly, be sure to find us on iTunes and rate us or leave comments there. You can also email us directly at emplify@ebmedicine.net with any comments or suggestions. Talk to you next month!

I begin my journey through the IRONMAN© Canada weekend with my friend and Louisiana Native Michelle Myer. Michelle shares her experience about this race and while it was a tough day and she was unsuccessful in completing the race, she will go back. She points out that she trained her best and showed up on race day at the very best ever going into this race. There is a lot to learn from Michelle’s experience. Thank you for sharing your race with me and I look forward to following you Michelle!Enjoy the show. To see pictures from her race, go to https://www.coachterrywilson.com/perfectrace/109-Weather that day: 55-96Water: 55-Age Group: F 50-54Swim – 1:40:03T1 – 7:30Bike – n/aT2 – n/aRun – n/aTotal Race Time: DNF-Follow Michelle,Facebook: Michelle Myer-Follow Coach Terry:Instagram: @CoachTerryWilsonInstagram: @PerfectRacePodcastFacebook: www.facebook.com/CoachTerryWilsonWebsite: www.CoachTerryWilson.com

I begin my journey through the IRONMAN© Canada weekend with my friend and Louisiana Native Michelle Myer. Michelle shares her experience about this race and while it was a tough day and she was unsuccessful in completing the race, she will go back. She points out that she trained her best and showed up on race day at the very best ever going into this race. There is a lot to learn from Michelle’s experience. Thank you for sharing your race with me and I look forward to following you Michelle!Enjoy the show. To see pictures from her race, go to https://www.coachterrywilson.com/perfectrace/109-Weather that day: 55-96Water: 55-Age Group: F 50-54Swim – 1:40:03T1 – 7:30Bike – n/aT2 – n/aRun – n/aTotal Race Time: DNF-Follow Michelle,Facebook: Michelle Myer-Follow Coach Terry:Instagram: @CoachTerryWilsonInstagram: @PerfectRacePodcastFacebook: www.facebook.com/CoachTerryWilsonWebsite: www.CoachTerryWilson.com

I conclude my series of the IRONMAN© Boulder with my new friend Brian Aubuchon. He is such an amazing person and I’m truly in awe of how humble he is and how much perseverance he has. In case you didn’t catch the video prior to Boulder this year, he was the athlete in the video where Bek Keat and Siri talked about him in pursuit of his finish line. He had toed the line of five IRONMAN© races prior to Boulder without officially completing any of them. His journey has many struggles, hardships, and even more happy memories made along the way. At Boulder he unfortunately did not get his finish. Keeping in mind he is a father of five amazing children, two of which have autism, and a loving wife that supports him. Not including the fact that he is the owner of two bowling alleys. With a lot on his plate, he is still going to become and IRONMAN© one day and this is only a snapshot of his journey along the way. I look forward to following Brian at IRONMAN© Mont Tremblant. This is by far one of the most information packed episodes I’ve done so far!Enjoy the show. To see pictures from his race, go to -Weather that day: 67 - 95Water: 67-Age Group: M 40-44Height: Weight: 260lbsCalories per hour: 480PSI for this course: 105F-110RSwim – 1:56:58T1 – 12:35Bike – n/aT2 – n/aRun – n/aTotal Race Time: DNF-Gender Rank: n/aDivision Rank: n/aOverall Rank: n/a-Follow Brian,Instagram: @HollyLanesFacebook: Brian Aubuchon-Mentioned on this episode:Peaks Apparel: https://peaksapparel.com/Siri Lindley: https://www.teamsiriustriclub.com/Team Sirius Tri Club: https://www.teamsiriustriclub.com/ -To learn more about me, go to www.CoachTerryWilson.com

I conclude my series of the IRONMAN© Boulder with my new friend Brian Aubuchon. He is such an amazing person and I’m truly in awe of how humble he is and how much perseverance he has. In case you didn’t catch the video prior to Boulder this year, he was the athlete in the video where Bek Keat and Siri talked about him in pursuit of his finish line. He had toed the line of five IRONMAN© races prior to Boulder without officially completing any of them. His journey has many struggles, hardships, and even more happy memories made along the way. At Boulder he unfortunately did not get his finish. Keeping in mind he is a father of five amazing children, two of which have autism, and a loving wife that supports him. Not including the fact that he is the owner of two bowling alleys. With a lot on his plate, he is still going to become and IRONMAN© one day and this is only a snapshot of his journey along the way. I look forward to following Brian at IRONMAN© Mont Tremblant. This is by far one of the most information packed episodes I’ve done so far!Enjoy the show. To see pictures from his race, go to -Weather that day: 67 - 95Water: 67-Age Group: M 40-44Height: Weight: 260lbsCalories per hour: 480PSI for this course: 105F-110RSwim – 1:56:58T1 – 12:35Bike – n/aT2 – n/aRun – n/aTotal Race Time: DNF-Gender Rank: n/aDivision Rank: n/aOverall Rank: n/a-Follow Brian,Instagram: @HollyLanesFacebook: Brian Aubuchon-Mentioned on this episode:Peaks Apparel: https://peaksapparel.com/Siri Lindley: https://www.teamsiriustriclub.com/Team Sirius Tri Club: https://www.teamsiriustriclub.com/ -To learn more about me, go to www.CoachTerryWilson.com

In this episode, Dr Matt & Dr Mike cover the most common anti-hypertensive medications and how they work! Expect to hear about beta-blockers, calcium channel antagosnists, AT2 receptor antagonists, ACE inhibitors, diuretics, and more!!!!

Fast Times At In Beta High : In Beta is going back to school, HIGH SCHOOL! @QueenKellz87, @CEOHaize and @At2_4real all step in to share some high school stories down MEMORY LANE Fame Black pitches new classes for students and of course, a very high school playlist IB

In Beta welcomes you to Wakanda! If it was a real place! We’ve redecorated the set and changed up the furniture so sit down and get comfy as we get a clip from “The Awakened Soul” reviewing BLACK PANTHER. Fame Black and AT2 debate Black Panther as well. FACTS SEGMENT: CHRISTOPHER COLUMBUS Jam Of The … Continue reading In Beta: Wakanda Isn’t Real

Merry Xmas! This weeks post was inspired by a recent unexpected case of severe hyperkalaemia in a severe pre-eclamptic - I have put together a fictitious case which is a little more severe in order to illustrate the principles of managing hyperkalaemia - I hope you enjoy & take it easy over Xmas! CASE HISTORY (*A fictitious patient history ) Your pager goes off - code blue medical labour ward! On arrival you are told the patient for whom the code was called has just arrived following an urgent transfer from another hospital. She presented to their service at 31 weeks with a headache, BP 190/100, proteinuria and mildly raised creatinine. She was diagnosed with severe pre-eclampsia, given labetalol, nifedipine and then transferred. She now appears confused with the following vital signs: HR 33/min, BP 74/55, SpO2 92%, RR 17/min (*Image courtesy www.lifeinthefastlane ) An immediate venous blood gas shows the following result: Na 139, K 8.4, pH 7.23, pCO2 37, pO2 63, Lactate 1.8 How are you going to manage this patient?   Immediate Standard Mgmt 1 - Is it real? Common causes of high potassium includes hemolysis of red cells from the sampling and handling process.  Always do an ECG whilst awaiting a repeat result - if the patient is compromised and the ECG is abnormal / consistent with hyperkalaemia then assume it is real and don't delay your treatment! The quickest way to get a repeat sample is usually a VBG this usually only takes a few minutes and will also give you the glucose and pH - important values to know for both mgmt and diagnosis. 2 - Prevent an arrhthymia Immediate mgmt - stabilise the cardiac membrane with intravenous calcium. Most guidelines recommend calcium if there are ECG changes or the absolute K level is over 7mmol/L. *Calcium chloride has 3 times more calcium than calcium gluconate. 3 - Shift K intracellularly a) Insulin / Glucose. Usual dose 10units actrapid + 25-50ml 50% Dextrose Stimulates Na/K/ATPase Give glucose to prevent hypoglycaemia' Lowers K by 0.5 -1 mmol/L per hour b) Salbutamol 20mg neb Good choice if the patient is bradycardic (common in severe hyperK) Stimulates Na/K/ATPase also c) NaHCO3 (if acidotic) When acidosis exists H+ is exchanged for intracellular K+ Makes sense to consider NaHCO3 if acidosis is present 50-100ml of NaHCO3 8.4% 4 - Eliminate K from the body (usually renal) - Enhance renal elimination - diuretics (e.g. frusemide), K free crystalloid (if indicated - saline) or both! - Dialysis - institute early in patients with complete renal failure -  GI exchange resins (eg resonium) most guidelines now consider they have no role in the acute management. 5 - Identify and treat the cause! - You need to address this issue to stop if from recurring! Usually multiple factors combine to lead to hyperkalaemia. Fix reversible causes especially drugs! Don't rely on your memory - get their medication chart out then google all the known drugs that can cause hyperkalaemia! Drugs Known to Cause / Contribute to hyperkalaemia (either impair excretion or promote transcellular shift) ACE inhibitors / AT2 antagonists Spironolactone / Amiloride NSAIDs Beta blockers (see discussion below) Trimethoprim Heparin Pentamidine Suxamethonium Renal dysfunction - almost always there is a degree of renal impairment preventing excretion of the excess K load. Make sure you aren't missing important reversible causes - e.g. obstruction (consider USS renal tract urgently).  Cell release (eg hemolysis, tumour lysis, trauma or extensive surgical injury). In our O& G patients this includes widespread tissue injury especially after major surgery or perhaps chemotherapy. BUT This is a pregnant woman with PET - renal impairment, acidosis, hemolysis, transfusion - these are common events in our pregnant patients. Cardiac Arrest Secondary to Hyperkalaemia

“In Beta” is back with a new logo, a new intro,, a new announcer and the SAME ATTITUDE! AT2 and Fame Black discuss Thanksgiving and new developments. They also ask the question: Is Tinder/Plenty of Fish/ OK Cupid dating sites or hook up sites? In Beta ep.11

No white noise, no transitions, no holding back! Fame Black and AT2 talk about one subject all episode and ask a very important question: What would you do if a good friend’s partner came on to you?  Go to @inbetapodcast on Instagram to leave your thoughts and comments! In Beta ep. 10

“I Barely Watch TV” Fame Black and AT2_4real chat about religion, but venture off on TV before it gets too deep. They discuss all the reboots coming to air, plus all the cool things Netflix has to offer. Finally, they talk about “Single Levels” and what they mean. In Beta ep.9

The Creepcast is back! AT2 and Fame Black speak on name calling in the bedroom,  as well as how many slaps SHOULD an ass be taking? Also the debut of the “Question of the Pod” What would you do if an old lover asked you to help give sex advice to their new partner? Comment … Continue reading In Beta Episode 8: Creepcast #2

WARNING: LISTENER DISCRETION IS ADVISED! Fame and AT2 discuss the finer points of everyone’s favorite adult topic: sex! Put the kids to bed and strap in…or on? In Beta ep. 4

At KansasFest 1992, Tom Weishaar presented this prerecorded interview he conducted with Steve Wozniak, co-founder of Apple Computer Inc. and inventor of the Apple II. This recording, digitized by Antoine Vignau, was originally distributed by Resource Central (catalog product number AT2-31) and has been generously reclassified under a Creative Commons 3.0 Attribution License. A video […]

GateWorld catches up with SG-1 actress Amanda Tapping at Gabit's AT2 event in London!