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Hemoglobin is 11.2. Sorry. Okay. Touch on the low side, I guess. Okay. A little bit low. So then the first thing is we want to know why is it low, right? Because whenever we see someone with an abnormal platelet count, you want to know, is it an isolated thrombocytopenia or is it with something else? And so let's say we work that up a little bit. Iron studies are normal. The RITIC counts a bit low, what you'd expect for a hemoglobin that's low, but nothing too crazy. And her multiple sclerosis has kind of been quiescent. And her medications, have they changed recently? Not really. Just what you see here. She's been on them kind of consistently. Or maybe we take the hemoglobin out of it. Because I think in real life, it's often like, you know, it's rare that they would just have the isolate. Okay. So we have someone with isolated thrombocytopenia, right? So the question would be, you know, is it a platelet production problem or is it a platelet destruction problem? And so that's like the first question that we're getting at. When someone has isolated low platelet count. Oh, before you go on to that, should we do the Paul Williams method? Well, we've repeated it, but do we need to do the EDTA thing, like the whole... What? That's the method? No, no, no. Sorry. Do we have to always go down that to send a different tube in order to make sure this is real? So your question is, is this real or not? Yeah. Right? So yes. Right. But do you have to do that using a different tube? Not necessarily. Right. So normal CBCs run with an EDTA purple top tube. The problem is that sometimes the platelets can kind of like bunch together or cause what we call platelet clumping. You can detect this on a peripheral blood smear. Right. So when you're looking at the peripheral blood smear, the platelets should be kind of nice and spread out. But if all of a sudden you see like a bunch of platelets just like lumped all together, that would be what we call clumping. And that could give you a falsely low platelet count. Okay. And so one way to get around that would be to run it through a blue top tube, right? The same kind of tube that you would send coags, you know, and that's a citrated tube and gets rid of the clumping issue. And I'm sorry, I cut you off as you were going in. You were talking about the platelet destruction or the platelet production problem. So what's next in your algorithm there? So then I typically think of other things, right? So could this be ITP as kind of a diagnosis of exclusion? For ITP, there's really two things that you have to cross off the list, HIV and hepatitis C. But then there are other things that could cause thrombocytopenia as well, right? So B12 and folate deficiencies, thyroid disorders, liver dysfunction, particularly if they might have cirrhosis. My husband's a hepatologist and he says that's very frequently someone's primary presentation of cirrhosis with, you know, portal hypertension and splenomegaly. Sometimes H. pylori infection has been associated with thrombocytopenia. Although I've treated plenty of H. pylori and haven't seen the platelets come up, interestingly enough. And then you want to, you know, see if there's other things going on, other rheumatologic disorders. This patient has MS, which might be an autoimmune condition, which might make you think of other autoimmune conditions. And so those are the things that I'm thinking about in the back of my head. So the hypersplenitis, you were talking about with cirrhosis, there's hypersplenism where portal hypertension is just sort of causing blood to kind of pool in the spleen and the platelets are being just stored in there? Is that the idea? So I think they're more being like captured maybe by the spleen, right? As the spleen is becoming enlarged. Yeah. Are there any medications that raise your eyebrows or particular culprit meds that you worry about when you see platelet count like this? Yeah. So like the big scary ones are heparin, right? Because HIT and thrombocytopenia, no matter what the actual platelet count is, if it's, you know, falls a certain percentage from their baseline and the timeline is right, that's pretty scary. So certainly heparin products, chemotherapy in my world. But also, you know, even things like maybe, you know, Zantac or possibly, you know, antidepressants, antibiotics, many, many, many medicines are associated with thrombocytopenia. And so we look for those culprit medicines as well. So before, let's say we checked HIV, it's negative. We checked hep C, it's negative. When I was looking this up, it said if the patient has dyspepsia, they would send the H. pylori study. But I like your point that you haven't really seen it make much difference in the platelet count anyway. I've diagnosed a lot of H. pylori this week. You have done? Okay. Yeah. Okay. Anything, and we did our peripheral smear to kind of look at the platelets. Is there anything else? Like what about if they don't have any features of like a connective tissue disease, do you, do you bother sending ANA in those type of labs or the, the ASPEP? Can you comment on that? Yeah. So, um, you know, you mentioned earlier on that, um, I did, you know, some research in multiple myeloma. And so a lot of my patients get ASPEP. Yeah. We might have to have you back for multiple myeloma. No joke. But I think those are very reasonable. But I don't know that I would necessarily send to ANA if they didn't have symptoms of a connective tissue disorder because I don't think you can make a diagnosis without symptoms, right, of lupus or other connective tissue disorders. I have kind of a question as an aside. So we do serotonin release assays for platelet function. The medications that you had mentioned that cause thrombocytopenia typically either block or increase the endogenous levels of serotonin. Is it the actual, is it, are these specific serotoninergic medications themselves that are associated with thrombocytopenia, or is it just a correlation or association that's been found? Is there something with the serotonin that's affecting platelet function that then is causing destruction? That's a great question, and I don't know the answer. I know that these medicines are on a list that cause thrombocytopenia. The list is long, though. I'm not sure about the mechanism exactly. That is such a classic Stuart question. It just harkens back to some of the research that I'm participating in. Okay. I'm going to look at the database again. I think we need to at least think about wrapping up. Oh, actually, I promised I would ask you this question, and then you can go into your take-home points. What is the most annoying thing that general internists send to you? Like what can we do better? Give us some feedback. Constructive, please. Of course, yeah. I have one. One pet peeve. All right. Please repeat a CBC if it's abnormal. Such good advice. This is like Paul's best day. It's like the best day of Paul's life. Sometimes we'll get referrals for abnormal counts, low or high, whatever. But when they show up in our office, it's completely back to normal again. And it's pleasant. They think we've done a great job. But maybe unnecessary. Yeah. Their primary care is probably like, I'm going to send you to Mary. She's going to do a bone marrow biopsy. And then they get there. You repeat the CBC, you're like, you don't need to do anything. And then they give you a big hug and you seem, you're the hero. So wait, so what are you complaining about? Her Joe scores are so great now. Okay. Why don't you give us your take-home points? So the take-home points, we talked about a lot of different things.
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I would say the take-home point is this, is do a really good history and physical exam because I think most of what you, you could narrow down your differential so much just by that history and physical. Even if you can't feel the spleen tip like Paul? Even if you can't feel the spleen tip, but you have to try to feel the spleen tip a lot of times, and then eventually you will feel it. Did you hear that, Paul? Paul's also working on his POCUS skills, so I think it's going to be fine. He's got a pocket ultrasound now. He'll be good. And then also think about if it's one cell line that's elevated or multiple cell lines that's elevated or low. Because if it you know, neutropenia or just isolated thrombocytopenia, that totally changes your differential from if it would be like two cell lines down or three cell lines down, because that makes you more think about a bone marrow problem. And then let me think. For erythrocytosis, please check an EPO level first. I think that takes you down two very different pathways. And then I actually think those are my big take-home points. All right. Thank you so much. I don't think anyone's ever complained about a conference ending on time. No, I don't think so. Actually, before we get rolling, I did want to ask Dr. Kwok if you had any disclosures that you would like to have. Yes, I have a disclosure. I should disclose that these are my personal views and do not represent those of the Army or the Department of Defense. Should we record an outro? Yeah, we can. Okay, go ahead. Yeah, this feels like a lot of pressure. All right. This has been another episode of The Curbsiders, bringing you a little knowledge food for your brain hole. Yummy. Get show notes at thecurbsiders.com forward slash podcast and sign up for our mailing list at thecurbsiders.com forward slash knowledge food to get our weekly show notes in your inbox. That's right, Paul. We're committed to providing you with high-value practice-changing knowledge. And to do that, we need your feedback. So please subscribe, rate, and review the show on iTunes or contact us at thecurbsiders at gmail.com. A special thanks to our producers for this episode. Any producers who helped the show notes and figures for this episode. I don't know who's going to help with this one. And to our social media team, Hannah R. Abrams on Twitter, Beth Garb, Garba Telly on Instagram, and Crystal Chumanchu on Facebook. Until next time, I've been Stuart Kent Brigham. I've been Dr. Matthew Frank Watto. I'm Dr. Mary Kwok. And I remain Dr. Paul Nelson-Williams. Thanks. Goodbye. All right. What are you, what? I don't know. This thing's not working at all. Well, you have to make deep eye contact when you're in your person. Like, that's not necessary. This is pretty much how most recordings go. A little bit of infighting that I cut out before I send it out to iTunes. How does this not work? Do other presenters have the same issue with this thing? Did I not predict that this would be a sideshow with him and the thing?
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All right, welcome. My name is Devine. This is episode 476 of the Devine Intervention Podcast. In today's podcast, we're going to be continuing the Rapid Review Series for the USMLE Step 2 CK and Step 3 exams. This is going to be Series 100. That's a big milestone, Series 100. Let's just get right into it. Now, what if they give you a question about a 20-year-old female? They tell you that she has never had menses before. They tell you that her breasts are Turner stage 5 but her axillary and pubic hair are Turner stage 2. What should you be thinking about? What's your diagnosis? Well I would hope you're saying that Divine, this sounds an awful lot like androgen insensitivity syndrome, AIS. I remember our friends at the USMLE, sometimes they call this a different name. They call it testicular feminization syndrome. Just be careful of that. Remember our friends at the USMLE and this whole business with derivatives. Really, take what you know and just give it a bunch of different names. So just be careful, right? Androgen insensitivity syndrome is the same thing as testicular feminization syndrome. So what are the key details of this disorder? Well, the critical detail here is that these people genotypically, right, at the genetic level, they're actually male. They're actually 46XY. But phenotypically, at the I am looking at you level, they look female. So what's the pathophase behind this disorder? Well, the pathophase behind this disorder is that the testosterone receptor is not working great. If your testosterone receptor does not work great, then you won't respond to testosterone. So on the outside, you're not going to look male. You're not going to look male on the outside. You're going to look female. Because remember, testosterone doing its job is what causes the wolfian dots to develop many of the male internal structures. And, you know, DHT also kind of makes you look male on the outside and stuff like that. So for the most part, these people just really struggle with the testosterone receptor. So again, genotypically, they're males, but phenotypically, they're females. And one common cause of concern on step two, step three is, man, Devine, how do I tease this apart from malaria and Agenesis? You know, many people know about malaria and Agenesis, where, you know, sometimes it's called Meyer-Rokitansky-Kosterhauser syndrome, MRKH syndrome. You should learn malaria and Agenesis. That's kind of like the big thing. But if you notice here, the critical thing with malaria and eugenesis is that these people, their malaria dots just does not form for whatever reason. But one critical thing that people forget, and you'll see this as a very critical point of differentiation, is that malaria and eugenesis, when you have malaria and eugenesis, you still have intact ovaries. You still have intact ovaries. So these people on the genetic level, they're actually women. And phenotypically, they're also women. So they're 46XX and phenotypically, they're also women. So their malaria duct does not develop, but they still have ovaries because the ovaries are not derived from the malaria duct. So because the ovaries are still intact, these people are going to be making good amounts of estrogen from the granulosa cells, and they're going to be making good amounts of testosterone from their thicker cells. So honestly, these people, they have good breasts. So let's say the person is like in their 20s, and they have primary amenorrhea. They're going to have good breasts. So their Tanner stage for their breasts will be pretty advanced. But also the Tanner stage for the pubic and axillary hair will also be advanced. It'll be like tanner stage four or five. Because again, estrogen controls your breasts. Androgens control your pubic and your axillary hair. People that have AIS, androgen insensitivity syndrome, they don't have any estrogen problem. So their breasts look great. But their pubic and axillary hair does not look good because they have an androgen issue. On the flip side, people that have malaria and Agenesis, their breasts are great because estrogen is not a problem, and the axillary and pubic hair is also great because androgens are also not a problem. That's a very critical difference between these two things. And again, another critical difference, which I've mentioned already, is that people that have AIS, they are genotypically 46XY, but phenotypically females. But people that have malaria and agenesis, they are genotypically 46XX, and phenotypically, they're going to be females as well, right? And again, you know, people that have androgen insensitivity syndrome, you may wonder, okay, Devine, so why do they not have menses? Well, the thing is, if you remember, one of the things that are produced by the testes is this thing called malarian inhibiting factor. Sometimes it's called anti-malarian hormone or malarian inhibiting hormone. All different things for the same things. It's going to basically nuke your malarian duct, right? So because it nukes the malarian duct, you will not produce those malarian structures. And what are the things that are derived from the malarian duct? Well, it's going to be your fallopian tubes your your uterus your cervix and your upper vagina all those things do not develop when you have ais because those testes those that gonad because the person is 46 xy is producing amh or mif or mih whichever name you you know the floats your boat and that's going to basically nuke the malaria duct. And you won't produce any derivative of the malaria duct. So why do people that have malaria in Genesis also... Because think about it. It's kind of hard to have kids if you don't have uterus. But if you also look at it from the flip side, in malaria in Genesis, again, the malaria duct does not develop. So they don't have fallopian tubes, no uterus cervix no upper vagina they don't have any of those things again kind of hard to have menses when you have no no uterus right but again if you notice the gonad in people that have ais is like a test is a testes the gonad in people that have malaria genesis is an ovary again these things i feel like people over complicate them uh They're just like two or three things that help you differentiate them. And the USMLEs, many times, they'll include adequate information for you to differentiate these two things. Okay. Now, what if they give you a question on, in fact, let's maybe do a few vignettes related to the anemias, right? So what if they give you anemia in a person that has lost weight and the person is over age 50, right? And let's say the person, they tell you that a hemocote test is positive. Well, we want to think about some kind of GI malignancy, right? In that case, you probably want to think about some kind of iron deficiency anemia. Remember, iron deficiency anemia causes some microcylic anemia, right? And again, your stores are depleted. So your ferritin is going to be low. If your ferritin is low, then you're going to be hungry for iron. TIBC, your total ion binding capacity is going to be pretty high. And your transferrin saturation, again, transferrin literally shuffles iron around in your blood. You don't have enough iron, so it's not going to be full. So you're going to have a decreased transferrin saturation. Now, what if they give you a question about a person that's from Vietnam? And this person has a microcytic anemia. And they tell you that many family members are transfusion dependent. And they give you a blood smear. You see target cells. Although many times they don't do that anymore in exams. But they can also just say that, oh, they perform hemoglobin electrophoresis. And you notice that, well, the hemoglobin A2 is elevated. If you see that, then obviously this person has beta thal major. Remember, beta thalassemia is another cause of microcytic anemia. And again, you're going to see target cells on a blood smear. Now, beta thalassemia, for this person to be transfusion dependent, it pretty much tells you that the person likely has beta thal major, right?
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So if you have beta thal minor, one gene is kind of screwed up. So, you know, you still have one gene that's kind of helping out, right? But beta thal major is where both are messed up. So you essentially don't have any beta globin. If you don't have any beta globin, you're going to have a helping out, right? But beta-thalmogen is where both are messed up. So you essentially don't have any beta-globin. If you don't have any beta-globin, you're going to have a few problems, right? Like number one, you won't be able to make adult hemoglobin because adult hemoglobin is alpha-2, beta-2. Well, it's kind of hard to make alpha-2, beta-2 if you don't have beta-globin genes, right? But these people have an increase in hemoglobin A2. Hemoglobin A2 is alpha-2, delta. Alpha 2, delta 2. Clearly, that does not involve beta globin genes. So the person is going to be fine, right? I'm telling you this. There are many causes of increased hemoglobin A2. But on the USMLE Step 2, Step 3 exams, if you see an increase in hemoglobin A2, they're pretty much testing some variant of beta thalassemia. If the person has very significant symptoms, they're transition dependent, it's probably beta thal major that they have. They probably do not have beta thal minor. And one thing I also want to say here is between the two, because obviously there are two kinds of thalassemias. There's the alpha thalassemias and there's the beta thalassemias. The thing is, when people think of hemoglobinopathies, they always think that, oh, every kind of hemoglobinopathy is diagnosed with hemoglobin electrophoresis. That is absolutely not true. Okay. Sickle cell disease is in fact diagnosed with hemoglobin electrophoresis. Beta thalassemia is in fact diagnosed with hemoglobin electrophoresis. But it is floridly high yield to know that you should not do hemoglobin electrophoresis for alpha thalassemia because hemoglobin electrophoresis may distort, basically it may be normal. You may notice actually it's normal in many people that have alpha thalassemia. Well, why is that? Because the thing is, I kind of think of the alpha globin gene, the alpha globin chain, as almost like a rate limiting step of every kind of hemoglobin, right? I mean, think of any notable hemoglobin you know contains alpha chains, right? Like hemoglobin F is alpha 2 gamma 2. Adult hemoglobin is alpha 2 beta 2, which is hemoglobin A. Hemoglobin A2 is alpha 2 delta 2, right? So the thing is, hemoglobin electrophoresis is almost like a test of proportions. So because pretty much all your major hemoglobins have alpha chains in them, if you have a deficiency of alpha chains, then everything will be proportionately decreased. So you will not see any proportional differences in the kinds of hemoglobins for most kinds of alpha thalassemia. But if you look at beta thalassemia, for example, the thing is beta is only found in one kind of hemoglobin, adult hemoglobin, alpha-2, beta-2, that's hemoglobin A, right? So if you do hemoglobin electrophoresis, you'll notice that, man, this person's hemoglobin A is pretty low, but the others are kind of going through the roof. Because again, these ones do not include the beta-globin chain. So again, it's very, very high yield to know that beta-thalassemia can be diagnosed with hemoglobin electrophoresis. Alpha-thalassemia absolutely cannot absolutely cannot be diagnosed right so we've talked about like the two big causes of microcytic anemia i've talked about iron deficiency anemia we've talked about thalassemia the other one i'm going to talk about is it's going to be lead poisoning right so usually on the exams they'll give you some question about a person you know that's maybe like an immigrant or they deal with like old pottery or the person who works with car batteries, stuff like that. When you see something like this, think of lead poisoning. And many times, they're going to have peripheral neuropathy and abdominal pain. That's very high yield to know. Peripheral neuropathy and abdominal pain. Because why do you think lead poisoning causes microcytic anemia? Well, here's the thing. Here's the thing. In general, if you have any problem with the synthesis of heme or globin, you will get microcytic anemia, right? Literally, if you have any problem with the synthesis of heme or globin, you will in fact have a microcytic anemia. Well, why is that? Well, think about it. The thing is hemoglobin, look at the name, hemoglobin, it's made of heme and globin. Well, globin, we've talked about it at the genetic level, right? Globin is made from a gene, you know, transcribe said gene, make mRNA, translate said mRNA, make protein, right? Fine. So that's the globin part. We've talked about that part, right? Because again, the thing is, if you're able to organize things in your head, it's just a lot easier to remember these things, right? But if you have a globin problem, well, you're going to have a hemoglobin problem. So you're going to have microcytic anemia. If you have a heme problem, then you will not be able to make hemoglobin. And that's also going to cause microcytic anemia, right? And I will explain why that microcytosis is a thing. Because many people just kind of memorize it, but there's actually some pathophase there. I'll give you like a pretty good description of why that happens. But if you look at the heme, so we said that hemoglobin is heme plus globin. I've talked about the globin part. The heme part, heme is made of iron plus protoporphyrin. Iron plus protoporphyrin, right? That iron, if you have a deficiency of iron, you have iron deficiency anemia. You're going to have a reduced, you're going to have a microcylic anemia from that. So we've talked about that part. But the other part is the protoporphyrin part. Well, protoporphyrin is made in the heme synthesis pathway. And the thing is, lead, it just so happens that it kind of crushes two key enzymes in that pathway. It crushes ALA dehydratease, aminolevolinic acid dehydratease. And it also shuts down our ferrochilates. Ferrochilates actually is what combines iron and protoporphyrin to make heme, right? So because lead inhibits those processes, it's going to cause people to have, it's going to cause people to have a microcytic anemia, right? So why do these problems with hemoglobin synthesis specifically cause microcytic anemia? Well, the reason that they specifically cause microcylic anemia is that typically red blood cells, like the thing is, let me introduce a concept. I mean, I've talked about this in previous podcasts, but it's a concept that I should talk about here. It's actually very important. Many things in the body are not controlled necessarily by just amount. They are controlled by concentrations. I'm going to say that again. Many things in the body are not controlled necessarily just by amount. They are oftentimes controlled by concentrations, right? So the thing is, we know that concentration is mass over volume. Many of you remember this from general chemistry, you know, C equals M over V. Concentration is mass over volume. Well, the thing is, mass in a red blood cell many times is constituted by hemoglobin. Volume, right, is, you know, the dimensions of the cell. So the thing is, your body wants to keep your hemoglobin concentration fairly constant, right? Your body wants to keep hemoglobin concentration fairly constant. At least this is the way I love to think about it.
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Because if you think about it, the numerator going down is causing the concentration to dip. Well, if you want to bring that concentration back almost to like a state of homeostasis, the denominator of that fraction has to go down as well, right? Because if you think about it, if you decrease volume, then you can bring concentration back up. Because again, by having thalassemia or iron deficiency or lead poisoning, your mass of hemoglobin is going down. That's bringing down your concentration. You don't want that. You want to bring that concentration back to homeostasis. So what are you going to do? You're going to crush the volume of the cell, make the cell smaller so that even that smaller amount of hemoglobin will still give you a decent amount of concentration. Because you may wonder, Divine, why does concentration matter? Concentration matters because many things in the body work with a gradient. Many things with the body work with a gradient. Things have to go from an area of high concentration to an area of low concentration, right? That's how things flow, right? And again, you know, you may think the red blood cell is just like some tiny cell, no one cares. Well, you should care because here's the thing. If your red blood cells don't work great, you're going to have tissue hypoxia. And tissue hypoxia carried over time can lead to heart failure. It can just cause many things to not work right, right? It can cause many, many things to not work right. So this stuff is kind of important to keep at the back of your mind, okay? So the red blood cell basically reduces in size, almost like a compensation for the reduced amount of hemoglobin. So that's why you're going to get a microcytic anemia. That's why you're going to get a microcytic anemia. You know, anemia of chronic disease kind of straddles both edges of things. You know, it's kind of like, how do I put it? Sometimes it can be normocytic. Sometimes it can be microcytic. Usually we're going to find it in people that have like chronic inflammatory diseases, right? Like Crohn's disease, ulcerative colitis, scleroderma. You see a person has like some kind of vasculitis, right? Or you see a person has like rheumatoid arthritis. All these chronic inflammatory diseases, they can all cause that problem, right? Anemia of chronic disease, right? Even anemia of chronic disease, believe it or not, again, it can be normocytic, but it can also be microcytic, right? The big agent there, obviously, is hepcidin, right? Hepcidin pretty much does two things to you. One, you don't reabsorb iron in your gut. And two, it pretty much prevents your bone marrow macrophages from releasing the iron you have. So your iron stores are good. Your ferritin is actually pretty high, but your TIBC is low, right? Because again, when your body sees inflammation, it thinks that, wow, bacteria are around. And the thing is, bacteria, they do actually need iron to survive. So if you keep the iron in the bone marrow macrophages, the bacteria will clearly, what bacteria wants to go inside a macrophage? Sounds like a death wish, right? So the bacteria will not want to, you know, if you keep that iron away from the bacteria, they will not reproduce and that would help, right? So anemia of chronic disease, right? It's caused by hepcidin. It's a cytokine that kind of does those things. So your ferritin is going to be high. Your TIBC is going to be low. And again, transferrin, again, like I said, is the protein that shuffles iron around in your bloodstream. If the iron is stuck in your bone marrow, in those bone marrow macrophages and not in your bloodstream, then that's going to cause you to have a decrease of transferrin saturation. If you're thinking about normocytic anemias, many people just memorize all this less and less and less. But honestly, normocytic anemias, the easy way to categorize them is as follows. One is the anemia hemolytic. If a person has some kind of hemolytic anemia, or if they have anemia from chronic kidney disease, all those things are going to be your normocytic anemia. So any kind of hemolytic anemia, right, like hereditary psoriasis, that's a hemolytic anemia. Hereditary lymphocytosis, that's a hemolytic anemia. Autoimmune hemolytic anemia, right? Like hereditary cirrhosis cytosis, that's a hemolytic anemia. Hereditary lipocytosis, that's a hemolytic anemia. Autoimmune hemolytic anemia, that's going to be a normocytic anemia, right? If a person has kidney disease, if you have CKD, well, you're not going to be making EPO because EPO literally is made in your kidneys. If you don't make EPO, then you'll be able to stimulate your red blood cell precursors or you're going to get in a lot of trouble, right? You're going to get in a lot of trouble with anemia, right? You're going to get in a lot of trouble with anemia. Remember, hereditary sclerositosis is more of an autosomal dominant disorder. You know, spectra and ancrein, those band proteins, you notice that those are red blood cell membrane proteins. So these people, there's no problem with their hemoglobin, right? The problem is with the red blood cell membrane. In fact, that's why the MCHC is up. The hemoglobin is fine, but the size of the membrane of the red cell is diminished, right? So going back to that concentration business I discussed, the MCHC is going to go up, right? And again, because the hemoglobin is so concentrated, if you dump it in hypotonic solution, that red blood cell literally will explode. That's essentially the basis of the osmotic fragility test that we see with a hereditary spherocytosis. Although these days, we also love this eosin-5-malamide acid, right? And then if you're thinking about macrocylic anemias, if you're thinking about macrocylic anemias, right, you want to think about B12 deficiency, Foley deficiency, right? Those things inhibit DNA synthesis. And again, you may wonder, okay, why will inhibiting DNA synthesis cause me to have macrocytosis? Well, let me explain. If you think about it, when your DNA synthesis happens, you know, like during the S phase, right, you know, of the cell cycle, right? I know, surprise, surprise. You're studying for step two, step three, you're like, oh, gee, divine S phase, wait, what? Yeah, yeah, yeah. Those things you learned back in the day after step one are kind of important, or, you know, maybe back in undergrad, actually. So, you know, so the thing is, as DNA is being synthesized, if you notice, when, you know, mitosis is about to happen, for example, the cell actually does increase in size. Because if you think about it, the cell, when mitosis happens, the cell is basically going to be splitting into parts. Well, if you want to split into parts and you want the parts that you're making to be the same size as the ancestor, then you better believe that that cell is going to get bigger. Right. But the thing is, the way I think of B12 or folate deficiency is that these people kind of hit a roadblock of some sort. Right. They're like, man, OK. Gee, like, OK, the cell is getting bigger and bigger. Hmm. This is getting bigger and bigger. Gee, this cell is getting bigger and bigger. But man, where's the DNA that we can use to separate, you know, make DNA material for this new cell, DNA material for this new cell? So you kind of have a bottleneck there because the cell is getting bigger, but the DNA synthesis is not catching up with that size of the cell. You end up having a macrocytic anemia. That's actually a nice way to kind of think about it, right? That's a very nice way to think about it. So just kind of categorize these things in your mind.
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They can have subacute combined degeneration of the spinal cord where the corticospinal tract and the dorsal columns does not work. So they're going to have upper motor neuron symptoms. And then you're also going to notice that they're going to have problems with fine touch and proprioception, right? Fine touch and proprioception, right? And also vibratory sensation. So they're going to have all those problems. They're going to have all those problems. And you know, they're going to have like an increase in their homocysteine, and they're also going to have an increase in their methylmalonic acid levels. Because remember, methylmalonyl-CoA mutase, right? It's an enzyme that converts methylmalonyl-CoA to succinyl-CoA. It uses vitamin B12 as a cofactor, right? It doesn't use folate at all, right? So that's why folate deficiency, the only thing it does is that it raises your homocysteine. Folate doesn't do anything to your methylmalonic acid levels. Okay, so this is a rapid review. I'm going to go ahead and stop here. If you're taking step two or step three or step one anytime soon, I have classes that literally start tomorrow, right? I literally have a biostatistics class it's a four-hour class it's for step one two step three it's tomorrow it's a four-hour class if you're interested it's in the evening shoot me an email i'll give you some more information and then i have a social sciences ethics quality improvement health care systems communications professionalism class it's a five-hour class that one is actually going to be taking place on Friday. It's a five-hour class. It's going to be taking place on Friday evening. Again, if you're interested, it's for step one to step three. Shoot me an email. And then I have a test-taking strategies class also for step one to step three. That's on Saturday. It's also in the evening. It's from like 5 to 7.30 p.m. Pacific time. All these classes are over Zoom. If you're interested, just shoot me an email. I'll give you some more information. And then if you're taking step two or step three, you're trying to get your scores before the ERA deadline or whatever, I have a class that starts next week. It's going to be next week, Monday, Tuesday, Thursday, and Friday. Next week, Monday, Tuesday, Thursday, and Friday. 20-hour class for step two, step three. And also, if you're taking your shelf exams and you want a very good board of review, that class is exactly what you need. Again, there are many people that have taken these classes, done extremely well. And these classes are not lectures. They are pretty much all based on scenarios. Pretty much all based on scenarios. Many people have taken these classes. Again, like literally, I've gotten emails. I get emails almost every day. Wow, they've gone into 260s, 270s or whatever after taking these classes. These classes are all scenarios, lots of integration, lots of explanation of pathophase. So I think it's something you're going to find to be helpful. And then finally, I do offer these podcasts on the major apps, Apple, Google, Spotify. I have a YouTube channel, Divine Intervention, USMLE Podcasts and Videos. That's where I post the videos that I make. And then I also have, I also offer one-on-one tutoring for all the USMLE exams, you know, like med school exams as well and shelf exams. And I help with ERAS applications, right? You know, personal statements, rec letters, editing your ERAS applications, supplemental applications, doing mock interviews. And then I also have another website called divineinterventionalifelessons.com. Many people have been like, wow, Devine, I love your life lessons. So I set up from a separate website. It's Bible-based. Many of you know I'm a Christian. It's a Bible-based website. And right now we have like, I think almost 210 podcasts. I post like two podcasts every week. Just check out divineinterventionlifelessons.com. There's actually an Apple podcast associated with that called the Divine Intervention Life Lessons Podcast. Okay, so thank you for listening to me today. I hope you find this stuff to be helpful. I promise you this episode 100 is actually pretty high. I mean, this rapid review, you know, series 100 is actually pretty high yield. So I will see you in episode 477. God bless you. Have a wonderful rest of your weekend. Bye for now. Thank you.
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Welcome back to the USMLEguides podcast. My name is Dr. Paul. In today's episode, we're doing a short 15-minute rapid-fire drill session on the topic of microbiology. The session will be broken down into six rounds of approximately 10 questions, with each round touching on a different subtopic, and you'll get five to seven seconds to come up with your answer. If you find this type of rapid review strategy to be beneficial in helping you solidify your knowledge of the most important and high-yield USMLE Step 1 exam facts and details, be sure to check out how we can help you get ready for your Step 1 exam by visiting USMLEguys.com. When you're done with today's drill session, don't forget to download a free copy of my Medical Student Survival Guide, which will help you better understand how you can position yourself for success on your USMLE exams and to match into your dream residency program. Now, let's dive in with today's high-yield USMLE Step 1 drill session. Round 1. What is the most common cause of community-acquired pneumonia? Answer. Strep pneumonia. Which organism is responsible for causing a skin infection that presents with honey-colored crusts? Answer. Staph aureus. Which organism is known for causing scarlet fever following a case of infectious pharyngitis? Strep pyogenes. Which organism is most likely responsible for food poisoning following ingestion of reheated fried rice? Bacillus cereus. Which gram-positive organism is associated with urinary tract infections in young, sexually active women? Answer. Staph saprophyticus. What severe form of diarrhea and colitis is associated with antibiotic use? Answer. C. difficile-associated diarrhea. Which gram-positive organism is responsible for a foodborne illness that is particularly dangerous in pregnant women? Answer. Listeria monocytogenes. Which gram-positive-related syndrome is characterized by desquamation and rash, especially around the mouth, hands, and feet? Staph scalded Skin Syndrome Which gram-positive rod can result in myonecrosis and gas production in the tissues? Clostridium perfringens Round 2 What's in the outer component of the gram-negative bacterial cell wall that contributes to its unique staining properties? Answer, lipopolysaccharide. Which structural component of gram-negative bacteria acts as an endotoxin and can trigger septic shock. Answer. Lipid A. What is the name of the space between the inner cytoplasmic membrane and the outer membrane in gram-negative bacteria? Answer. Periplasmic space. What type of protein channels are found in the outer membrane of gram-negative bacteria, allowing for the passage of small molecules? Answer, porins. Which gram-negative bacterial component is specifically targeted by polymyxin antibiotics? Answer, the outer membrane. What is the main component of the inner cell membrane of gram-negative bacteria, similar to other bacteria? Answer, phospholipid bilayer. In gram-negative bacteria, what is the thin layer located between the inner and outer membranes that provide structural support? Answer. Peptidoglycan. What structure on the surface of many gram-negative bacteria aid in its attachment to host cells? Answer. Pili, or fimbria. Which gram-negative bacterial structure is involved in DNA transfer during conjugation? Answer. Sex pillus. Which bacterium is the most common cause of urinary tract infections? Answer. E. coli. Round 3. What is the primary cell wall component of the bacterium responsible for tuberculosis? Answer. Mycolic acid. Which outer membrane component acts as an endotoxin in the bacterium causing typhoid fever? Answer, lipopolysaccharide. What is the major structural component of the cell wall in the bacterium responsible for strep throat? Answer, peptidoglycan. Name the specific part of the outer layer responsible for the unique staining properties of the bacterium that causes whooping cough. Answer, lipopolysaccharide. This is Bordetella pertussis. What is the key cell wall component of the bacterium causing diphtheria? Peptidoglycan. This is carine bacterium diphtheria. What is the primary cell wall polysaccharide of the bacterium causing cellulitis? Peptidoglycan. This is Staph aureus. Name the outermost layer component that is a target for antibiotics in the bacterium responsible for gonorrhea. Answer. Lipopolysaccharide. This is Neisseria gonorrhea. What is the distinctive cell envelope lipid of the bacterium that leads to leprosy? Answer. Mycolic acid. Which cell wall structure is thick and retains the primary stain in the bacterium causing anthrax? Answer. Peptidoglycan. This is Bacillus anthracis. Round 4. Which organism produces a toxin that increases intracellular cyclic AMP in enterocytes, causing watery diarrhea? Answer. Vibrio cholera. Which bacterium forms a pore-forming toxin that leads to cell lysis and is a common cause of food poisoning? Answer, Staph aureus, produces the alpha toxin. Which organism utilizes a type 3 secretion system to inject effector proteins into host cells, leading to cell death and intestinal invasion? Answer. Salmonella species. Which bacterium's virulence factor inhibits protein synthesis by deactivating elongation factor 2, leading to cell death? Answer, C. difficile. This is toxin B. Which organism produces a toxin that degrades cellular GTPases, leading to actin depolymerization and cell rounding in host cells. Answer. C. difficile. This is toxin A. Which type of E. coli adheres to and effaces intestinal mucosa leading to diarrhea without toxin production? Answer. Enteropathogenic E. coli, also known as EPEC. Which organism deactivates snare proteins at the neuromuscular junction, resulting in muscular paralysis? Answer. Clostridium botulinum. Which class of bacterium releases endotoxins that activate the host immune system, leading to inflammation and potentially septic shock? Answer. Gram-negative bacteria. This is due to the lipopolysaccharide in their outer membrane. Which organism secretes enzymes that break down hyaluronic acid in connective tissue, facilitating spread through host tissues? Answer. Strep pyogenes. Round 5. What common adverse effect is associated with aminoglycosides like gentamicin? Answer, autotoxicity. Which class of antibiotics is known for potentially causing tendonitis or tendon rupture? Answer, fluoroquinolones. What is a frequent GI side effect of broad-spectrum antibiotics like amoxicillin? Answer, diarrhea. Which antibiotic, often used for MRSA infections, can cause reddening of the skin? Answer, vancomycin. What hematologic adverse effect is associated with the use of chloramphenicol? Answer, aplastic anemia. Which antibiotic class can cause QT prolongation leading to potentially fatal cardiac arrhythmias? Macrolytes. What eye-related reaction can occur with the use of tetracyclines? Phototoxicity What serious mucocutaneous reaction may occur with the use of sulfonamides? Stevens-Johnson syndrome Which class of antibiotics is most commonly associated with allergic reactions? Answer. Beta-lactams. What neurological adverse effect is associated with the use of metronidazole? Answer. Peripheral neuropathy. Round six. How does methicillin-resistant Staph aureus exhibit resistance to beta-lactam antibiotics? Answer. Altered penicillin-binding proteins, PbP2a, with reduced affinity for beta-lactams. What mechanism of antibiotic resistance is commonly seen in gram-negative bacteria like Pseudomonas aeruginosa? Answer, efflux pumps. Through what genetic means do bacteria, including both gram-positive and gram-negative, often acquire resistance to multiple antibiotics simultaneously? Answer. Plasmid-mediated resistance. What is the mechanism by which vancomycin-ADLAC or DALADSER, preventing vancomycin binding. How do some gram-negative bacteria, like certain strains of E. coli, become resistant to cephalosporins and penicillins? Answer. Production of extended-spectrum beta-lactamases. What mechanism of resistance allows bacteria, such as Mycobacterium tuberculosis, to survive exposure to drugs like rifampin? Answer. Alterations in the RNA polymerase target, reducing drug binding. How does C. difficile exhibit resistance to certain antibiotics, leading to overgrowth and infection? Answer.
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In what way do some gram-negative bacteria resist the effects of aminoglycosides. Answer Enzymatic modification of aminoglycosides, such as acetylation, phosphorylation, or adenylation. What resistance mechanism is employed by gram-positive bacteria like Staph epidermidis to evade the effects of methicillin? Answer. MECA gene encoding altered penicillin-binding proteins. How do some gram-negative bacteria exhibit resistance to carbapenems? Answer. Via the production of carbapenemases, which are enzymes that hydrolyze carbapenems. of your friends or colleagues who you think could also benefit from listening to the podcast and free drill sessions. And of course, if you need help with your own step one prep, be sure to learn how you can work with me directly by visiting usemlyguys.com. And don't forget to check the show notes to download your free copy of my medical student survival guide. Thanks for stopping by. I will see you on the next episode.
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Hello and welcome to the Annals of Internal Medicine podcast. This is Dr. Christine Lane, Annals Editor-in-Chief, and I'm here to share highlights from the August 21, 2012 issue with you. The accuracy of screening methods, the incremental benefits of early detection, the effectiveness of treatment, and the harms of screening and treatment. A few studies showed that screening resulted in increased hearing aid use, but none examined whether it improved emotional and social functioning, communication ability, or cognitive function. While no studies evaluated adverse events of screening for hearing loss, screening and confirmatory testing for hearing impairment are non-invasive and serious harms of treatment are rare. So the task force concluded that there are likely little to no adverse effects of screening for hearing loss. In the end, however, with many existing research gaps, the task force could not recommend for or against screening for age-related hearing loss in the primary care setting, leaving primary care physicians to base screening decisions on their and their patients' preferences. These recommendations apply only to screening asymptomatic patients. Physicians should, of course, evaluate any patient who presents with a reported hearing impairment for potentially treatable causes. Second-generation antipsychotics for treating schizophrenia were developed to address the safety and efficacy issues associated with first-generation antipsychotic agents. Today, three-quarters of adult patients prescribed antipsychotic medications for schizophrenia take second-generation agents, accounting for 93% of the $2.8 billion spent each year on these medications. But questions have emerged about whether there are clinically important differences in patient outcomes between first- and second-generation agents. Aiming to answer these questions, researchers at an agency for healthcare research and quality-funded evidence-based practice center reviewed 114 studies involving 22 comparisons of first- and second-generation agents, and analysts published their findings online first on August 14. The researchers assessed differences in symptoms, adverse events such as diabetes, mortality, tardive dyskinesia, and major metabolic syndrome in adult patients with schizophrenia and related psychosis and found little research to support clear benefits of second- versus first-generation antipsychotic agents and insufficient evidence to compare the safety of these medication groups. The researchers conclude that the current evidence is inadequate to inform clinical decisions. In 2011, 40 years of investigation into lung cancer screening came to fruition with the National Lung Screening Trial. This trial found that in persons at high risk for lung cancer, three rounds of annual screening with low radiation dose CT scanning reduced the relative risk of lung cancer death by 20% when compared to chest x-ray screening. A commentary published online first on August 14th argues that the 20% relative benefit observed in the National Lung Screening Trial is not the most relevant metric to a person who is considering screening. Authors, Drs. Peter Bach and Michael Gould, illustrate that the potential benefit of screening varies by several orders of magnitude across individuals who differ in their baseline risk of lung cancer mortality. They estimate that the number needed to be screened to prevent one lung cancer death varies from 82 to over 35,000. Read the full article on annals.org. Now on to the August 21st issue. The first article in this issue concerns colorectal cancer risk following colonoscopy. Risk of subsequent colon cancer following polyp removal is known to be associated with biological characteristics of the polyps that are removed. However, to date, studies have not examined whether colonoscopy-related factors also contribute to subsequent cancer risk. This population-based case control study found that colonoscopy-related factors, such as the interval until the next colonoscopy and completeness of polyp removal, also predicted subsequent cancer. These observations suggest that future studies should evaluate whether improving colonoscopy performance reduces the risk of subsequent colorectal cancer after polyp removal. Current U.S. national standards consider blood levels of lead less than 1.2 micromoles per liter to be acceptable. However, there is evidence that some lead-associated diseases occur at levels lower than this accepted standard. The second article in the August 21st issue reports a large population-based study in which the risk of gout increased with increasing blood levels even within the range of lead levels considered to be acceptable. The findings suggest that there is no safe level of lead exposure and very low levels of lead may still be associated with health risks. Future studies should assess whether efforts at further reducing exposures to lead will result in health benefits. In an accompanying editorial, Dr. Ash Siegel, Analyst Associate Editor for Nephrology, discusses these findings in light of other evidence of the health risk of low-level lead exposure. He writes, lead and its myriad uses will remain an integral part of our external environment. However, both children and adults deserve an internal environment that is as unleaded as was our evolutionary past. As Bakken-Gould noted in the online first article I spoke about a few moments ago, we currently lack useful strategies to determine which patients will benefit from computed tomography-based lung cancer screening. One such method is the Liverpool Lung Project Risk Model. The next study reported in this issue validated the Liverpool Lung Project Risk Model in three populations of patients who underwent computed tomography screening for lung cancer and then used decision analysis methods to determine the performance of the model with regard to maximizing net benefit of screening. The researchers found that the model performed well in predicting clinical benefit across a range of thresholds of possible risk compared with other approaches to risk stratification. Such analyses may help in planning the implementation of lung cancer screening programs. In an accompanying editorial, analyst statistical editors Russell Lacalio and Stephen Goodman note that how well an algorithm or test predicts or diagnoses disease is an inadequate measure of its clinical usefulness. They applaud the current study because it uses decision modeling methods to address the question, are people better or worse off if the test or algorithm is used in clinical care? Next in the issue are two systematic reviews that both address lipid-lowering therapy in the setting of chronic kidney disease. The first review summarizes evidence from 18 trials that reported on cardiovascular kidney and adverse outcomes associated with lipid-lowering therapy in persons with chronic kidney disease. It found that lipid-lowering therapy does not improve kidney outcomes, but does decrease the risk for cardiac mortality, cardiovascular events, and myocardial infarction. The authors note that a high degree of heterogeneity among available studies precludes conclusions regarding whether therapy influences all-cause mortality. The second review explores whether the effects of statin therapy in persons with chronic kidney disease vary with severity of kidney disease. The authors reviewed 89 trials and found that statins decrease mortality in cardiovascular events in persons with early stages of chronic kidney disease, have little or no effect in persons receiving dialysis, and have uncertain effects in kidney transplant recipients. Read both reviews at annals.org and test your knowledge and earn CME credit with the quizzes that accompany them. Next is an update that summarizes studies published in 2011 that the authors consider highly relevant to the practice of hematology and medical oncology. Read this update and those for other specialties on annals.org. Next is an academia in the profession article that initially appeared on annals.org in July to coincide with the release of the innovative curriculum that it describes. Postgraduate trainees have historically received little specific training in the stewardship of health care resources and minimal feedback on resource utilization and its effect on the cost and quality of care. This article describes a new curriculum developed by the Alliance for Academic Internal Medicine and the American College of Physicians to address this training gap. The curriculum introduces a framework for delivering high-value care and focuses on teaching trainees to incorporate high-value, cost-conscious care principles into their daily clinical practice. It is important to note that the curriculum aims to be fun and interactive, involving games such as team-based efforts to reduce the cost of a patient's medications upon hospital discharge. Thank you. Next in the issue are two commentaries. The second commentary reflects back on the Physician Charter for Professionalism that the American Board of Internal Medicine Foundation, the American College of Physicians Foundation, and the European Federation of Internal Medicine released 10 years ago. The charter aimed to promote contemporary principles of medical professionalism. The authors take stock of the charter's accomplishments and where challenges to physician professionalism persist. The issue includes an On Being a Doctor essay and an ad libitum poem. Go to annals.org to read them both or to listen to a recording of Annals' associate editor, Michael Lacombe, reading them. As always, the second issue of the month includes ACP Journal Club. Go to annals.org for summaries of a dozen articles that your internal medicine colleagues rated to be of high quality and of high clinical relevance. While you're at annals.org, you can also link to journalwise.org to learn how you can register for a personalized medical literature alerting service fed by the same engine that feeds ACP Journal Club. That's all for this issue. Stay well and thanks for listening. Thanks to Chris Capuccio, Andrew Langman, and Neil Cole for providing technical support for this podcast.
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Welcome to the October 21st, 2014 Annals of Internal Medicine podcast. I'm Dr. Christine Lane, Annals Editor-in-Chief, and I'll be summarizing Annals' most recent issue, as well as several articles that we published online first since the last podcast. On October 14th, as the Ebola epidemic raged on in West Africa and cases occurred in the U.S. and in Spain, we published a commentary that urges caution in the use of experimental medications and vaccines in the management of Ebola, despite such use being judged as ethical by a World Health Organization advisory panel. Go to annals.org or the iPad edition to read why these authors fear that the use of these experimental agents could lead to poorer outcomes for the treated severely ill, missed opportunities for realistically treatable patients, and a possible induction of drug resistance. The FDA's cost-benefit analysis of its proposed cigarette labeling regulation has a major flaw, according to another Ideas and Opinions piece published online first on October 14. Federal agencies proposing any significant regulatory action are required to evaluate Thank you. deter consumers from smoking. Among other components, cost of implementation, FDA administrative and enforcement costs, the FDA included the cost to consumers or consumer surplus. The consumer surplus is the pleasure smokers derive from smoking over and above the price they pay for cigarettes. A group of prominent health economists say that including lost pleasure from tobacco use as an element of economic impact is flawed thinking because most tobacco users derive little consumer surplus from smoking. Rather, they struggle with trying to break an addiction, regret having ever started smoking, and face psychological costs from being addicted and unable to quit. These authors urge the FDA to consider this reality in future economic evaluations of proposed tobacco regulations and outline why they fear that application of similar methods threatens implementation of other public health regulations. Although high-value care that balances benefits of tests and treatments against potential harms and costs is a recently emphasized competency for internal medicine residents, it is challenging to assess residents' knowledge in this domain. On October 14th, we published an article that described the development of a high-value care subscore from a set of 38 items of the 340 questions including on the Internal Medicine in Training Exam, or IMITE. The IMITE is a multiple choice examination developed by the American College of Physicians in collaboration with the Alliance for Academic Internal Medicine to help residents, along with their program directors, assess their knowledge of internal medicine and identify areas for improvement. The authors found that the high-value care subscores correlated most strongly with overall IMITE performance, but there was also some association between program-level subscores and the Dartmouth Atlas hospital care intensity for the hospital where the residents train. The subscore also correlated to residents' attitudes about high-value care, with positive attitudes associated with more favorable high-value care subscores. Now on to the October 21st issue. Genetic and Environmental Risk Assessment, also known as JIRA, uses genetic and environmental information to identify an individual's risk for a disease and has been suggested as a means to motivate adherence to recommended cancer screening and other health-related behaviors. The first article in the October 21st issue is an innovative randomized controlled trial that evaluated whether individualized Jira of colorectal cancer susceptibility improves adherence to screening in average-risk persons. The researchers hypothesized that providing average-risk patients with a personalized genetic and environmental risk assessment would increase colorectal cancer screening uptake compared with usual care. They randomized about 780 participants at average risk for colorectal cancer who were not adherent to screening at the time of the study to usual care, or JIRA. Based on specific combinations of genetic and environmental risks, JIRA participants were informed whether they were at elevated or average risk for colorectal cancer. After six months, there was no significant difference in screening uptake between the two groups. The researchers suggest that their findings debunk a common claim in the media that enhanced knowledge of individual genetic makeup will promote a healthier lifestyle. Apparently knowing their individual risk for disease was not enough to persuade previously non-adherent patients to undergo recommended colorectal cancer screening. In an accompanying editorial, J.S. Blumenthal-Barbee and Amy McGuire from Baylor and Peter Yubel from Duke note, quote, much energy and money are being invested to integrate genome-wide testing into routine clinical care to improve health, but achieving this goal may be more difficult than anticipated, end quote. More than 500,000 incarcerated persons in the United States have chronic hepatitis C virus infection. The recent availability of short-duration, highly efficacious treatments may enable incarcerated patients to receive a full course of treatment for hepatitis C while in prison. The authors of the second article in the issue sought to analyze the cost-effectiveness of sofosbuvir for hepatitis C virus treatment in incarcerated populations. The results suggest that sofosbuvir-based treatment is cost-effective for this population, although its affordability may be an issue. Delirium is common in hospitalized older patients, but it often goes undiagnosed. Widely used since the 1990s, the confusion assessment method, or CAM, test is regarded as an accurate assessment tool for delirium. However, the CAM can be challenging to use in clinical settings because it requires cognitive assessment and significant training for the interviewer. Seeking to develop a shorter method of diagnosing delirium using the CAM algorithm, the authors of this article developed a 3D CAM, a short, structured diagnostic assessment that can be administered by healthcare staff with minimal training. Psychologists and advanced practice nurses conducted a face-to-face standard assessment for delirium in 201 patients, taking approximately 1.5 hours to complete. A 3D-CAM assessment was also completed for each participant, and a second 3D-CAM assessment was done in half of the participants chosen at random. Compared with the reference standard for diagnosing delirium, the 3D-CAM was 96% sensitive and 98% specific. The authors conclude that 3D-CAM is quick to complete, highly reproducible, and a valid tool for diagnosing delirium. Clinicians at all levels of training and specialties frequently do not know which of their patients have central venous catheters currently in place, according to the next article. ascertain the presence of central lines and then surveyed clinicians to determine their knowledge of the patient's central line status. They found that over 21% of clinicians did not know that their patient had a central line. Hospitalists and teaching attendings were less likely to be aware of central lines in place than were residents and interns. Critical care attendings performed best but were still far from perfect. The authors suggest that these findings have significant patient safety and policy implications and recommend policies and procedures to oversee the visibility of central lines, especially in non-intensive care unit settings. In an accompanying editorial, Dr. Darren Taichman, Annals Executive Deputy Editor and a pulmonary critical care specialist, asks, quote, whose line is it anyway, unquote. Dr. Taichman wonders whether forms, electronic health records, and other aspects of increasingly standardized hospital care might help here, but he believes that even these things won't work without mindfulness and a sense of accountability among physicians. At least a third of common symptoms have no clear-cut disease-related explanation, and this fact challenges the disease-focused model of care typically followed in clinical practice. In a narrative review, Dr. Kurt Kroenke observes that clinician training focuses relatively little time in preparing physicians to understand, evaluate, and manage common symptoms, which account for more than half of all outpatient visits. Commonly, the initial approach to symptoms starts with the goal of identifying a precise cause and a targeted treatment. Dr. Kroenke suggests an approach to symptoms organized to answer four common epidemiologic questions about the condition. The thoughtful approach that he outlines in this review just may help to redefine the clinical approach to symptom-prompted office visits. I urge you to go to your print journal, annals.org, the iPad edition, to read this review. You can test your knowledge and earn CME credit by completing the associated quiz. This issue includes the U.S. Preventive Services Task Force recommendation on behavioral counseling to promote healthy diet and exercise to prevent cardiovascular disease among adults aged 18 years or older who are overweight or obese and have known risk factors for cardiovascular disease. The task force recommends offering or referring such patients to intensive behavioral counseling interventions to promote a healthful diet and physical activity. Thank you. that all initially appeared online first. The National Quality Forum recently convened an expert panel to make recommendations on whether to risk-adjust healthcare performance measures for patient sociodemographic factors in addition to clinical factors present at the initiation of care. The first commentary discusses why the panel chose to recommend such adjustment and why the topic is so hotly debated. The second commentary describes the Veterans Health Administration's demonstration project Thank you. editor and an infectious disease specialist writes about safety lapses in U.S. government facilities that work with deadly pathogens. We initially published this commentary online in July, but the messages it conveys hold new relevance in the face of the current Ebola situation.
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The study found that the cost of paying a penalty for not buying health insurance would be lower than buying the least expensive insurance plan for many individuals, and young persons would tend to pay more than older ones. Findings that have implications as the second round of health insurance sign-ups begin. And the issue includes an On Being a Doctor essay about a doctor who struggles with recurrent depression, low self-esteem, and nightmares. And as always, the second issue of the month includes ACP Journal Club. Go to annals.org or the print issue for summaries of a dozen articles that your internal medicine colleagues rated to be of high quality and high clinical relevance. Thank you. connective spread infection. You can earn CME credit for listening and remember also that you and your colleagues can send your own tough clinical questions to the consult guys. Maybe they will choose yours as a topic of a future episode. That's all for this podcast. Thanks for listening and thanks to Beth Jenkinson, Megan Caffrey, and Andrew Langman for their technical support.
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Hello, my name is Nina Puttness and welcome to this month's The Lancet Global Health Podcast. Today we'll be discussing two highly interlinked topics. The first, stillbirth and the death of a newborn, still a significant problem globally, and the second, quality maternal and newborn healthcare. This is the topic of two papers in this month's issue, released today, the 22nd of July 2020. In this podcast, we will, with two of its authors, be discussing the original research paper, a randomised facility-based trial called the Effect of Quality Improvement Package for Intrapartum and Intermediate Newborn Care on Fresh Stillbirth and Neonatal Mortality Amongst Pre-Termterm and low birth weight babies in Kenya and Uganda. The second article in this month's issue is the links comment by Aluvala and English who discuss especially the challenges of implementing complex change at scale to improve quality, something we too will touch on in this podcast. In 2018, neonatal mortality, which is defined as the death of a baby within 28 days of life, globally was estimated to have claimed the lives of 2.5 million babies. Stillbirth, defined by the World Health Organization as a baby that dies after 28 weeks gestation, was estimated in 2015 to claim a further 2.6 million lives. A major cause of both neonatal mortality and stillbirth is pre-term delivery, which accounts for 35% of neonatal mortality and 30% of stillbirths. While the last two decades have seen improvements in these numbers, we clearly have still some way to go. Quality in health systems is vital. Our 2018 commission estimated that around 5 million people per year die in low and middle income countries due to poor quality health care, which represents now more of a burden than insufficient access to healthcare. Nowhere is quality more important than in the intra- and postpartum care of premature newborns. The 2014 WHO UNICEF Every Newborn Action Plan, based on evidence from the Lancet's Every Newborn series, outlines how quality, equitable, accessible care can save babies' lives. These include cost-effective and simple interventions such as the use of steroids, resuscitation, kangaroo care and the proper management of infection. The study we are discussing today looks at the impacts on neonatal mortality and fresh stillbirth, meaning that a baby has died either recently before or during delivery, of implementing a quality improvement package, the East Africa Preterm Birth Initiative, which is in Kenya and Uganda. This is a randomised controlled trial, so generates really important evidence to inform other systems globally. In both Uganda and Kenya, the neonatal mortality rate in 2018 was almost 20 per thousand live births, which is some way off the sustainable development goal of under 12 per thousand by 2030. Today, we're joined by two authors, Professor Dilys Walker and Tepita Waiswa. Dilys Walker is a professor in the Department of Obstetrics, Gynaecology and Reproductive Health Sciences at the Institute of Global Health Sciences at the University of California, San Francisco. She has spent much of the 20 years of her professional career working with colleagues in limited resource settings to design, implement and test interventions to improve the quality of care around the time of birth for mothers and babies. Peter Weiswa is an associate professor in the Department of Health Policy, Planning and Management in the School of Public Health at Makerere University in Uganda and a visiting researcher at Karolinska Institute in Sweden. Thank you so much. Happy to be here. Yeah, thanks for the invitation. So this, of course, is a critical topic globally and, of course, also in Kenya and Uganda. Could you perhaps start by briefly describing the context where you are and where this study is based and the background to this trial? Maybe I'll start first, Nina. Thanks very much. And then I'll pass it to my colleague, Peter Wisewa, to talk much more clearly about the actual geographies. But I just wanted to set the stage and let you know that when we began this project and the initiative in 2014, we were really set out being tasked with decreasing the burden of preterm birth. And it was also right at the time, as you mentioned, that the Every Newborn Action Plan came out. And, you know, very close in our mind was how do we do something that is actually driven by the countries and the geographies where we need to work that really takes to heart those recommendations from the Every Newborn Action Plan? And then we partnered with Peter Wisewin, his team at Macquarie, Felgona Otieno, who's at the Kenya Medical Research Institute in Nairobi. And together, we really approach this as what are we going to do that will put into action the Every Newborn Action Plan, focusing less on what to do, the kangaroo mother care specifically, or some of the other actions, and much more about how. So how do we get providers to and systems to adopt those practices that we know already work? And from the locations where we worked, it was critical that whatever approach we took, they wanted us to address morbidity, mortality of all babies and mothers and try to approach this in a way. And Migoli is known to be having the highest preterm birth in Kenya. Thank you. high fertility, but source a region with high child and maternal mortality, and is considered a representative of Uganda. This study took place in about 20 hospitals across Uganda and Kenya. And we who did the work, we are basically local researchers from Uganda and Kenya, and we partner with our colleagues in the United States from the University of California in San Francisco. We work very closely with the government of Uganda, and we have a very good understanding of the local health systems. Some of us have been staff of districts. So we are also, besides being academics, we are champions for improving newborn health. In both these places, we took on a regional approach to improve care for preterm babies because we thought that when we bring regional hospitals and regional health centers, then they are able to work together and reinforce each other. But most importantly, they bring care closer to communities because one of the things as a history of this country and both countries, care for preterm babies was always just in the capital. But for the first time, we are bringing it closer to communities so that they don't have to spend so much. We know that care for newborn babies, care for preterm babies is very expensive. And yet the context we're working in is that of poor populations. So this is the context in which this work was done. Thank you both. That's a really useful context understanding. So in these settings, I understand you use the East Africa Preterm Birth Initiative interventionvention Package. Could you perhaps describe to us what this includes and why the quality of these interventions is so vital? The Preterm Birth Initiative Intervention Package relied on four components. And two of those components we actually implemented in all 20 hospitals. And then two additional components were in just the intervention facilities for the research. Those components started with a foundation of data strengthening. We were committed from the start to using routine birth registry data as our data source to get gestational age, birth weight, and status of the baby. So it was important that we strengthened all of that data across the board. We also introduced the Safe Childbirth Checklist that was modified for preterm birth to help guide providers if they had what they thought might be a preterm labor and to manage the preterm birth in the immediate postnatal period. And then in the intervention facilities, the half of those facilities were randomized to get two additional components, one of which was an innovative simulation and team training program delivered through local mentors adapted from Pronto International's other simulation curricula with a focus on preterm birth, but it actually really addressed quality of intrapartum and immediate newborn care across the board. And then finally was quality improvement collaboratives where QI teams worked individually within their own facilities and then came together collaboratively to agree on certain indicators and benchmarks that they would work on through the standard quality improvement plan-do-study-act cycle. And then I'll let Peter comment a little bit more on, as you said, the quality of that package and the implementation of that. So the package we took on actually tries to operationalize a WHO approach, which was launched a couple of years ago, called the Quality of Care Initiative. This initiative aimed to reduce maternal and child mortality in health facilities by 50%. And so we designed a package that we thought is a fit for purpose in our context. Such a package, we want a package that is not complex, in other words, simple. It builds on the use of local resources. It strengthens local teams, and it builds champions. But most importantly, it provides quality.
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And we thought about the importance of use of data as an important tool to monitor what is going on and to guide the implementation, but also later to guide the estimation of the impact of what we're doing. This data would actually also help reinforce the efforts of providers because when they see that they are improving or that mortality is going down, then this motivates them. We thought this would raise awareness among the providers, would also improve the use of the data. In fact, one of the things we found at the beginning is that the quality of the data was quite poor, even in hospitals. By measuring, which was done by providers and facilities, we were able to improve data, and this in turn led to improvement in terms of the services that were being provided. Most importantly, the approach that we took built teamwork among the providers. Teamwork is important in saving preterm babies. And to harness all this, we engaged the leaders in these hospitals. Leaders are critical because they are the ones who deploy staff, but also they are the ones who give resources. In the end, we ended up with providers who became champions for preterm survival in these two regions. So moving on to the results of these interventions, your study indicated that out of the 20 trial sites overall, which included almost 3,000 babies being followed up, in the 10 sites where the additional interventions were implemented, fresh stillbirth and neonatal mortality was 8% lower than in the control sites, which was also a statistically significant difference. Even after accounting for other variables such as delivery type, multiple gestation, birth weight, etc., the overall odds of babies dying was lower in the intervention group. This is an important finding, but could you comment on what this means now for women giving birth in Kenya and Uganda, or indeed elsewhere? By that I mean, what should we do with these results now? Well, in fact, just like you said, our results didn't just improve the outcomes for preterm babies, but also improved the care that is provided to mothers and it reduced mortality among stillbirths. This is so important because stillbirths are so many in our context. And, you know, when a mom gets stillbirth, we say she suffers in silence without support from the community or from the government. These results are important because the approach we took improves quality, but also it strengthens systems. And we think that so far our approach has been sustainable. These facilities where we did this intervention are continuing to provide good care. And during this time of COVID, this is even so important as there is reduced attention to other cases than COVID. But because our providers have skills, have passion, and are champions, they are able to provide care to these mothers and newborns. We think this approach should actually be expanded to the rest of the country. And here we are engaging the government in Uganda, the government in Kenya, and hopefully by engaging organizations like WHO, UNICEF, our experience could be taken to other countries. Because in all over Africa, in sub-Saharan Africa, we still have very high mortality. And I just want to tell you a story, one of the stories for me, which comes out from my work. Towards the end of the study, we had a mother in a rural area give birth to quintuplets. She gave birth to five babies. She went into labor in the community, was rushed to the care center, and then was taken to one of our hospitals, Egan Hospitals. But we were so happy that one of the nurses whom we had trained was able to save these babies, all of them. This gives evidence that the interventions that we've tried to use, work, and what we've left behind can actually have impact on the lives of mothers and babies. And we hope that those with the resources can take up the experience from this study and be able to make it policy and program and scale it up so that it benefits all mothers and babies, not only in Uganda and Kenya, but throughout Africa. Could I maybe just add very briefly to that, Peter, what you so eloquently stated? But one of the things that has really struck me about this study is how it seemed as though both providers and women sort of transformed their expectations of what can and should be done for these small and preterm babies. And that instead of any sort of hesitation about the potential for survival, they just swung right into action from the moment they recognized a woman in preterm labor through after the time when the baby was born. And I think that that was both rewarding to everybody involved and has really helped in creating the champions that Peter has talked about that were critical to the study. Absolutely. And as you've both said, we're becoming increasingly aware and knowledgeable about the importance of such quality, comprehensive, inclusive care. But the realities of implementing this globally, as we would all like, are often very different on the ground with many, many facilities, for example, not able to achieve even basic safety and quality standards. What challenges or did you come across challenges during implementation in this study? And in terms of real life implementation, what would you say is important nationally or perhaps globally to raise quality standards for maternity care? For me, one of the important challenges and lessons that I saw from this work, and that we already know, is the importance of governance, leadership, and management. To that, you can add accountability. So throughout Africa, and even while we did our work, we found that these were weak. But later, the strengthening of leadership was important for the intervention to take effect. So this is an important part that until leaders prioritize maternal, newborn, and child survival in Africa, we are not going to succeed. We do not have the resources, neither shall we be able to count every newborn, every stillbirth, and every preterm. The second one was the importance of resources. Resources include people. The people here must say the staff, but I must say also the moms are an important resource because they provide things like kangaroo mother care that are important. The other resource that is important are medicines, equipment. Those are important. And space. These hospitals are getting congested. They were built many years ago. And we are adding services such as care for preterm babies that require additional space. So these are challenges that need to be addressed. In Kenya, there was a strike, but actually also in Uganda, a strike of providers. And a strike in Kenya took almost a whole year. In Uganda, it took about a month, meaning that these issues of staff are important. Again, coming back to the issue of the management of staff and taking this stuff as an important resource. But we also had problems with supplies. We had, of course, communities are poor, and yet they're spending a lot of time in hospitals. Pre-term care is actually a lifelong thing. Even if a baby is saved at birth, it may require care for the rest of the baby's life. And so it is important that families can afford these issues, and the governments need to support these kind of families because whereas we are providing money to support the care of people with HIV, with malaria and TB, we are forgetting that pre-term care is so expensive and important and in order not to put families into poverty, these families need to be supported. Finally, one of the other important challenges we had in our context, both countries, is actually the importance of electricity. You know, you are running an incubator or an oxygen concentrator and the power goes off. Most likely, you are going to lose that baby. So some of these systems issues are important to be worked on as you work on quality improvement. Quality improvement cannot work in a vacuum. So we've been talking so far about these really important interventions and the system, as you say, Peter, once a baby is born preterm. But of course, there are other factors and interventions to prevent mothers from going into labour early in the first place. You mentioned a few there, Peter, but with other causes globally, for example, being infections in general, malaria, HIV or adolescent pregnancies. How do you see your quality improvement intervention sitting within this whole picture? Yeah, thanks for that question. And that's critically important because I think as public health professionals, we all really do want to focus on the prevention of these conditions and these causes of increased morbidity and mortality. However, as I mentioned early on, we made the decision to focus on, based on the modeling, the time and the space that had the potential to save the most lives, which turned out to be right around the time of birth for these fragile babies. Prematurity in itself is a complex outcome. There are lots of contributing and causative factors that were well beyond the scope if we wanted to make actual impact, just as you have mentioned. And because there's not one pathway to the outcome of preterm birth, it's really difficult and challenging to understand what is the best path or the best approach for a given driver of that preterm birth.
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And if they're given sort of minimal extra support, they can survive and thrive, which is really what we wanted to show. And as Peter said, there are so many systems and economic and political and leadership factors. We wanted to really say, what could we do tomorrow without having to introduce a lot of new technologies that are out there for preterm births. We believe that all women deserve to get the most up-to-date technologies, but in order to build a system that can really benefit from that, you have to start from the bottom up before you start introducing some of the more advanced technologies. Thank you, Dennis. So unfortunately, to our final question question and something that you already mentioned, Peter, actually, and that's our current reality. So the impact of the COVID-19 pandemic. The Guttmacher Institute recently estimated that even a modest reduction in sexual and reproductive health services and maternal and newborn care, even by just 10%, which is sadly potentially way under the real impact in many countries, could cause an additional 28,000 maternal deaths and 168,000 neonatal deaths globally over the course of a year. And of course, it could be much more than this. This is devastating. What would you quite fragile. Fragile health systems where minor perturbations in staffing, in resources, etc., can actually lead to a lot of devastating impact. Our work in Uganda and Kenya shows potentially what could be done. But I first wanted to tell you that we are much involved in monitoring the continuity of services in Uganda. And we've already seen that fewer people are coming for antenatal care, are coming for delivery care. When they come for emergency section, they are coming quite late and outcomes are not good. There's also evidence of an increase in stillbirth. So the COVID is having impact, but our work shows that if we applied the approach that we did in the preterm birth initiative, potentially we could mitigate some of these issues. For instance, I foresee a situation in which providers can continue to be mentored so that they are able to provide quality improvement, they're able to improve data, they're able to do simulation, and they're able to actually use evidence-based practices and work in teams. So things like QI applied to COVID are important. Can we have a COVID-rated data system, a COVID checklist, or COVID QI teams, COVID stimulation? The approach we have does not work just for preterm babies, but I think it can be applied to all clinical settings in our context. And I hope this is one of the things that we can learn. And we are trying to find resources to see that we can integrate the learning that we've had from this project and apply it to maternal, neonatal, child care, but perhaps to all other health systems so that we can save lives. So this is what I see is the application and the learning so that we could mitigate with the resources we have the effects of COVID. Yeah, and I just want to add to that, that, you know, COVID is a real reminder for people like myself and the United States to recognize how much we have to learn from our global partners and the approaches they're taking to these public health issues. And I think that, you know, we have seen a very good example of something that we could take from global experience and learn locally here in the United States. Peter Dillis, thank you so much for joining us today and talking about your important research. And I really look forward to hearing about the next steps that come from the results that you've found. Thanks very much. We have a lot of additional insights that will be coming out over the next few months and a number of other sub-studies and discovery grants that we have and we will be reporting on shortly. Thank you so much for the opportunity for us to bring our local learning to a global audience. Thank you. And listeners, please do check out the full article available from today on the Lancet Global Health Online for free. Thank you.
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Ah, yes. Hello. Hello, everyone. This is Matt with the Curbsiders. And this week, we have two great episodes on addiction medicine with a particular focus on opioid use disorder and patients with chronic pain. This is a topic that has really been a struggle for me in both clinic and on the hospital wards. So I think we got some great information from our two wonderful experts. Definitely some of the topics here are going to be controversial. We'd love to hear your feedback on how you're handling these situations when you see them. I hope you enjoy both of these wonderful episodes. The second one will come out on Friday. Thanks for listening. Thank you. Welcome back to the Curbsiders. Well, hello, Matthew. Hi. This is the Internal Medicine Podcast that uses expert interviews to bring you clinical pearls and practice changing knowledge. I'm Dr. Matthew Watto, here with my two co-hosts. Dr. Stuart Cantbrigham. I figured I had to introduce myself this time. Yeah. And Dr. Paul Williams. How many of these have we done? done a few hey there was this awkward pot i wasn't sure because i keep going he changes the outro every time i'm trying to keep it fresh for the audience excellent all right guys paul did you have a pick of the week yeah i guess so i you know in keeping with my habit of doing things i love until i hate them i actually Yeah, I'll die a happy human being. And he's fine. I used to like him, but I just don't do that. So that was apropos of nothing. So now I'm trying to recover from that and actually rush it back up on my classics. So I'm reading Moby Dick right now. I'll report back if that's going to be a pick or not. Wonderful. I will one up you, Paul. I'm going to recommend, it's a fantasy book series. It's called The Wheel of Time series. It's like, it's 14 or 15 Bible-sized books. I've read all of them. Great. Yes, I know. That'll be my next step in self-flagellation. But I think the pick I'm going to make this week for no one to look at will be actually a collection of T.S. Eliot poems. So, I don't know, everyone knows quotes by T.S. Eliot, but the one poem, The Love Song of J. Alfred Prufrock, is probably my favorite piece of American literature. Hopefully he's American, otherwise I'll look foolish. But how about we say English language? And it's one of my favorite things, I think, that I've ever read. But it's all of his works have quotes that you've heard. So I'm going to recommend the collected works of T.S. Eliot, specifically The Wasteland, Proofrock, and Other Observations is a nice book that actually has some good annotations. So read some poetry, class yourself up a little bit. Wonderful. And my pick of the week will be very quick. It is another podcast, an internal medicine podcast. Actually, it's the Hospital and Internal Medicine Podcast by Gil Peratt. And he did a recent episode, which relates to this episode we're doing now, on urine drug screens, false positive urine drug screens, and some of the stigmatization that that can cause for patients and some of the conflict that can cause between you and the patient. And he talks about what can cause false positives. It's about a 20-minute listen. It's good. I recommend it. So check that out. Excellent. All right. This episode is on the first of two episodes that we'll be doing on addiction medicine. Specifically, this one's focusing on opioid dependence and opioid therapy. It's a controversial topic. And we had two great speakers, Dr. Stephan Cortez. He's a physician in internal medicine and addiction medicine at the University of Alabama at Birmingham School of Medicine, and also at the Birmingham VA Medical Center. He grew up in California. He has a 20-year history of providing and researching healthcare services for vulnerable populations. He leads a VA-funded research on homeless healthcare and housing. He serves on his hospital's opioid safety initiative and has written several articles for scholarly and lay press on problems in our current response to the opioid crisis with a focus on the harm to patients. He was recently invited to the Center for Medicare and Medicaid Services at an upcoming opioid summit. So he was invited there as an advisor. And Dr. A.J. Manhapra is the interpreter of maladies at Advanced PACT Pain Clinic at the VA Hampton Medical Center in Hampton, Virginia. He is an internist and ABAM Fellowship-trained addiction medicine specialist. He is a research scientist attached to the VA, New England, MIREC, and Yale Department of Psychiatry. His clinical focus is on developing a cognitive paradigm for primary care physicians to conceptualize the problem of disabling chronic pain in individuals, especially those with complex dependence and addiction to various substances. The goal is to shift the high-quality treatment of complex pain to primary care. Thank you. Pain and Addiction Curriculum Development. He also teaches pain and addiction topics at the Eastern Virginia Medical School. We are so happy to feature both of these great speakers. We talk about the treatment of chronic pain or acute pain with opioids. We talk about tapering off opioids for people who have been on them chronically, some of the controversy around the CDC guidelines, naloxone therapy, and some of the partial agonists like methadone and suboxone and how those can be used. It's a very informative discussion. I hope you enjoy it as much as we did. That's right, Matt. Hey, Matt, you know what I heard about the opioid use epidemic? What? It's at an all-time high. Hi. Gentlemen, thank you so much for coming on the show. Yep. AJ, I'll go to you first. If you had to describe yourself as a one-liner, what would that sound like? Oh, just a curious internist. That's about it. Okay. Very brief. That practically describes my entire career. Okay. Stefan, how about you? I would say I'm an idealistic, obsessive, and slightly insecure internist who's learned to live with it. Okay, I like it. Stuart, you've been on the show before. Oh yeah, sorry. So, AJ, what's the best advice you ever received as a learner or you would give as a teacher? So, this is a funny story. I met this guy who gave me the best advice in my life. It's not about learning or anything. And like 25 years later, and I asked him, do you remember me giving this advice? He had no clue. advice you know i was i was at a uh at a i was in india i came from india so i was making a decision whether i should come over here or not it was a big move right so and it was a lot of uncertainties at that time so he gave me this fantastic piece of advice that there are no good decisions or bad decisions. You just make informed decisions and it turns out to be good or bad. So that rather defines my medical practice too. I found that to be rather useful advice in any facets of life. But he doesn't remember giving that. So you should absolutely take ownership of that quote then. That is now yours. If he doesn't remember it, it belongs to you. Yes, exactly. Stefan, what about you? What's the best advice you ever received as a learner or gave as a teacher? That's a hard one. I guess a couple of things come to mind. If you're like me and you're somewhat insecure about whether you're doing things well enough, the important thing is to realize we're all doing the best we can with what we have. And the goal is to sort of maximize what you can accomplish with the tools you've been given, which are not infinite, and you have to recognize your limitations. Yeah, I think that that's a good point. And something that I've been trying to do lately is surround myself with people that have different skills than I do, and just kind of recognizing where I have these limitations and trying to fill in those gaps by learning from good people that have strengths that I don't. So I like that advice. Yeah, it's interesting how often this has come up. I feel like that's been a theme with the people that have seemed to be the best internists. They also happen to be really good at self-flagellation and are all kind of dealing with that. So I think that's excellent advice.
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I'm going to ask if you guys have read a book that kind of goes along. It's called Multipliers. Have you ever heard of it? It's from the business literature. I have that book on my shelf. I have not read it yet. I think you could probably, if you read the cover jacket, it probably gives you the gist of the book pretty well. But I've said this before. I don't remember if I've said it on air, but basically I think that medical school kind of breeds you to be like, to show like, Yeah. basically like you don't want to be the genius in the room you want to be the person that brings genius out of other people that's how you have a great team i love that book and i think every doctor should read it yeah that sounds interesting uh you know you have you heard about you all harari no i don't think so he's this guy who writes about this history of science and he's a a kind of philosopher of science. So he has this very interesting quote, you know, the greatest discovery of mankind is the discovery of ignorance. So ignorance allows you to, you know, to be curious about the rest of the world. So, rest of the thing. So, in medicine, I have found that you have to reach a certain level of career to say, oh, I don't know anything about that. Right? And that is, knowing what you don't know is a pretty critical quality of an internist. It's actually kind of liberating in a way to be able to say, I have no idea. Like, kind of freeing when you get to that point. So I feel very free much of the time. I'd take Xanax. Well, what do you say we move on to the main topic, which is going to be addiction medicine? And I did want to mention that a lot of the questions for this and setting up this interview was done by a medical student, Elena Gibson from University of Alabama, and a third-year resident, Carolyn Chan, who is a resident. I'm not sure if she wants me to say where, but she's in Ohio in the primary care track. And she helped write these questions and do a lot of the background research for this talk. So thank you to them. And this case is a case from Cashlack that's, I guess, adapted from a real-life patient, not one of mine. Mr. C is a 52-year-old male. He has a history of hypertension, COPD, CKD, and a remote history of polysubstance use, cocaine, and heroin, but has maintained sobriety for over two years. So now he's coming to clinic. He's had right hip pain, but now it's substantially worse. Before, he was using occasional NSAIDs, maybe a few days of narcotics here and there, but now it's been worse. And an x-ray shows he has severe avascular necrosis of the hip related to chronic steroid use. The orthopedic surgeons are planning a total hip replacement in a month, but he needs to get by until then. And he's saying Tylenol doesn't work. He doesn't see a pain management doctor. So he wants you as the primary doctor to manage his pain. So I think this is a pretty typical case for us to see in primary care, somebody with unmanaged pain. Before we address the case, I wanted to go ahead and start defining some terms. So, Stefan, what would you say, if you had to define some of the terms related to like substance dependence, substance abuse, substance abuse, or hazardous use, what are the simple terms that our audience should know? Well, there's use, there's hazardous use, and I guess dependence, and then substance use disorder. So use is straightforward. Do they use something or not? Cigarettes, alcohol, an illicit drug, those are sort of straightforward. Hazardous or at-risk use is a little trickier. With regard to alcohol, there are identified thresholds, which reflect somebody who might be more likely to have an adverse health outcome. With men, it's something like more than 14 drinks in a week or more than four drinks on an occasion. AJ can correct me if I got it wrong. It's a lower amount for women, but that has nothing to do with defining dependence or addiction. It just is hazardous. And obviously, drinking while driving, having equipment, for instance, might count as hazardous use. Then we get into, you know, there's no actual definition for hazardous use of illicit drugs. Typically, we've just talked about either dependence or substance use disorder or sometimes abuse. Dependence is somewhat straightforward in the following sense. Dependence means a person has problems if they stop using. Addiction is compulsive use with loss of control. That is the kind of colloquial definition of addiction. So addiction, in addiction, the purpose of use disappears and it becomes an automatic behavior. So the transition, neurobiologically transition from a purposeful use with a repeated use, creating a predicted pattern of use is dependence. When that purpose of use is lost and in an automatic behavior, it becomes addiction. That's a kind of simplistic way of thinking about it. Yeah. Can I ask a quick question of my friend AJ? AJ, would you want to draw a distinction between simple dependence, such as one might have for an SSRI or a beta blocker where stopping it leads to an adverse consequence? Maybe simple dependence on an opioid where the person's functioning well, but basically has tolerance and can't stop easily, but is otherwise not going to have a lot of compulsive behaviors, and something more like complex dependence, which borders on addiction. How do you think and speak about that level of dependence, if you will? So addiction is a continuum of things. It's not a static, it's not a bifurcation of definitions. It's a continuum. That's why they change from dependence to substance use disorder, recognizing the end of the continuum. So, substance use, the end of the continuum. Substance use disorder, only when severe substance use disorder is quote-unquote addiction. So complex dependence is when dependence becomes problematic. So simple dependence, you know, you run an opioid, you stop, you have some withdrawals, and after a few days, you're well. Right? In complex dependence, you know, you stop an opioid, you have withdrawals, but you are not well after that. It takes, you know, you continue to have significant pain, dysphoria, you know, sleep problems and all those, disability for weeks, months and all those things. These are people, you know, typically you see this after high-dose opiate tapers. And we do not recognize that enough, you know, in the sense that people can have complex dependence and it can be pretty disabling. Well, for this gentleman, where would you go next? Stefan, I'll go to you for this. What would you sort of, how would you start to have the conversation with this gentleman about what we're going to do for pain control? And then AJ will let you weigh in next. A lot of what would happen for me is to understand how does he live today? What does he do today? What are the things he does each week? Does he go to social groups? Does he have a job? What are his relationships? What I'm trying to figure out is essentially how secure is the recovery and the life that he's established for himself and the investments he has. All of this becomes the context for understanding whether opioids as a possible intervention among many for his continuing pain would pose extremely high risk or just moderate risk. After that conversation about how the individual lives, how they're functioning in daily life, I would ask them about what they're doing for their pain currently. And I would certainly explore a variety of non-medication options that might assist them. Let's assume for sake of discussion that some have been tried and are not really helping that much. I then would want to learn when is the last time they've taken an opioid for pain, what impact did it have, and did it raise any concerns for you in regard to your recovery? And all this presupposes an open conversation and that I'm an interested partner, not really an interrogator, even though in a way I am interrogating. So that's the kind of conversation I would have is where are you at? What are you doing? What's your life like? And how did opioids work out the last time you took them? And what would be your go-to screening tool to screen for their risk for opioid use or substance use disorders, in this case for opioids? So, to a degree, I don't routinely pull open a standardized screening tool, but the questions I ask are most closely related to something called the two-item conjoint screen. Yeah.
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So, in this patient, you know, this is the concept. We are journalists. We got to think through these things. So who are the people who are at risk of developing opioid dependence or problematic dependence or addiction when you start them on long-term opioids? So typically, they are people with prior substance use disorder, prior mental health disorder, and multiple comorbidities, polypharmacy. So these are the four sets of things that typically leads to problematic opioid use. So that is what I go by, you know, the prior substance use disorder, active substance use disorder, mental health disorder, especially PTSD, polypharmacy, and multiple comorbidities. So say this patient raises some red flags for you where I don't even want to frame it like that, but so some of the background factors raise concerns that maybe opioid use might be a bad choice for pain control. Can you maybe talk us through how you contextualize that conversation in a role of an advocate in sort of a non-confrontational, non-judgmental way? Because I feel like it's a very hard discussion to have without feeling like you're apportioning some degree of blame. So there is some inherent risk with it. You just have to acknowledge the risk, right? And pull up your big boy pants and prescribe opiate for this patient. But at the same time, have a discussion about this, you know, with the patient. Patient understands these things. People with substance use disorder understand these things. The problem is that we typically have these discussions after they get into trouble and they are, you know, 200 MME of morphine, right? So these discussions have to happen right up front. You have identified that this is a very easy criteria. Prior or active substance use or dependencies, multimorbidity essentially, psychiatric comorbidity, and polypharmacy. This essentially defines your problematic patients. Yeah, he's at risk, but he's been, you know, let's assume that I don't have many other options. My goal is to come up with a way to successfully care for him, and it might well involve opioids that are monitored fairly closely with a fairly frank and open discussion about that. I assume that there's going to have to be a closer level of relating and monitoring that I might do with somebody who has no such history. I agree. And I think what you're both saying is kind of radical thinking in my mind, but I like what you're saying, and I want to start to talk about the CDC guidelines here, but I think a lot of people would look at this patient and say, prior history of opioids, can't treat their pain with opioids no matter how severe, and that patient would probably suffer and maybe be forced to get those medications in an unsafe way. So I think what I'm hoping to gain from you all is like ways that we can safely do this and responsibly do this, because think a lot of people with the new guidelines which are so strict have just sort of, and I'm probably guilty of this myself, have just kind of written off using opioids in patients that are higher risk. So in this patient, when you start off this opioid, this is starting an opioid, which is very different from continuing a long-term opioid, okay, which is two different things. Starting an opioid, you should clearly discuss the exit plan. So, if he is having a one-month surgery, you should have, you know, you should very clearly tell him that, you know, we have to control your pain, but if you're on opioids, you're going to have a risk of developing dependence and it might be difficult for you to get off. So you have to give them an option of, okay, can you manage this without opioids? Okay. Then if you start opioids, there should be a very clear exit plan. In the sense that, okay, you're going to do the surgery. It takes six weeks of recovery. How are we going to plan the opioid therapy during those weeks? The first few weeks, you will need a lot of opioids. The second week, you know, the next two weeks, probably not that much. And third and fourth week, we'll taper it off. So the expectation is already defined. I've got somewhat of a practical question. Is there any difference in the specific opioids as far as their risk for addiction or dependence is concerned? Not really. Okay. Now, you know, there's some statistical data that suggests overdose risk might be higher with long-acting opioids, but I am not 100% convinced. Yeah, you know, you go for the lowest dose that is effective. And you should give them the idea that it's not going to fully control his pain, especially in a patient like this, who typically substance use, prior substance use disorder patients have lower thresholds for pain, and they have more pain, and they require more opioids. Now, the CDC guidelines, I think some of the things they said most patients only need for acute pain only need about three days of pain medication. Most patients won't need more than seven days. And I think some of the useful things they did is highlight if patients taking more than 50 milligrams morphine equivalents, or if patient is also on benzos or patient has history of substance abuse, then those patients should get Narcan, which is naloxone. And I think that's been the good thing about this. Can you talk a little bit about the duration of the initial prescription and how that relates to the potential long-term substance use disorder or chronic opioid therapy? I mean, it is pretty simple equation, right? You know, the more you use, the more risk of substance use disorder. So there is no mystery there. The more you use, the higher the dose, the higher the risk of substance use disorder. That's a very simple formulation. So the three-day use. So have any one of you tried an opioid? Only recreationally. Stuart's on them right now. So if you look at the opioid, you know, the current surgical literature that is coming out, you know, 70-80% of the opioids that is prescribed stay at home unused. So most people cannot tolerate opioids for more than one or two days. They just stop it. So for most procedures, you know, simple procedures, there is no point in giving them more than three days. It's just a waste of prescription. So most people, you know, don't use it. Even people who use it can use it only one or two days. So it is a good practice to, if it's a small procedure, if it's for three days, and if it's a slightly larger procedure, if it's for seven days. There was just an article in JAMA in September 2017 that it was called Defining the Optimal Length of Opioid Pain Medication Prescription After Common Surgical Procedures. And basically, depending on the procedures, I think MSK procedures required some of the longer duration of opioids. The gynecologic surgeries were in the intermediate, and then the lower end was your simple appendectomies. And it was ranging 4 to 15 days. And the longer, as you already said, the longer people were on opioids, the more likely they'd still be using them at a year, especially if they filled a second prescription for them after surgery. Yeah, this is very simple science. So most people have to understand, if you give a prescription to an opioid naive patient, around 80% cannot tolerate it. So let's go to this case, this gentleman that you saw. So first, let's take the instance that you saw him in clinic, you've done your spiel, you've counseled him, because of your history, you're going to be at risk. Over that month, how often are you going to see him? How often are you going to drug test him? Let's give some practical pearls for what our audience should do if they were seeing this gentleman and how they could safely guide him through this period. So you have to make an assessment of this patient. There are no rules for this game. So you have to make an assessment for this patient. How safe do you feel about this this guy being on opioid right so so typically i really don't test you know if you're really concerned you can test it every week if you if you degree if your severity is every week urine talks so that uh but you already know about him, whether he's relapsing. He has been, you know, sober for two years, I think, you know, from the history. So it is unlikely that, you know, if you have tested him for two years and he's, you know, he's shown sobriety, it is very unlikely that he will, you know, he will show any problems at this point. So my thing is that I wouldn't get in such a short use. You know it is a very short use.
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I don't think you should worry too much about diversion or other substance use or things like that. So this is just a medical issue. So you might give him two weeks or one month supply? Yeah. Okay. What about tramadol? Can we use tramadol? Yeah. I mean, start with the smallest one. Try tramadol first. And if tramadol doesn't work, go for hydrocodone or oxycodone. I don't think in this patient with a short exposure like this, I would not use long-acting opioids at all. And, Paul, you had sent me some articles about the hospitalized patients with this. Did you want to comment on that or ask any questions? Like, say, this guy was coming into the hospital in this situation. No, I don't think I have a specific question. I mean, I think the article I sent in particular was the one from the Journal of General Medicine from I think a few months ago that just demonstrated nothing that we didn't know already. Whereas if you discharge an opioid naive patient on opiates, they're more likely to end up on long-term chronic narcotics than patients who are not discharged on opiates. So it's just another article sort of elucidating the potential risks in prescribing narcotics. a diagnosable addiction disorder. So on the one hand, long-term receipt is most assuredly associated with some form of dependence, even if that long-term receipt is at low dose. But the percentage of people who receive opioids long-term who would then qualify for a new onset substance use disorder diagnosable by compulsive use despite harm in their life is likely to be low, probably less than 10% on average, maybe more like less than 5%, albeit higher if you're dealing with younger adults. Does that distinction make sense? Absolutely. Yeah, absolutely. And so these patients, I mean, they're coming into the hospital. It sounds like the main thing we can do with this information, knowing that the longer we prescribe, the more risk there is, and the more we prescribe, the more risk we're generating, is to really counsel the patients and come at it from this kind of shared decision-making. You're advocating for them. You're understanding their pain. You're not making them feel stigmatized because they need narcotics, which sometimes people do. That's kind of typically is a paucity of long-term data regardless of whether it's a medication or not a medication. And so I try to keep expectations relatively low with an eye on function, and I'm very open and honest that I'm trying to think about risk of medications but I'm not necessarily ruling them out. I have to pick a kubel with that. This whole idea that opioid is not effective is to me is a whole lot of crap. Opioid is the best pain medication available to us right now. There is none better than that. And there's a particular reason for that. So we look at pain reduction as just analgesia. Pain reduction also involves the pain relief also involves analgesia, emotional distress reduction and relief, which is a separate phenomenon. So the pain analgesia is mostly mediated through the pain pathways. Emotional distress reduction through emotional pathways. And the relief is actually mediated through reward pathways. Right? So the NSAID acts only on one, this analgesic pathway, whereas morphine acts on these three pathways. So it is a perfect pain medication. So it's the boon and the curse of the opioid because it has got analgesia, substantial emotional distress reduction, analgesia, and an effect on reward pathways. That's the boon and the curse. Because of its simultaneous effect on the reward pathways, let's say, now we're at the point where maybe this patient admits that he's actually been using narcotics off the street and he's actually addicted to narcotics or has a substance use disorder. And let's say we'll take the surgery out of the equation. So he's been using them. He now wants you to help him get off of chronic narcotic medications. I wanted to talk about the options for tapering and correct me if I'm wrong. As I was reading it, there's about three options. You can just go straight abstinence, where you just let the patient stop the medication, maybe taper off and they just stop totally. You could do the partial agonists. You can use like buprenorphine or methadone. Are there other options? Stephan, I'll throw the question to you. In this case, in this hypothetical, is he taking opioids every day? Is he likely to have physiologic dependence? Yes, yes. We're saying he has physiologic dependence and also has been kind of, he was being prescribed opioids by you, but later he admits that he's actually been going beyond what you give him and buying more on the streets when he runs out. So maybe he's treating pain still, but he's also in a very high risk situation and it very well likely would correspond to substance use disorder. On average, I would want him to look at a therapy like Suboxone or Methadone. And in a practical way, in my particular setting, getting him started on Suboxone would be easier to do than going to a methadone clinic, of which there are just a few in my area and are quite inconvenient. And Suboxone being buprenorphine and naloxone, and Suboxone is the branded formulation? Yeah. So it's approved for physicians who possess a special waiver to prescribe that for the purpose of treatment of addiction, if that's what you've diagnosed. Now, if you actually haven't diagnosed addiction, but somehow still think that what this guy is just a very maladaptive pain patient, any doctor can prescribe that same medicine as an off-label pain medicine. AJ can give us, I think, a better exposition on the merits and downsides of that approach. But I would be pretty reluctant to start out with a simple taper to abstinence unless he tells me that he actually has done that before and it's turned out to be very helpful provided he had the right supports. Okay. So this is a phenomenon that we are seeing right now. If you have opioid use disorder, which is dependence with problematic behaviors, if you have that, pain is often a symptom of the dependence. So treating the substance in opioid use disorder is actually the treatment of pain. So the dependence, biological dependence has got one drive to keep your opioid intake at a particular level, right? So it will change your expectancy, your behavior, your emotions to match, you know, to elicit that supply, give you that supply. So if you don't treat the dependence, you know, people call it the, in the wrong term, opioid substitution therapy, which is not the appropriate term for that. Methadone and buprenorphine are treatment of opioid dependence. So if you treat the dependence, you can expect the pain to come down, mostly. Stefan, when you put someone on Suboxone in your clinic, is the goal to eventually taper them off of Suboxone as well, or is that a lifelong therapy in some cases? It's a lifelong therapy in many cases, And I should confess that I personally am not currently wavered to prescribe it for addiction, although I'm working on my waiver course. But I have someone right upstairs for me, and usually the expectation is it's going to be long term. But the patient themselves will often make a choice at a certain point where they feel their life is such that they might wish to come off. But I don't, you know, there's no data to suggest that suboxone short-term with a taper coming off is protective of the patient. And AJ, do you want to add to that? So, two things. One, in standard run-of-the-mill opioid use disorder, we know very clearly that discontinuation at one year carries somewhere around 80% to 90% relapse rate. So we have tested it up to one year. You know, what happens if you continue? Yeah, so it doesn't work. So up to one year, it really doesn't work, So in specific to pain, prescription OUD, the port study looked at this. They took a bunch of patients, gave them buprenorphine, and first tapered them off in a month. And it's like 99%, 96%, 94% relapse. So they took them again and put them on a 12-week buprenorphine taper. Again, huge failure rates. So the tapering quickly in a year typically doesn't work. That doesn't mean it's not always. It typically doesn't work in most opioid use disorder patients. So typically what I tell, you know, what addiction does is that we all have this rich, wide life, right?
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Your entire life spectrum narrows. So what I typically tell patients is that you treat dependence. Don't think about coming off for a little while. Reconstruct your life, right? And when your life is reconstructed and stable, we'll talk about that. Well, I know one of the qualifications to even prescribe Suboxone to actually get the DEAX license is you have to sign, literally sign a paper saying that you have social support available in your practice to help with addiction management. So I wonder, are there any additional resources that you use and how important is the role in sort of mental health services above and beyond just the drug-assisted therapy for opioid use disorder? Here's the thing. If you think about treatment of addiction and opioid use disorder, there are two arms to it, right? One is the medication treatment. One is behavioral treatment. So most people, when they get the medication treatment, they kind of modify their behavior because they are already, most people who come into your office are the guys who want to quit, right? So this medication treatment enables them to quit. So they don't need much of a psychotherapy. There are about 20% of people who will require psychotherapy. It is the key to identify these people and have a resource to refer these people to, you know, if they need. Stefan, I had a question about the risk of abstinence and some of the adverse outcomes that have been reported in the literature that just for our audience to be aware of what some of the extreme cases, what these people go through. So, first of all, thinking about people who have known opioid use disorder who are not making this choice to, you know, there are some people who say, literally, I want to stop. I don't want medication. I want to go through a residential program, which doesn't have a ton of data for who's getting Suboxone and they go off to some residential program and they stop it, what I'm worried about is that that patient is going to have a lower level of tolerance for the time that they are abstinent. And then when they relapse, they're going to buy what's on the streets of my city and your city too, which is heroin laced with fentanyl or a product that is fentanyl, which is extremely high potency, that's being sold under the name heroin. At that point, they're going to die. So, you know, I look upon the medication that they're receiving, particularly if they're a high-risk patient, as protection against overdose from what's being sold on the streets. So, it's a, you know, so there are two aspects that comes to this. One is, what is the effect of stopping opioids? Is therapeutic opioids or drug use opioids, abstinence in a drug use culture? So therapeutic opioids, people think the effect disappears after the first few days of withdrawals. That's not true. In a proportion of people, they have what is called a protracted abstinence, meaning abstinence syndrome or protracted withdrawal syndrome, which can last for months to weeks, which makes them extremely vulnerable to adverse outcomes, suicides, violent behavior. So if a person is behaving abnormally after stopping opioids, you have to consider the diagnosis of protracted withdrawals in that. I think it's in March, we wrote an editorial, David Feilly and Bob Rosenhag wrote an editorial in BMJ that in opioid use disorder, there is a golden month. So there's a golden month of first four weeks of treatment when the mortality risk is high. That is when their mortality risk is high and the first four weeks of discontinuation. So you should have special attention to these things. So induced abstinence is a high-risk venture. Anybody who says otherwise is probably wrong. Can we clarify one piece there? I spoke about overdose risk in the patient who I think of as my addiction patient. And I think that what AJ has said applies to those people, but it also applies to another group. It applies to patients who have been on long-term opioids for chronic pain, some of whom would have something like a complex form of dependence, many of whom now are being tapered or taken off of opioids in the name of their safety. And what we're saying is that that is an unproven proposition that they're being made safer, particularly if it's being done involuntarily, and that, in fact, we are observing, at least anecdotally, considerable risk for that exact population. I have a piece in thehill.com describing a patient who had never really shown signs of addiction per se, but had been on high-dose opioids for many years, where the discontinuation of opioids from high-dose eventually to 10% of his original dose resulted in his withdrawal to bed, his not taking his medicines for other medical problems, and the loss of his transplanted kidney. And all of that opioid change was undertaken in the service of his safety. So, I will give you a perspective, I will give you a case to give you a perspective how this protractor end of withdrawal syndrome is exhibiting. So I had a patient who was on 180 milligrams of morphine per day. And suddenly this just stopped. For chronic pain, he was on it for 20, 30 years, and they just stopped. They just tapered off. Not stopped in the sense that tapered off. So since then, for the past one year, he has been in the hospital 15 times for chest pain, hypertensionensive crisis. Nothing else. Chest pain, hypertensive crisis. Every single time they give him nitro, they work him up for EKG, they give him antihypertensives, nothing works. Then they give him a little bit morphine for his pain and everything comes under control. Then they send him home without any opioids. And recycle the same symptoms. Again and again. So in pain patients, if there is hypertensive crisis, it would make much sense at this period to ask whether they have been tapered off opioids. So there are symptoms like that that is coming along the way, you know, with clinical pictures that is emerging with this whole opioid taper. And when I attend on the wards, the same business, when we have a mystery case, I say, please review the last three months of the chart to find whether opioids were discontinued recently. And when it's a mystery case, at least half the time, I'm right in asking for that. Oh, I can't wait to look like a genius on rounds for suggesting that. Yeah, despite my previous comment about the book multipliers. Okay, so I think we have, I'm being hypocritical, and I have audio. Yeah, anyway, I think we should start to wrap up for interest of time. But luckily, we're going to have you gentlemen back next month to kind of continue this discussion. I kind of see next time going as being like a random pearls in addiction medicine. We can kind of explore some other issues related to substance use disorders and other substances. Stuart, do we have any questions from Facebook that you think could be quickly answered? We just have the one, and it was specifically about what are some of your thoughts of the ethical considerations of naloxone autoinjectors available without a prescription? In my state, there is an statewide order that comes from the medical officer for the state that essentially covers every potential patient in the state. You can walk into any pharmacy, request naloxone, and get it. And that's from the very not liberal state of Alabama. There's no evidence that having access to naloxone leads someone to develop an addiction. It's unpleasant to take naloxone if you're receiving opioids. So I think it's basically a reasonable thing to do. So there's a misconception about overdose. People mostly think about overdose as you take excessive amounts of medication, hence the term overdose. Most people, if you do the autopsy studies and the blood level studies on heroin overdoses, they typically have lower than normal, what is called therapeutic level of heroin. Typically, what causes death? It's true. This is playing out in the fentanyl overdose death too, if you look at the literature, read carefully. Fentanyl is a strong, pure strong pure drug no most overdoses are due to polysubstance use you have to really understand that so if polypharmacy is a big issue along with prescribed opioids so in heroin use most overdoses are polysubstance use and typically they have psychiatric disorders and comorbid medical disorders so these are the people who die from heroin dose in opioid prescribed opiates i get asked this all the time about whom should we prescribe naloxone to right that's a fairly question we have the dose description but know, if you end up giving everybody about 50, above 50, you know, it just doesn't make sense, right? So, I typically follow the last four categories I said.
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These are my high-risk patients. So they get naloxone. Well, our internal medicine patients check most of those boxes, comorbidities, a lot of them have mental health issues, of course, polypharmacy. So even if they don't have prior substance abuse, they are at risk. So that's great. That's really helpful. At this point, can I ask, Stephan, could you give us your take-home points, and then AJ, I'll ask you for yours next. Yeah, the decisions we make with patients when it comes to opioids should involve just a decision about understanding who they are and then calibrating risk against benefit. I am reluctant to embrace absolute rules in this area. When I read the CDC guideline, I actually think, as written, it adopts that perspective. Unfortunately, many physicians today will come under pressures that seek to essentially weaponize that guideline into a set of absolute rules. Legislators may do it. Pharmacies may do it. Insurers may do it. But the guideline as written really talks a lot about assessing the risk, the benefit, and the observable harms to your patient. And that's where I land. That pretty much sums up my advice too. So, I mean, so one thing you have to realize is that, you know, we don't know a lot about opioids. We don't know a lot about dependence. So when I hear physicians talk about this as certainty that stopping opioids, you know, it will improve risk. It doesn't work out that way all the time. So you just have to have some humility in recognizing that we don't know everything about opioids. In some certain people, it can be helpful. It's a terrible drug. It's a poorly tolerated drug, but it has its role. I'm going to encourage our audience. I have an ask for the audience is find out who in your practice or who in your area can help put people on these medications like Suboxone. Most internal medicine patients, I think, Right. I just moved locations and I need to find out because this conversation for me, you guys are really highlighting the point that just stopping tapering people off these medications has a fair amount of risk and it's probably not the right thing to do for most patients. So I think, I hope the audience heard that message and can kind of seek out resources to do this more responsibly and more, I don't know, humanely or safely, whatever the right word is. So tapering has its role. I don't want to deny that. But be cognizant that it is associated with risk. It's not a risk-free venture. Even if the patient wants to taper, you should be aware that it could become a very risky venture and be prepared for that. Gentlemen, this is awesome. I learned a lot. We look forward to talking with you again next month about some related issues, but some different areas that I also need a lot of teaching on. So thank you. Pleasure. Thank you for having us. Thank you so much. I'll Lake City articles, books, websites, or apps mentioned on the show at thecurbsiders.com forward slash podcast. You can also sign up for our weekly mailing list at thecurbsiders.com forward slash knowledge food, where you'll get our expertly done show notes. Are you ever going to update this outro? No, I don't think so.am. And good night. And I remain Dr. Paul Nelson-Williams. Good night. Well, hi, Paul. Hi, Paul. Classic bit. you
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Welcome to Intention to Treat from the New England Journal of Medicine. I'm Rachel Gottbaum. Today, the plight of primary care. Why we're losing the battle and seeing more doctors flee primary care and fewer entering the profession at all. It's turned us into a widget factory of just throughput, getting people in, getting people transferred onto money-making specialties without really addressing their healthcare needs. And it's demoralizing and it's not good care. This is Intention to Treat from the New England Journal of Medicine. My name is Jim Williams. I'm a family physician. I have run a small concierge medical practice for eight and a half years. Prior to that, I worked with my father in the primary care practice. He operated for 49 years. After he retired, I worked for a large healthcare company that owns multiple hospitals for three years, and then I started this concierge practice. My father's practice, he started it in Woodbridge, Virginia in 1962. I joined him in 2001 and we practiced in that same office until he retired in 2011. I chose family medicine before medical school when I participated in a seminar with my dad and I heard him talking about these families. He was taking care of four generations of families. And so it was the chance to join this community, join this family business, you know, our family's history and tradition in Woodbridge. My father's medical practice survived just fine with very few changes. In fact, patients would comment it was the same furniture from the 1960s. But we didn't have to change much. In fact, in 49 years, he had only three different receptionists. They came, they stayed, they retired. When the Affordable Care Act passed, all of a sudden, so many changes came to us. We had to convert to an electronic medical record, and we had to increase our HIPAA compliance in so many ways. And all of the bundled expectations that came, we needed completely new staff to handle all the technology that needed to be incorporated into the practice. And overnight, our costs soared and everyone was working harder to accomplish less, seeing patients every seven or eight minutes. My dad was 78. I needed to find another doctor and I couldn't. No one wanted to join the school. Everyone was going to work for the hospital-owned practices and the hospitals were calling. They were cold calling me offering to buy it. So there I was with a retiring father and a retiring staff. I had two hospital systems offering to buy the practice and I became a corporate employee in 2011. The hospital company that took over the practice wanted things done a certain way and there was really no room for personalization of the experience between doctor and patient. What was lost was the little room with the little paper chart and just the chance to really talk and have time to really talk. You know, if you go to the doc and you've just got a sore throat and that strep test is positive, seven minutes is plenty really. You just need your penicillin. But if it's an 84-year-old who's slow because of the arthritis and memory is not what it used to be, and there are six problems, it's an hour. And probably also a phone call to her daughter as well afterwards. And so a lot became impossible overnight. The office was managed in a very compartmentalized fashion. The scheduler was generally not on site. It was a call center. And you got to work and you saw what was on your schedule. And it was the day divided up to 10, 15, and 20-minute slots. 20 minutes was a yearly physical. And then as the day goes by, you click on your inbox on your computer medical record. And by 10 a.m., there were 15 prescription requests, refill requests. And three, you know, please call this person back. She has a cough or she has this problem. And some of these were people I had never met. So, you know, by three o''clock you're just thinking to yourself, how am I going to finish this safely without really making anybody mad at me? And if one of my patients ended up in the ER, I'm the primary care physician, I'm the one person on the hospital campus they know. They're in the ER and I don't even know it. What was quickly missing, you know, the key things we go into medicine for, you know, we want to help people. And the way we can help people, yes, it's based on our knowledge, but the knowledge isn't nearly enough. It's got to be the relationship. When you find cancer and you know that this person is going to need, in the coming days and weeks, someone's going to need perhaps a CT scan and then a consultation and get a biopsy and then maybe a consultation with an oncologist and then maybe here comes surgery or here comes chemo. That protocol, that's easy to find. And often the patients have already sketched the outline of what that's going to be. But talking someone through all of that and making sure they understand so that this person is going to be able to sleep at night knowing they've got help. That takes a relationship. The information doesn't help the person sleep at night. That's, in fact, to the opposite. They stay up all night reading the internet. But having that relationship with a physician where you can talk it all through and now you're not just getting the right information, but you're getting great care. I'm in this new corporate job. It had been about two years and some of my patients were making the commute from Woodbridge, Virginia up to Washington, D.C. to stay with me. And so patients like that and other patients, I started giving them my cell phone number and my email. I didn't want them to end up in the ER again and me not know about it. If there was one way or another I was going to try to make a difference and I was taking these calls and these emails after hours and I realized hey this this is the only way to practice. This is the only way to keep the relationship in the practice to keep-focused. But it's also completely incompatible with the job I'm in. As I was practicing, I wasn't providing great care to my patients, and I wasn't going to be able to keep it up. So I started talking to other doctors who had found a way to keep their independence. And the more people I talked to, the more I heard about this concierge model and how it worked. So what it means is this. Patients pay an annual membership fee. It's like your Netflix or your Costco. And after that, there are other charges. You know, if you come to the office and have a flu shot or medical exam or whatever else might be, those charges go to your insurance plan. With the revenue from the annual membership fee, I can keep the practice a size that is a fraction of what it was in the corporate world. So instead of having 3,000 or 4,000 patients assigned to me, it's just a few hundred. Appointments can be 30, 60, or 90 minutes long. There's always an hour available the same day. If someone were to call right now, I could see them at 1 p.m. And I also have time to coordinate care, and my staff does too. It makes me feel like I'm much more valuable to my colleagues, the specialists, who don't get the chance to know my patients as well, and they can rely on my staff and I, such that we become far more integral in all of their care, not just the care they get from us. My medical IQ is way up because I have the time to communicate with their specialists, even accompany them to some office visits and be there when they're in the ER. And every day when they're in the hospital, I get to go over there and be a part of their hospital care. I never got to do that. It's a harder job. You're on call. But it feels a lot less like work and just a lot more of who I am. On my wish list is to figure out how to demonstrate to Medicare and other health insurance companies how much money we save them. Because with our same-day availability, our house calls, our close communication with the family of our patients, our ability to keep people out of the emergency rooms. You order fewer CT scans. You order fewer lab tests. All those things that Medicare can't even afford now, we don't need as much of because with our time, with the human touch, we reduce costs. People like me, we have our independence dream. We feel like we're the doctor. We should be making these decisions. We should be the one directing care. This is why we're here.
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You've got to let us do it, and we need time to do it. This is Intention to Treat from the New England Journal of Medicine. I'm Rachel Gottbaum. To discuss the state of primary care and how we got here, we're joined by Chris Kohler. He's president of the Milbank Memorial Fund and former insurance commissioner of the state of Rhode Island. We're also joined by Dr. Kavita Patel. She's a primary care physician in Maryland, and she's former director of policy for the Office of Intergovernmental Affairs and Public Engagement in the Obama administration. So, Chris Kohler, I want to start with you. You folks did a report card on primary care and had some pretty startling findings about access to primary care in an era when we have more insurance, more people are insured, record numbers that indicate why and how we're doing worse here with primary care. What did you find? And let's talk about what's behind that and what's the significance of it. Primary care is the only part of the healthcare system where we've been able to show that an increased supply is associated with improved health, improved lifespan, and improved equity. The Milbank Memorial Fund looked at the status of four aspects of primary care, of financing, of access, of workforce, and of research. And primary care is fragile and weakening in the United States. The portion of dollars that's going to primary care in the U.S. is declining. It's declining across all payers. We're stuck in a payment system for primary care that does not reward team-based care. In terms of access to primary care, what we found is that even though we have increased the portion of people with insurance coverage in the United States to record high levels, there are fewer and fewer people who report having a usual source of care. Care is fundamentally about a relationship, about a place that we go when we're not feeling good, when we're trying to figure out how to navigate the health system. And fewer and fewer people report having that. And the supply of primary care clinicians varies by up to 50% across the country. And there's an increasing gap between the haves and the have-nots, the areas that have a lot of primary care and those that don't. Our workforce training is failing the United States. It's training fewer primary clinicians. It's training them on the coasts and in hospitals and not in communities where it's needed. It's going to get worse. 2010, one in three doctors was practicing primary care. In 2020, we were churning out one in five medical school graduates going into primary care. And then finally, overall, we spend about 6% of our healthcare dollar in primary care. That's less than other countries. But we only spend 0.2% of our research funding on primary care. So we're much more concerned with end-of-life diseases than we are with these basic medical services that can improve the health of populations. So in other words, we have more insured people who aren't having access to continual preventative care through primary care. Dr. Patel, perhaps you can address what you're seeing here. So on a typical full day, I'll see anywhere between 24 to 32 patients. And a lot of those visits are double booked, sometimes triple booked. And it's really because I have somebody that I have a continuity relationship with, someone who knows me as their primary care doctor. And the truth is that if I were to just hopefully find an open spot, Rachel, with just even the most nimble of scheduling, we're all so far booked with primary care visits that the earliest I could get people in would be like six to eight weeks. And it doesn't make you feel good when you have a problem and you need to see your doctor who knows you and has had a relationship with you for years in six to eight weeks. My happiest time is when I'm sitting in the room. I try to put the computer away. Even I'm sick of looking at a screen and they're really not looking forward to having me looking at the screen. But at some point I got to get all the screen work done. So I try desperately. I've taken classes. Many of us are trying to take classes on the side on how to chart more effectively so that we can make more out of our time in that 15 minute visit. And so there is no way for anybody to get access if they need to outside of a very well planned, thought out primary care visit that one might say schedule six months in advance. That's just not what care is. Care happens in that 99.999% of a person's life. And I have no time to have access to it. And they have no ability to get me. And I was part of the senior staff in Congress when we put forward the provisions that mandated the use of electronic health records. Along with that came very generous financial incentives because the data had been mounting that that's just better and safer for patients. I will tell you that, you know, inbox fatigue, all of these things that people describe are very real because there is a palpable sense of dread every time I look at the message portal. And what we've done is we've facilitated what I think is terrible triage. You think, Rachel, that you as a patient with your chart and access to a patient portal means better access to your doctor. But if I were to tell you that I have hundreds of messages, I try to read through and see which ones are the ones that I really need to deal with. It's very daunting. And so I, as a hack, have given my continuity patients my cell phone. I've hacked around what I would say is this incredible, well thought out, you know, what we thought policy to let people coordinate their care and have better access in general. And, you know, my better access is my phone. And that's how patients actually get real stuff done with me. So what happened here? Maybe Chris Kohler, you can address it. And then Dr. Patel as well, because Obamacare happened. We invested in medical homes. We insured people. But yet, somehow, the system is squeezing out primary care. What is going on? It's not new news that we undervalue primary care in the United States. We've always underpaid for primary care. What's made it worse? Why is there, as Kavita says, a palpable concern about access that wasn't there 10 or 15 years ago? I think the digital demands are really part of it. I talked to primary care clinician friends, and they share Kavita's palpable sense of dread at the inbox and not being able to keep up with the demands, with the expectations that are placed on them. So we have increased digital demands. We also have increased, let's call it measurement demands, in this move towards population-based accountability. We're not asking our dermatologists to assume population-based accountability. We're not asking our emergency room clinicians. We're asking our primary care clinicians. So you have a digital demand, you have a workload demand, and you have increasing economic opportunities created by pharmaceuticals, created by payment reform that has created increased consolidation, that has created other options for primary care clinicians to do their work in ways other than the population-based, relation-based care that Kavita was speaking to. So 15 years ago, we didn't have this quasi primary care option of being a hospitalist, of taking your primary care trade and practicing it inside a hospital to help get patients out. So all that has made the practice of, I don't even want to call it traditional primary care. I want to call it community-based primary care, less and less attractive for clinicians. And we know how to do high-quality primary care. We know how to do team-based care that releases some of the pressure that Kavita spoke to. We just don't know how to encourage it. We don't know how to scale it. We don't know how to replicate it. Dr. Patel, primary care, as Chris Kohler says, it's not valued, but it's used to help make money for the system. As we see more hospital-based systems buy up primary care practices. What happened here? If you look at an average Medicare patient and how many specialists they see or how many medications they take, they often have more than one or two or even three doctors. In primary care, everything just rolls down to us. If it's something that one of their other specialists can't deal with or they can't get a hold of, et cetera, comes to us. In turn, we are also that platform, that bench foundation for which every health system and specialist needs for their referral base. So you could not run a health system without a primary care strategy.
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Like, well, we can't, even though primary care often lost money, that there was never a conversation about changing that finance dynamic because the downstream referrals into all the other specialties or into imaging and hospital-based services was so lucrative that you had to keep primary care clinicians. But it's further alienated many of my physician colleagues who, at the end of the day, were tired of being called providers. We want to be called physicians. And so it's begging the question of honestly, Rachel, what is the value of a primary care physician? And will that such unicorn of a person exist in 10 years? And there's been a lot of speculation about artificial intelligence and some people who have said, artificial intelligence will replace your doctor. Part of me says, bring it. Like if somebody can effectively replace me and it can be done so that people have better access, bring it on. I'm happy to see it. So far, I have yet to see proof that technology can replace the work that I do. And patients are sicker. I mean, just the complexity of what we're dealing with, because 10 years ago, if I had somebody that came in with stage three, four, non-small cell lung cancer, that was kind of a death sentence. If I had someone who came in with, you know, a certain type of lymphoma, that was a death sentence. We've advanced the biotechnology landscape where I can take someone with stage four lung cancer, and I can see them through to actually having a great quality of life potentially. But then that means that I'm now taking care of patients who have had not one, not two, not three, but four primary cancers. So we're doing a really good job helping people live longer. But when I have a new patient that's over the age of 60 or 70, and many times I'll have patients in their 80s and 90s, how am I expected to do that in a 15-minute visit? That's insane. Could you imagine wanting that kind of care? No, but that's what we have because the way we reimburse, I'm just constantly trying to shove more in. I don't even like talking about it as burnout. We're treating people what we think they're worth. And we're telling people in primary care, they're not worth that much. So Chris Kohler, why are big hospital systems buying primary care? If they're such money losers, why are they buying primary care? What is this consolidation doing to access? Hospitals are economic actors. And if they don't need a profit, they still want to grow. And the way to grow is to gain leverage in negotiation with commercial insurers and extracting higher prices from them. In that, primary care is a very valuable asset because as Kavita said, they generate referrals for the high volume specialties and they're historically undervalued. So I don't have to pay them everything that they're worth. So you have created a set of economic incentives that reward growth, reward size, reward transactions, not care, and primary care clinicians are a pawn in that. And I think what Kavita is saying is those are completely misguided in terms of what patients want when they get sick. When they're really sick, they want a trusted relationship, and that's what good primary care can provide. And we're at the risk where it's not going to be around. I have to interject here because I trained in a primary care residency track in internal medicine. I did that with full gusto and pride because I really do, did, do, and still believe in the value of a primary care. The ability I have to come into someone's life and be dropped in, even in like non-moments of crisis, I think that's a privilege. I think it's why a lot of us got called to medicine, but why I really enjoyed primary care. I get to know people over time. I will tell you, I have more and more colleagues that work around me, myself included, who are willing to give up money if they can get some of that autonomy back. When I say autonomy, it's the ability to create your work environment that allows for you to deliver better patient care. The autonomy that I have always been looking for is some ability to influence how my own schedule is created. A lot of what I think physicians struggle with is that they feel like so much of what we walk into, we come out of medicine, we're incredibly well trained, but we walk into environments where we're just kind of, I feel like I'm just a little widget. I'm a square peg and I'm hammered, hammered, hammered to fit into this circle. And nothing makes me sadder, Rachel, than when I lose one of my colleagues to a concierge practice or to a cosmetic boutique or a medical spa, or they become a physician burnout coach, which we desperately need because those opportunities give them that autonomy. And there's the phrase moral injury, and I don't want to misappropriate it. But if you've been in primary care long enough, there is an incredibly distressing psychological aftermath of what has happened practicing primary care. And again, this is not, I hope that somebody smarter than me and with support of leaders like Chris can fix this. But my hope for that window to happen in my lifetime is quickly dwindling. That's Dr. Kavita Patel. She's a primary care physician, and she's also former director of policy for the Office of Intergovernmental Affairs and Public Engagement in the Obama administration. And Chris Kohler, he's president of the Milbank Memorial Fund, and he's also former insurance commissioner of the state of Rhode Island. This is Intention to Treat from the New England Journal of Medicine. Next time, can we fix our broken system of primary care? We have to make it more relational. Less of a business and more relational. We need to create more time for that relationship development so that primary care doctors have fewer patients and can actually focus in and be present with the ones they do have. That's next time on Intention to Treat from the New England Journal of Medicine. I'm Rachel Gottbaum.
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Welcome to the New England Journal of Medicine audio summary for the week of December 31, 2009. We wish you a Happy New Year. I'm Dr. Michael Bierer. This week's issue features articles on MMP12, lung function and COPD in high-risk populations, genetic susceptibility to infection by Mycobacterium leprae, household transmission of 2009 H1N1 influenza, outbreak of 2009 H1N1 influenza at a New York City Thank you. and on industry influence on comparative effectiveness research funded through health care reform. MMP-12 Lung Function and COPD in High-Risk Populations by Gary Honihake from the Channing Laboratory and Center for Genomic Medicine, Boston. Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease, COPD, particularly in high-risk groups. These investigators tested for an association between single nucleotide polymorphisms in the gene-encoding matrix metalloproteinase 12, MMP12, and a measure of lung function, FEV1, in children and adults. The minor allele, G, of a functional variant in the promoter region of MMP12 was positively associated with FEV1 in a combined analysis of children with asthma and adult former and current smokers in all cohorts. This allele was also associated with a reduced risk of the onset of COPD in a cohort of initially healthy adult men, hazard ratio 0.65, and with a reduced risk of COPD in a cohort of smokers, odds ratio 0.63, and among participants in a family-based study of early-onset COPD. The minor allele of a SNP in MMP12 is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers. In an editorial, Guy Bruxelles from the Ghent University Hospital, Belgium, writes that the observation that genetic variants in MMP12 influence lung function both in children with asthma and in adult smokers supports the Dutch hypothesis, which states that asthma and COPD, encompassing chronic bronchitis and emphysema, are different manifestations of a single disease entity. This study also adds to the accumulating evidence that several mechanisms may lead to the development of COPD. Genome-Wide Association Study of Leprosy by Fu-Ren Zhang from Shandong Academy of Medical Science, China. Leprosy is a chronic infectious disease caused by mycobacterium leprae. It affects the skin and peripheral nerves and can cause irreversible impairment of nerve function and consequent chronic disabilities. The narrow host range of mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. This genome-wide association study implicates variation in genes encoding molecules in the Nod2 signaling pathway, which regulates innate immunity, in susceptibility to infection with Mycobacterium leprae. Erwin Schur from McGill University, Montreal, writes in an editorial that although the results of this study are exciting, additional experiments are required to validate and refine their conclusions. Although genome-wide association studies rarely identify causative genetic lesions, they do point to specific genes and biologic pathways that can be targeted for pharmacologic intervention, irrespective of the mechanism underlying genetic susceptibility. A particularly attractive aspect of this study is the apparently narrow focus of the genetic control, which highlights early antigen sensing and signaling in the pathogenesis of both leprosy and Crohn's disease. Such a link may broaden the therapeutic treatment options for both diseases. Household Transmission of 2009 Pandemic Influenza A H1N1 Virus in the United States by Simon Koshamaz from the Imperial College London in the United Kingdom Factors relating to the transmission of the 2009 H1N1 virus from an index patient to a household contact are poorly understood. In this study, an acute respiratory illness developed in 78 of 600 household contacts, 13%. In 46 households, 21%, illness developed in one contact, and in 14 households, 6%, illness developed in more than one contact. Household contacts 18 years of age or younger were twice as susceptible as those 19 to 50 years of age, relative susceptibility 1.96, and household contacts older than 50 years of age were less susceptible than those who were 19 to 50 years of age. Relative susceptibility, 0.17. The mean time between the onset of symptoms in a case patient and the onset of symptoms in the household contacts infected by that patient was 2.6 days. The transmissibility of the 2009 H1N1 influenza virus in households is lower than that seen in past pandemics. Most transmissions occur soon before or after the onset of symptoms in a case patient. Outbreak of 2009 Pandemic Influenza A H1N1 at a New York City School by Justin Lessler from Johns Hopkins University, Baltimore. In April 2009, an outbreak of 2009 H1N1 influenza occurred at a high school in Queens, New York. From April 24th through May 8th, infection with the 2009 H1N1 virus was confirmed in 124 high school students and employees. In responses to an online questionnaire, more than 800 students and employees, 35% of student respondents and 10% of employee respondents, reported having an influenza-like illness during this period. No persons had severe symptoms. A linkage with travel to Mexico was identified. The estimated median incubation period for confirmed 2009 H1N1 influenza was 1.4 days, with symptoms developing in 95% of cases by 2.2 days. The findings from this investigation suggest that 2009 H1N1 influenza in the high school was widespread but did not cause severe illness. Public Reporting of Discharge Planning and Rates of Readmissions by Ashish Jha from the Harvard School of Public Health, Boston. that discharge instructions were provided to patients with congestive heart failure and patient-reported experiences with discharge planning. They found a weak correlation in performance between the two discharge measures. Although larger hospitals performed better on the chart-based measure, smaller hospitals and those with higher nurse staffing levels performed better on the patient-reported measure. They found no association between performance on the chart-based measure and readmission rates among patients with congestive heart failure, and only a very modest association between performance on the patient-reported measure and readmission rates for congestive heart failure, readmission rates 22.4% versus 24.7% respectively, and pneumonia, 17.5% versus 19.5%. These findings suggest that current efforts to collect and publicly report data on discharge planning are unlikely to yield large reductions in unnecessary readmissions. Activated Protein C for Sepsis, a Clinical Therapeutics article by Suzanne Toussaint from the Vivantes Klinikum Neukölln, Berlin. Sepsis is a systemic inflammatory response to presumed or known infection. It is a leading cause of in-hospital death in adult patients, and the incidence is increasing worldwide. An important feature of the pathophysiology of sepsis is the development of a procoagulant state. Disseminated intravascular coagulation, one of the most feared complications of sepsis, is a manifestation of the dysregulation of coagulation. Protein C is a soluble, vitamin K-dependent plasma serine protease that plays a central role in endogenous anticoagulation. The activated form is generated when thrombin, bound to the cofactor thrombomodulin, interacts with and cleaves the zymogen protein C. Activated protein C is a potent anticoagulant and pro-fibrinolytic enzyme capable of inactivating clotting cofactors 5A and 8A and plasminogen activator inhibitor 1. Pro-inflammatory cytokines, such as tumor necrosis factor, induce a decline in thrombomodulin activity and thus a decrease in the generation of activated protein C. Reduced levels of protein C in patients with sepsis have been correlated with an increase in the risk of death. These observations led to the hypothesis that the administration of activated protein C might be beneficial in patients with sepsis. The clinical benefit and recommendations for use of recombinant human activated protein C are controversial. The risk of bleeding is increased with use of the drug. A 16-year-old boy with hypothermia and frostbite, a case record of the Massachusetts General Hospital by Robert Sheridan and colleagues. A 16-year-old boy was admitted to the hospital after being found unconscious in a snowbank on New Year's Day. The night before, he attended a party where alcohol was consumed. He was last seen at approximately 11 p.m. At approximately 6 a.m., he was found unconscious in a snowbank by local firefighters and police officers. He was partially undressed, with his pants down and his right boot off.
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On initial examination, he was drowsy and slow to respond, but oriented, with spontaneous respirations and no shivering. The rectal temperature was 31.3 degrees centigrade. Both hands and the right foot were cold and hard to palpation. The left foot was cold, but soft. This patient sustained cold injuries that were both systemic, hypothermia, and local, frostbite. Paradoxical behaviors of burrowing and undressing are seen in up to half of patients dying from hypothermia. It is thought that these behaviors may be due to hypothalamic dysfunction, which occurs at a core temperature at or below 32 degrees centigrade, 89.6 degrees Fahrenheit, and gives a sensation of extreme warmth. This case discusses the management of this patient's injuries, which had both physical and emotional consequences. Aging. Lost in Translation? A Clinical Implications of Basic Research article by Pankaj Kapahi from the Albert Einstein College of Medicine, Bronx, New York. Extending the span of a healthy life has fascinated humanity ever since Gilgamesh failed to prevent his dying friend Enkidu from descending into the horrific netherworld, as described in the epic poem from ancient Iraq. Recent discoveries in the research on aging suggest that modern science is more adept at keeping aging at bay, at least temporarily, and thus far only in worms, flies, and rodents, than at halting it completely. A recent study has identified ribosomal protein S6 kinase 1, S6K1, as a molecular player in the aging game. These investigators observed that deletion of the S6K1 gene leads to an increased lifespan and resistance to age-related diseases in mice. As compared with their wild-type littermates, S6K1-deficient mice were protected against age-related declines in motor, bone, and immune function, but not against cancer, and had elevated sensitivity to insulin in old age. Abortion Politics and Health Insurance Reform, a perspective article by George Annis from the Boston University School of Public Health, Boston. President Barack Obama has made it clear that he does not want abortion politics to sabotage health care reform. In his September 10th speech about health care reform law at all. The current abortion controversy concerns the Stupak Amendment, whose presence or absence from the final bill may determine the votes of enough members of Congress to determine the outcome. This makes it critical to understand both this amendment and the current state of the law on federal funding for abortion. The Stupak Amendment provides that, or physical illness that would, as certified by a physician, place the woman in danger of death unless an abortion is performed, including a life-endangering physical condition caused by or arising from the pregnancy itself, or unless the pregnancy is the result of rape or incest. End quote. The current version of the U.S. Senate bill does not contain the Stupak Amendment, but specifically excludes federal funding for abortions as prohibited by any federal law that was in effect six months before the beginning of the plan year involved. Australia's Winter with the 2009 Pandemic Influenza A H1N1 Virus, a perspective article by James Bishop from the Department of Health and Aging, Canberra, ACT, Australia. When the World Health Organization declared a public health emergency of international concern on April 25, 2009, after the emergence in Mexico of pandemic influenza A H1N1 virus, Australia activated its well-rehearsed plan for response to pandemic influenza. The Australian Health Management Plan for Pandemic Influenza is a strategic outline based on evidence and international best practices of actions and interventions that the healthcare community should consider taking during a pandemic. It describes the planning assumptions, the phases of a response, and the key actions that minimize a pandemic's effects on the population and the health care community. Over the subsequent six weeks, the implementation of border control measures, including requirements that travelers entering Australia declare whether they have symptoms of influenza or have been in contact with someone with severe respiratory illness and that contacts of persons with known influenza be traced, gave the health care community time to learn more about the natural history of the new influenza strain. Key lessons so far from this experience in an unprotected population suggest that important elements of the response were a national coordination of efforts and the use and modification of the national pandemic plan framework, focusing on persons who were most at risk. The Emotional Epidemiology of H1N1 Influenza Vaccination, a perspective article by Danielle Ofri from New York University School of Medicine and Bellevue Hospital, New York. Just as there are patterns of infection, there seem to be patterns of emotional reaction, emotional epidemiology, associated with new illnesses. When 2009 H1N1 influenza was first detected, it fit a classic pattern that Priscilla Wald recently outlined in her book Contagious. It was novel and mysterious. It emerged from a teeming third world city, and it was now making its insidious and seemingly unstoppable way toward the civilized world. As the novel disease establishes itself within society, a certain amount of emotional tolerance is created. H1N1 infection waxed and waned over the summer, and Dr. Ofri's patients grew less anxious. By late summer, the perceived mysteriousness of H1N1 had receded, and the number of messages on the clinic phone followed suit. But emotional epidemiology does not remain static. As autumn rolled around, Dr. Ofri sensed a peeved expectation from her patients that this swine flu problem should have been solved already. The dramatic shift in public sentiment over the course of this H1N1 epidemic is both fascinating and frustrating. It is clear that there is a distinct emotional epidemiology and that it bears only a faint connection to the actual disease epidemiology of the virus. Much attention has been focused on the ongoing efforts in Washington to pass a health care reform bill. Thank you. To do that effectively, we need data on the comparative effectiveness of therapies and medical tests, which unfortunately we currently lack. Recognition of this lack of data has resulted in the inclusion of increased funding for Comparative Effectiveness Research, CER, in current versions of the health care reform legislation. However, there are significant differences between the approaches. Although all versions include a trust fund that will provide approximately $600 million per year for CER, there is considerable controversy over how that money will be allocated and, most important, whether industry will have a part in controlling the allocation of the funds, the design of the studies, and decisions about which results can be published. Although most observers agree on the value of funding CER, many are unaware that embedded in the legislation are provisions ceding substantial influence to the medical products industries that have a major interest in the outcomes of such research. The images in clinical medicine features a vanishing mediastinal mass. A 39-year-old man was being examined because of a transient ischemic attack. On a chest x-ray, a mediastinal mass was detected when the patient was in the supine position, but disappeared when he was standing. This finding indicates an aneurysm of the superior mediastinal venous system. Also featured in the images in clinical medicine is a 58-year-old woman with a history of stage 1 cancer in the right breast who presented with a two-week history of shortness of breath and cough. Eight months before presentation, she had undergone lumpectomy and adjuvant radiotherapy to the affected breast. Over a period of five weeks, the patient had been treated with a total dose of 50 gray of radiation over the targeted field, which included breast parenchyma and a portion of the anterior lung. Subsequent CT showed typical features of radiation pneumonitis. This concludes the summary of the December 31st issue of the New England Journal of Medicine. We are interested in your feedback about our audio summaries. Any comments or suggestions may be sent to audio at nejm.org. Thank you for listening.
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This audio summary is sponsored by Ortho McNeil-Janssen Pharmaceutical, Inc. Visit topamax360.com for practice management podcasts, sample and patient education resources, and much more. Welcome to the New England Journal of Medicine audio summary for the week of August 21, 2008. I'm Dr. Lisa Johnson. This week's issue features articles on variants of SLCO1B1 associated with statin-induced myopathy, preeclampsia and the risk of later end-stage renal disease, adalimumab in juvenile rheumatoid arthritis, and the health and economic implications of HPV vaccination in the United States, a review article on idiopathic sudden sensorineural hearing loss, a case report of a woman with headache and behavioral changes, and perspective articles on health of the nation, coverage for all Americans, on the McCain and Obama plans for U.S. health care reform, and on the politics of clean water and sanitation. SLCO1B1 Variants and Statin-Induced Myopathy, a genome-wide study by the SEARCH Collaborative Group. Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications. This genome-wide screen of patients with myopathy who were taking high-dose simvastatin, 80 mg per day, showed a strong association between myopathy and variants of SLCO1B1, which encodes an organic anion-transporting polypeptide. Approximately 60% of the cases of myopathy could be attributed to these variants. The association was replicated in an independent study. Genotyping SLC-01B1 variants may be helpful for tailoring the dosage of statins and safety monitoring. Yusuke Nakamura from the University of Tokyo, Japan, writes in an editorial that since approximately 60% of the cases of simvastatin-induced myopathy were attributed to variant SLCO1B1, avoiding the administration of high-dose simvastatin to those who are homozygous or heterozygous for the variant allele, could reduce the incidence of myopathy by nearly 60%. Alternatively, one might choose to avoid prescribing simvastatin only to those who are homozygous for the risk allele, which could reduce the incidence of myopathy by 25%, and prescribe a relatively low dose of the drug to patients who are heterozygous for the risk allele. A global mechanism for collecting data on patients with severe adverse drug reactions would benefit the field of pharmacogenetics enormously and encourage the development of new technologies. Preeclampsia and the Risk of End-Stage Renal Disease by Björn Egelvikse from the University of Bergen, Norway. It's unknown whether preeclampsia is a risk marker for subsequent end-stage renal disease. These authors linked data from two large registries in Norway to assess the association between preeclampsia in one or more pregnancies and the subsequent risk of end-stage renal disease. End-stage renal disease developed in 477 of more than 570,000 women, a mean of 17 years after the first pregnancy. Overall rate, 3.7 per 100,000 women per year. Among women who had been pregnant one or more times, preeclampsia during the first pregnancy was associated with a relative risk of end-stage renal disease of 4.7. Among women who had been pregnant three or more times, preeclampsia during one pregnancy was associated with a relative risk of end-stage renal disease of 6.3, and preeclampsia during two or three pregnancies was associated with a relative risk of 15.5. Having a low birth weight or preterm infant increased the relative risk of end-stage renal disease. Preeclampsia is a marker for an increased risk of later end-stage renal disease, although the absolute risk in women who have had preeclampsia is still low. Ravi Thadani from the Massachusetts General Hospital, Boston, and journal editor Karen Solomon write in an editorial that although in the current report the relative risk of the development of end-stage renal disease was significantly elevated among women with a history of preeclampsia, the good news is that the absolute risk was quite low. Indeed, the likelihood that chronic renal failure did not develop, even among women with three previous episodes of preeclampsia, was greater than 99%. Nevertheless, the accumulation of data, including those from the current report, suggests that a history of preeclampsia may provide a glimpse into the future, with attendant opportunities for reducing the risks of later disease. by Daniel Lovell from the Cincinnati Children's Hospital Medical Center, Ohio. Tumor necrosis factor has a pathogenic role in juvenile rheumatoid arthritis. This study evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, alone or in combination with methotrexate, in children with polyarticular course juvenile rheumatoid arthritis. Among patients not receiving methotrexate, disease flares occurred in 43% of those receiving adalimumab and 71% of those receiving placebo. Among those receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo. At 48 weeks, the percentages of patients treated with methotrexate who had American College of Rheumatology pediatric 30, 50, 70, or 90% responses were significantly greater for those receiving adalimumab than for those receiving placebo. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients, including 7 patients with serious infections. Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. vaccination in the United States by Jane Kim from Harvard School of Public Health, Boston. The cost-effectiveness of prophylactic vaccination against human papillomavirus types 16 and 18 is an important consideration for guidelines for immunization in the United States. This study evaluated the cost-effectiveness of vaccinating 12-year-old girls and of temporary catch-up programs. On the assumption that the vaccine provided lifelong immunity, the cost-effectiveness ratio of vaccination of 12-year-old girls was $43,600 per quality-adjusted life year, QALY, gained, as compared with the current screening practice. Under baseline assumptions, the cost-effectiveness ratio for extending a temporary catch-up program for girls to 18 years of age was $97,300 per QALY. The cost of extending vaccination of girls and women to the age of 21 years was $120,400 per QALY, and the cost for extension to the age of 26 years was $152,700 per QALY. The results were sensitive to the duration of vaccine-induced immunity. If immunity waned after 10 years, the cost of vaccination of pre-adolescent girls exceeded $140,000 per QALY, and catch-up strategies were less cost-effective than screening alone. The cost-effectiveness of HPV vaccination will depend on the duration of vaccine immunity and will be optimized by achieving high coverage in pre-adolescent girls, targeting initial catch-up efforts to women up to 18 or 21 years of age, and revising screening policies. In an editorial, Charlotte Hogue writes that the base case assumptions in this study are quite optimistic. They presume lifelong protection of the vaccine, that is, no need for a booster dose, that the vaccine has the same effect on pre-adolescent girls as on older women, that no replacement with other oncogenic strains of HPV takes place, that vaccinated women continue to attend screening programs, and that natural immunity against HPV is unaffected. Whether these assumptions are reasonable is exactly what needs to be tested in trials and follow-up studies. With so many essential questions still unanswered, there's good reason to be cautious about introducing large-scale vaccination programs. Instead, we should concentrate on finding more solid answers through research rather than base consequential and costly decisions on yet unproven assumptions. Idiopathic Sudden Sensorineural Hearing Loss, a clinical practice article by Stephen Rauch from the Massachusetts Eye and Ear Infirmary, Boston. Idiopathic Sudden Sensorineural Hearing Loss is unexplained unilateral sensorineural hearing loss with onset over a period of less than 72 hours, and it has an estimated incidence between 5 and 20 per 100,000 persons per year. The likelihood of recovery of hearing has been reported to vary with the severity of hearing loss at presentation. Sudden sensorineural hearing loss is often accompanied by intense oral fullness or pressure, as well as tinnitus. It is considered by otologists to be a true otologic emergency, given the observation that there is less recovery of hearing when treatment is delayed. An office evaluation and complete audiogram is indicated if there is any suspicion of sensorineural hearing loss.
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In the absence of these findings, sudden sensorineural hearing loss is the presumed diagnosis. Treatment should not be delayed, even if imaging cannot be obtained promptly. Although supporting data are limited, corticosteroid therapy is the current standard of care, according to a randomized trial suggesting that it may improve or restore hearing, and because of the absence of other known effective therapies. A 26-year-old woman with headache and behavioral changes. A case record of the Massachusetts General Hospital by Thomas Sabin and colleagues. A 26-year-old woman was admitted to the hospital because of headache, behavioral changes, abnormal movements, and inability to communicate. Seven weeks earlier, generalized diffuse headache developed. It was most severe in the occipital region, with associated neck stiffness, sensitivity to sounds, intermittent blurred vision, nausea, and vomiting. Somnolence, dysphoria, short-term memory problems, confusion, agitation, and symptoms of depersonalization developed. A variety of psychopharmacologic medications failed to alleviate these symptoms. An evaluation for infection was negative. A tonic-clonic seizure with marked bradycardia was followed by several days of unresponsiveness with pinpoint pupils. Fever and elevated levels of creatine kinase raised the suspicion of the neuroleptic malignant syndrome. The clinical picture was then complicated by the infections and drug effects that often occur with intensive care. Imaging studies showed a normal brain and an ovarian mass consistent with a dermoid cyst. Within 48 hours after an operation, the patient was able to answer basic questions appropriately and write her name. Health of the Nation, Coverage for All Americans, an editorial by journal editors Stephen Morrissey, Gregory Kerfman, and Jeffrey Drazen. After 117 Shattuck lectures delivered since 1890, the lecture this year took the form of a seminar discussing the topic Health of the Nation, Coverage for All Americans. The panelists included physicians, academics, and leaders from business, the insurance industry, and politics. In this important election year, with health care as one of the principal campaign issues before the nation, we wanted to present the perspectives of a number of experts representing many parts of the health care community and different political persuasions. What are the prospects that the proposals of Senators John McCain or Barack Obama will result in meaningful reform of the U.S. health care system? There is some reason to be pessimistic. The journal editors believe, however, that it would be a mistake Thank you. The time is right for reform. The opportunity is here, and the Massachusetts Medical Society brought together 13 panelists, physicians, academics, and business, insurance, and political leaders for a seminar on U.S. health policy and health coverage. In a discussion moderated by Arthur Miller of the New York University School of Law, the participants identified important challenges to the U.S. health care system and debated possible solutions. The group addressed the dissatisfaction among physicians in general and primary care providers in particular and considered its relationship to a reimbursement system that rewards high-tech procedures rather than cognitive work and time spent with patients. Various approaches to payment reform were proposed. Thank you. that other countries have seen. Several participants expressed concern about the disproportionately high costs of new drugs and end-of-life care in the United States and broached the topics of negotiation of drug prices, cost-effectiveness analyses, and rationing. After some consideration of the political, social, and economic obstacles to achieving universal access to Care, the seminar concluded with remarks on the politics of health care reform and speculation about change under a new administration. This seminar is available on video at NEJM.org, together with an area where we welcome viewers to comment and participate in a poll. Thank you. uneven quality of care, and the growth of the uninsured population, there's broad agreement that the U.S. health care system requires reform. However, Democrats and Republicans remain sharply divided over how to reform it, as evidenced by the health care plans offered by the party's presidential candidates. The ambitious reform agendas of Senators John McCain and Barack Obama would take the U.S. health care system in very different directions. McCain's plan embraces market forces and promotes individually purchased insurance. Currently, workers do not pay taxes on health insurance premiums paid by their employers. The McCain plan would eliminate this tax exclusion and use the revenue generated, projected to be $3.6 trillion over 10 years, to pay for refundable tax credits for Americans obtaining private insurance, $2,500 for individuals, $5,000 for families. Barack Obama's reform plan relies on an employer mandate, new public and private insurance programs, and insurance market regulation. The core of the Obama plan is a requirement that employers either offer their workers insurance or pay a tax to help finance coverage for the uninsured. Some small businesses would be exempt and others would be subsidized. Oberlander writes that the McCain and Obama health plans are best viewed as sketches rather than finished portraits, with many important details yet to be revealed. Talking Dirty The Politics of Clean Water and Sanitation A perspective article by Michelle Barry from Yale University School of Medicine, New Haven, Connecticut. In the wake of Cyclone Nargis, which devastated the Myanmar Delta in early May, and the seismic earthquake that shook China shortly thereafter. Access to safe drinking water and proper sanitation have become top priorities among those attempting to prevent epidemic diseases. But even without catastrophic disasters, the lack of access to clean water and basic sanitation represents a silent crisis affecting more than a third of the world's population. Some 443 million school days are lost annually to water-related illness. Millions of women and girls spend up to two hours a day collecting water. And every day in Bangladesh alone, 28 to 35 million people consume drinking water containing dangerously elevated levels of arsenic. Given that the United Nations has declared 2008 the International Year of Sanitation, and that in the United States, this year marks the 100th anniversary of the first chlorination of a public water supply, this seems an appropriate time to re-engage in an ancient conversation about safe water and sanitation. The necessary political will has not been mustered to address the water and sanitation crisis, among the most neglected of the United Nations Millennium Development Goals. Political support is urgently needed at all levels for the development and implementation of evidence-based recommendations to improve access to safe water. This week's Images in Clinical Medicine features a 23-year-old male Marine recruit who passed out while bending over after a 1.5-mile run. Prominent varicosities were noted on his chest. Contrast-enhanced CT of the chest revealed a large anterior mediastinal mass with fluid, fat, and calcific densities that was compressing the right pulmonary artery. The mass was resected and a benign teratoma with components of all three germ cell layers was diagnosed. Also featured in the images in clinical medicine is a 63-year-old woman who presented with a one-year history of vague pelvic and back pain. She had undergone laparoscopic surgery of the fallopian tubes 27 years earlier, owing to infertility. CT of the abdomen showed an 8-centimeter pelvic mass. She underwent an exploratory laparoscopy. Attempts to dissect the mass led to its rupture, revealing contents that were suggestive of a dermoid cyst. However, on aspiration of the contents, an old swab was identified and removed. This concludes the summary of the August 21st issue of the New England Journal of Medicine. We're interested in your feedback about our audio summaries. Any comments or suggestions may be sent to audio at NEJM.org. Thank you for listening.
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This is the New England Journal of Medicine COVID-19 update for June 10th, 2020. I'm Stephen Morris, the managing editor of the journal, and I'm talking to Eric Rubin, editor-in-chief, and Lindsay Baden, deputy editor. This week, we have a guest as well. Dr. Michelle Evans is a senior investigator and the deputy scientific director at the National Institute on Aging, part of the National Institutes of Health. She's also a member of our editorial board. Her research spans epidemiologic and basic science approaches to understanding Thank you for the invitation. One of the striking observations throughout the current outbreak is how it's had unequal impact. In particular, minority communities have been particularly hard hit with both higher rates of disease and more morbidity, more death. Last week, we published a study that addressed one aspect of this. What did the investigators in that study find? Steve, this was an observational study that was done in Louisiana. It was performed in a large healthcare system, a network, the Ochsner Health System, which serves a large number of patients in that area. It's the largest healthcare system in Louisiana. Roughly half a million people who are cared for by the Ochskosh system, about two-thirds self-identify as white non-Hispanic, and most of the rest identify as Black non-Hispanic. So the investigators looked at electronic health record data to find out how people fared once they presented and what were the impacts on both the black and white communities. They found that about 3,600 people had presented with COVID-19 and the people who presented were disproportionately black. In fact, about 70% of the patients with COVID-19 self-identified as black and non-Hispanic. And remember that they represented only about a third of the patients who got their care through this system. These patients, the Black patients, also had more comorbidities with a higher prevalence of obesity, diabetes, hypertension, and renal failure than white patients. And all of these, of course, are known risk factors for poor outcomes of disease. However, despite that, their hospital courses were fairly similar. First, a similar percentage were hospitalized. About 40% of Black and white patients were hospitalized. There certainly was more morbidity among Black patients. More of them ended up in the ICU. More of them ended up on mechanical ventilation. But when you adjust for the poor prognostic factors, being black was not a risk factor for death. In other words, what determined the ultimate outcome of disease was largely their health at the time of admission, not their race. So there's good news and bad news in that. The good news is that all patients seem to be getting good care, at least in this healthcare system, independent of their race. But of course, Black patients came in with much more serious health problems. And to a great extent, that could represent unequal access to care as outpatients and earlier in life, and certainly unequal access to public health measures. So there are still serious inequalities. They're happening in this case before they get to the hospital. Well, I think at this time that we're faced with longstanding and persistent serious health disparities among the poor, among minority populations in general, and particularly for African Americans. And this exists for most chronic diseases, be it cardiovascular disease or diabetes. And these, of course, were the important risk factors for the more severe course in COVID-19 infection. The African Americans also have higher incidence and mortality from many different forms of cancer. And if we look at the beginnings of life, pregnancies are more frequently complicated, resulting in maternal morbidity and mortality among African-Americans. And this is independent of education or income. And so once these disparities begin at birth, if we don't have the economic supports, the health system supports to work against what happens at birth, we wind up with these serious persistent health disparities. If you look at life expectancy at birth rates in the United States, African-American men are particularly disadvantaged. They have a life expectancy at birth that lags Hispanic men by around seven and a half years and lag white men by at least five years. So this certainly ties into what Dr. Price-Haygood and colleagues found in that when you look at their COVID positive patients who were hospitalized, African Americans were younger than the white patients, 60 compared to 69. Although this may not be statistically significant, it perhaps is a subtle sign of the accelerated aging phenotype or the weathering that's associated with health disparities and premature mortality among African Americans. Certainly, pre-existing health conditions play a major role in outcome. But as you're beginning to suggest, Michelle, many investigators have found that minority communities have increased rates of even less severe disease, which doesn't necessarily bring them to the hospital. So why is that likely to be true? Well, I think that there may be four things to consider. Employment status, residential segregation, economic inequality, and healthcare access and quality, as we've already touched on. In terms of employment status, many African Americans and other minorities occupy jobs that are classified as essential workers that do not provide the privilege of working from home. These jobs include public transportation workers, healthcare workers, food service, and other commercial workers. For example, about 50% or so of essential workers in food and agriculture are people of color. We must also consider the gig economy, where we have these non-traditional full-time and part-time jobs that are predominantly occupied by African AmericansAmericans and Hispanics. Almost 50% of African-Americans rely on these types of jobs as a primary source of income. So these workers, they could not distance themselves or substantially reduce their exposure. And we also have the issue that is also pointed out by Dr. Hager-Price in terms of residential segregation. While the demographers are predicting that the United States will, by 2050 or so, become a majority-minority nation, there are still pockets of segregation within many cities. Hence, we have the existence of what we're calling COVID-19 hot zip codes. For example, a city I'm most familiar with is New York, where I was born and bred. The hot zip codes in New York City that are close to me are 104.75. That's the Co-op City zip code where I spent my teenage years. And there we have deaths per 100,000 of 368 with a positivity percentage of people tested at 29%. I went to high school adjacent to there in 104.66 in the Bronx. Again, a case positivity rate of 31% and a death per 100,000 rate of 220. When you compare this to Manhattan zip codes, for example, the Upper East Side Yorkville 10028, which is the zip code where the late former First Lady Jacqueline Kennedy Onassis lived, they had a death per 100,000 rate of 61, and only 13% of people tested were positive. So zip codes are predictors of health, of school quality, of job access, of housing quality, population density, city services, as well as even the availability of high quality food. Now, this is not to say that zip codes that have a high COVID positivity rate are not educationally representative of future accomplishment. I went to high school with Justice Sonia Sotomayor, who was also my neighbor in Co-op City. So these are places of great academic and intellectual potential. But we have to realize that residential segregation has substantial effect upon health care outcomes, and in this case, for an infectious disease. Michelle, I wonder too, you brought up the point that many African Americans are working in the gig economy in a country where much of insurance is tied to employment and many gig economy jobs don't supply insurance. I wonder if there's also unequal access to health care as a result of their employment circumstances. Yes, that's very true. And I think that's one of the problems that needs to be evaluated. When we tie health insurance, health care access to occupation and employment, we significantly disadvantage those who have unequal occupational opportunity and who sometimes fail to have persistent and consistent occupation. So it's almost even worse to have insurance for a period of time and then not have insurance, have insurance for a period of time, because that sometimes causes the worsening of some chronic medical conditions, as you're well aware. So Michelle, I mean, the challenges seem to be at almost every level in the community where you live with crowding and density of individuals that may lead to transmission, to employment where one has to continue to be an essential worker and commute and therefore exposure, and prior health care, which can lead to comorbid illness that may be inadequately addressed, has led to quite a synergistic illness in this population. Am I hearing you correctly? Yes. Income inequality is a severe problem, and that drives people to decrease their ability to protect themselves from, in this case, the virus. You have to remember that for every dollar earned by a white man, an African-American man, earns 87%.
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And when you look at African-American and Hispanic females, the pay gap is even worse. So that economic lack of opportunity, even in the face of pursuing educational outcomes that would, we think, provide that economic footing in this country, really substantially influences the development of health disparities and the development of multiple comorbidities that in this case have put African Americans at significant disadvantage of being able to survive COVID-19 infection. And one thing that we have to think about, we don't know what the outcome of COVID-19 infection is. So those who survive it, what are the long-term ramifications on health going to be? So this has now introduced perhaps a new health disparity that will be related to the sequelae from COVID-19 infection. So how much of what we're seeing here is new and how much is simply revealing the underlying problems of racism in medicine? I think that there actually are two pieces to that. There's racism in the medical field and in how patients are treated that is very longstanding. And as Michelle is illustrating for us, there are racism issues in public health and what happens in our communities outside of healthcare institutions. And I think that with the recent defense, the killing of George Floyd, I think that we have an opportunity to look at that again. and legitimize preferential treatment for one group over another, privilege of one group over another, this causes societal problems that result in chronic adverse outcomes, or in this case, for people of color. And it psychologically reinforces the belief that African Americans are inferior to whites in all aspects of life. So once this is codified into an infringement on human rights, we have to recognize that. Now, I will say in medicine, we have recognized the existence of health disparities. We have recognized the influence of social determinants of health, but we have not really fully marshaled our intellectual resources to prioritize this as we did with the war on cancer that Nixon funded or the quest for us to unravel the human genome led by Francis Collins. Racial discrimination as a social determinant of health causes real harm and causes real disease. There are numerous studies that link racism and discrimination to accelerated aging, to poor brain health, to chronic kidney disease, and subclinical atherosclerotic disease in African Americans. It's not a political agenda. We need to be approaching it as an etiologic factor in disease more commonly. So obviously we're talking about longstanding issues, 400 years, as you suggest, Michelle. It though, that today increased sensitivity to issues of racism might provide an opportunity to act. So what should we be doing right now? Well, I think first off, we must all listen and acknowledge the facts as we find them in this country. And also understand that many African Americans wish that our white colleagues would recognize that our American journeys are conjoined. We have to get through this together. But to do that, we have to recognize that our journey is inextricably bound to our history that has included kidnapping and enslaving human beings who ultimately built this country, defended this country in war, and continue to valuably contribute in every aspect of American life. This is the 2020 truth that we must respond to. We have to, as medical professionals, focus our efforts on attaining health equity. We must act and respond to the words of Congressman John Lewis, who says that we need to stand up for what is right, what is fair, what is just. Healthcare is a right, not a privilege. This has to continue to be our mantra. We need to push this continually, consistently. And we have to try to protect our patients from this environmental toxicant racism by working to understand and to try to mitigate its wide-ranging effects on health. And we have to recognize the vulnerability of African-American and minority students and trainees already in the biomedicine pipeline at the undergraduate, medical school, and postgraduate levels. Listen to them. Acknowledge their experience. Reject being a bystander by becoming an upstander so you can advocate for your colleagues and these trainees through the educational process. We as a field have an underrepresentation of African Americans, not just as practicing physicians, as academics and medical institutions, and also as biomedical researchers. We have to fix that. We have to fix the funding gap between African American and white scientists by understanding and examining how to equitably ameliorate the gap that occurs at each stage of the funding and grant review process. And NIH is actively taking steps to do this, but all funding agencies need to do this. We also need to expand the research resources that are allocated to understanding and ameliorating health disparities and conditions that disproportionately affect African Americans and minority populations. And probably most importantly, as citizens, we're not just physicians and healthcare providers, we are citizens. We must hold our country to its founding ideals that all men and women are created equal and that they are endowed by their creator with certain unalienable rights and that among these are life and breath, liberty and the pursuit of happiness. Frequently, it has been African Americans who have held this country to its ideals. It is time for all of us to do just that.
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Hello out there. This is Dr. Kathy DeAngelis, the Editor-in-Chief of JAMA, the Journal of the American Medical Association. And this week, I'm going to tell you about the March 2, 2011 issue. And as usual, I'll start with the art on the cover, which this week features a painting by Eustace Paul Ziegler, who lived from 1881 to 1969. And it's entitled A Tanana Squaw or Woman and Dog. It was painted in 1939. Now, the painting title says Tanana Squaw Woman and Dog. However, it fails to mention that Tanana's son Basil is on her back, so it's a woman and dog and son. Now, Mr. Ziegler painted the essence of Alaska. He humanized it. He and his three brothers followed his father's vocation as Episcopalian priests, but he also was an incredible artist. I think you'll like this one. And the first article deals with inhaled nitric oxide in acute sickle cell crisis. Experimental data suggests that nitric oxide inhibits platelet aggregation and modulates ischemia, reperfusion, injury. And some preliminary clinical data suggests potential Thank you. randomized trial that enrolled 150 patients with sickle cell disease who were hospitalized with vaso-occlusive pain crisis, Dr. Mark Gladwin from the University of Pittsburgh School of Medicine and his colleagues assessed the effect of up to 72 hours of inhaled nitric oxide gas compared with inhaled nitrogen placebo on time to resolution-resolution of vaso-occlusive pain. The authors report that compared with placebo, inhaled nitric oxide did not improve the time-to-resolution of vaso-occlusive pain crisis in these patients with sickle cell disease. And the second article, HMGA1 gene variants and type 2 diabetes mellitus. The interaction of insulin with target cells is mediated by insulin receptor INSR gene expression. Previously, Dr. Esebio Schiaffari from the University of Cantanzo in Italy and his colleagues reported that the high-mobility group AT-HOOK1-HMGA1 protein is a key regulator of INSR gene expression, and they described two patients with a functional HMGA1 gene variant who had type 2 diabetes mellitus. In this issue, the same authors report the results of a case-controlled study from three populations of individuals of white European ancestry in which they examined the association of HMGA1 gene variants with type 2 diabetes. The authors identified three additional functional variants of the HMGA1 gene and found that presence of the gene variants was associated with type 2 diabetes mellitus in Persons of White European Descent. In an editorial, Dr. Abhinaya Garg from the University of Texas Southwestern School of Medicine discusses novel gene loci that may influence susceptibility to type 2 diabetes melitus. And the third article deals with antihypertensives and secondary prevention of CVD. Use of antihypertensive medications in patients with a history of cardiovascular disease, or CVD, or diabetes, and without clinically defined hypertension, has been debated. In a systematic review and meta-analysis, Dr. Angela Thompson from Tulane University School of Public Health and Tropical Medicine and her colleagues evaluated the association between antihypertensive treatment and secondary prevention of CVD events and all-cause mortality among persons with systolic blood pressure less than 140 millimeters of mercury or diastolic blood pressure less than 90 millimeters of mercury. The authors found that compared with controls, patients who received antihypertensive therapy had decreased risk of stroke, myocardial infarction, congestive heart failure, composite CVD events, and all-cause mortality. In an editorial, Dr. Hector Ventura from the Ochsner Medical Center discusses pharmacologic treatment of prehypertension. And the clinician's corner, this one deals with perinatal care in incarcerated women. This is a clinical crossroads. Ms. A, a 25-year-old unmarried woman who is gravida 3 para 2, received a one-year jail sentence during the second trimester of her current pregnancy. Ms. A is addicted to heroin and is a long-standing pack-per-day cigarette smoker. Drs. L. Adassi and Jennifer Clark from Brown University School of Medicine discuss the health care needs of incarcerated women who are pregnant. Among the issues they address are the management of addictions, work assignments, safety and nutritional requirements, the controversial use of restraints during delivery, and factors to consider when planning postpartum return to the correctional system. Boy, you talk about multiple problems. And the JAMA patient page has information for your patients about sleep apnea. We have four commentaries in this issue. The first deals with biosafety concerns involving genetically modified mosquitoes to combat malaria and dengue in developing countries. And this one was written by Professor Lawrence Gostin and Graciela Ostera from Georgetown University Law Center. And the second deals with aligning incentives for academic physicians to improve health care quality. This one by Dr. Alan Detsky from Mount Sinai School of Medicine and Irfan Dalla. And the third, the need for systems integration in health care. This one by Dr. Peter Pronovost and Mr. Simon Matthews from Johns Hopkins University School of Medicine. And the fourth commentary, Preserving Rights for Individuals Facing Guardianship. This one by Professor Jennifer Moy from Harvard Medical School and Hanan Naik. And the medical news and perspectives. Scientists are exploring experimental therapies that one day might help restore neurological function in patients with multiple sclerosis. Study looks at PTSD among workers in Twin Towers during 9-11 attack, and report weighs the options for bulimia nervosa treatment, NUZA JAMA from the JAMA Daily News site. And laboratory reports, infectious airborne prions, heart condition model, tuberculosis protection, and pancreatic tumor genes. And from the Centers for Disease Control and Prevention, updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine from the Advisory Committee on Immunization Practices in 2010, lead poisoning of a child associated with the use of Cambodian amnolet, New York City, 2009, and vital signs, nonfatal motor And a piece of my mind, this one written by Mr. Andrew Van Weeren from Brown Medical School. Having seen my dad shamelessly discuss his Christian faith with even near strangers during my childhood, and not always with the most gracious responses, I nearly exclaimed aloud, oh no, not again. And that's from Shall We Pray. And the author in the room teleconference, we invite you to join Dr. Gabriela Smarczek on Wednesday, March 16th from 2 to 3 p.m. Eastern Time when she will discuss appropriate prescribing of disease-modifying anti-rheumatic drugs for patients with rheumatoid arthritis. And the readers respond, a challenge. Go to www.jama.com, read the case, and submit your response by March 6th for possible online publication. That's it for this week. Thank you very much for listening. Please let me know if you have suggestions to make this podcast more educational or interesting to you. This is Dr. Kathy DeAngelis, the Editor-in-Chief of JAMA, speaking to you from beautiful downtown Chicago, where the wind blows mightily, but the patients are always our top priority.
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Hello and welcome to another Lancet Psychiatry podcast. My name is Niall Boyce, I'm the editor, and today we're talking about virtual reality. Now, virtual reality was the subject of newspaper articles, documentaries, and science fiction films 25 years ago, and then nothing. However, recently there's been a resurgence in the interest in virtual reality in the electronics industry, the entertainment industry, and now in mental health research. So I'm very pleased to be joined today by the lead author from a Lancet Psychiatry paper called Automated Psychological Therapy Using Immersive Virtual Reality for Treatment of Fear of Heights, a Single Blind Parallel Group Randomized Controlled Trial. And that is an open access paper. You can read it on our website. The author is, of course, Daniel Freeman from Oxford University. Hello, Dan. Hello. So my first question is this. What advantage does virtual reality have over good old-fashioned reality? It has an amazing potential, I think, extraordinary potential here. Because there's a real issue. We all know that many people have mental health problems, perhaps one in five of the population at any time. Yet most of them don't get treatment. And if they do get treatment, it's often medication, when often psychological treatment can be the most effective treatment, and also the preference of individuals. So there's a real issue about how do we get the very best psychological treatment to as many people as possible. And I think VR is an incredible way potentially to get so many more people access to the very best psychological treatments. And we've done that by automating the delivery of therapy using virtual reality. So let's talk about the trial. The first thing which I'm interested in really is the treatment which you offered. You were treating people for fear of heights. You were using virtual reality for this. So the scenario, I think I've used it actually in your lab, consists of a platform, which you then gradually crank up. So you may have seen some old VR a while ago. We spent a lot of time doing something that's not happened with VR mental health treatment before. Previously, VR, and in fact for the last 25 years, has been used with therapists there and basically for exposure therapy. So the therapist is still in the room and it just saves going outside to the real stimulus. And of course, that still relies on finding a really good therapist. So what we've done, we've reprogrammed a basically six-session treatment. There's a virtual coach who guides you through the treatment and provides reassurance and clinical advice and also gets feedback so it tailors the treatment and it starts off an assessment session where the virtual guide explains what keeps fears of heights going and explains the treatment so you do an and you get feedback. And then you're taken into this sort of large office block, virtual office block with 10 floors. And you get to choose which floor you want to start off with. But we restrict it to one of the lower floors. And then you basically go up the floors doing a series of different tasks. And they vary. Sometimes it's just going near the edge and the barrier comes down. And later on, it gets more difficult going on a platform to rescue a cat. Or sometimes we get you throwing things off the edge. But a whole range of tasks that help people understand their fears, their cognitions about heights are inaccurate when you've got fear of heights. So people often fear the building's going to collapse or they're going to throw themselves off, they're going to fall off in some way. And we have a whole range of tasks near virtual heights that helps the person to test out their expectations and form new memories of safety around heights. Okay, and the cat gets rescued? It does. Occasionally it's been dropped. Oh dear. Okay, well we'll move swiftly onwards. So how many people did you recruit into this trial? So it was a hundred people and they were recruited via playing radio ads in Oxfordshire and they all had at least a moderate fear of heights, most of them met the criteria for agoraphobia. And you then randomised them into two groups. You've described your intervention, the control group, what exactly happened there? That was treatment as usual, which in effect was nothing. No one was getting treatment for fear of heights. You ran the trial of six sessions over how many weeks? Over a fortnight. Fortnight, right. And then you followed up at what time point? Another couple of weeks after treatment. So we did both post-treatment and two weeks later. And what did you find? The results were extraordinarily good. On average, the reduction of fear of heights was 68%. Another way of putting this is that half of the participants had a reduction of fear of heights of at least three quarters. Three quarters of the participants had a reduction of fear of heights by at least a half, and 90% had a reduction by at least a quarter in their fear of heights. The effect size is two, which is extraordinarily good. And what about adverse events? There were no adverse events in this group. Okay, so moving forward with this, I think the thing which I always find interesting about digital mental health interventions, which are almost removing the therapist from therapies, is that one thing which keeps being repeated is the dodo bird effect, that what matters is the therapeutic relationship, not the individual type of therapy. So how does this work when we don't have a therapist? Well, I guess, first, I don't really believe in the dodo effect. I think there are certainly studies that show if you've got a very good treatment, and David Clark's PTSD treatment earlier, their treatment of PTSD and social anxiety, those treatments, I think, have been showed to be better than other treatments. I think the right treatments are better than others. So it isn't necessarily sufficient just to have a warm and engaging therapist. And therefore, delivery of the techniques matters. But of course, you need a good therapeutic engagement even to deliver those treatments as well so the therapeutic relationship is important but of course that's one model of doing things there's no reason why there are other ways to access the psychological process that underlie disorders and of course it's also the case that many people are put off by seeing a real therapist now I know I think we need more therapists more highly skilled therapists doing the treatments. But if we're going to meet this huge unmet need for mental health difficulties, we're going to need technological innovations. And I think VR actually potentially could be fast and more potent than many face-to-face therapies because it goes right to the heart of what I think characterises the best treatments, which is about making change in day-to-day life. All mental health problems play out in day-to-day situations, and I think the best therapy coaches people in those situations to think, feel and behave differently. And VR, that's exactly what we do. We recreate the simulations of the situations that trouble people. They find it easier to go into these situations that are not that real. We can push it to the extremes of doing things like rescuing a cat on a platform you'd never do in real life. You can really push it, and yet the learning you make then transfers to the real world. So it's taking the sorts of visualisations which have been used previously in phobia therapies and moving them into a virtual environment. I think you could say this. I mean, VR is more powerful than that. It's hard to understand how good VR is until you've actually been in it. It's still tough doing our VR work. We've got fun tasks, but some of our patients in the trial, they're starting off pretty much on their hands and knees by the edges of the heights. It's hard work. They're sweating. So it feels more than just doing imaginary work in the clinic room. And with this virtual reality therapy, at the moment, people are coming to your lab. Is it the case that this could be delivered at home? Because that would be the challenge, I think, for scale. Yeah. So this actually was going to Oxford VR, which is a university of Oxford spin-out company's office, which is ordinary office block near a train station and the equipment we're using is inexpensive consumer equipment so it can certainly be used at home we're certainly also going to be doing some work at home for patients with this kind of kit too so that's why things are really taking off in VR because the investment for large companies such as Facebook and Sony and Google, this means the headsets are much cheaper, they're usable at home, and this means we could in the future provide these sorts of treatments at home. We know that phobias, I'm oversimplifying a bit, but they tend to be a fairly straightforward model in terms of treatment. They tend to be treatment response prevention. And that's pretty much what's happening here.
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I know that there's a great deal of controversy over psychological therapies in that area anyway, but could you see VR being applied successfully there? Well, I think you may oversimplify even the anxiety disorders work. What I think actually makes the success of the treatments for anxiety disorders is not the simplicity of the disorder, but the precision of the treatments. The developers are very precise about what cognitions to go after and the sorts of behaviours that prevent the change. And then they've developed very powerful treatments that target that. And I think some of the problem with the psychosis work has been the lack of the precision. But actually, if you apply that, I think pretty much to mental health, any mental health disorder, you get big change. And in psychosis, you're actually dealing with many of the same issues. Many patients with psychosis are left fearful. Despite the best current treatments, they are frightened maybe because of voices or paranoia or social anxiety. They're frightened of situations and they withdraw, as people do when they're frightened. And actually, many of the same techniques we even use in the fear of heights are relevant for people with psychosis to get them back re-engaged in the world. We're again dealing with this kind of overlay of fear around problems of psychosis. So in psychiatry, I think we're very used to seeing promising studies coming out and innovation. And there always seems to me to be some sort of barrier to actually getting these things into regular practice. What do you think the big barrier is for VR and how would you get around it or get over it? It's an absolutely huge task to take a treatment from a research setting and apply it in practice. This week I had a kick-off meeting for a new research project that we have that's funded by the NIHR. The Eye for Eye research programme has funded a large team of us, a team at Oxford, the Royal College of Arts, NIHR MindTech, the McPinn Foundation and many other partners to really get to grips with this issue. And we're doing a VR treatment for patients with psychosis. We're reprogramming everything to scratch using Oxford VR, using artists, using people from video games designed to make the treatment loved by both patients and staff. In actual fact, MindTech are doing a lot about the barriers, but also facilitated using VR in practice. We're doing all the health economic evaluation work on this too and developing a way to roll this out across the NHS because we do think and all our pilot data shows it's a very powerful treatment and we think actually, well I know from my experience, patients really love it. They love trying the new technology. They have delight in when they find out actually working through these simulations affects their real world so it is a huge task to do we had a 30 odd people in the room debating all this there are many issues to do the simple fact of finding a room sometimes in mental health services alone could be a problem although i think with some of kit we can do stuff at home you know and it's a change and that's always hard to implement but um we're determined to do it over the next three years. Thank you very much, Daniel Freeman. So perhaps one day the Lancet Psychiatry Podcast will arrive in virtual reality, but for now, I'll just say goodbye. Thanks for downloading, and I hope you'll join us again next time.
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Hello and welcome to another installment of the Lancet Global Health Podcast. My name is Nikolai Humphries. Today we'll be discussing diet. Insofar, they'll be looking at a paper titled Dietary Quality Among Men and Women in 187 Countries in 1990 and 2010. To walk us through the paper, I am joined on the line by Dr. Dariush Mazafarian. Hello, Dariush. Hello, Nikolai. Great to be here for Lancet Global Health. Pleasure to have you on board for the podcast. Could you begin by explaining what gaps in the global dietary knowledge base you were aiming to fill with this study? Well, you know, we're all concerned about diets and trends over time. And remarkably, there hasn't been really much data or evidence available on this. Most of the prior studies have utilized evidence on kind of overall food availability within a country. And so we focused on actual intakes. What are people actually reporting that they're eating in countries around the world? And that allows us to really hone down on what people are actually putting into their bodies. We also focused on foods and nutrients for chronic disease as opposed to malnutrition. And many prior global analyses were more worried about deficiency diseases and malnutrition. But we know about, you know, pandemics of obesity and cardiovascular diseases and cancers. And so we were looking really at dietary factors related to those things. And so, you know, focusing on intakes and kind of these key foods and nutrients for chronic disease. And we were also able to look at differences by age and sex within countries, which hasn't been done before across multiple countries. Again, because prior analyses mostly just had overall country availability of food rather than actually intakes reported by individuals. So we really wanted to find out what people are eating around the world. How does this differ by age, by sex, by country income, by world region, and how is this changing over time? Thanks. I'm interested to know what sources of data you used for your analysis and what the overall quality or reliability of that data was. So we compiled over several years as part of the Global Burden of Diseases study, all of the available national and subnational surveys on dietary intakes in adults that we could find. And ultimately, we identified and received data from 325 dietary surveys from around the world, most of which were nationally representative. And since these were mostly from many of the larger countries of the world, with multiple surveys in many countries, we actually overall had 89% of the global adult population represented by these individual-based surveys. Of course, we didn't have full data available for every country, and for some dietary factors, we had much less data available. So we supplemented the individual survey data with what had been previously available and was used for prior analyses, which was the Food and Agricultural Organization's food disappearance data. And then we also used some industry data that was global for things like trans fats. And so by combining the Food and Agricultural Organization disappearance data, which is kind of food availability data around the world, with these individual level dietary surveys, we came up with the best possible global dietary database that one could assess. And so I think that, you know, as with anything that you measure globally, whether it's blood pressure or whether it's cardiovascular disease or cancers, you know, the data are not perfect, but this is really the world's best current available data on intakes combining and using information from all available sources. Overall, you find that over the past two decades, although consumption of healthy foods such as fruit, vegetables, and fish has increased worldwide, consumptions of unhealthy foods such as sugary drinks, processed meat, and salt has increased even further. Can you comment on why this might be the case and give a brief summary of the global disparities in these types of dietary patterns? Yeah, well, one of the most interesting things we found was that assessing diets like this across the world, it makes quite a difference whether you look at healthy foods people are eating or unhealthy foods people are eating. And typically, those things tend to be blurred. So you say, let's look at somebody's overall diet or a country's overall diet and kind of add up the healthy and add up the unhealthy and kind of put it together. But we found actually that both within countries, changes over time within neighboring countries, looking by country income, that it was very important to separate this out. And I'll explain why. So healthy overall in the world, actually people are starting to consume more healthy foods between 1990 and 2010. And that's probably related to increased production, increased availability, increased awareness about the importance of healthier foods, increased seasonal availability of things like fruits and vegetables. But this was very different by country income. And so the high-income countries and middle-income countries had significantly increased their intakes of healthful foods. But the lowest-income countries, the low-income countries, have not at all. So there's a real disparity there. And then the other interesting thing is, you know, the intakes of unhealthy foods, which is where most of the global focus has been for preventing chronic disease, things like saturated fat, meats, sugar, sweet beverages, sodium, and so forth. That's gotten worse over time. And so while diets have gotten better in some regions in terms of more healthy foods, in many of those same regions, especially in middle-income countries, they have had profound increases in unhealthy foods. And so unfortunately, for many countries, So why is it even important to separate out the healthy and unhealthy dietary patterns? Don't they almost cancel each other out to an extent? Well, if they did, that would be terrible, right? Because we don't want them to cancel each other out. We want people to eat more healthy foods and less unhealthy foods. And so if there is a country where they're canceling each other out, just knowing that is very important because, you know, you're basically spinning in place if you're increasing your healthy foods and simultaneously increasing your unhealthy foods, right? That's a bad thing to do. But, you know, what was quite remarkable is across countries, the correlation between the changes in these things was almost zero. So countries are independently altering because of changes in production, changes in marketing, changes in industrialization. They're relatively independently altering their intakes of healthy versus unhealthy foods. And as one example, India, you know, one of the largest countries in the world, they actually do pretty well. They rank 23 out of 187 nations in terms of lower intake of unhealthy foods. So if you look at, you know, sugar-sweetened beverages, meat, saturated fat, salt, trans fat, dietary cholesterol, India is doing pretty well, 23 out of 187. But if you look at their intakes of healthy foods, fruits, vegetables, fish, nuts, beans, healthy vegetable oils and so forth, they rank 149 out of 187, almost at the bottom of the world. And so for India, the major priority for the next decade should be increasing the intakes of healthy foods. You know, of course, politicians and policymakers should focus on reducing or preventing the increase in unhealthy foods, but their major problem is insufficient healthy foods. And so that's very, very informative. And so I think that's one example. Even neighboring countries like Argentina and Brazil, we found differences in their intakes of healthy versus unhealthy foods that would be masked. And so I think that's kind of one key message we need to think about both from a scientific perspective and a policy perspective when we think about diets around the world is most of the focus from the World Health Organization and the United Nations and governments has been on, you know, reducing fat or saturated fat or salt. Now there's a new focus on sugars and sugar-free beverages. It's fine to do those things. And it's not that we shouldn't do those things. But there hasn't been nearly enough focus on increasing healthy foods. And that's what's missing from many countries, in particular, middle-income countries and low-income countries. Thanks, Dariush. That leads me nicely on to my final question. What do you think are the policy implications of your findings? Well, as we discussed, you know, first, countries need to know what the people are eating in their country. And so some countries didn't have excellent dietary information. And so I think every country should make it a priority to survey their population and understand what they're eating and how this is changing over time. By 2020, 75% of all deaths and 60% of all morbidity will be due to chronic diseases. And a large proportion of that will be due to diet. So this is the single leading cause of poor health in the world today. And so we really need to understand what people are eating and how this is changing over time.
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Because if you try to look at diet altogether, you'll be misled. You might think you're doing very well, or you might think you're doing poorly. So I think there's, you know, pretty enormous implications for thinking about agriculture, production, availability. How do we increase healthy foods around the world? Not just calories, because we don't want to provide calories and prevent calorie malnutrition and then just have epidemics of chronic disease, but increase healthy foods as part of those calories. Simultaneously, while we're focusing on the countries, especially Western countries, that need to decrease the intakes of unhealthy foods and really prevent the rapid explosion in those unhealthy foods in middle-income countries. We know that chronic disease is a priority now for the United Nations and the world, and a diet is really the place to start. Professor Dariush Mazafarian, thank you for speaking with me on the Lancet Global Health Podcast. Thank you very much. A pleasure to be with you.
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Hello and welcome to JAMA Network Open Conversations. I'm Angel Desai, Associate Editor for JAMA Network Open. Today we are speaking with Dr. Gwen Lapham and Dr. Catherine Bradley about prevalence of cannabis use disorder and reasons for use among adults in a U.S. state where recreational cannabis use is legal. Welcome to the both of you. To begin, can you please introduce yourselves? Sure. Hi. Thanks, Angel. I'm Gwen Lapham. I am an assistant investigator at Kaiser Permanente Washington Health Research Institute and an addiction health services researcher. And I'm Katherine Bradley. I'm a primary care internist and senior investigator at Kaiser Permanente Washington Health Research Institute. Thank you so much for coming to speak with us today about this really interesting paper. Cannabis use for recreational purposes and the regulation of this is a topic of great interest right now. With that context, could you tell us a bit about the background of this study and what you did? Sure. We chose this topic, whether the prevalence of cannabis use disorder was different for patients who report cannabis use for medical reasons or non-medical reasons, because of the perception that cannabis use for medical reasons is without risks. And it's important to consider the current context of cannabis legalization. 23 states have legalized recreational use of cannabis. That means that more than half of U.S. adults now have legal access to recreational use of cannabis, with high-potency products being widely available in those markets. In most states with legal recreational use, provider authorization or recommendation is not necessary for patients to use cannabis for medical reasons. And we know that many patients who use for medical reasons also use for non-medical reasons. So in this context, it's unclear whether patient medical use of cannabis with or without non-medical use would lead to a difference in a risk of a cannabis use disorder. And so it's important to help providers understand the risks of a cannabis use disorder among their patients. Now, let me just add on that one of the issues is about 30% of people who use daily develop cannabis use disorder. And so as people use more, there's concern about whether that's going to be more and more of a problem. And so then the question is, does it differ for those who are using for medical reasons versus non-medical reasons, just to kind of frame that. And how do you assess cannabis use disorder for the purposes of this paper? So for the purposes of this paper, we did a cross-sectional survey with primary care patients in our health system. And the cannabis use disorder was assessed with a gold standard measure, a diagnostic questionnaire about the symptoms of a cannabis use disorder. The questionnaire provides a scaled score of a DSM-5 cannabis use disorder severity. And so what did you do in this paper and what did you find? Well, in terms of what we did, we did a cross-sectional survey among the primary care patients attending our health system. We had patients who completed a routine cannabis screen as part of integrated behavioral health care and primary care. They were randomly selected to receive a confidential survey about cannabis use. We oversampled patients who are underrepresented in racial and ethnic groups. And we also sampled patients who were not using cannabis, but we mostly oversampled patients who reported higher frequency cannabis use. So patients in the clinical setting who reported monthly, weekly, or daily use. The sample we studied here in this study included those survey respondents who indicated cannabis use in the past 30 days. So the population-based design allowed us to weight results so that they are representative of primary care patients who use cannabis. What were some of the main findings in the study? We found that among primary care patients who use cannabis, the prevalence of a cannabis use disorder did not vary by patient-reported reasons for use. Patients could report to us whether they used for medical reasons only, non-medical reasons only, or both reasons for use. So the cross-sectional survey asked patients to report their reasons for cannabis use, whether for medical use only, non-medical use only, or they were using for both reasons. And then patients were also asked to complete a gold standard diagnostic questionnaire about symptoms of a cannabis use disorder. This questionnaire provides a scaled score of a DSM-5 cannabis use disorder severity. And so for this study, we reported on the prevalence of those 11 symptoms, as well as the prevalence of any cannabis use disorder, which includes anywhere from mild to severe cannabis use disorder, as well as the prevalence of moderate to severe cannabis use disorder. And what we found was that among primary care patients who use cannabis, the prevalence of any cannabis use disorder did not vary by patient report of reasons for use. The overall prevalence of any cannabis use disorder in our population was 21%. However, we did find that the prevalence of moderate to severe cannabis use disorder did vary by patient-reported reasons for use. And this was 1.3% for patients who reported medical use only, and a little over 7% for patients who reported non-medical use only or both reasons for use. You mentioned that the prevalence of any cannabis use disorder was 21% and that moderate to severe cannabis use disorder was 6%. And these numbers seem fairly high. How does this compare with national trends or what we know of them? I'll pop in there that, remember, this is people who have used cannabis in the past month. So it's not all patients. And then I'll let Gwen take over. We know that this is actually comparable to more of what we're seeing in states with legal recreational use. States with legal recreational use are seeing increases in both cannabis use and cannabis use disorder. And so this prevalence is high, but it's actually fairly on par with what we're seeing in terms of the context of the past 10 years of legalization. Very interesting. And not to go too much out of the scope of the study, but based off of this, what do you think are some of the public health implications of these findings? One of the important take-home messages is that cannabis use disorder is common among primary care patients who use cannabis in a state with legal cannabis use, and that patients who use for non-medical reasons are most at risk for moderate to severe cannabis use disorder. And that as legalization of recreational use continues to expand across the U.S., the results of the study underscore the importance of asking patients about cannabis use in clinical settings. You know, I think the biggest thing I'd add is the fact that this is common in primary care and that we need to figure out ways to implement that. We have validated a single item. Gwen led the project that validated a single item screen, and we need to find ways to get that more widely used in primary care settings in states where medical and recreational use is legalized. Definitely a very important point. What do you think are some of the next important and potentially unanswered questions in this area or that you may be conducting in the future? Well, we know that asking patients a single validated question about past year cannabis use is feasible in primary care. We still need to explore how to best assess and document patient reasons for use in a fast-paced, busy clinical setting where there's not a lot of time to add additional questions. We really need to explore how best to do that for our providers and our patients. And patients identified in primary care settings with moderate to severe CUD are not necessarily interested in treatment right away. And so we need to explore patient-centered ways to engage patients around their symptoms in order to reduce their symptom burden. Both really important points. I really enjoyed reading this study and I just wanted to know if there were any final thoughts you had or anything that we hadn't had a chance to cover. I think the one other thing I'll just say is that it appears that people who use medically only are actually used in a different way that probably exposes them to significantly less cannabis. And so I think that'll be one of the future areas to understand is how to measure patients' exposure to the different topical applied use as one of the primary modes. But our sample was not powered to explore those important patient characteristics and those important ways of using by patient-reported reason for use and the risk of cannabis use disorder. So it's going to be important in a future study to be able to explore those associations based on how patients present and how they're using cannabis. Just to flesh that out a little bit. So, you know, many patients just apply topically for pain, but others smoke or vape or dab or eat. And so it's these different modes of use that we think might be an important thing to measure in the future. Those are some great thoughts to end on. Thank you so much to Dr. Gwen Lapham and Dr. Catherine Bradley for speaking with me today about this very interesting and very relevant topic. This episode was produced by Daniel Musisi at the JAMA Network. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com. Thanks for listening.
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From the JAMA Network, this is JAMA Oncology Author Interviews, conversations with authors exploring the latest clinical research, reviews, and opinions featured in JAMA Oncology. Hello and welcome to this author interview from the JAMA Network. This is Deanna Balandi with JAMA Oncology. What is the association of a prophylactic surgical approach to stage four small intestinal neuroendocrine tumors with survival? Doctors Cosmis Daskalakis and Peter Stahlberg of Uppsala University in Sweden are here to talk about that and their new article in JAMA Oncology. Dr. Daskalakis, let's start with talking about these tumors. Tell me about the clinical course they generally have, what stage theseINETs, reflecting improvement in therapies according to recently published data from the SEER database. SINETs are indolent neoplasms, often diagnosed at the late stage, with a different metastasis usually in the liver, present in up to 60% of patients at diagnosis, and then the disease is classified as stage 4. Generally, there are two types of symptoms in these states, local tumor-related symptoms such as abdominal pain, bowel obstruction, and intestinal ischemia, and on the other hand, hormonal symptoms such as flossing and diarrhea. Hormonal symptoms are usually well-controlled with somatostatin analogs as shown in the clarinet and the promed trials. Of course, patients with local tumor-related symptoms are subjected to surgery, local regional surgery, which is the resection of the primary tumor and the lymph node metastasis in the mesentery. And this, in many cases, is performed on vital indications. The clinical dilemma at this stage is whether we should perform prophylactic local regional surgery and liver surgery before these patients develop local tumor-related symptoms or progress in their disease. To date, there are no prospective randomized control studies on these matters and this makes surgical management of these patients at stage 4 quite challenging. Additionally, the disease course is unpredictable, and various clinical outcomes are hidden with the overall favorable survival rates reported, which makes it also impossible to have one fit for all therapy. So, Dr. Stahlberg, the study focused on patients with asymptomatic stage 4 small intestinal neuroendocrine tumors and distant metastases. Can you tell me a little bit about what you examined in the study, how you did it, and why you undertook it? So we have a prospective database in Uppsala that started in 1985. So we included all the patients with SINET disease and looked at those up until last December in 2015 to be eligible for the study. And then we excluded all the patients with stages 1 to 3. And then we excluded the patients with local tumor-related symptoms. And then also some patients that had absolute contraindications to surgery, like technically inoperable disease or comorbidities and such things. And then we ended up with 363 patients that we could study in this paper. So then we want to find out if this approach that has been accepted in the guidelines since many years, that asymptomatic patients, even though they have stage 4 disease, that's usually spread to the liver, if they should have prophylactic surgery to prevent abdominal complications from bowel ischemia or small bowel obstruction. And we questioned that approach in our hypothesis and wanted to see if this standard approach actually was good for the patients in terms of survival or in terms of complications. Dr. Deskalakis, tell me what you found. And in terms of overall survival, there was no difference between the two groups, both in overall survival and cancer-specific survival. So the median overall survival was 7.9 years in the prophylactic upfront surgery group versus 7.6 years in the delayed surgery group. There was no difference in 30 days post-operative morbidity and mortality, length of hospital stay due to the disease, and specifically due to local tumor-related symptoms, and no difference in seasonal hernia repairs whatsoever. However, these patients from the prophylactic surgery group underwent more reoperations compared to the delayed surgery group due to intestinal obstruction. And we were actually surprised with this higher re-operation rate in patients receiving upfront prophylactic surgery, leading to the conclusion that prophylactic surgery early in the disease course burdens patients with more re-operations. So Dr. Stahlberg, what do the results mean considering this has been done previously? I should say that this is the first study that actually tries to look at this in an unbiased way, because with doing this propensity score matching, we try to take out biases in terms of comorbidity, age, and immortality bias. So we think that this study means that there are no evidence that this prolongs survival for the patient to do upfront prophylactic surgery and that delayed surgery with oncological treatment is as safe as doing upfront surgery and and it might prevent unnecessary reoperation. So, Dr. Daskalakis, what research is needed next? Maybe a clinical study? Generally, clinical, translational, and laboratory studies are necessary in assigned patients with advanced and disseminated disease to better identify and select best candidates for local regional and liver surgery as well as for targeted and systemic treatments. For these specific findings in the clinical setting, despite the sophisticated methodology and the design of this study, it is clear that a multicenter prospective randomized controlled trial in a national or international level is needed to further elucidate the value of prophylactic surgery Thank you. or possibly developing symptoms may be more feasible than overall survival as an endpoint in such a future task. Well, thank you both so much for talking to us about your work. This is Deanna Balandi with JAMA Oncology. For more author interviews, please visit us online at jamanetworkaudio.com. You can also subscribe to our podcast at Apple Podcasts and on Stitcher.
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In this week's Lancet News, we take a look back at 2012's biggest medical stories. And if that's not enough, we talk to Astronomer Royal Lord Rees about the end of the human race. I'm Dara Mohammadi. And I'm Tim Danil. Cambridge University has just established the Centre for Existential Risk. A lot of media coverage has focused on artificial intelligence and the sort of terminator effects of artificial intelligence outstripping human beings. Their aim is more than that though, it's also to look at developments in biotechnology, nanotechnology and climate change to see what extinction level risks might be in the near future. I'm delighted to be joined by Professor Martin Rees who's based at Cambridge University. Hi Martin. Hello, good to be on the programme. Could you explain to us a little about who's involved in this project and why have you set it up now? Well, there were several of us from different fields who felt it was important to give more attention to a class of risks that aren't studied enough. These are the risks which have perhaps low probability, but which if they happened could be really catastrophic, so that one occurrence would be too many. And three of us in particular, myself, Hugh Price, the Professor of Philosophy, and Jan Tallien, who is an artificial intelligence expert, have got together in the hope that we can set up a research programme to bring to bear some serious expertise on this very wide range of threats. Yes, you mentioned artificial intelligence there. There's a sort of obvious tipping point sort of seemed to come into a lot of these factors. Things like artificial intelligence when computers become smarter than we are, things like climate change if the West Antarctic ice sheet melts, there'll be catastrophic events for us. Where do you see your role maybe in artificial intelligence as an example? Are they going to sort of out-compete us in a Darwinian fashion? What's the thinking behind it? Well, we thought there were really four classes of threats. One is, of course, a nuclear war, and that threat is simply in abeyance and may recur if there's a new confrontation between new superpowers. The second is what I might call bio-error and bio-terror, pandemics, etc. The third is, as you mentioned, runaway climate or environmental change. And the fourth is machine intelligence. And that, of course, attracts a lot of press interest when we announce this. Yeah, we saw the headlines. Well, that's right. The idea there, which is taken quite seriously by a number of experts, is that computers obviously are approaching human intelligence in many respects. And the idea, which is still rather speculative, of course, is that a computer network may, as it were, develop a mind of its own and be a threat to us. And this is at least worth discussing, along with all the others. And I think what we want to do really is not to be scaremongers, but to give a bit of serious attention so that we know which of these ideas that are talked about a lot and written about a lot are really science fiction and which we need to think about in order to perhaps take measures to minimise the risk of them happening. Yes, something which we're very familiar to Lancet readers is the H5N1 influenza debate. Well, that's right. I mean, there were clearly arguments pro and con, but it is scary that the kind of people with the mindset who now design computer viruses may be able to design real viruses in the near future. And that is a threat, as of course, are naturally occurring pandemics, which in our ever more network world with more rapid communication could have more disastrous downsides than in the past. So where do you see your role? Where are you fitting? Are you going to be advising governments? Well we're an academic group and I think our main aim is to try and enlist expertise from different areas to try and do a somewhat more detailed study of these to see which are the serious ones. It's a very interesting issue and lots of risk analyses are done, but we would claim that not enough attention is given to the extreme high consequence risks, even though they're rare. And there was a lot of focus on the sort of low risk things which get a lot more attention. That's right. We think that we ought to consider more the improbable but massive consequence events. And I think if we think of people's attitudes, they're rather irrational in their response to risk. They fret far too much about carcinogens in food, train crashes and things like that. And they're not concerned enough about the possible risks that may be global in their consequence. Hard for an individual to think about, but good for someone to be thinking about it. Well, indeed. And I think the main point is that some of these risks are global in their consequences and they may be remote in the future. And of course, it's hard to get people to give attention to things both remote in space and time. The urgent and immediate always trumps the political agenda and that's another reason why we as a group of academics think it's important to do what we can to raise these long-term global threats up the agenda because obviously smaller the chance of them happening may be it's worth a bit more effort to try and minimise that chance. It certainly is. So where do you see yourself in five years' time? Is the group expanding? It depends, obviously, on getting funding and support. We'd like to be able to have a research group who can focus on these issues, and that is our first aim. We are starting a research programme. We hope we can get some funding for it. And we hope that five years from now we will have helped to, as it were, change the general conversation so that people are more mindful of these risks and see them in proper perspective. Fantastic. Yes, that sounds very good and good luck with it. Thank you very much for your time. Thank you. Thank you very much. Thank you. Welcome to part two. In this section, we're going to discuss the big stories in medicine this year. We've got a couple of pages on it in the Lancet This Year in Medicine section, two pages written by none other than our own Dara Mohammadi. Hello, Tim. Hello. How do you feel about being interviewed on your own podcast? I feel it's an honour to be getting interviewed by my esteemed colleague Tim Daynell. Good, shall we crack on? So we're going to run through them quickly one by one. The breast implant scandal was a big story earlier in the year. Medical devices, 40,000 women in the UK received industrial grade silicon breast implants and there was a lot of debate and a lot of discussion about how well medical devices were regulated in the UK. Anything to add? No, I think you've covered that one. Cool. Okay, so the next up is India versus Big Pharma. Dara? Yeah, two cases. In March, India granted an Indian drug company a license to make a generic version of Bayer's cancer drug, Nexavar. So in exchange for this license, Natco Pharma, which is the Indian drug company, have to sell the drug at a fraction of the cost that Bayer charged, but also have to pay Bayer 6% of its net income. So Bayer were unsurprisingly annoyed with this decision, but many people are actually hailing this judgment as a precedent-setting model that can improve access to medicines in low-income countries, but also compensate patent holders. Brilliant. And there was another one as well. I think Novartis were doing something with their patents. Yeah, Novartis were appealing to the Supreme Court in India because India were refusing to give them a patent on a drug that is ostensibly the same as a previously patented drug, but that patent's expired. This is the evergreening thing where you tweak it slightly and get a new drug out of it and a new patent out of it. Brilliant, thanks for that. And on to H5N1, which is something which happened at the tail end of 2011 into 2012. Yeah, so the tail end of 2011, there were two papers that were submitted to Science and Nature, and these showed that experimentally tweaked mutant strains of H5N1 were transmissible between mammals and therefore the H5N1 had I think it was changing four small parts of the viral genome and you could increase the transmissibility. They basically showed that H5N1 had pandemic potential so they wanted to publish their whole study in full and a US National Science Advisory Board for biosecurity said that they could only have a redacted publication. So only the aims and what was it, the conclusions. So lots of people were irked by this decision.
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They're also worried about the kind of, you know, the chill of government involvement in science. But on the other side, you had people that said the risk of either accidental or deliberate release of these strains just wasn't worth the risk. True. And this, the National Science Advisory Board have recently, they backtracked on those two papers, but recently they've been working on a set of rules and a framework to get people to think about and enforce whether people are doing this kind of research for the right reasons. In order to apply for grant funding, you have to prove that it could occur naturally that you can't get a super strain. Also, you have to prove that there's no feasible alternative methods for it and that you can contain bio-safety risks and the like. So the story rumbles on. GSK. Talk about GSK. GSK. What did GSK do this year? They were busted big time. GSK were fined or ordered to pay $3 billion in settlements in July. And this is one of the biggest cases of fraud in both size and scope to hit the US pharmaceutical industry. So what they were charged with was various things, but they included the promotion of two drugs, two antidepressants for unapproved use and failure to report safety data about a diabetes drug to the FDA. They were also found guilty of giving kickbacks to doctors. Now, this included holidays to Hawaii, and I think embarrassingly for everyone involved, tickets to Madonna concerts. So heads have rolled at the company, people have been fired, and GSK have agreed to have governmental monitoring for the next five years. You've written a story about Europe's health crisis, but I think we all know there's no money. Health is in crisis. Next, the big story. The big story for one disease at any rate, HIV-AIDS and the triumph for Truvada. Yeah, Truvada. It's just another kind of, it seemed every year, like every of these kind of most recent years have seen a really encouragement development for the fight against HIV and HIV and AIDS. 2009 the Berlin patient, 2010 the Caprissa trial, drugs like nifarapine preventing mother to child transmission, HIV AIDS is on the way. So this is the latest so basically the FDA have approved the drug Truvada as a combination of tenofovir and emtritatabine and so they've approved it for use pre-exposure use in HIV negative individuals at high risk of contracting the disease this comes on the back of results from the prep trial earlier this year which showed that use of Trivada reduced the risk of contracting HIV by up to 73 percent in serial discordant couples there's one kind of caveat to this. The drug's going to be a bit too expensive to make an immediate impact. I think a year's course costs between $6,000 and $14,000. Now, that puts it out of reach of a lot of Americans, let alone people in sub-Saharan Africa, where the lion's share of the HIV burden is born. But anyway, encouraging nonetheless. Yeah, encouraging nonetheless. Shall we move on to another disease which is less encouraging in a way but also very important? The XMRV debate finally dies in chronic fatigue syndrome. Yeah, this is the end of the quite contentious link between XMRV virus and both chronic fatigue syndrome and prostate cancer. Basically, in September, findings from a study that was designed and executed with the full participation of the authors from the only two papers to have shown a link between XMRV and chronic fatigue syndrome showed a definitive failure to detect a link. And also in September, the 2006 paper to first describe the virus and also the one to link it to prostate cancer, that was retracted as well. Good news. So, probably possibly the biggest story. I think definitely the biggest story. Definitely the biggest story of the year. Certainly the one with the future. This is future-proofing ourselves. Decoding DNA. Released in September, the ENCODE project was released and it's shown that a huge amount of junk DNA, what was previously viewed as junk DNA, is in fact important. So yeah, it's come a decade on from the Human Genome Project. That was promising to be the book of life. But it turned out that that book wasn't quite as readable as we'd have liked. It showed that only 2% of our genome coded for proteins and it kind of basically wrote off 98% of our genome as junk. Now, encoders come along and assign biochemical functions to 80% of our genome. So this means that researchers who were previously constrained to digging around in the 2% of the kind of protein-encoding genes can now kind of probe around in much of the DNA between these genes and discover how kind of specific elements determine how genes... Robbing their hands with glee, data miners and people are going to love it. But it's a massive advance and it's going to be huge and editors and authors across the country are going to be, across the world, are going to be digging into this for years and years to come. So 2012, the first year. Well done, ENCODE. Well done, ENCODE. Yes, thank you for every paper in the future. What else happened in 2012? We're running rapidly out of time. USA? Yeah, should we do USA as the last? USA and UK political parties. USA. President Barack Obama in his Affordable Care Act, which aims to substantially reduce the number of uninsured Americans. That came over two big challenges. One was a Supreme Court appeal, which it won. And the other was, of course, the presidential elections with Mitt Romney, the Republican candidate, vowing to take action to dismantle the legislation on his first day in office. But luckily, Obama won out and so did health. So USA are moving kind of slowly towards universal health coverage. So back home in the old UK. The old UK? Yeah. Is it because it's older than USA? Back home in the little old UK. The little old UK! In the UK, health reform's not doing quite so well, I think we'd have to agree at the moment. Things took a slightly regressive step in the start of the year with the Health and Social Care Act. Encouragingly, more recently, there's been a new political party form to fight the top-down reorganisation of the NHS. It's called the National Health Action Party, and they're targeting 50 seats in the next general election, being careful not to split votes by standing against individuals who share their views on the NHS. So, mixed from the UK political scene this year for medicine. And that's all the time we've got for this section. You can read all of these stories and a few more in Dara's piece on thelancet.com. So before we wrap up the podcast, Tim, can you take us through what else is appearing in The Lancet this week? Yes, elsewhere in The Lancet family, there is a news piece by Angela Pirisi in The Lancet Oncology on improvements in mammography. And in the main weekly journal, other than Dara's Fantastic This Year in Medicine, we have the essay competition winner, the Wackley Prize 2012. James Nielsen has his entry published in full, so worth checking out. So thanks for that, Tim. And thanks as always to Nikolai Humphries, our producer. This is our last episode in 2012. So from everyone here at The Lancet News, we wish you very happy holidays and we'll see you again in 2013. Bye. Goodbye.
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Hello and welcome to In Conversation With, a podcast of the Lancet Oncology. My name is Marcia and today I have the pleasure to speak with Dr. David Pinato about the OnCovid registry and more specifically his and his colleagues' article on prevalence and impact of COVID-19 sequelae on treatment and survival of patients with cancer who recovered from SARS-CoV-2 infection. Dr. Pinato, welcome. We know that COVID-19 can have long-term consequences in some patients. What is known so far about common sequelae in patients with cancer? Well, we know that COVID-19 imposes a lot of long-term challenges to patients in the general population, but until the results of Oncovid clarified this aspect in patients with cancer, we didn't really know what the real impact in patients with malignancy was from the point of view of COVID-19. So a lot of previous research efforts have mostly looked at mortality rates from COVID-19. We are showing with this new piece of research that 15% of the patients with cancer from our own registry, the ones that actually survived the acute infection and recovered completely from a virological point of view, were still affected by consequences when they were first evaluated by the treating oncologist on average 44 days after the end of the COVID-19 infection. We think that the most common complications that affect patients in the long term, so the median duration of follow-up was around 120 days from the diagnosis of COVID, are things like fatigue, respiratory symptoms, neurocognitive impairment. So in terms of the type of consequences, they're actually quite similar to the ones that we observe in the general population. So the two populations seems to be sort of very reproducible in terms of the type of consequences. And could you please give us a brief overview about the aims of your study? So OnCovid is a fairly broad registry study that has started back in February 2020 to collect all the consecutive patients diagnosed with COVID-19 and all the type of cancers, either in remission or with presence of active disease, across a growing number of institutions that are based across Europe. So far, OnCovid is the largest European study of COVID-19 and cancer and has collected approximately 3,000 patients on this particular registry. The aim was very broad. So when we initially started this project, we didn't really have one specific aim. We wanted to document the natural history of patients diagnosed with COVID-19 and that were at cancer. So the inclusion criteria for this project were kept broad for that reason. In this particular aspect, in the research that is being published now, we are particularly looking at the consequences, but we had published before a lot around mortality and sort of short-term adverse events from COVID-19 in these patients. And what were the main findings of this paper, both in terms of patients and treatment characteristics associated with COVID-19 sequelae, but also the impact of cancer therapy resumption? So I think two take-home messages in my mind. The first one is that we have a population of patients that despite doing well from the point of view of COVID-19 in the sense of not suffering fatal outcomes, they are still characterized by a number of adverse outcomes that we as oncologists in particular may not be fully prepared to face or prepare to solve. So I think this gives us the sense that we should be aware of long-term consequences from patients that have recovered from the disease. From that perspective, our study is very destructive. We are simply looking at what happened to these patients without having any predefined aim. What we found was that actually in patients where there is a documented evidence of COVID-19 related sequelae, the survival was significantly shorter. This is very, very important because we might think that when patients have, you know, have sort of gone past the acute phase of the illness, you know, there is no more danger for them. This is actually not true. Those 15% of patients that had long-term consequences had shorter survival. And we looked at the survival both from the point of view of the cancer as well as COVID-19. And we think that a big element to the impact on survival has got to do with resumption of treatment. So obviously last year, there was a lot of tendency to stop, withdraw or delay cancer treatment because of the risks of COVID. Now, we're a little bit more comfortable, and especially now with vaccination and with a lot of therapy specific to COVID, that COVID per se is less lethal in patients with cancer. However, we have to bear in mind that if people have long-term consequences from COVID, they tend to, at least in our study, they were less likely to receive further anti-cancer therapy. And those were the patients where actually the survival outcomes were much, much worse compared to the general population. So this is a very important message that suggests that we should perhaps do something about it. I don't know what that something is because those sequelae were mostly symptoms. And I know that there are a lot of programs looking at, for example, rehabilitation, early diagnosis of the symptoms so that patients can have the best quality of life and the minimum type of impairment of their overall health. But I think there is also the need for mechanistic research, sort of trying to understand what are the molecular causes of this sequelae. Is there anything immunological, for example, that can point towards, you know, this sequelae being more prevalent in a proportion of cancer patients? And I think that's where we should concentrate in going forward. Yeah, so based on the findings of your study, what would be your main recommendations, both to the oncological community, but also ministries of health? Well, I think the very strong recommendation is to increase the awareness for COVID-19 consequences in patients with cancer. This is likely to require more education from our end. So as practicing oncologists, we have to understand more what it means to be dealing with patients who have recovered from viral illnesses. Not all of us have got that particular background. We are more used to be looking after patients with, for example, side effects from treatment rather than from long-term consequences of viral infections. So this is definitely something that we need to learn. Secondly, we have to factor in this particular percentage. So 15% is quite high in my mind. And these are patients that would otherwise be well, apart from obviously that oncological diagnosis that they carry. Interestingly, the presence of long-term consequences was independent from any tumor-related factor, was more present in patients with severe COVID, but interestingly, is also present in patients who had mild COVID who were never hospitalized for the disease. So this is something that we should keep in mind. We should learn from our study. And thirdly, I think we should, as I said before, try and develop more research aimed at long-term survivorship of these patients. Unfortunately, in most of the studies in other viruses, such as, for example, MERS, for which we have more data, we know that the duration of sequelae can be as long as 40 months. So, I mean, for some of our cancer patients, we can't really wait that long for all the long-term consequences to have completely reduced and abated or have gone back to normal because obviously the survival for patients with advanced cancer is much, much inferior to that amount of months. So that is another area that requires research, identifying who are the patients that will get the consequences and what can we do to treat those. Thank you very much for agreeing to speak with us and to all our listeners.
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From the JAMA Network, this is JAMA Cardiology Author Interviews, conversations with authors exploring the latest clinical research, reviews, and opinion featured in JAMA Cardiology. Hi, this is Clyde Yancey, Deputy Editor of JAMA Cardiology. I'm delighted to bring you yet another podcast featuring work recently published in JAMA Cardiology. Today, we're having really a wonderful discussion about anticoagulation in the setting of left ventricular dysfunction, ostensibly heart failure in sinus rhythm. Wondering, have we gotten any closer to identifying a therapeutic intervention that will further reduce morbidity, not likely mortality, by targeting the thrombotic complications of heart failure. To start off this conversation, I'm going to refer to one of the leaders in heart failure, Dr. Marvin Constand from Tufts New England Medical Center, who really has been on the leading edge of heart failure for several decades and has thought carefully about these issues. Dr. Konstantin, welcome to today's podcast. Thanks so much. Great to be here. I'd like to turn to you to generate a historical perspective. Why did we even bother to raise this question? Why is this even a topic of the day? Yeah, that's a great question, Dr. Yancey. So actually, I think the question about antithrombotic therapy in heart failure goes back at least 50 or 60 years. In the 50s, I think early 60s, anticoagulating with warfarin was not an uncommon practice among practitioners at that time for patients with heart failure. And there were some early clinical studies in those days, not really up to the standards that we use today in randomized controlled trials, but some suggestive evidence that they were of value. The difficulty there is that such a high preponderance of patients with heart failure at that time had rheumatic heart disease. And so that really, I think, convolutes the issue of whether antithrombotic therapy is of value in patients with heart failure per se in the absence of valvular heart disease and the absence of rheumatic heart disease. Fast forward, and not a great deal was done over the coming 10 or 20 years. We published a paper in the early 2000s that is derived from the studies of left ventricular dysfunction, originally published in the early 1990s. And we did a retrospective observational analysis of those patients. and we found that after adjusted for baseline variables, patients who were receiving warfarin therapy had improved survival and reduced hospitalization for heart failure. And this obviously was an observational analysis. There was no difference in that analysis whether patients were symptomatic or asymptomatic, whether the patients had ischemic heart disease known or not, or remarkably, whether they were in atrial fibrillation or not. So that's really where it becomes incredibly interesting, right? Because we are very accustomed and understand that it's a guideline directive imperative to anticoagulate the patient with heart failure and atrial fibrillation because of the very high incidence of stroke. But these very relevant data that really represent foundational information about heart failure suggested that perhaps there was another potential benefit. But admittedly, that was during an era where the background therapy was largely limited to digoxin, diuretics, and ACE inhibitors, right? Absolutely right. And so we get to this next point in time where we begin to test this prospectively. And as you and I both know, those trials were not always executed as well as they could have for lots of reasons. But this question became more of a top of mind issue, correct? Yes, it definitely did. And this was, of course, at a time when people still had warfarin as the tool, but there were a couple of studies that were done fairly large scale. One was the WATCH trial and one was the WARCEF trial. One of the problems was that people did not feel comfortable because there was a fair number of patients included with ischemic heart disease. Folks did not feel comfortable comparing against placebo without use of antiplatelet therapy. So in each of those cases, there were active controls with antiplatelet therapy serving as the active controls. And patients had a low ejection fraction. Many of them had heart failure in those two trials. But the net result was nil. There was no significant difference. There was no significant benefit for warfarin therapy over the control group was using antiplatelet therapy. And so to further complicate this issue, we always had these questions, at least in the past, about whether or not concomitant aspirin therapy would minimize some of the potency of the ACE inhibitors. So this was really a convoluted discussion, I would think that's fair to say. That's totally true. Yeah. So what effect the aspirin was having in those trials is very difficult to understand. Dr. Constem, thank you very much. That was really an excellent review of a very important topic. I'm delighted now to pivot and turn to my good friend and colleague, Dr. Barry Greenberg, who was one of the lead investigators for the Challenger set of studies. The lead results haven't been published in the England Journal of Medicine, and now we have the post-hoc secondary data that have just been published in Gemma Cardiology. Barry, welcome to this podcast. Talk to us about Challenger, the parent study, and then your most recent data. Yeah, thank you very much, Clyde. Commander was a very important clinical trial and it built on the work that Dr. Constan has already alluded to. We looked at patients who had worsening heart failure, they had coronary artery disease, and they were in normal sinus rhythm. So we took patients who were hospitalized with a recent decompensation very shortly after discharge, randomized them to low-dose antithrombin therapy with two and a half milligrams of rivaroxaban each day. And it turned out that these individuals did as well with the placebo as they did with rivaroxaban. In other words, there was no real effect of therapy on outcomes, which were a composite of all-cause mortality, myocardial infarction, and stroke. Well, when we looked at that data, we were very struck by the fact that mortality was the main driver of that composite and that in point of fact, mortality was a lot higher than in some of the studies that had been done with low-dose rivaroxaban, such as in a stable coronary artery disease population. And we thought that what we were seeing here was that there was an excess of deaths in this population that were pump failure related, and that in point of fact, what we had shown was that low-dose rivaroxaban, two and a half milligrams twice daily, had no impact on the pump failure deaths. But what was curious to us was that in the background, there were sterile deaths that were due to presumed thrombotic causes, such as MI and stroke, and it looked like there was a signal there that the rivaroxaban might be having a favorable effect. So what we did was to perform a post-hoc analysis, including all presumed thrombotic events, that is ischemic stroke, myocardial infarction. We included sudden cardiac death because we felt that many of these were likely due to a thrombotic cause. And then we also included DVT and pulmonary embolus. And what we found was indeed there was a substantial percentage of patients that went on and had these thrombotic events over the course of two and a half plus years and that there was a significant risk reduction in the group that was treated with rivaroxaban, suggesting that there was ongoing thrombotic events in this heart failure population and that you could lower that by treating with an antithrombotic therapy. So that really does raise a very important question, correct? Because we've always discussed the modes of death and heart failure, and we have restricted most of our conversation to sudden cardiac events and pump failure, but we've known all along that that was insufficient to capture all of the mechanisms of death in the setting of heart failure. And so these thrombotic events that you've identified, albeit in a post-hoc analysis, do raise the possibility that we continue to treat heart failure without sufficient therapies to protect from this other set of circumstances that might lead to poor outcomes. Yeah, I think that's exactly right, Clyde. There's ongoing thrombotic risk in this population. These patients have identified themselves as having atherosclerotic disease because they needed to have evidence of coronary disease to get into the study to begin with. And in that population, there's ongoing risk of sudden cardiac death, of myocardial infarction, of ischemic stroke, and so on. And what this post hoc analysis showed us is that we could actually reduce that risk with low-dose rivaroxaban. I think that was an important insight. So, Dr. Constem, I mean, I should call you Marv because we're good friends.
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But we've heard a really great summary from Dr. Greenberg about, yes, the primary endpoint of Commander HF was negative, but then we see these retrospective data that at least target the numerical difference in thrombotic events, post-hoc at least, and continue to raise the question, is there a role for an antithrombotic? And this time, the approach was not with dual antiplatelet therapy or with warfarin, but with the direct oral anticoagulants. So what are your thoughts about what you've heard? Yeah, thanks very much, and I'll call you Clyde. Okay. So I think that Dr. Greenberg's contribution and his colleagues is very important. To go back to the commander study itself, a couple of things need to be pointed out. One thing is we were no longer using warfarin. So now we have newer anticoagulant therapy that are more direct acting agents that have advantages, at least in certain populations, particularly atrial fibrillation. These agents have been shown to be superior to warfarin in bleeding and or in preventing thrombotic events. So we have a better tool, I think, if this hypothesis is going to be correct, to test it. And I think that the basis for Commander was two earlier studies, neither of which was directed on heart failure, but was using low-dose rivaroxaban in patients with ischemic heart disease, either acute coronary syndrome or chronic stable angina, chronic stable coronary disease. And both of them had positive results, but particularly of note is that there were heart failure subgroups, and the findings in the heart failure subgroups were consistent with the broader population, sort of giving further advancement to the hypothesis that this therapy would be of value in patients with heart failure, at least in patients with heart failure and atrial fibrillation. So the results of Commander HF were disappointing in that they were not positive. And so we leave it as that as the major take-home of the study. But we don't stop there. And I think Dr. Greenberg and his colleagues really have done a service by looking further specifically at those events that are known to or suspected to be thrombotic. Specifically, they looked at myocardial infarction, stroke, and sudden cardiac death, in addition to pulmonary emboli and deep venous thrombosis. Now, in their analysis, as Barry, Dr. Greenberg, has mentioned, they did see favorable effects. Now, in terms of those endpoints, particularly the MIs and strokes. So one thing I really want to congratulate Dr. Greenberg and his colleagues about is in the really excellent scientific approach that they used in describing their results. So because this is a post hoc analysis, none of these results can be considered definitive. Absolutely. And I think we're all in agreement about that, I believe. But nevertheless, they certainly are intriguing and they certainly were based on a very reasonable hypothesis that thrombotic events would be where the money is. And so I feel strongly that those results move the discussion forward, if not being definitive in their own right. They provide us additional information to the puzzle, and I think they provide us with direction about where we might go from here. So I like that statement. And I think that as we bring this podcast to a close, all three of us have probably taken something uniquely away from the conversation. I'll start by simply saying, I think once again, we recognize how important it is to respect evidence-based guideline-directed medical therapy, particularly for reduced ejection fraction. Heart failure, the benefits are real. And whenever we test something new, it has to be against the best possible outcomes that we can now achieve, which are pretty good when prescription and adherence is intact. I think it is absolutely worthwhile to continue to test this prospectively in a higher risk population. There may be some real advantages here with low-dose direct oral anticoagulation. Dr. Constand, your closing thought? Yeah, I want to close with some specific take-homes for future investigation that Dr. Greenberg and his colleagues pointed out, but I'm going to emphasize. One is that the commander population had sicker heart failure patients than in those previous studies. And so a greater number of the endpoints were probably driven by heart failure events. So one possible direction to go is to investigate patients who are less sick with heart failure than the patients who were studied in Commander. The second is to recognize the issue of net clinical benefit. And so the benefit that is posed in terms of a stroke or MI could be countered by bleeding events. And depending on what you consider for that definition, it may or may not somewhat negate the favorable effect. I think one direction is to identify populations who have a higher base rate of MIs and stroke and a lower base rate of bleeding events who might really be particularly appropriate for benefit with this therapy. And I think that would be another important direction to explore. Terrific. And now, Dr. Greenberg, your takeaways, your closing thoughts. Well, I think there is a takeaway message, and that is that there's good evidence from studies like the COMPAS study that patients that have atherosclerotic disease will benefit from treatment with low-dose antithrombin therapy. And that risk for patients with atherosclerotic disease seems to hold forward in the heart failure population. Now, the fly in the ointment for us was that we looked at patients who had decompensated heart failure. We studied them immediately after that. And that's a different population. We need to recognize that. I think that right now what we need is a good clinical trial in the area of patients with stable heart failure, including both HEF and HEF-REF, to see what the effects of this therapy, low-dose antithrombin therapy, is going to be on outcomes. But I think that the data that we've provided should both provide a background for such a study and give us some optimism that that study would have positive results. This has been a fabulous discussion concerning the appropriateness of anathrombotic or anticoagulation therapy in the setting of reduced ejection fraction heart failure in sinus rhythm. I think the best summary is the subtitle from Dr. Constem's brilliant editorial, The Clot Thickens, just really brilliantly done. I want to thank our guests today, Dr. Greenberg and Dr. Constem, for illuminating a very important issue for which we need to pursue ongoing discussion and investigation. Thank you, gentlemen, very much for today's podcast. Thank you for inviting me. Thank you, Dr. Yancey. It's been a pleasure to be on this podcast with you and Dr. Konstan. This is Clyde Yancey from JAMA Cardiology. Thank you so much for listening in to today's podcast. For more podcasts, visit us at jamanetworkaudio.com. You can subscribe to our podcast on Stitcher and Apple Podcasts.
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This is Matt with a quick announcement before we get into today's show. I just wanted to address that in every episode, you can pretty much count that the first 15 minutes are usually going to be sort of a mentorship, faculty development, picks of the week, kind of us easing into the clinical topic, putting our guests at ease. So if you want to skip that, you can generally skip ahead 15 minutes. You can look at the show notes where we will have timestamps that say right when the clinical case starts. That way you don't have to guess. And finally, I'd like to say that on this episode, there are a lot of visuals that go along with this one. Joel Toff made a wonderful PowerPoint that is available on our website. And a lot of the slides will be in the handout that we sent out to you in email this week. So make sure you check that out to follow along. The topic is acid base. And without further ado, here is the show. Thank you. Welcome back to the Curbsiders. Hi, Matt. How you doing? I'm trying to squeak out a voice here for this episode. But I'm excited because Shreya's here. And so am everybody. I don't care for any of that. Please, from now on, even if they have nothing to do with him, please put hashtag free Paul in all your tweets because I find it funny and Paul finds it annoying. Sure. We'll set the Twitterverse on fire. Paul's Twitter goes crazy Friday nights. He makes the best jokes. Just another plug. Paul, did you want to tell them what the show's about since I don't have a voice? Sure, I would love to. This is an internal medicine podcast and we use expert interviews to bring you clinical pearls and practice changing knowledge. That's right. That's right. As I'm coughing through. As I'm coughing through. Yeah, so Shreya, what do we do on this episode? Because I really don't have a voice. All right. We're going to talk to Dr. Joel Toff about acid-base, probably one of the most confusing, anxiety-provoking topics, causing people to be probably in chronic respiratory alkalosis. So we're going to learn a lot with Dr. Toff today. That's right. Okay. So we go through, basically, there's about five steps to determining the acid-based disorder and figuring out any second acid-based disorders that are present. And if you're confused about this topic, which I think a lot of people are, but are afraid to admit, then this is going to be a really useful episode. If you don't know who Dr. Toff is, then you're, you're in luck. You're in luck. That doesn't make sense. If you don't know who Dr. Toff is, then you're in luck. You're in luck. That doesn't make sense. If you don't know who Dr. Toff is, then I'm excited for you to hear him talk for the first time. He's been on several episodes with us, which you can go back and listen to after this one. But Dr. Toff, he's known in nephrology circles for his blog, Precious Bodily Fluids, The Musings of a Salt Whisperer. He's a board certified. Oh Oh, and of course on Twitter at Kidney Boy is where he spends lots of time and answering questions from whoever asks them on Twitter. He's a board certified nephrologist and partner at St. Clair Nephrology. He holds academic appointments as assistant clinical professor at the Oakland University William Beaumont School of Medicine and is academic faculty for the St. John Hospital and Medical Center Nephrology Fellowship. So Dr. Toff is a celebrated educator and this year won a major teaching award at the American Society for Nephrology's Kidney Week, which we were all very proud of and happy for him, feel that was very well deserved. So without further ado, here is our thorough discussion of acid base with Dr. Joel Toff. Back with us tonight is a big crew recording. And of course, everyone's favorite, Dr. Joel Toff. Hi, Joel. Thanks for coming back on. Oh, I'm super excited to be here. This is gonna be a great one. Yes, this topic. Right. Yeah, I am too. You know what? I want to start off. Shreya, why don't you lead us into the reflective. We're talking about acid-base today. Acid-base has a lot to do with compensation for a primary insult. So in terms of compensation, I was thinking about your life and how do you compensate or cope whenever you're faced with an insult or a conflict usually? Well, I think like a lot of people, I retreat to things that I'm very comfortable doing. So anytime I'm given a challenge, things to do that are difficult or challenging, I retreat, let me give a lecture on something else, right? So it's a great way to be both productive and to delay things that are inevitable. And so I don't think it's a good strategy. It's just, it's what I find myself doing repeatedly. So things that I'm good at, I like to do. And if that means he basically said that people who procrastinate, there's actually something to it. And he wrote a whole book about it, how it's actually beneficial to start a task and then finish it midway because your mind is still thinking of it until that task is completed. It took him 74 years to write that book. Supposedly, it boosts your creativity to procrastinate. So I found that comforting. I'll think about that later. Yeah, we can put the link in the show notes. All right. Sorry, Shreya, I cut you off. No, no, all good. So on that role, in terms of kind of your success and being this mid-career faculty who's so big in the nephrology world, what would you say is your key looking back on these years in terms of your success? Sorry, I stumbled there. Success. No, no. So I guess I'd like to point out some important things. So one, any success that I've had is kind of an orthogonal success. There's a set route that you're supposed to go through to reach success in nephrology or any kind of academic field. You need to go to an academic institution. You need to work your way up the academic ladder by publishing. You need to get grants. All that is hard work, and the people that have accomplished it are amazing people, and I didn't do any of that. You went rogue. No, I really did. I found a, quote, third way. But I feel uncomfortable when you say I'm someone who's super successful. I've reached a level of notoriety more than. Like I think people know of me because I do a lot of stuff that's very public. But I, it's, you know, it's funny. What is Isaac Newton said? He, if I could see far, it's because I stood on the shoulder of giants. Like I've stood on the shoulder of giants, but I didn't look forward. I looked backwards, right? I just looked at what has already been done and then talked about what's already been done. It's what's already been researched. And that's not nearly as accomplished as someone who's actually defining and determining new information. And I think those are the people that we really need to champion in medicine are the people that are pushing back the barriers of knowledge. And I'm just kind of going through what they've already discovered and trying to make it a little bit more clear and to teach it to people, which I think is a noble task, but I think is not the highest degree of accomplishment. I think they're both very important roles. One cannot survive without the other. Right. As a bunch of medical educators, let's talk about how important medical education is. As a bunch of us who are doing the same exact thing you just described, yeah, we'd like to think there's some merit. Well, you know what they say about those who don't do. generation was like the gap generation, like computers became more powerful enough and connected enough to be effective, but they weren't, we were too late to like learn them early on. And so there was just a few of us that had the skills to use, to do a blog and to do sophisticated presentations and do your own desktop publishing. Like all those were skills that were available and people could learn them, but there weren't a lot of doctors doing them.
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Right. But it was an accident of timing more than skill. I've got one. Please answer. I got to think about this. Okay. So if I could choose anything, it would be nitric oxide because it's both free and radical. What? I think if you Google a pun and then ask Joel the question, it's a little unfair. I didn't do that. I didn't Google this one. I was thinking about possible answers. Right. Do you want to hear a sodium joke? Sure, why not? No, no. The correct answer is nah. And then I say, do you want to hear a potassium joke? Okay. There you go. You're a natural. Maybe we can let people answer on Twitter what electrolyte they think Joel is most like. And then, you know, we'll let the fans answer. I would want to be sodium because it's kind of mysterious. It's like super common, but nobody really gets. I think I'm actually just magnesium, which is mostly irrelevant but can still be measured. I am impressed. Hold on, let me check that. Paul? That's the correct answer, actually. No, I think magnesium, too, just because residents pay an inordinate amount of attention to it. And that's why we're going to pregnant ladies. It's beyond... If you get to... When I was a fellow, I was given the assignment to write a chapter on magnesium, and I had no idea what kind of quagmire this was going to be there is so much mysticism surrounding a magnesium lots of people think magnesium can cure anything and everything there's an entire journal about magnesium like and so once there's an entire journal about magnesium your pub med search is wasted right, right? Because whatever you look, there's going to be something on it. And so you can get lost looking through magnesium stuff. And there was some really interesting research, but just so little of it has panned out. There's a lot of suggestive things like, oh, magnesium should be great for diabetes. It seems to improve insulin sensitivity. But you just don't see the final piece being put together where it becomes super important, though all your diabetics are magnesium deficient. And oh, and then there's this huge field about magnesium where they have functional magnesium deficiency. Like, don't be fooled by that normal magnesium level. They're still magnesium deficient, right? And so with all kinds of advanced testing where you would give magnesium loads and measure 24-hour urine magnesiums after that to look at what percentage of magnesium was excreted, and if it doesn't reach 100%, that means they're absorbing magnesium because they're magnesium avid. So there's a pseudo hypomagnesemia. It's the worst. And as a fellow, it took me way too long to get what kind of quagmire I was in. I was like, oh my God, this stuff is so fascinating. And he lost hours. Paul, rather than give you a chance to ask a question, I think we should just go on to picks of the week. Because generally this is your time to shine. So Paul, did you have a, do you want to start us off with a pick of the week? Usually just by making fun of yours. Yeah, I will. So I was watching the new movie Mute that is now streaming on Netflix, which is not my recommendation because it is a deeply flawed movie. But the director who directed Mute also came out with a great movie called Moon. So the director's name is Duncan Jones. He came out the movie Moon. I believe it was 2009. It is a science fiction movie occurring, weirdly enough, on the moon, starring Sam Rockwell. Basically, he's the only guy in the movie, the voice of Kevin Spacey, if that matters to you. And I don't want to give too much away, but it's sort of a study of identity. It's got this amazing score by Clint Mansell. The performance by Sam Rockwell is astonishing. The plot's great. It'll blow your mind if you're a science fiction fan, and probably even if you're not. So the movie is Moon by Duncan Jones. Do you memorize all of that before you come on, or are you just... No, this is just freestyle, Stuart. This is all... You're really good with names. I'm very impressed by it too, Stuart. I often wonder the same thing. It's just like throwing it off. I'm just reading off the Wikipedia page right now. Okay, cool. Shreya, did you have a pick of the week? I did. Okay, I want to plug something on Twitter. It's Women in Medicine Chat. It happens every Sunday at nine o'clock and we discuss all sorts of topics from like leadership and women, maternity leave, how as females we can better advocate for each other. Honestly, for me, it's just become a really amazing virtual community and just has given me a great sense of belonging outside of my own institution. And it's just great to hear other women who have similar struggles or women who've overcome it and are now kind of inspirational mentors for me. So I wanted to plug that out there for our listeners. Both men and women can join along the conversation. And yeah, 9 p.m. Sundays, guys. Okay. Joel, did you have a pick of the week? So right now we are in the middle of our giant social media campaign called Neff Madness. And this is – we're in year six of Neff Madness. So the idea for this is to take – we have March Madness, the basketball tournament, and we substitute all of the basketball teams with nephrology concepts. We have a field of 32 nephrology concepts distributed over eight different academic regions. And if you go to nefmadness.com, you will see our brackets and you will be able to then submit your guesses for which ones will win and if you want to dig deeper I recommend going to AJKD blog this is the official scientific blog for the official journal of the National Kidney Foundation and we have what we call scouting reports. And we've gotten experts in the field that have gone over the four teams in each one of those regions. And we've written up evidence-based descriptions of all of them so you can get background on them. Because we're not talking, this is not like nephrology 101. We are working at a very high level, but you can catch up on all of this. My favorite bracket is Animal House is what we call it, and it is a region for the phenomenal electrolyte somersaults that some animals can do. So we have how camels can store water and how toads can store water, which are completely different, right? Like the toad bladder, an amazing organ, right? And so, and how about, you know, did you ever think about how crazy it is that salmon can go from saltwater, freshwater? Like that's like a total osmotic somersault, right? It's amazing. And so we go through all the physiology of this and you get to pick which one of these animals really is the best, which of course is going to be the shark, right? Because sharks rock. But I don't know, camels are great too. So you got to pick this and you can go through all 32 of them. If you read all of the stuff on AJKD blog, all the scouting reports, we'll even give you eight hours of CME credit. Like this stuff is awesome. And then you submit your brackets with what you think. We have a blue ribbon panel of nine nephrology leaders that vote. They determine the actual winners. How well your votes match up to their votes, you'll get points. And the person with the most points wins. And we have prizes, textbooks. It should be great. When do I have to submit by? March 30th. Okay, I can do that. When you submit, there's an opportunity to associate yourself with a group. And so I think you guys should have a curbsider group and you should get all your listeners to submit under curbsider. If they don't want to already submit under their residency program or their fellowship or what have you, that would be awesome. You guys could, like, I think the biggest group last year was 30. You guys could rock that. I think we could probably beat that. Yeah. So 30 people was actually my institution last year and everybody got a backpack, a little like a little Neff Madness backpack. It was pretty cool. Sweet.
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Okay. but we have people participate from all over the world. Like I said, it's in our sixth year. It's been a lot of fun. All right. Well, Stuart, I'm not going to give a pick of the week. I think we should move on unless you really have one because this is a big topic and I want to allow it enough time. This is my pick of the week. Let's get into it. Let's do it. All right. Yeah. Awesome. I mean, Joel, this is such a big topic. Did you want to give us a case to build this off of? Or where do you like to start when you're teaching acid-base? Okay, so let's frame acid-base. Because the more you look at the sensitivity and specificity for much of what you do during the physical exam, the less excited you are about doing the physical exam. But it's still like it's like a ritual that we all do. And acid-base is somewhat, and I am so sad to say it, is a lot like that, is that we've created this internally consistent, beautiful logic, the way an acid-base works inside of that. And then when you start to judge it by kind of the hard, you know, rules that we do, like the, the anion gap, which has this beautiful way of breaking down the differential diagnosis has a sensitivity for lactic acidosis of like 50%. That's not good enough to do anything. Right. And so, and so it kind of breaks down and some, but whatever, you're still going to be tested on it. It's still going to be on boards. You still need to know it. Competent physicians can work their way through an acid-base question and understand an ABG. And so I'm tortured, right? I want it to be better than it actually is. And I hate to say that you need to know it because you need to know it. But I think in the end, it's just a skill you need to know. And it's difficult because it's so much different than the type of information that you're used to learning. I don't think it's difficult on its face. Everybody in medicine is intelligent enough to do it. But it is materially different than everything you learn in rheumatology or hepatology. It just feels different. So let's walk through that. I think we can start with what's different and what makes it very different from everything else in nephrology is we're used to balancing atoms at millimolar quantities, but now we're talking about protons that are at nanomolar quantities. A normal pH of 7.4 is a hydrogen ion concentration of 0.00004 millimoles per liter. It's ridiculously small. And the solution for this in all of its insanity is to measure it on a negative logarithmic scale, right? Because we're so used to working in a negative logarithmic scale. That should be. And so the first absurdity is the lower the pH, the higher the hydrogen ion concentration. And you could wrap your mind around that, but then we're going to make it a curvilinear relationship so that as we go down the pH scale, we get larger and larger changes in hydrogen ion concentration compared to going up the pH scale. To make it clear, a change of 0.3 on the pH scale is a factor of two in hydrogen ion concentration. If we're going for 7.4, which is 40 nanomoles per liter, to 7.1, you double to 80. Go to 6.8, you double again to 160. You go from 7.4 to 7.7, you cut it in half. You go from 40 to 20. So the delta from 7.4 to 7.7 is only 20, but 7.4 to 7.1 is 40. So, I mean, I remember as a sub-I getting pimped by the dean of students, and he was like, what's better tolerated, acidosis or alkalosis? Answer is alkalosis, much better tolerated than acidosis. And he started going into this long-winded explanation about compensation, et cetera. It was all BS. But the reason alkalosis is better tolerated is because of this curvilinear relationship. You're talking about a smaller change in hydrogen ion concentration. So you just got to, again, the idea that putting this on a negative logarithmic scale helps anything is absurd, but that's what we've got. The next thing that tortured me for a long time was just I misunderstood the value of the ABG. I thought it was a therapeutic tool, that I would get an ABG and I would see the pH was low and the PCO2 was high, and I said, oh, we need to intubate this patient. Or I'd say the pH was low and the bicarb was low and I need to give bicarb to this patient. And I am sure that I harmed a number of patients using this. And, you know, it is the ABG is not useful for guiding therapy, right? And I think the best example of this is you get a patient with a pH of 6.8 and your mind explodes. You're like, oh my God, this patient is profoundly ill. And then if someone tells you they just had a grand mal seizure, you're like, oh, okay, we'll just check the ABG again in five minutes and it's going to be fine, right? But if that pH of 6.8 is due to methanol toxicity, it's like game over. That patient is going to die, right? You've missed your opportunity to treat them. And the difference is not the pH between those two differences. The difference is the disease, right? So the ABG tells you what the pH is, but it doesn't tell you anything about the patient. You need to use the ABG, blood gas, as a diagnostic tool, as a way to get to a diagnosis. And then you can figure out what you need to do. If it's a seizure, you just need to wait. They're going to get better on their own. If it's methanol and it's not too late, you can give them femepizole and dialysis and take care of them. And so it's the disease. That's what you need to focus on. It's not necessarily the pH. I like that. I think it's going to be very different than as an internist. As an internist, we're really just using these tools to come up with a diagnosis. And what we're really looking for, we're going to use, every time you get an ABG, you need an ABG and a basic metabolic profile. And we're going to go through five steps to fully dissect the ABG and get as much information out of it as possible. And I've got this image that I think is going to be on the Curbsider website. And it's this five-layer cake, essentially. I always think of it as kind of like an archeologic dig and you start at the top and you start to dig down deeper and deeper and you can get as much information as possible from this chemistry. And I think it's pretty incredible the amount of information that can be abstracted from an ABG and a basic metabolic profile. It's one of the things that's so intoxicating about the subject. Joel, I wanted to say, did you want to tie this? You had given us a case. This was this guy that you were seeing, which is changed from a real world case, but it was a paraplegic gentleman. He had a chronic indwelling Foley. He was admitted with urosepsis from Klebsiella and the basic metabolic panel showed that his bicarb is 16, his anion gap is 8, and the residents are calling this a metabolic acidosis and they started him on sodium bicarbonate. But day after day, like the bicarb is just being stubborn. It's not correcting. So finally they give him a bicarb drip and they call a nephrology consult. And am I missing anything from the case? I guess you asked for an ABG. Right, but before we get to the ABG, the key there is they looked at the bicarb level of 16, and they saw that it was decreased. That is one component of your Henderson-Hasselbalch variables, but it's not all of them. From that bicarb, you can't actually diagnose whether the patient has metabolic acidosis or not. And the other important key there was that the patient did not have an anion gap. And so they started a bicarb drip treating presumed metabolic acidosis without diagnosing metabolic acidosis.
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And so the decreased total CO2 or bicarb on the basic metabolic profile was secondary to compensation and not the primary disorder. And so, you know, and we tend to not treat alkalosis with bicarb, right? That's not what you want to do. I'm not sure if we should treat acidosis with bicarb. We certainly shouldn't treat alkalosis with bicarb. And so. So where should they have started here? Like what steps should they have walked through as you were about to get into before I interrupted you? Yeah, that's perfect. Right. Okay. So essentially the primary buffer in the body is bicarbonate. So you have this central equation, which is a water plus CO2 is an equilibrium with carbonic acid, which is an equilibrium with hydrogen and bicarbonate. Because the body has carbonic anhydrase, the fastest enzyme in the world, or excuse me, in the body, 6 million reactions a second, I think that's what it is. We drop out carbonic anhydrase and we just put water and CO2 in equilibrium with hydrogen and bicarbonate. And you can rearrange that using the law of mass action and simple algebra, and you end up with what we call the Henderson-Hasselbalch formula, which is the pH is equal to pKa plus the log of bicarbonate over CO2. The important part of that, which I call the mantra, is that pH is proportional to bicarbonate and inversely proportional to CO2. And so if the bicarbonate goes up, the pH goes up. If the CO2 goes up, the pH goes down. And that from there, we can define the four primary acid-based disorders. There is metabolic alkalosis, which is an increase in bicarbonate, increase in pH. Metabolic acidosis, a decrease in bicarbonate, decrease in pH. Respiratory acidosis, an increase in PCO2 and a decrease in pH. And respiratory alkalosis, a decrease in PCO2 and an increase in pH. And then compensation is the body trying to re-establish the ratio of bicarbonate and CO2 so there's a minimal change to the pH. So if your CO2 falls, your bicarbonate will fall as compensation to minimize the change in that ratio. And if your bicarb goes up, your PCO2 will rise to, again, try to minimize changes in that ratio. And so the key fact that the compensation always going to be in the same direction as the primary disorder. And that the last part of that, since there's three variables, would be the pH. And then in metabolic disorders, primary disorder and compensation will be in the same direction and the pH will be in the same direction. While in respiratory disorders, primary compensation in the same direction, pH in the opposite direction. I just wanted to plug one thing from one of your slides that I loved, that metabolic acidosis is like a boy band. Everything goes in the same direction, and it's all down. Yeah, but you're missing – Like one direction. Yeah, it's not the same direction. It's one direction. Come on. Sorry, you can say the joke. I totally messed it up. That's Shreya's – Shreya's our expert on messing up jokes. So I think it might be more memorable that way, Shreya. That's a good learning tool. It's all going down. You know, it's so sad. I was just waiting for him to finish. All I could think about was that joke. And then I messed it up. You could say they're on sync. That is perfect. Yeah. And Joel, I think I agree with what she's saying though. Like it's just – it's so easy now. You just look at the ABG and if the pH, the CO2, and the bicarb are all going in the same – all going in one direction. Trey, you got me saying the wrong thing. If they're all going in one direction, it's metabolic. And if the pH is going in a different direction, then it's respiratory. And have a pile of 20 questions. We'll go through the room, and there'll be 20 out of 20. Once they learn the secret, nobody gets it wrong. They start to roll their eyes. They can't believe I'm asking them these questions because it's so trivial. Getting the primary disorder puts you ahead of a lot of interns. You've got that part. It's easy, but a lot of people miss that. Literally, I take an arrow, and I just draw little arrows. Is it up or down? Is it up or down? Is it up or down? Once they're all going in the same direction, oh, it's metabolic, and then you just look at the pH up or down, and then acidosis or alkalosis. That's exactly right. Why is metabolic acidosis like a boy band? Everything moves in one direction. Now, are you claiming credit for that joke joke or did someone else come up with that? I'm taking full credit for that. Okay. And it's all down from there. I will say that memory is not a very reliable source of evidence, right? Like I literally, I told a story from my residency for years about how while I was a resident, Dan Quayle had a pulmonary embolism and was in the hospital. And that there was a secret service there and you had to have your badge and all this. And I'd literally been telling this story for years. And then I looked it up and I realized that Dan Quayle being in the hospital was a year before I showed up for my residency. I have all these memories that just never occurred. So I'm pretty sure I made up the boy band joke. And my evidence is that I've got a 15-year-old daughter. And so she was like 12 at that time. So who knows? But I do believe that's my joke. All right. We'll allow it. So what's the next step? Now we know what the primary disorder is, and we know it's acidosis or alkalosis. Stuart, did you want to ask your acidemia versus alkalemia question? That's a dumb question. Just for nomenclature purposes, is it acidemia or alkalemia or acidosis or alkalosis, and why? So those refer to different things. Okay. So acidemia actually means the pH is below 7.4 and acidosis is any process that tends to lower the pH, but the pH may still be above 7.4, but you can have an acidosis, right? So if you have, if you've been vomiting for days, okay, so you have this wicked metabolic alkalosis, and then you develop DKA, so now you have a bunch of ketones floating in your bloodstream, that DKA is going to cause a metabolic acidosis, but it may not cause acidemia depending on if it's more severe or less severe than the metabolic alkalosis. Does that make sense? Absolutely. So in terms of the earlier theoretical case where the patient had a pH of 6.8, it's not the acidemia that kills you, it's the acidosis that kills you. Do I have that correct? That's good. I hadn't thought about that way, but yeah. It's a disease that's important. That's exactly right. So when we were talking about compensation initially, we said that compensation always goes in the same direction, the one direction. Same direction. Shreya derailed the whole thing. If my skin wasn't brown, I'd be bright red right now. It's okay. You need some sleep eventually, Shreya. Why is there a mark out of just one guy's head in that slide? The answer for that is I'm blanking on the name, but one of the members of One Direction left. I think it's Zane or One Direction. Oh, Zane. Zane? Is that who it was who left? Zane. Yeah, Zane. That's spelled Z-A-Y-N. Yeah, so Zane laughed. Big deal. It was a big deal. Usually when that slide builds and the little anti comes across him, I then ask everybody to pour one out for Zane, right? And the medical students, half of them look at me with respect because I know one direction, and the other half of me look at just horror that I know one direction. Joel, I have no idea your knowledge of one direction. I'm just a poser. I'm just a poser. I look it up on Wikipedia right before I go into the lecture. I'm the worst.
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And then the worst is it's not cool at all, right? So, okay, so let's back. We said that compensation is always in the same direction as the primary disorder, but it's actually even more advanced than that, that you can not only determine the direction of compensation, but you can determine the degree of compensation, the specific amount of compensation, just from the severity of the primary disorder. And so when you have a metabolic acidosis and you've dropped your bicarb down to 12, you need to hyperventilate down to a PCO2 of 26. That's the proper amount of hyperventilation, the proper amount of compensation, the predicted amount of compensation for that degree of metabolic acidosis. So if you hyperventilate down to 30, yeah, you're doing great. You're breathing faster than you should, but you're not breathing what a healthy human breathed down to. You're not hyperventilating enough. Inadequate ventilation is what's going on there, and we have a name for that inadequate ventilation. We call it respiratory acidosis. If on the other hand, that person hyperventilates down to 20, right? I have residents will say, oh my gosh, this patient is like overcompensating for their metabolic acidosis as if like the patient has three lungs, right? They have some kind of alien technology that allows them to really breathe very well. No, that's not what's happening. They are hyperventilating beyond what they should be for that degree of metabolic acidosis. We have a name for that too. We call that respiratory alkalosis. And so by knowing where the PCO2 should be for that metabolic acidosis, you know, you can then look at that ABG and see if there's a second primary disorder going on that's affecting compensation. Okay. And this is, this is, this second level, usually where, well, it's an important, it's a huge important part of doing your analysis of your ABG. You determine the primary disorder and then you look to see if compensation is appropriate. It is also the primary pain point for ABGs because there are four primary disorders, and you need to learn four different equations to understand them. They're not hard equations, but you just need to sit down and memorize them. You're a medical student. You're a resident. You're good at memorizing things. It's just different than the stuff you're used to memorizing because it's an equation. There are lots of programs that you can get for your smartphone that will interpret the ABG for you. The ones that I've used have all been accurate. I don't think there's a problem with it. It's pretty mechanical to do, but you can't use them during boards. And honestly, when you're taking care of patients, taking out the phone, unlocking the phone, finding the app, inputting all the data, or going to the web and searching for it, it takes forever. It's worth it if you do these enough just to memorize it. The last three months of CCU, medical ICU, med consult, how many rapids have I run where I need to think on the spot what the ABG was telling me for this patient. And, you know, I didn't have a app on me. So more evidence for, not evidence, more support for, you know, knowing this offhand and not just relying on the app. app. Joel, is there a specific app that you did want to recommend? Is there any specific one? I'm a big fan of MedCalX. It is not a free app, but it is excellent. Your clock is programmed Q12 minutes. So the audience should know something. Joel has a grandfather clock at his house, which rings every 15 minutes. We're just going to keep it in there. It's kind of a metronome for the pacing of the show. Okay, so MedCowX. Four. Yeah, Med-Cow X. Four more. Three more. Two more. One more. That should be it. Why was this not a problem last time? His wife's away. Oh. His wife guards the clock. Here's the story. Here's the story. As part of my wife getting ready to leave, she wound the clock, right? Because that's the kind of woman she is. She's like, oh, I'm going to get everything ready. And the clock got wound. Perfect timing. Perfect timing, of course. So, yeah, MedCalX. These guys have been making medical calculators since 1997. They were on the Palm Pilot initially, they're a great group. And they have an excellent ABG analyzer. And there's some ABG specific ones that I've used that are fine also. Okay, so there's four equations, and I'm going to go through them because I think I have a way of describing them that makes them a little bit easier to memorize. So the first one is the only one that has a name. It's Winter's formula. It's for metabolic acidosis. If you are going to memorize only one equation, this is the one to memorize. Metabolic acidosis is the one that comes up all the time. And on boards, I swear to God, half of all the ABGs are going to be metabolic acidosis. So this one's easy. You know the bicarb. You're trying to figure out the CO2. You take one and a half times the bicarb. You add eight to that, and then you put a plus or minus two on it. The deal about the plus or minus two is that all of these equations have a little bit of slop, plus or minus two on all of them for metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. So for me, since they all have plus or minus two, I just don't really think about that as being part of the equation. It's just one and a half times the bicarb plus eight, boom, that'll get you the answer. There are other shortcuts that you'll be taught that residents will be saying, all you got to do is take the bicarb plus 15. And what they don't tell you is that those shortcuts don't work for all ABGs. They work for most ABGs. And so if you want to use the shortcut, you also have to remember the exception for where they fail. And then you need to still know Winter's formula. So when that, except when you run into that exception, you can do the calculation. It's just not worth it. The equation is simple. One and a half times the bicarb plus eight, done. Metabolic alkalosis, again, we know the bicarb. We're trying to figure out the CO2. And so what we do is we take, figure out how much the bicarb has gone up from 24. So if you've got a bicarb of 36, it's gone up by 12. I call that the delta. You have a delta of 12. You take two-thirds of the delta, which in this case is eight, and you add that to a normal PCO2 of 40, and you get 48. So two-thirds of the delta bicarb plus a normal PCO2 is what your PCO2 should be in metabolic alkalosis. Easy. The respiratory disorders are a little bit more complex because, and it pains me to tell you this, the kidney is slow to respond compared to the lungs to these metabolic disorders or these respiratory disorders. So if you have a respiratory acidosis or respiratory alkalosis, you'll have the first 24 hours in which you do not have good compensation by the kidney. And then after that, you get excellent compensation by the kidney. And so you actually have to calculate both an acute change in the bicarb and a chronic change in the bicarb. And so we do this for every 10 of the PCO2. So for every 10 that the PCO2 rises in respiratory acidosis, the bicarb goes up one acutely and three chronically. And I want you to think about what actually is happening with this ABG. In acute respiratory acidosis, the bicarb is just about normal and the pH is whacked. And then over time, that bicarb starts to go up higher and higher and higher, and that pH gets more and more normal, right? So you trade your abnormal pH for an abnormal bicarb. That's what's happening during this process where you're accommodating. In respiratory alkalosis, for every 10 that the PCO2 falls, the bicarb falls two acutely and four chronically.
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And if you kind of think about what the kidney is actually doing, the fact that you have a larger change with respiratory alkalosis makes a little bit more sense. With respiratory alkalosis, to lower the bicarb, all the kidney needs to do is fail to reabsorb all the filtered bicarbonate in the proximal tubule. It just needs to do less work. It needs to put its feet up and not do so much work. It'll just piss off that bicarb, and the bicarb will fall like a stone. For respiratory acidosis, not only does it have to reabsorb all the filtered bicarbonate in the proximal tubule, it has to then synthesize additional bicarb in the distal nephron to compensate for just the bicarb that's consumed with normal metabolism and then generate even more bicarbonate to raise the serum bicarbonate up. It's a lot of work for the kidney to do. And so that's kind of a teleologic explanation for why it's less than you get with respiratory alkalosis. That's great. Those are the four equations. Yeah, and I was just going to say, I mean, we're going to have the PowerPoint on the website and the way that you visually put this together makes it really easy to remember, especially with the respiratory compensation. You have it in a two- two, three, four, and it resolves perfectly. I used to do this before tests, just in the margins, I would just write this little table down so I could then interpret all the ABGs for the test. There are nephrology recertification boards, there are lots of ABGs to interpret. It's like, here's 1,000 ABGs to go to work. I thought you were talking medical school. I didn't realize you were talking like recent times. Okay. So what you're going to do in, so that's your second major step in interpreting the ABG is you've determined if the compensation is appropriate, and then you can look for a second primary disorder. And I just, because I'm a nephrologist, I'm going to get pedantic for a moment. Oftentimes, people will say, we've looked for, we found a secondary disorder. And that's not what you're seeing here, right? So we talked about the person who had a lot of vomiting and then developed a DKA. That's not a great example for this. Let's talk about a person who has a PE and then develops DKA. And so, their PE causes respiratory alkalosis, right? Any type of insult to the lung will stimulate hyperventilation that was the other thing that was wild to learn right because you think about the mechanics of what happens during a PE and you think that must cause respiratory acidosis right you've whacked off a bunch of the lung you don't get good you get ventilation without perfusion there that must cause respiratory acidosis and it, right? That a PE and pneumonia and aspiration and lung cancer and chemical pneumonitis, like it doesn't matter what the primary insult to the lung, asthma, it doesn't matter what the primary insult to the lung is, the pulmonary response is to hyperventilate. So you get respiratory alkalosis in all of those, hypoxia, right? Anxiety. Anxiety, right. Medical students all the time. Chronic respiratory alkalosis. I think the lung is just a nervous organ, Joel. I think that's it. Well, and I think it's like the way the lung, you know, again, teleologically speaking, the way the lung was designed, like the lung's like, I may fail, but I'm not going to fail by not breathing fast enough. Like if something's going wrong, I'm just going to breathe as fast as I can. I'm going to leave it all in the field. And it's just like the kidney's response to any type of injury is I'm going to retain sodium. I don't know what's going on, but I am not going to pee myself to death, right? It's just like there's these inherent fail modes, right? So yeah, so anything that doesn't cause respiratory alkalosis. I forget. How do we get to respiratory alkalosis? Oh, we were talking about the two primaries. Okay. So you have a PE that cause respiratory alkalosis and the patient gets DKA and now has metabolic acidosis on top of that. That metabolic acidosis, that DKA is not secondary to the PE in any way. It's a second primary disorder. And the only reason it comes up second is that in this case, the respiratory alkalosis was more powerful and raised the pH. So the patient has an elevated pH. So when you went through the primary disorder, you found an elevated pH and a decreased PCO2 and a decreased bicarb. And then since the lines going in opposite directions you have a respiratory disorder it's a respiratory alkalosis you look at how much the pco2 fell and you looked at how much the bicarb fell and whoa the back up fell a lot further than that there's an additional metabolic acidosis not secondary but a second primary that's like it's just pedantic i don't think it's super important, but I want to point that out. When we're looking at the respiratory compensation, acute versus chronic, you don't necessarily know at the time that you're diagnosing the patient. So how do you like to suss that out? with what you had, that can determine whether you have acute or chronic. It was kind of like Occam's razor for ABGs, that if you could explain the bicarb better by making the patient have chronic respiratory acidosis versus acute respiratory acidosis, then they have chronic. If you had to then employ that they have an additional metabolic alkalosis if they have acute, then don't do that. Just make it chronic and everything gets easier. And that's just, you know, in medicine, we don't use Occam's razor. We use Hickam's dictum, right? And Hickam's dictum, Occam's razor says, you know, if you have two explanations that both satisfy the facts, the simpler one is probably true. But Hickam's dictum says patients can have as many damn diseases as they want, right? You can't predict that from that. And so, you know, I tell medical students, if the patient's there because someone stuffed a pillow over their face, you know, the respiratory acidosis, that's acute, okay? Right? And if they're there because they've been smoking cigarettes for 60 years and they got emphysema, they're carrying their oxygen container behind them, they got the little concentrator. Yeah, that patient has chronic respiratory acidosis. There's nothing in the ABG that guides you to the answer. You actually have to look at the patients and do a physical exam. And I know how upsetting that is to a lot of nephrologists that we can't use the numbers to determine whether it's acute or chronic, but that's just the way it is. You need to look at your patients. And in fact, you can make that determination before you even do the ABG. You're like, oh, this is going to be acute or this is going to be chronic. You only have to do one of the calculations, right? Because the numbers don't help you with that. You have to do that, get that from the second primary disorder. So you're telling us kind of call it a second primary up. And if the patient's PCO2 is, in a case of metabolic acidosis, if their PCO2 is way lower than predicted, you have an additional respiratory alkalosis. If it's higher than predicted, you have a respiratory acidosis. And so that's how you get your second disorder. And then after that, time to look at the anion gap. Okay. And so, you know, the anion gap, you know, when I was a resident, we had to calculate it ourselves, right? And now it shows up right on the Chem 7, comes right out there. And it's a bit abstract what it actually is measuring. And so everybody's probably seen these things. They're called Gamblegrams. And they set up two columns, an anion column and a cation column. And the cation column is just sodium. And then the anion column is a chloride, bicarbonate, and other anions. And the key here is that the total number of anions must equal the total number of cations. And the joke is otherwise, if you touch blood, you'd get a shock, right? And since you don't get a shock when you touch blood, cations equal anions.
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That's the defining characteristic of metabolic acidosis. But the anions and cations still need to equal the same. I've turned off that damn clock. Hold on. It's every 12 minutes. I think it is. I think it is. Clock is off. Let me put that on my checklist. I'm kind of sad to see it go. Wedding gift from the in-laws. I'll pass that on to them. It was a big hit on our podcast. We're back to the Gamblegrams. You have metabolic acidosis. The bicarb goes down, but the anions must equal the cations. And there's just two possibilities. Either the chloride compartment gets larger or the other anion compartment gets larger. And that's what we're determining when we measure the anion gap. If the anion gap is large, that means the other anion gap compartment has gotten larger. And if the anion gap is normal size, less than 12, then the chloride compartment gets larger. And that's the whole root of, you'll hear people talk about a hyperchloremic metabolic acidosis. That's just another way of saying a normal anion gap metabolic acidosis. And so one way know, one way to think about this is that, you know, with metabolic acidosis, you know that the hydrogen ion has gotten high. You have an elevation of the hydrogen ion concentration, and it has to come with an anion, and that anion is either chloride or something else. And if it's something else, we call it an anion gap metabolic acidosis, and it's chloride. It's a non-anion gap metabolic acidosis. And then calculating the anion gap is totally trivial. You take sodium and you subtract that from the sum of bicarb plus chloride. Normal value is 12. It'll vary a little bit from hospital to hospital. And then there's this interesting kind of subgenre of acid-base which looks at calculating an individual anion gap, normal anion gap for individual patients. And the thought here is that a large component of those normal anion gap is albumin and phosphorus. And assuming that your individual patient's albumin and phosphorus is normal may be wrong, especially in a sick patient. So which equation, are you talking about like correcting the anion gap? Is that the same thing or is that a little different? You want to correct the anion gap. You can add two and a half to what your calculated anion gap is for every one gram per deciliter that the albumin is decreased. So if the patient has an anion gap of 14, which is a small anion gap, but they have an albumin of two, it's like they have an anion gap of 19. You add two and a half times two, add that to your 14, now you've got a pretty big anion gap. And you can add, and you can adjust also for the phosphorus. This is deep into the not very well supported by evidence. It doesn't help very much increasing the sensitivity or specificity for anion gap. It is the kind of thing that people that really like to do ABGs like to engage in. And so, again, it's part of this internally consistent logic of how this stuff should work and then doesn't work so well when you actually measure it against real patient data. That said, you'll probably get asked about this, especially in an ICU rotation. Have you guys run into this, people asking you about the low albumin and adjusting the anion gap, or is this me just fictionalizing? No, all the time. And base excess and deficit and stuff like that. Yeah, I was going to ask. If you hadn't asked, I was going to ask because this is something that I had never really been strongly encouraged to do it. I mean, I've heard the albumin thing, so I do look at that just to see if it's a normal anion gap and their albumin is low. I will take a look at it just to take a guess if there's something going on, but I don't know how clinically useful it is. We are all here for your wisdom, so tell us the way that you do it. Sure enough. Oh, my God. This will be my undoing, I'm sure. Yeah, so I do adjust anion gaps for albumin when I'm looking to see if there's an anion gap. That's how I do it. Sounds like this is something you guys all run into. You take the, you know, the way you would do it is four minus their current albumin, multiply that by 2.5 and add that to their calculated anion gap. So if they have an albumin of four, four minus four is zero, nothing to add to the anion gap. If they have an albumin of 2, 4 minus 2 is 2 times 2.5 is 5, add that to their anion gap. That's a fine way to take care of it. The other thing that's like a favorite PIMP question is what causes a low anion gap. You'll come across a patient who's got an anion gap of 3, and every attending has the same story of the time they diagnose somebody with multiple myeloma from the low anion gap, right? And it's a great moment, right? They've converted a basic metabolic profile, totally routine lab into a pretty advanced diagnostic test. It is pretty cool. The problem there is just thinking that it's only multiple myeloma that causes a low anion gap. Decreased albumin and decreased phosphorus can cause a low anion gap. Hyperkalemia, hypercalcemia, hypermagnesemia, lithium can cause a decreased anion gap also. And so a number of things, it's a larger differential than just the one great story that they have. I have a slide here in this deck, and it was a patient that I was taking care of in the hospital. And before my eyes, like over four or five days that I was taking care of them, their anion gap went negative, right? It started at six. And between a drop in their albumin and an increase in their potassium, they developed a negative anion gap, which was the only time I've ever seen that. And so I immediately went to the medical literature. I was like, oh my God, what causes a negative anion gap? And it was the number one cause of a negative anion gap was the most disappointing thing ever. It was lab error. I was just about say that i was like that's not very satisfying um but uh right so so this patient uh had been on high dose bactrim for a resistant urinary tract infection which caused the hyperkalemia and the urinary tract infection urosepsis had caused uh an acute drop in the albumin which is something i see more than I've seen documented about why people's albumin drops before your eyes, but happens in the hospital. So yeah, I thought that was pretty cool. Can you just briefly comment, why does hyperkalemia cause your gap to drop? And why does the multiple myeloma patient have a gap that drops? Yeah, that's a great point. So when we drew the Gamblegram, we said that the sodium was the entire column of the cation column, which is not true. Sodium is 90 some odd percent of the cation column, but there's also unmeasured or uncounted cations. Right. And you can think of all the cations in blood. There's potassium and there's calcium and there's magnesium. Lithium is a cation that's not normally in blood, but if you are on lithium, it'll be in blood. And IgG is cationic. And so if you have multiple myeloma with elevated IgG or Waldenstrom's macroglobulinemia, you'll get a low anion gap. If you have IgA, which is anionic, that'll cause an increased anion gap if you get increased IgG, IgA. IgA is anionic and IgG is cationic. Okay. And so an elevated IgG is going to cause a small, a low anion gap. An elevated IgA will cause an increased anion gap. And so the anion gap metabolic acidosis, that's where the action is. Every field has that disease that's like the go time, right? Like for cardiology, it's acute MI, right? For nephrology, it's like the methanol toxicity. Like, you know, alarm bells go off, we get super excited, right? Oh, you know, so.
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And you guys were all taught, which ones were you taught. What was the mnemonic that you guys were taught? Mud piles? Mud piles. Our producer, Javi, has one that's shorter. It's KULT. K-U-L-T that he wanted me to bring up and see if you've heard of that one. Ketoacidosis, uremia, l and t toxins toxins oh cult okay i can get behind that so and so when you and so then my next question always is so what did you have for the p and mud piles paraaldehyde yeah i was taught paraaldehyde right and then and what was the what was the next thing you were taught about paraaldehyde? Yeah, I was taught paraldehyde, right? And what was the next thing you were taught about? Paraldehyde. I think that was Tylenol. It had something to do with Tylenol, right? So paraldehyde was a hypnotic sedative last used in 1972. The current use of paraldehyde today is the pee in mud piles. That's a noble place. Right. And I is INH. And it is – INH toxicity can cause a fulminant liver failure. And then once you have fulminant liver failure, you can get lactic acidosis. It's like six derivatives down does it take to get an anti-angiotymetabolic acidosis. They just needed an I. And so those are kind of the weaknesses in the MUDPILES acronym. And there have been some adjustments. People have tried to change the P and tried to make it a little bit better. But Michael Emmett, who is chief of nephrology, he might even be chief of medicine now at UT Southwestern and just a giant in the field of metabolic acidosis. He had one of his fellows over for dinner and his son, who was a medical student. And apparently, dinner conversation at the Emmett House was, how can we improve Mutt Pyle's mnemonic? And they created Goldmark, which is what I think a lot of people that teach this stuff are starting to use as a better mnemonic. So G stands for glycols, O for oxoproline, which is the sepsis plus Tylenol equals big anion get metabolic acidosis. It's a pyroglutamic acidosis is the acid itself. L is for L-lactic acidosis, D is for D-lactic acidosis. D-lactic acidosis is a crazy disease, right? Like when you learned about chirality, all biological molecules have the levo chiral formation. So some bacteria produce a D-lactic acid, but the body can't handle D-lactic acid. And so it behaves bizarrely. So for one, normally lactic acid is scavenged as a high energy resource by the kidney. So L-lactate, when it gets filtered by the kidney, is reabsorbed by the proximal tubule. So your lactic acidosis is kind of self-perpetuating. But D-lactate, totally not recognized and you just piss it out very quickly. And then the assays that we use for measuring lactic acidosis, literally it's a biological assay. We mix your blood with an enzyme and we look for the products, but the enzyme that we mix it with, lactic dehydrogenase, can't recognize D-lactic acid. So it's not detected by your normal hospital assays. You'll get zero lactic acidosis if they have D-lactic acidosis as the cause of their metabolic acidosis. And so it causes confusion. So usually the clinical descriptions, patients have waxing and waning, altered mental status and waxing and waning, high anion gap metabolic acidosis, and it goes away because you piss it off and then it'll accumulate again later. Usually these patients will have a blind loop, so usually a Roux-en-Y or some other kind of surgical change to their gut, and giving them simple sugars in their diet can feed these bacteria and cause this, and you can just decontaminate them usually with vancomycin or some other antibiotics to clear it out. But it's a pretty cool disease. Then M in Goldmark is methanol, A is aspirin, R is renal failure, and K is ketoacidosis. So Goldmark. It's much cooler than mud piles. I think you have a blog post, in fact I know you do because I'm staring at it, of potential alternate names that were considered before Goldmark, which are just delightful if you get a chance to look at them. So I think Lame Sudoku is my favorite, but I think you were a fan of Smoking Ale. From the Anand Gatmetabhaka Acidosis, and talking about methanol and ethylene glycol, that leads to the fourth of five things that you do with an ABG, and this is looking at the osmolar gap. And the hook here is two of these toxicities, the T and cult, as you guys are aware of, are methanol and ethylene glycol toxicities. And these toxins are unique in that they have a very low molecular weight. And so because they have a low molecular weight, an ingestible amount has a lot of osmoles, right? So a few ounces, many osmoles because the molecular weight is low. And in fact, an ingestible amount has enough osmoles to change the, meaningfully change the osmolality of the entire body. You have 42 liters of water in a normal adult, and when you eat, when you take in a few ounces of methanol, it has enough osmoles to change the osmoles, meaningfully change the osmolality in the body. And this is important because these ingestions, methanol and ethylene glycol, are highly toxic. And most hospitals don't have a reliable and quick assay to get that. So in my hospital, somebody gets a presumed methanol toxicity or ethylene glycol toxicity. We draw a blood sample, we put it in a FedEx envelope, and we send it to Utah, right? And maybe 36 hours later, you'll get an answer whether they have ethylene glycol toxicity or methanol toxicity. But if you wait for the confirmation, if you wait for the biochemical confirmation, it'll be too late to treat this disease. You need to treat it very quickly. You need to put them on some, you got to shut down alcohol dehydrogenase either by getting them drunk or by putting them on a drug called femepazole, which is an alcohol dehydrogenase inhibitor. The unique thing about methanol and ethylene glycol is the parent compound, non-toxic. It is just the downstream metabolites, formic acid in the case of methanol and oxalic acid in the case of ethylene glycol, that are highly toxic. And so if you can stop the metabolism to these downstream metabolites, it's fine. And so the therapeutic strategy is block the metabolism with either ethanol or ethylene glycol or femepazole and then dialyze off the parent compound. Can you give an example of a patient, like a methanol toxicity patient that you saw at Cashlack, just like what this person looked like and like how you knew it was methanol? Right. So they come in two varieties. So the typical one is patient found down in a coma, brought in by the ER, and they look completely septic, but they're hypotensive. They have a severe acidosis. They've got a huge anion gap. They're unable to tell you anything about their story. trying, you're starting from scratch. And then the other ones are the suicides. The patients are trying to commit suicide by either drinking antifreeze, which is ethylene glycol, or methanol, which you'll find in different kind of fuels for like stoves. And you may be able to get a history out of them depending on how cooperative they're going to be and how far gone they are by the time they get to the hospital. Okay. But, you know, it's not the anion gap of 14. You're like, oh, it's a positive anion gap. No, these people have an anion gap of 26 or 30. It's a huge anion gap. The interesting thing is anion gap comes from the downstream metabolites. The parent compounds are nonpolar, or they're not ions, right? They're neutral compounds, so they don't produce any type of anion gap. So early on, they'll have this big osmolar gap, which we'll talk about shortly, As the parent compound is metabolized, the osmolar gap gets smaller and smaller, and the anion gap gets larger and larger. They actually can trade places.
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And then you dialyze these patients to treat them? First thing you need to do is you need to make sure they have an alcohol level over 100 or you put them on femepizole. If they have an alcohol level over 100 milligrams per deciliter, that effectively shuts down. They get no metabolism by alcohol dehydrogenase, and that temporizes the situation. You can take your time about getting dialysis access, get a dialysis nurse in there and dialyze them. If they don't have a high alcohol level on board, then you need to give them a dose of femepizole, which is a specific alcohol dehydrogenase inhibitor. Okay. And just to mention it since we're on the topic, isopropyl alcohol, how does that case differ clinically? And Javi had a great case that I just wanted to mention after you tell us about that. Right. So isopropyl alcohol will cause intoxication. Patient will be intoxicated. They will get a large osmolar gap, which we'll talk about shortly, but they don't get an anion gap and they don't get metabolic acidosis. suggestive that this might have been isopropyl alcohol. And he actually found in the guy's coat pocket, it was called Rush. And it was some sort of nail polish remover with acetone and isopropyl alcohol. But the brand name is called Rush. And the guy told them when he woke up that he was snorting it. So I just wanted to, I was like, Javi, that's amazing. I had to let him know that the audience know that that's out there. And at that point, we get with normal gap and ended up having an elevator, a smaller gap. So that kind of like took us to the level that could be isopropyl alcohol. And it was one of those amazing cases where you ended up going to the jacket, pulling out actually a nail polish remover. And in the back, it actually said acetate and isopropyl alcohol. So it is something to always keep in mind and consider. So calculating the osmolar gap is kind of a hassle because the American units come back to bite us. We need to convert. And what we do is we calculate an osmolality and that calculation will include everything except for these toxic alcohols. And then we measure the osmolality in the body, which will include those toxic alcohols. And if there's a big difference between a calculated osmolality and the measured osmolality, that's an osmolar gap, and that's presumptive evidence for these low molecular weight toxins. Again, it's not great. There's a lot of false positives. But the key here is you need to be able to calculate the osmolality, and we double the sodium. So the sodium, for every cation, there has to be an anion. We don't care what the anion is. We just know that if we double the sodium, we'll cover for it. Then we take the BUN divided by 2.8, the glucose divided by 18, and the ethanol and you divide it by 3.7. You add those all together and that's your calculated osmolality. All the medical calculators will do this. The weird one, the divisors there are one-tenth of the molecular weight. So the molecular weight of nitrogen is 28, so you divide it by 2.8. Molecular weight of glucose is 180, you divide it by 18. The molecular weight of ethanol is 46, and so we should divide it by 4.6. And if you have an old calculator, it will, but there was some empiric data that was done recently and shows that alcohol does not act like an ideal solvent in the body, strangely enough. And so the correct divisor is 3.7. I don't quite understand why, but that's is more than 10, it's considered positive. But the specificity for toxic alcohol really starts to rise as that osmolar gap goes above 20. You'll get a lot of false positives between 10 and 20. So in addition to our true positives, which are ethylene glycol and methanol, isopropyl alcohol will also cause an elevated osmolar gap. Ketoacidosis and lactic acidosis can cause one. Manitol infusions, hypertriglyceridemia, and pseudohyponatremia can also cause osmolar gaps. So there's a number, this is not the most specific test, but you're not using this in all patients. You're really using it in very specific patients that have bad metabolic acidosis and a big anion gap, and that should narrow it down. Yeah. And all three of the alcohols can cause inebriation and hypotension if it's a severe ingestion, correct? So you would be looking for those things too, which hypertriglyceridemia, to my knowledge, is not going to cause altered mental status and hypotension. Yeah, that's right. an additional acid-based disorder tucked away, hidden in the ABG. Okay. And so you only can do this if, well, not only, but generally you'll do this if they have an anion gap metabolic acidosis. And if you remember, we said if they, we went back to the Gamblegrams, we said anions equal cations. And we said the bicarb goes down. And if you have an anion gap, the other anions rose up to replace the bicarb. And if you look at the Gamblegram, you're like, you know, not only is the bicarb going down and the other anions are going up, but that's going to be at a one-to-one ratio, right? In order for it to remain the same as a sodium, for every one that the bicarb falls, the other anions need to go up by one. So what that essentially means is that the change in bicarb equals the change in anion gap, right? For every one that the bicarb falls, the anion gap goes up by one. So the delta bicarb equals the delta anion gap. So we can just use algebra then to solve for the bicarb before. So the bicarb before, and what that literally means, that means the bicarb before they develop the anion gap, right? So this is like, you know, we got like an acid-based time machine. We're like, we're going to go back before there was an anion gap. It's going to equal the current bicarb plus the current anion gap minus the normal anion gap of 12. So if you have a person with a bicarb of 8 and an anion gap of 14, we take 8 plus 14 minus 12, which is 2, so that's 10. So they have an anion gap metabolic acidosis. But if you remove that anion gap metabolic acidosis, that bicarb was 10. So before they had the anion gap metabolic acidosis, they already had a severe metabolic acidosis that dropped their bicarb from 24 to 10. That's all we're doing there. And I call it the bicarbonate before. It's generally called the gap-gap, which is a totally different calculation than what I did. I think the gap-gap calculation, it obscures what you're actually calculating. I don't think it's as good as what I've just talked about. The slide deck walks through all the mathematics and has a couple of example questions to show how this works. I guess my question is like clinically, why does that step matter? Because it's a, I can't say it's something I'm doing on a regular basis, but. Okay, let's walk through. Here's a great example. We're going to use the exact same number that we just did before. So we said that the guy had a bicarb of eight and had an anion gap of 14. And I'm also going to tell you that you dip their urine and they were positive for ketones and the glucose was 460. Okay, so you have a diagnosis, right? This patient has DKA. You do the gap-gap calculation and you find that their bicarb without the anion gap was 10, right? I already did that math, right? And so this guy, the DKA brought their bicarb all the way from 10 to 8. In fact, the patient has the world's most mild case of DKA, right? All you need to do, you take the insulin bottle, you pop off the top, you waft it under this guy's nose, and that's going to be enough insulin to reverse his ketosis, right?
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I don't know, maybe he's got cholera. He's just pooping himself to death, right? And we tell people, you do not treat DKA with bicarb. We have multiple placebo-controlled, randomized controlled trials showing that bicarb and DKA is bad, right? It perpetuates ketosis. It increases electrolyte abnormalities. It's a no-no. But in this case, his DKA is almost incidental to his primary disease, right? If you just do the surface calculation, you have an anti-gap metabolic acidosis with ketones and a glucose and a type 1 diabetic, it's a perfect fit, but this guy does need bicarb because his DKA is mild and not that important. The real problem here is his severe non-anti-gap metabolic acidosis, and if it's due to diarrhea, you're going to need to replace that bicarb. And so this is a situation that uncovering what's below that anion gap metabolic acidosis totally changes your management. How did you know from – I might be missing this. How did you know from that equation you calculate the bicarb so you can tell that the bicarb was low before? How do you know it's a non-gap acidosis remove the anion gap, and I don't know if it's all DKA. It also removes the lactate. You could have DKA plus lactic acidosis plus oxopropylene. Okay. All those anion gaps are removed, and all that's left for a decreased bicarb is a non-anion gap metabolic acidosis. Okay. And sometimes you'll do this calculation, and you'll'll find out that the bicarb before was 32. Oh my God, they had this wicked metabolic alkalosis before they developed their anion gap metabolic acidosis. Right. So you, things are revealed that can help you understand the natural history of the disease that you're dealing with. Got it. All right. Excellent. So you mentioned during that there, you mentioned sodium bicarb for DKA. Can you just talk about, I mean, I see a lot of non-gap acidosis from sodium chloride. Can you just comment on LR versus sodium chloride versus bicarb drip where we're trying to resuscitate patients or give them IV fluids? Which choice do you use? Yeah, so there is a raging debate in critical care about which crystalloid solution is better, saline or lactated ringers or what they call balanced solutions. And when I say they, I mean me. Like, that's just the terminology. So, is it saline or balanced solutions? Talking about, like, plasma light and things like that? Plasma light is one. And Hartman solution is another one. There's a number of these. And the biggest published study is called the SPLIT trial. and it showed no difference between these um and there was a study presented in abstract form only and rumor has it this month it'll be published we'll see if that really happens and that showed a survival benefit from using balanced solutions i haven't all i've been all i've done is i've seen the abstract so i i don't you know i can't comment on how good a study that is. But survival benefits are pretty important. We tend to change everything we do if there's a real survival benefit. So if it pans out, you're going to see that. But we definitely know that giving patients normal saline generates a non-anion gap metabolic acidosis. And it's not hard to believe that that's not ideal for taking care of patients is to give them metabolic acidosis. And if you give them these balanced solutions, they don't develop that. Is there any, and what situations are you reaching for a bicarb drip? I like to treat most of, you know, if they are losing bicarb from diarrhea or from a surgical drain, I like to replace that bicarb. If they have a renal tubular acidosis, you're going to need to replace that bicarb. There are some patients with severe, they have compromised respiration, and they have a bad metabolic acidosis, and they're just not going to be able to breathe fast enough to compensate for that metabolic acidosis. You can help them out by giving them some bicarb. And the biggest error I see with bicarb grips is they mix it with normal saline, and you should never add bicarb to normal saline. You can add bicarb to D5W. You can add three or four amps of bicarb to D5W, and you get something close to isotonic. Four amps will be slightly hypertonic. Three amps will be slightly hypotonic. You can add one or two amps to half normal saline, but never add bicarb to normal saline. Just don't do that. Okay. Yes. We were mentioning how bicarb is just a bad idea in DKA a little while ago. Up to date, the algorithm that everyone follows for DKA management says if pH is less than 6.9, do bicarb in the solutions that they're getting. Would you agree with that? Or just increase the ketones, leave it alone? Yeah. I mean, I think I will admit that I've not looked at a lot of the literature of the sub-7 pH. I think you're deep into mechanistic medicine, just trying to take a look at it. And we have good data that shows that our inotropes stop working at those low pHs, that the heart stops working that effectively. We know the proteins start to denature down that level and enzymes don't work as well. So it's not surprising that you're going to want to just focus, and that's a situation where you'll just want to focus on Okay. I've just never seen data that shows that improving the pH with bicarb really improves patient outcomes. I think they're probably relying on mechanistic medicine. You'll usually see this, usually not 6.9, but below sub 7.1. People start to get pretty uncomfortable and want you to raise the pH. There it is. There's our clock. I think that's a good time to end this episode. I think we probably should do RTAs on a future episode. I think that's something else that people misunderstand and that we certainly don't have time tonight to go through. Right. So if you look at kind of what we went through, we did not go over any of the non-anti-metabolic acidosis, and that's RTAs. And the reason we didn't do it, that's an hour on its own. Yeah. But yeah, I'd love to come back and do that sometime. Anything you'd like to plug before we let you go? If you have not filled out your brackets for nef madness, I don't know what you're waiting for. This is the biggest deal in nephrology social media, right? This is A1 type of encounter. We have free CME. We've got prizes. We've got lots of humor. There's memes. It should be a blast. Check out nephmadness.com. This is awesome. I am going to put in a bracket this year. This will be my first Neff Madness uh, we're going to try to get a curbsiders team in there. Isn't that right? Uh, curbsiders. Yay. It's 11 PM. All right, Joel. Thank you so much. You guys take care. Thanks a lot. This is great. Take care. This has been another episode of the curbsiders bringing you a little knowledge food for your brain hole. Stuart Kent Brigham's mic is, Oh, thank you. I was going to explain that Stuart's on mute right now, and I imagine this might be one of the curbsiders at gmail.com. You can recommend a future topic or tell us what you love or hate about the show. And please follow us on Twitter at the curbsiders until next time. I've been Dr. Matthew Frank Watto at Dr. Watto on Twitter. Javi, you still with us? All right. And I'm a hobby. He met us and he's out. Test, test, test. Oh, there you are, Stuart. How, how long have I been, have I been muted? This is ridiculous. Until just this second. How about you say something? Oh my gosh. I'm just disgusted. This is Dr. Stuart Kent Brigham. And this is Dr. Shreya Trivedi. And this is Paul Williams. I can be found at BrighamSK on Twitter. And do not follow where I should put it. Apparently not. This is excellent.
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Folks, thank you for joining us. A quick announcement before we jump into part two of our interview with our colleagues from Italy. In light of the COVID-19 pandemic, the majority of in-person educational conferences have been canceled across the U.S. and the globe. To help address this void, the Clinical Problem Solvers have started a virtual morning report. Every weekday, we meet for 30 to 45 minutes to discuss a case in true morning report style. We think this is a great way to continue to develop our clinical reasoning, but more importantly, for a way to nerd out, laugh, learn, and stay connected in these tough times. Social distancing is life-saving, but it's not incompatible with learning and connection. To learn more about this fun initiative, click the morning report link below. Okay, now back to the episode. Mike, take it away. Welcome back, Clinical Problem Solvers, for the second part of this special interview with Drs. Giacomo Monti and Marco Ripa from San Rafael Hospital in Milan. In part one, we discussed some diagnostic and treatment related pearls regarding COVID-19 infection. And in today's episode, we shift gears to talk a little bit more about systemsrelated factors and wellness related to the epidemic. I hope you enjoy. Hey folks, just a quick reminder that this episode is not meant to be used for medical advice, just good old-fashioned education. All patient information has been modified to protect their identity and the views expressed in our podcast do not necessarily reflect the opinion of our employers. One thing we wanted to make sure that we save time for is the importance of the health system related questions that are really at the forefront of this epidemic as well, and that many clinicians are, you know, serving administrative roles addressing as well. So if we could switch gears and talk more about some system and workflow related questions that we had. Thank you, Mike. How has your hospital managed the expanding need for workforce in the face of decreasing supply from sick providers? Have you guys had to utilize providers who are quarantined through telemedicine? And when do those providers typically return to help out with the increase in demand? Let's say that all doctors and nurses work harder and harder. So the first expanding workforce was the time that all nurses and all physicians spent in the hospital. Then we have people that usually worked in other places of the hospital that start to help with the COVID patient. Let's say about all people working in the operating theater, the elective surgery activity was completely reduced, so we don't perform any non-urgent surgery. So we nowadays perform only urgent oncological surgery and trauma patient, brain injuries and so on. But we have stopped all electives and this gets a huge amount of people coming from the operating theater, both nurses and both anesthesiologists that luckily in Italy has training also as ICU physicians. And so we have a lot of help from people from that places. But we have also general surgeon or head and neck and throat physicians. Everybody is doing their best, looking for things that they can do. And so this is the first solution. Then I must admit that we have changed our ICU practice a little bit. So we are reducing the amount of invasive hemodynamic monitoring. We are not using in every patient monitoring of neuromuscular blocking, monitoring of deep sedation, because we have to cut down some, let's say, details. They are not details, but are things that you can manage also without these instruments. And so we have changed our activity a little bit and we have got a lot of help from a lot of people. Also residents are a huge supporter to our activity. They have been involved in every situation. The older one, they are helping in clinical practice, the younger are helping in data extractions. Because one important thing that we are trying to do in our hospital is to collect data because we strongly believe that this epidemic has huge needs of good data because we must share our experience and we must use our experience to understand how things are going and which treatments are helpful. So we are trying to do our best to make clinical research during this problem and I think younger residents are doing wonderful work for that point. Then your question, we are not using providers that are in quarantine so they stay home and we have developed a quick pathway to come back to work so nowadays the solution is people stay at home after two days of well-being from a clinical point of view so after 48 hours of clinical well-being they are asked to make a throat swab and if it's negative they can come back at work so this accelerate a little bit the time of quarantining people at the beginning of the history it was thought that they will require the 15 days at home now we require two days of well-being and then the swab. If it's negative, then they come back. If it's positive, case by case, we plan a new swab and we wait for the negative test to readmit people at work. And those are all excellent pearls. I'd like to also touch a bit on sort of the relationship between physicians or providers and the public. And as case numbers in the U.S. rise, we physicians are often struggling to emphasize the importance of social distancing, which Dr. Monti talked about before, to the public. And as a medical illustrator, Thank you. And if so, what communication strategies did you find most useful in getting that message out, whether it be through social media or through sharing statistics or sharing links to articles? during the first days, during the first weeks of the epidemics is that probably we as healthcare providers and also probably the government, we were not able to communicate adequately to people what was the best way to deal with this new epidemic. So I don't really have an answer because I think that the strategy depends on your target population. So I would say that very few people actually is able to process complex data, to process statistics, to process articles. So obviously you have to give the people the possibility of getting to the heart of the topic and to access to the raw data, let's say. But probably for the general public, it's more important to do campaigning through social media. Yeah, I think so, because it's going to reach more people. But the thing is that you have also to fight the disbelief that people have in most of the classic media and also you have to fight all the misinformation that you see around not only in the web, not only on the internet, but also on the television and other means of communication. So I don't really have an answer. It's not something that I usually deal with, but I say that in order to have a successful strategy, you have to think about something that may reach the largest number of people and to focus on the groups that are probably more at risk of spreading the infection. So younger people, they need to understand that during this period is very important to do the so-called social distancing that we spoke about. And also, I mean, you have to make sacrifices for a greater good. And it's something very difficult to communicate. But I think that right now, probably given the experience from countries which are not maybe perceived as far as China, but countries in Europe and what's beginning to happen also in the US, maybe this will be easier because, let's say, frankly, when you listen about something that's happening in Asia or in China, well, think, well, that's not going to happen here. But it happened here in Italy. It's happening all around Europe. And it's starting to happen also in the United States. So maybe let them know what happened here also in Europe. Let them know what are we facing right now, what we are facing right now. And this way, maybe we will be able to tell the people, just make a few sacrifices for a brief period of time. And this will usually help in containing the epidemic. Marco, that was extremely helpful. I was curious if you can elaborate a little more on what type of misinformation is out there that you wish people would know about. Meaning, what is it that they're believing that is false? Like, what are the myths about coronavirus? Because like you said, it's now easy to convey to the Italian people how dangerous this is because probably so many of their loved ones have unfortunately been affected. But for other countries who haven't experienced yet what Italy, China, Iran, South Korea has experienced, what misinformation do you think that the people are feeding into? Well, first of all, it's very important to stress that the transmission from asymptomatic patients is possible. So when you think about patients who actually don't appear sick, you cannot be safe. So social distancing also is something that you need because you cannot know who is going to be able to transmit the infection. So it's very important to tell the people that it's not just avoid people who are currently sick, but also people who are maybe asymptomatic or maybe incubating the virus. So this is the first thing.
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So this is something that we have to stress in order to make the people understand why it is very important. And the other thing that it's very important to fight as misinformation are all the different, I don't know how to call them, all the different strategies that appear on social media about treating or preventing the infection from the viruses. There's actually a lot of them. They say from getting a lot of vitamin C supplement to just drinking strange stuff. Yeah, I saw large amounts of water and salt and vinegar rinses and some of the misinformation stuff that I've already seen on my social media feeds from friends and family. Yeah, these things, they don't work. And it's very important to guide the people and to tell them just trust your sources when they are verifiable sources. Just don't trust whatever gets to your computer, to your phone, or whatever you get from social media. Marco, you know, one of my mentors once said that vitamins result in expensive urine. That they're only useful in it. Anyways. Except for our thiamine case a few weeks ago. You know, I think this brings a very big point that I think is that all of us have experienced to some extent of with this epidemic and with any epidemic, we are left thinking, man, if I would have worked on this a week ago or two weeks ago, or if I could have known this sooner, things would have been much better. So to kind of leave with some big take-home points for our audience from both of you, if you can reflect back to one or two weeks ago when this virus was really ramping up in Italy, what are some things that you know now that would have been incredibly valuable to know then? for having dedicated wards before the explosion of the epidemics. And also maybe try to treat all patients with clinical syndrome suggestive of COVID as patients with COVID even in the first phases of infection. Maintain a high degree of suspicion even sometimes regardless of the clear epidemiological link because right now what we know is that the epidemiological link is something that actually didn't work from the beginning. Actually the first cases in Italy were diagnosed without a clear epidemiological link with other cases. So if I could go back in time, what I would say is that, well, right now we have very few cases. Just treat and isolate all the patients with respiratory symptoms, with a suggestive clinical syndrome, as if it were COVID. We will use a lot of resources but maybe we will be able to control better the epidemic. I would say also that another hot point is protection of the healthcare associated people. So if I have more time, I would stress that we are not used to work with such protection. We are not used wearing all the stuff that you need to wear to treat a COVID patient, especially in ICU. Yesterday, we have done a tachyostomy in a COVID patient. And I must admit that I was completely hot and sweet after staying for 45 minutes wearing two personal protective dress, three pairs of gloves, helmet, glasses, the high-filtrating face mask. And so I think that a part of having the personal equipment, you have some time to practice to use it because it's not so easy to do all the things that we normally do with all this stuff. maybe you can have some time to simulate to test your ability of doing things wearing all these stuffs and maybe this will protect also better people because we have some issue for physicians and nurses that get sick and so this is a very sad point we are doing all our best but we would like to stay safe and we need to take care of ourselves and And this requires a little bit of preparation. So if you have time, try to optimize this point also. Wonderful. Thank you. And it seems like I have the honor of wrapping up this particular section on sort of systems-related questions. And you've both obviously seen the worst of the worst in this global crisis. And as you've shown today, you've harnessed all of the modalities at your disposal to care for those who have fallen victim to this pandemic. And I wonder if both of you could share maybe one thing that you've really learned from this experience or what kind of hope or inspiration that you've drawn from your and your team's efforts? Can I start? I would say that people became fantastic. So I have to thank nurses, all physicians, all students, all people that clean the floor in my CU because everybody is doing an excellent and harder work than usual and everybody is now committed to taking care of all the part of a process of care. And as physician, my hope message is that COVID patients are very hard and demanding, probably harder than usual for many reasons. But if you work hard, you can save many patients. So if you work hard, you can get the result. And I think that more than ever, as an ICU, my job is save lives. And I think that we are doing that in a strong and very good way. So I think that this is our hope. We have to fight, but if you fight properly, then you get the result. And this is a big hope for physician job. I totally agree with Giacomo. I don't think I have better words than what he actually already used. And I would like to add to what Giacomo said that the collaboration between people and the possibility of working together which was something that we already did but right now is something that we are doing even more than before and being there working with these patients who are sick and who most of the time are also psychologically demanding because these patients are isolated. They cannot see their family. They cannot speak with their family. They are in isolated room. They don't have any possibility of communicating with other people. And so we work very hard for them. We work hard and harder and harder every day. But we developed a sense of collaboration with other physicians and we developed also a very profound insight about what is the psychological situation of these patients. And I would say that this will make us better physicians in the future because we understand what is the sense of solitude, of despair of these patients because we are with them every day, more than 12 hours per day. And we are together in this with all our colleagues. So I think that the hope is that this experience will make us stronger and better people and better physicians in the future. Wow. I just have to say that I'm literally in tears here for a number of reasons. One is not only did you highlight the collaboration that's happening there in your hospitals, in your community, But now you are representing Italy and you're collaborating with us representing the U.S. And you want to teach us so that we don't face this adversity that you have faced to the degree that you have faced. So I just want to, I mean, I just can't thank you enough. I hope one day when the social distancing is over, when I visit Italy, I can take you out for some dinner and some drinks and give you guys a big hug. So I just want to thank you so much. And the last question that I have for you is, how have you and your colleagues been holding up? What practices have you found useful to prevent or combat depression and burnout? Because you guys are facing long hours, you're seeing so many patients pass away. If you can just speak on that, how have you countered this unusual circumstance in the midst of social distancing and the high morbidity that this fucking virus has had on all of us i have the first answer margarita i'm joking or the cocktail the cocktail course. Let's say that it's not easy to stay head safe and not become quickly crazy in this situation because it's emotionally very, very hard. I'm used to tell people your your loved is dead that's part of my job but it's very difficult to say the same thing by phone and telling you can't come in hospital you can't come to see your loved you have to wait for the funeral but funeral now in Italy are stopped because they can't be done because they will put too much people together so it's very very hard to stay to stay okay I think that we have to take care of our families and our families are taking care of ourself so I thanks to all my loved for what they are doing for that and friendship and you can stay physically, but you can have phone calls, you can have video calls. So we can have different ways of staying together. And I think that in Italy, a lot of physicians that work together are also friends. So in a way, we are a little bit lucky because we can see friends at work and so I think that in these days it's one of the most important things is that we can share feelings with our colleagues and I am quite happy because my colleagues are also my friends. And then for sure there are psychological support and so on, but I must admit that the time is not long, so I don't have a lot of time to dedicate to these things.
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I should find some time also for this, nowadays not possible maybe in the next future and I think that professionals will need will help us but probably after after some times Marco did you have any anything that you'd like to add on the on the subject just just one thing very quickly speaking about the the support I I agree with everything Giacomo said and I would just like to add that even in in the the artist times so when for example you have to call a relative to say that the patient is not going well patient needs even if you are doing everything that you can it's not going well and it's probably going to die to hear the people on the other side of the phone telling you, thank you for doing what you're doing. Thank you for being there. We understand your situation. Thank you for taking the time to call us. I mean, it's something very, very simple, but it's something that gives you the strength to go on, to know that the people outside, they understand what we are trying to do. And we are not heroes, obviously, but we are trying to do our best. And knowing that the people outside know that we are doing so is something that helps you going home every day. Yeah, yeah. This is incredibly true. We have a pizzeria that has decided to adopt our word. So we get pizza every day. And this is a very stupid thing, but I must admit that finding time to go to the cafeteria removes all things that you must wear to work with COVID patients. So we don't have a lot of time. So even these funny things are very useful and important because they let you feel how much all the country has the feeling that the health system is working really at 500% of its capabilities to get the right result. So I think really, I really agree with Marco. Families are supporting us in every moment. Families of the patient are supporting us in every moment, even when things with their loved ones are going bad, they are supporting us and this is a really huge source of energy and strength every day wow well um a couple of things but first off um i'd like to put I speak on behalf of all of the Clinical Problem Solvers family and our listeners that this conversation and this episode will provide us with incredible support and strength and encouragement given your guys' incredible words that you've shared with us today. And I just wanted to pass along a message that Robbie sent as he was leaving to put in context how impactful this conversation has been for us all. And that Robbie said he has never been as inspired for a shift in his entire life as he was leaving this conversation today, heading to the emergency department at UCSF. And I know that I feel like that today, and I know many of our listeners will as well. And from the bottom of our hearts here at Clinical Problem Solvers, thank you so much for all that you've done, taking care of patients in Italy, and for so generously giving your time, which is of, as we know, opportunity to interview you all stay safe. And thank you again for your incredible work that you're doing. That's a wrap, folks. And again, a lot of margarita. Which works also as a disinfectant. That's why we use it. Yeah, I have developed a theory that if you find enough alcohol in your air going out from the lungs, then this will kill the COVID infection. Exactly, speaking about misinformation. So please cut because people will start to do that.
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Welcome to the New England Journal of Medicine audio summary for the week of June 17, 2010. I'm Joe Elia. This week's issue features research articles on nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia, or CML, dasatinib versus imatinib in newly diagnosed chronic phase CML, maternal or infant antiretroviral a boy with elevated HIV RNA levels despite antiretroviral medications, and perspective articles on enrolling pregnant women in research, lessons from the H1N1 influenza pandemic, on health insurance reform and the tensions of federalism, and on Justice John Paul Stevens, the practice of medicine and the rule of law. This week at NEJM.org, we feature a new interactive medical case called A Rash Hypothesis. A 40-year-old woman presented to her physician with diarrhea. She had experienced loose stools for two years, with four to five bowel movements per day, progressing over the last six months to 15 large-volume watery stools daily, including nocturnal stools. She had also begun vomiting over the last two months. What diagnostic and management steps do you choose? Receive feedback on your choices and learn more about her condition and optimal treatment steps at NEJM.org. Thank you. Hospital, Orbacino, Turin, Italy. The treatment of chronic myeloid leukemia achieved a great leap forward with the development of imatinib, a BCR-ABL kinase inhibitor. Structural alterations have produced inhibitors that are more potent in vitro. These authors evaluated the efficacy and safety of nilotinib as compared with imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia, or CML, in the chronic phase. At 12 months, the rates of major molecular response for nilotinib, 44% for the 300 mg dose and 43% for the 400 mg dose, were nearly twice that for imatinib, 22%. The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib, 80% for the 300 mg dose and 78% for the 400 mg dose. Then for imatinib, 65%. Patients receiving either dose of nilotinib twice daily had a significant improvement in the time to progression. Gastrointestinal and fluid retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic phase Philadelphia chromosome positive CML. Dasatinib versus imatinib in newly diagnosed chronic phase chronic myeloid leukemia by Hagop Kantarjan from the University of Texas MD Anderson Cancer Center, Houston. These authors assessed the efficacy and safety of desatinib as compared with imatinib for the first-line treatment of chronic phase CML. After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with desatinib than with imatinib, 77% versus 66%, as was the rate of complete cytogenetic response observed on at least one assessment, 83% versus 72%. The rate of major molecular response was higher with dasatinib than with imatinib, 46% versus 28%, and responses were achieved in a shorter time with dasatinib. Progression to the accelerated or blastic phase of CML occurred in five patients who were receiving dasatinib, 1.9%, and in nine patients who were receiving imatinib, 3.5%. The safety profiles of the two treatments were similar. Dasatinib, as compared with imatinib, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term progression-free survival, Dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic phase CML. Charles Sawyers from the Memorial Sloan Kettering Cancer Center, New York, writes in an editorial that these two studies cap a remarkable decade of progress in CML therapy and, for some, may raise the question of whether we have reached the limit of what we can hope to achieve. We know that imatinib induces a long-lasting remission, but not a cure. Presumably, dasatinib and nilotinib will perform similarly, but with deeper, longer-lasting remissions. But the history of cytotoxic chemotherapy teaches us that remission is converted to a cure only through optimal deployment of combination therapy. In contrast to the empiricism that drove the development of combination chemotherapy, our precise molecular understanding of resistance in C1 annually through breastfeeding. The prevention of maternal transmission of HIV-1 is a priority. In this randomized trial involving 2,369 mother-infant pairs in Malawi, the use of either maternal antiretroviral therapy or infant nevirapine through the age of six months was found to significantly decrease the rate of maternal transmission of HIV-1 during breastfeeding, from 5.7% in the control group to 2.9% in the maternal therapy group and 1.7% in the infant nevirapine group. The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7% in the control group, 4.1% in the maternal regimen group, and 2.6% in the infant regimen group. The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breastfeeding. Antiretroviral regimens in pregnancy and breastfeeding in Botswana by R.L. Shapiro from Beth Israel Deaconess Medical Center, Boston. This double-blind, randomized trial in Botswana compared two different highly active antiretroviral therapy regimens in HIV-1-infected pregnant women, CD4 count equal to or greater than 200, from pregnancy through six months postpartum when breastfeeding ceased. The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery, 96% in the nucleoside reverse transcriptase inhibitor group, 93% in the protease inhibitor group, and 94% in the observational group, or throughout the breastfeeding period, 92% in the nucleoside reverse transcriptase inhibitor group, 93% in the protease inhibitor group, and 95% in the observational group. By six months of age, 1.1% of live-born infants were infected, six were infected in utero, and two were infected during the breastfeeding period. All regimens of highly active antiretroviral therapy from pregnancy through six months postpartum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%. In an editorial, Lynn Moffinson from the National Institutes of Health, Rockville, Maryland, writes that given two similarly effective interventions, the choice of prophylaxis involves several considerations, including relative costs, feasibility, and risks and benefits. But success will be tied less to what regimen is provided than to the integration of services for the identification, care, and treatment of women with HIV-1 infection and their infants. The implementation of these new options for the perinatal prevention of HIV-1 infection in resource-limited countries offers a unique opportunity to link prevention and treatment efforts rather than view these as competing efforts. We now have the tools to make a considerable difference in controlling the pediatric HIV-1 epidemic. Currently, about 45 million Americans smoke tobacco. 70% of smokers say they would like to quit, and every year, 40 percent do quit for at least one day. Some highly addicted smokers make serious attempts to quit, but are able to stop only for a few hours. Moreover, the 80 percent who attempt to quit on their own return to smoking within a month, and each year, only three percent of smokers quit successfully. Unfortunately, the rate at which persons, primarily children and adolescents, become daily smokers nearly matches the quit rate, so the prevalence of cigarette smoking has declined only very slowly in recent years. This article focuses on nicotine as a determinant of addiction to tobacco and the pharmacologic effects of nicotine that sustain cigarette smoking. Tobacco addiction, like all drug addictions, involves the interplay of pharmacology, learned or conditioned factors, genetics, and social and environmental factors, including tobacco product design and marketing. Craving, induced by smoking cues, stressors, or a desire to relieve withdrawal symptoms, triggers the act of smoking a cigarette, which delivers a spike of nicotine to the brain. Nicotinic cholinergic receptors are activated, resulting in the release of dopamine and other neurotransmitters, which in turn cause pleasure, stimulation, and mood modulation. Receptor activation also results in the development of new neural circuits, neuroplasticity, and, in association with environmental cues, behavioral conditioning.
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A case record of the Massachusetts General Hospital by Tammy Myers and colleagues. A seven-year-old boy was seen in an HIV clinic of a hospital in Durban, South Africa, for treatment of infection with HIV-1. His mother had received prenatal care without testing for HIV infection. He was breastfed for the first three months, and then he was fed formula. When he was three years of age, pulmonary tuberculosis was diagnosed and was treated with isoniazid, rifampin, and pyrazinamide. At five years of age, a diagnosis of HIV-1 infection was made and antiretroviral therapy was initiated. Despite 19 months of therapy, viremia persisted. This case highlights the continued challenges in the clinical management of HIV-1 infection in children, particularly in developing countries. This seven-year-old boy with HIV-1 infection was started on antiretroviral therapy, and although he had an initial immunologic and virologic response to therapy, serial measurements of viral load show that even though the HIV RNA level decreased, full viral suppression was not achieved. Before addressing the issue of antiretroviral treatment failure, the discussant of this case reviewed the events leading up to this patient's presentation and discussed the potential benefits of early intervention. Regulation of Smoking in Public Housing, a Health Law, Ethics, and Human Rights article by Jonathan Winokoff from Massachusetts General Hospital for Children, Boston. Although the hazards of exposure to tobacco smoke are well established and laws mandating smoke-free indoor air are widespread, private homes have long been considered spaces beyond the legitimate reach of regulation. Reflecting this view, the federal government has not required public housing units to be smoke-free. Historically, the Department of Housing and Urban Development has maintained that although local public housing authorities may opt to ban smoking, they are not required to do so. This policy choice has important public health implications, given the difficulty of containing smoke in multi-unit housing. More than 7 million people live in public housing in the United States, with 4 in 10 units occupied by families with children. Residents have had little recourse when they are exposed to tobacco smoke. However, policy and practice in this area are changing. On July 17, 2009, a shift in federal policy occurred when a key department within the Department of Housing and Urban Development issued a memorandum that strongly encourages public housing authorities to implement non-smoking policies in some or all of their public housing units. This development makes it timely to critically examine the state of the law and policy in this area. This article explores current law concerning residential smoking regulations and considers whether the implementation of a nationwide ban on smoking in public housing would be desirable. Acute myeloid leukemia and the WNT pathway, a clinical implications of basic research article by Connie Eves from the British Columbia Cancer Agency, Vancouver, Canada. Using mouse models, the authors of a recent study found that the manipulation of the WNT signaling pathway can alter the genesis of leukemia derived directly from normal hematopoietic stem cells or from late granulocyte monocyte progenitors transformed by certain leukemogenic gene vectors. The transformation causes hematopoietic stem cells and granulocyte monocyte progenitors to acquire properties of leukemic stem cells. WNT-beta-catenin signaling enhances the self-renewal of hematopoietic stem cells and is critical for the development and self-renewal of leukemic stem cells. Enrolling pregnant women in research in Research, Lessons from the H1N1 Influenza Pandemic, a prospective article by Sarah Goldkind from the FDA, Silver Spring, Maryland. The global H1N1 influenza pandemic disproportionately affected pregnant women, drawing attention to the fact that although they need safe and effective medical treatment, they have always been a marginalized study population. Thank you. Despite the understanding that physiological changes associated with pregnancy, such as changes in renal and hepatic function, can markedly alter pharmacokinetics, pharmacokinetic studies have not routinely been conducted in this population. Not only could the lack of these data result in incorrect dosing and ineffective or sub-therapeutic treatment for pregnant women, but inadequate dosing could also potentially accelerate the development of drug resistance and negatively affect the general usefulness of antiviral treatments during a pandemic. In the early 1990s, the FDA removed restrictions on and actually began encouraging the inclusion of women of childbearing potential in clinical studies. These authors argue that it is not only permissible, but also imperative, that pregnant women be judiciously included in research. Health Insurance Reform and the Tensions of Federalism, a prospective article by Christopher Jennings from Jennings Policy Strategies, Washington, D.C. Thank you. care system. The flexibility that allows states and local governments to move quickly to address varying needs, to innovate, and to set geographically sensitive priorities locally also permits the creation of tremendous disparities in the availability of high-quality, affordable health care. Insurance coverage rates for the non-elderly, for instance, range from about 75% in Texas to about 94% in Massachusetts, and state approaches to insuring and enforcing insurance market protections for the sickest Americans vary widely. Our ability to achieve a workable federal-state balance will be seriously tested as the Obama administration and the states define and apply their roles in implementing the myriad new policies Thank you. of a minimum national standard for coverage and greater equity among Americans without sacrificing the state's traditional roles, responsibilities, and flexibility. Done wrong, implementation will create excess layers of bureaucracy, and delay will ensure that this historic health care reform legislation falls far short of its goals. Justice John Paul Stevens, The Practice of Medicine and the Rule of Law, a perspective article by George Ennis from Boston University School of Public Health, Boston. U.S. Supreme Court Justice John Paul Stevens will be missed by physicians and patients. Stevens believes that the Constitution prohibits government from interfering in personal decision-making, including medical decisions that belong in the hands of physicians and their patients, not politicians and regulators. It was for this reason that he was Justice Harry Blackmun's staunchest ally in upholding the Roe v. Wade abortion rights decision. One clear articulation of this belief can be found in Stevens' 1991 dissent in Rust v. Sullivan, in which the court upheld the gag rule prohibiting government-funded physicians from discussing abortion with patients. In his dissent, Stevens wrote, Roe v. Wade and its progeny are not so much about a medical procedure as they are about a woman's fundamental right to self-determination, free from governmental domination. Similarly, in a 1990 dissent in Washington v. Harper, Stevens objected to what he saw as an abuse of medicine, the drugging of a prisoner for security reasons rather than health reasons. Stevens carefully examined the medical facts, including the side effects of the drug in a patient like the prisoner, Harper, who already had dystonia and akathisia from previous forced medication with psychotropic drugs. Close attention to both statutory language and the facts of the case before him are hallmarks of Stephen's approach to adjudication. And by paying close attention to the facts of cases, he learned about medical practice on the job. The images in Clinical Medicine features a 25-year-old man who presented with a four-month history of pain and restricted movement of his right shoulder. On physical examination, he was unable to abduct his arm. On the right side, he had four-fifths muscle strength in the scapula girdle musculature and three-fifths muscle strength in the infraspinatus and supraspinatus muscles. Examination also revealed atrophy of the right shoulder musculature with lowering and protrusion of the shoulder blade. On the basis of the clinical syndrome, the patient received a diagnosis of neuralgic amyotrophy. Also featured in the images in clinical medicine is visible peristalsis, a 52-year-old man presented with lethargy and acute hyponatremia associated with alcohol intoxication and poor oral intake. He had a history of total esophagogastrectomy with jejunal anastomosis owing to necrotic injury from ingestion of a lye-containing cleaner 20 years earlier. On physical examination, isoparastaltic movements were visible in the area where the jejunum had been transplanted to replace the esophagus. A video related to this case is available at NEJM.org. This concludes the summary of the June 17th issue of the New England Journal of Medicine. We're interested in your feedback about our audio summaries. Any comments or suggestions may be sent to audio at NEJM.org. Thank you for listening.
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Hello and welcome to The Lancet Podcast. Richard Lane here on Friday, May the 27th. This week we're focusing on an article published online on thelancet.com on Tuesday, May the 24th, and it will be in the June 4th print issue of The Lancet, and it concerns a fascinating, worrying and controversial issue about selective abortion in India. Earlier I spoke to one of the authors of the study, Professor Prabhat Jha, who is Professor of Public Health at the University of Toronto and also Director of the Global Health Research Programme, also at the University of Toronto. And I began by asking him what was the trigger for his and his colleagues' research into abortion in India. Like many people, I was quite concerned when the 2011 census results came out showing that the overall child sex ratio at ages 0 to 6 had dropped even further than that recorded in 2001. Many of us who follow Indian demography were expecting that the child sex ratios would have stabilized, but in fact they continued to go down. So this spurred us to quickly complete some analysis we had already begun of the National Family Health Surveys in India, which are a representative snapshot of all the births in India. They collect other information, but we focused on the births and the birth histories from 1990 to 2005. And so we analyzed those, and we also looked at all of the census results from 1991, 2001, 2011 to try to get some sense of how much this large reported gap in missing girls in the 2011 census could be reasonably attributable to selective abortion. And needless to say, we came up with numbers which surprised even us. Indeed. Go on and tell us about those numbers. Well, the overall finding was that selective abortions of girls has increased over the last two decades or so. And particularly what appears to be happening is many of the families in India are choosing to abort a second daughter if they've had a first daughter. If you look at the ratios of boys and girls for the second birth, depending upon whether there was a first born boy or girl, that can give you some sense of what kind of decisions families are making. And what we found is that there was no change really in the sex ratio over time for any firstborns, meaning it was reasonably stable. And similarly, if the firstborn was a boy, then the ratio of girls to boys for the second birth didn't really vary much over time and was close to the so-called biologic range, which is between 950 to 975 girls per thousand boys. Not quite 50-50, you know, a slight excess of boys, but it was very close to that. But if you then look at what happened to the sex ratio if the first born was a girl, well, it was low at around 906 per thousand girls in 1990, but had dropped to 836 by 2005. So, you know, an average decline of about half a percent a year. And we also found that this decline in the second girl, basically, or the missing second girl, was greatest in the educated, those that had more than 10 years of education. This is mothers that had more than 10 years of education versus illiterate mother. And it was greatest in the 20% of the richest households versus 20% of the poorest households. So we looked at those numbers, and then we looked at the census data. And, you know, they basically collect 21 years of data. Each census has information on children 0 to 6 that they report. So we looked at each of those 21 years for the three years, the three censuses, 1991, 2001, 2011. And then with some adjustments for the excess of child deaths that occur in girls after birth, we then were able to estimate how many girls were missing as a result of selective abortion. And what we estimate is between 4 to 12 million girls have been aborted between 1980 to 2010, with roughly half of that, something like 3 to 6 million, just in the last decade from 2010. And we also then looked at, well, where is this occurring? In fact, it has spread from a pattern that is described just in certain parts of India, meaning in the north and west states, to large parts of southern and eastern India, such that today about 90% of India's population live in states where selective abortion is commonly practiced. And again, this was startling to us to note such a dramatic shift. Yes, compelling data, compelling statistics. The obvious question, why is this happening? And how is it happening? Technology must be playing a part here, particularly ultrasound. Yeah, it certainly is. Well, I think the most plausible explanation is as follows. If you do surveys about ideal family composition, boys, girls, composition, they haven't changed much over time, and they don't vary much between rich and poor, or between the south and north, or a little bit between rural and urban areas. So boy preference really hasn't changed much over time, and it's pretty constant throughout India. But what has changed is the fertility has dropped, such that the average family size has dropped from 3.8 children in 1990 down to 2.6 as of 2008. So if families are getting smaller or family size is getting smaller and fund preference is fixed, then those families that have the means to, in their words, balance a family so that they have a boy and girl are likely to use the technology. And what we observe is that most families appear to be letting nature decide the gender of the firstborn. But if they get a girl, they, given the son preference and given that if they can't afford and access ultrasound and selective abortion, they will definitely choose a boy for the second child. So this explains the phenomenon very much. Now, on top of that, the welcome growth in education and income in India, education has grown remarkably in India. The census confirmed that literacy levels are up. Incomes have been rising at about 10% a year. And ultrasound access, at least in the supply of ultrasound, appears to continue to increase. Put all of that together and it's not a, in that sense, it shouldn't be a surprise to see that families are really acting on this strong son preference. Thank you very much. And in terms of the way the paper, the findings have been received, there's been quite a bit of press coverage, hasn't there, about it, both in India and in other countries too. How do you think the media have handled it? They seem to have dealt with it fairly calmly. Well, I think so. And I think one of the important roles that comes in in terms of getting good scientific rigor around the numbers and avoiding any undue claims, for example, our results do show that, and our earlier paper which came out in The Lancet in 2006, show that female infanticide is not the major driving factor here, but female feteticide, meaning before birth, is the major factor. The fact that it was published in The Lancet, which has basically become an institution in India, sometimes controversial, as in with the superbug from Delhi, but otherwise it's viewed as a very convincing and credible source. The fact that it came out in The Lancet, the fact that we had good, credible institutions working with us, the International Institute for Population Sciences and the Postgraduate Institute in Chandigarh, and Jayant Banthia, the former Registrar General of India, was a co-author. It put all of that together. I think the press viewed the paper as credible, and we certainly put a lot of effort into making sure that there was fair expose of the numbers, that it really just emphasized what the numbers were, and not really got into, if you will, the politics or the causes of this. Because obviously a lot of the newspaper reports have commented, given their explanations to the findings, talking about the dowry effect of Indian families, why having a male in the family is so important and the relative financial effect of having a girl or more than one girl. But in terms of what this means for policy, how is policy set in India? Is it done at a federal level or do different districts or states set their own laws? There was passed a law in 1996, wasn't there, saying that sex determination should not be done by ultrasound. Is that right? That's right. There was an act passed in 1994-96 called the Prevention of Premature Sex Determination, or sorry, prevention of sex determination tests. But that act is very hard to implement, given that 80% of primary health care in India is in the private sector, mainly in the way of out-of-pocket, unregulated private providers. And they have all sorts of easy ways of skirting the law. Basically, a family can go and have an ultrasound.
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Or they can stay silent and the families quickly pick up what the result is just based on body language and motions. So technically they're not breaking the law. They're not revealing the results of the ultrasound, but the families quickly figure it out. And there's well-organized networks of doctors that not just do ultrasound, but also then refer to a friendly clinic which can do an abortion separately. There's a money-making exercise here, is there, in the medical community? Well, I mean, I think a big lesson of what we know in public health over the last century or so is never get in the way of a doctor wanting to earn money because they'll figure out how to make money one way or the other. And this is clearly one of the key drivers of the supply side. So what needs to be done? You've raised a really important public health concern here. Well, I think the long term best option for India would be to move to an NHS or Canadian-type health financing situation, basically where it's publicly financed with strong regulation over the private sector. You can still have lots of private doctors, but they really would be paid for and regulated in the way that we're used to in Canada or in the UK. That's the best long-term solution for not just this kind of practice, but all sorts of catastrophes that happen in private sector care in India. In the medium term, the efforts to try to better enforce the PNDT Act to get more public debate at a local level would be effective, I believe. One of the most obvious things that could be done is to have the Registrar General release for each of the districts, or even the sub-districts. The district is the administrative area of India, roughly with about 2 million people in each of the 600 districts. But they have sufficient data, just based on the last census census to actually give a snapshot of which are the areas where there's the biggest queue between boys and girls. And it is possible to put more pressure on them, both social pressure, but also administrative pressure, which is where the enforcement of the act comes in. That might help in the medium term to attenuate the practice. But in the long term, the best option is for India to move to a UK NHS or Canadian Medicare type system. Well, it's a fascinating study, Professor Prabhat Jha on the line from Toronto. Many thanks indeed for talking to The Lancet. I'm happy to. Well, that concludes this week's podcast. Many thanks for listening. See you next week.
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This is Jan Engmeyer with the Archives of Ophthalmology. I'm speaking with Dr. Patricia Chavez-Berrios. She's a professor of pathology and ophthalmology and genomic medicine at the Weill Cornell Medical School. Also has an affiliation with the Methodist Hospital in Houston and the Retinoblastoma Center of Houston. She's one of the authors on a study, Outcomes of Integrating Genetics and Management of Patients with Retinoblastoma. Welcome. Hi. Thank you very much for joining us. What's the primary rationale for genetic testing in retinoblastoma and of this particular study? As you know, retinoblastoma is the most common malignant tumor in children, and it could be caused by a germline mutation, hereditary mutation, in about 40% of the patients. So it's very important to identify this population of patients that have the risk of developing more tumors or that the families of these patients, either their own children or their siblings, may develop retinoblastoma. So it's important to identify these patients through molecular testing. And although since 1990 this test is available, not many centers do this in a consistent way. So our study was designed to analyze the results of following through the genetic testing in a multidisciplinary way for this patient. There are many reports of how to use this test, but there are no reports of the results of using this testing. So that's what we did. We did it in a multidisciplinary way, so involving the ophthalmologist, the geneticist, the genetic counseling, the oncologist, and the ophthalmic pathologist. And we look at eight years of our practice, and these are the results that we report. Tell us about the testing that's performed at your institution for those children with and without the known RB1 mutation. The way we do it is when a patient with retinoblastoma that has affected only one eye, so it's a unilateral retinoblastoma, has an enucleation, so the removal of the eye as part of the treatment, the eye is immediately sent to the ophthalmic pathologist to me and I retrieve the fresh tumor within 10 minutes after the enucleation and freeze it at minus 70 degrees. So we keep this frozen tissue until the patient is then seen. After everything has finished the surgery, the initial diagnosis is talked to the patient's parents. And after that, the oncologist refers the patient to the geneticist. And so they will talk to the patients about the risk of having a hereditary disease and they ask for consent and then they consent. After that, the patients know exactly what we are talking about. We send the tumor and the blood of the patient because that's the only way to know if this is a hereditary disease, germline mutation, when the mutation found in the tumor is the same found in the blood. For those that are sporadic patients, we will find only one or two mutations in the tumor, but nothing in the blood. So those patients are not at risk of being hereditary for the most part. So when we have the results back, the patients are counseled by the geneticist. And if there is a positive IV mutation, germline mutation, then the patient, even that is a unilateral, needs to undergo a clinical screening for the other eye. So the way we do that is every three to six weeks, the patient is put under anesthesia to have a very good exam of the other eye to notice any small tumors that may arise there. And this is done until one year of age. And then every three months until age three years. And then every six months until age six years to be sure that we cover any small tumor because this disease is better treated when the tumors are small. Now, if we have no RB mutation, if it is sporadic unilateral, we will still look at this patient, the problem, because there's a possibility of mosaicism where it's a mutation that is only found in few cells. There's a possibility that the test didn't find those few cells. But in the family members of these patients, so if we have a positive germline mutation, then we can counsel the family members to look at the siblings and for parents when they are planning to have more children to look at the specific mutation in blood. So if these family members do not have the mutation, they don't need to undergo any screening whatsoever. In contrast to what is done before or without genetic testing that everyone has to go the same type of screening as I talked before. So there's many, many EUAs involved that can be spared for these patients when the testing is done. You mentioned that this was a multidisciplinary team approach. Can you tell us who all is on that team and what the functions are of each member? Yes. So we start with the ophthalmologist that is usually the one that will see for the first time the patient. So the ophthalmologist will look at the patient and make the diagnosis and decide if this patient needs an enucleation or which kind of treatment. And then if this patient undergoes enucleation and the eye is removed, then the pathologist, ophthalmic pathologist, comes into play to retrieve the tumor and to adequately sample the eye to assess other risk factors that we have not even talked about, but risk factors for metastasis versus those that are less possibility for metastasis. And then after the result of the pathology is back, then the ocular oncologist comes into play because many of these patients may need either adjuvant therapy, chemotherapy for high-risk features found in the histopathology, or because they are bilateral and the other eye needs to be treated with systemic chemotherapy. And then the ocular oncologist will refer these patients to the geneticist because they have to be the ones talking about these possibilities of germline mutation and hereditary tumors. And so they see the geneticist and the counseling. Then they go back, they send the tumor and the blood, and they come back to the geneticist for counseling. At this time, if there's any positive germline mutation, they will receive a letter with the counseling for them, repeating everything they said, and then also a copy of the results so that the family members may have one of this and everyone will know which exact mutation they have. And then again, they go to the ophthalmologist to continue the screening and the treatment. And in this group, we always have a meeting either every month or every two weeks to talk about all the patients in a multidisciplinary way. So everyone is aware of all the findings. There's no patients falling through the cracks that everyone has gone to all these multidisciplinary points and discussing the prognosis of each patient. Can you just briefly summarize the findings of your study for us? What we found is that we evaluated in eight years of the practice. And we did that because we had these eight years were the ones that we have most of the, we initiated the regular testing of these patients. So we had a similar percentage of unilaterals and bilaterals patients tested. So that was about 65% from each group. And we did use two different labs. The initial laboratory that was doing the testing did a more simple analysis. And the second one we changed after 2004 for another lab that incorporated a DNA copy number analysis and methylation, which is a more extensive study of the probable mutations for this patient. So we increased the possibilities of catching any type of mutation. And we found mutations in 90% of the bilateral patients and documented hereditary retinoblastoma in 17% of the unilateral patients. So these are the most important ones because they are the ones that appear to be sporadic, but they are actually hereditary. We also, in addition to that, we study 48 relatives at risk, predominantly parents and siblings, which were identified, only six of them were identified to have the mutation. So 42 patients at risk didn't need further screening, only six of them. So I think this is the main point of the paper. How can we streamline all this testing? And, you know, it's not only because this is less expensive at the end, but also decreases the possible morbidity of exams under anesthesia and screening for the family members. Okay, thank you. Is there anything else that you'd like to add that you think we haven't covered here? In our study, we did a little study about the economics of this because one of the arguments that people that do not do this testing have is the cost. This study that we did was in 2010 for the economic analysis of this. So in 2010, the RB1 sequencing and detection of this analysis was about $1,800 per patient, proband patient, but only $340 per any family member. So that was the cost.
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That's a big difference. It's a lot of difference. And actually, that's the way we have, you know, we have not had any problems with reimbursement because the moment the people start to know it's too expensive, we show this number and it just really speaks by itself. Well, our thanks to Dr. Patricia Chavez-Berrios for talking with us about integrating genetics in management of patients with retinoblastoma. This is Jan Engmeyer with the Archives of Ophthalmology.
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This week in The Lancet News, India passes a new anti-rape bill, problems for a Filipino reproductive health law, and an interview with Eric Goosby, the head of the new Office of Global Health Diplomacy. I'm Dara Mohammadi. And I'm Tim Dayton. It's Friday the 29th of March and you're listening to The Lancet News. We've got lots to get through this week. In part one, we look at reproductive health in the Philippines, and then a report from the USA about an alarming number of deaths from Alzheimer's in the USA. In part two, we look at the UK aid budget and then India's anti-rape law. And in part three, we have that interview with Eric Goosby. Thanks very much for that, Dara. Just a tiny bit of admin. We're away for an Easter break, so we'll be back on the 12th of April to continue the Lancet news. But first up, Dara, so we are looking at the Filipino government. So late last year, the Filipino government passed the Responsible Parenthood and Reproductive Health Act, which aimed to ensure universal access to effective reproductive health care. The act was due to come into full effect at the end of March, but campaigners have won a victory in the Supreme Court, meaning that the law will be put on hold for 120 days until further arguments against it can be made. Tim, would you like to tell us a bit more about this? Yes. So this reproductive health law, as it's known, it really seemed to be a good step in the right direction towards improving maternal health in a country with almost 100 million people, 14% of who live on less than $2 a day. So like you say, the law was meant to come into force in January,G goal of universal access to reproductive health by 2015. So can you explain why there's opposition to it? Sure. So one of the obvious reasons, I suppose, is that the Philippines is a deeply Catholic country, which has a fairly regressive stance on some aspects of the proposed law. So abortion in the country is illegal. One of the provisions of the law was to ensure that IUDs and morning after pills, which obviously act after fertilisation, were provided and paid for by the government. The reproductive health law would keep abortion illegal, but post-abortion care was intended to be provided without prejudice or stigma. So entrenched religious attitudes is an obvious point, but I suspect not their only argument? No, so opposition groups also argue that money should be going to other healthcare projects, or any money to provide contraceptives should be given to citizens themselves so they can make their own choices. You have to admit that a new law that guarantees universal and free access to nearly all modern contraceptives for all citizens is a major shift. Previous governments advocated family planning, but not through free contraception. Opponents also suggest that the law could be used as a form of population control, sort of akin to the one-child policy in China, which opponents say is not beneficial economically or socially. So what side do you fall on, Tim? So at the Lancer, we'd fall down on the side of the right to free and accessible maternal health care. The sponsor of the bill points out that the maternal mortality ratio in the Philippines is rising, with up to 221 deaths per 100,000 live births in 2011. The law aims to provide effective and quality reproductive health care, but also provide antiretrovirals for people with HIV infection, treatments for breast and reproductive cancer, as well as for people with obstetric complications, amongst various other fringe benefits within the law. And I know I can see now that the law has been discussed on and off for the past 10 years, and hopefully this is going to be the last roll of the dice for its opponents. But willingness to postpone this enactment is a bit unsettling. You know, it's the poorest and most in need of the services who are going to suffer while we wait. Absolutely. Should we cancer, heart disease, stroke, have plummeted. So what's going on with Alzheimer's? A lot of things. Perhaps the most interesting is that research and drug making attention has shifted towards people in the earlier stages of the disease, you know, people with few or no symptoms. And that's because drugs aimed at the later stages have had very little effect. So now, you know, this attention is shifting to identification of biomarkers and early diagnostics. However, the CDC data show that deaths have been increasing steadily over a long period, about 30 years. So before this shift, this R&D shift to the earliest stage of the disease, which suggests other reasons. What might they be? Well, the usual suspects, really. An ageing population is likely to be behind the increase. Also, increased attention, recognition and diagnosis. And actually, increased recognition will also mean that people previously classified as dying from old age are now going to be captured as dying from Alzheimer's. This is something I wanted to ask. I'm not a slightly embarrassing question, but how exactly do you die from Alzheimer's? I didn't know. Well, in the very end stages of the disease, people become prone to pneumonia because of immobility. And as brain cells die, the person may not be able to recognise sensations such as thirst or hunger, or the person may not be able to eat, drink or swallow properly. So people die from complications like malnutrition, dehydration, choking or infections elsewhere in their body. I mean, we think of Alzheimer's as more of a degenerative memory robbing disorder, but it's actually a big killer too. As the report stated in the USA, it's the fifth biggest killer in patients older than 65 and the sixth biggest killer overall. And welcome to part two. Before we go on and have a look at India's new anti-rape bill, we're going to have a quick look at news from the UK. On March the 20th, the UK Chancellor of Exchequer, George Osborne, delivered some rare good news in the annual budget. That for the first time, the UK is going to commit 0.7% of its gross national income to development aid. To find out why that number is significant, let's turn to Tim. Can you tell us more? Yes, well it's good news indeed. 0.7% translates into £11.3 billion going into provision of things like education, health, improved water supplies and sanitation, as well as disaster relief and economic development. It's all under the umbrella of poverty reduction, which is what the UK's Department for International Development, DFID, and the Foreign and Commonwealth Office has pledged the money towards. The 0.7% target has been around since the late 60s. It's a sort of significant global target, but only Sweden, Norway, Denmark and Luxembourg have met the pledge so far. Good company to be in then. It is. There are specific commitments within it as well this time to combat malaria and improve maternal and child health. The UK is the first of the G8 to make the 0.7% target, which has been widely welcomed. Overseas development aid is something the UK does extremely well, through direct investment but also through being an effective member of institutions like the World Bank. So it all sounds good, but are there any problems? Who's saying what about this? Ensuring the money will be spent in the right places is the big one, I suppose. There's a suggestion that the 0.7% target wrongly prioritises how much should be spent rather than what should be achieved. So, say, would you rather your government said, we've got £11 billion to spend, or would you rather them to say, we need, say, this number of bed nets, let's see how cheaply we can get them for? The latter, most definitely. So this is the problem, possibly. A European Commission report also suggested that aid wasn't the biggest contributor to development, but remittances from migrant workers were more important. Also, that aid changes the focus for governments from concentrating on what their citizens need to concentrating on what donors want them to do. I don't think these are particularly strong arguments against development aid. Yes, there'll be waste. Yes, there'll be corruption. And yes, there'll be other sources of financing for development, but that's no reason to cut off aid itself. One aside is that DFID has a cap on the number of staff it's allowed to employ, but not the money it can spend, which could mean more outsourcing and therefore less control. So some issues, but obviously a great achievement for the UK and hopefully the money will be spent in the right places. Yes, absolutely.
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The drafting of this new bill is in response to the violent and fatal gang rape of a 23-year-old medical student in Delhi last December. That attack sparked huge protests across the country with people pushing for tougher punishments and provisions to stop atrocities like this happening again. Dara has been looking into this and would like to tell us more. Yeah and actually since the case that you were talking about we've had a few highly publicised cases involving tourists but there are certainly many other cases. Now according to official government figures a rape takes place in India every 21 minutes. Obviously a very worrying statistic. What's in the new bill? Well it's very strong. It includes the death penalty for the most extreme cases and introduces punishments for stalking and assaulting women which weren't previously covered by the law. Also it aims to tackle quite a big problem which is that the police force is quite male dominated and reports from women who have been raped have been known not to have been registered. But now if officers fail to report an initial report of rape they can receive jail terms of six months to two. Yes, now this story has been covered quite widely. I read an article in The Observer suggesting, based on a journalist's conversation with a group of young men, that many young men in India see sexual violence as a sort of legitimate retaliation for women spurning them or dressing provocatively and being out late at night. Yeah, I saw that article too, and while it touches on quite a serious issue, that's that many women are afraid to be out alone after six or seven in the evening. I think we need to remember, and as the journalist himself stated several times, this piece was written using statements from a very small and perhaps unrepresentative group of men. So it shouldn't be extrapolated to the entire Indian population. India's population are very religious and this kind of violent behaviour against women isn't in line with their spiritual teachings. But yes, the article was very worrying and might give a glimpse of the scale of the problem at hand. Absolutely, we shouldn't extrapolate it to the whole population. But it's worrying that there is a small group of people who think this. Is there anything else from? Yeah, one thing to remember is India hasn't had a sexual revolution. It's still commonplace for, you know, especially in the poorest populations, families to marry off their daughters at a young age. So the country still has these gender inequalities that allow women to become victimized and don't necessarily give them a voice to speak out against it or a chance to do anything when they have been victimized. It's changing, but slowly. One of the slightly odd things in the new law is that the age of consent is being raised to 18 in a country where over half the population gets married before they're 18, which raises all sorts of issues. That's actually one of the difficult and tricky things about India and trying to tackle this problem is that there's so many different cultures, so many different religions and so many different languages in the countries that it needs this overarching governmental response. Well, it's very encouraging then that India are taking this response at a governmental level, as you suggest, and saying, if you commit these crimes, this is what's going to happen. There is a clear and structured system of legal retribution for people who do this. Welcome to part three, where we've got a quick interview from Susan Jaffe, who's written in the World Report section and is interviewing Eric Goosby, who is the new head of the Office for Global Health Diplomacy. I'm Susan Jaffe. I write about health policy from Washington, D.C. for The Lancet. And I'm here today speaking with Eric Goosby, the U.S. global AIDS czar. And recently he was named head of the new Office on Global Health Diplomacy by Hillary Clinton as one of her last acts as Secretary of State. So thank you, Ambassador, for speaking with The Lancet today. You've said that there's a huge diplomatic tool chest to use to save more lives. What resources do you have that you hope to use in this new office, global health diplomacy? The global health portfolio for the United States approaches $7 billion a year. It goes out every year to about 80 countries. It's not spread all over the world, but it's in about 80 countries. That portfolio drops a lot of morbidity and mortality out there. This office will do is add the embassy, the ambassador, the staff in the embassy that articulate with many elements of civil society, including the medical community, and link the importance of health care in the minds of the ambassadors. So in all of their discussions with country leadership, presidents, ministers of finance, often, departments, ministers of defense, ministers of health, will link that agenda kind of front and center in the ambassador's mind that this is an agenda that the American people have invested in and want to be strong stewards of it delivering program and services to the people that need them. And what do you think is the most important challenge at this point right now in terms of institutionalizing this? I think getting a comfort with this agenda on part of all the agencies that have historically for many years been doing this work around a common voice and themes that can be introduced kind of dumbed down almost for that ongoing diplomatic dialogue. So it becomes part of not some agenda, but every agenda. You said in a lot of ways we haven't really grasped this yet and marshaled these resources. You said we've been punching below our weight. What did you mean by that? Well, we have this huge volume of resource coming into a country that is having stunning impact on morbidity and mortality, but have not concretized those services as permanent in the eyes of the country. It's been more of a donor insertion and creating a parallel system. It's our hope that the diplomatic discourse will now allow those discussions to happen, not as we exit a country from a program, but on day one of a program entering a country. What are you, country? What do you want? What do you want to continue? What can you continue? How can we, over the next few years, as we set this program up with you, make sure that your ability to run and oversee the program is achieved and that your resources are identified that will be the core of sustaining the program, not as we exit, but as we enter. What kind of technical resources are needed to promote sustainability? The countries in which we work, virtually every one of them, do not have the ability to effectively, the tools to effectively manage and oversee programs, have a robust monitoring and evaluation system, have that information feed into planning and implementation around a budget, so strategic planning and budget development. All of those are essential pieces of programmatic success and really no countries we're working in have all of those pieces in place. The human resource deficit is huge. You have leadership that's well-educated and ready, but the Minister of Health then turns around to nobody to implement the idea. So the policy can be great, but if there's no one implementing, you don't have a program. You can't sustain a program. And are there particular parts of the world or some chronic diseases that you want to focus on? We've done communicable diseases. We'll continue to do that. HIV-AIDS is a very complicated communicable disease that moves into a chronic progressive disease. The kind of NCDs out there are right on the horizon now because the people have stopped dying from communicable diseases. That's the good news. We're not there yet, but we've taken a big step towards it. Finish that and now start planning for non-communicable diseases because those we've cared for with HIV, for example, are going to die from hypertension, diabetes, and coronary artery disease. We've shown this. We know that that's the natural history of what will happen, and countries now need to start planning and putting those systems in place on every level, from patient information systems to laboratory to procurement distribution systems to make that system work for these non-communicable diseases. If they can work for HIV, a very complicated disease that requires orchestration of a lot of resources and capability, they can do it for hypertension, diabetes, and coronary artery disease. Well, thank you very much, Ambassador, for speaking with The Lancet today. You're welcome. Pleasure. So that's it. That's all we have time for. Thank you very much to Susan for that fantastic interview there at Goosby. But quickly, before we do shut down, Tim, do you want to have a look at what else is happening in the Lancet world? Yes. So just one big theme for you this week, really. It's the Health in Europe series launching in the main journal.
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This is the New England Journal of Medicine COVID-19 update for January 27th, 2021. I'm Stephen Morris, the Managing Editor of the journal. I'm talking with Eric Rubin, Editor-in-Chief, and Lindsay Baden, Deputy Editor. And today we're joined by someone who scarcely needs an introduction. Dr. Anthony Fauci has been Director of the National Institute of Allergy and Infectious Diseases for about as long as anyone can remember. In this role, he does just about everything. He's continued to direct his own lab and perform clinical research, still sees patients, and directs an institute that's the largest funder of infectious disease research in the world. Given his involvement in disease research, he's also been a key contributor to setting policy. By his own account, he's testified in front of Congress more than anyone in U.S. history. And his contributions to policymaking, which were critical during prior outbreaks, influenza, Zika, Ebola, have never been more important than they are now during the COVID-19 epidemic. Over the past year, Dr. Fauci has added to his portfolio as a ubiquitous and trusted public communicator. There's really no better person to help us understand both the science and the policymaking around COVID-19. So today we'd like to cover several topics and look toward understanding where things are today and where they might be in the next several months. I'd like to start with testing. In a perfect world, how would implementing COVID-19 tests be what's on the horizon in the near future that might change the approach we are now taking? Well, in the very beginning, testing was really fundamentally directed at people who were symptomatic in the context of when you get a case that is a clear-cut case of COVID-19, you would do the typical standard identification, isolation, and contact tracing with a highly sensitive, highly specific PCR assay. What has evolved now as we understand so much better, beginning somewhere in the early spring of 2020, that the outbreak is really driven in many respects by people who are without symptoms. In fact, recent papers that have come out show that approximately 50 plus percent of all transmissions occur from a person who is either asymptomatic and will remain asymptomatic or is asymptomatic in the sense of being pre-symptomatic and then will develop symptoms days or whatever following a particular encounter with another person. And so right now we've evolved in having to know what the penetrance of infection is in society. So what we're seeing going forward, we're getting there step by step in the sense of getting point of care, highly sensitive, highly specific assays that are inexpensive, not requiring a prescription from a physician that can be used by virtually anyone anywhere on a personal basis. For example, if you want to know if you can gather people in your own family or friends in your house, you could just get this done. If a storekeeper wants to know whether or not the employees who walk in that day are positive or not, that is really getting away from what we had before where we were saying not everyone who wants a test can get a test. Only people who need a test can get a test. Now it's anybody who wants a test can get a test. And there are many, many good reasons besides identification, isolation, and contact tracing that would warrant the test. How close are we to that test and having that test be affordable so that you could do it every time you walked into a school, for example? Is that on the horizon? You know, Eric, I think it is. The thing that needs to be perfected, and I don't see any reason why we cannot do that given, you know, the technologies and the expertise we have. We have everything in place except the degree of sensitivity, because what we're working on right now is that if you look at the sensitivity of these antigen rapid inexpensive tests that you're referring to, they are good when you're doing them multiple times in a particular setting, because the averaging out is that you will pick up someone who is at least transmissible. They may be infected, but have such a low level of virus in their nasal pharynx, that you want something that really is truly 98%, 99% sensitive for someone who is without symptoms. The idea about expense, I think, is not going to be an issue. The idea about accessibility, I think we have to just work on the degree of sensitivity in the context of someone who is without symptoms. Dr. Fauci, I think what you're getting at is there are different ways that tests are used. And if we're using it to diagnose somebody with acute illness coming into the hospital, we may have different expectations of the testing than if we're doing serial testing for occupational or school participation. Don't we have to help set that framework for our community to better understand? You know, absolutely, Lindsay. I mean, that's the whole issue. And I believe that there still is as much as we try, you know, and there have been a number of papers and commentaries published, including in the journal, is that what we really do need is we need to get people to understand just what you're saying. I mean, this is so critical now for schools. If by the time we get to the point where we get a number of people vaccinated and we have a situation where we feel somewhat more comfortable in getting children back to school, the idea of getting teachers tested, students tested would make the entire situation of the policies of schools, of restaurants, of gatherings at sports events and entertainment events, it would turn it around completely. So you're right. We really have to reorient people in understanding the difference between testing somebody who comes into the hospital with symptoms and you want to make sure that they are indeed infected versus whether or not you want to have a sports event. Because along these lines, Dr. Fauci, the sensitivity you mentioned, particularly with serial testing, but the specificity side of the equation has also created a lot of headache. And in a lot of our schools in the Commonwealth or colleges, serial testing has been deployed. And what's been a challenge has been interpreting a positive because of the implications it's hard to ignore. But we all know when you do tens of thousands of tests, not all are true positives, which gets to the science behind the application. Exactly, Lindsay. Particularly when you have a population in which the overwhelming majority of the people are actually negative. The chances of getting into trouble with a false positive there are considerable. So that needs to be worked out on both ends of that spectrum, both sensitivity and specificity. But the issue of testing, Dr. Fauci, is a capacity issue in that how do we go to scale and how do we deliver to scale? And I worry that over the last year, the science of SARS-CoV-2 has been such a tremendous undertaking that we haven't spent as much time thinking about the less interesting side, which is how do you manufacture the reagent? How do you deliver it? How do you actually deploy it? How do we enhance our ability to deploy these technologies in a way that serves the public health best? You know, I don't have an easy answer for that, Lindsay. But when you say deploy, in other words, how do you get them out to wherever they need to be? Well, I think the first thing we need to do is we need to be able to produce them literally in the sense of millions and millions and millions, as much as you want. And there's no reason why we can't do that. I know the RADx that you're aware of, the endeavor on the part of the NIH to get involved in the field of diagnostics, to be able to essentially do, I believe what you're maybe indirectly pointing to is how you can actually get almost an unlimited supply of tests. That what I would see, and the reason is because I so often get so many calls, as I'm sure you all do, is that why can't we have something that essentially is in the pharmacy for a dollar and a half or for 50 cents? So you can go in and just get it yourself. You know, it's very interesting because over the holidays, I don't know whether you all do it. You know, I have a daughter in Cambridge where you guys are. And the question is, should she come home to her 80 year old daddy or not to determine if she is infected? And with all of the tests and the lack of specificity, it really would be great if she could get in her car or on a plane, you know, get off at National Airport, take a test that's 98% sensitive and specific, and then walk in, you know, and give her daddy a hug for the first time in a year. That would have really been nice. I would have paid a lot of money for that test. She's not alone, nor are you. So clearly over the past year, there's been considerable effort in developing therapies for people who do contract COVID-19.
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And what do you see on the horizon? What are we going to see over the next several months? Well, you know, I have to say without adding an element of discouragement on this, that the arena of therapy really lags significantly behind the quality of the science and the results that we've gotten with vaccines. I mean, not even in the same ballpark, if you look at that. So if you look at therapy at what stage of disease, it seems interesting, I might say, from someone who spent the earlier part of my career with inflammatory diseases, that the best that we have right now that you know works by a clear-cut good trial is that when someone has got advanced disease in which the virus is less of an issue than the aberrant inflammatory response, that in people who are hospitalized, either requiring a ventilator or high-flow oxygen, that dexamethasone, six milligrams for up to 10 days, is about as good as you get. It has a major diminution of 28-day mortality. But then once you get past that, the thing that's really been a stumbling block is, you know, we have a lot of experimental approaches with blockers of inflammatory response and various elements, you know, IL-6 receptor inhibitors. We have blockers of JAK kinase. We have a whole variety of things that are in the mix. The thing that we sorely need is a medication to give to someone who is infected and beginning to be symptomatic, to give them an oral medication that would prevent them from advancing to the point of needing hospitalization. So what do we have? Well, we have a confusing element of therapies, I think. You have convalescent plasma in which the results to say have been mixed is an understatement. We know it needs to be given to people who have not yet mounted an immune response, because if you give it to an individual who already is making antibody, we know from a number of studies, it doesn't work. Then you have a whole array of monoclonal antibodies, which almost the logistic aspects of it make it inherently problematic, because you want to give it early, which means you want to give it before a person gets into the hospital. But it's intravenously administered. And you want to do it in an infusion center. You know, when I was sitting in the situation room talking about, okay, we got these monoclonal antibodies, we'll get infusion centers, we'll get people to stick the IV in. And you find out that when you're in a city, a town, or a state in which the medical staff is completely overwhelmed with desperately ill people, nobody's going to want to come and stick an IV in, wait an hour before, an hour during, an hour after, for someone who barely has some symptoms. So even though you have the Regeneron antibodies and you have the Lilly antibodies, that in the number of tests, some of which came out yesterday in some of the preprint literature, that in fact, it still is not adequate, even though it would work theoretically. If you can get antibody into somebody who's not making an adequate antibody response as the antiviral component of it, and then you have a number of other therapies, anticoagulants, you have a variety of others. The thing that I believe, and that when I was looking at the question, when you said, what will we likely see over the next months? If we could extend that and say several months to a year or so, what I think we absolutely should do, and there's no reason why we can't do it, is exactly what we did for HIV and for hepatitis C, to get a direct acting antiviral agent that you could give orally. You don't have to give it for life the way we do with HIV. We don't even have to give it for eight weeks the way we do with hepatitis C. You need to give it for about 10 days. So we're putting in a lot of effort now, and I hope we get the collaboration and the cooperation of the pharmaceutical industry to get the direct acting agents. So when someone comes in, mild symptoms, you're afraid they're going to go ahead and advance into something that would require hospitalization, you know, almost like a Z-Pak. I'm not trying to be facetious, but almost when you come in, you get five to 10 days of a direct antiviral. That's really what we need. Everything else we're doing is laudable, but it is really not getting at the problem that we're facing. So sorry for being a little long-winded on that, but I think you're sensing my frustration in not having something that's a great point. And that's exactly what we're talking about. You know, I have been talking about, you know, getting a universal influenza vaccine. And then we were talking about a universal coronavirus vaccine. Well, before we try to get every single one of these, we should think in terms of exactly what you are referring to. Find the common denominator vulnerable part of the replication cycle of coronaviruses in general, and even SARS-CoV-2, because we're getting mutants now that it's looked like we could possibly be dealing with multiple pandemics at the same time, which is, you know, a single pandemic is frightening enough, but multiple ones overlapping in different parts of the world with the South African, the UK, the Brazilian mutants, and they're going to be more. The answer to your question is absolutely right. We should be looking at drugs that are specific for a particular family of viruses. If we had that, that would really be good because the pharmaceutical companies would be making an investment of something that would be for the future in addition to what we're dealing with now. So I couldn't agree more with what you said. But there's a larger strategy here, which when we spoke about testing, if we actually had home-based testing where I could test the way I wanted to, not what capacity allows, that also allows triggering of treatment earlier because cases get identified before they come to the health care center. And I think the testing approach for infectious diseases has not kept up with what technology allows, at least until the last few years. And so I see a potential strategy that could really allow us to attack these kinds of infections much earlier with a package of response modalities. Yeah, I agree, Lindsay. You're absolutely right. Absolutely. You know, and the interesting thing is you wouldn't be confined to people who were symptomatic and were all of a sudden starting to progress. I think that's what you're alluding to, Lindsay, is that you go in, you're positive, take your medication because you don't know if you're going to be the one that's going to progress. Dr. Fauci, like your daughter, your daughter takes the test before she comes visits you. She has no symptoms. She's positive. At that point in time, we now have a moment to intervene before transmission occurs, before illness occurs. Of course, we don't know if she would become ill, but it's a moment of intervention much earlier than all our current strategies are based. Yeah, I agree with you completely, totally. So as you say, the greatest success we've seen has probably been in the development of vaccines, but the logistics involved in producing them and administering them have been challenging. Do you see innovations that are going to make a real difference in how we get these vaccines out to the public? Yes, absolutely. And that's something that is really on the front burner in an intense way with what's going on right now with the medical team that I'm privileged to be part of in the Biden administration, even though it's just a few days old. And to give credit where credit is due, I believe that the Operation Warp Speed group of the prior administration really was very successful in many ways, and we should give credit there. The answer to the question is that there are multiple phases in the vaccine endeavor, and I would think that the public hopefully will begin to appreciate that. There's the scientific effort of the development of the concept and the proof of the concept with the trial and a successful vaccine that's efficacious and safe. That was a resounding success. Then there's the production. There's the putting it into the fill and finish. There's the allocation. There's the transportation. There's the distribution. and then it's sticking in people's arms. And as you get from the actual concept production down to getting into people's arms, it gets to be more complicated from the standpoint of where you are and what the community is. For example, getting vaccines shipped to a hospital and having hospital personnel give it to hospital personnel is relatively easy, as is getting it to a nursing home and getting it there. What things are really going to get complicated is how do you get it to the underserved communities that live in what they call pharmacy deserts, where there's not a pharmacy around?
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The next is pharmacies. I mean, if you really wanted to get quantitatively a lot of people, you just have them get it in a pharmacy. Same as Lindsay was saying, you go in, you get a test, you get a drug, you get a vaccine right in the pharmacy. And then there's mobile units where you could actually go out into the community. All of those things right now are being planned. What we're seeing, and I was literally on the phone last night with the health officials from multiple different cities and saying, you know, I'm hearing that there's places where there's vaccine on the shelf, but we don't have enough people to give it out or we don't have the logistics. And then other people say, you know, I'm dying to get more vaccine. I'm just, the supply completely does not meet the demand. So I asked, what is the real answer to that question? What is the problem? And overwhelmingly, with very few exceptions, in fact, no really substantive exceptions, it was that the supply is not meeting the demand. And that is just absolutely true, which is the reason why, as I got up and read in the Washington Post this morning, but I knew about it because I was literally talking to the team last night, is that the president has now made further arrangements with both Pfizer and Moderna to get an additional 100 million doses each from them, which means the total now will be 600 million just from those two companies. So no matter what happens with Janssen and Novavax and the others, we still now will have a confirmed 600 million. So the real question is going to be, how do we efficiently get it out into the community in a way that is actually equitable? And I think that's the one thing we really got to be careful of. We don't want in the beginning that most of the people who are getting it are otherwise well middle-class white people. You really want to get it to the people who are really the most vulnerable. You want to get it to everybody, but you don't want to have a situation where people who really are in need of it because of where they are, where they live, what their economic status is, that they don't have access to the vaccine. I'm keenly aware of this right now because at midnight last night, I got up to schedule a vaccine appointment for my 88-year-old mother-in-law. And it took 20 minutes online. And it's fantastic that she's getting her vaccine next week. It was a terrific outcome. But she couldn't have done it, not by herself. And there aren't that many 88-year-olds who could pull that one off. And my stepmother spent six hours waiting in line after a 90-mile drive in Florida. So it's clear there is a real patchwork approach right now. I guess one of the questions for you is, should there be a more coordinated federal response that helps eliminate some of those inconsistencies? Great question, Eric. And that's exactly what's part of the plan. You might recall a few days ago, I mean, these days go so quickly, it was just the middle of last week, like literally two days after the inauguration when President Biden got up and put up a 101-page national strategic plan for COVID-19 and pandemic preparedness. And part of this was something that I believe is going to address what you're talking about, that in our country, I learned this, you know, it was sort of, I learned more civics in some respects than anything else I learned, you know, over the last year, is that in our country with the federalist approach, that there's this tendency to let the states and the locals do what they feel they need to do for good reason, because there's a lot of good reasons because of the diversity of states, demographically, culturally, and otherwise in our very large country. So if you leave it all locally without any federal help or plan, even though the states in many respects really know what they're doing, some get it right and some don't. And I think that's what we learned clearly. So there are probably areas, Eric, that are doing it easily and very well. And there isn't that concern that, you know, you're not able to negotiate whatever electronic or computer terrain that you have. The other thing is you don't want the federal government to do it all. So what has happened in the past is that we've leaned a little bit too much towards the federal government telling the states, do it the way you want to do it, you're on your own. And then instead of sharing what works across the board, some are struggling and some are not. So the bottom line is that we need a much better collaboration and cooperation between the federal government and the states in implementing this. We have to get a system that works well regardless of what your circumstance is. A lot of the issues that you're illuminating for us, Dr. Fauci, has to do with how do we get vaccine to the willing, which is a Herculean undertaking. But there's a lot of concern that certain communities don't trust the science, the results, the potential benefit versus unknown risk. And that's disproportionate in certain communities. What strategies do we need to develop to help with this vaccine hesitancy concern? Because that may undermine much of the successes you have shared with us. Okay, so that is literally a full-time effort that's going on right now that even antedated our realization of the success of the efficacy and the safety. And that is to, in a very proactive way, engage the community in general, but particularly the brown and black community. And what we've learned from experience, and I've had to learn this from my brown and black colleagues and friends, because I have spent, Lindsay and Eric, interestingly, I wouldn't say a disproportionate, but a clearly significant proportion of every single day being on the phone with a podcast, with an Instagram live, whatever, with black churches, with congressional caucuses, black caucuses, Hispanic caucuses, black bishops. Yesterday I was on this mega church. It was really terrific. I mean, you know, hundreds of thousands of people follow this church and you're there talking about it. And the one thing I've learned is the first thing you've got to do is absolutely respect the hesitancy of the minority population. They keep coming back and saying the history of Tuskegee. And some people may say, oh my goodness, that was so long ago, forget about it. But no, they don't, can't, and should not forget about it because it happened and it was shameful. But what we have got to convince them of in an outreach way is that the safeguards that have been put in place since then, without putting it aside or forgetting it, would make it essentially impossible for a Tuskegee situation to arise again for so many reasons. And it's at multiple levels. I mean, you guys know that because when you get a paper that you even look at it and judge it as to the ethical aspects of it, and which is very, very appropriate that you do that, that wasn't in place decades and decades ago. So that's the first thing. Once you get them to realize that you respect their hesitancy and their concern, Then in a stepwise fashion, you go through what is it about the process that is concerning you. The one that's very common is you did it so fast, you must have been cutting corners. And then you go by and explain to them that the speed is, first of all, not related at all to cutting corners, but it is a reflection of the extraordinary advances in vaccine platform technology that allowed us to do things in months as opposed to years. That's the first thing. The second thing is that don't measure speed by the time a virus gets put on a public database with its sequence to the time the vaccine goes into a person. But look at the 10 years that it took scientists like Barney Graham to figure out how to get the right confirmation of a pre-fusion molecule to be stabilized with various mutations so that it is not only stable, but it's highly immunogenic. They don't understand that until you tell them, all right, it took 11 months, but the process took about 10 years to do. So the next most common question that I get is, okay, speed is all right, but how do I know it really is safe and effective? I hear so many things about political influence, about rushing, you know, the companies, maybe they just want to make a lot of money. And you explain to them something that many of them don't realize, that the companies in many respects don't even have access to the data until the Data and Safety Monitoring Board looks at it, examines it, and then says, okay, now the data can be looked at, examined, presented to the FDA.
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It was astounding to me how few people really realized that the examination of the data starts with an independent group that's beholden to nobody, not the federal government or not the company, and that the decision to go out, A, is independent and transparent, and B, ultimately, everybody's going to see the data because it's likely going to get published, likely in the New England Journal of Medicine. So they've got to understand that their concerns are understandable, but there's an answer for each of those. And we just have to keep going over and over and over again. So we're expecting to see new data in the days ahead on new vaccine candidates from Janssen, Novavax, the companies you talked about. What are you going to look for in these new trial data that will be important in understanding how we're going to use these new vaccine candidates? Well, there are a couple of interesting things that almost accidentally are going to partially answer some of our concerns about how effective the vaccine are going to be against these evolving mutations. Because take, for example, the Janssen trial. You know, by coincidence alone, the data are going to be from the USA, from South Africa, and from Brazil. And that's exactly what we want to know. We want to know, I mean, that's the burning question that we will hopefully, literally in the next week or so, maybe less, we'll know that a vaccine, namely the Janssen, whose spike protein is against the current wild type virus? How is it effective, relatively speaking, in the United States versus South Africa versus Brazil? So I have to be quite honest. I do not know what the data are. They're being looked at by the Data and Safety Monitoring Board, and I have been very meticulous about not getting myself to know the data until the appropriate time for me. But it would be really interesting if there was a differential efficacy, which would tell us how well the current vaccines that we're using are going to be if, and it's a big if, the South African as well as the Brazilian becomes dominant in our own society, if it ever does. It might not, but if it does, we're going to know that. So that's one of the first really important things we're going to learn from that trial. But also, it's a single dose trial. So it's going to be very interesting to see what is the relative efficacy against wild type of a single dose. It doesn't have the same cold chain requirements, and it's less expensive. So it would be good for us here because we always would be interested in additional doses of vaccine, but it also has major implications for the developing world. So a lot of people are looking very closely at what's going to happen, I believe, literally in the next several days to a week or so. So that's very interesting. I've got a couple of follow-up questions to what you said. First, is viral sequencing of the people who do develop disease part of the Janssen trial? Was that built in or is that easy to do at this point? Well, right now it's pretty easy to do. You know, literally, Eric, that's what they're doing as you and I and Lindsay are speaking. They're doing that right now. And that's the reason why I believe they're not coming out yet with the data because they want to have the whole package. They want to take a look at what the sequence of the virus that is infecting people who've been vaccinated in the breakthrough infections. That's exactly what they're trying to find out. You know, getting to sequencing, obviously, we as a nation need to, and we're already starting to do it, need to have a much more organized, comprehensive genomic surveillance sequencing capability. There's a lot of sequencing going on in this country, but it's done at different institutions, academic and otherwise. And the CDC is finally now has a unit called SPHERES, S-P-H-E-R-E-S, which is going to be coordinating and consolidating all of the efforts that are going on in different parts of the country. But we have been really in a difficult situation that we, in some respects, created for ourselves, where, you know, a year into the outbreak, and we only have a relatively small percentage of the isol isolate sequenced, or at least sequenced in a way where we have a database where everyone knows what it is. Now, somebody may have sequenced it, but it isn't connected. And it's going to get connected very soon. Yeah. And I'd add a lot of these are convenient sampling, which is not necessarily going to tell us what's really out there. There's not a systematic look. To change the streams a little bit, some of the vaccines that have been tested in other countries have come in with efficacy results that are in the 80% range instead of the incredibly good 90 to 95% range for the mRNA vaccines we have right now. What do we do with vaccines that are good but not great? How do you use those? Well, first of all, we want to make sure that if you don't hit the 94 to 95 and you're in the 80-ish, as you mentioned, Eric, we want to look at what it does against serious disease, because the primary endpoints of the Moderna and the Pfizer were clinically recognizable disease, not necessarily infection. We're going to get some data on that a little bit later. But they were even better against serious disease. So I think there's going to be a utility purely on the basis of we've got to have enough vaccine for the world, for the, you know, seven or eight billion people in the world. But it's going to be a messaging difficulty. And I'm going to tell you, likely as someone who is there out in the public trying to explain things, it's going to be a headache where people are going to say, ah, so 80 percent effective. So you're going to give it to the developing world and you're not going to give the one that's 90 something. I mean, you know, that's coming. You could see that 10 miles away, but there likely would really be a utility for a vaccine that is really good against serious disease, may not be in the 90s for clinically relevant disease, but it's inexpensive, doesn't have a cold chain requirement, and is capable of making billions of doses. And that's exactly what some of those companies are able to do. So I think there really will be a utility to it, provided we can get by what would easily be sort of a sand trap when it comes to a messaging. I mean, the other side of that equation is transmissibility. And how much do we know the impact of these emerging vaccines on transmissibility? And how would that fit into potential deployment strategies? Well, it's a great question. Yes, we don't know enough about it. What we do know, and we'll be finding this out, you could do it by serial quantitation of viral load in nasopharynx in those who get infected asymptomatic being vaccinated and those who get infected asymptomatic not vaccinated. So we can get that answer. But the idea of what the impact is on infectivity is really going to be critical. Yes, theoretically, and we've seen it already, that someone can be vaccinated, can be protected against clinical apparent disease, but has virus in their nasopharynx. The thing that we don't know, which is really important, is does that not make any difference? Because the immune response in the person keeps the viral load so low in the nasopharynx that even though they're infected, so you haven't protected in the sense of sterilizing immunity, you really have protected against transmission. And that is the absolute critical thing. Because if you have a vaccine, one of the ones that are coming up that may not be as effective as it were in preventing clinically apparent disease, but are really good in preventing the spread of infection, you can have a major impact on the dynamics of an outbreak in a country by a vaccine that on paper does not necessarily look as good as the 95% effective vaccine. So that is something we need to really take a close look at because that could really have an important impact. So we're coming to you from Boston and we used to have a really good quarterback on our football team who was often referred to as the greatest of all time, the GOAT. And you've been in this odd situation where back in the days of HIV, where you really led the national response and really the international response as PEPFAR came around, you were in this funny position of being goat in both senses at the same time. Certainly among scientists and among much of the public, you were really thought of as the person who really helped guide us to finally a therapy that really worked. But among activists, you were being burned in effigy for a time.
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And at least in the last several months, there's this very negative reaction. Were there any lessons you took from your time during the HIV outbreak, not that it's gone, but during the early days of the HIV outbreak that you've been able to apply this time around? Yeah. I mean, it's complicated, Eric, to make a direct, precise comparison because there are so many other extenuating circumstances and aspects of it. But there is one thing that does stand out in my own mind, and that really is that when you're dealing with a public health problem of the extraordinary impact of HIV, as well as COVID-19, that there are a lot of other things that are out there that can be distracting. And the one thing you really got to focus on, and that's the lesson I learned, is to focus on the enormity of the task and what you can do to make a positive impact on it. And whether there are good things or bad things that are peripheral, you've got to remember that they're peripheral. And I get asked that question a lot right now. You know, this adulation that I get, and it's mostly not me, Tony Fauci, that you guys know because we're in the same field together, but it is, you know, being a symbol for what the country craved, which was clarity, honesty, integrity, and science. And I became the symbol of that. So I think that's a good thing. The one thing you don't want is to let it go to your head and think that there's something special about you. It's something that the country needs. On the other hand, when you have people who are extremely hostile to you because you're trying to deliver a public health measure, in my mind, rather than getting distracted by that, I just say it's a reflection of the divisiveness in society. So the lesson that you're asking me about, Eric, is that focus on what your job is and what you need to do. And the other stuff, as interesting and extraordinary as it is, is really a distraction, one way or the other. Distraction in the positive sense and a distraction in the negative sense. So lesson learned, do your job, focus on what you need to do, and always let the science be what directs you. Always let the science be what directs you. That's the lesson. It was that way back in the days of HIV, and it's absolutely what's going on right now with COVID-19. So Dr. Fauci, there is something special about you. There's also something special about our many readers and listeners and our practitioners who we struggle to inform. What advice can you give to our listeners as to what they can do to help with this response, given where we are today? Well, the one thing that I, I mean, it's a complicated issue, but I was so impressed by our community, Lindsay, the people who read the journal, the people who are there either directly taking care of patients or are in a situation related to what's going on with patients, is how this extraordinary challenge that we're facing has brought out, in my mind, the best of the biomedical community, the best of the healthcare providers. So when people talk about who are the heroes and the heroines in all of this, you know, a lot of them reading the New England Journal of Medicine, that's for damn sure. And they're out there in the trenches and it's just extraordinary, you know, how brave they are out there. It's kind of what we went through, Lindsay, back in the early years of HIV in a relatively smaller population. It's now the entire biomedical community of healthcare providers are all involved in it. So there's a lot of analogies between the dedication that a small segment of us were doing in 1981, 2, 3, 4, 5, 6. Whereas now, I mean, there's not a hospital in the United States where health care providers are not impacted by this, and they've really, really risen to the occasion. So, I mean, to me, that's the thing that impresses me most about this. Thank you, Dr. Fauci, and thank you, Eric and Lindsay.
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This is Jan Engmeyer with the Archives of Surgery. I'm speaking with Dr. Edward Livingston from the University of Texas Southwestern Medical Center in Dallas. He's the lead author on a study about the effect of insurance status or socioeconomic condition on disparities in minority appendicitis perforation rates. Welcome, Dr. Livingston. Thank you. In this paper, you set out to estimate how much of the gap in appendicitis perforation rates between minority and white children is explained by differences in socioeconomic and insurance factors. Why were you interested in this question? We were interested in it for two reasons. One is that the conventional thinking is that people who develop appendicitis ultimately perforate if they're not treated quickly enough. And we've published a couple of studies and archives of surgery looking at the epidemiology of appendicitis, finding that that probably is not the case, that there doesn't seem to be a relationship, in time at least, between perforating and non-perforating appendicitis. That's important because some people believe that you can assess the adequacy of health care systems based on appendicitis perforation rates because that assumption is out there that if you don't treat the disease quickly enough, it'll perforate, and therefore if you don't have good access to health care, it'll be manifested by a high perforation rate. The second thing that came up that led us to this work was stumbling across my co-author, Dr. Fairley, who's an economist. And the economists have an interesting set of statistical tools for looking at data in ways that we in medicine typically don't. And he had a very interesting technique that's called gap analysis that would enable one to look at how much an individual variable contributes to some outcome in a way very differently than most of the statistical techniques that are used commonly in medical research. So what were your findings in this particular study? So what we found is that if we looked at the data relating appendicitis perforation rates to various socioeconomic factors like insurance status, you know, Medicaid status, or poverty levels, that we were able to duplicate the results that other authors had found in their studies if we use the same kinds of statistical techniques that they did. But when we added the gap analysis, we found that the socioeconomic variables, specifically insurance status and poverty levels, really, although statistically significant, contributed very little to the overall outcome. So that there is an effect of poverty and effect of Medicaid insurance, but it's really small and probably not clinically important. Were you surprised by those findings? I wasn't because my belief that the perforating and non-perforating appendicitis are two really distinct diseases and that my working hypothesis was that we would not find an important relationship between the rate of perforating appendicitis and some insurance status. How does this information help clinicians and would it even help healthcare policymakers? Both. I think it adds to the body of literature that my group has been putting together showing that appendicitis does not behave the way we think it does. And so that if you believe what I believe, which is that people who perforate are going to perforate no matter what we do in the healthcare system, then when people come in with appendicitis, for one thing, it doesn't have to become an emergency in the middle of the night, which is always not a good thing to have to do, and being a surgeon who doesn't like to get up at night. And the other is that there are now four randomized controlled trials that show that quite a few people with appendicitis can probably be treated without surgery and just with antibiotics. So the whole scene for appendicitis could potentially change if these hypotheses are true. From a policy perspective, I think this paper is very important because it shows that you cannot use appendicitis perforation rate as a marker of healthcare system adequacy. And there are a number of papers that claim that to be the case, and I think it's very important to recognize that you really can't do that. What kind of research do you think is needed next? Well, I think the next big step in this are large-scale, multi-center, randomized, controlled trials looking at antibiotic treatment for appendicitis. I think there's very compelling evidence that at least two-thirds of cases of acute appendicitis can be treated successfully with antibiotics. And that would be a huge change. That would be a big change. But as I mentioned, there are four randomized trials. None of them on their own are adequate to prove the case, but they're strongly suggestive that this could be the case. And coupled with our epidemiological work that suggests that there is not a relationship between perforating and non-perforating appendicitis, that we really need to look at this disease in a different way. Well, our thanks to Dr. Ed Livingston for talking with us about disparities in minority appendicitis perforation rates, which according to this study are not explained by insurance status or socioeconomic conditions. This is Jan Engmeyer with the Archives of Surgery.
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The following episode of Annals on Call is brought to you by Annals of Internal Medicine. For more episodes and links to CME and MOC, visit go.annals.org slash oncall. Participant statements on this podcast reflect the views of the participants and not Internal Medicine in which we discuss the implications of the article for you, the listener. This is Dr. Bob Centaur. I'm Professor Emeritus at the University of Alabama at Birmingham and former chair of the Board of Regents for the American College of Physicians. This episode of Annals on Call features two articles from the August 31st, 2021 issue of the Annals of Internal Medicine. The first is Acute Consumption of Alcohol and Discrete Atrial Fibrillation Events, and the second is an editorial titled Holiday Heart Confirmed Alcohol-Associated Atrial Fibrillation. Joining us is the author of this paper, Dr. Gregory Marcus. He is Associate Chief of Cardiology for Research at the University of California at San Francisco Health. His particular research interests include cardiovascular effects of alcohol and caffeine and other common modifiable lifestyle factors. We hope you enjoy this podcast. Greg, thank you so much for joining us on the podcast. I was really fascinated by this. I'm going to start out with an anecdote. A number of years ago, we had a resident who told me that he was from Louisiana and he had gone to Mardi Gras and had to be admitted to the hospital for atrial fibrillation. And you can imagine why he had that. And I'd always heard about Holiday Heart. I thought it was just didn't need to be proven. And so why did you even do this study? And was there a controversy you're addressing or an unknown you were addressing? We were seeking to prove in an objective fashion this relationship between alcohol consumption and a discrete acute episode of AFib for several reasons. One is that alcohol consumption is so ubiquitous. And so we didn't know for sure whether there could be a sort of availability bias or immediacy heuristic meaning people get AFib, you know, at apparently random times. And clearly it can occur in the absence of alcohol. But we know that alcohol is so commonly consumed and it's quite natural when one suffers a concerning, uncomfortable, especially scary event without any explanation to look back and kind of grab on to, well, what did I just do that was unusual that could have triggered this? So there was always that possibility, again, because alcohol consumption is so common that there was a spurious correlation made. And it was only, you know, I agree with you that there's this conventional wisdom that the holiday heart exists, but it was really always based on fairly anecdotal case series. And then that was then extrapolated in large epidemiologic studies where investigators sought to test this hypothesis. But really the only way to feasibly do that was to look at baseline reports of how much alcohol one tended to consume, which was pretty much invariably just their chronic pattern of alcohol use, and then look at them over time to see if indeed they were at a higher risk of developing incident atrial fibrillation. And that's just a property of the nature of existing data sets that you don't generally have the specific timing of discrete AFib episodes, much less the exact timing of when one tends to drink. And so this relationship that has been reproducibly demonstrated, and we've published on this using this sort of study design as well, didn't really address that more acute question. It just demonstrated that those who tend to drink more over years and years and years are at higher risk of eventually developing a diagnosis of AFib. And so we really wanted to demonstrate or at least seek to understand whether there was this nearly immediate time-sensitive relationship. And then in the process, sort of test the more broad hypothesis that atrial fibrillation events themselves, when they occur or the reason they occur, it's not purely due to random chance alone, but maybe there is some modifiable exposure that influences the risk of a discrete event. And in the process, hope to understand the timing of that relationship to see if there were any thresholds of alcohol needed and maybe have some clues to underlying mechanisms. I love the methods of this study. You went to so many interesting details to make sure that you weren't just dealing with recall bias. It was like you collected data and you confirmed the data in two or three different ways. So if you could explain the methods, because I think that understanding the methods, everything else follows beautifully. Yes. Thank you for the kind words. We did try to put quite a bit of effort into making this as rigorous as we could. So we ascertained alcohol consumption in really four different ways, three of them being this more time-sensitive assessment. So first, like all studies, we asked people about their normal drinking patterns. I think that's the least interesting, certainly the least novel contribution of this paper. Two, we asked our participants to press the button on their ECG monitor whenever they had a drink of alcohol. So this is the same button that patients use clinically to identify when they have symptoms so that we can line up the timing of their symptoms with whatever their heart rhythm is. We made sure they understood not to use it for that purpose, but just for each drink of alcohol per the kind of standard glass of wine, 12 ounce can or bottle of beer or shot of hard liquor. One advantage of that approach is because it was ascertained in real time, that should mitigate against recall bias to some extent because it's occurring as they drink. Clearly, people could have forgotten to do it. We did also check in with them at two weeks and then at four weeks to make sure they didn't inadvertently hit the button. And thankfully, they never reported that. They also really had no incentive to be dishonest. Unlike in, for example, if this was a study of alcohol use disorders, where maybe there was this sense or concern of stigma, here, these patients are highly motivated to understand why they're getting AFib. They were highly motivated to contribute. And in fact, one incentive for them was when they were done, we provided them with their data. And we showed them with a little Excel kind of figure, the exact timing of when they said they drank versus the timing of their AFib. So that was the second way we ascertained it. Third, we fit everyone with continuously recording alcohol sensors in the form of an ankle device that essentially infers blood alcohol concentration from sweat. It's the same device that's used in law enforcement called the SCRAM device. We recognized very quickly that there was concern about, you know, participants being embarrassed or, you know, what others may think of them walking around with these ankle monitors. So we think we successfully mitigated that by slapping a big UCSF cardiology sticker on there so they could say, yeah, I'm working with cardiology or I'm doing this study. So that was the second way or third way, sorry. And then the fourth way we obtained blood at two and four weeks that we tested for a compound called phosphatidyl ethanol, also known by investigators that frequently use it as PETH, P-E-T as in Tom H. And this is kind of like a hemoglobin A1C for alcohol consumption. It's not super sensitive, but is very specific. There's really nothing other than the metabolism of consumed ethanol that will produce this. And then if once one reaches a threshold, it is quantifiable. And we use that primarily to validate the button presses and demonstrated, in fact, that the presence of phosphatidyl ethanol and the amount of it correlated very well with the button presses. We did the same between the alcohol sensor and the button presses and the alcohol sensor and the PATH. In our analyses, we did really two completely independent sorts of assessments when it comes to the predictor. So we analyzed the button presses as a predictor and then separately we analyzed data from the alcohol sensors as the predictor. So to make this even more useful, the study population, how many people did you study and what was the criteria from a cardiology standpoint for getting into the study? So we studied a hundred people. The inclusion was essentially paroxysmal atrial fibrillation patients. The reason, you know, there isn't any reason to believe that these findings shouldn't be relevant to persistent atrial fibrillations. After all, those with persistent AFib had to have an initiation of their AFib at some point. But of course, then you don't have the benefit of multiple episodes per individual. And so that we couldn't employ the case crossover design where each person served as their own control over this relatively limited period of time of one month. People had to report drinking at least once a month. We certainly didn't want to take people who had some sort of allergy or hypersensitivity to alcohol. And we generally didn't want to encourage more drinking. What we instructed them to do was just drink as they normally would. Similarly, we excluded individuals with known alcohol use disorders.
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Again, just ethically didn't want to include those folks in the study. And they couldn't have any major changes in their management planned for the month of the study. So if they're going to get ablated, you know, 10 days in, that wasn't going to be helpful. They could be on antiarrhythmic drugs, but that antiarrhythmic drug needed to be consistently prescribed and they needed to have evidence of recurrent atrial fibrillation despite that drug prior. So after going through this really beautiful way of assessing whether there's a timed relationship between drinking and having an episode of atrial fibrillation in someone who's prone to have episodes of atrial fibrillation, what'd you find? Yes, so we found, oh, and importantly, you know, a big question was, well, what is the timing? What time period do we look at? And so we asked everyone ahead of time, first we asked them, does alcohol trigger your AFib? And about half said they thought yes. And then we asked them when it triggers your AFib, how long does it take after you start to drink that an AFib you attribute to alcohol occurs, an AFib episode occurs? The median answer was four hours. So that was kind of our initial a priori target. And indeed, we found that one drink was associated with an approximately twofold higher risk of an AFib event happening within four hours. We did look at various time points, and it looked like that effect peaked right around four to six hours, and then gradually diminished, and then was lost after about 12 hours. And then there was an apparent dose-response relationship. So if someone hit that button twice, for example, their risk of an AFib event happening in the next four hours was threefold higher, suggesting the more they drank, the higher the risk they would experience of a discrete AFib episode. And then, as I mentioned, we separately looked at the alcohol sensor and found that the higher the alcohol concentration, the higher the risk an AFib event would occur. As I read the article, which I really like, I like this article a lot, I want to figure out how to use it. So I did primary care earlier in my career. I'm mostly a teaching academic hospitalist now. I get people admitted to my service periodically who just went into AFib. And the most recent one that we had, it was definitely related to alcohol. What should primary care physicians take from this? And what should hospitals take from this? And when should cardiologists be called about this? How much patient education should we be doing as opposed to cardiologists? I would like to emphasize to the hospitalists that may be listening that, you know, it's really a special opportunity that you have, especially if it's a first episode of AFib that's landed them in the hospital to help them kind of, or to emphasize lifestyle changes that may affect their overall health. And our study, as well as others, including a randomized trial that didn't look at necessarily acute effects, but more chronic effects, comparing abstinence to ongoing drinking, that one being in fairly heavy drinkers, and other studies, all provide quite compelling and very consistent evidence that alcohol consumption is indeed a risk factor. And I think that these data, by demonstrating this immediate effect, perhaps may be more compelling to atrial fibrillation patients. We know in behavioral kind of modification research that people tend to be more motivated by concern about something that might happen immediately, as opposed to some long-term effects, such as smoking and the risk of lung cancer seems kind of theoretical. It's like climate change has had been for a very long time. So perhaps this is a good motivator, especially for those who drink heavily. For our atrial fibrillation patients, I think it's safe to tell them that minimizing alcohol and likely avoiding alcohol will reduce their risk of recurrent episode. And especially for atrial fibrillation patients that want to know, and they often ask this question, you know, what can I do to reduce my risk? Telling them there is evidence that alcohol acutely increases the risk for an event. And so avoiding alcohol is likely to be helpful in avoiding atrial fibrillation. I think that that's a reasonable message to share. Now, the common question is, well, what about the general population? Can we extrapolate these findings to the general population? And so it is important to acknowledge that this study was indeed only among those already with a diagnosis of atrial fibrillation. Clearly, the effects of alcohol are multifactorial. There's the remaining open question as to whether light regular drinking may have health benefits. We don't know. We need a big randomized trial, and we're working on trying to get funding actually to do exactly that. But in the interim, the way that I've thought about this and how to counsel folks who don't have AFib is to point to this apparent dose-response relationship. So if we think of these individuals in our study as especially prone to atrial fibrillation, because they've already demonstrated they have AFib, and we think of people in the general population without the diagnosis as therefore less prone to AFib, and yet we found this sort of dose-response relationship. So the more you drink, the higher the risk, at least in atrial fibrillation patients. My take on this for the general population is to use it as further evidence of the harms of excessive alcohol consumption and really to caution against drinking more than, certainly more than two drinks in 24 hours. And my read of the literature is to avoid more than one drink in 24 hours among the general population. To address your question about when to refer to a cardiologist, and this obviously gets into broader topics related to kind of modern day therapies for atrial fibrillation, including catheter ablation, antiarrhythmic drugs, new evidence that perhaps suppressing atrial fibrillation may really have benefits in terms of long-term outcomes, which is contrary to what Affirm had taught us a while ago. I would favor a low threshold for referral to a cardiologist. I think there are a lot of beneficial things, including lifestyle management, but many things we can now offer our atrial fibrillation patients that we weren't able to provide even a few years ago. We did a podcast on the benefits, at least in heart failure, of pulmonary vein ablation for atrial fibrillation. And since then, I've been much more quick to call cardiology when I have such a patient. Let's finish up. After you've analyzed these data, do you have any good anecdotes of seeing patients and being able to use this information to talk to patients or make decisions with patients? Yes, I mean, absolutely. I think, you know, our atrial fibrillation patients seem extraordinarily motivated to identify triggers. In fact, we had a summit that was funded by PCORI, the Patient-Centered Outcomes Research Institute, that brought together patients and investigators. The theme was really cardiovascular very broadly, and we formed interest groups organically. I, not surprisingly, ended up in an atrial fibrillation interest group along with multiple atrial fibrillation patients. And part of our charge in this meeting was to identify areas of interest to patients that they felt like we as investigators had failed to fully address. And when we asked our AFib patients about that, they said, triggers, we want to know about triggers. We want you to study what the acute triggers of AFib are. And in my experience, seeing as a cardiac electrophysiologist and having a very busy practice of arrhythmia patients, the great majority of whom have atrial fibrillation, I will tell you that sharing this evidence with them is extremely powerful, and they're very appreciative. They will, and again, prior to publication, they ask me very frequently, what can I do to prevent AFib? They also ask very frequently, why did I get AFib Monday? I didn't have it on Sunday. I had it on Monday at 1.30, 1.35 PM. They know exactly when to quit in and they really want to know what happened. Why did that happen at that time? And so to be able to give them some evidence that there is an exposure that is under their control that can influence their disease, they find to be very helpful. And that's, you know, extremely gratifying for all of us. Well, thank you so much for doing the study and for joining us on the podcast. I love the study and I love the message that you've brought to it. So thanks once again. Thank you so much, Bob. Appreciate the kind words and opportunity to talk about it with you. Now it's time for Bob's Pearls. This fascinating article teaches us a lot about paroxysmal atrial fibrillation and likely much about atrial fibrillation and alcohol. We've all known for years about the concept of holiday heart.
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One drink increases the risk of paroxysmal atrial fibrillation by as much as two times, and two or more drinks have even a greater propensity towards causing atrial fibrillation. Patients are interested in the immediate effects of any triggers of atrial fibrillation, and this can be used in order to give patients with paroxysmal atrial fibrillation a better idea. There are already data that long-term alcohol use is a risk factor for atrial fibrillation, and this will be important as we talk to our patients who either present with paroxysmal atrial fibrillation or with a new atrial fibrillation that is not paroxysmal. We hope that listening to this podcast has MOC, visit go.annals.org slash on call. Participant statements on this podcast reflect the views of the participants and not necessarily those of the Journal or the American College of Physicians, unless so identified. The information contained in the podcast should never be used as a substitute for clinical judgment.
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Hello, and welcome to JAMA Evidence, our monthly podcast focused on core issues in evidence-based medicine. I'm David Simel, the editor of the Rational Clinical Examination Series and professor of medicine at the Durham Veterans Affairs Medical Center and Duke University. Today, we're discussing the clinical evaluation for childhood pneumonia. Joining me to talk about this topic is Dr. Sanal Shah, assistant professor of pediatrics and emergency medicine at Harvard Medical School. Dr. Shah, a discussion about childhood pneumonia has to start with an agreement on the ages of children that fall into this category and consensus on what we consider the pragmatic reference standard test and usual clinical practice. Can you define those two things for us? With regards to the reference standard, the true reference standard for diagnosis of pneumonia is an aspirate from bronchoalveolar lavage. But such invasive measures are reserved for children with life-threatening conditions. A more pragmatic reference standard is a chest radiograph. And although it's true that the chest radiographs don't distinguish bacterial from viral disease, it's widely accepted that alveolar pneumonia represents the radiographic pattern of pneumonia most frequently associated with bacterial infections. So radiograph findings are used to guide therapy for pneumonia. As an adult physician, I know that we often get sputum cultures in our patients where we suspect pneumonia. Does that have a role in pediatric pneumonia? In pediatrics, we do not use sputum cultures. Kids' coughs are often not productive. They don't have the ability to produce a sample for us. So we do not use sputum cultures in the pediatric population. So as you know, I work at the Veterans Administration Medical Center here in Durham, where I don't see too many children other than as visitors. But I do know that most pediatricians and emergency physicians who evaluate children brought in for a cough or a fever evaluation are at least going to have a suspicion of pneumonia. So what is the pneumonia prevalence among these children? The prevalence of pneumonia varies depending on what region of the world we're discussing. So among kids in Canada and the United States, the prevalence of pneumonia is about 19%. But outside of North America, that prevalence can go up to 37%. Dr. Shah, a lot of our advice to patients is given in the absence of patients, like during a phone call. So let's say the mother of a 12- or 14-month-old child calls you up, and she's concerned because her child has developed a fever, the overall symptoms seem to be getting worse, and the baby has become a little irritable. What factors would make you think about pneumonia and ask her to bring the child in for an evaluation? I think the main things that I would focus on in a conversation over the phone with a parent is the general appearance of the child, if she was concerned about how the child appeared, or more specifically, if she was concerned that the child's breathing pattern looked different to her. If any of those two things existed, I would certainly refer her in to be seen. In the emergency room, our patients are going to typically be triaged by a nurse. And when they have, the patient has a cough and fever, we are typically going to look at the vital signs even before we see the patient. The ones that catch our eye are going to be the degree of the fever itself and the respiratory rate and whether there is hypoxemia if the pulse ox was measured. So let's talk about each of these and their diagnostic accuracy for identifying pneumonia among children with cough and or fever. That's absolutely right. We always look at the vital signs right before examining the patient in the emergency room. Interestingly, fever is not strongly associated with pneumonia diagnosis, and that's true for any temperature threshold. With regards to respiratory rate, in contrast to the WHO guidelines, we did not find that tachypnea was associated with an increased likelihood of pneumonia. What is true, however, is that in children less than five years of age, the absence of tachypnea makes pneumonia less likely. Oxygen saturation is the most useful vital sign in identifying children with pneumonia. Children with normal oxygen saturations are less likely to have pneumonia compared with hypoxemic children. And by normal, we mean greater than 96%. However, the strength of that association is not consistent among those children with hypoxemia. Children with severe hypoxemia, that's less than 90%, have a statistically lower likelihood of pneumonia. So in the most hypoxic children, other causes should be considered. Well, it's counterintuitive that a lower oxygen saturation makes childhood pneumonia less likely. Can you tell us about some of the diagnoses we ought to be considering for the child with very low oxygen saturation? So in children with more severe hypoxia, the differential can be more complicated pneumonia, bacterial sepsis. The hypoxia could result from a cardiac etiology or even a pulmonary embolus. Well, on meeting the child, we tend to focus on how they are breathing and we then auscultate the lungs. Does the observation, the general observation of watching the child breathing and or lung auscultation add to the information provided by the vital signs themselves? That's a great question. Among physical exam findings, worker breathing is the most useful for diagnosing pneumonia in pediatric patients. And although often thought of as a hallmark of pneumonia, osculatory findings were not correlated with the diagnosis of pneumonia. And that's true of any type of osculatory findings, such as crackles, rails, wheeze, or ronchi. Well, that's a little disappointing, but I can live with the data. The range of ages for childhood pneumonia include both verbal and pre-verbal children. Do symptoms obtained from an older verbal child help us to identify those with pneumonia? Yes, there is some hope there. Among adolescents, chest discomfort is associated with an increased likelihood of pneumonia. What do you mean by chest discomfort? Patients' report of chest pain has been associated with an increased likelihood of pneumonia with a positive likelihood ratio of anywhere from 1.5 to 5.5. So don't get a cardiac cath, think about pneumonia. That sounds good for an adult physician to think about. It sounds like the general appearance of the child and the presence of hypoxemia are more important than the respiratory rate and or auscultation. What do the guidelines say about the role of radiographs after considering these clinical findings? Well, you're absolutely right about hypoxia and the appearance of the child. Among children with cough and fever, a child's general appearance and oxygen saturation are key determinants in evaluating for pneumonia. Hypoxemia and increased work of breathing outweigh tachypnea and auscultatory findings in identifying children with pneumonia. With respect to the guidelines, the guidelines published in 2011 by the Infectious Disease Society of America and the Pediatric Infectious Disease Society discourage routine chest radiograph use for children not requiring hospitalization. The guidelines recommend relying upon symptoms and exam findings to diagnose pneumonia. Well, thanks, Dr. Shah, for this interesting discussion. Is there anything else you would like our listeners to know when evaluating the child with cough and or fever or pneumonia? Just remember, there's no single finding that reliably differentiates pneumonia from other causes of childhood respiratory illness. But hypoxia and increased worker breathing are more important than tachypnea and auscultatory findings in attempting to identify patients with NEMOTE. Well, I'm not going to put my stethoscope away yet, but I believe the data. More information about this topic is available in the Rational Clinical Examination and on our website, jamaevidence.com, where you can listen to our entire roster of podcasts. I'm David Simel, and I'll be back with you soon for another edition of JAMA Evidence.
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This audio summary is sponsored by Ortho McNeil-Janssen Pharmaceutical, Inc. Visit topamax360.com for practice management podcasts, sample and patient education resources, and much more. Welcome to the New England Journal of Medicine audio summary for the week of March 6, 2008. I'm Dr. Lisa Johnson. a major parathyroid autoantigen in autoimmune polyendocrine syndrome type 1, and on coordinating care, a perilous journey through the health care system. Review articles on urinary stress incontinence in women and on acute pulmonary embolism, a clinical problem-solving article describing a key miscommunication, and perspective articles on consumer protection for patients with implanted medical devices Thank you. by Gustavo Palacios from Columbia University, New York. was the cause, the investigators turned to unbiased high-throughput gene sequencing. This sequencing yielded over 103,000 sequences, of which 14 represented an old-world arena virus. Additional sequence analysis showed that this new arena virus was related to lymphocytic choriomeningitis viruses. Thereafter, the infection was confirmed by means of culture, electron microscopy, and specific immunohistochemical and serologic tests. The presence of IgG and IgM antibodies confirmed recent infection. Unbiased high-throughput sequencing is a powerful tool for the discovery of pathogens. The use of this method during an outbreak of disease facilitated the identification of a new arena virus transmitted through solid organ transplantation. In a perspective article, Richard Whitley from the University of Alabama at Birmingham writes that in the short term, the findings of Palacios and colleagues clarify some aspects of the natural history of a renavirus infection in immunocompromised patients at high risk for infection. More significantly, this new application of metagenomic pyrosequencing may well aid in the identification of unknown microbial agents that cause human disease. Genetic Determinants of Response to Warfarin During Initial Anticoagulation by Uta Schwartz from Vanderbilt University School of Medicine, Nashville Oral anticoagulation with the vitamin K antagonist warfarin reduces the rate of thromboembolic events for patients in a variety of clinical settings. However, warfarin therapy is challenging because there's wide variation among patients in response and therefore in dose requirement. Variants of the genes CYP2C9 and VKORC1 contribute to differences in the anticoagulant effect of warfarin among patients. The relative roles of these variants were studied in a cohort of 297 patients starting warfarin therapy. The major finding was that genetic variation in VKORC1, but not in CYP2C9, modulates the early response to warfarin. Patients carrying VKORC1 haplotype A had significantly higher international normalized ratio, INR, values in the first week than did non-A homozygotes. These differences in response occurred despite empiric dose adjustment of warfarin. In contrast, the CYP2C9 genotype did not significantly affect INR responses during the first week. The VKORC1 haplotype predicted both the time to the first INR within the therapeutic range and the time to the first INR of more than four. Although both genes influenced the response to warfarin over time, only the VKORC1 haplotype had a significant effect on the initial response. In an editorial, Susan Shuren and Elizabeth Nabel from the National Institutes of Health in Bethesda, Maryland, write that these findings add important information to the body of knowledge about the pharmacogenetics of warfarin, but they also remind us that the warfarin story is far from complete. Fortunately, much basic research is underway to elucidate the pathways by which CYP2CP genotypes and VKORC1 haplotypes, acting alone, with other genes, or in combination with environmental factors, influence sensitivity to warfarin. A Parkinsonian Syndrome in Methcathinone Users and the Role of Manganese by Einar Steppens from Riga-Stradens University, Riga, Latvia. A distinctive extrapyramidal syndrome has been observed in intravenous methcathinone users in Eastern Europe and Russia. These investigators studied 23 adults in Latvia who had extrapyramidal symptoms and who had injected methcathinone for a mean of 6.7 years. The methcathinone was manufactured under home conditions by potassium permanganate oxidation of ephedrine or pseudoephedrine. The patients reported that the onset of their first neurologic symptoms occurred after a mean of 5.8 years of methcathinone use. At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward. 11 patients were falling daily, and one of these patients used a wheelchair. 21 patients had hypophonic speech in addition to gait disturbance, and one of these patients was mute. T1-weighted MRI showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and enomenata in all 10 active methcathinone users. Whole blood manganese levels, normal level less than 209 nanomoles per liter, averaged 831 nanomoles per liter in the active methcathinone users and 346 nanomoles per liter in former users. The neurologic deficits did not resolve after patients discontinued methcathinone use. These observations suggest that manganese in the methcathinone solution causes a persistent neurologic disorder. A Parathyroid Autoantigen by Mohamed Ali Mohamedy from the University Hospital in Uppsala, Sweden. Autoimmune polyendocrine syndrome type 1, APS1, is a multi-organ autoimmune disorder caused by mutations in air, the autoimmune regulator gene. Though recent studies concerning air deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS1, and its most common autoimmune endocrinopathy, has not yet been identified. These authors performed immunoscreening of a human parathyroid complementary DNA library using serum samples from patients with APS1 and hypoparathyroidism to identify patients with reactivity to the NACD leucine-rich repeat protein 5, NALP5. NALP5-specific autoantibodies were detected in 49% of the patients with APS1 and hypoparathyroidism, but were absent in all patients with APS1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells. NALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APPS-1. Urinary stress incontinence in women. A clinical practice article by Rebecca Rogers from the University of New Mexico Health Sciences Center, Albuquerque. Urinary incontinence is common and costly. Yet fewer than half of women who consider their incontinence a problem seek help, and many primary care providers feel unprepared to provide treatment. Stress incontinence, defined as involuntary urinary leakage on exertion, sneezing, or coughing, occurs when bladder pressure exceeds urethral resistance under conditions of increased abdominal pressure. The balance between urethral and bladder pressures is influenced both by intrinsic factors, such as urethral musculature, blood flow, and innervation, and extrinsic factors, such as degree of urethral support and the weight and physical activity of the patient. Evaluation for stress incontinence includes history taking and physical examination, completion of avoiding diary by the patient, urine testing for infection, and simple tests conducted in the physician's office, including assessment of the post-void residual urine volume and a cough stress test. A frank discussion regarding the degree to which the patient is bothered by her symptoms, as well as expectations and goals after surgery, can help guide treatment choices. The management of urinary stress incontinence may involve absorptive devices, pelvic floor exercises and various behavioral modifications, device therapies such as tampons and pessaries, and surgical procedures such as the Birch-Culpo incidentally discovered emboli to massive embolism causing immediate death. Acute pulmonary embolism may occur rapidly and unpredictably and may be difficult to diagnose. It usually originates from the deep veins of the legs, most commonly the calf veins. These venous thrombi originate predominantly in venous valve pockets and at other sites of presumed venous stasis. If a clot propagates to the knee vein or above, or if it originates above the knee, the risk of embolism increases. Thromboemboli travel through the right side of the heart to reach the lungs. Untreated pulmonary embolism is associated with high mortality. Suspected pulmonary embolism demands prompt diagnostic testing and assessment of risk factors and clinical probability, with empirical clinical assessment and a validated clinical prediction score when possible.
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Otherwise, there should be a low threshold for diagnostic imaging. Treatment of acute pulmonary embolism has been shown to reduce mortality, and appropriate primary prophylaxis is usually effective. Risk stratification of patients with this disease is necessary to optimize decision-making with regard to the use of thrombolytic therapy. This review focuses on the pathogenesis, diagnosis, and treatment of acute pulmonary embolism of thrombotic origin. A Key Miscommunication A clinical problem-solving article by Melissa Kong from Duke University Medical Center, Durham, North Carolina. An 81-year-old woman presented to the emergency department with increasing abdominal distension, nausea, and vomiting. She also reported increasing shortness of breath and fatigue. She had a history of congestive heart failure, mitral regurgitation, hypertension, atrial fibrillation, hypothyroidism, peptic ulcer disease, and depression. During the year before presentation, abdominal distension had developed. According to the medical records, ascites had been found. The patient had been treated for presumed congestive heart failure. On physical examination, the patient appeared to have a long-term illness, but she was in no acute distress. A prominent systolic CV wave was visible in the neck veins. A diastolic murmur was audible at the left upper sternal border. Abdominal paracentesis yielded 2 liters of red, hazy serous fluid. In this unusual case, the patient's slowly progressive symptoms were attributed to her known chronic coexisting conditions, and thus the diagnostic evaluation was delayed. This case underscores the need to pursue further evaluation when a salient finding, in this case the diastolic murmur, appears incongruous with the presumed diagnosis. Coordinating Care, A Perilous Journey Through the Healthcare System A health policy report by Thomas Bodenheimer from the San Francisco General Hospital, California. In the United States, 125 million people are living with chronic illness, disability, or functional limitation. The nature of modern medicine requires that these patients receive assistance from a number of different care providers. Patients with several chronic conditions may visit up to 16 physicians in a year. Care among multiple providers must be coordinated to avoid wasteful duplication of diagnostic testing, perilous polypharmacy, and confusion about conflicting care plans. Given this level of complexity, the coordination of care among multiple independent providers becomes an enormous challenge. Care coordination has been defined as the deliberate integration of patient care activities between two or more participants involved in a patient's care to facilitate the appropriate delivery of health care services. Care coordination is required when traditional continuity of care, the relationship between a single practitioner and a patient that extends beyond specific episodes of illness or disease is lacking. Recent research strongly suggests that failures in the coordination of care are common and can create serious quality concerns. This report assesses the quality of care coordination, lists barriers to coordinated care, and discusses some solutions to improve care coordination. Semper Fidelis Consumer Protection for Patients with Implanted Medical Devices A perspective article by William Maisel from the Beth Israel Deaconess Medical Center, Boston. When the Food and Drug Administration, FDA, approved the Medtronic Sprint Fidelis Implantable Cardioverter Defibrillator, ICD, lead in 2004 on the basis of bench testing but no human clinical data, there was no public outcry. Physicians rapidly incorporated the new electrode into their practice, welcoming its small diameter and ease of implantation. During the ensuing three years, 90% of Medtronic ICDs were implanted with this lead. After concerns arose about the performance of the Fidelis, Medtronic notified physicians by letter in March 2007 of a limited number of physicians who were seeing a higher-than-expected rate of lead fractures. But in October 2007, after 38 months on the U.S. market and 268,000 implantations worldwide, the Fidelis was voluntarily recalled by Medtronic because of its propensity to fracture. Medtronic had confirmed the occurrence of 665 fractures in returned leads, 5 patient deaths to which a Fidelis lead fracture may have contributed, and a 2.3% fracture rate within 30 months of implantation. The large number of affected patients, the billions of dollars at stake in the ICD market, and the controversy surrounding the timing of communication with physicians and patients about the lead's performance highlight the shortcomings of the regulatory system for medical devices and underscore the urgent need for legislation that will ensure adequate protection for the patients receiving them. This week's Images in Clinical Medicine features a medical mystery. An 82-year-old woman presented with respiratory symptoms and a chest film was obtained. Six years later, she presented with epigastric pain, nausea, vomiting, and an unusual chest x-ray. What is the diagnosis? We invite our readers to submit their answers at NEJM.org slash mystery. We'll publish the diagnosis in the correspondence section of the May 1st issue and email it to everyone who submits an answer. All answers must be received by March 19th. This concludes the summary of the March 6th issue of the New England Journal of Medicine. We're interested in your feedback about our audio summaries. Any comments or suggestions may be sent to audio at NEJM.org. Thank you for listening.
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Hello and welcome to a special podcast brought to you by The Lancet and The Lancet Oncology. I'm Richard Lane. In this podcast we'll be discussing the use of radiotherapy in the treatment of early breast cancer. The current standard of practice is for a patient to undergo external beam radiotherapy after surgery, which improves survival but can be associated with side effects. Two studies look at the use of intraoperative radiotherapy, which is radiotherapy given during surgery. ELIOT is a randomized trial published in The Lancet Oncology, directly comparing the effect of intraoperative radiotherapy with external beam radiotherapy, whereas the TARGET trial published in The Lancet uses a risk stratified protocol to determine which form of radiotherapy patients receive. First, we're going to discuss the TARGET trial. Earlier, I spoke to the lead author of the study published in The Lancet, Professor Jayant Veja from University College London in the United Kingdom, and I began by asking him to describe the design of the target study. Now, every patient with breast cancer is different, so we designed our study in such a way that resulting treatment could be tailored to an individual woman in daily clinical practice. We recognized from the outset that while targeted intraoperative radiotherapy, or TARGET for short, may prove to be effective for the majority of patients, others might require additional whole breast radiotherapy. So a woman diagnosed with invasive ductal carcinoma of the breast was suitable for the TARGET-A non-inferiority trial if she was at least 45 years old and suitable for a lumpectomy. The cancer should be less than 3.5 cm in size and should be a single lesion on clinical examination and routine imaging. In the experimental group, the lumpectomy to remove the cancer was immediately followed by single-dose Target under the same anesthetic. With the Target technique, one dose of 20-gray radiation is delivered by carefully placing a spherical applicator accurately within the tumor bed. Target IORT given to the fresh tumor bed also changes the surgical wound fluid, which is the tumor microenvironment, making it less favorable for cancer growth and spread. Our risk-adapted design meant that on final histopathological examination, if high risk factors were found, then whole breast radiotherapy was added. This occurred in about one in five women. Therefore, each woman in the experimental arm got the optimum treatment tailored for her cancer, and 80% of them completed their full local treatment, that is surgery and radiotherapy, in a single sitting. Patients in the control group received the standard fractionated whole breast radiotherapy requiring 15 to 30 hospital visits over several weeks. Target A, therefore, was a pragmatic trial and compared two treatment policies rather than comparison between two treatments in isolation. This was our original protocol. When the Australian center joined the trial, they found it logistically difficult to give target at the same time as lumpectomy as per the original protocol. And they suggested that they would give target as a second procedure by reopening the wound after a few weeks. Although this needed a second operation, theoretically, the case selection could be more stringent. And their patient would rather have this single extra procedure than remain far away from their homes for several weeks of conventional radiotherapy. So being a pragmatic trial of localized radiation, this method of delivery was thought acceptable. It was added to the trial as a separate stratum with its own randomization table. It was called a post-pathology stratum, which ultimately contributed to about a third of patients in the trial. Very, very interesting. So in terms of giving us top-line findings, you've got results for the pre-pathology, the target given at the time of lumpectomy, compared with patients in a control group given conventional external beam radiotherapy. You've also got post-lumpectomy target compared with that as well, and a difference in between the two. So can you give us the top line findings? and with longer follow-up, we found that the results have remained stable. Secondly, when target was given at the time of lumpectomy as per the original protocol, the five-year local control of breast cancer was similar to the several weeks of conventional whole breast radiotherapy. But this was not the case if target was given as a delayed second operation by reopening the wound, as in the post-pathology stratum. So the immediacy and accuracy of delivery of target to the fresh tumor bed appears vitally important and achieves excellent results. Finally, we found that with Target, there were significantly fewer deaths from causes other than breast cancer, mainly because there were fewer deaths from cardiovascular causes and other cancers. This reduced mortality statistic has a p-value of 0.0086, which means it is unlikely to be purely a chance finding. Our results, in fact, are in line with other studies which have recently been published which have demonstrated cardiotoxic side effects of standard radiotherapy which are avoided when you give target IORT. So the main message from these updated results is that when patients with breast cancer, carefully selected as per the target A trial protocol, are treated with a single dose target during lumpectomy, the five-year breast cancer outcomes are similar to whole breast radiotherapy. The local toxicity is lower, and deaths from other causes are reduced from 4.4% to 1.3%, a significant reduction by 3.1% in absolute terms. And all these benefits with a treatment that is so much more convenient for the patient, as they don't have to travel to the hospital every day for six weeks. And thousands of patients of breast cancer around the world are still obliged to choose a mastectomy just because they cannot go through the prolonged and expensive course of radiation therapy. Now they could have the choice of having Target during lumpectomy, an effective and safer option. A final thought, take-home messages for clinicians but for patients as well. So do you see clinical practice being able to change straight away? I mean clearly guidelines are going to have to be rewritten, various cancer organizations around the world will want to discuss these findings. Yes, the ultimate decision about implementing treatments proven in large international randomized trials rests with the clinician and the patient. These updated results give confidence about using Target for patients who fulfill the eligibility criteria for the Target A trial. Clinicians should discuss these updated results with their patients when planning their surgery and radiation therapy for breast cancer. Now, such discussions should happen before their surgery so that women will have a chance to consider this option and make an informed choice about which treatment they should receive. We do recognize that this equipment is not yet widely available in all countries. It is a bonus that using Target would actually be less expensive than conventional treatment. The projected cost saving with Target annually is in the region of several million pounds in the UK and substantially more in the USA, even without including the savings of cost and time to the discussing, that's the paper in The Lancet, with the Elliot trial, that is, they both tested IORT for breast cancer, there were some differences, three main differences, really, in patient selection, in trial design, and in actual technique of IORT. And there appears to be a difference in results. Now, these different results could give us valuable insights into understanding of breast cancer and its treatment. That is the beauty of randomized trials. So, firstly, the Elliott trial had slightly more higher risk patients than target A trial, but not that much more. Secondly, the experimental arm in the target A trial was risk-adapted radiotherapy. So the protocol recommended that the addition of whole breast radiotherapy to target in higher risk patients so that each patient got the best treatment based on her risk. Such provision was not there in the Elliott trial protocol. Thirdly, the IORT technique itself was different. One should recognize that there is intraoperative radiotherapy, IORT, and there is targeted intraoperative radiotherapy, target. And results of different techniques of IORT may be different. With the target IORT, the fresh tumor bed after lumpectomy is left intact and undisturbed, and target is delivered over a course of half an hour, 20 minutes to half an hour, within the breast without jeopardizing the blood supply of the tissues, which is an important consideration for effectiveness of radiation. For the earlier technique, the breast gland needs to be dissected off the overlying skin as well as the chest wall. Then the edges of tumor bed eye pose to each other, and radiation is delivered from outside. So this dissection could, in theory, temporarily reduce the blood supply of the tissues receiving radiation. In terms of the results of the TARGET-A trial, we should recognize that these excellent results of TARGET during lumpectomy in patients who participated in the trial have been obtained without restricting the analysis to any selected subgroup of patients. Professor Vaidya, many thanks indeed for talking to The Lancet. Thank you. Now let's discuss the ELLIOT trial. This is published simultaneously in The Lancet Oncology. Earlier I spoke to lead author Professor Umberto Veronese from the European Institute of Oncology in Milan, Italy.
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The first important thing is that the survival is the same in the two groups. Therefore, the curability of the patients is without question. There are no difference. Distant metastases are identical, somewhat higher in the external radiotherapy group, surprisingly. On the contrary, the true local recurrences, I mean the recurrences which occur in the area where the tumor was located and removed are low at 2.4%, but in this trial, surprisingly, much higher than in the patient receiving external radiotherapy, who developed two local recurrences in an exceptional 0.5%, which is abnormal. So this is good for the institute because it means we have a good radiotherapy. But of course, in the trial, it showed this difference. How does your study, this is the Elliott trial, methodologically and the way that radiotherapy was given intraoperatively, how does your study differ from that of the target group that we've just heard from? Results are very similar. We don't have much difference. There's some difference in the sense that in the target trial, they gave intraoperative in a portion of patients, but also postoperative in another portion. In addition, 15% of their patients received, in addition, external radiotherapy on the whole breast, which we didn't know. The equipment of Target is much simpler and less expensive. But the type of treatment is longer. It's 30 minutes compared to about 3 minutes with the electrons. So the actual technique of administering the radiotherapy is quite distinct, very different between the Elliott trial and the Target trial. Exactly, exactly. What do you think clinicians should do now? Because my understanding is that results of these two trials do show overall that, I guess, the main message is that clinicians and patients have another option, a new option, when looking at radiotherapy for early breast cancer. So if that is correct, what should clinicians be doing from now? Well, the main problem is that not all hospitals have this equipment. Therefore, if an hospital, in my opinion, is treating more than three or four hundred patients with breast cancer every year, they should buy either a Target system or an Elliot system with electrons. It's a linear accelerator, which is mobile. However, this must be bought, otherwise the clinician cannot do nothing. And these are not common in the hospitals in Europe. But as this intraoperative radiotherapy will be the future, in my opinion, so I think that they should equip their radiotherapy with this new machine. The second problem is that not all patients will benefit from this radiotherapy. Perhaps 80% of the patients will benefit, but some 20% should not receive because they have a high risk of local recurrence. High risk means 5%, not very high, but more than the external. And therefore, we have already identified which patient with large tumors, more than 2 cm, with no positive estrogen receptors, and so on, which is in the paper on this selection. Then the problem is the priority of which patient, because many patients live close to the radiotherapy centers. They can go up and down for two months without difficulty. But many patients, they live far away. In Italy, they live in the mountains, in small villages, and on the islands. And so I have no means to come. Only very rich women can afford to make such a long way every day, up and down. And so the tragedy is that many patients, they prefer to have a mastectomy instead of a conservative surgery because they cannot cope with the radiotherapy. Again, one of the main messages from both papers is that once adopted, and if this is giving clinicians and women another option, it's also giving them an easier, more practical way of getting radiotherapy. Yes, exactly. I think we should, of course, make the patient decide as usual, but we have to offer this alongside the Target trial published in the Lancet, published on Monday, November the 11th. But in the meantime, Professor Umberto Veronese on the line from Milan in Italy, many thanks indeed for talking to The Lancet Oncology and The Lancet. Thank you. Thanks to you. Well, many thanks to both our contributors to this combined podcast. And do look out for the comment published alongside these articles today on thelancet.com. Thanks for listening. See you next time.
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My name is Ben Bobrow and I'm a professor of emergency medicine at the University of Arizona College of Medicine and the medical director for the Bureau of Emergency Medical Services and Trauma System at the Arizona Department of Health Services. Cardiac arrest is one of the leading causes of death in the United States. And the real therapy we have, the best therapy for out-of-hospital cardiac arrest is CPR. And bystander CPR is a critical intervention that can improve survival. Unfortunately, most people don't get bystander CPR when they need it. We have seen from some other communities when they focused on the 911 dispatcher giving pre-arrival CPR instructions that those communities were able to significantly increase bystander CPR rates and survival. The objective of this study was to implement a telephone CPR bundle of care including a unique protocol, a special training, data collection, and quality improvement in two large regional 911 dispatch centers, and over time to measure the proportion of cardiac arrest victims who got telephone CPR instructions and the time that it took to get those telephone CPR instructions started as well as patient outcomes such as survival to hospital discharge and functional outcome. This was a prospective observational study where we studied adult cardiac arrests that happened outside the hospital over approximately a three year period of time in the Phoenix metropolitan area where there are approximately four million residents. We studied over 2,300 cardiac arrests where we were able to link telephone 911 calls with the EMS call and the hospital outcome. What we found was that in our post-intervention period, we had significantly more patients receive telephone CPR instructions, approximately 10% more patients receive telephone CPR instructions, and the time that it took to get those instructions started was decreased on average by 44 seconds for each case. As far as our outcomes, we found a 32% relative increase in survival to hospital discharge, and a 43% relative improvement in functional outcome. Implementing a bundled approach to telecommunicator CPR, we were able to improve the proportion of patients who received telecommunicator CPR instructions, the proportion of patients that received any bystander CPR, and get CPR started earlier for those patients. And most importantly, this was associated with a significant 32% improvement in survival to hospital discharge and improvement in functional outcome. What we're hoping is that this model of continuous data collection, quality improvement for the telephone CPR intervention will be adopted by many more 911 dispatch centers and will help improve bystander CPR rates and survival across the country.
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Okay, welcome. My name is Divine. This is episode 300 of the Divine Intervention podcast. And I'm going to be calling this the Coronavirus slash COVID-19 podcast for the USMLEs. This podcast, actually, I guess maybe I should first start off by saying, you know, I'm pretty grateful first to be seen the first day of April. I mean, with this coronavirus, COVID-19 pandemic, there's been, you know, millions of people that have lost their lives all over the world. So I guess one message I guess maybe I want to put out there today is just be grateful, just be thankful. I know many people about two weeks ago, they found out that they did not match or, you know, they had to go into the soul process or they did not match to their preferred program. But remember that when there is life, there is hope. And the fact that you're alive means that, you know, you still have something to do on this planet. So, you know, there are many people that there are definitely some people that probably plan to go through the soap process or go through the match process that because of COVID-19, their lives were taken away from them and they were not even able to see the match, the soap or whatever. Those people, I'm sure if they were given the opportunity to be alive now, even if they didn't match or even if they couldn't get through the soap or whatever those people i'm sure if they were given the opportunity to be alive now even if they didn't match or even if they couldn't get through the soap process they probably choose that so again you know bad circumstances happened to some people two weeks ago but let's remember to be grateful um i mean there's this part of the bible that says in all things give thanks because this is the will of god the father so So I'll encourage you to be thankful. I most certainly am thankful. I mean, I've just heard of so many things, many families. I mean, like I'm a big watcher of the NBA and just people who their family members have perished from COVID and stuff. You know, so it's pretty rough on a lot of people, right? So the fact that you are complete or you have a complete family right now is reason enough. Just the fact that you can take a breath is reason enough to be thankful. So I think I'll encourage you to be thankful. And I guess I'm also thankful that, you know, we've hit a big milestone on the website. This is episode 300. This is just, I don't think we've even started as a podcast website. At least that's my personal belief. I believe that, you know, God is taking us to bigger places, more and more podcasts, even better podcasts than currently exist. But I'm grateful to have episode 300, right? Because, yeah, you know, by the grace of God, we've come a long way. So, you know, 300 podcasting, I'm very happy with that. But again, it, I guess, almost reminds me that, Divine, you could do better. You could have more than 300. So, you know, just thankful for that. But, you know, also like a reminder to work harder and do better work out there. Okay, so we're going to be talking about coronavirus COVID-19. This podcast, I'm intentionally going to say that this is for all the USMLEs. The thing is, I will discuss many things that you would potentially see on the USMLEs. And I will try to discuss again a lot of pathophysiology because this is just one thing that many people still struggle with. The coronavirus is just understanding pathophysiology. There's a lot of misinformation out there. Understanding the mechanisms behind the vaccines, why the vaccines were made a certain way. So we'll talk about it from pretty much every angle. So if you're studying, if you're taking any of the USMLE exams, step one, step two, CK, step three, I'll encourage you to pay close attention. The thing is, God willing, I'm going to be making a lot of integrations today, like a lot of integrations today. So I will strongly encourage you, if you can, to just really try to get those integrations down. I'll make integrations with immunology, with pharmacology, with cardiology, with pulmonology. So even if this is, again, a coronavirus or a COVID-19 podcast, you'll learn a ton, right? And again, obviously, this podcast, I need to throw in the legal disclaimer that it's not meant for clinical care. But the thing is, you'll learn a lot from this podcast. Again, it may be on the lengthier side of things, but it's going to be a floridly high-yield podcast. And I think it's going to be very worth your while. And I've also designed this podcast to be very thorough, right? So you will have like an extremely solid basis in understanding pretty much everything about coronavirus, COVID-19 from this podcast. Or at least I'll say the high-yield bits of information, right? So, you know, for the folks that are taking step one, well, what do we know about coronavirus? Well, again, they could easily make this a question about a person that has some kind of travel history, right? Or a person that works in some kind of occupation where they interact with lots of people, right? And then they will tell you that, oh, you know, the person over the last like 24 hours the person has uh you know been crashing and burning they've been having profound shortness of breath they may have like a dry cough or they may have a productive cough they may be having high fevers right and you notice that you know their o2 sats are really low right if you see that you know again especially on the newer usmle exams you really want to think about a person having coronavirus right remember it's an enveloped uh linear single stranded rna virus right and it actually has a helical capsid right so you remember for people that are taking step one unfortunately your friends at the mb, they still love to test those identification things, right? So, you know, all these identification, identification. But the thing is for coronavirus, though, there's a lot of stuff they could potentially test, right? And the thing is, some of these questions that describe experiments, those are very easy fodder for COVID-19 because, and again, instead of saying coronavirus, I'll just say COVID-19, right? Because there's just lots of integrations with immunology that you can really throw in on a test. So again, if you pay attention, take good notes on this podcast, I think you'll find it to be extremely helpful, right? So the thing is, when a person gets the coronavirus, right, what's going to happen? Well, the thing is, you know, many times they'll be symptomatic a few days after exposure, right? They'll be symptomatic a few days after exposure. And, you know know many times you're still going to be infectious for about 14 or more days after you've been exposed right now one other thing your friends at the mbme care about right is knowing what are the risk factors again we live in this mbme era of risk factors right so what are some risk factors that put people at you know high risk for like really bad disease with covid 19 right remember if you're old being over the age of 60 like over the age of 60 for the most part Diabetes crushes a person's immune system. All those things can place a person, or if the person is immunocompromised, let's say they have HIV, or they have an immunodeficiency disease, or they are on immunosuppressive therapy because they are transplant recipients. All those people, again, these are all risk factors for a person having a really bad disease, right, with coronavirus. Now, how is this stuff transmitted? Well, for the most part, it's transmitted by the respiratory route, right? It's transmitted by the respiratory route, right? So many times people can get this through like aerosols, through respiratory droplets, right? You can even get it from contact, right? But again, for the most part, that's not the main route of transmission. The main route of transmission is the respiratory route, right? And the thing is, there are some risk factors that increase your risk of receiving the illness from someone that has it, right? The first one is if you interact with those people closer, right? That's why we advocate for the social distancing. The closer you interact with these people, the higher your risk, but also the longer you interact with these people, right?
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Now, one thing that's actually hard to understand is that people that work in health care, it's actually high to understand that these people, aerosol generating procedures can potentially be the thing that gives them COVID-19. In fact, many hospitals, they've implemented many algorithms or many initiatives to try to curb the use of aerosol generating procedures or maybe use alternative procedures that give you the same effect to an aerosol generating procedure so that you reduce the risk of these healthcare workers getting these problems, right? So, you know, things like, you know, the obvious ones like intubations, right? But other ones we don't really think about, like if you're getting like some kind of nebulized treatment, this is something that happens on many medicine floors the icus people getting like nebulized bronchodilators and stuff those things are aerosol generating procedures they are very high risk procedures for people contracting covid-19 right if you're a pulmonologist if you're performing a bronchoscopies right or you're doing like this non-invasive positive pressure ventilation right so like cpap bipap right those things can increase the risk of a person getting COVID-19, right? So those aerosol generating procedures, they are things you want to keep at the back of your mind as things that are very high-risk procedures in healthcare workers for potentially getting a coronavirus, right? So the thing is, how do we diagnose this stuff? Well, for the most part, you want to go ahead and pick performing some kind of nasopharyngeal swab, right? And remember, you know, in general, when you take these, although you can use sputum samples or whatever, but in general, most people, vast majority, again, the classic thing is to do a nasal pharyngeal swab, right? And then you'll send that swab for reverse transcription or PCR, right? Usually within a few hours, you can get those test results back, right? So you do RT-PCR, again, reverse transcription, because remember, it's an RNA virus, right? It's an RNA virus. So that RNA, it will make sense that reverse transcription PCR, right? Because again, you want to do reverse transcription to convert that RNA to DNA, right? I mean, it's kind of amazing how far along PCR has gone in this world. I remember when I just moved to the US, you know, I used to do, you know, some research with PCR and stuff. This was maybe like eight, nine years ago, something like that. And it's just amazing how quickly the technology has kind of advanced, right? Now, you know, they may try to trick you on an MBM exam into picking a chest CT. A chest CT is not recommended. Even if you have chest CT results that look like a person, looks like a person has coronavirus, you need to confirm, right, with reverse transcriptase or PCR. In fact, one very smart thing your friends at the MBM can do is they can make this a biostats question, right? So the thing is a chest CT is probably pretty sensitive. It's not probably probably it is pretty sensitive for identifying people that potentially have coronavirus but remember whenever you have a test that is very sensitive you're very likely going to pick up a lot of a lot of false positives right so a chest ct can almost be like a screening test you can employ in an ed right but the thing is if you want to confirm you need to do the rt pcr right you need to do the rt pcr right so again the need to do the RT-PCR, right? So again, the chest CT is very sensitive, but again, there are many things that have similar findings on chest CT as coronavirus that are not coronavirus, right? So chest CT, very sensitive, right? But it is not specific. So you absolutely, absolutely still need to confirm the diagnosis by using reverse transcriptase PCR, right? And what will you find on a chest CT, right? For the most part, again, because it's like a pulmonary interstitial disease, you're going to find bilateral ground glass opacities, right? And the thing is, usually it's typically asymmetric, right? So one side of the lung will not look like a carbon copy of the other side of the lung. And typically it's also peripheral, right? So it's going to be predominantly subplural. So just below the plural lining in predominance, right? So that's usually what you're going to find on a chest CT. And usually, these people, they actually don't have pleural effusions, right? They really don't have pleural effusions, right? And remember, when people have COVID-19, right, many of them that die of respiratory failure, ARDS is the thing that usually kills them, right? But again, we're going to talk more about treatment down the line, right? So let's talk about how do we prevent the spread of coronavirus. Again, the classic public health measures. Again, the friends at the NBME with the newer exams, they really, really love public health measures, right? So you want to keep things like physical and social distancing at the back of your mind, right? So remember, you want to keep at least six feet apart, right? So you want to practice, again, social distancing. That's really helpful. Quarantining, right? So if, for example, you've been exposed to a person that potentially has the virus, right? You want to at least self-quarantine for roughly around 14 days. You know, again, some of these things I'm seeing in this podcast are very fluid, right? This pandemic has been evolving. There's all these first wave, second wave, whatever wave, right? So, you know, but for the most part, the things I'm going to discuss today are pretty accurate, right? So in general, if you've been exposed to a person, if a person has been exposed to some individual that has been discovered to have the virus, right? You want to self-quarantine for about 14 days, right? And then remember, hand washing is also a very effective technique. I mean, basically like household soap for the most part explodes like the viral capsid, right? So it pretty much destroys the virus, right? And if you're using a hand sanitizer, you need to make sure that you're using a hand sanitizer that has at least 60% alcohol, right? Now, also using masks, right, is very helpful, right? Like homemade masks, surgical masks, these are all things that are helpful for preventing the spread and also preventing you from getting it. Right. But if you have it, it also prevents you from spreading it to other people. Right. And also the vaccine. Right. Getting the vaccine is also helpful. I mean, at least I believe like the Pfizer or Moderna vaccine or whatever has been shown to be greater than 90 percent effective. And I'll say some more things, because, again, for people that are taking step one, I can see the NBME going the immunology route with a lot of these COVID-19 questions. Right. You'll see why in a few minutes. Right. But again, you'll see why the stuff is pretty high to understand. Right. And, you know, also like increasing ventilation indoors. Right. So I know this is pretty common in certain populations of people where for some reason they don't turn on fans, they don't turn on air conditioning in their homes. If that's a crowded home, and that's why unfortunately, it's a problem in developing countries, right? Because I remember, you know, in Nigeria, at least back in the day, I remember that there'll be times for months, no electricity, right? So if there's no electricity, obviously your fans are not running, your air conditioning is not running, right? In a crowded environment, that significantly increases the risk of people contracting COVID-19, right? And again, other things that help is, again, don't touch, if you have an unwashed hand, right? If your hand is unwashed, don't touch your eyes, don't touch your nose, don't touch your mouth. That's a very effective means of preventing the spread of the virus, right? It always just kind of boggles my mind when I see people, they literally have just shake someone's hand or they've just touched the surface that many other people have touched. And then you see them cleaning out their eyes, putting their fingers in their nose, putting their hands in their mouth, right? Again, those people are just putting themselves at unnecessary risk, essentially, right?
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A mask with an exhalation valve. Because guess what? Those masks and many of these things that have these exhalation valves are like some of these N95 masks. Again, it's good. It's protecting you, the wearer, right? But the thing is, if you have COVID-19, those exhalation valves are essentially helping you spread that to others. That's why, for the most part, many of these airlines or most of these public buildings, they don't let people that have masks with exhalation valves kind of get into them, right? So I know at least that's a big thing with the airline industry for sure, right? And then remember, if you're a healthcare worker and you're working with people that potentially have COVID-19, you want to use a respirator. That's the buzzword you want to remember for NBM exams, respirators, right? Respirators. And the respirators you want to use on NBM exams are N95 respirators, right? So what in the world do these things mean? Literally, let's deconstruct the term, right? So what does the N stand for? The N means that the respirator is not resistant to oil, right? R, which you may see on some respirators, tells you that, oh, it's resistant to oil. But typically, it means that you're only going to use that thing once, right? You're going to use that respirator once. It's like for single use once, although unfortunately, you know, with the limited supply of PPE in certain healthcare systems, you know, people had to reuse, reuse, reuse many of these things. But then the P, right, means that it's oil-proof, right? So N means not resistant to oil. R means resistant to oil. P means that it's oil-proof, right? And you can reuse it a lot, right? I mean, one thing that kind of boggles me sometimes about the way healthcare systems work is, you know, you kept reusing these N95s. But the thing is, right out there in the world, there's all these P100 respirators that are sold quite widely, right? And even provide somewhat better protection than the N95 respirators, right? And you can reuse them, right? So it's like it offers every single advantage. But some healthcare systems say that, oh, you know, it doesn't look cosmetically good. We don't want to scare our patients. But the thing is, you know, we're in the midst of a pandemic, right? It's a pretty bad pandemic. You need to make some concessions, right? And you also need to protect your healthcare staff that are working with you, right? But that's a different conversation, right? So again, it'll protect you, the wearer, but if you have COVID-19, it would not protect the people that are necessarily around you, right? And then it's also high yield to know that vitamin D deficiency actually increases a person's risk of having like a severe COVID-19 infection. Again, it's limited data, but it is definitely positive data, right? So if a person is vitamin D deficient, right? So let's say a person has like a dark skin, right? Or you work in radiology, for example, we're in a dark room all the day, or you live in a very cold climate, right? Especially in this pandemic, taking vitamin D is very helpful. I mean, vitamin D is also just helpful for many different things, right? So that's actually one high yield thing to keep at the back of your mind. Okay, so now that we've done away with many of these social science things, let's begin to go into the basic sciences. Let's begin to go more into the clinical sciences that your friends at the MDMU really, really love, right? So the thing is COVID-19, the virus, right? It has four key proteins, right? These are four key proteins you want to remember for your exams and i'm gonna use a mnemonic i call them like men's so like m-e-n-s men's to remember the proteins right so there's obviously the m glycoprotein right the m glycoprotein is essentially um like a protein that actually helps in in uh bringing like nutrients into, right? So it helps for like transmembrane nutrient transport, right? And then there's the E protein. The E protein is the envelope protein, right? And then the N, the N is the nucleocapsid protein, right? And I'll argue that probably the most important protein here is the S protein, right? The S protein is the spike protein. In fact, I'm going to spend quite a bit of time on the spike protein, right? Because it's very helpful to understand quite a bit of pathophysiology with the virus, right? So the thing is, why is that spike protein pretty virulent? Well, let's look at how people get COVID-19 essentially, right? So remember, in the lungs, we have two major kinds of cells, right? Two major kinds of pneumocytes. There's the type 1 pneumocytes, right? They are simple squamous epithelium. They allow you to have gas exchange. And then there's the type 2 pneumocytes, right? Which are cuboidal epithelium. Remember, those type 2 pneumocytes, one thing they do is they have the ability to produce surfactant. Remember, they store that surfactant in those lamellar bodies, right? That's a high-yield tidbit of USMLE information to know, right? But those type 2 pneumocytes, they also have the ability to undergo metaplasia when a person has lung injury to type 1 pneumocytes, right? So remember, it's a kind of metaplasia, right, where you're going from one cell type to another, right? So you're going from simple cuboidal epithelium to simple squamous epithelium, right? So they have the ability to undergo metaplasia. The only problem with these, I guess it's not a problem, but many of us also kind of know this basic science detail that angiotensin 1 being converted to angiotensin 2 happens in the lungs, right? Under the action of angiotensin converting enzyme, right? So the thing is many of these type 2 pneumocytes, they have a lot of ACE2 receptors, right? They have a lot of ACE2 receptors. It's a protein, right? It exists on the surfaces of these type 2 pneumocytes. The thing that happens is that these ACE2 receptors on type 2 pneumocytes actually binds the spike protein that comes from COVID-19, right? And the thing is this spike protein actually has two subunits, right? So it has the S1 subunit. The S1 subunit is the part of the protein that literally binds to the ACE2 receptor, right? So that's the receptor binding domain for the ACE2 receptor, the S1 protein. Remember, again, I said the spike protein has two subunits. It has the S1 subunit and it has the S2 subunit. The S1 subunit is the receptor binding domain, right? So in fact, the S1 subunit is ultimately what you should think of as the antigen that is in many of the vaccines that have been produced for against covid 19 right because again if you can make something that can essentially obliterate the s1 you know obliterate binding of the s1 to the ace2 protein then that will prevent uh uh binding of that uh of of the virus to your to your type 2 pneumocytes, right? And then the S2 is the portion that mediates fusion of the virus to our pneumocytes, right? So S1, again, is for receptor binding to the ACE2 receptor. The S2 domain of the spike protein mediates fusion. If you notice, many of these RNA viruses, they're operated by a somewhat similar mechanism, right? Again, like HIV virus, we know of many of those receptors, GP41, GP, all those things, right? This is not a HIV podcast, I'm going to kind of hold myself back there so that this podcast does not become unnecessarily long, right? But again, it's kind of high yield to understand that. So if you kind of think about it, we know that the titanium oxides, they help us regenerate the lung, right? They literally help us regenerate the lung after injury. So if you're infecting the type 2 pneumocytes, you can see why it's very hard for these people, for their lungs to repair itself after they've had a potential injury, right? After they've had potential injury.
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We also find them in many other parts of the body, right? So ACE2 receptors, you can find them in the heart. You can find them in the stomach, right? Like your gastric epithelium. You can find them on your duodenal epithelium. You can even find them in the rectum, right? So the thing is, you can see that many people can get COVID-related like myocardial injury, right? They can get COVID-related intestinal injury. They can get all these things because, again, the virus can potentially be tropic to these organs in the body, right? And the thing is, again, when the virus infects, right, there is a massive inflammatory response. In fact, many times, if you're measuring these people's labs, you'll notice that their CRP, their LDH, their ferritin, their D-dimer is elevated, right? These are all inflammatory markers. They'll be elevated in these people, right? So the thing is the massive inflammation, again, is going to cause like septic shock, right? Increased vascular permeability in the lungs, right? So fluid begins to seep into the person's pulmonary interstitium, right? And that can cause like a non-cardiogenic pulmonary edema, right? In fact, it can also torch the person's kidneys and cause an acute kidney injury, right? So again, I think one thing that's very high you have to understand here, right, is again, that increased vascular permeability from the massive inflammation, right? Again, you can put fluid in the lungs, right? So the person, that's kind of essentially the pathophys behind these people getting ARDS, right? Remember, ARDS is an example of a non-cardiogenic pulmonary edema, right? It's an example of a non-cardiogenic pulmonary edema, right? So those people's pulmonary capillary wedge pressures, right, which is essentially a surrogate for left atrial pressures. It's going to be less than 18 on an NBM example, right? So what, so obviously, right, if you kind of perform histology on these people, you're going to see like a lot of, you know, diffuse alveolar damage, right? Because again, of the massive inflammation, and again, the virus is very immunogenic, right? It's super, super immunogenic, right? So it causes lots and lots and lots of problems, right? So let's talk about the vaccines, right? Because again, this is an area where you do need to understand there's a lot of cell biology. There's a lot of immunology of friends at the NBME can integrate with this, right? So let's kind of talk about the vaccines, right? So the thing is actually, at least as of today, if I'm not mistaken, there's been roughly 12 vaccines made against the COVID-19, right? So they kind of fall into, I would say maybe like four major categories, right? So the first major category are these RNA vaccines, right? They are RNA vaccines. In fact, like the Pfizer-BioNTech vaccine and also the Moderna vaccine, these actually are RNA vaccines, right? So you may say, okay, Devine, well, this is a new class of vaccine. What's the mechanism of action of these vaccines? Well well it's actually relatively interesting and relatively simple if you just actually take the time to understand it right so the thing is these are RNA vaccines you're essentially giving an I'm giving mRNA to an individual right so if you give mRNA to an individual essentially the thing that's going to happen is when the mRNA gets into the cell, the body is going to use its own translation machinery inside the cell, right, to make this mRNA into like a foreign protein, right? And then that foreign protein will then be broken down by proteasomes, right? It can be broken down by proteasomes if we're talking about the MHC1 response, right? But it can also be presented on MHC2. So essentially, this protein, you know, it can be picked up by dendritic cells. So when you inject the mRNA vaccine into an individual, right, it will be picked up by dendritic cells. Those dendritic cells, again, you will translate the mRNA into protein. And then the dendritic cells, they'll be able to present that protein on MHC2. So you can develop humoral immunity in response to the vaccine. But also because you can make that foreign protein, right, in the cytosol, you essentially can break down that protein with MHC1. I mean, break down that protein proteasomes, right? And then when that protein is broken down by proteasomes, remember there are these TAP proteins, right? TAP proteins, there's TAP1 and TAP2. They will get those broken down proteins into the endoplasmic reticulum, right? And then remember, you can ultimately go ahead and load that foreign protein on MHC1, right? And if you load it on MHC1, obviously you're going to be able to also degenerate cellular immunity, right? So it's actually very high yield to know for exams that the mRNA vaccines have the ability to develop cellular and humoral immunity. And you will notice there are some subtle things I'll talk about here, but again, they're very high yield to understand. This is especially important for people that are taking step one, right? Because again, these mechanisms, right, are things that people don't understand or cannot give up up on but you really don't need to right so the thing is again you're getting an adaptive immune response to this you're getting cellular immunity to this you're also getting humoral immunity to this right i mean the thing is if you'll be like okay divine how does this compare to other vaccines the thing is other vaccines have the antigen prepared in the lab and given to you but, when you're getting an RNA vaccine, you're essentially creating the antigen by yourself, right? It's almost like you're getting like the starter pack, right, to make the antigen yourself. And then because you make that antigen endogenously, because you're making it within your cells, that's why your body is able to generate humoral and cellular immunity, right? And cellular immunity, right? So unlike the lab-prepared antigens, right? In this case, you are making the antigen inside your cell, right? You're making the antigen inside your cell. Believe it or not, your cell is actually way more efficient at creating antigen than trying to make it in the lab. Again, this is one of the reasons why the vaccine was very quick to come out, right? it is way easier it is way faster making an rna vaccine than making like an antigen like a protein-based vaccine right because you have to like design the organisms that are going to get the vaccine get the get the genetic material or whatever into you but now you're just literally giving the genetic material although in many cases you are delivering them with nanoparticles obviously the nanoparticle information is proprietary information to those companies, right? You know, they're like lipid nanoparticles, if I'm not mistaken, right? So, you know, you're going to stimulate cellular immunity, right? Because again, the antigen is produced inside the cell, right? It's not produced outside the cell, right? And the thing is, some of you may wonder, oh, Devine, why did we have to store these vaccines at such ultra-cold temperatures? Well, think about it. mRNA is very easily degraded, right? I mean, you've probably learned this from your studies that, you know, for mRNA, many times before we even send it into the cytosol, right? We're going to put the 5-prime methyl guanosine cap, right? And then we're going to put the poly-A tail, right? the poly tail we add that with poly a polymerase right so we're putting all those things because the cytosol right is a rough neighborhood for for uh mrna right so if you already think about that you can already begin to see why wow we need to keep these things at cold temperatures because mrn is not very stable right so it's easily degradable right so you have to store it at those at those cold temperatures, right? So that when you're injecting it into the patient, you can have like an effective immune response, right? You can get an effective immune response. Now, the thing is, why is this mRNA vaccine good? The reason mRNA vaccines are good is because think about it again.
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But the thing is, if you're just giving the genetic material, and notice the kind of genetic material that's been given. You're giving mRNA, right? You're giving mRNA. So that thing is not, like, you're not giving an actual organism, right? So you're essentially almost eliminating the risk of the person getting infection, right? This one very good advantage. Over live attenuated vaccines. Because again. Essentially what I'm trying to teach here. Is that mRNA vaccines. Generate humoral and cellular immunity. Live attenuated virus vaccines. Also generate humoral. And cellular immunity. But the thing is. Live attenuated vaccines, they come at the risk of the live attenuated virus reverting, right? So like the intranasal influenza virus is an example of a live attenuated virus, right? So you have the small risk, right? It's non-zero, it's extremely small, right? That's why these vaccines are still safe. It's extremely small, but there's a non-zero risk of the live attenuated virus reverting, right, to a pathogenic state. And when it reverts to a pathogenic state, you can cause infection, right? You can have like an outbreak in the lab that's also like actually like creating the vaccine or whatever, right? But these mRNA vaccines are good, right? Because again, you're not giving an actual organism, right? So that risk of reverting to a pathogenic state, you're essentially eliminating that risk, right? You're essentially eliminating that risk. In fact, I would not be surprised in the future because many times, you know, when people have HIV, for example, and their CD4 count has plummeted to less than 200, right? Or people are pregnant, right? Or people are less than a year old, right? We don't give these people live at 10 with it virus vaccines. With the advent of these mRNA vaccines, those restrictions may be lifted because again, you're essentially getting the same benefit from a vaccine, but you're getting that much less risk, right? So mRNA vaccines, again, this is maybe me being a little prophetic here, but I strongly suspect that they're going to be the vaccines of the future all over the world, right? All over the world, all over the world. And some people may say, oh, Divine, are there other benefits of this? Can this mRNA thing go into our genome, right? Because again, that's one common misinformation that is out there. Can this thing, you know, integrate into the genome and cause lots and lots and lots of problems and alter our DNA and stuff? Really, it cannot, right? Because again, first things first, look at what is happening, right? The vaccine that's being given, again, I'm still on the first kind of vaccine, right? The vaccine that's being given, it's an mRNA vaccine. It's an RNA vaccine, right? So because you are giving mRNA, right? Again, notice you're not giving DNA. You're not giving something that can integrate into the genome, right? You're not giving something that can integrate into the genome. And the thing is that mRNA, right after it's translated, right, in the cytosol, remember mRNA translation, for the most part, does not happen in the nucleus. It happens in the cytosol, right? The moment it's done being translated, it's going to be degraded in the cytosol, right? So again, the risk of that in filtrating into the person's DNA and integrating is really low. But again, I know some people that have very good viral knowledge here will say, Divine, come on, give me a break. Can't this mRNA encounter, like, you know, can't it maybe somehow by some magic get into the nucleus, encounter reverse transcriptase, be converted to DNA, and then integrate into the genome? Yeah, that's a good thought. But let's think about this. The thing is, mRNA, right, you know, let's say, again, by some miracle, it makes its way into the nucleus and encounters reverse transcriptase yes reverse transcriptase can convert that mRNA to DNA and then that DNA can integrate into the genome but but think about this the mRNA vaccines that are being given many of them are not given with primers of any sort right because again Because again, you need like almost like viral primer to make all those things happen, right? So the thing is for reverse transcriptase to work, it almost needs to be activated by primer. So the thing is, even if that mRNA were to get into the person's nucleus, there's literally no primer available for that mRNA to then binds to reverse transcriptase to initiate that reverse transcription process, right? So again, essentially the risk of this, at least these mRNA vaccines integrating into a person's genome is almost zero, is essentially zero. But you know, in science, you should probably never say, oh, a hundred percent or zero percent, right? But the risk is pretty close to zero, if not essentially zero, right? So the thing is, for the most part, again, it essentially does not integrate into the person's genome, right? So again, these vaccines, they're pretty decent. And again, they are made pretty quickly, right? I mean, like the Pfizer vaccine, the Pfizer BioNTech vaccine, I think it was made in like 22 days. Although, you know, they had to do all this optimization or whatever. The Moderna vaccine, I think it was even made in a shorter period of time, right? So again, very high yield. Again, like if you notice some of these things I'm explaining, right? They're just applications of basic science principles that, you know, most people should know, right? at least people that are studying for step one should know i would hope right so the thing is uh so that's the first class of vaccines right so again these mrna vaccines there there's two of them right i said there are 12 vaccines total right now there are four vaccines that actually like inactivated or killed virus vaccines right these are inactivated or killed virus vaccines and remember if a person has is taking an inactivated or killed virus vaccines, right? These are inactivated or killed virus vaccines. And remember, if a person is taking an inactivated or killed virus vaccine, these vaccines should technically only generate humoral immunity. They should not generate cellular immunity. In fact, I'm going to take a small sidebar here and maybe kind of make this point very, very clear and obvious, right? It's a concept that I don't know for whatever bizarre reason, people just get the fact in many of these resources that exist out there that, oh, you know, a live attenuated vaccine will generate lifelong immunity. It will generate cellular and humoral immunity. But, oh, a killed virus vaccine only generates humoral immunity. It almost never generates cellular immunity. If it does, it does it in very small measure, right? So many times people just accept this fact, but the thing is, it actually makes sense if you really think about it. So what's the pathophysiology here, right? Think about it. When you give a person a live attenuated vaccine, you're giving vaccine that is an organism that is not dead, right? You've attenuated the ability of the organism to cause disease, but you've not attenuated the ability of the organism to infect a cell, right? I'll say that again. When you give a person a live attenuated vaccine, you've attenuated the ability of the organism to cause disease, but you have not attenuated the ability of the organism to infect a cell, right? Because remember, there are two kinds of antigens. And again, maybe I'll probably do like an immunology review so that I can really buttress these points. There are two kinds of antigens. There are exogenous antigens and there are endogenous antigens. Exogenous antigens are antigens that are outside of a cell, right? So you can bring them in by phagocytosis and, you know, you can present them on MHC2. Endogenous antigens are antigens that you make within your cells, right? Those antigens, right, they go through a different pathway so they can be presented on MHC class 1, right? And when something is presented on MHC class 1, then you have the ability to generate cell-mediated immunity, right? So again, the long and short of this is that a live atinomycin vaccine, it still has the ability to infect cells, right? So it can become an endogenous antigen. It can be presented on MHC class 1, and it can generate T-cell immunity. That's what That's what we usually call cell mediated immunity.
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These killed vaccines, they lack the ability to infect cells. So the thing is because they lack the ability to infect cells, right? So the thing is, because they lack the ability to infect cells, these antigens remain exogenous, right? They remain exogenous, right? The thing is, exogenous antigen can only be presented by antigen-presenting cells on MHC class 2, right? And in that MHC class 2, you know, bind to these CD4 positive helper T cells, right? And then, you know those cd4 helper t cells they will produce uh cytokines and stuff for class switching right so this is why killed vaccines only generate humoral immunity again it's a mute point but this point is floridly high yield to know right i can imagine some people listening to this podcast now like wow i've never really understood this stuff before right again the first time I learned this information a couple years ago, I was like, wow, why does this thing just not show up in any resource, right? So again, this is something that you actually need to understand, right? So believe it or not, there are killed virus vaccines. I almost feel like I'm doing an immunology review right now. But again, I'm going to title this the COVID-19 podcast, right? So there are like four inactivated or killed virus vaccines that are currently available actually for COVID-19. So again, I said that the mRNA vaccines, there's two of them. Those generate cellular and humoral immunity. These inactivated or killed virus vaccines, they only generate humoral immunity. They should not induce cellular immunity. Again again if we're just going with the science here right and then there's also four vaccines that are viral vector vaccines right essentially you're essentially using like a modified virus right uh so it may not even be a coronavirus maybe like a different kind of virus right and you're essentially delivering uh the genetic material of the coronavirus right like to or you know or, you know, or like, you know, basically you're delivering material from, I won't necessarily say genetic material, but you're delivering material from the coronavirus using a modified virus, right? To human cells, right? So that the immune system can respond, right? There's again, about four vaccines that kind of fall under this category. In fact, the AstraZeneca, the Oxford vaccine, is a viral vector vaccine. The Johnson & Johnson vaccine is also a viral vector vaccine, right? And actually, one thing that may help here is to actually remember that the Ebola, because there is actually a vaccine against Ebola, the Ebola vaccine is actually a modified virus vector vaccine, right? So in general, again, these things, you don't have any integration into your own DNA, right? You don't have any integration into your own DNA with these vaccines. And then there are also protein-subunit vaccines. There's about two of those, right? So two of total, right? So the four classes of vaccines for coronavirus, there's the mRNA vaccine, right? There's two of those. And then there's the killed virus vaccines. There's four of those. There is the viral vector vaccines. There's four of those, right? So that's 10 total. And then there's the protein subunit vaccine, right? There's two of those. That's 12, right? There's 12 vaccines total, right? So how do we manage people that have COVID-19? Well, well for the most part we manage these people with supportive care right the money is people supportive care um we give them nseds right to help with their fevers and some of the inflammatory symptoms right now the thing is if you see any evidence of hypoxia right the presence of two sets alone the big big thing you want to remember for mbm exams is to give these people steroids give them deamethasone. Dexamethasone is actually one of those things that has been shown to improve survival in people that have COVID-19, right? It actually has a mortality benefit. I think there were some studies that were done, I think, in the UK that showed like a 30% reduction in mortality, right, in people that got dexamethasone, right, in the setting of a severe COVID-19, right? Now, obviously, these people are hypoxic, right? You're also going to give them other stuff, like you can give them like 100% oxygen, right? Usually, there's like an oxygen chain that is followed in managing these patients, right? You know, if they're hypoxic, you're going to start off by giving them 100% oxygen, right, by a nasal cannula. But then if that doesn't work, you then have to switch to one of two options, right? You can either do like high flow nasal cannula, right? Again, maybe in the future, you know, God willing, I'll make podcasts on like oxygen delivery and how like different methods for delivering oxygen or like ICU machines and all that stuff. Maybe I should even do an ICU series. But again, that's in the future, right? So you can do like high flow nasal cannula. But another thing you can also do instead of high flow nasal cannula is non-invasive positive pressure ventilation right so like bipap essentially although in general uh high flow nasal cannula is preferred over a bipap right high flow nasal cannula is preferred over bipap i mean there's actually been studies i think some of these studies were actually done pretty early when our covid 19 was a thing that showed that high flow nasal cannula in general was, I believe it reduced the need for intubation compared to having BiPAP, right? And again, another thing you kind of need to remember about BiPAP is that it's an aerosol generating procedure, right? So it's kind of a high risk procedure for healthcare workers, right? And then obviously, if this non-invasive positive pressure ventilation or high flow nasal cannula doesn't work, right? You're going to go ahead and proceed to intubation, right? You're going to proceed to intubation. And if intubation is not really helping a person, right? And you have like profound hemodynamic compromise, then sadly you have to proceed to ECMO, right? Extracorporeal membrane oxygenation. Again, I'm really, really hoping that I can have an ICU series in the future where I talk about some of these machines that we use in the ICU. It's actually a lot of fun, right? Like ventilators, ECMO machines, high flow nasal cannulas, swangans catheters, right? Not just telling you, oh, this is what the machine does. Obviously, that'd be a waste of your time. You can look that up on your own. But kind of going into detail of like the pathophysiology, the physiology behind these machines, right? And what they record, right? And how they help. Like, I mean, ECMOs are very fascinating, right? There's like a ton of stuff with ECMOs, like how they oxygenate, how they take over your heart and your lung function and all that fun stuff. But, you know, that's a future podcast. That'll be too much for this, right? I mean, this is almost an hour already, right? Now, another thing you also want to think about that you hear is the drug remdesivir, right? Remdesivir. For the most part, remdesivir is used in people that, you know, are not going to require intubation, right? Not going to require intubation. For the most part, yes, it's approved in certain countries, but in general, it's not super recommended, right? Because the thing is, pretty much all it does is it kind of shortens your time to recovery, right? But for the most part, it doesn't really, at least as far as I know from my research, it doesn't seem to have much of any mortality benefit, right? It doesn't seem to have much of any mortality benefit, right? So it shortens the time to recovery, right? So it's kind of like the way when a person has the flu, if within 72 hours of the onset of symptoms, you give them like, what am I trying to think about here? You give them a Tamiflu. What's the name of this thing? Yeah, Oseltamivir, right? Oseltamivir, Zanamivir, right? Those things, they don't necessarily cure the infection, but they reduce your number of symptomatic days.
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It shortens your time to recovery, but for the most part, as far as I know, at least again from the research I've done, it's not really recommended. In fact, there are certain organizations that do not recommend remdesivir, right? Now, the thing is, again, these people, when you're giving them oxygen therapy, again, you want to give them oxygen therapy and go no more than 96%, right? Because again, many people don't realize this. Oxygen is a metabolic toxin, right? Oxygen is a metabolic toxin, right? So just like hypoxia is bad, hyperoxia is also a problem, right? Because again, remember when you have tons of oxygen around, it can cause a lot of free radical damage, right? I mean, this is one of the reasons why bleomycin is such a toxic drug to the lungs. Right. Bleomycin literally sensitizes the lung to oxygen mediated ferritical damage. Right. That's one. That's literally the primary mechanism behind bleomycin causing pulmonary fibrosis. Right. So hyperoxia, I mean, like, again, if you even think about kids that have neonatal respiratory distress syndrome. Right. And you see them developing like retinopathy of prematurity, interventricular hemorrhage, bronchopulmonary dysplasia. Again, many of those things are free radical mediated issues, right? So hyperoxia is a problem. In fact, you would see that in certain circumstances, giving oxygen is not the fix for someone's hypoxia. Again, this is something I'll probably go ahead and talk about in my, you know, I think I'm pretty resolute on maybe starting, going ahead and doing some kind of ICU series. But again, I think I want to establish this fact. That's why, again, it's really sad that many people are going into, again, it's one of these sad things that happens with this memorization heavy generation we're currently living. You see many people, many healthcare practitioners or, you know, some people that are, you know, practicing healthcare that are not physicians, right? They just know certain, you know certain things, but you don't necessarily understand, right? So that's where you need to be careful. I'm not saying that, you know, oh, we should disenfranchise some part of healthcare. No, no, no, no. What I'm saying is, as you're learning, put mechanisms in place to actually make sure people are actually understanding what's going on. Again, oxygen is not always the fix for hypoxia. Again, I know some of you may be like, no, Define, this doesn't make any sense. If a person has low oxygen, give oxygen, right? But that's algorithm-based thinking. Algorithm-based thinking is not always smart, right? That's why usually some of the best ICU physicians, people that have actually spent time, and you see that they actually think about the patient, they think about the science, they think about the pathophysiology, right? So those people are usually a lot more targeted in their approach to care. They're usually a lot more structured, a lot more prudent in their approach to care because they just have that salient understanding, right? They have that salient understanding. So I think it's kind of an important thing to actually keep at the back of your mind as a physician, right? Or as, again, a healthcare practitioner, right? Even if your school that you're going to as a healthcare practitioner is not teaching you pathophysiology, take it as your own responsibility that you know what, I want to take good care of my patients, right? So let me actually understand pathophys, so I don't kill patients for any reason, right? Again, I'll say this, but again, I think I'll examine this thought more when we go into the ICU series. But in general, there are certain situations, right? There are certain situations where oxygen is not the best immediate treatment for a patient's hypoxia, right? Oxygen is not always the solution to hypoxia. Again, the meat is in the pathophysiology, right? But again, that's a conversation for a different day, right? And then obviously, these people go into shock, right? So again, sorry I went off on that rant, but I think it's kind of a message that needs to be heard, right? But again, I think I also need to be prudent in the way I express some of these messages, right? Again, because again, we live in an atmosphere where everything is offensive, right? So, you know, kind of have to be careful with your speech in this day and age, right? So if these people go into shock, right? Again, obviously, have, they will likely have some kind of septic shock. Remember when a person has septic shock, right? So, you know, it's a distributive shock, right? So these people, they have a decrease in systemic vascular resistance, right? So because the systemic vascular resistance goes down, right? So the cardiac output is going to go up, right? The cardiac output is going to go up because it's just easier for the left ventricle to eject with blood that's one factoid right and then remember that in people that have septic shock right their pcwp so their pulmonary capillary wedge pressures which is a surrogate for left atrial pressure and your central venous pressure which is a surrogate for right atrial pressure remember all the all the veins draining to the right atrium right so it makes sense that the central venous pressure, the central hub for all your veins pressure, right? Should be a good surrogate for right atrial pressure, right? And then it's also high yield to understand, right, that when people have septic shock, right, their MVO2 is actually high, right? Their MVO2 is actually high. Again, I don't want this podcast to get unwieldy here. But remember, people that have septic shock because they have that decrease in systemic vascular resistance. Blood flows very quickly. Right. Flows very, very, very quickly through their tissues. Right. And again, as the blood flows very quickly through, you know, zips through your tissues, there is inadequate oxygen extraction, right? Happening, right? So because there is inadequate extraction of oxygen, the oxygen tension of the blood that gets to the right atrium actually ends up being higher than you would imagine, right? So MVO2 is usually high in, especially in early septic shock. And by the way, for those of you that are taking MBM exams, the numbers they always request, because I know some Q banks get a little excessive here, and they talk about early septic shock and late septic shock. On MBM exams, if you get a septic shock question, assume that they are testing the values in early septic shock. So the cardiac output is up, the systemic vascular resistance is down, the pulmonary capillary wedge pressure, which is the left atrial pressure, is down, the CVP, the central venous pressure, which is the right atrial pressure, is down, and the MVO2, which is the mixed venous O2 saturation, is up. Those are the numbers. And again, I've kind of explained the pathophase there. Those are the numbers that go along with septic shock, right? So when people have septic shock, obviously, you're going to give them antibiotic therapy if you can find the infection. Although, remember, for coronavirus, there's no real antibiotic that can really help you here, right? So when people have septic shock, obviously you're going to give them antibiotic therapy if you can find the infection. Although remember for coronavirus, there's no real antibiotic that can really help you here, right? So we're going to be going more into pressors, right? So usually you want to use norepinephrine. Remember, norepinephrine is the first-line pressor in the treatment of septic shock, right? That's what's called LevoFed in hospitals. It's the first-line pressor in septic shock. But let's say for some reason, norepinephrine is not doing diddly squat for your patient. What can you do? Well, your second line pressure in the management of septic shock, and this is actually very high yield to no frame beam exams, is vasopressin, right? Vasopressin is the second line pressure that's used in the management of septic shock, right? And then your third line pressure is epinephrine, right? So remember NVE. You start with norepinephrine.
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If that doesn't work, proceed to epinephrine. So the thing is, back in the day, there were guidelines that said to use dopamine. But don't use dopamine. Again, you may see some old MBME questions where, oh, giving dopamine in the setting of septic shock is the right thing to do. But not these days. Dopamine is no longer indicated. I mean, this has been for years. Dopamine is no longer no longer indicated for the management basically don't use it as a pressure in septic shock right and when people have septic shock go ahead and give them fluids right so if you're giving them fluids don't try to use uh colloid solutions don't try to use albumin no don't do any of that stuff if you're pressing a septic shock you can use either normal saline or you can use uh lactated ringer solution although one problem with normal saline is that it can potentially cause like a hyperchloremic metabolic acidosis again the mechanisms behind these things that's for that's for the icu series right again hopefully you know god makes it possible for me to make those podcasts right but uh so if a person is developing like a hyperchloremic metabolic acidosis you may may want to go ahead and use lactated ringers. But for the most part, if a person is going through septic shock, normal saline, usually on NBM exams is the right thing to do, right? But lactated ringers, if you don't see normal saline as an answer, if they tell you that, oh, the patient has a hyperchloremic metabolic acidosis, then you can go ahead in those patients and use lactated ringers, right? If a person has hyperchloremic metabolic acidosis, lactated ringers is great in these people, right? And again, remember, when a person has septic shock, usually your goal for the mean arterial pressure is somewhere between 60 and 65, right? The mean arterial pressure, you want to keep it somewhere between 60 and 65. Remember, 60 and 65 for your mean arterial pressures, right? And again, obviously, these people, if they're having like very severe respiratory failure, you need to put them on a ventilator, right? So on a ventilator, again, since these people for the most part have ARDS, for the most part, you're going to put them on low tidal volumes, right? Because again, you don't want them to suffer barotrauma, right? You want to cut down on this thing called ventilator-induced lung injury, right? So you put them on low tidal volumes right usually you do like a tidal volume of like six million six milliliters per kilogram of predictive predicted body weight right so if for example a person's predicted body weight is 70 kilograms right they should be on roughly a tidal volume of about 420 milliliters, right? 70 times 6, right? And you also want to put these people on high PEEP, right? If you put them on high PEEP, again, you're essentially going to be recruiting more alveoli to participate in gas exchange, right? And usually also these people that have like really bad respiratory failure, one thing you can also do for them is actually being shown, I believe, to improve survival is to put them in a prone position, right? So basically like these people on their chest and on their bellies, right? The thing is, it essentially reduces the shunt fraction in the lungs. Again, these terms you're hearing me spit out, right? I'm going to talk about them in the context of the ICU series, right? Because again, if you remember, a shunt is where you have regions of lung that are ventilated, but they are not being perfused, right? In general, when you put the person in a prone position, again, usually you want to do it for about 12 to 16 hours. When you put a person in a prone position, that's actually going to increase perfusion. I don't know, but like maybe to give some people like a hint of why this is important. Some of you may potentially remember that, oh, wow, like, you know, there's like zone one, zone two, zone three of the lung and those differences in pressures of the pulmonary capillaries versus the alveoli and stuff. Basically, when the person gets in a prone position, you're optimizing those pressures to increase perfusion of many parts of the lung. So you're kind of cutting down on that shunt fraction. But again, we will say some more things about that. Again, remember, shunt is you're being perfused, but you're, you know, you essentially have regions of lung that have been oxygenated, but they are not being perfused. Sorry if mix that up there so let me say that again shunt is when you have regions of lung that have been oxygenated but they are not being perfused right they're being oxygenated but they are not being perfused they're being oxygenated they're not being perfused right i don't know i feel like i'm saying the wrong thing for shunt i hope i'm not mixing this up up. Yeah, because, okay, let me try to reason this out, right? So right to left shunt, right? So the blood is basically skipping the lungs. It's not getting oxygenation. Oh, okay. My apologies there. My apologies there. So actually a shunt is when you have the lungs, they are being perfused, but they are not being oxygenated, right? They are being perfused, but they are not being oxygenated. They are being perfused, but they are not being oxygenated. Sorry about that. My apologies there, right? So those regions of lung, again, they are being perfused, but they are not being oxygenated, right? So basically by being in a prone position, you reduce that shunt fraction, right? You basically take away that shunt physiology. So that's part of the reason it improves survival, right? And then, so again, low tidal volumes, high PEEP, prone positioning, low plateau pressures, right? So plateau pressures are basically pressures you get where if a person takes a full inspiration, like literally at the end of inspiration, you pause and then you take the pressures in the airway, right? That's essentially what the plateau pressures are. You want to keep those plateau pressures low again so that you can reduce the risk of barotrauma, right? So it's going to be less than 30. You want to keep that below 30, right? Because believe it or not, for some bizarre reason on step one, they do actually ask about plateau pressures every now and then. And then just two quick tidbits of information I want to say here. In kids, sometimes they can have this thing that is related's related to covid19 but it's called pediatric multi-system inflammatory syndrome uh it's kind of similar to kawasaki's disease actually right and um it can actually cause death in covid19 although in general kids that get covid19 their mortality rate is way lower and then the final thing i will say is that the case fatality rate for COVID-19 globally is roughly 2.2%. So for every 100 people that get COVID-19, about 2.2 of them are going to die, which is really sad. So hopefully with the injection of the vaccine, that can cut down on some of this mortality. So as I do at the end of every... I think I'm going to go ahead and stop here. I mean, this is more than an hour already. So this is not unwieldy. As I do at the end of every podcast, please subscribe to the podcast website, divineinterventionpodcast.com. And I also have, basically, if I make a new podcast, you'll get an email notification. And all the podcasts from episode one all the way to, I guess, 300 now, they are always going to be on the website. because, you know, I also have these podcasts on Apple Podcasts, on Google Podcasts, on Spotify. The only problem with those is it's like a WordPress role. You can basically only see the first one, the most recent 150, right? So if you want all the podcasts, you have to go to the website and actually like download it there or listen to it from there. And then I have a YouTube channel, Divinemle podcast and videos uh that's where i post the videos that i make so subscribe and if i make any videos which i do uh you'll be able to view them there and then um uh if you need tutoring i offer one-on-one tutoring for the usmle exams so step one step two ck step three uh preclinical med school exams, third year clerkship shelf exams.
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And then for those of you that are taking step two, CK, step three anytime soon, I do offer a comprehensive course. I have an MBME test taking strategies course that's two and a half hours. It's on the 27th of April of this month. And then if we go to the very end of the month from the 20th of April to the 1st of May, I have a 20-hour. So it's five hours for four days. Super comprehensive Step 2 CK Step 3 course. Covers, again, PEDS, Psych, Neuro, IM, Surgery, OB-GYN. And even the new changes that have shown forth on the exam. Biostats, Ethics. I cover all those things. Healthcare systems. All those things are amply covered in the course. So, if that's something you're interested in, just shoot me an email through the website and I'll give you more information on the cost and things of that nature. So thank you for listening to this podcast. I will see you next time. God bless you and have a wonderful day and stay safe and practice social distancing. Thank you.
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I'm Stephen Morrissey, Managing Editor of the New England Journal of Medicine, and I'm talking with Stephen Schroeder, Distinguished Professor of Health and Healthcare in the Department of Medicine and Director of the Smoking Cessation Leadership Center at the University of California, San Francisco. Dr. Schroeder has co-authored a prospective article on the Joint Commission's new tobacco-related performance measures for hospitals. Dr. Schroeder, a new report from the U.S. Surgeon General focuses specifically on smoking among young people in the United States, and it reveals that almost a quarter of high school seniors and a third of young adults in this country smoke. Do those findings surprise you? No, because they're really an extension of previous years, Steve. The good news is that the smoking rates are excruciatingly slowly on their way down. And by two different surveys, one of them shows that approximately 19% of seniors in high school are currently smoking. Actually, it's 18.7. And a different survey shows it is about 25%. So they've been coming down. That's the sort of good news. The bad news is they're coming down way too slowly, and it's still far too many young people smoking. Now, I should say that this is have you ever smoked in the last 30 days. And so one of the other trends has been that people in general and young people as a part of that, they smoke are smoking less frequently so that's a ray of sunshine. The Surgeon General's report concludes that to reduce the initiation of smoking among these young people we should be looking at mass media campaigns, comprehensive community programs, specific kinds of school-based programs, statewide tobacco control programs, and that we should be increasing cigarette prices. What do you see as the most effective interventions? The data show that the two most effective for people in general are raising the price of a pack of cigarettes. And we, in 2010, passed a 62 cent per pack federal tax. So that means that the federal tax on a pack of cigarettes is a dollar and a penny. And states vary. Some states have taxes as high as $2.50. Others, it's as low as $0.25. In general, southern states tend to have lower taxes. But taxes really, the price really works, especially kids are price sensitive. The thing that works better for adults is smoke-free areas. It's not as clear that smoke-free areas are good at discouraging young people from starting. And then a counter-advertising campaign aimed specifically at young people, such as the Legacy Foundation's Truth Campaign, has been shown to lower the rate of youth starting to smoke and also keep smoking. Speaking of advertising, just this week the federal government announced a new anti-smoking ad campaign from the Centers for Disease Control and Prevention in which former smokers are going to talk about the dire consequences of smoking to their health. Have you seen any of these ads? Do you think this sort of thing will work? I've seen them. They're really grim. There is some data that they will work. There are really three different themes that advertising campaigns have taken. One of them is the one that the CDC is going to roll out, and that's rolled out in some other states. The second is what the Legacy campaign did, which is to focus on youth. And instead of getting young people to have a rebellion against their parents, they portray the tobacco industry as bad guys and basically say, if you smoke, you're helping these bad guys. And the data are that the more young people are exposed to those counter-ads, the less likely they are to smoke. And then Legacy Foundation also had a campaign called Become an X. And this really tries to create empathy with how hard it is to quit smoking and shows that if you persevere, you can do it. Now, this comment about it takes a lot of different efforts to drive down smoking rates is sort of poignant today because many of those efforts come from states, and states are facing fiscal crises. And one of the first casualties when the Budget Act gets swung are the public health programs that drive the advertising messages, the staffing of the quit lines, and other things. So we're really not doing as well as a country in the last couple of years, really, especially at the state level. So is that what's brought the federal government to this point? I think to some point it has. I think also the stimulus act, the ARA, the $54 million is going to be spent on this new anti-smoking campaign. That sounds like a lot of money. The tobacco industry sends $15 billion a year in trying to promote its products. So that's about a day or two of money when you compare it to the $54 million. Your perspective article addresses one aspect of what clinicians can do in this regard, the opportunity they have for smoking cessation interventions while patients are hospitalized. Are there data about hospitalized patients showing how many of them continue to abstain if they have stopped abstaining while hospitalized? Yeah, there are two components to this. One is that it's been shown that having a critical illness, like a heart attack or a pneumonia, is a wonderful stimulus to get people who used to say, I'm not going to quit, to say, you know, it's time. And so that's called a teachable moment. And then there are data from the Mass General and the Mayo Clinic and elsewhere showing that you can use the hospital as an opportunity to get people to quit, and the quit rates are higher. The normal cold turkey rate of quitting is about 3% to 4%, and the data show that the rates can be 15%, 20%. What Mayo does, Mayo actually hospitalizes people who would like to quit smoking. I don't think they're covered by a health insurance policy, so they've got to be able to pay out of pocket. But these are really hardcore smokers, and they get a 50% quit rate. Hospitals can choose four of the 14 Joint Commission performance measures. How many hospitals do you think will take up smoking as one of those core measures? That's a great question. We don't know yet. I am worried that many won't because it requires an extra step, which is calling patients after they've been discharged. And if that's so, hospitals will have missed a huge opportunity to improve the health of the patients that they serve. You can argue that it may be one of the most important post-discharge functions they can do. But in asking around, I am worried that many hospitals may pass on that opportunity. The National Quality Forum and CMS are also considering this and actually may mandate it. So I would urge hospitals who have read the article and anyone working in hospitals who is listening to this conversation to say, you might as well get in it now because it looks like it's going to happen later and you might as well get the experience in doing it the right way now. The Joint Commission, whose new measures you describe in your article, originally exempted psychiatric and drug treatment units in hospitals from its ban on tobacco use. Has that changed? No. The Joint Commission still gives them a waiver, but there has been a movement separately, sponsored by the National Association of State Mental Health Program Directors and others to make those facilities smoke-free. And the data are good. So in 2006, 41% of such hospitals were smoke-free, and in 2010, it went up to 79%. So I think over time we're going to move towards every health care facility, whether it's psychiatric or substance abuse treatment, is going to be smoke-free. And that's very good news because, as you probably know, smoking takes a terrible toll on these populations. In another area, a federal district court judge recently ruled that the FDA's requirement for graphic warning labels on cigarette packages violated the First Amendment rights of the tobacco companies. Have those graphic warnings been effective in other countries? Yeah. In Australia, in Canada, in the UK, the data seem to show that they work. The little sort of wimpy warning in our country doesn't work at all. In some of the Latin American countries that are very macho, they actually show a picture of a limp cigarette. And on the package warning, it says, warning, smoking can make you infinite. And that gets a lot of heads turned. If the ruling, in fact, stands on appeal, are there other effective tools? Are there other ways to accomplish the same end? Well, the CDC advertising of the campaign that we talked about would be good, but that's short time only. The beauty of the warning insert is that every time you look at a pack of cigarettes, buy it, put it in your shirt pocket, you see two things. You see these grisly labels, and you see the 1-800-QUIT-NOW.
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And then I would like to see the counter-marketing budget of programs that many states, like the state of California, have done very well, and the Legacy Foundation. We'd love to see more of that, but those are costly, and the revenues for those seem to have dried up. Last year, the FDA's new Tobacco Product Scientific Advisory Committee issued a report on menthol cigarettes. Many people felt that was too weak a statement of the risks involved. Can you tell us a bit about the science and the politics behind menthol? Well, the politics and the science are really, really kind of fascinating. The idea of putting menthol in cigarettes is that it's cooling, and it blunts the irritating sense of smoke. For reasons I don't fully get, it's been the mentholated brands have been marketed much more intensely in inner cities. So African Americans have a much higher rate of smoking menthol cigarettes. African Americans also have, African Americans who smoke have a higher rate of lung cancer, and the lung cancer is more apt to be in the periphery. And it's thought that this is because they may inhale more deeply because of the menthol. That said, the science base on how much adding menthol adds to the risk of illness and makes it harder to quit is not iron tight. And I think the FDA is really worried that if they go beyond their scientific mandate, they'll have a whole raft of suits from the industry. And I think that's why they've been acting with caution. Overall, do you feel optimistic about smoking cessation in the United States? I'm feeling more optimistic now about getting on top of the smoking problem than I did four or five years ago. Why? Well, because we're noting a lot of progress. In California, the smoking prevalence now is just under 12 percent, lowest it's ever been, the second lowest in the country, second only to Utah, which has half its population as Mormon and therefore don't smoke. The national prevalence is at an all-time low. It's at 19.3 percent. And of those smokers who continue to smoke, they're smoking fewer cigarettes. So it's not that the residue of the smokers are sort of hardcore. Even smokers who keep smoking are really smoking less. There are more and more smoke-free areas. We know that certain groups like doctors have dropped down to a 1% smoking prevalence. Lung cancer deaths in women are now starting to fall. They started falling for men a good maybe 10 or even 15 years ago, but they're starting to fall in women, showing that women's smoking rates have come down too. Smoking is more stigmatizing. And if people take up the new regulations from the Joint Commission and if the FDA warning labels go in, I think the climate is increasingly favorable to lower the rate of smoking, which is good news for anybody working in healthcare. Thank you, Dr. Schroeder.
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Hello and welcome to the latest Lancet UK election podcast. I'm Richard Lane and in this podcast we're going to hear the views of the Scottish Nationalist Party, SNP. On the line is Dr Philippa Whitford who, in addition to being a breast cancer surgeon, is also going for a Westminster seat for the SNP in the constituency of Central Ayr. Philippa Whitford, many thanks indeed for speaking to the Lancet election podcast. Thank you very much for asking me. Can you just explain to our listeners and to myself the Scottish situation? It is different, isn't it? Obviously, you have a Scottish Parliament at Holyrood in Edinburgh with a health minister. Also, you have NHS Scotland, which operates quite differently to NHS in England. And you are actually going for a Westminster seat as part of the UK election. So it's potentially a bit confusing. Can you just give us some background? Sure. Yes, obviously we've had our parliament since 1999 and health has been a devolved issue. So we have a cabinet secretary or minister for health. So the decisions about how we deliver health within the NHS in Scotland are made in Edinburgh, but Westminster still hold our purse strings, so the budget we get given to work with is controlled at Westminster. Now, what happened after 1999 is gradually over the following years, we reversed what Mrs Thatcher had set up, which is the trust system, and we eventually worked our way back to being a single, unified Scottish NHS. Now, we had always been separate. People forget that actually the Scottish NHS was established in 1948. But you just wouldn't have noticed because, you know, when I was, we all worked together. What we do have that's different is obviously we do have a unified system. We don't have the current outsourcing and privatisation that is unfortunately causing problems in England. We have free prescriptions. And basically, we try and work together across the NHS in Scotland. How would you summarise what SNP health policy is then, given the different context in Scotland to England and other parts of the UK? Well, within Scotland, the SNP policy is actually trying to tackle our underlying health problems. Obviously we've often been called the sick man of Europe and a lot of that relates to poverty and deprivation and the hopelessness that goes with that and obviously that has actually got worse since the 80s when we lost our industrial base and had more and more unemployed. They take quite a strong public health approach. Obviously, we brought in the smoking ban a little bit earlier than yourselves. We're trying to bring in plain cigarette packaging, minimum price alcohol, but we're struggling to actually get those things through. And that's something that worries us about TTIP and the free trade agreement between Europe and America, which would allow big companies to actually sue governments for taking these kind of actions. And that's something that we can only have our voice heard in Westminster. We don't have a voice in Europe. We would support an NHS re-establishment bill for England because we think in the long term if citizens in England lose their public NHS service eventually that would threaten us. There's no way we'd get to keep what we have as people south of the border lose the NHS that we've all depended on. That's interesting then. So although the NHS in Scotland is going to remain the NHS in Scotland, you actually politically therefore have aspirations to influence health policy in the next UK government. Obviously, the SNP is not going to be in power of the UK government. It has its Scottish Parliament, obviously, at the moment in Edinburgh. So how do you see the SNP's role then in potentially modifying health policies of the next UK government? Well, I think if we manage to send a strong team of SNP MPs, what we will at least have is a voice and some influence. And depending on how we might be working with a Labour Party after the election, if there's a hung parliament, it's get to put that forward and our leader Nicola Sturgeon has certainly already committed to supporting the NHS re-establishment bill which the National Health Action Party and our NHS have put together and that's along with the other progressive parties such as the Greens and Plaid Cym And so in that sense, we feel that it would help to protect our NHS in the future, because there's no way they're going to send a generous budget to us if people in England are being herded towards private insurance in the future. And also, we would be able to actually do some good right across the UK. So what do you make of what the two largest parties, obviously the Conservatives and the Labour Party, are saying about the NHS, notwithstanding the finances that are being bandied around at the moment and the funding, some uncosted funding promises that are being made. But in terms of the actual policy, because we've interviewed Andy Burnham already for the podcast, we hope to interview Jeremy Hunt, our colleague for the Conservatives, before the election. The main difference, as I can see, obviously, is that the Labour Party are wanting to get rid of the Health and Social Care Act that was introduced by this government in 2012. But also the Labour Party are calling for the NHS to be a preferred supplier. So that's not the end of privatisation. No, not at all. Whereas the Conservatives, presumably, haven't interviewed them yet, but obviously we can tell they're not going to repeal the Act, the Health and Social Care Act that they introduced in 2012. How do you see the main differences between those two main parties? Well, obviously, Andy Burnham and Labour are talking about rowing back a little from what happened, But, I mean, it was Labour that actually laid the original foundations with foundation trusts, with changing to any qualified provider, and by setting up independent treatment centres. So they were the ones that kind of prized open the door. And then, of course, with the Health and Social Care Act, you know, the doors basically came off. And I think that that's something where there is a drive within Labour to see that things are really falling apart. And obviously, if we were working with them on any basis, then us pushing to, you know, go right back might actually have an influence. If you look at the new contract that's being discussed in Staffordshire for cancer services, where they're going to insert a prime provider, then what you're talking about is up to £100 million is envisaged as being sucked off into that company. Well, we already had a prime provider. It was the NHS. And yet the commissioning groups in Staffordshire are finding it really hard to work with all these disparate little private providers. You actually have to go back and take that out of the system. What they're saying to citizens in England is simply that the NHS is unaffordable. We have to just accept that our NHS is too expensive and too inefficient. We need to get wealthier people to take private insurance. More of us have to pay for more of our treatment. And yet, if you look at research like the Commonwealth Fund report last year, it still shows that the UK-style NHS of tax-in and health-delivered is the cheapest and most efficient way to do it. And therefore, I feel that it's an ideological decision and not actually a financial decision. And while Labour want to go back a wee bit, they're not talking about amount of that can be achieved through cost savings. Well, not while you're planning to insert more and more complex administration for bidding and tendering and private companies who need to make profits. To me, the best way to save money would actually be to simplify it. These companies are not in it out of charity. They're in it to make profit. And that's what's actually making it more expensive. I mean, Stephen's vision, the five-year forward, is actually, you know, reads very similarly to the Scottish 2020 vision, which came out a couple of years ago. And our integration of health and social care is starting now, this month, the first project. Thank you. So given that you don't see the money coming, therefore, from these efficiency savings, you'd be very much upfront calling for increasing taxation? Well, to me, the efficiency saving you could make is to get rid of, you know, the Health and Social Care Act, to get rid of this outsourcing and fracturing and actually work your way back to the NHS. I can't believe the Conservatives are going to give another £8 billion when they've signed up to £30 billion more cuts. And indeed Labour have walked through the lobbies with them. So I can't see how that will actually deliver more money to the NHS. But what money they are delivering to the NHS, a lot of it will end up in private company profits. Whereas I would rather see a lot more of it going to the coal face. Now, unusually for politicians who I've been speaking to around election time, you are actually a doctor.
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Well, I'm a consultant breast cancer surgeon in one of the local hospitals here. You know, this was not a career plan, let's just say. I really feel I do value the NHS incredibly. And I worked in the Middle East, in Gaza and Lebanon as a volunteer for two years. And I saw literally people suffer and die for lack of access to basic health care. And that gave me such an appreciation of what we have. And when I returned in 94, it was the beginning of the changes that the Conservatives brought in. Purchase or provide or split, let's all pretend we're shopping around for health. And you could already see the waste in that. What I see as the challenge we have now is a UK-wide challenge, which is increased demand. We do have an ageing population, but I get really teed off when people talk about it as a catastrophe. You know, have they thought what the alternative is? And I definitely remember at medical school being told that was the whole point. It's not people living longer. It's the fact that our people aren't living healthily. And that's what we need to change. And up here in Scotland and certainly in parts of England, that is very clearly related to poverty and deprivation. So to me, some of it is a bit like the impact of clean water back in the 18th and 19th century. It's all very well to talk about the NHS, but that doesn't give people health. It's just there to catch you when you fall. And it's marvellous to know that it will be there to catch you when you fall. But what gives you health is kids having a good start in life, having decent chances at school, people having the opportunity to work, feed their families, have a roof over their head, etc. And so to me, I kind of eventually reached the point of thinking, you know, I'm looking after people one at a time. I'm doing my absolute best and I, you know, really loved my job. But in actual fact, we have these deeper fundamental problems, both of tackling our underlying ill health and also protecting the principle of the National Health Service. Can I just ask you a tiny bit more about integration of health and social care? Because obviously this is the new vocabulary coming out of the Stevens Report. The other parties are talking about it. In Scotland, that's already beginning to happen, you're saying. Do you see that as the correct way forward? Do you see any problems in the short term as people in the health sector and the social care sector work out what integration means? Is there potential for confusion, overlap and a bit more chaos as this gets sorted out? I think it's immensely challenging. But yes, I do think they have to work together because, you know, we've all had patients in hospital because, well, if the patient's there, it doesn't come out of such and such a purse. But equally, if they're somewhere else, it comes out of a different purse. And obviously that's very inefficient. And we do get patients who are stuck in hospital because the next step of their journey isn't there. What they've done in Scotland is they've created integration boards where funding is coming from both sides and they're at the moment working out how to do that. I would say one of the biggest challenges for us in Scotland is the fact that our NHS is a unified public service whereas social care is not. It is much more outsourced, much more private nursing homes and care homes. The care delivered in people's houses, etc., is also often done by private companies. And how to put that together is going to be very challenging. But in Scotland, we already have free personal care. So, you know, that is one of our policies, that we will try to deliver care in the homes of the elderly to let them stay at home for as long as is physically possible. And that's, again, one of the advantages we have. But it's trying to knit it all together into a coherent package. And a final thought, Philippa Whitford, what do you think is going to happen on May the 7th? Well, that's up to the voters, but it's looking pretty hopeful at this end, it has to be said. There's just an absolute wave and an absolute disgust with Labour here in Scotland. So I'm not particularly expecting to be back in the clinic. I may have to learn a whole new way of working. So you're confident of being an SNP Westminster, having a Westminster seat for the SNP for Central Air. Dr Philippa Whitford, many thanks indeed for talking to the Lancet Election Podcast. Okay, thank you very much, Richard.
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Welcome to the New England Journal of Medicine audio summary for the week of October 6, 2011. I'm Dr. Lisa Johnson. This week's issue features articles on adjuvant trastuzumab in HER2-positive breast cancer, acyclovir and neurodevelopment after neonatal herpes, oral teraflunomide for relapsing multiple sclerosis, adverse outcomes in women exposed in utero to DES, and the uncertain future of Medicare and GME. Thank you. sweats, and prospective articles on routine HIV screening, on reforming provider payment, and on critical moments between doctors and patients. Adjuvant Trastuzumab in HER2-Positive Breast Cancer by Dennis Slayman from the University of California, Los Angeles. Trastuzumab improves survival in the adjuvant treatment of HER2-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. This study evaluated the efficacy and safety of a new non-anthracycline regimen with trastuzumab. The estimated disease-free survival rates at 5 years were 75% among patients receiving an anthracycline-based regimen, 84% among those receiving an anthracycline-based regimen plus trastuzumab, and 81% among those receiving a non-anthracycline regimen plus trastuzumab. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy, disease-free or overall survival were found between the two trastuzumab regimens, whereas both were superior to the anthracycline-based regimen. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving the anthracycline-based regimen plus trastuzumab than in the non-anthracycline group. The addition of one year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the non-anthracycline regimen over anthracycline plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. In an editorial, Daniel Hayes from the University of Michigan Comprehensive Cancer Center, Ann Arbor, writes that the study does not show the hoped-for superiority of the non-anthracycline regimen over anthracycline plus trastuzumab. However, the findings suggest that a non-anthracycline regimen is an acceptable standard of care. The present is clearly brighter for patients with HER2-positive breast cancer, and the future promises to shine even more. Oral acyclovir suppression and neurodevelopment after neonatal herpes by David Kimberlin from the University of Alabama at Birmingham. Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus, HSV, disease. In this study, neonates with HSV and central nervous system, CNS, involvement, or skin, eye, and mouth disease, were treated with IV acyclovir for two to three weeks, then acyclovir suppressive therapy or placebo for six months. The Mental Development Index of the Bailey Scales of Infant Development, in which scores range from 50 to 150, with higher scores indicating better neurodevelopmental outcomes, was assessed in 28 of the 45 infants with CNS involvement, 62% at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bailey mental development scores at 12 months than did infants randomly assigned to placebo, 88.24 versus 68.12. Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group. Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for six months. Anne Gershon from the Columbia University College of Physicians and Surgeons, New York, writes in an editorial that, metaphorically, the three musketeers can represent our defenses against viral pathogens. Actually, there were four musketeers. The hero d'Artagnan was an add-on. In Dumas' novel, the musketeers' motto, one for all and all for one, indicated a synergistic approach. Our four antiviral defenses include specific and nonspecific antiviral therapy, passive immunization, and finally active immunization, represented by d'Artagnan. With respect to HSV, passive immunization was never developed, nor is there a vaccine that could be a d'Artagnan to take on this virus. Extended oral acyclovir therapy should improve the lives of babies who have survived neonatal HSV. It is hoped that specific antiviral therapy will be joined by the active immunization musketeer to prevent maternal HSV infections. Randomized trial of oral teraflunomide for relapsing Multiple Sclerosis by Paul O'Connor from the University of Toronto, Ontario, Canada. Teraflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis. In this trial, teraflunomide reduced the annualized relapse rate 0.54 for placebo versus 0.37 for teraflunomide at either 7 or 14 mg, with relative risk reductions of 31.2% and 31.5%, respectively. The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teraflunamide at 7 mg, and 20.2% with teraflunamide at 14 mg. Both teraflunamide doses were superior to placebo on a range of endpoints measured by MRI. Diarrhea, nausea, and hair thinning were more common with teraflunomide than with placebo. The incidence of elevated alanine aminotransferase levels was higher with teraflunomide at 7 mg and 14 mg, 54.0% and 57.3% respectively, than with placebo, 35.9%. Teraflunamide significantly reduced relapse rates, disability progression at the higher dose, and MRI evidence of disease activity as compared with placebo. Adverse Health Outcomes in Women Exposed in Utero to Diethylstilbestrol by Robert Hoover from the National Cancer Institute, Bethesda, Maryland. Before 1971, several million women were exposed in utero to diethylstilbestrol, DES, given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. This study involved long-term follow-up of women exposed in utero to DES and unexposed controls. Cumulative risks in women exposed to DES as compared with those not exposed were as follows. Loss of second trimester pregnancy. Ectopic pregnancy. Preeclampsia. Stillbirth. Early menopause. For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. Filaggrin mutations associated with skin and allergic diseases. A review article by Alan Irvine from Our Lady's Children's Hospital, Dublin, Ireland. Mutations in the filaggrin gene, FLG, are among the most common and profound single gene defects identified to date in the causation and modification of disease. FLG encodes an important epidermal protein abundantly expressed in the outer layers of the epidermis. Approximately 10% of persons of European ancestry are heterozygous carriers of a loss-of-function mutation in FLG, resulting in a 50% reduction in expressed protein. The critical role of filaggrin in epidermal function underlies the pathogenic importance of this gene in common dermatologic and allergic diseases. The spectrum of such diseases encompasses monogenic disorders of keratinization through complex abnormalities of epidermal transport of lipids and allergens. FLG mutation carriers have a greatly increased risk of common complex traits, including atopic dermatitis, which affects 42% of all mutation carriers, contact allergy, asthma, hay fever, and peanut allergy. These genetic variants also influence the severity of asthma and alopecia areata and susceptibility to herpetic infection. The biology of this molecule and the role of mutations in its altered function offer new insights into a range of conditions not previously thought to be related to one another. It's not all in your head. A clinical problem-solving article by Catherine Towns from the University of Toronto, Ontario, Canada. A 63-year-old man presented to the emergency department with shaking chills and drenching sweats of four days' duration.
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Approximately six months earlier, he had had similar symptoms in addition to myalgias and fatigue. The onset of these symptoms coincided with the initiation of minocycline for the treatment of rosacea. The minocycline was stopped and the influenza-like symptoms resolved. The patient's medical history was notable for benign prostatic hypertrophy, a single episode of atrial fibrillation that was successfully managed with cardioversion to sinus rhythm, gastroesophageal reflux disease, and rosacea. On physical examination, his temperature was 39.2 degrees Celsius. The abdomen was soft with mild tenderness in the right upper quadrant on deep palpation. The alkaline phosphatase level was 429 units per liter, Thank you. MRI of the thighs bilaterally revealed diffuse symmetric soft tissue, interfacial, and muscle edema. A T2-weighted image showed multiple small punctate foci of high signal intensity scattered within the spleen. Over the next week, the fevers persisted. The alkaline phosphatase level increased further to 962 units per liter. All medications were discontinued. Extensive testing had failed to yield a diagnosis. A liver biopsy was performed. The Uncertain Future of Medicare and Graduate Medical Education, a health policy report by John Iglehart, a national correspondent for the Journal. The author anticipates reductions in funding for graduate medical education. However, once President Obama signed the Affordable Care Act into law, the government, in essence, took on a new obligation to ensure that the millions of people who gain coverage in 2014 will have access to adequate health care. This surge in demand raises the question, who will care for these previously uninsured individuals if reductions in Medicare's GME support should cut the capacity of programs to train new physicians? In this report, the author briefly describes the recommendation of the National Commission, appointed by President Obama to reduce excess payments to hospitals for medical education, that has served as the basis for budget deficit discussions to cut these payments. The author takes stock of other workforce issues that apply to doctors, including current estimates of physician shortages and the absence of a consensus on how many physicians are enough, provisions in the ACA to expand the number of primary care practitioners, and implications of the payment cap Congress imposed on Medicare's article by Mark D'Esposito from the University of California, Berkeley. An epidemiologic study in Finland documented that 76% of persons over the age of 60 years reported problems with their memory. A recent study, however, provides hope that discoveries of the biologic mechanisms of the aging process can lay the foundation for clinical interventions. The investigators made recordings from neurons in the prefrontal cortex in three pairs of monkeys, young, middle-aged, and old, while they were performing a task involving working memory. The firing rate of the neurons was markedly reduced in the middle-aged and old monkeys as compared with the rate in young monkeys, which suggested a neural basis for an age-associated decline in working memory. Thus, these investigators measured and attempted to augment persistent neuronal activity in the prefrontal cortex in older monkeys by iontophoresis of drugs, for example, guanfacine, that either inhibit cyclic AMP signaling or block potassium channels near the neurons. Remarkably, this approach was successful. The memory-related rate of neuronal firing in the prefrontal cortex in older monkeys was restored to youthful levels. Pharmacologic interventions accompanied by cognitive training interventions may be effective in the remediation of diminishing cognitive abilities. Routine HIV Screening What Counts in Evidence-Based Policy? A perspective article by Ronald Bayer from Columbia University, New York. Should U.S. adolescents and adults be screened routinely for HIV? The same evidence has led the top U.S. public health agency and the body charged with providing scientifically grounded recommendations on preventive interventions to dramatically different conclusions. In January, the President's Advisory Council on HIV-AIDS called on the U.S. Preventive Services Task Force to reconsider its 2005 determination that the scientific evidence did not justify routine testing for HIV in adolescents and adults in the general U.S. population. In July, the Institute of Medicine issued a report calling for annual HIV screening in all sexually active women. These are the most recent episodes in a struggle that began in 2006, when the Centers for Disease Control and Prevention recommended routine HIV testing. In 2005, the task force concluded that although targeted HIV screening misses a substantial proportion of HIV-positive patients, universal screening would result in large numbers of patients screened for each clinical outcome prevented. The task force is revisiting its 2005 determination and may reach a decision by the end of 2011. But this saga underscores a broader matter of critical importance to anyone committed to evidence-based practice in medicine and public health. What is from one perspective methodologic rigor may be viewed by others with public health responsibilities as methodologic zealotry. Reforming Provider Payment – The Price Side of the Equation, a prospective article by Paul Ginsberg from the Center for Studying Health System Change, Washington, D.C. For some time, public health care payers, such as Medicare and Medicaid, have focused much of their cost containment effort on constraining the prices they pay for health care services, which they set administratively. But public payers recognize the limits of this strategy and hope to develop better methods of paying providers that will create incentives for treating patients using services more efficiently. In contrast, private health care payers have traditionally focused more on the quantity part of the equation. But prices becoming a bigger headache for private payers as dominant health care providers, especially large hospital systems, have been using their market power to command increases in payment rates that exceed increases in unit costs. Moreover, hospital leaders often cite inadequate Medicare and Medicaid payment rates as the reason they must demand higher rates from private insurers. Although many private payers share the enthusiasm for reforming provider payment, they realize that attempts to encourage hospitals, physicians, and other providers to integrate and align to improve care coordination are likely to lead to greater consolidation among providers, increased market power, and higher prices. Public and private payers alike should keep their focus on payment reforms that address both the price and the quantity of health care and avoid inadvertently working at cross-purposes. Critical Moments Doctors and Patients A perspective article by Lenore Buckley from Virginia Commonwealth University School of Medicine, Richmond. A pale, thin, anxious 9-year-old boy sits in front of Dr. Buckley. He is in pain, stoic, and not very verbal. She glances down and notices a markedly swollen ankle. He has been losing weight and uncomfortable for months, his anxious parents report. Have you had diarrhea? Dr. Buckley gently asks the boy. Yes, he nods. His mother looks startled. Any blood in the diarrhea? He nods again. And now Dr. Buckley is also startled. The boy looks even more anxious. It's then that Dr. Buckley realizes that this is one of those critical moments. Such moments occur at most a few times a month. She walks into an exam room prepared to hear about a straightforward problem, and then, as she listens, she realizes that the person in front of her is seriously ill. The dawning of this realization is followed by a call to full attention. In the next hour and over the next few months, what she does or doesn't do will change the life of this child and family. What she says and how she says it will be critical, providing the information, reassurance, and hope to keep everyone moving forward. The challenge is to continue to notice these critical moments, to remember the personal impact of the diagnoses we make and our ability and obligation to soften the blows, to build a protective wall around the patient and his or her family to hold back waves of fear, vulnerability, and loss of control that is rushing in as they realize something serious has occurred. The images in clinical medicine features a one-day-old male neonate who was seen for evaluation of a 2.5-centimeter mass arising from the umbilicus. The mass was covered in granulation tissue. When the patient cried, straw-colored fluid leaked intermittently from an orifice in the lesion. Infusion of water-soluble, radio-opaque contrast material into the orifice under lateral fluoroscopic imaging showed a fistula tract leading from the urinary bladder to the umbilical lesion. Surgical exploration confirmed that the tract was a developmental abnormality known as a patent uracus. When the uracal tract is not completely obliterated during embryonic development, a bladder diverticulum, uracal cyst, umbilical polyp, or patent uracus may result. A six-year-old boy presented to the hospital after several hours of vomiting and dyspnea. He had been in a motor vehicle accident six months earlier and sustained a seatbelt injury that necessitated surgical repair of a right diaphragmatic hernia. At the current evaluation, an anteroposterior plane X-ray of the chest showed a large, gas-filled structure in the left hemithorax, near complete collapse of the left lung, and a marked rightward shift of the mediastinum.
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The patient had a left posterolateral diaphragmatic rupture and underwent emergency surgery during which the stomach, spleen, left kidney, and part of the transverse colon were repositioned within the abdomen and the rupture repaired. This concludes the summary of the October 6th issue of the New England Journal of Medicine. We're interested in your feedback about our audio summaries. Any comments or suggestions may be sent to audio at NEJM. Thank you for listening.
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Hello and welcome to the podcast for the April 2008 issue of The Lancet Infectious Diseases. Richard Lane here with TLID's editor John McConnell. John, we're going to cover three topics. Your leading edge, which we'll start with in a moment, which is looking at regulatory control and trial design, which is interesting. We're also going to cover endocarditis and a fairly interesting review too about syphilis, which has gotten the press this past couple of days. But let's start with your leading edge editorial. Very interesting read. It's basically, if I've got it correct, saying that regulatory agencies, particularly the FDA in the United States, seem to be wanting to move the goalposts in terms of what type of trial research they think is now required in order to get drugs on the market. That's right, Richard. It looks as if the Food and Drug Administration in the USA is moving towards requiring trials of new antibiotics to be either against an existing antibiotic and for the trial design to be a superiority design whereas up until now it's been what's called a non-inferiority design or even it's possible that the FDA may actually call for placebo-controlled trials to be done. And what we're talking here particularly is about trials of antibiotics for community respiratory tract infections. Now the issue here is that the drug industry is concerned that if the goalposts are moved or the barriers to introducing a new antibiotic are too high, then the costs will be so great for them and the chances of making a return on their investment will be reduced. And therefore, they won't want to participate in trials of new antibiotics. And the market for new antibiotics may well be strangled. So what we have to do here is we have to balance the need for new antibiotics to come onto the market with the desire to limit antibiotic resistance. So antibiotic resistance is a growing problem. And on one hand, you could argue that using antibiotics to treat fairly mild self-limiting infections, as most respiratory tract infections are, is a bad thing to do because that actually encourages the development of antibiotic resistance. On the other hand, these infections are a huge market for the drug companies. And if the drug companies are not encouraged to develop antibiotics for these markets, then those antibiotics will not go on to be used to treat much more severe infections. So the balance here is really between the practicalities of running trials and encouraging drug companies to develop new antibiotics, and the desire from the FDA for theoretical perfection in trials, which is perhaps just not possible. And interesting as well that you talk mainly about the FDA in the United States, but it's interesting that the European equivalent hasn't suddenly changed its tune because the FDA is making rumblings in this direction. Well, that's right. The European Medicines Agency certainly did not change its recommendations on a antibiotic called telithromycin in the wake of the FDA removing its approval for a couple of respiratory tract infections removing its approval from FDA from telithromycin for those infections. The European Medicines Agency did not change its recommendations and, the European Medicines Agency has shown no indication yet of wanting superiority or even placebo-controlled trials to be done for approval for new antibiotics within its territory. So there's definitely a need here for the various drug-related agencies to get together and to agree on some international harmonisation. And presumably one of the other key issues here is it's not a case of one size fits all. Oh, absolutely not. I mean, we have tried to write a very balanced editorial here, and I think you could make a reasonable case for doing placebo-controlled trials for such things as otitis media or sinusitis. I mean, The Lancet itself has just published a paper in the last week saying that antibiotics really don't need to be given for sinusitis. So I think there's a pretty reasonable case for at the very least demanding superiority trials when the indications are sinusitis or otitis. And perhaps there's a very good case indeed for having placebo-controlled trials for those indications. However, one of the indications which the FDA is looking at is community-acquired pneumonia. And in that case, that is probably not a trivial illness. And some doctors believe that it would actually be thoroughly unethical to do placebo-controlled trials in community-acquired pneumonia because it's a potentially life-threatening illness. And that no clinicians would actually want to participate in trials of that sort of design for fear of endangering the lives of patients who are given a placebo. Interesting topic. I'm sure we'll hear a lot more about it as well. Moving on, John, you've got a review which is looking at prophylaxis for endocarditis. This is always an interesting topic because this is obviously a very serious, I mean, before antibiotics, it was 100% fatal, wasn't it? Heart condition with very high mortality. Yeah, with an infectious cause. What's this review saying? Well, this is about bacterial infections of the heart. So there are certain patients who are at very high risk of such infections. Those with, for example, with prosthetic heart valves, those who've got some sort of heart valve defect, just for example. Now, there's been a thinking for some, a very long time, that ever since antibiotics have been available, that these patients, before they have any sort sort of particularly dental procedure then they should receive antibiotic prophylaxis and the theory here is that the dental procedure will cause bacteria from the mouth to get into the bloodstream where they will be seeded to the heart and may potentially cause cause heart disease however the recommendations are actually very gradually moving away from treating every patient who might be at risk of endocarditis to just focusing on the very high risk groups. And the research that these authors have managed to get together does seem to indicate that you have to give prophylaxis to a very, very large number of patients in order to prevent just one case of endocarditis. And of course, if you look at it in a sort of more more global sense rather than just looking at patients who are about to have a dental procedure it's well known that even something as simple as brushing the teeth can cause bacteria to get into the bloodstream and potentially go to the heart so obviously the number of times a person who's at risk of endocarditis brushes their teeth is far far greater than the number of times they're actually likely to have an invasive dental procedure so over over the course of a person's lifetime, just prophylaxing them at the time of those dental procedures seems to be actually quite a trivial intervention, really, in the terms of reducing their risk. And it's probably of very limited value indeed. Thanks, John. And finally, let's discuss the venerable venereal disease. I've been practicing saying that for the past half an hour. Joking aside, you know, this is a review looking at syphilis. It's got a bit of press coverage over the past couple of days, certainly here in the UK, that I've spotted. And I guess the reason this is relevant is that basically we're seeing a re-emergence of syphilis after the incidence and prevalence really went down in the 80s and 90s. That's right. This is a review looking particularly at syphilis in high income settings, so in the Western world, in Western Europe, North America, Japan, Australia, New Zealand. So what happened, certainly well into the 90s, is that the incidence of syphilis dropped to an incredibly low level. I mean, I think there was something in the mid-90s in the UK, for example, there were well under 200 cases of primary syphilis. So it practically disappeared. However, in the last 10 years or so, the number of cases has gone up tenfold or more. So the absolute number of cases in the States, the UK, for example, is still pretty small. It's still in the low thousands. However, there are particular populations such as homosexual men who, in which this epidemic continues to grumble along because of various sort of high-risk behaviours and considering that syphilis if left untreated is a potentially lethal disease but we do know how to treat it the antibiotics that we can use to treat it are the same as they've been for the past 50 years it is a shame that this epidemic continues to go on when we have a disease which is pretty easy to spot and very easy to treat. Indeed, and I see even Christopher Columbus gets a mention in this review. Well, Columbus's return from the New World is supposed to have introduced syphilis into Europe in the 1490s, though that theory is actually very controversial. Syphilis may well have been around for much longer in Europe and it had just gone into a non-verulent phase. But I think probably the key message, one of the key messages to take away from this particular review is that doctors in general practice, in family practice, are, because syphilis has become rare, they are not used to seeing it and they might not spot it because they don't have the experience.
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Great, John. Thank you very much. That's a good way to end. Those are a few highlights from the April 2008 issue of The Lancet Infectious Diseases. Thanks for listening. See you next month.
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Hi, and welcome to In Conversation With, a podcast from The Lancet Diabetes and Endocrinology. It's January 2022, and I'm your host, Jack Williamson. Young people who have type 2 diabetes are at a much higher risk of several negative health indicators, such as poorer treatment response, more complications, and worse overall prognosis than older adults who also have type 2 diabetes. Within Australian, Aboriginal, and Torres Strait Islander communities in particular, rates of type 2 diabetes are known to be higher than for non-First Nations communities, but data exploring these differences, specifically in young First Nations people, are extremely scarce. Moreover, concerns that First Nations communities have limited access to and engagement with health services sparks additional conversations around the ongoing legacy of historical and socio-economic inequities that are indelibly linked to the health of First Nations young people. Today I'm joined by Dr Angela Titmuss from Charles Darwin University, whose research letter on type 2 diabetes among First Nations young people in Northern Australia was published in our January issue. Hi, Angela. Thanks so much for joining us and for waking up so early this morning. Hi, Jack. Your work raises awareness for the high prevalence of type 2 diabetes in First Nations people. Why is type 2 diabetes becoming more common in these communities? Yes, I think it's more prevalent in all First Nation communities across the world. And I think there are common historical experiences in those communities that contribute to that, such as poverty, high rates of educational disadvantage, food insecurity, and kind of rapid societal change in those communities. And there's also a big contributor from intergenerational transmission of diabetes. So women having diabetes in pregnancy, their children then develop type 2 diabetes at an even younger age. And then that keeps on occurring in each generation. And that's because of intrauterine programming of organs. And it really changes how the body responds to metabolic primers that set up type 2 diabetes. Walk us through what you did in your study and could you tell us some of the key findings you found and were these what your group expected before you did the study or were these unexpected results? So our study was looking at primary healthcare data across northern Australia, which is quite a remote region covering three different states as well of Australia. And the difference in our study compared to previous studies in Australia that we were using primary healthcare data and outreach data to ascertain cases of young people with type 2 diabetes. And that compared to all the previous studies in Australia and mostly also around the world relied on hospital data or administrative billing data. And a lot of young people with type 2 diabetes don't access hospital services. They're known primarily to primary healthcare services. So I think it's not surprising that the prevalence rates that we found in our study were much higher than what had been reported elsewhere. So our prevalence rates of about one in 150 young people being affected by type 2 diabetes was 10 times higher than what had been previously reported in Australia, First Nations young people, and also much higher than what had been reported in other First Nation communities across the world in the last 25 years, including Canada and the US. One of the biggest things I took from your research letter was how few studies have been done in this community. How much data was there for your team to go by? And you talk about your results being much different. How much different were your results compared to that existing literature? Yeah. So all this very scarce data generally, and I think that it's because a lot of the data has relied on hospital data and it accurate data through primary healthcare is quite a time-intensive process and also requires collaboration between many, many different services to be able to obtain that data. Our data indicated our prevalence rates were 10 times higher than what we had known in Australia previously, though we had no data to go on for our region of northern Australia. And our rates were about three to five times higher than men reported in First Nation communities in the United States or Canada, who probably have the most complete data previously, and were higher than had been reported in any population of young people in the world in the last 25 years. So do note that over 25 years ago, it was very high rates reported in the Pima community in the United States, but we don't have any more recent data from prevalence data from that community to know how our results compare to that. What changes need to happen to prevent and manage types of diabetes in First Nations people? So this is probably the golden question and the reason why you probably undertook your research letter. What kind of lessons can be gleaned from your research? So I think there's been work over probably the last five years that have clearly shown that the young people that are affected around the world by type 2 diabetes primarily come from vulnerable, socioeconomically disadvantaged groups. And so there was a research letter published in The Lancet five years ago which clearly clearly said it's type 2 diabetes and new physio disease of poverty. And I think that is true for our population as well. And so therefore any approaches to managing and preventing need to be quite holistic. And that includes outside of the health sector. We need to address the underlying socioeconomic inequities that contribute to this, food insecurity. And we really need to address the intergenerational transmissions. We need to be thinking of strategies early in childhood, preconception and during pregnancy to try to reduce the risk for offspring. And we need to be thinking about how we really engage young people. I think what we do know from around the world is that these young people are quite vulnerable, often quite isolated. And I don't mean just physically, but I mean kind of isolated from healthcare or have limited access to healthcare. And therefore, these young people have even worse outcomes from a condition that we already know affects young people much more severely than it does older people. Could you talk about that a bit more? I think not many people, I imagine, might know that young people who have type 2 diabetes often have more chronic conditions associated with more comorbidities. What are the differences, the main differences between youth-onset type 2 diabetes and adult-onset type 2 diabetes? So we classify youth-onset type 2 diabetes as being that's diagnosed before the age of 25, I suppose just to clarify what that means. And we know that the pathophysiology is different, firstly. So we know that young people with type 2 diabetes have lost more of their beta cell function, which is beta cells produce insulin. We've lost more of that function right from time of diagnosis. And then the function loss progresses more severely in young people than it does in, and more rapidly than in adults. We also know that they have more complications at the time of diagnosis and develop complications more rapidly after diagnosis. That includes dyslipidemia, renal complications, neuropathies and other cardiovascular complications. We also know that they unfortunately don't respond to treatment as well as adult people, even when you're kind of controlling by adherence factors. It seems to be that the treatment response or the pathophysiology is quite different. And that may be because it's really prompted by intergenerational transmission and that interuterine programming of organs. And we also know that their mental health is a bigger issue in these young people. So the Canadian studies have shown that there's high rates of distress and anxiety and depression in these young people, but also that mental health appears to influence your risk of complications. And that may be because you have more inflammatory cytokines, for instance, in your body, and that increases your risk of renal complications. You've mentioned some limitations already of your studies, such as that there's limited access and limited engagement by First Nations young people in healthcare services. What are some other limitations you can think of about your study? And could you talk more about how those limitations could be overcome in future studies? So we're already working on repeating this audit. So one of our limitations is that not every service was included in every region. So in some regions we had all services included and we feel very confident in the accuracy of the data, but in some regions it's probably an underestimate as we had less services included, though we included the total number of young people as a denominator of our prevalence. So it's probably an underestimate. And I think it's already shown because services have been very interested in these results. Services that weren't involved initially will be involved in the next audit. So I think it's the communities themselves think that it's a very relevant and important study. Some of the issues can be that there's only not electronic data collection or records in some of our services. So we're relying on paper records to be able to extract that. And so we're having to work on systems to be able to electronically extract that data for the next audit. And we also, it's probably an underestimate, is that a lot of these young people are asymptomatic. They don't know they have diabetes.
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And so therefore they're not diagnosed and they don't count in our number of cases. So we were very concerned to make sure that we weren't over-diagnosing young people to have an over-estimate. And so it required a lot of confirmation and communication back to health services to clarify data that had been provided and to confirm that if at all possible by collaborative evidence such as antibody results, C-peptide results, physician letters. And so we feel that the risk of overestimate is probably quite small because of the steps that we took, but the risk of underestimate is probably substantial. So the true prevalence rates are probably much higher than what we've reported. Thank you very much for joining me today, Angela. It's a real pleasure speaking with you. Thanks very much, Jack, for the invitation. You can read the original research letter now at thelancet.com. Thank you for joining us today. And remember, you can subscribe to In Conversation with wherever you normally get your podcasts.
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Welcome back to the anti-racism and medicine series of the Clinical Problem Solvers podcast, where as always, our goal is to equip our listeners at all levels of training with the tools to practice anti-racism in their health professions careers. This episode is the third and final episode of our three-part series on dismantling race-based medicine titled Towards Justice and Race-Conscious Medicine. I'm excited to be joined by my colleagues, Derek and Michelle, who I'll let introduce themselves, today's topics, and our guest. Hi, everyone. This is Derek Paul. I can't say how excited I am for this episode. In part one of our sub-series on dismantling race-based medicine, Professor Edwin Lindo, he talked us through defining race, understanding race as a social and political construct. He talked us through the history of race and its origins as a categorization of people. And he talked about the role that the profession of medicine has played in reinforcing race and racism throughout history. In part two, we talked with Dr. Nanya and Dr. Sai about the way they've seen race-based medicine play out in their clinical practice. They talked about race-based calculators, harm that it's done to patients they've cared for, and they talked about current movements to re-examine and change and some of these practices. So today in part three, we get to talk about what lies ahead when it comes to some of the hardest questions, research, personalized medicine, genetics, diagnostics, race-based pharmaceuticals. How do we move forward with a lens of justice and race consciousness in medicine? How do we reimagine this world and this profession? And so we are so fortunate to have a groundbreaking pioneer, visionary, world expert on this topic with us today. And I'll hand it over to my colleague, Michelle, to introduce our guest, Professor Dorothy Roberts. Thanks, Derek. Hey, everyone. This is Michelle. And I know I speak for all of my colleagues and the CP Silver team when I say that we're really thrilled and honored and a little bit starstruck to welcome our guest, Professor Dorothy Roberts. Professor Roberts is a George A. Weiss University professor of law and sociology. And she's also the Raymond Pace and Sadie Tanner Mosel Alexander Professor of Civil Rights, as well as the founding director on the program on race, science, and society at the University of Pennsylvania. She is a prolific writer, and we'll be sure to include all of her books in our show notes. But we are really thrilled because her writing provides this unique clarity on really complex issues. And I think we'd be hard pressed to find a better person to really help us wrap up this series on dismantling race-based medicine. And so, Professor Roberts, we look forward to your voice and the clarity that you can help us get as we navigate this discussion. Welcome. Thank you. Thanks for inviting me to this wonderful podcast. I've already enjoyed meeting the staff here and the crew, and I'm just thrilled to join you in this important series. Wonderful. Well, I'll kick us off. I think before we jump into the discussion about dismantling race-based medicine, I wanted to start with the basics of defining race. And I know the listeners may recall that we've talked about this before on our podcast, and certainly it's been a part of the previous episodes in this sub-series. But it's such a foundational place and piece of this discussion that I think it's worth going over again and really hearing different explanations. And so, Professor Roberts, I think it would be extremely helpful for our audience to hear your definition of race. And particularly if you could walk us through how the political motivations for creating racial groups helps us better understand that race really is not a natural grouping or in any way tied to biology. Yeah. Well, I define race as a political invention. I know that a lot of people use the term social construction, and it is socially constructed. But I found as I was working on my book, Fatal Invention, and talking to different groups about it, that people could hold in their minds at once the idea that race is socially constructed and that it is biological. Because they would think, well, it's really a biological category, but it's constructed differently in different societies. It has different implications in different societies, but it's really biological. Whereas it is not biological. It may have certain effects on biology because of the way in which it helps to create social inequality, but it is not a biological category. So I like to say it's an invented classification of human beings to govern them. It's a way of managing and implementing racism. Racism comes first, and then governments and societies have to invent ways of racializing populations, classifying populations by this made-up idea of race in order to put into practice racism. If you want to subordinate a group of people and claim that you're superior to them by making up that they belong to another race. You've invented race in order to support the political project of inequality. One example I like to give is interracial marriage bans. So interracial marriage bans were implemented in order to support white supremacy and an idea of white racial purity, which was created to give white people a superior position in society. Totally political, right? Totally political project of domination. And in some parts of the United States, actually in most states, they decided to ban interracial marriages in order to support the privileged position of white people. And so in order to do that, now, again, note, this is all to support white supremacy, okay? It has nothing to do with actual biological divisions between people. It has to do with identifying a group of people in society who are supposed to run things and, you know, can enslave other people and make them seem as if they're superior. Well, now, in order to do that, and to prevent anyone who's not white from marrying a white person, again, completely for political reasons, you have to identify who's white and who isn't white. And so to implement this aspect of white supremacy, you need a racial classification system. I just give that example to show that racial classifications or the idea of race, that human beings are divided into races, is a way of implementing racism. You cannot disconnect them. That's the purpose. The very purpose of inventing race was to support and promote white supremacy and racism and a way to manage the various populations that fit into a hierarchy that a dominant group creates. So that's why I say it was invented. It's the very idea that human beings are divided into races is an invented idea. There is no natural division of human beings into races. Another aspect of it, I think you asked me about where does it come from, you know, so it comes from European exploration and colonialism and a desire by certain Europeans to conquer other people, take their land, take their wealth, exterminate them, and enslave them. And in order to do that, number one, to justify it. Originally, they had to justify doing this to people who converted to Christianity. Because at the time, if you were a Christian, you weren't supposed to be enslaved by other Christians. So they had to figure out at some point when, you know, African people were smart enough to convert and to escape enslavement, right? And so they had to figure out at some point when, you know, African people were smart enough to convert into escape enslavement, right? And so they had to figure out, well, what are we going to do now? We want to enslave people who convert to Christianity. So they began to create a concept of race that certain people were not human. They didn't deserve the way in which Europeans valued other human beings. And all of that stems from Christian theology that is pre-modern, the idea of who you could enslave and who you couldn't be linked to conversion, and the idea that God created the races. You know, this is a creationist idea. And then enlightenment scientists in the 1700s imported that idea into modern science, into the enlightenment, which was supposed to be a break from theological thinking and spiritual thinking. It was supposed to be empirical. And it was also supposed to be connected to certain political principles like equality and tolerance and liberty. So you have scientists borrowing from pre-modern concepts of some kind of creation of the races, totally unscientific, right? It's folklore, it's made up. And then importing it into science in order to help justify violent actions, justify domination and violence and inequality that violated enlightenment principles. But the way to do that is to invent a concept of race where certain people are supposed to be naturally superior, naturally entitled to enslave others.
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Dr. Roberts, Professor Roberts, that makes a lot of sense. And I think it's very helpful for me to think about it as a political invention. And I've also run into exactly what you're talking about, where folks can hold multiple contradictory ideas in their head as well. So what happens often, I'm in the classroom as a medical student and the PowerPoint will go up and you'll be presented with a diagnosis and they'll show you a race associated with this diagnosis. They'll go to the next slide, right? Right. And when I was reading Fatal Invention, I went, oh, my gosh, I had never heard so much clarity and thinking about these, the nuances in why these are there. Edwin Lindo talked to us a little bit about sickle cell and malaria and malaria belts in places like Greece and in other places. I'm wondering, can you talk to us a little bit about why, how we should think about those associations between those things that folks often bring up and say, hey, this is evidence that race is biological and I should practice medicine. I should practice race-based medicine. Yeah. Well, as Edwin Lindo, I'm sure said, I haven't heard the podcast, but I'm sure he made the point that these diseases that are linked to, you know, clear, that have clear genetic associations. Of course, most disease and illness doesn't, right? So already we're talking about a very small number of illnesses that are so associated with one genetic mutation. That's extremely rare. But anyway, it is an adaptation to a particular environment. And that's all it is. It has nothing to do with huge socially constructed and invented groups of people where there is no way you can identify who belongs to that group without referring to the current social and political definitions of the group. And so whatever disease we're talking about where there are populations that perhaps because of adaptation reasons are more likely to have a disease, that because they're more likely to have the genetic mutation. We have to disconnect that from the concept of race, that it's like apples and oranges or putting, you know, a square peg into a round hole. They're just, they're not the same thing. It just doesn't make medical or scientific or even logical sense to try to take a process of adaptation to a particular environment, which may cut across the lines that we think about as our current definitions of race and use race as a way of describing it. It's a bad way of describing the biological phenomenon we're talking about. And so doctors and biomedical researchers tend to rely on race when it just doesn't fit what they're trying to do. I mean, to me, so many of the questions about what to do about race in medicine are solved if you just understand what it is and what it isn't. It's an invented political classification. So we should not use it in describing genetic variation and ancestry that helps to explain why a particular group of people may have a higher likelihood of a disease, race just doesn't fit that. So if you, you know, if you want to understand sickle cell or cystic fibrosis or, you know, or any, any illness. Number one, there's the first question of whether genetics is going to help you to understand it. Most illnesses are affected far more by the environment than by genetics. So, and especially if we're talking about health inequities, those aren't caused by genetic differences. Those are caused by differences in social status, living conditions, experiences of discrimination, and everything that goes into health inequality in the United States and, you know, and around the world. But even if you're talking about a disease that can be connected to a particular genetic mutation, then that's what you should be focusing on, not on race, which is not determined by genes. It's determined by political classification. And I just think if you understand what race is, you shouldn't be. I mean, I think people use it anyway for lots of reasons we can get into that are not, you know, they're not evidence-based or scientific. They have to do with politics. But if the goal is to have more precise, as they say, medicine, then why would you rely on a giant, permeable, flexible, unstable social category like race? Yeah, absolutely. And as I was, I've been walking around thinking about this conversation coming and thinking about to the four of us that would be on the call. And, you know, I remember as I was walking down the street, I was imagining, you know, I bet, you know, and I won't speak for anybody, but I bet we all would identify as Black Americans. But I also bet we have vastly different ethnicities, ancestries, and genetics. And I wonder though, but at the same time, we're all sort of living in the same social environment of the U.S. Do you think that, is race a proxy for racism? Is it a proxy for the effects of racism in a society? Yeah, so I do think that race is a relevant factor or variable for studying racism. In fact, I think that's the only place it's relevant. I think any other medical question you have, whether you're talking about research that's looking for the causes or the cures for illness, or if you're talking about diagnosing a disease in a particular patient or providing therapy for a particular patient, race is not a good category to use. It's always being used for a proxy for something else, even with sickle cell, it's being used as a proxy for the mutation, you know, the genetic mutation. And this is 2021. By now, we should be able to come up with better ways than using these categories that were imported from false Christian theological thinking in, you know, into the Enlightenment era in the 1700s. That makes no sense to me why anyone would cling to those categories that we know the origins of them. And we know that they're being used for proxies for other things. Why can't we study those other things? Now, when it comes to racism, though, as I said before, there is a connection between race and racism. You know, race is invented to promote racism. So yes, people will experience racism differently depending on their race, because the racial classifications are there to manage people in a racist society. Now, the thing, though, about it is we also have to recognize that race intersects with other statuses as well. It intersects with socioeconomic status, with education, with geography, with sexual orientation, with religion. We could go on and on. And all of those statuses I just mentioned in our racial capitalist, anti-immigrant society also affect, well, and gender, you know, all of that. These are all hierarchies that intersect in our lives. And so, and they intersect in society. And so we have to have more sophisticated ways of even understanding the impact of racism on people's lives. I mean, clearly, it's very likely that if you're Black in America, okay, you're going to experience anti-Black racism, but you'll experience it differently if you're a man or a woman. You'll experience differently differently if you're queer or straight. You'll experience it differently if you're rich or poor, you know, if you're a doctor or if you're a janitor in the hospital. You know, we have to take all of that into account. So even though race is relevant, it's not the only factor in determining outcomes of an individual or a group. But at least it's relevant to, you know, it's relevant to understanding racism. It's not relevant to figuring out the genetic predisposition of an individual or in general, the relationship between genetics and illness. I also want to stress though, that genetics isn't the be all and end all of understanding disease. And so it's true that part of the problem with using race to study disease is that race is made up and people who are identified as belonging to a race may have very different genetic backgrounds. But that's not the only reason why it's bad to use race. It's not as if, oh, well, if we get the genes right, we'll solve health inequities. That's not true either. And that's part of the problem with focusing on race is that I think part of the reason why race is so popular as a way of understanding health in the United States is that this nation is obsessed with DNA as being the answer to everything. And many people connect race and DNA. So they put this together in their heads. And so they think, well, race must be a good way of figuring out how to cure diseases and then health inequities, because it's determined by people's DNA, and DNA is the answer. And so I think when we, you know, when to be anti-racist, it doesn't mean, well, then let's just be more precise in our genetics.
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They work in our society to exclude and marginalize people and target punishment and disadvantage on them. That cannot be addressed by being precise as to someone's genetics. And so I think we have to understand all of this complexity and why it is that race is not a biological category and should not be used. That doesn't mean replace it with another biological category is the answer. It means be anti-racist and understand how the biological concept of race is related to racism. So, you know, I oppose the biological concept of race. Yes, partly because it's false, but mainly because it is an instrument of racism. That's why. I'm not doing it because I want to come up with a better way of identifying race, I once was in a workshop at NIH that came out of an article that I co-authored with three other people, including two geneticists, Take Race Out of Human Genetic Variation Research. And there was a workshop called at NIH about it, and all these famous geneticists were there. And I and others were trying to explain to them why they shouldn't be using race as a category in their genetic research. And at the end, one of the researchers said, okay, you know, this was all day we're talking. Okay. And he says, I've had the solution. We can now move forward. I am going to come up with a more precise genetic definition of each race. Where have you been all day? That's the opposite of what we've been trying to get across. You know, that's not the answer, right? So nor is the answer to focus entirely on genetics as if that's going to be a cure. There's absolutely no evidence that genetics has closed the gap in health between Black people, Indigenous people, other people of color, and white people in America. It's only going to be closed by ending the political inequalities that we have. in other words, ending white supremacy and racism in America. And that can't be done by being more precise in your understanding. I'm not saying that it's not important to do genetic research and other kinds of research to understand disease better, but we shouldn't pretend that that's the solution to the really staggering and abominable health inequities that we have in the United States. Yeah, that's such a wonderful overview from the what is race to how does ancestry and genetics play a role. I think another way where individuals have tried to kind of solve this health disparities question and such a really key part of your book, Fatal Invention, was this conversation about race-based treatments. And you provided the excellent example of BIDO, which, you know, I was just on the wards a couple of days ago, and we're still wondering, you know, why shouldn't we be prescribing these medications to our Black patients versus others? I wonder if you could walk us through a little bit of that story. And again, till today, how are you thinking more specifically around race-based medicine? Do we just need to throw this out once and for all? How do you think about it? Yeah. Well, so first, just in terms of the terminology, I use the term race-based medicine to describe all the ways that medical professionals and researchers use race in their diagnoses and treatment and understanding of disease. So race, you know, it shapes medicine and medical practice in so many ways, you know, not just in pharmaceuticals, but in the very concepts of disease, the very idea that people of different races have different diseases and experience common diseases differently. That is so foundational to medicine. But a part of it, and what this leads to, you know, in the 21st century is the idea of developing race-specific pharmaceuticals, so drugs, therapies that are developed and marketed to specific racial groups. And that's what BIDAL kind of was. It was marketed to Black people as a therapy for heart failure. It actually wasn't developed for Black people. It was developed for anyone who was suffering from heart failure on the theory that this drug, by dilating the blood vessels, would make it easier for the patient's heart to pump blood, and therefore they would have a higher chance of surviving heart failure. And the cardiologist who developed it at University of Minnesota, by the way, was a cardiologist, not a geneticist. And he developed it without regard to race. His first patent on the drug did not mention race. It was for any patient suffering from heart failure. Again, based on the theory that the human heart would be benefited by a drug that dilated human blood vessels. Now, the FDA did not approve the drug on his first application because he hadn't conducted new clinical trials. He was basing this on old data from prior Veterans Administration tests of the generic drugs. The drug is a combination of two generic drugs. The drug is a combination of two generic drugs, but this cardiologist wanted to patent it as a single pill. And so he now had to figure out what to do. The company he had licensed it to backed out because it was taking so long. He needed a new patent. And so to apply for the new patent, you need a novel claim. And so he added that it was a drug for African-Americans. So it was for commercial reasons, not for health-based reasons that it became a black, you know, drug for black people. Now I should mention that there were lots of Black people that supported this drug. The Black Cardiologists Association conducted a clinical trial that was eventually done in order to get approval of the drug, a clinical trial only involving African Americans. And members of Congress supported its approval as a race specific drug. And there were some people who the NAACP was in on it, they got a contract from the company that marketed the drug to convince black people to use it. And there was this idea that, well, look, the FDA now finally is attending to the health inequities that Black people experience. But there were also lots of people who opposed it, including myself, and ordinary, everyday Black people who were skeptical of a drug just for Black people. I quote in Fatal Invention, a woman, a Black woman at a meeting where they were trying to convince, you know, the attendees to persuade their doctors, you know, to prescribe Bidol for heart failure. And she got up and she said, give me the drug that white people get. Why would we think that a drug for Black people is going to be the best drug? So, but for me, it was the message that this sent and the, both the message it sent and the false message it was based on. You know, what would, what gives the FDA the idea that this drug would only work on Black people or that Black people's, either their reaction to the drug or their heart failure itself would be so peculiar, you know, to use Samuel Cartwright's term from the 1850s about Black people's bodies, you know, that we're so peculiar that we need our own drug and you can't guarantee it would work on other human beings just because it works on Black people. You know, like where do they get that idea? I mean, that's the message I got from it and many others did as well. Why are Black people over and over again singled out as having bodies that work differently from all other human beings. You know, that's the message I get from the EGFR that reports the results as non-African American, African American. So African Americans can be singled out from all other human beings so that the results of the test have to be adjusted just for us. And over and over again, Black people are singled out as especially peculiar. Now, race-based medicine applies across the board. There are diseases associated with white people as well, with Asians, there's different kinds of calibrations for people of different races. But I'm telling you, the idea of bodily distinction and peculiarity applies mostly to Black people. We get separated out from other human beings in so many diagnoses and treatments in medicine. And the FDA, simply in hearing this kind of objection, said, well, we're using race, self-identified race race as a proxy for genetic difference. Where did that come from? You know, Bidil, genes were not involved at all in the development of Bidil. They assumed that there was some gene or set of genes that made it work in these clinical trials, which again, only had Black people in it, made it work for Black people, and that Black people were genetically distinct enough that that could be a basis for approving the drug just for us. Again, as I said before, there is this, I think, even if it's not articulated, this idea that race is genetic, which is just, you know, the modern version of God created the races, and then nature created the races, and now it's evolution created the the races and so it's in our genes. But it's the same idea just borrowed generation after generation.
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