Split (1)

train · 35.6k rows

text stringlengths 5 11.1k
From the JAMA Network, this is the JAMA Pediatrics Editor's Summary, a discussion of the most important articles published in the latest issue of JAMA Pediatrics. Here are your hosts, Frederick Rivara and Dimitri Christakis. Hi, podcast listeners. This is Dimitri Christakis, Editor-in-Chief of JAMA Pediatrics, coming to you as always with my friend, colleague, mentor, Editor-in-chief of JAMA Network Open, Dr. Fred Rivara, a man who needs no introduction. Hi, Fred. How are you today? Well, this is a little bit of a time capsule because it is March here, early March, and we're coming to you from the Husky Den in Seattle Children's Research Institute in the heart of COVID. The epicenter of the COVID epidemic. And by the time you all hear this in April, we'll see where we are. But for right now, we are practicing hand hygiene very aggressively and trying to see what's going to happen. Things changing by the hour. Literally by the hour. I wish we actually had some science to talk about related to COVID-19. But instead, we have two papers that are important, particularly for those of you that are in primary care. So Fred, you want to go first? Well, the first one is a very nice systematic review and meta-analysis from the folks at Boston Children's about prophylactic treatment for migraine. So migraine, as we all know, is a common problem that we see in practice. The paper starts off with a sentence that says the prevalence is 8% and up to 23% among adolescents. So it's a very common problem. And we have some medications for treatment of it. But the question is, what do we do for prevention of it? There's been more work here in adults, but some work in adolescents and children, as these authors summarize. It's a typical standard emitter analysis. So they fortunately just focused on randomized controlled trials of prophylactic pharmacological treatment for children and adolescents under 18 years of age that had migraine headaches, as defined by the International Headache Society classification system. And these folks looked at the outcomes being changed in the frequency of migraine attacks, the number of migraine days per month, number of headache days per month, and the headache index activity composite index, which includes frequency and duration. And they found 23 studies that were good randomized control trials, and they did a network meta-analysis. And what they found is that only two treatments were significantly better than placebo, propranolol and topiramate. So all the other drugs that we have been talking about, know about, were not found to be effective. And they have some really nice forest plots here looking at this. And things like riboflavin, which I know is pretty popular, really was very ineffective. Valproic acid, sodium valproate, was also not effective. And they also found, looking at the problems of safety, is that propranolol is actually pretty safe. Topiramate and flunarazine actually had less safety than these others. So the two drugs, propranolol and topiramate, are effective, although topiramate has kind of a cost-benefit ratio, which may, in fact, not be all that great. Now, these results support- Yeah, let's talk about the effect size. Okay, go ahead. The effect size is not great. I mean, that's the problem, is these things seem to work, but they don't really work all that great. I mean, they standardize mean difference for proprolol is like 0.6. So it's really not great. This meta-analysis really supports the CHAMP study that was published in 2017. And that found no significant difference between topiramate and metriptyline placebo in reducing migraine headaches. And I think that that's really important. Now, why is that? Well, one of the things is that there's a big placebo effect. In the CHAMP study, 61% of kids seem to get better on the placebo. And that's important. I think, too, is that I see some of our docs giving amitriptyline to patients for headaches, particularly headaches in kids with concussion. And amitriptyline is an old medication, a tricyclic antidepressant, that has a really poor safety profile. Well, not to mention the fact that it's a potentially lethal drug. That's right. That's what I'm saying. No, but I mean accidentally or intentionally. Right, intentionally. Right. You don't want to have it around. Right, and particularly for a teenager who might be depressed. So, you know, I think that, in fact, it really should not be on someone's armamentarium of drugs that they want to try. A, it doesn't look like it works, and B, it potentially is dangerous. So the study is what it is. It says that propranolol might be the drug of choice to go to for prophylactic against migraine in kids. Now, there are some new drugs that are coming out, and these are calcitonin gene-related peptide receptor antagonists. And they are drugs that can be given by injection monthly or even quarterly. And they look like they're quite effective. Now, the randomized trials have just been done in adults with these medications, but they may be coming down the pike for adolescents. So I have two comments on this paper. The first is that they limited, understandably, their search to studies that specifically study children. But given this is prevalent in adolescence, it brings up one of the age-old questions in evidence-based medicine. You know, do we apply literature in adults? You know, how do we magically draw the line at 18 or 21 and say, these studies don't apply? I can see where they don't apply in toddler, you know, well, we don't really see it in toddlers, but in school-aged children. Because, you know, there have been randomized controls, for example, aspirin prophylaxis, baby aspirin prophylaxis for adult migraine has been shown to be effective, I think, randomized controlled. Well, not included here. Fairly good safety profile. Should we be using that? That's the first question I have. And then the second is, when you do see such large placebo effects, one of the limitations of evidence-based medicine is to then conclude this therapy doesn't work better than placebo and then prescribe nothing, which really— So you're saying you should prescribe placebo? We don't do that, right? But that's what's weird about— Right, because we think it's unethical. We think it's unethical, but it's a weird decision we make because if we think it's no better than placebo and we prescribe nothing, we're not even giving the benefit of placebo effect. Right, you're not giving the placebo. So should there be a three-arm trial, which is nothing placebo and active? In terms of your latter point, I think there probably should be. And it clearly indicates that you really can't tell anything from observational studies. Right. You've got to do randomized trials to look at this. And you're right. It may be that we need three-arm trials. In terms of using drugs like 81 milligram aspirin tablet for prophylaxis, I mean, clearly that's going to be safe even in young kids. Right. And it probably is right. On the other hand, you know, some of these other newer drugs, these calcitonin gene-related peptide receptor antagonists. You want to have a safety profile in kids. You have to have a safety profile. We know that adolescent brains are still developing, and we don't really know what the long-term effects of these might be on starting them on a 15-year-old. But I think it really raises important points. And the FDA and the different acts that have been put in place over the last 10 years to try to get more research in kids, you know, it's still a problem. And we still don't see enough studies that have been done in kids because the market may not be big enough. All right. The next paper we have is called Trends in Pediatric Primary Care Visits Among Commercially Insured Children in the United States from 2008 to 2016. So this is a fairly large study using data from a single private insurer that's present in all 50 states to really try to ask the question or answer the question, what are we seeing in terms of visits to primary care pediatricians? The reason I think this is important is because we have seen this rise in these retail clinics, the drop-in docs, and the question is what percentage of kids are now going there either for primary care or for acute care?
And what they found was that if you looked at overall primary care visits, there has been actually a significant decline from 260 in 2008 to 227 on average per 100 child years for a decrease of about 14.5%. On the flip side, preventive care has actually gone up from 75 per 100 child years to 83 per 100 child years. If you take it all together, it looks like there's been an increase in primary care visits and a decrease in acute visits to primary care doctors. They're all going to Dr. Google. So they're doing a mixture of telemedicine, Dr. Google, and these drop-in-the-box clinics, presumably. That didn't go up all that high. No, it didn't increase that much. That increased really actually very little. So the question is, what's happening and what does this mean as a primary care pediatrician? More importantly, what does it mean for kids? So what I found interesting about this was, you know, I started my health services career looking at kind of continuity of care as a predictor of child outcomes, meaning how regularly a child sees a provider and has a relationship then with that provider or their family does, and how that impacts the quality of the care they deliver and the outcomes of that care. And that's clearly diminished in situations where you're not having as much contact, which seems to be happening here. On the other hand, maybe that's achievable through telemedicine. It's certainly not achievable through drop-in docs. Right. You know, I think these changes are actually good. Preventive care visits are actually going up slightly. But the fact that problem-based visits going down may mean that parents are just better educated. Oh, really? And not coming into the doctor where they don't need to? Yes. You know, and you start off with talking about COVID-19. And in fact, that's what we're telling people is not to come into the doctor unless you really need to and then call first. Because we don't want you coming in with contagious illnesses and infecting a bunch of other kids in the waiting room. And in all seriousness, I think that parents may be using social media, may be using available information on the internet to decide whether or not they need to bring their child in for a cold. Now, unfortunately, we all know that the information on the internet is highly variable, including information that don't vaccinate your children. You're really breaking down with protocol here because they did see also an increase in the co-pays, which might be part of what's driving it as well. Yeah. You think it's truly like, they studied and answered this. Your speculation is that this is like volitional on the part of parents. They're voting with their feet. They're deciding, I don't need to go see my doctor. Yeah, they don't need to. And that's good. I mean, if there's no evidence that kids are suffering from not coming in for these illness visits. Right. You know, when I attend on the wards, I feel like we routinely tell families to follow up with their doctor. It's part of the standard of care. When you're being discharged, go see your doctor. And I often wonder, what's the utility of that? Like, you know, I can understand saying, go see your doctor if X, Y, and Z happen, like your child is not getting better or getting worse. But to put that in position on a family, you need to go follow up with your doctor after discharge. Why? Right. And I'm sure that your colleagues in the emergency department do the same thing. Right. It's, you know, you're fine here tonight or, you know, you don't need to be admitted to the hospital, but go see your primary care doctor tomorrow or the next couple of days. Yeah. You know, and some of those may be appropriate, but, you know, for most of the influenza-like illnesses and probably for kids, most of the COVID illnesses, which we know are out there, we don't know, we haven't diagnosed them yet, you probably don't need to see your doctor because A, there's no treatment for it, and B, it's probably going to be a mild illness. Oh, and C, you could infect other people in the waiting room while you're there. Right. So I'm curious, I mean, we haven't done this before, but many of you are probably in primary care, so you can get back to us via social media or email or whatever. Let us know your thoughts on whether or not we should be discouraging acute visits to primary care in the future or being more selective about who gets them. So you can listen to other podcasts at JAMApediatrics.com and you can certainly subscribe to this podcast wherever you get your podcasts. I get it through Apple and believe it or not, I've started listening to our own podcast. Have you? I have. You're hilarious. We're really actually very popular. Yeah, leave that in there. Leave that in there. Okay. Thanks, everyone. Talk to you next month.
Hello and welcome to the latest Lancet podcast. I'm Richard Lane on Friday, June the 5th. This week we're introducing a new Lancet commission, the Lancet Commission about Women and Health. Earlier I spoke to the lead author of the commission, Professor Anna Langer at the Harvard T.H. Chan School of Public Health, and I began by asking her what was the main concept behind this new commission and what progress have we made in women's health in recent times? A lot of progress has been made in terms of women's health, in particular maternal health and to some extent reproductive health as well. But there are many needs women have throughout the life cycle that haven't been addressed yet and the maternal and reproductive health agenda of, is far from finished. So health systems are failing women to a great extent yet. So we came up with this novel idea that why would health systems fail women if most health workers are female? Women who fully empathize with women's health needs, women who can serve other women well because from a cultural perspective, they are acceptable, women who share an understanding of the main challenges, both social and biological, that women face. We came up with this idea that it would be very important to address women and health, not women's health only, meaning the interactions between women as users of the health system and women as providers of health care, and how these dual roles overlap and what can we do to strengthen those interactions. The timing of the commission and your work at Harvard, which we'll talk about as well, is crucial, isn't it? Because it's 2015 and obviously the Millennium Development Goals expire, as it were, in 2015. And we're shifting. There's a shift now, isn't there, between the MDGs, the Millennium Goals, in terms of human development broadly and sustainable development goals. So how does the Women and Health Commission fit in with sustainable development? You are right. We are at a quite unique juncture here. The end date of the Millennium Development Goals is fast approaching and the international community is about to embrace a new set of goals for the next 15 years, the Sustainable Development Goals, that, as you probably know, are going to be many more than the MDGs, that were only eight, and we had three health MDGs, which was quite a privilege for us working in the global health arena. Now, with the Sustainable Development Goals, we will share that visibility with many other goals. So we need to work hard so women's health and girls' and women's rights don't get lost in the midst of so many other competing priorities that are equally important but are not necessarily so much focused on women and girls or not so obviously focused on women and girls. The work of the commission will hopefully shed light on women, the roles that women play as both informal and formal health care providers and the needs that women have. And there are some recommendations that we are making as part of the commission's work to move the women and health agenda forward, both at the global and national levels. So the report will be published in mid-September, right before the UN General Assembly, at which the Millennium Development Goals will be embraced. So this is a critical time. And of course, those big policy commitments will have to be translated into action. So we hope that the usefulness of the recommendations that the Commission makes will continue and very much help with that translation. It's still important to recognise the previously more narrow but previously more important sphere to focus on women's sexual and reproductive health. That was the way the women's health movement was some years ago. The Women and Health Commission is still saying that is important, isn't it? Although some progress, some good progress has been made, the Commission and Sustainable Goals is not sort of turning its back on sexual and reproductive health, is it? Absolutely not. Definitely that's one of the most important dimensions of women's health that still need a lot of attention. That's an unfinished agenda. But at the same time, there are other issues that have increased in their importance over the last 15 or 20 years, namely non-communicable diseases and chronic diseases that affect women disproportionately in many cases, for which women very often, due to gender-related misperceptions, receive later care, poorer quality care than their male counterparts for the same diseases. So definitely, sexual and reproductive health is still very much part of the agenda, but we are now looking at it in the broader context of women's health throughout the life cycle. Of course, the health of girls and adolescents is still very much an area of focus as well. And in fact, adolescents has been, adolescent sexual reproductive health has been recognized as one of the areas in which less progress has been made since the Cairo Conference 20 years ago. So what we are trying to do is to look at women's health comprehensively and get rid of those artificial stages because to a great extent, the health of a girl will influence her health as an adolescent and health during adolescence will strongly influence health throughout the rest of a woman's life. So this is something we try to present differently in the Commission report. The Commission, is it of most direct relevance for women and policymakers within the field of women's health in low and middle income settings, or are there messages here for the entire global population? Yeah, we're trying to hit the right balance here. Definitely, the commission focuses more on the challenges girls and women face in low- and middle-income countries or women and girls in the most vulnerable population groups in developed countries. Well, living in the U.S., I know about those challenges here. They are big. And in fact, they are equally severe as in many developing countries. But we also make some recommendations and state some facts about women's challenges and opportunities in developed countries. So we have quite a lot of content on the situation of women's health and women as healthcare providers in developed countries as well. Would you like to just walk through some of the key recommendations, Anna, for the podcast to make it clear what this commission is calling for and how it hopes to influence the sustainable development agenda from September 2015 onwards, because there are a number of very important Thank you. a few of those recommendations, what would they be? Yes, we group the recommendations in four categories. And I will just mention those categories and maybe give one or two examples. We talk about the importance of valuing women, counting women, compensating women, and being accountable to women. So within those four groupings of categories, we make recommendations mostly for global stakeholders, policymakers, researchers, advocates, program implementers, civil society groups, recognizing that the way that these recommendations should be operationalized at the country level will depend on each context. It's difficult to offer recommendations that would work for the wide range of situations in different countries. So we make that very explicit. For instance, in terms of counting women, we know that in, well, and therefore global aggregates don't disaggregate health statistics by sex. So we don't really have information about the challenges that women face when it comes to conditions they share with men. In the case of immunizations for girls and women, we don't have data broken down by sex. So we don't know. We have some studies that show that women, girls in particular, sorry, are discriminated against and they don't have the same kind of access to vaccines that boys have. But we don't have a way to look at that at a higher level. We only have data from specific studies. So that's one recommendation we make, disaggregate data by sex. Also for the research community, we know that women too often are not included in clinical trials and in other research projects that are very, very important to come up with solutions for women's health needs. But then the findings of clinical trials that have not enrolled women in them are applied for the treatment or whatever of women's health. So that's a situation that needs to change. We also hope that, well, clinical trials will explicitly disclose the sex composition of their sample to make much more visible the contribution of women or the focus on women in those specific studies. In terms of compensating women, one of the most exciting parts of the report is an estimation of the financial value of women's contributions to health care. Yes, that was my next question. It's intriguing, this financial evaluation. Sorry to interrupt. Do go on. Thank you. the Lancet and read the paper, but an estimation of the huge contributions that women make to health care that are completely invisible. That's an invisible subsidy to health systems and health accounts. So we hope that that will become a powerful advocacy tool that people can use to advocate for a better compensation for women or for compensation at all. I mean, with the exception of a few countries, women are not compensated by the health care they provide at the domestic level. Community health workers are very, very often volunteers, and they, well, in the best case scenario, they get a stipend only.
And women, because they need to integrate their professional roles with family obligations and with their own reproductive health needs, very often don't reach decision-making positions. So we need to make that much more visible and encourage country policymakers and global policymakers as well to develop new policies that will help women reach their full potential. Final thought, Anna, for the podcast. Universal health coverage, this is all relevant as well. And it's obviously tied up with sustainable development as well. Universal health coverage isn't the end result, is it necessarily? Because one thing you're very clear about, you've talked about, is the need for not just access, but quality. Do you want to just comment on that? Because it's relevant, isn't it, to this commission? It is very relevant. Universal health coverage is definitely a very important tool to get us closer to where we need to be. But you are right, ensuring access to care is not necessarily the solution. It's part of the solution, but it's not the full solution. Quality and equity are incredibly important in terms of access and quality. There are some interesting examples from the maternal health field from countries that, thanks to conditional cash transfer programs or other financial incentive programs have significantly increased women's utilization of health institutions for delivery. When you look at maternal health outcomes, they have not improved. And although we are still looking for an explanation about why that is so, the most obvious hypothesis is that that is because the quality is still poor in those places. So women go to health institutions where they don't find the care they need for their needs. So you are right. What we need is effective coverage or, in other words, coverage that addresses women's needs effectively. Thank you very much. And just a reminder of the political timetable, the Lancet Women in Health Commission is being published in June. But a reminder that the UN, the important UN Sustainable Development Meeting, that's happening in September. Yeah, that's correct. But what we hope to definitely influence is the translation of those very high level global policy commitments into action at the country level, which is where the changes need to happen. Ultimately, it's there where women and children are most disadvantaged. The most disadvantaged women and children suffer conditions that should have been eliminated by now. So we hope that the Women in Health Commission report, in the context of the Sustainable Development Goals, will provide a roadmap for countries and development partners to translate those global policy commitments into policy and concrete action. Many thanks to Professor Langer. Also to mention that The Lancet has produced a Women and Health Commission podcast in Spanish. More details online. Thanks for listening. See you next time.
Hey, Paul, I'm excited to tell you that we are launching a Curbsiders Patreon. Have you heard about this? I did because I work with you, but tell me more about it. All right, Paul. Well, we want to be able to keep offering this great free content, and we're doing things like upgrading our website. We offer transcripts now for episodes, recording new seasons of our mini series, Teach and Addiction Medicine. The Digest is growing its staff. And Paul, now we're on video. People could see us as we're talking right here. What a treat for our listeners. That's right. So with Cash Slack admitting privileges, they're going to get all episodes ad-free. That's the whole back catalog plus future episodes. And twice monthly, there's going to be bonus episodes where me and you recap a show and answer some listener questions. So people should sign up today at patreon.com slash curbsiders. and you get a whole lot more friends. We are at ACP. This is our recap episode for day one. I'm going to throw it to my wonderful co-host, Dr. Paul Nelson-Williams. Paul, how are you doing? Great, Matt. Thanks for asking. How are you? Good. So we are going to be recapping some of our favorite pearls from day one. We'll be doing this again, you know, throughout. I think we're going to do two recaps this time, Paul. All right, hold. But from day one, we tried to furiously go to a lot of sessions. Maybe I'll, since we're on video here, I probably should introduce our co-hosts before we go to the video. I think better to have them just sitting there awkwardly. The furious transition. Speaking of furiously, let's start. So the hosts of the Cribsiders, both med-peds physicians. What's up? Dr. Justin Burke, how are you, Justin? Doing great. It's exciting to be here back with you guys in person. And you are, even though you've done this for the Cribsiders for years, you are officially here as a recap. You're on the big stage at this conference. That's right. I'm doing a highlight session where at the very end, the very last session where everyone has their suitcases, we're doing a quick recap of the entire conference in case anyone missed the first two and a half days. Now, did they book you or did they book Shrabies for the recap? It's a Shraby. We only come in, we talk to our publicist and we only come in a pair. That's the right move. Yeah. Okay. Chris, Chris the Chew Man Chew. Everybody knows you, Chris. How are you doing? Great, man. I love being here. Well, yeah. As always, Chris, I think you've been on like all conference recaps for ACP and probably several SGEM. Now AAP if you guys are PEDs. Okay. So we're going to go first. First topic of the day, hypogonadism. Paul, episode number one of Curbsiders was hypogonadism. High time that we, almost 400 episodes later, update this. And Paul, you had some great stuff. So let's start us off here. Sure. I will mention that since I wasn't on that episode, it was before I was part of Curbsiders. It's basically not even a real episode, but I will mention this this is this was a great talk by uh dr brad and a walt at the university of washington who talked about the not screening for which we'll get into and management of fibrogynism so the point being he started out with you don't screen so this is not something that you're just sort of shotgun testing for necessarily like it's i think testosterone is checked for a lot of reasons a lot of times patients ask, they may be reporting symptoms of fatigue or maybe they feel decreased attention, but these are not typical symptoms of hypogonadism. The most, I thought this was a funny way to say it, specific, nonspecific symptom of hypogonadism is actually decreased libido. Right. So of all of them, that's maybe the one that should maybe make you think about it. And that requires the presence of a previously intact libido. So it's, if you always had a little libido, that's different than someone who had a libido that was quote unquote normal. And then I could just see Justin suppressing multiple comments here. I'm not going to go. How do you validate what an increased libido? What's a baseline libido that we can use? The Burke libido scale. That's right. You have to be valid. So you're, it's just a test waiting for you to design it, Dr. Burke. I'll work on it. So don't go shotgun testing. Have a relatively high threshold to be looking for. And then in terms of the testing, why don't I jump to that right now? Did you guys know that the CDC cares about CRMT levels? I did not know that. So we are to be looking at, I want to find the exact words here, a validated harmonized assay, which I think is lovely. So the CDC now has a program for validation of this test. You can go to the CDC's website and look for validated labs on their site so that you're making, because we know testosterone testing can be widely variable, and I'll talk about that in just a minute. But to at least have validation within the test itself is helpful. So you can actually check to make sure that your lab is a validated, harmonized site for testosterone testing. So like the INR for testosterone then? Yeah, sounds like it. I don't know. Does that work out well? I don't know. Yeah, so we'll say yes, like the INR for testosterone testing. Other things in terms of testing. So again, if you have, we talked about this, there's a lot of day-to-day variations. So if you have this sort of marginally low level because someone checked your patient comes to you and their testosterone is a little bit low, you must confirm this with a morning fasting sample. The morning sample, I think I knew. I don't know that the fasting part was on my radar at all. Yeah, it is. I think it's hard to always get the morning sample, let alone morning and fasting. But yes, that was Dr. Col audience of these great guests. I do ask, Dr. Xu. It is between 40 to 50 nanograms per deciliter higher in fasting samples. So you can have like this marginal level if you repeat it with fasting and morning sample because it doesn't always have to be, well, we won't get into that, but the fasting samples have less variability among them and also tend to be higher in general. So you can do sort of your initial screening test, but you must confirm with a fasting morning sample. Like 200 tends to be like the low for a lot of different labs, right? So that's a huge difference. It's a big difference. Yeah, that's right. And depending on your reference range, there are maybe less reputable places that have funny names like the Adonis, you know, virility restoration center, I think is one that was cited that might have a higher reference range. So as a result, it's easier to be low. So it's better to, again, the validation makes a difference. often present as infertility in men in their 20s and 30s. And these patients, if they do have Kleinfelder, it's almost always have an elevated FSH and LH, and the testosterone decrease may lag behind that. So you may have a normality at first that then declines over time. And there's a huge phenotype of Kleinfelders. It's not always clearly obvious. About 50% of the time, it's undiagnosed, which I thought was a stunning number. And it matters, especially for these younger patients, because it doesn't necessarily mean there's no reproduction. They actually, 50% of men with Klinefelters have extractable sperm. So if they're interested in having children, there's still things that you can do to make sure that that actually happens. Any tips on recognizing Klinefelters? Because I have limited memory of what that is and how to recognize it. I'm so glad you asked. There was a lot talked about the physical examination specifically and looking at testes volume, which is I've read the reports of my endocrinology colleagues. I'm like, good for you.
It turns out, as you guys apparently have discussed on episode that I didn't pay any attention to, there is an orchiometer that you can actually get from endocrine.org that is like this series of beads and the reproducibility between examiners is extraordinarily high for this. Like it's better than most of physical examination things that we have. So when you're, when you're checking, so 15 CCS is the lower end of normal. So lower than that, maybe think about it and you must measure the testes themselves and not the scrotum or the fluid around them. So you have to actually sort of pull away from the body a little bit when you're comparing to the speed. So it's, that's something I'll work on learning at some other point. And as a pearl to you mentioning how much the misdiagnosis in adolescence, if you talk to an adolescent medicine specialist, they always kind of repeat this about why it's so important to be checking testicular volume after puberty and why pediatricians, not us, but some pediatricians aren't very good at doing genitalia exams in adolescence. So that's an awkward thing to do. And I imagine that contributes to why it can often be missed. I'm so thrilled to have our medipedalist here. For those who are just listening and didn't watch, that was a high five in case you didn't hear it. Which we probably missed. That's better. It was a deeply depressing high five, but it was a high five nevertheless. And then I'm taking too long, so I will just, I think, end with talking about some of the reversible secondary hypogonadism causes so things that we think about that you can actually address are things like obesity opioids sleep apnea acute systemic illness those are all potential reversible causes the obesity one is particularly interesting so if you can you can improve testosterone with increasing your daily exercise with weight loss and and um or the speaker focused specifically on waist circumference when talking to his patients, which I thought was a little bit more satisfying probably to deal with. And then the number I thought was stunning. So in general, over the age of 65, you have this acceleration as you're in the decrease in your testosterone. If you have a BMI over 30, that also causes a decrease. It causes a drop in your testosterone as well. So he made the point that a BMI greater than 30 is the equivalent of aging 10 to 15 years in terms of testosterone loss. So obesity, a really critical thing that you can actually address to fix testosterone levels or at least make them a little bit higher. So I thought all that stuff was super high yield. Yeah. And the waist circumference, you know, it is, we talked about how BMI is not the greatest marker of actual obesity. So it makes sense that that would be, that that would be part of it. But Paul, I wanted to ask you, because you were giving us some pearls about this in pre-recording. Do I have to check like PSA and CBC? Like, what do I have to do before I start someone on testosterone? Like how much monitoring do I have to do? Because that seems like it could be a barrier. Terrific questions. Yeah, and I see a lot of the stuff done in terms of even doing like screening polysomnography in the absence of sleep apnea. So the 2018 Endocrine Society has some safety guidelines about how to deal with this kind of stuff. So you should probably, not probably, you should check a hematocrit in advance of treatment. The one thing that you worry about with actual treatment is erythrocytosis. But you would check a hematocrit three to six months after initiation of therapy and then annually thereafter. PSA testing, you don't have to do unless you've already opened that door. So the PSA recommendations are the same as for you gonadal men. So if you've already started it, you keep doing it. If not, it should be a shared decision-making conversation, but it's not a requirement prior to starting therapy. And it is not necessary to screen for OSA in the absence of clinical suspicion for it or do lipid testing or LFTs or osteoporosis screening unless there's some other reason to be doing it. So you don't have to do those things necessarily before to start treatment. So I thought that was actually really helpful too, because usually the workup that I've seen is really time- time consuming and delays therapy for a long period of time as you're trying to make sure everything is perfectly safe. And I think we maybe worry to be sincere, sometimes that can be misinterpreted as, I don't know, withering or sarcastic, which is why I'm thrilled to talk to you about Grammarly Premium's Advanced Tone Suggestions, which help you reframe your words to be more positive and productive. And this way, your team will be on the same page and your projects get done on time. Competent communication suggestions help you build strong relationships and get things done at work. So for instance, rather than saying something sort of passive, like we may want to consider providing an update, it would tell you to reframe that as we should consider providing an update. And that sounds a little bit more positive, proactive, and will get your team to be more productive. It also helps you reframe negative language, which I need all the help I can get with, to be more solution focused so you can better collaborate with your team, team, your coworkers, and your clients. So rather than saying that marketing strategy isn't right, you would say that marketing strategy needs to be different. And it sounds more positive and people feel less quietly judged, which is, again, something that I struggle with consistently. I have used Grammarly, and I've used Grammarly's tone in speeches and in talks that I've given to kind of help me overcome my tendency to revert back to irony. And it's been very helpful to frame my communications as positive. Thank you. So Grammarly works everywhere that you do, so every important project gets done on time. Grammarly Premium's tone suggestions take your writing to the next level, keeping you professional as you balance being direct and friendly while finding solutions with your team. Plus, Grammarly has a ton of other great features like advanced spelling, grammar punctuation, and concise suggestions to ensure your writing is professional, mistake-free, and clear. The right tone can move any project forward when you get it done right with Grammarly. Go to grammarly.com slash tone to download and learn more about Grammarly Premium's advanced tone suggestions. That's cash lack who he kept like, he had sleep apnea and then he was on testosterone for testosterone replacement. And we were running into problems with his blood, his counts being high. And they actually did therapeutic phlebotomy for him so that he could, because he was one of those patients that just like, he swore like he needed his testosterone replacement. He felt so much better on it and we wanted to keep him on it. And the hematologist was actually doing therapeutic phlebotomy for this guy. Probably part of it was his CPAP wasn't getting like, you know, a hundred percent adequate, but anyway, you know, so there's sometimes there's outside the box thinking, and I thought that was a pretty cool case. I know Stuart, Stuart and I are very proud of that. I recall it being discussed before. All right, but we have the great Dr. Justin Burke here. Justin, what would you like to get into? Tell me, you want to talk some frailty? Let's talk about some frailty. Yeah. We can do a quick review. That was one of the first ones this morning at 7 a.m., but it was a very well-attended show by Dr. Dave Rubin from UCLA, a geriatrician. And one of the big takeaways is that frailty, this relatively ambiguous term that means you're vulnerable for poor outcomes because you're aging. There's 67 instruments as of 2016. So this was even outdated, but 67 instruments to measure this ambiguous term of frailty, which seems overwhelming. And documenting frailty can be helpful to not just predict, but also just kind of really classify what risks your patients are at and to facilitate conversations. My takeaways were here are the actual frailty scores that I think I'm going to go away with and forget the other 64. Okay. All right. So score number one is appropriately named the frail score, F-R-A-I-L. It's a self-report question. It's five questions. Frail is an acronym that's basically asking, you know, how they're getting around and demonstrates very good associations with outcomes, including falls, fractures, post-surgery outcomes, hospitalizations, and mortality. So it does what it's supposed to do, and it's relatively easy to administer.
So like you, Matthew Waddle, exactly, you. Exactly. That's what I was going to say. You would be a one on the clinical fidelity score. Whereas nine is closer to like terminally ill. Like the Williams level. Right, the Williams level, yeah. I was just going to awkwardly pause. My slightly older co-host, Paul Williams, yes. This seems pretty well. It's easy to look up and there's some nice documentation. There's some nice tips on how to incorporate into primary care screening. And then there's the deficit accumulation scale, which also has been very validated to work very well. There's two downsides to the deficit accumulation scale. One, it incorporates up to 70 variables, which is tough to do on a screening. It's a lot. Yeah, that seems somewhat burdensome. It takes time. The other is it is Canadian. Oh, yikes. Sorry to our listeners, at least 5% from Canada, Justin. I'm not valid in the United States necessarily. Oh, okay. Yeah, because I love Canada. I don't know if you have a personal vendetta. Maple syrup and hockey. Tim Hortons. Moose. Yeah, we're doing great. We're building a lot of rapport with Canada. Excellent. Those are my big takeaways from the frailty thing. Did you ever see the movie? Canada? Frailty. I haven't. I just wanted to ask, so, what are we going to do for our patients with frailty? Any things there that we should recommend to them that they can do? This is a great example, and I have two answers. The first answer has six answers. The first answers are there are some interventions that help prevent the worsening of frailty, debility, and outcomes. And these are the classic things we think of, like Tai Chi and yoga movement, some resistance training, nutritional supplements, occupational therapy can kind of help people get around. Specifically, he said not testosterone. So this aligns with the hypogonadism tour. Synergy. But synergy, actually, the callback to the hypogonadism episode. Goal-oriented care is really the other one. And that's going to segue into the second answer is that when someone has frailty, we're not only just trying to prevent it, but it's really to help kind of approach what would you like to do better? And are those things that can be changed as far as getting around the house, spending time with your family, avoiding going to the hospital, and then trying to have those conversations of what interventions might align with those goals, or using these as kind of a stepping point for conversations to have some kind of hard conversations that are really focused on what does the patient want? What are their goals? I like that. Yeah, I like that too, right? Yeah, because if they're like, I just want to be better, it's kind of vague and it's hard. You need like a specific targeted goal that you're looking at. Okay, let's get into blood pressure, Justin. So I'm going to throw something at you here. You know, this is, I'm sure this is true. We are fantastic at treating blood pressure. Most patients that have high blood pressure are at goal. How are we doing overall? Am I right? We're doing great? I think the four of us are probably thriving. You know, I like to think that the four of us are- Especially America's PCP, Dr. Paul Nelson-Nelson. National treasure. Yes. But so here's what I took away from the hypertension. A couple of big things about national trends. First, as you all know, in 2017, the new guidelines made stage one hypertension at systolic blood pressure greater than 130. So that in and of itself increased the prevalence of hypertension, which I think was an oops. I think that was, we didn't see that coming. 30 million, by the way, like not a small delta. Not a small amount, a very large number. They wanted us to treat more people or just recognize it and get more people into treatment early. I know, I understand where it was coming from. It's all about maximizing, optimizing outcomes, preventing mortality. A lot of the details from the SPRINT trial of really trying to work towards improved outcomes with more aggressive blood pressure. So because we know all this information, I agree with you, Matt, we would think we're doing stellar, but it turns out that not only are we not doing well at getting our patients' blood pressure under control, but there is a decreasing proportion of patients who have their blood pressure controlled over the past decade, even without those guideline changes. Yeah. Yeah. Even if you look at the 140 over 90 goal, we were still not doing that great. So then when you lower it, when you lower the bar, it just made it even harder to get to the right. Yeah. So, you know, I think that as we talked about, this is all meant to really identify. We need to be more aggressive in part because it's a form of primary prevention of preventing heart attacks and stroke. We need to be getting people on medications. And in part, you know, one of the slides that she showed from the 2017 guidelines that you saw a lot of foams come out to take photos of was the the algorithm and pathway that basically shows if you have someone in stage one hypertension with a systolic blood pressure greater than 130, so someone coming in 132 over 82, the recommendation is to do a calculation to look at their ASCVD risk score. And if they're over 10%, you need to be aggressive with their hypertension. And so the recommendation is to start BP-lowering medication right then and there. And Paul, you pointed out, I think this is a consensus recommendation, not a, you know, based in... Right, because this risk calculator was designed to calculate ACPD risk for lipid control in patients 40 to 70 and not for the specific group. And this is not something that was looked at specifically, I don't think so. I mean, it makes sense that a high-risk patient should have tighter control, but it makes sense it's not the same as a randomized control trial using this actual calculation. Essentially, what we know about blood pressure is that lower is better for the most part. It's hard to get people too low, so we'll just say lower is better, meaning closer to normal, and then that the longer you have high blood pressure, the worse it is, even talking about dementia prevention and things that's, I think that's why we're trying to identify people early and be more aggressive about treating. It all makes sense. Like when you're thinking, sorry, I don't have to run away, but if you talk about sort of toxic exposures, whether you're talking about too high blood pressure, too lipids, too hyperglycemia, all of it is like the duration of exposure matters. Like it makes sense, but also again, makes sense is not how we should be building a lot of these recommendations definitively. Like we should, hopefully, and I'm sure it is. Yeah, and I think a lot kind of does still fall on expert opinion, and she was a wonderful expert. I didn't mention Dr. Shauna Nesbitt from UT Southwestern, who's the director of their hypertension clinic there. And in line with what you're saying, she really brought up this life's essential eight concept of eating better, being more active, quitting tobacco, sleeping better, managing weight, controlling cholesterol, managing blood sugar, managing blood pressure, all of these kind of holistic approaches. And one that I admit I was not aware of, it's a study from 2018 that kind of looks at the social factors of some of the racial disparities, you know, some of the social determinants of health are a major part of cardiovascular risk. But there's a study in the Regards study from 2018 that looked at what are the clinical and social factors that are associated with excess hypertension risk in Black communities. So in Black communities, we know that they have a higher risk of hypertension. There's a higher risk of heart disease. You know, what's going on there? And one of the biggest mediators of hypertension difference in this study was linked to diet, which attributed to about 50 percent of the access hypertension risk in black men. I think reinforcing this idea that race is not genetic, that, you know,-based medicine is not good medicine. We need to be approaching it from understanding the social differences.
All right. Well, we have, check out, we have lots of blood pressure episodes, one with Dr. Von Pattenasson from UT Southwestern, and then two recent ones with Dr. Jordy Cohen from Penn. So lots of great stuff. My take home is be more aggressive early on, especially if people are very far off goal and I'm using a lot more combination medications, even at low dose, I find I have just better control that way rather than starting one agent. And then I feel like I'm getting people under control faster when I'm using combination therapy earlier on. Yeah, I found doing nothing doesn't seem to help as much as adding stuff. Yeah, don't just stand there, give them blood pressure medicine. Yes. All right. Now let's get into sleep apnea, I know can sometimes be related to high blood pressure. And wouldn't you? Thank you. And my takeaway is that my father-in-law should get a home sleep study. My wife should not. Okay. And that's, I'm not a sleep specialist, but I am, they both have a very high pretest probability in my opinion. So is this because you don't care about your wife then? Or I'm just trying to- I care very much about my wife. And now I know exactly what to recommend for her concerning apnea as well. She's asleep. So one of the big questions that was really talked about is who should get a home sleep study. And there was really kind of a four point test that the doctor recommended. First is a high pretest probability for moderate to severe disease. So someone you think, I'm pretty sure this person has sleep apnea. They're great for a home sleep study. The second is that making sure the insurance will actually approve it. And she talked about how there is a geographic variation. There's insurance variation. Some will only approve home sleep studies. Some will not approve home sleep studies. So this is a frustrating factor for primary care physicians. Making sure they don't have any contraindications. If they're on oxygen, if they're on chronic opioids, if they have neuromuscular disease, if you're concerned about a secondary disorder like narcolepsy, home sleep studies just don't have the technology to kind of identify those nuances. And then making sure the patient is actually able to perform this home test and put stickers on them. There's different ones. There's different ways to do it. But high pretest probability with insurance, no contraindications in the ability to do it. So how do we know what high pretest probability is? What a perfect segue into the next thing. It's like Stockton and Malone over there. We're so close. We're finishing each other's. 30-year-old reference. It's like we're finishing each other's... You taught jazz? Yeah. Stop, bang. Stop, bang is a wonderful pre-test scoring system that we've talked about a lot that she references. Really wonderful to predict someone's likelihood of having obstructive sleep apnea to the point where if you're really scoring high, there's almost 100% chance you have obstructive sleep apnea. But where is this validated? What population was this? It was mostly older, obese men. And so if you are looking at a younger, thin female, the stoppane score essentially underestimates sleep apnea in young, thin females. And so it's not a great test for people who are younger, thin female, the stop-bane score essentially underestimates sleep apnea in young, thin females. And so it's not a great test for people who are younger, who are people of lower BMI, and people who are female. And so even if the stop-bane is low in that population, there's still kind of a concern, I would say a low pretest probability of obstructive sleep apnea. And that would be a patient, like my wife, who would really need to get an in-lab sleep test done to rule out sleep apnea. And that would be a patient like my wife who would really need to get an in-lab sleep test done to rule out sleep apnea. So you're saying if you're witnessing apneas and they're snoring loudly and, you know, they have other symptoms of sleep apnea, but their stop bang is low, you would do an in-lab study for those patients. Absolutely. And as you mentioned, Chris, when we were beforehand, if someone has a high Epworth sleepiness, sleepiness scale score or has other symptoms that you're concerned about obstructive sleep apnea, the stop pain probably wouldn't rule them out if they're this phenotype. Can I ask you a question? I know we didn't talk about this ahead of time. Let's try. Did they talk at all about the procedures for sleep apnea? I know like I get a ton of questions about that. Like patients don't want CPAP. That feels like a of worms, but. Oh, boy. So they did talk about that. And I'd say there's a lot of different alternative treatments that include things like oral. Like the oral appliance that is fitted by a dentist, like custom made, that thing. Exactly. The oral appliance therapy. There are like nasal EPAP devices. There was a handful of other alternative treatments that don't require surgery that can actually be helpful for someone who has a low AHI or someone who has kind of mild sleep apnea. Okay. But those don't work well for someone who has an AHI over 15 where they have more moderate to severe. But you specifically asked me about surgery, so I don't want to ignore your question. For the people who have moderate to severe sleep apnea, CPAP's first line, if they don't tolerate that, fail it for whatever reason, surgery can certainly be an option. And there is multiple different types of surgeries that can be considered, one of which that is actually one of the more successful is actually bariatric surgery for someone who has OBC, which was, I think, fascinating. That is going to be, they're developing new guidelines currently, so they'll be forthcoming within the next year. But that was going to be essentially one of the first-line people with first-line therapies for anyone that has obstructive sleep apnea. Yeah. And nowadays it's probably going to be GLP-1 agonists since it seems that they're working so well that maybe metabolic surgery might be less and less common, at least in the near future. I don't know. Paul, you were at this too. Anything else to add about sleep apnea treatment of that or sleep in general? The prevalence, I thought, I mean, I think we know this already, but it is OSA, sleep apnea, obstructive sleep apnea specifically is the most prevalent sleep disorder, even above, I think, insomnia. 935 million adults, 30 to 70, and I think the number that she said was 70% of patients with sleep apnea are undiagnosed, which I thought, again, was a stunning number. So again, it's worth asking about the symptoms and thinking about it for, you know, if you're seeing like the, if you're concerned for secondary hypertension or the patient supporting fatigue or sort of all the stuff that we know about, like it just, it's worth thinking about because it's extraordinarily common. But other than that, no, I don't think anything specific to add to the great Dr. Burke summary. The one thing that you actually reminded me that was really great from that was after doing the sleep study, a lot of times it will show the central sleep apnea. You did it so articulately. I want to, I want to hear your voice again. So central sleep apnea is something that I don't think about other than like, I feel like there's what, Ondine's curse because it's interesting. And then other than that, I just like saying that, but it's more common than you give it credit for. It's associated. And Matt, I think when we were talking ahead of time, you mentioned like chain strokes, respiration. So you see it with a lot of atherosclerotic cardiovascular disease or cardiovascular disease in general. So it's prevalent in CHF. You see it with patients with atrial fibrillation. You see it in patients after stroke and not necessarily right after stroke. It can be sort of emergent in the years following. There's also a fair amount of opioid-induced central sleep apnea, which is not surprising, but also something I didn't think of very much. So 50% of patients on chronic opioids have central sleep apnea.
So if you have patients like this, I think this is one of the reasons why, if you have significant cardiovascular disease, this is someone who probably should have an in-lab study as opposed to the home sleep study because it's a little bit more complicated than you might think. Yeah, they could have central coexisting with the obstructive sleep apnea. And it's important because there's really great treatment for central sleep apnea now with the phrenic nerve stimulator. She talked about this pivot trial that really demonstrated central sleep apnea can be just very, very well treated with a phrenic nerve stimulator. We also talked or plan to talk a little bit about insomnia. So, because I know this is a big deal. Obviously, sleep medications, not something that you want for long term, specifically the Z drugs, benzodiazepines. Hydrosbenzos for everybody. Right. Melatonin doesn't work too well. And there's, you know, it's not totally benign. So what was the recommendation there as far as treating insomnia? Absolutely. So first line insomnia treatment was, in fact fact not medication, but psychotherapy called CBTI, cognitive behavioral therapy for insomnia, shown to be first line. It can help early on. It's usually a, you know, under eight week program. There's more practice parameters. She kind of hinted at that there's going to be insomnia guidelines forthcoming where this is going to be slam dunk evidence-based first line. But CBTI in person or online. She mentioned apps and online therapy works well. Yeah. So, Chris, tell us about how practical was this to implement at your version of CashLack? At CashLack State? At the Cash Lake State, you know, in our division, we did a great job at being able to send all our social workers to get CBTI certification. They're like, if you look online, they're like one or two day courses where they can get syllabi and get teaching and they get some great materials on how to do it. A lot of our social workers who do a lot of counseling, it's been actually great because they can do CBTI instead of group therapy things. So it can be something a little different if your counselors want to do something outside of like just doing depression, anxiety, and things like that. But, you know, we're also talking about some online resources. Like our sleep docs at the CashLax, they have like mentioned, you know, a lot of them may cost money. Like one that's been recommended is sleepio, S-L-E-E-P-I-O.com. I think there are a couple other ones that I think you saw, Matt. Yeah, the book, I believe it's called Say Goodbye or Say Good Night to Insomnia by Dr. Greg Jacobs. It's an older book, but I've read it. I actually sort of went through the course myself because as I've talked about on the show in the past, I have had some trouble with sleep, particularly like waking up and not being able to fall back asleep. And I found it was really helpful to like, CBTI is basically where you just like sort of teach yourself to retrain your negative thought patterns around sleep. And it's the most effective therapy. If you don't want to read the book, which is like $10, you can get it on, you know, everyone's favorite big online retailer. Or you can go through, there's a, there is an online CB, it's, it's cbtforinsomnia.com. This is Dr. J, Greg Jacobs site. And it's anywhere between like 50 and $70. There's a couple of different tiers and you can actually go through. It's a five-week course to do this. And I think it worked really well. And I think I've been recommending this to more patients, especially the ones that seem like motivated that say they would like to read something about this. Oh, before we move on, there is a free app from the VA called CBTI app. So I think it's on Android and Apple Android and, um, and, uh, Apple devices. Um, obviously a lot of, a lot of our veterans have sleep issues and it's a great app. Our trainee listeners and people who have yet to take their boards. So I'm now going to give you three things that are on every single board examination ever is. And the first is that CBT is first line therapy for insomnia. That will be on every single test that you ever take until you're dead. And then Vibrio. If you have liver disease, that's on every single board. Scorby Mites. Hep B serologies. And then there you go. I've given you three questions. So memorize your hep B serologies. Tell people with liver disease to not step on shellfish. And CBTI is first-line therapy for insomnia. And you've now passed the boards. You're welcome. Okay. Is hiring challenging? Yes. Do you love a challenge? Also, yes. You need a hiring partner that can help you rise to the challenge you need. Indeed. Indeed is the hiring platform where you can attract, interview and hire all in one place. Instead of spending hours on multiple job sites, searching for candidates with the right skills. Indeed is a powerful hiring platform that can help you do it all. Indeed streamlines hiring with powerful tools that help you find match candidates. With Instant Match, over 80% of employers get quality candidates whose resume on Indeed matches their job description the moment they sponsor a job, according to Indeed Data US. One of the things the curbsiders love about Indeed is its hiring platform. Indeed's hiring platform does all the hard work for you. It shows you candidates whose resumes on Indeed fit your description immediately after you post so you can hire faster. Indeed's hiring platform matches you with quality candidates instantly. Even better, Indeed is the only job site where you only pay for applications that meet your must-have requirements. Indeed is an unbelievably powerful hiring platform delivering four times more hires than all of the job sites combined, according to Talent Nest 2019. Join more than 3 million businesses worldwide that use Indeed to hire great talent fast. So start hiring now with a $75 sponsored job credit to upgrade your job post at Indeed.com slash Internal Medicine. Offer is good for a limited time. Claim your $75 credit now at indeed.com slash internalmedicine. That's indeed.com slash internalmedicine. Terms and conditions apply. Need to hire? You need Indeed. Justin and Chris, so I want to switch gears slightly here. Chris, you went to a press briefing on firearm safety that the ACP did because you're here as official press, right? So that's pretty cool. Yeah, that's right. Tell us about that. No, I think it's interesting that all our major organizations are really looking into this and doing like sort of a coalition thing. I was at AAP pretty recently, and they also had similar discussions on this. I mean, really, everyone's sort of looking at this as a really big public health crisis. Thank you. sort of be non-judgmental and then how to talk about safety around firearms. They actually have this brand new online hub for education, which has resources. They made all the annals, publications for free for access. What I found interesting was they also have this recent forum with experts that sort of has all this practical advice on how to talk to patients in a special way. But I think they also rightly recognize that talking to patients with education is one important thing because it's difficult for primary care providers who may not know a lot about guns to even feel comfortable enough to talk about it. But also, you also need to talk from a legislative way. And they also have this online toolkit, which have things like letter templates on how to talk to congressmen and things like that. So I think it was just really the importance of the press briefing really was to show that the ACP really, and many other organizations, find that it's really important to talk about firearm safety. And this is coming from Sue Bornstein, who's actually apparently a gun owner. She understands this. But helping out doctors like, feel more comfortable being able to talk about these things and how to interact in whether with patients or with government entities, I think is important. And Justin, from a similar, like, you know, in the legislative arm where it touches the clinical medicine, you had some stuff you wanted to talk about as well. Yeah. One of the more inspiring talks that I went to was caring and advocating for patients involved in the justice system by Dr. Newton-Kindan, Dr. Scott Allen, and Dr. Emily Wong.
There's a great ACP policy position paper that came out with 22 policy recommendations about caring for people who are incarcerated. The speakers talked about the poorest nature of jails and prisons and that prison health and jail health is community health is public health because people are coming in and going all the time. And it is a public health issue in part because active incarceration worsens chronic medical conditions, increases risk of hospitalization. But one of the core policy components that they talked about is this new, it's called a Medicaid 1115 waiver, where states for the first time can apply to have Medicaid cover people while they're incarcerated. And in fact, California recently put in one of these waiver applications that got approved. And so for anyone in California, up to 90 days prior to their release, they are now Medicaid eligible. And so internists can be going into the jails and prisons to provide care. It's going to be something that tons of other states are doing to get Medicaid dollars. And so for internists, it's going to be something where I think we're going to be caring for these patients more and more, have the opportunities. Wait, Medicaid or Medicare? Medicaid. Medicaid. So it will be state level. So it will be state level. And it would be while they're still incarcerated? That's right. And it would carry over once they're released as well? That's right. And one of the big goals is to kind of help with longitudinal care. So you're getting people hooked into appointments. You're getting people started on hep C treatment. You're getting people on medications for opiate use disorder to make that transition, which is a very vulnerable time for people on reintroduction to the community, making sure that they have all the health care services they need. And we talked about that problem where sometimes patients are actually getting better care and have access to insulin and meds when they're incarcerated. And then when they leave, they lose access and where they don't know what they were getting because it was just being given to them. They had no- Such a passive process. It was a passive process. So- That's really exciting. It's great. Definitely check that out if you're interested. And to round things out here, I just wanted to mention, I went to an aortic stenosis talk. Oh, no, wait. You know what, Chris? I want to go to your phenobarbital alcohol withdrawal to totally change gears. Inpatient alcohol withdrawal. Yeah, yeah, totally. And I actually went to a lot of talks this time, which if you follow us on Twitter, we might post some of that stuff about pain control and OUD and stuff like that. And we also obviously have a great series on addiction medicine. And honestly, that's just an area that I don't have, I'm still learning a lot about. I think one of the more interesting things that was discussed was about alcohol withdrawal syndrome and treating alcohol withdrawal while in the inpatient setting. I think several years ago, I first learned about using phenobarb with like Josh Farkas over on Polmcrit and EMcrit. And, you know, phenobarb has been traditionally used long time before the use of benzodiazepines. And then it fell out of favor and looks like, you know, we're sort of going back to using that more often. Even at my institution at the Cashlack State, you know, we actually have protocol for use of Funobarb early on, which, you know, due to some of these studies possibly looking at decreased use of benzodiazepine and some other outcomes. But I think one interesting thing about the discussion is really during the discussion in our session, they were saying like a lot of these studies actually were small retrospective studies. And they really only compared phenobarb to either placebo or to symptom-triggered benzodiazepines. Some of these patients may actually need like long-acting benzodiazepines, which has sort of been the care for some of our patients who are withdrawing a little harder. Patients with more, right, like a fixed dose benzodiazepine regimen rather than a symptom triggered. And so comparing it to that now. Yeah, yeah. So, and I think one of the cool takeaways from that was she was telling us about this phenomenal trial, because I know Paul loves names of trials. Phenomenal, sure did. But it's spelled- Sounds like a cardiology trial. It's spelled P-H-E-N-O-M-A-N-A-L trial. So hopefully that'll come up soon, but each of the arms are actually comparing phenobarb with long-acting benzodiazepines. So we can look forward to maybe having some better studies that might reflect what we're doing now. And we look this up because it's not just in the intensive care. Patients were recruited from either the ICU, the wards, or the emergency department, at least in the pilot study of the phenomenal trial. So this might be something that touches hospital medicine as well. And I'm interested in it. So Dr. Joji Suzuki, who we had on our inpatient alcohol withdrawal trial, that was a treatment that he really liked. It's institution dependent and he recommended that you just follow whatever protocol is in place in your institution. But maybe if this comes out and the evidence is good, it's gonna be, you're gonna see it in more and more institutions. So keep an eye out for that. To round out this day one, man, we had a lot of good stuff here today. To round out this day one, I went to an aortic stenosis talk, very technical talk, a lot of the imaging findings for aortic stenosis and how to recognize those. But some of the stuff that I think would be interesting to our audience is just thinking about the approach to valve, what type of valve the person gets. And she was talking about how there's, she had a slide that was like, okay, some patients might get a SAVR, which is like the surgical aortic valve. And then they might get a TAVI, which is like the trans aortic valve implant. I remember learning these studying for boards and I was so good at them and now the annotations. it has to be sewn into place. And that ring of sutures makes it usually a smaller valve area than if someone has a TAVI. So we know that patients can get a TAVI and then another transaortic valve inside that. And then maybe even another, this is like Russian nesting dolls type stuff. Like a turducken. Right. Yes, their turducken method. And she said, so some patients might get a SAVR and then a TAVI, and then could they get another TAVI? She said, or the third option is, do they start with the TAVI, which lasts about eight to 10 years, and then they get a surgical valve, which could last up to 20 years if it's a mechanical valve. And then they get, when that fails, they put another valve inside the surgical valve. A little saver sandwich. Yeah. And so I don't know. But she was saying that those are all things that are being looked at right now. And a lot of it depends on age. But if someone gets a TAVI, it's about an eight to 10 year life on that valve. As far as we know right now, that's about as long as the The other thing I was going to say, just because, you know, Paul, you know, I love LP little a, just because we talked about it with Dr. Aaron Mekos. Well, maybe in the near future, we're still waiting on these outcomes data from the LP little a drugs. If some butts were candy nuts. Yeah, sure. But she did mention that people with LP little a tend to calcify their native valves much faster, as do people with bicuspid valves. And just talking about how much calcium burden is on a valve is something that they can estimate it from echo, but also they can actually do like cardiac CT and they can also give a valve calcium score, a work valve calcium score. And that factors into some of the recommendations for severity and things. So as far as the severity goes, you really just have to look it up to categorize your person. But that is, I think that's something just to keep in mind. If you're following your person in primary care, Paul, because I know this probably comes up all the time, like your person is mild or moderate or severe, how often do you follow them? She said it's very individualized. It sounds like you can kind of make it up, but the less severe it is, the longer you can wait between.
But if it's really severe, every six to 12 months is reasonable for echo. If it's moderate, it might be every year or two. And if it's just mild, three to five years would be reasonable. So eventually we'll be doing prophylactic TAVR so that we can do this save her, save I. I've lost track. The other question that we wanted from her was like, so what are we doing with anti-platelets and anticoagulation and valves? And she's like, it's all over the place. So recently. Didn't you say something about like if they're on oral anticoagulation with a VKA for after a while, she'll actually start an aspirin on them Yeah, this was a highly expert opinion But she said that for mechanical valves once they get into that ladder like part of the valve life like the 15 year and on Even if there's there's still beyond warfarin vitamin K antagonist, but she will actually add an aspirin on top of that Assuming that the valve is you know forming, you know changes that might increase the risk of thrombosis. But yeah, it's highly individualized. I have a friend who's a cardiac surgeon. I asked him about like some of this stuff and he's like, if you call a cardiologist and ask them what to do for a valve, they're going to call me and I'm going to tell them what to do. So for our primary care colleagues, just call your, if you have access to the surgeon that put the valve in, ask them what they want to be done because it's all expert opinion right now for the most part. There's newer and newer valves are coming out. They're trying to like go with lower INRs or ones that can get by with just, you know, aspirin, whatever. But that's, it's constantly evolving and we're not going to be able to keep up with it as general internists. So ask your friendly neighborhood thoracic surgeon and see what they want to do. I listened to a thoracic surgery podcast. If there is one, I don't know. Yeah, I was going to say, I thought you said you were listening to a thoracic surgery podcast. All right. So with that, we'll wrap it up for day one here. I want to say one more thing, Doc. Okay, sure, sure. So lest you think this is all purely clinical stuff or even policy stuff, I went to a wonderful workshop about career and promotion that actually featured one Dr. Matthew Watto as well as Dr. Tracy Henry from Emory and Avitalo Glasser, Curbsider's favorite from OHSU. I won't go too deep into it because I don't want to embarrass you, but it was a way about talking about promotion through, quote, non-traditional methods. So a lot about making advocacy and your passions count in terms of your promotion and making your institutions sort of recognize the work that you do, which may not be the necessarily traditional scholarship, but it's still valid and still important. You and Avi talked a lot about sort of social media and how that's gaining some legitimacy and how to talk about that and how to document it and include it on your CV. So again, unless you think the ACP conference is pure clinical, there are actually some really great professional stuff. And I just want to call out Matt doing a great job this morning. Thank you, Paul. And everybody at this table either has been or will be promoted based on things they're doing on social media, digital scholarship, one project or another. So I do think it is something. But yeah, anyway, let's end there. We will come back with some more pearls later in the conference. But this is a good wrap for day one. This is our second recap session, but it's the last day of the conference. Justin is going to be later today, furiously recapping everything on the main stage. He's a professional recapper, but he's lent us his services. So we have him for a little while here. We are going to go through a bunch of stuff. Starting off, Paul, our perioperative chief, Dr. Avital Oglasser, she talked about, what were we calling it? Periatrics? Perioperative geriatrics? When you say we, that's something you were saying. Okay, fine. So it's perioperative geriatrics. She was talking about how this is almost becoming its own field within perioperative medicine. And she talked about physiologic reserve in patients, specifically patients with frailty. Do you want to riff on that a little bit? I mean... Sure. I can tell you what she means by that. So talking talking about you know she she made the example that a 27 year old who has um hemorrhagic shock from a trauma is going to probably have a better outcome than someone who is a million years old not maybe millions overstating but say in their 70s or 80s who does not have a lot of physiological reserve who's had who's lived a lot of life and as a result does not have the same sort of capacity this almost reminded me of like stable angina where like someone is doing everything they can to maximize their blood flow at rest. And then when they exercise, they just don't have any reserve left. She said these patients that are frail just to like get through their day, they're like using everything their body can can like do just to just to get them through their day. So then suddenly you put them under the stress of a surgery and they're not going to do as well. And, uh, you know, she also said the Perry, as, as you told us the other day, Justin, you know, choose a perioperative risk calculator. You gave us a couple ones, um, that we said, I guess earlier in this same episode. And so people can use any of those they want when they're and talk to their patients about this physiologic reserve idea and that it's going to be harder to get through a surgery if you're older and have frailty. Just a quick hit, but actually, you know, since we're talking about ischemic heart disease, and I hope you appreciate that transition. I do. For the perioperative risk assessment, I think so often we think about an ischemic event as one of the reasons for doing our perioperative restraint, but actually heart failure has far worse outcomes perioperatively and post-surgically than, you know, than worrying about sort of an ischemic event actually happening. So I just, we should worry about all of it, but I do think that she spent a fair amount of time talking about looking at LV dysfunction because the worse the LV function, the worse the perioperative outcomes are in there. You may even be a little more aggressive in anesthesiologist is very important. If they see you have a periop test, they that's a big, a big flat red flag for them. So they may use it even if we think it might not change our management, it may change theirs. Chris and Justin, let's go to you guys. We talked to Joel Toff and we talked to a bunch of nephrologists recently on the show about blood pressure and things. Tell us a little bit about the nephro protection lecture that you guys went to. I guess blood pressure control, should we be aggressive there? What should we be doing? You want to talk about the blood pressure? Yeah, I think, you know, he really had three big categories of treatments that you can do other than ACE inhibitors and ARBs. One was aggressive blood pressure control. One was alkali therapy. One was SGLT2 inhibitors, our friend. Specifically, the aggressive blood pressure control is some new data that has really come out that shows even if someone does not have proteinuria with chronic kidney disease stage three to five, aggressive blood pressure control does have positive outcomes. And this is based on a multi-center trial or a meta-analysis of trials that was published in March of 2023, including Sprint, Accord, MDRD, but that essentially demonstrated the probability of kidney failure decreases if a patient has more aggressive blood pressure control. By aggressive, we're talking like systolic plus the 120. Is that right? I think that's their goal is I think, you know, it is really trying to just make it so that it's not. Almost just normal, probably normalizing. I mean, Paul, we've talked about this. Essentially, lower is better with blood pressure. I do think it probably matters how you get there. So I imagine they're not recommending you just like get the blood pressure lower with a Tenelol. Therapeutic phlebotomy. Yeah. Yeah, therapeutic phlebotomy.
Not so much with blood pressure. I think we can talk about some of those other medications. I think by looking at these different trials, they all had different definitions of low blood pressure. So again, sprentacord, MDRV, had different kind of, but to your point, the big picture was more aggressive is better. And so for people who we want to continue to protect their kidneys and put off dialysis or kidney failure, blood pressure is really something that we need to be more on top of. And we've talked about this repeatedly. It's just, it's so easy to fall into therapeutic inertia and think, well, this is close enough. And maybe this is one more reason to not fall into that trap. So Chris, I'm going to set you up here. And I'm sure I'm right about this. When I start someone on an SGLT2 inhibitor, I'm going to tell them that their GFR is going to get better for sure right away. No, totally not. I think Joel also said this when you guys talked to him as well. But, you know, there's actually going to be a dip in your GFR as soon as you start it. And so don't check that chem afterwards because you're going to see it drop. But the thing to know is, you know, even though you get like a three to six dip in your GFR and they even quote it as much as 30%, you'll actually see it start first, but then it slows the long-term, well, it gives you long-term kidney preservation. So even though you have your initial dip in GFR, it'll be much slower in your dip versus if you just didn't do anything without protection. In the placebo arm on some of the studies that they were talking about, you'll just continue to see it go down. So even though they'll cross, just don't check it. This feels like, this is a torture analogy, but this feels like the tobacco cessation thing where you're going to have a steady decline in your lung function no matter what, but the tobacco is much, much steeper. Maybe this is a bad analogy. I'm going to walk it back and just forget we said this. I get it. But I do think that we talked about this with Joel, just sort of SGLT2s. He's not routinely checking. It's not like an ACE inhibitor or diuretic where you check within two weeks or four weeks after starting it. You don't necessarily have to check afterwards. And this is what our expert, David Ross, who did the presentation also said. He does not check in the first few months after starting someone. Okay. And then alkaline therapy. This is in the guidelines. We talked about this with Joel, how there have been negative trials that are well done, but there's also been a lot of positive trials with alkaline therapy. Joel was advocating fruits and vegetables. It seems like that actually can help with this problem. But what did the experts say about that? Yeah, I think our expert really did kind of double down on the KDGO guidelines that talked about how a target bicarb of 22 to 24, at least in some studies, really has shown a decrease in dialysis inception or decreasing people who need to go on dialysis. And there are certainly side effects of the sodium bicarb, most notably things just like GI upset and bloating. And the standard dosing, 650 milligrams three times a day, he was saying it's easy, it's done, but it's three times a day dosing. some there's some pharmacy burden. And to your point, which maybe you're about to say the times when the bicarb might dip down under target, but then self-resolve with just kind of going back to the regression of the means might mean that this is something you only really want to think about if there's consistent bicarb that that is low, below 22 or below 20. I think that was Joel's point about why, or hypothesis about why maybe some of the trials were negative is because maybe the people in the arms, like they had a temporary drop in bicarb that recovered just spontaneously. So therefore, they weren't going to need treatment anyway. So thinking about that. I do want to add one caution to using bicarb too, because I've definitely seen some of my own patients come back from nephrology with it more. And that's one of the reasons why I wanted to do this talk. But, you know, our heart failure patients often have CKD. And so really have to use caution in those patients due to edema and all the excessive sodium that you might see with sodium bicarb. So check out our recent episode with Joel. It was a CKD update episode, which we went into way in depth about this. But Paul, that was a recent episode, but way back, Paul, maybe episode 21 or 22, in-flight emergencies. We talked to a chief resident who had delivered a baby on a plane. And Paul, did you learn anything in this in-flight emergencies talk? Yeah, it was given by Jason Napolitano out of UCLA. And it gave me a lot of fresh nightmare fuel. So that was great. I appreciate that, Dr. Napolitano. I think there are a couple of new things for me to worry about. And so he spoke initially. There's a long list of things that we should worry about that can happen in flight. A lot of them, as we talked about in the show, can be sort of alcohol or medication related. Cabin pressure changes are something that I have not thought too much about, but apparently they can cause wound dehiscence if you're not careful. So if you have someone with a major abdominal surgery, maybe don't throw them on a plane right away because the last thing you want is stitches popping open. He also mentions that because of the changes that happen in flight patients, well, in general, you can see your PAO2 drop by about 25 millimeters of mercury when you're up in the air. So people who have normal functioning, good reserve, you're not going to feel that. You might be a little bit more tired, but it's not going to make all that big a difference. But if you have severe COPD, it can cause an acute decompensation, which feels bad. You can have this hypobaric hypoxemia, which is what you don't want to happen to someone who has bad lungs. Not bad lungs. It's someone who has sick lungs while flying. He also talked a little bit about sort of the practical considerations for supplemental oxygen. I won't get too deep into it, but there's things that pulmonologists can do to determine who needs supplemental oxygen, who doesn't. But you can't just drag your oxygen tank onto the plane. Because it's a bomb. conditions that probably you shouldn't be flying immediately thereafter. So, for instance, if you've had a recent myocardial infarction, at least three weeks after that, before you start flying again, two weeks after stroke, three weeks after pneumothorax makes sense, and then you shouldn't be flying if you're greater than 35 weeks gestation with pregnancy. Also, something that would not have occurred to me... That patient, the one that Angelica then delivered was clearly not following that. And is that because you might deliver on the plane? I think that's exactly it. I don't think it's like the baby's going to come flying out because of cabin pressure changes. But if someone has a recent sickle cell crisis, that's also something to at least be mindful of because the oxygen changes can certainly potentially precipitate that. And then the last thing I'm going to mention is this air rage, which I think we've all been reading about because as the human population just becomes increasingly more awful, people are getting angry on flights. They're yelling at people. These are not surprisingly often alcohol related. Why should we as physicians care? Because you may at some point be called upon to consider chemical sedation for these patients, which sounds extreme until you think about the patient or the passenger who punched a window at altitude and caused a decompression of 35,000 feet. So it can be a problem. And if you're talking about administering medications, you may at least be asked, and I know ethically it feels kind of weird. There was a case of someone who actually got, I think it was 10 milligrams of diazepam who was intoxicated and violent and strapped into the airplane, had seatbelts and stuff tied around the guy just to kind of keep everybody else safe. And probably the guy ultimately passed away from positional asphyxia. So just because of the way he was positioned, and then you add benzos to the mix of alcohol, and unfortunately the patient had a bad outcome.
So at least be mindful. Do they have IM benzos on board? Like, do they have, I think there are feet, uh, at a van. Typically benzos involved in the flight emergency kit. He did go through the list of stuff that's typically involved that, which, and the ingredients and things in that have not changed for like decades at this point. I think, yeah, we, we talked about was an emergency kit and then there's sometimes an in advance airway emergency kit too. You have to ask for it if you want. Well, this was, yeah, I have the list from our episode 19 with Angelica Zen. Also, she was a chief resident at UCLA. I believe this speaker, he hooked us up with her actually way back when. I don't see it on here, but we can, I'll try to look up a more recent list for the show notes to put in there. I always bring on intramuscular benzos onto the airplane. For yourself. Yeah, no, I mean, I have a whole, basically, pharmacy cabinet in my bag, but it's for me. It's not for passengers. Well, let's leave the plane. Let's get into some hospital medicine pearls. I know we just had a hospital medicine recap because we had a team at SHM, but I know some of these pearls don't overlap. So, Justin, I'm going to set you up here. When you're in the hospital and let's say you think someone has like a pneumonia, and of course, I'm going to want to give that vancomycin first. That's the most important. Just get that in there. Beta-lactams, they can wait. Am I right or am I wrong? The vancomycin is the big drug. Unfortunately, you are incorrect, Matthew Otto, and I appreciate that setup. The recent study by Moa and colleagues from Clinical Infectious Disease 2022, hospital-acquired pneumonia, while we'll often treat with vancomycin and a beta-lactam, a beta-lactam going in first has actually been shown to reduce mortality by 50%, 50% improvement in mortality, both at 48 hours and at 78, and at seven days later. And the thought is that because if you have gram-negative sepsis, if you have gram-negative bacteremia, this is really an urgent time to antibiotic. It's important. And unless they have MRSA, like, you know, these beta-lactams are going to be killing lots of gram-positives too in most cases. I'm so confused because I thought vancomycin was the most powerful antibiotic known to man. This doesn't make any sense to me. It totally messes with your mind. And so you might say, you know, well, what about if a patient has MRSA? Are those patients more likely to die if they're getting beta-lactams first? If there's a delay in vancomycin, how does that affect patients with MRSA? And in fact, administration of vancomycin prior to a beta-lactam was not associated with improved survival in patients that ultimately had MRSA. So you're not, even if you have a high suspicion of MRSA, delaying the vancomycin to get the beta-lactam in first did not have any negative effects. It's beta-lactam first. And some hospitals, I think, are now starting to make that a part of the order set, where if those antibiotics go in together, beta-lactam first. Because this came up, I sort of, I'm glad we have evidence for this, but I've had nurses ask me that, you know, you're in a rapid response or something, you order the antibiotics, they come up from pharmacy, they're like, which one do you want me to give first? I have one line. And, you know, I think this is very clear that we should give the beta-lactam. So, love this pearl. And we should mention, it was Dr. Bradley Sharp from UCSF. He was the best. This was like a comedy show disguised as a hospital update. He's done this three years in a row. I didn't see his talk this year, but the last two years I saw, he's fantastic. I'm a fan. He was great. There were so many great... He was sharing pearls like a hippie commune at a seaside retreat. Okay. I don't get the reference, but... Because they share because it's a commune and they're by the seaside. There's a lot of pearls. Are there? Wow. That's pretty good, right? That was pretty good. It is not. I'm pretty proud of that, actually. Yeah. You can use that later, Paul. Thank you. I appreciate that. All right. Time-wise, Justin, let's get one more pearl from this. Can I prompt you, if I want to make the patient feel like they really know what's going on, has anyone looked at, like, does that actually help? Because patients are like, I don't know who's taking care of me. I don't know when they're coming by. And you're like, good, and slam the door. This is a great question. And what a great QI project for every resident or early faculty member in the hospital. There's a study from Journal of General Internal Medicine by Abedin College that basically demonstrated having standardized hospitalist information cards that explained how to reach your attending and when people are coming around. This is when we round. This is when we put in orders. This is when we are doing discharges or seeing new patients. Giving a card like that with that information to the patient improved patient satisfaction, both in a pre-post analysis and comparison to groups that didn't have their card. It increased, quote, top bots excellent patient satisfaction from 50 to 70 percent, increased the likelihood of excellent patient satisfaction by 2.3 times. People really liked understanding how the process worked and understanding how they could contact their team if they had questions. And this is like an easy thing. It doesn't take a lot of effort. Personally, I have business cards printed up with Paul's information, cell phone number, home address, email address. And I just say, this is America's primary care physician. He can handle anything you need. All right. So I want to move on and get to Paul. The genitourinary symptom of menopause. You went to a talk. Former Curbsiders guest, Dr. McNeil. Former favorite, well, still current favorite, Dr. Melissa McNeil, now at Brown. So great talk. And I'll go sort of broad strokes for this. But we talked about the genitourinary syndrome of menopause. And basically, this reflects a deficiency of estrogen on the entire female genital tract. So this includes the vagina, the labia, the urethra, the bladder. The points to be made here is that a lot of patients who are experiencing this are not going to be currently seeing a gynecologist. This is the domain of an internist because these patients may have aged out of cervical cancer screening. They may not have a need for contraceptive management. So they may not have a gynecologist that they're talking to about these symptoms, but they may not also volunteer them. So the prevalence in terms of reported symptoms is wide. It's between like 27 and 84% of postmenopausal women are reporting these symptoms, which can include things like vaginal dryness, painful sex, urinary burning or dysuria, urinary incontinence, vaginal discharge, counterintuitively burning or bleeding. So the point being is that you have to ask about these symptoms and you should also ask about sexual dysfunction and then specifically the impact on quality of life, like how much does this bother you? And particularly patients with cancer history, so breast cancer is of particular importance or gynecologic cancer is obviously asking about where the cancer was, when it was diagnosed, what treatments the patients underwent, because even things like aromatase inhibitors can cause significant symptoms of these genitourinary urinary syndromes of menopause. From an exam standpoint, you know, you're not doing a pap necessarily, so you don't need to visualize the cervix, but you should look, obviously. That's, I think, where a lot of learners perhaps fall down. Externally, you'll see things like reduced tissue volume and so narrow introitus. You'll be using a small speculum for this. You'll be using lots of lubricant and you may see things like loss of vaginal rugae. You may see pale vestibular tissue. There's a lot of other findings that you can see with this.
Most women with GSM have a pH greater than 5.0. On a wet mount. If you do one, you'll probably see more than one white blood cell per high-powered field because there is some inflammation there. And you'll also see immature vaginal epithelial cells with these large nuclei that have a name that I have immediately forgotten. So, sorry. And then the treatment, it's probably a lot of time was spent talking about this. You have the option of using moisturizers and lubricants. There's water-based lubricants and oil-based lubricants, all of which have their own potential pitfalls. So the water-based lubricants can cause epithelial damage. The oil-based can erode condoms, importantly. You can increase sexual activity. That's where it's recommended. Dr. Neil nailed me the point a couple of times. If you don't use it, you lose it. So it's by, you can do sort of do gentle stretching on your own, but if you can remain very sexually active, that is also encouraged. Pelvic floor PT can also be helpful. And more fun. And more fun, for sure. If done correctly, at least. And then we spent a lot of time discussing vaginal estrogen and the different formulations therein. So there's the topical cream. There is a pill that can be used. There is a ring that can be placed every 90 days or so. And each has their different benefits. It's importantly, it's the one that the patient likes the best and the one that insurance covers because there's a lot of insurance variability. But these medications are extraordinarily effective. They improve quality of life. They can improve urgent incontinence significantly. They can reduce recurrent UTIs. Patients just feel better using them. And they're very, very safe. There's no, there are very few contraindications that most patients qualify for them. We just don't. They're widely under-prescribed. The only things to be thoughtful about are your patients who have the history of malignancy. Maybe not the only thing, but probably the most important thing is estrogen-sensitive cancers you want to be a little bit careful about and make sure that you're talking to the patient's oncologist if you have any kind of concerns, just making sure that you're okay to do what you're going to do. But for the most part, patients would qualify for them and would do well with them. So just don't be shy about using them. Yeah, don't be shy about asking about this condition because it's, I think when we've talked to other experts about this, people are not often volunteering this information. So it's something you have to ask about if you're going to be helping patients with this. All right, So switching gears here, Paul, a friend of the show, Dr. Amy Oxentenko, did another updates on gastroenterology. They ask her back every year to do this because she is fantastic. Yes. And so she talked about two fun studies. So Justin and Chris, you guys are pediatricians. You're familiar with the Bristol stool scale? Very familiar. Yes. Yeah. So it's the three and fours. That's where you want your stools to be. These are like the sausage-like, the softer ones, I think. It's really one in five, I feel like, that you want to stay away from. One in five. Okay. Those are the ones you don't want. Yeah. So one is like pebbles. One is pebbles. Five is like all water or something. Five is diarrhea. Diarrhea. Okay. All right. So three and four, that seems to be the, I don't know, it feels weird to call it the sweet spot. It's the sweet spot. Let's say it. Let's say it. Okay. So patients with hepatic encephalopathy. So because not all bowel movements are created equally, Paul, you're going to groan through this session. Not all bowel movements are created equally. So if someone's having two or three bowel movements with like Bristol stool scale one, like pebble-like stools, that's probably not helping as far as preventing their hepatic encephalopathy. So they tried to look and see if incorporating the Bristol stool scale into patient counseling about how to avoid hepatic encephalopathy worked. And it actually looked like when they were being treated for their hepatic encephalopathy with, let's say, lactulose and told to have two or three bowel movements a day and hopefully having Bristol stool scale like three or four stools rather than one or, you know. Or seven, I apologize. One to seven, one to seven, one to seven. I'm a bad pediatrician. You're a bad pediatrician. Okay, one to seven. So anyway, these patients, when they were having those Bristol three and four stools two or three times a day, they had lower admissions, less hepatic encephalopathy related admissions, and they were more stable on their hepatic encephalopathy therapy. So I'm going to definitely, this practice changing for me, I'm definitely going to start incorporating that into, it's fun to talk with any patient about, you know, the Bristol-Stool chart, but I think especially for these patients. People love talking about their poop. They do. Yeah, it's a weird thing. That's one of the weird benefits of being a doctor. People will talk, they'll meet you for one minute and they'll immediately start talking to you about bodily functions, which normally they don't talk to anybody else about. Okay, the other one, and I know we've talked about this on the show before, the pickle juice stuff, right? Justin, you- This is one of my favorite anecdotes. Evolution of pickle juice? How the podcast affects medical education in that we had a episode with Joel Toff about chronic kidney disease when I was a resident. So it was five years ago or so. And he dropped this pearl that pickle juice can help with muscle cramps that I remember doing the fact checking because I was the correspondent at the time. And there was no evidence for this. It seemed like he was just kind of pulling it out of thin air. And then I was a senior resident at the Johns Hopkins Hospital. And I was looking at an H&P from an intern that specifically said with a little open checkbox, pickle juice for muscle cramps. And I remember thinking like, this is the power of podcasting. There's no way this guy heard it from anything other than the curbsiders. And now, six years later. We have a study. Yeah, the pickles trial. And I'm not sure, I haven't confirmed this with him, but Elliot Tapper, he has claimed he listens to the show, which I don't know why he would, Paul, but he says he listens. So maybe he heard pickle juice on the show. Suspiciously, the exact amount of time to do a pickle juice study would be about five years. He picked the wrong organ, though. So pickle juice in the pickle study, spelled P-I-C-C-L-E-S was in the food as a medicine issue of the American Journal of Gastroenterology in 2022. And I mean, there was a lot of great stuff she talked about with this, but essentially it did pickle juice, a tablespoon of pickle juice did help compared to placebo to, and of course, this couldn't be a blinded trial. They were doing tap water versus pickle juice. So it's hard, it would be hard to blind this. They could have done better than tap water. Maybe they could have. All right. Sorry about that, Elliot. We don't mean to criticize. We love this study. So this was, they limited the patients to three tablespoons per day, worried about sodium loading. And it was like 69% versus 40% of patients had their cramps aborted with pickle juice compared to tap water. So a 29% more reduction in leg cramps. On the visual analog scale, it was a reduction of about two points with pickle juice compared to tap water. There wasn't weirdly a difference in health-related quality of life, but they didn't find any adverse effects on ascites. So I think this is safe to recommend up to three tablespoons a day of pickle juice for your patients. Plus, it's fun to recommend and talk about. And I'm a fan, Paul. And did you specify what type of pickle juice? I feel like this is important. Thank you, Paul. Yes. So this was brined dill or kosher pickle juice, not the sweet or bread and butter pickle juice.
They're delicious, you psychopath. All right. Well, anyway, I am not on board with that. And by the way, never had a leg cramp. So I'm saying, just because they weren't studied doesn't mean they don't work. All right. I've totally lost track of thought, Chris. Chris, you know, we're talking about, there's a lot of sodium in pickle juice, but you went to a hyponatremia talk. And I want to know, I want to know about this U to P ratio. Tell me about that. Yeah, so it's Saturday morning and it was the seven o'clock session on Saturday morning. And I was very impressed by how many people were actually there learning about hyponatremia and SIDH. You know, we've talked about hyponatremia a bunch on the show with Joel. And I think one of the things that I don't think we brought up during that show was the use of the U to P ratio. So U P ratio, it's urine sodium plus urine potassium divided by plasma sodium. And using that ratio, I think one of the things out of the talk was discussing how actually how poorly people actually do respond to fluid restriction when you have hyponatremia. And so one good way to sort of see to predict whether they may respond is doing this U to P ratio. And so if that ratio is greater than one, then those are the people that you might want to try a different type of additional treatment besides fluid restriction. I think what was nice about the session is they talked about and actually brought some really good studies talking about, you know, things like Vaptans. And so they talked about the salt trials. But, you know, they tend to be very expensive. And they also, I think they limit the use to more than 30 days, to less than 30 days because of toxicity issues. But what Joel brought up before is the use of urea. And I thought that was really interesting. During the talk, he sort of did the comparison between how much osms there are. So usually it's like 30 grams of urea equals 500 milliosms of solute, which equals 15 grams of like salt tablets or 88 grams of protein, which is apparently a 16-ounce steak. And the joke was they'll probably die from MI before they get their hyponatremia fixed. But the point is when you're, and was this for the U to P ratio, were they specifically talking about SIADH? Yes, yes, yes. Okay, yeah. So with SIADH, would they respond to fluid restriction alone or are you gonna need to boost their solute intake as well? Correct, correct. Yeah, and we have some equations in our original hyponatremia show notes where Joel talks about like a person's solute intake is roughly like 10 milli equivalents per kilogram. So a 60 kilogram person would take in 600 milliosms a day. So when you're talking about 30 of urea is 500 milliosms, that's almost like doubling their solute intake for the day. And that favors these equations and it's going to really let them have much more liberal fluid intake and get rid of that extra free water. So, because you can't pee out just plain free water, Paul, you need some solute. Hard as I've tried, you're right. You're right, yeah. All right, that's great stuff. So, urea, I don't know. Did he talk about cost of urea? I mean, in the hospital, it hasn't been an issue, but I haven't prescribed it outside the hospital too much, but I think that might be a concern. Yeah, so the big thing is urea is considered a dietary supplement, so it's not prescribed. You can buy it. And one of the big things is it tastes pretty bitter, which is why they have to flavor it. It comes in lemon-lime flavor, which is weird. Here, taste it. Help with your urine. Take this lemon-lime flavored drink. But apparently the price goes between $90 to $240 a month, depending what type of version you have, whether it's flavored or not. So, but, I mean, you think about it, it's still cheaper than many of the VapTans, so, and probably can take it for a much longer time in terms of safe. Yeah. Here's this number we're not happy with that you're not feeling. You should probably take the stuff that tastes awful. It's $200 a month. You know, Paul, that cost gives me a little bit of, you know, discomfort right here, Paul. You might say I'm having some dyspepsia. I wouldn't just say that. That's not what dyspepsia is. Did you hear any good talks on dyspepsia, Paul? Are we still friends? Do you hate me? Should we end the podcast right now? Oh, that would be miserable. That's just the way that this works. Those patients are probably invariably going to get an upper endoscopy just to make sure that you're not missing anything scary because they are having persistent discomfort after meals. You have to investigate it. But she has this great way of framing the conversation where she tells patients, listen, I know that you have functional dyspepsia. You meet all the diagnostic criteria. We know what this is. We're doing our due diligence here. So we're going to do the test, make sure we're not missing cancer or anything scary, but we already have the diagnosis. And I think this framing happens because so often we send patients for testing that comes back negative and then patients interpret that as that means there's nothing wrong with me or that you don't think that there's anything going on with me at least. And this way, she's framing the conversation. She's setting expectations. We know you have this disease. We know that you're miserable. We're going to drop this to treat you. We're just checking to make sure we're not missing anything else. And that way patients feel validated. They understand the process and they're more likely to have a good relationship with you, which is, it sounds like 90% of the fight of actually treating this. So I thought that was a really great way to have the conversation with patients. And we probably missed that piece a lot of the time. Yeah. And she made the point because of a lot of the therapies for this are related. They can, medications like TCAs that are also antidepressants or anti-anxiety can be anti-anxiety medications. She tells them, I know these are medicines that are also used for anti-anxiety, anti-depression. In your case, I am using this for functional dyspepsia. And she sort of frames it that way because she says, if patients think you're just treating anxiety, they're not going to take the medication. So it's very important how you talk to patients about this condition. And we talked to her about disorders of gut-brain interaction at length, where she really gets into depth of this. So if you're interested in more, check out that prior episode with Dr. Wang. Paul, at the same session, and Justin and Chris, I think it sounded like you guys had a little more experience with Cystatin C, but I went to that because I'm interested in that. I have not used that. I don't think I've ever ordered it actually. And I'm sorry, I don't have the speaker's name in front of me right here, but he was talking about use of Cystatin C, saying that it's affected by fewer non-renal factors than something like creatinine, which we know is dependent on like muscle mass and it has its pitfalls in interpretation. So he did say that it is a good way in some patients to reclassify CKD. So based on their creatinine, their EGFR is estimated to be somewhere between 45 and 60, that actually Medicare will cover Cystatin C being sent because you can actually reclassify some patients as either having worse or better GFR compared to what you would have estimated with a creatinine. So I think this is something that maybe will become more common right now. It's a send-out test and it's a little more expensive than creatinine. So I think that's where it's been limited in usefulness. What in those patients, it can be very helpful. And I think that point of differentiating, especially like 3A versus 3B, can be, you know, a very different prognosis of a patient. And so I've used it a couple of times.
By that time, you know, the patient has moved out of state and, you know, you don't even see them anymore. Yeah. Although I do feel that, you know, as this test becomes probably more accessible, it's probably going to become our gold standard in the future. I just feel like we're going that way. You may be right. You may be right. And calling it on the show right now is just going to make us look good in a couple years. Because if it doesn't happen, no one's going to remember that you said that. If it does, you can always go back and mention this point. Off the cuff, I just wanted to, the other speaker there was Dr. Stephanie Mayer from Richmond, Virginia. And she talked about terzepatide, which I feel like there's a lot of interest. It's not yet as of today. And she made this point. She's like, you have to keep looking it up every day because any day now, it's probably going to be approved officially for weight loss, but right now it's just approved for type 2 diabetes. In the absence of diabetes, you mean? In the absence of, yeah. Right now it's only approved for diabetes, but it will probably be approved for weight loss even in patients who don't have diabetes in the very near future. She said that this is, it seems like it's more potent even in head-to-head trials of semaglutide, the one milligram dose for diabetes and lowering the A1C. The A1C drop is like more than 2% at several of the doses that were looked at. The weight, the people were losing something like 7.8 to 12.4 kilograms on this medication. And she said that we're still waiting for the cardiovascular outcomes trial with this, because, you remember the glitazones had, one of them was canceled. It was rosiglitazone was canceled, right? Because of worse cardiac outcomes. So that's how we accidentally found out that SGLT2s and GLP-1 agonists have all these other benefits because we were doing the safety trials. And we found out that this is like, wow, this is not only is it safe, it looks like it's really good for the heart. So we're waiting for the outcome trial for cardiovascular outcomes. That's expected October, 2023. So hopefully that'll be good. We know that there's black box warnings for thyroid C-cell tumors, which they saw in rats. So people with like medullary thyroid cancer or men, multiple endocrine neoplasia type 2A or B shouldn't take this. But the other point she made is that when patients are adjusting their doses of, and I believe she was saying either GLP-1 agonists or GIP GLP-1s, they should use an alternative contraceptive medicine for four weeks after the changing the dose or starting the agent, which I had never heard of before. And she said her and her clinical pharmacist looked it up and they couldn't find any like studies of this, but that they were just like, okay, people need to know about this because that's like a, you know. That's a class for all classes? It seemed like it was a class thing. Yeah. So I'll see what I can dig up in the show notes. Interesting. Because you remember with our metabolic surgery, there's sort of this period of hyperfertility sort of post-operatively where you had to be especially mindful too. It's like, I wonder if there's not some, now we're outside the realm of my endocrinology expertise, but like, it just, it's, it seems like a consistent theme. Interestingly. You can still fly on a plane though, right? It just depends as long as you don't have anything flying out of you. Paul, so, you know, you seem upset. And I know you're an endurance athlete, so I worry about your health. Is there a chance your CAC score is higher than a non-endurance athlete, and should I worry about that? I'm really stretching these transitions. I think they're doing great. Because also, by the way, my CAC score, I'm sure, is a bazillion just because of a number of lifestyle choices that we don't have to get into here. But this was almost a throwaway point on a recent talk, like a talk that happened as of this morning, and I just want to make sure I have the name here so that I'm giving sufficient credit. This was Dr. Lauren Weber from Confluence Health in Washington who gave the talk on cardiovascular risk reduction and lipid management. How low should you go? Answer, pretty low. But a point that she kind of threw out there is that endurance athletes tend to have higher CAC scores, weirdly, but also they also tend to have better cardiovascular outcomes. So they're sort of the one subpopulation to maybe use with caution when you're thinking about coronary artery calcium scoring. In most cases, all plaque matters and confers some risk. But in those patients in particular, it kind of muddies the waters a little bit. So just do bear that in mind when you're doing calcium scoring on patients who tend to be endurance athletes, which I'm sure we all have just hundreds of. It's a healthy type of calcium, I think. I don't. I mechanistically, I don't fully understand. I'm sort of curiously looking through articles, hoping that Matt wasn't going to throw it to me, but I've not found a super good explanation, but it's just something to be mindful of when you're doing your testing. Well, Paul, I'm sure we'll all be tearing our hair out about figuring out whether or not that was... But Paul, we have a chief of dermatology, Dr. Helena Pacheca. She was here giving two great talks. Her hair and nails talk, which she gave yesterday evening, but I watched this morning. The replay, I would encourage everyone to watch the replay of it. It's fantastic. She had some really great pearls. I'm going to focus on just one of the nail pearls here because this is something I've always been worried about. She mentioned that in patients with black or brown skin, a large percentage of them by the age of 50 are going to have at least one nail with hyperpigmentation. And what do we do with that? And there's some benign features that you can look out for, especially if the patient, you ever get the patient with that like hyperpigmented band across their nail. You have the longitudinal melanin, you see it in your heart goes a little bit faster. Yes, exactly. So what do I worry about here? For the longitudinal band, there are some things that should make us feel less concerned for malignancy. So do you want to take a guess at what any of those are, Paul? So I would guess, gosh, if it's on every single finger that is reassuring as opposed to sort of one that is focused, I would imagine. Yes, there you go. I feel like the one we're supposed to get really excited about. I feel like we should have Family Feud and like it flips down. Yes, good answer. Thank you. If it goes into the nail bed, I feel like that's one that I'm supposed to be a little bit panicked about too, which also makes sense. And then otherwise, no. Tell me what else should be concerning or reassuring to me. So what would you like to see? A streaky streak or just a uniform band with like very clear borders? i feel like the fact that it's even given the name streaky streak seems bad like if you're if you're calling it something that probably signifies something somebody gets clear borders are better if you're if you're yeah yeah so if it's a uniform uniform band uh clear borders like sharp borders that's that's better um if it you know from proximal to even if it goes proximal but i'm i'm not uh i'm not speaking well today paul yes, if it, you know, from proximal to, even if it goes proximal, but I'm, I'm not, uh, I'm not speaking well today, Paul. Yes. So if it's a clear band with sharp borders, that's better than if it's the band, it's kind of streaky and you're like, where does the border of this end? You know, that's the streaky streak that you should be worried about. You're right. Multiple digits is better than having it on a single digit. It's the, it seems like the thumb is the most common place that might be involved. Uh, what about, what if they say that they had a history of trauma? Like, is that reassuring?
Yeah, let's get some other people involved in this game. Okay, Chris, great question because weirdly, I would have thought trauma would be a benign thing, but she said that it seems like maybe this, it could be recall bias, but people who report a history of trauma to the nail actually more likely to have a melanoma, which is weird. That was not intuitive to me at all. Justin, what do you think about the onset? What's more reassuring, chronic or abrupt onset? I am going to say that chronic is more concerning. You're wrong, Justin, but that's a nice try. Thanks for playing. So chronic, yeah. So multiple digits, chronic, uniform band with sharp borders, that's all stuff that's good. And if you close your eyes and you feel the nail and it feels nice and smooth, that's also reassuring versus if you're feeling the nail and it feels very dystrophic and rough, that's a bad sign. If it's a single digit, older age person, abrupt onset, these are all things that maybe sort of raise your, they have the streaky streak. You got to raise your concern for a melanoma and you're going to send that person. Again, a regular border is being bad and skin stuff, so not surprising. pearls in that talk and maybe one hair one hair one Paul because we we talked about the three common types of non-scarring hair loss being alopecia areata androgenic alopecia which is like the male pattern baldness and then the other one was uh telogen effluvium where people are really stressed by something and their hair has just fallen out but the other one traction alopecia Paulcia, Paul, were you aware? Have you heard of this one? I have. And we talked about this ahead of time. This kind of crosses between, initially, it can be non-scarring, but if it's there long enough, you can get some inflammation. It can become scarring, can become a type of permanent hair loss. So those patients, they can be treated. There's topical things that can be done, but also just sort of avoiding the trigger, which is this really tightly pulled hairstyle, which you can get with gymnasts, nurses, people in the military that have to pull their hair back. So look out for that one. I would add that to your list. You seem like tight braids too is a common finding. Yeah. So I would add that to your list. But that's it. I mean, we recapped a lot, guys. I mean, I think probably this is going to be a 90, maybe 100-minute episode. But you know what, audience? You can enjoy it. I think our best one, maybe. Maybe our best ever. Also, Paul and I are wearing the same thing right now, which is great. We'll take a picture of that. Well, are you going to talk about the logo and why it looks different? Oh, that's nice of you to bring up, Chris. Yeah, it's because we now have some, if people want additional content and additional access to Paul and I and the team, we have a Patreon now. There's a Discord where Chewman's on there. Actually, our whole team's on there mixing up. We're getting questions from the audience. And twice a month we're doing bonus episodes. So if people want to check that out, they can go to patreon.com slash curbsiders. And did you guys want to plug anything? Because I know you guys have a podcast. Oh, yeah, we do. Yeah, the peds one. Yeah, for anyone who's interested in pediatrics, whether it's because they're a pediatrician who's accidentally watching an internal medicine podcast, if you're med-peds, if you interact with children at any point, we have a spinoff of The Curbsiders, The Cribsiders, where we do two episodes a month about pediatric core topics. Same great template, fun colors, and you should take a listen. And yeah, we're thecurbsiders.com. You can see all our podcasts there. All the Curbsiders podcasts and ours are on there. And with that, Paul, I think we should get to an outro. Yummy. Curbsiders Digest Net, which recaps the latest practice-changing articles, guidelines, and news in internal medicine. That's right, Paul. And we're committed to high-value practice-changing knowledge. And to do that, we want your feedback. You can subscribe, rate, and review the show. We're on YouTube, Spotify, Apple Podcasts, wherever. You can also email us at askcurbsiders at gmail.com. A reminder that most episodes, probably not this one, not this one, are available. I don't have the energy, Paul. Thank you. ACP IM 2023 conference and to ACP for having us, inviting us to be here. Thanks to their marketing folks who brought us in, made this happen. Our technical production for the show is done by the team at Podpaste. Elizabeth Proto runs our social media. Chris the Chew Man Chew is the moderator on our Discord. Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto. This has been Chris the Chumanchu. This has been Justin Lee Burke. And as always, our main Dr. Paul Nelson-Williams. Thank you and goodbye.
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. As a result, you get decreased uptake of iron from the small intestine, and you also get decreased release of iron from macrophages. Welcome to Annals on Call, a podcast based upon articles from the Annals of 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 an article from the April Annals of Internal Medicine titled Effects of Interleukin-1-Beta Inhibition on Incident Anemia, Exploratory Analyses from a Randomized Trial. Our guest tonight is Monica Vallurpali, who is the first author of the paper. Monica is a hematology oncology fellow at the Dana-Farber Cancer Institute, Partners Cancer Center, and a chief medical resident at Brigham and Women's Hospital. We hope you enjoy this podcast. Monica, thank you so much for joining us to discuss this very fascinating article. I remember back in the 70s when I was a student and house officer, the anemia of chronic disease was a big mystery. I knew who got it. I knew that I didn't know how to treat it, but I didn't have any idea about the pathophysiology. And then it got changed to anemia of chronic inflammation. And now sometimes I hear iron-restricted hematopoiesis. I was really attracted to this study because it starts to give me even more understanding of what's going on and why these patients are anemic. Before we get into the pathophysiology, let's just start out with the study that you used for this analysis, the CANTOS study. Could you give me a brief overview of that study? Oh, definitely. Thank you so much for having me on your podcast, Bob. So the CANTOS trial was a very large multinational randomized controlled trial of patients who had a prior MI and also had evidence of underlying inflammation. And in the study, they were specifically looking at elevated high-sensitivity CRP. And the trial was initially designed to test the hypothesis that reducing inflammation could, in part, reduce the risk of cardiovascular disease. And this was a hypothesis that had been percolating for many years, that inflammation plays an important role in the development of atherosclerosis. And it had been supported by some prior clinical and experimental data. And there was some correlative data showing that downstream markers of inflammation like CRP and interleukin-6 are associated with increased risk of cardiovascular disease events independent of lipid levels or cholesterol levels. And so this trial ended up enrolling about 10,000 patients who had a history of a prior MI and had elevated high sensitivity CRPs that were greater than two. And patients were randomized to either get placebo or one of three different doses of the monoclonal antibody known as canakinumab. And so canakinumab is an antibody that inhibits interleukin-1-beta, which is an inflammatory cytokine that is often elevated in the setting of infection, but also in certain chronic inflammatory conditions. And the study demonstrated that canakinumab treatment resulted in decreased markers of inflammation, including IL-6 and CRP. And there was a decrease in the rate of cardiovascular events in patients who were treated with 150 milligrams of canakinumab. But there have been numerous secondary analyses that have demonstrated other beneficial effects associated with canakinumab treatment. And that led to some of our interest in the study that we performed. Let's get the background for this study. I've been trying to learn about the three different labels that I mentioned. Could you talk about what we knew before this study about the role of inflammation and the relationship of inflammation to anemia? Yes, definitely. I think it's a very interesting question and one that I'm sure we only have a glimpse of a full understanding of. And we talked about how there's three different labels that often get thrown around to describe this process linking anemia and inflammation. One of them is anemia of chronic disease. Another is anemia of chronic inflammation. And then the third is iron-restricted hematopoiesis. And these labels sort of are encompassing in all the same process. Anemia of chronic disease and anemia of chronic inflammation refer to the same process by which there's underlying inflammation that results in an immune-mediated alteration in how the body handles iron. And this might have evolved because in the setting of infection, there's certain bacteria and certain microbes that can thrive when there's increased access to iron. So it may have evolved as a way of helping to fight systemic infections, but it's a process that also arises in the setting of systemic inflammation. And so you have the induction of certain cytokines and you also have the induction of an important molecule called hepcidin, which is really central to the pathophysiology of all of this. So Hepcidin is a small peptide that's produced by the liver, and it's often produced in response to inflammatory signaling, including interleukin-6 and IL-1 beta and TNF-alpha. And its production can also be stimulated in scenarios of iron overload. So when you have increased expression of hepcidin by the liver, what that does is it binds to a plasma membrane protein called ferroportin. And ferroportin is very important in allowing iron to travel in and out of the cells. And ferroportin is expressed in the small intestine, it's expressed on macrophages. And it's also expressed in the placenta. So when hepcidin is expressed, you get decreased expression of ferroportin. And as a result, you get decreased uptake of iron from the small intestine. And you also get decreased release of iron from macrophages. So these are both two places where you are able to mobilize and generate iron stores. And so when hepcidin is on, when hepcidin is elevated, you create the scenario where it's hard to mobilize your sources of iron, either from your gut or from macrophages. And so you have a process where inflammation leads to a state of iron restriction, and simultaneously, inflammation through cytokine signaling also leads to other processes that contribute to anemia through decreased proliferation of erythroid progenitors, decreased red blood cell turnover, and impairing or blunting the effect of erythropoietin. That is such a great explanation. I thought that I was making progress, and you've really helped me make better progress in understanding the problem of hepcidin and why it probably is helpful in certain situations. We have all this as a background. And now we have a data set where patients either got canakinumab or didn't, and we know that they're already have an inflammatory process. That stimulated you to do an analysis of this really nice database. Why don't you talk a little bit about the two different types of analyses you did on incident anemia and people who already had anemia? There's a lot of excitement to be able to use this database to try and answer this question. Even though the study had not been initially set up to look at anemia as an endpoint, and it wasn't set up in such a way that we could interrogate the specific causes of anemia in each of these patients. We did have a lot of data, a density of data, specifically looking at when people became anemic and were able to really course that out over the course of this study. And what we noted is that there was a subset of patients who were anemic at baseline in the beginning of the study. So out of the about 10,000 participants, 1,300 participants had anemia at baseline. And these individuals, compared to the individuals who didn't have anemia at baseline, tended to be older. They were more likely to be female. And they had a higher burden of comorbid illness, whether it was diabetes or chronic renal disease. And what we decided to do in this population of patients is to see what happened to their mean hemoglobin levels over the course of the study in participants who were treated with either placebo or canakinumab. And in that analysis, we determined that participants who were allocated to canakinumab had significantly greater improvements in their mean hemoglobin over the course of the study as compared to the participants who were allocated to placebo. So there was an improvement in their anemia markers over the course of the study if they were allocated to canakinumab. And then secondly, we also decided to look at the prevalence of anemia in these participants on canakinumab or placebo if they had baseline anemia.
But we wanted to go beyond this and also look at the larger cohort in the study who did not have anemia at baseline when they started out the trial and try and determine what the rates of incident anemia were if they were on placebo versus they were on canakinumab. And there's a few interesting things that we noted. One is that the baseline high sensitivity CRP was correlated with whether or not they developed incident anemia over the course of the study. So if they had higher levels of higher markers of inflammation at the outset of the study, they were more likely to develop incident anemia. And then secondly, canakinumab treatment was associated with a decrease in incident anemia at all the doses that were studied compared to placebo. And there was no significant effect modification that we could see based on gender or age, whether they had hypertension, whether they had diabetes, whether they had heart failure, or based on their baseline CRP. What mattered the most in terms of a reduction in instant anemia was whether or not patients had a robust response to canakinumab. So canakinumab is a monoclonal antibody that's given once every three months. And patients often have a very quick response to canakinumab if they do respond. And so we defined a robust response as participants at the three-month point having a high sensitive DCRP less than two after they got canakinumab. And those participants had the greatest reduction in incident anemia over the course of the study. Wow. If I remember right, there was that certain subgroups had more anemia than other subgroups. And unless I read the article wrong, people with type 2 diabetes were more likely to get it. But I guess, is that the people who already had anemia, or was that also incident anemia? And also older patients, and obviously people who didn't respond and had very elevated high-sensitive CRPs? Did I get that right? Yes. So the participants who had anemia at baseline, they were more likely to be older. They were more likely to have a higher burden of comorbid illness, including having diabetes and chronic kidney disease. There was a trend towards greater improvement in patients who were of older age in terms of decrease in incident anemia, but it wasn't significant effect modification. And it was probably that underlying inflammation was the key factor in whether or not somebody went on to develop instant anemia. Right. And because this is a retrospective study, there are other causes of anemia other than inflammation. And we didn't have a careful analysis of each patient's anemia. So we can only look at trends. One of the things that I loved about the discussion in your paper is that you pointed out that this is hypothesis generating. I'm really interested, and I know you spent a lot of time thinking about this, is what does this add to the story that is developing in understanding this type of anemia? I think it's very exciting because this is the first large-scale study of its kind in patients to suggest a role for targeting the interleukin-1 beta pathway in patients who have anemia of chronic inflammation. And it suggests an opportunity to develop new clinical trials using various targets that are involved in this pathway. So this signaling pathway is very interesting. It is a component of the innate immune signaling system, and the innate immune signaling system responds to infections and also other danger-associated signals that result in the stimulation of this pathway. And the interleukin-1 beta pathway is actually downstream of this multi-subunit composed protein called the inflammasome that is often activated downstream of either microbial signals like lipopolysaccharide or other danger-associated molecular patterns like cholesterol or urate crystals. And it leads to the production of a protein called caspase-1 that subsequently turns the precursor version of interleukin-1 beta to its active version. And interleukin-1 beta can lead to the stimulation of IL-6. So it highlights a role for potentially targeting different components of this pathway as a way of treating anemia of chronic inflammation and generating clinical trials to be able to test the specific hypothesis that we can target anemia of chronic inflammation through the inflammasome IL-1 beta, IL-6 pathway. And in addition to inhibitors of IL-1 beta, there's also inhibitors of IL-6, both monoclonal antibodies and other types of inhibitors that could be utilized and tested. Wow, that's really interesting. Just so that I understand better and our listeners understand better, how serious is the problem of anemia through this pathway? So we see a lot of people in the hospital all the time who come in with hemoglobins of 11 and 12, and we check studies and they don't have any nutritional deficiencies. They're not hemolyzing. They're not losing blood. How much should we worry about people who have hemoglobins in that range? Yeah, I think that's a really good question because you wonder sort of is the mild anemia actually contributing to anything in terms of how they're feeling. And there have been studies looking at older patients who have anemia. Sometimes it's termed the anemia of aging, but it's likely sort of, again, this phenomenon of inflammation becoming worse as people get older and inflammation contributing to anemia. And in those patients, it has been demonstrated that there's improvement in quality of life and improvement in overall symptom burden if their anemia is improved. Similarly, in patients who have heart failure, we also find benefit in improving their anemia parameters. And in patients who have chronic renal disease. So these types of approaches to targeting inflammation could be really beneficial in patients who have multiple comorbid diseases where it can be challenging to address their anemia otherwise. While we're waiting for these studies to come out, I've heard that you can overwhelm hepcidin by giving IV iron even to somebody with this type of anemia and get a response. Is that something that hematologists consider a strategy worth considering? I think it's certainly something to consider on a case-by-case basis, depending on whether there's also evidence of iron deficiency or bleeding and the risks and the benefits of giving IV iron. I think in heart failure patients who have mild anemia, there's some data that IV iron actually helps their outcomes, I believe. Is that correct? Yes, that is the case. So this has been great. I assume that this is going to lead to a number of different studies trying to look at different parts of the pathway and see if we can understand even better what is the real trigger to this very common problem that as a hospitalist I see all the time because I guess I'm seeing patients who are older and have more comorbidities and have more underlying inflammation. Yes, definitely. I think it's an insidious problem and after iron deficiency anemia I think it's probably one of the most common causes of anemia that we encounter. And there's been a lot of preclinical work looking at the mechanistic basis of anemia of chronic inflammation. And it's nice to at least have some initial clinical data that helps to validate those hypotheses. Thank you so much for joining us. I know that all the listeners will have a much better understanding of this common problem. Thank you so much for having me. Now it's time for Bob's Pearls. Anemia of chronic disease, anemia of chronic inflammation, or iron-restricted hematopoiesis. This very common cause of anemia is likely caused by chronic inflammation. This was described very well in the introduction to this study. The big problem is increased hepcidin levels, which decrease both absorption of iron and movement of iron into the bone marrow and that seems to be stimulated by an inflammatory process. This study generates a new pathway for study. We know that we can interrupt that inflammatory pathway and now further research will look at the individual parts of the inflammatory pathway to see whether or not there are ways to better treat this veryannals.org 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.
Hello and welcome back to Sharp Scratch. You're listening to episode 101, The Medical School Scaries. This is a podcast brought to you by the BMJ, where medical students, junior doctors and expert guests come together and discuss all the things you need to know to be a good doctor, but that you might not get taught at medical school. I'm Charlotte and I'm finally a final year medical student at the University of Oxford. Until recently I was working as the editorial scholar at the BMJ looking after all the content that BMJ student produced last year but as of July I'm now back in my final year which is in itself slightly terrifying. Today is a very exciting episode because we're joined by our panellist and new editorial scholar Eva. From next episode onwards, Eva is going to be taking over as the new host of Sharp Scratch. So yeah, would you like to introduce yourself? Hi everyone. Hi Charlotte. Thank you for the introduction. My name is Eva and I have just finished my third year at Lancaster University. And since the summertime, I have been working at the BMJ. I'm just about to start with Sharp Scratch but I have been in charge of all of the content that BMJ shouldn't have produced this autumn time and it's lovely to be here recording with you. Oh it's so exciting, I'm so excited to see what you do with all the episodes of Sharp Scratch that you're going to work on this year. And I'd also like to welcome our expert guest today, Dr. Megan Brown. Could you tell us a bit about yourself? Yeah, of course. Thanks for having me. I don't feel like much of an expert. I think that's always a strange dissonance to being introduced as an expert. So I am a medical education researcher, essentially. I work as a senior research associate in medical education at Newcastle University and I am a doctor turned academic so I went through medical school, got my degree and then moved into medical education, did a PhD in medical education and now it's my full-time gig so to speak. So yeah, lovely to be here. I'm really looking forward to the episode. It's such a fun theme and, you know, I love everything spooky. So this is just up my street. Oh, this is perfect then. Well, thanks so much for joining us today. So Eva, tell me your scariest medical school story. I had a real think about this, Charlotte, because there were some strong contenders. But when I came back to Lancaster after the summertime and saw that my housemates who are back in medical school had to get their bus to satellite placements at 6am, that kind of like put a chill in my bones, so to speak. It really did give me goosebumps. I'm so genuinely scared of the 6am bus to Barrow. It's not very far from Lancaster. It's about 19 miles away. It's just on a peninsula. So you have to go like the whole way up and around and back down to borrow in the dark in the morning and it's all country roads. So yeah, that's my go to medical school scary. I think what what is yours? Well, I'm on surgery at the moment. And I'm really not used to the like super early starts. After kind of a bit of a summer off. And then you know, the BMJ last year wasn't wasn't starting at eight o'clock in the hospital and yeah this morning it was so dark outside and like the walk to the hospital is like through like a bit of a park and it was like just dark and freezing but that's nothing on like a bus to a satellite a satellite placement there is nothing so scary as an early morning I have two small children so I'm afraid I'm really used to the early starts um yeah I went to um Hull York Medical School I mean I'm thinking back now but that's a very like it's like a two-site university so there was a lot of travel I mean to be fair they did give us accommodation when we had to go to the satellite sites when they farmed us out when we were in our sort of senior years of medical school but I remember my parents dropping me off in Scunthorpe and again you know nothing against Scunthorpe I actually had a really amazing time there but just the thought of being so far away and they dropped me off and honestly it was like that first day at uni again where you're just like please don't leave me I don I don't know what I'm doing. I don't know where I am. I don't know anybody here. Yeah, I can really appreciate why that's a scary, it is a contender. Yeah, and those away placements like really do feel like that. You're kind of just dropped in this new place. I used to find the whole concept terrifying. Like when I was in the earlier years of medical school, like first and second year and I'd hear about the fourth fifth and sixth years doing it at some point I'd just be terrified of the idea of that like leaving the things you know even if it's only like half an hour 40 minutes away but having to stay somewhere for a month or two months yeah it really I think it kind of tapped into a lot of anxieties that I had at the time it's like you know it's it's those basic things isn't it like where's the big shop like the essential things you need to know like you just I don't know about you but you didn't sort of get any like introduction to that and you're dropped in this place that you know every hospital has its own sort of unique ecosystem and ways of working and culture and you're kind of just like you said you're dropped in this place that, you know, every hospital has its own sort of unique ecosystem and ways of working and culture. And you're kind of just like you said, you're dropped into the middle of it, and you don't know how to navigate it. And I think that's part of the the scaries of the uncertainty of, you know, what's this going to be like? How am I going to be treated? Where do I find things? Where do I find food? Where do I fill my water bottle up? Those like really basic things. I don't know like how you felt about that but for me it was those foundational things that I was always like really worried about and maybe that's just because I'm like a naturally very anxious person but um yeah where's the nearest vending machine like I've got to know me and Eva are nodding so much at the like naturally very anxious person um yeah I and it's always like a Sunday night and it's always late and you arrive and you just don't know what you're doing every single time um yeah is it do you kind of relate Eva well yeah but I write my medical school don't give us accommodation hence the 6am buses so I haven't actually experienced that the one kind of thing that we do have like that is that our students get sent to the Isle of Man or can get sent to the Isle of Man which I you're saying like when you were in first and second year you were scared of it like I'm still scared of it again no disrespect to the Isle of Man but I am such a like comforts person. Like I love my little life in my little uni city with my little friends. I don't like change very much. I don't know if that's a part of it, that the thought of getting to that stage in my life and being like posted off to an island. Because at the moment, like the cohort that I started with are in final year. So like three of my very close friends are on the island and I want them back. But it's that it's that sense of community, though, isn't it? Like you rely so heavily on the people who are around you, whether that is, you know, friends, whether it's people within the hostel, whether it's like actually like teachers and tutors and things that you have, you form that network.
To just be like, OK, I've spent three years forming these connections and I guess now I don't have them anymore and I've got to start again and that's a lot of energy and effort that you don't often have when you're revising really heavily for exams or you're trying to kind of check off everything that you have to do it's yeah it's a lot it's like a lot to think about yeah the energy and effort thing is so true I was I was talking to like one of the kind of mentors at my uh university the other day and and she was just asking what placement I'm on next and I said you know I've just switched from oncology to urology and then after urology I'll be doing some upper GI stuff and it's two weeks on each placement and she just said well that must be exhausting and I was like oh actually someone's put it into words it is exhausting it is so tiring to do 10 days somewhere and then start or even if it's not on one of the kind of satellite placements or away placements even if it's in the same hospital to get lost again to meet a new team again nobody knows your name again it's that rotation that constant rotation we have it all the way through medical training you have at medical school like you said two weeks like you can't possibly become part of a team in two weeks um and you have it as a junior doctor as well like you know you kind of just get settled in a team and then after a few months it's like you're up and moved again um and you know I think we assume that's the only way that we can train people and do things but But we know that's not true. We know that there are ways of training people where you're actually in one place for an extended period of time and you become part of that team and you can find that kind of exposure to different specialties in other ways. So I think that's really interesting that, you know, I struggled with that rotational model as well. And then I actually did my PhD in like non-rotational models of training so I think it was something that I carried with me as a kind of something that I just yeah didn't really enjoy when I was a trainee myself it does it does make things harder I think to be moved around so frequently and I think it's just another example of the ways that medicine is really different from other degrees really and I know Megan when Eva was kind of asking you about some of your scary stories you talked about other ways that medicine is different from other degrees that our friends might be studying right yeah I think it's just do you know what it's I was thinking about it and I think anything that I think of that's kind of scary or was scary to me about medical school is to do with the body. It's my own body in terms of learning how to communicate or learning what like little gestures that I might make and how they might inadvertently communicate something I didn't mean to do or say in a kind of nonverbal way. In like casual jeans and a t-shirt in some seminar room at university. Like taking a history from an actor. I'm so different in that I couldn't delete them fast enough. I would take them home and I would watch them and do my homework and like pick out my learning points. And then it would be like, they're gone. They're in the abyss. I don't want to to see it again I think I just don't dare interact with the files again we weren't even like that's the thing is I think actually you know I appreciate it can be a really valuable learning experience I think if it's kind of structured and like facilitated well but we were given them we never had to like I don't recall ever having to actually watch them back again they were just there like in case I wanted to watch them during revision watch myself being horrendously awkward when I was revived what no here's a here's a video of what not to do when you interact to the patient like I mean yeah I think if you know there's a lot of value like you know GPs like they use videos um in teaching all the time and really can be really like ways. But you have to be in a position where you're kind of supported and encouraged and you're open to doing that. I think, you know, straight in the gates at medical school without any of the explanation of really what you're doing or why you're doing it, I think can be quite challenging. Yeah, I am so glad that I never had to go through that. I think that would have just killed any confidence that I had. To be honest, Charlotte, I've never had any of my peers take blood out of me. So like, I'm quite glad that I got away with without being like poked and prodded by my friends. I'll cut my losses. That's a swings swings and aroundabouts. Yeah, fair enough. Yeah, so that's definitely my scariest moment in, well, one of many scary moments in medical school. And maybe we'll come on to those big moments and how transformative they can be to how we learn right after this message from our sponsor. Okay, back to the show. So yeah, we've already heard how medical school can be a pretty spooky place and in this section I thought we'd go on to how we kind of learn from those experiences and what we kind of take away from them. For me one of the the scariest things I just started my fourth year of medicine which is our first clinical year and one of our first classes when we came back was a clinical skills class up in the skills lab, which we'd never been to the lab before, where we had to practice taking blood on each other after we tried taking it on the kind of plastic arms. And as someone who hates, I mean, like I hate having blood taken. I really, really don't like having blood taken at all. And I didn't know this at the time, time but turns out I absolutely despise doing it as well um this was not a fun class it's so tricky isn't it we we did uh peer blood taking as well when when we were at medical school and I think it's um I think you're totally right about that transformative nature of of those experiences I think for me it was sort of appreciating what patients go through as well, right? Like, at that time, I mean, I'm disabled now, I've had like a million blood tests. But at that time, I was a kind of fit and healthy young adult hadn't really had very few blood tests. Eva, when you asked me what my kind of scariest med school moment was, I kind of jokingly said I find everything about medical school terrifying. And although I was kind of being a bit flippant, like, Megan, you're right, I think there is this such fine balance. And I think I've too often found myself on the on the wrong side of it, where I am just overwhelmed and I am not learning. And I think either that's something we've kind of briefly talked about, you know, just between us before. It definitely resonates with me in my very first year. And our freshers week is at the start of October. So Halloween was like three, four weeks into medical school. I literally dressed up as a medical student for Halloween because I was like, there's nothing scarier than this. I think it is. It's like the disruption of, I think, well, maybe it was just me, but you hype medicine up to be this big, amazing thing. And you think you're going to arrive at medical school and feel like a fully cooked doctor who knows everything. And I know when I was in sixth form I certainly looked at medical students like wow look at them and then I was one all of a sudden and I think it was so disruptive for me to be like I am in out of my depth I'm not ready for this. It's like that meta idea of like identity though as well isn't it like it's so interesting to me that you literally dressed up as essentially yourself for Halloween, right? You like put the costume on of the medical student. So like, what, you know, at what point do you stop like feeling like you're wearing someone else's clothes? When do you stop feeling like you're wearing a costume? When do you become a medical student?
Like, that's a question of that process of identity development and identifying with the profession identifying with the role and that does take time like you can't just I know we always think that you know you're going to kind of snap your fingers during medical school and that's it you'll feel that way but that doesn't always happen it usually doesn't happen um so I think maybe yeah maybe a lot of the scaries kind of tap into that how you feel in yourself and whether or not you feel kind of part of the profession I think like that sentence alone might be one of the most relatable things we've ever talked about on sharp scratch for me all of these themes interlink and probably actually form a large part of why I have found medical school scary and in terms of ways of like learning to deal with that I think a big one is time which is unfortunate but true um and then I found in terms of like the practical stuff because I found that that like is a particular thing that I found difficult is trying to like lean into it which goes against every instinct to run away from something scary but um yeah I'm trying to put myself in more situations where I do have to take bloods or if there's a a class where you know you have to volunteer to do something I will try and volunteer now yeah that's kind of how I've learned to deal with the practical side of it and then um the kind of more emotional sense of belonging, do I fit? I guess that's something I'm still kind of grappling with, but yeah. Support helps though, doesn't it? Like, you know, it's so much easier if you can find a, like a doctor who likes to teach and you can go around and do bloods with them and you feel supported and you feel, you don't feel like you're kind of asking silly questions. No such thing as a silly question. 's the that's the old line isn't it but you don't feel like you've been put in that position so I think that's important and I think the other thing to say is that of course I think all these questions of belonging are really intersectional aren't they like you know we're discussing scaries I think some people that experience is going to be really heightened because of elements of themselves that they they can't. Maybe they feel like they can't bring those, their kind of authentic self to medical school. So I think, you know, it really, it's really kind of going to depend and vary on individual people, how they experience that kind of sense of scariness and fear and belonging, which is important, I think, when it comes to that piece about what can do and support um and mentorship and kind of all of those pieces of the puzzle that make you feel safe to engage with the skills that you you need to get make you feel safe to engage with that environment um yeah 100% I think mentorship is such a big part of that that's definitely like the times where I felt the most like I belong when I can see someone who you know does feel like they belong um and kind of relate to them in what in whatever way it might be in terms of other scary moments I guess something that a lot of people find kind of the icing on the cake of scary moments in medical school are exams and we've got a clip from one of our regular panellists Judy talking about her her top top moment in terms of medical school scaries. So it was a Friday and we were preparing for an exam that was due to be taken at the end of the month, suddenly we got an email that said that the exam would actually be on the Monday. This email was on a Friday and it was around three o'clock so we knew the office was closed and I kid you not, I could not eat. My stomach dropped, I texted frantically the group chat and I was like asking seen this, if it was real, what was going on. Safe to say I had a very sleepless night that evening. Thankfully all was sorted out and it had been an administrative mistake on the officer's side. No way. Can you imagine? Well, you can. Yeah. Yeah, there's just no words. There's actually no words. Absolutely terrifying. And I absolutely love how Judy sent that in, in two voice notes so that we were all left on the cliffhanger of thinking that the exam really was going to be on the Monday before kind of clarifying it in her second clip. But yeah, just terrifying. If exams aren't already scary enough, I don't think there's a way of making it more scary than having it suddenly be sprung on you in a couple of days time it's through like medical school coded it's such a it's such a uniquely Madison thing and you're paying for this sorry to bring that in but you are literally paying for this experience to be terrified and to be like you know that's one of the instances where there's just no need, right? Like that's just not good planning and administrative error. But I mean, you know, there's administrative errors and then there's something which means someone can't sleep or eat all weekend. Like that's... It wouldn't happen the other way around. I just feel like if medical students behaved or were as irresponsible with their emails as like sometimes trust or university staff or systems are like it wouldn't stand it's just not professional is it I mean at the end of the day and not to pinpoint blame on any one individual it's usually that kind of systems level of there's not enough staff and you know things all of the things that we know about kind of workforce issues and workload and things within the NHS just come to a head and then cause horrible things to happen like that yeah exam season is bad enough for you know some people find exam season really challenging me being one of them this whole podcast is me just saying that I am literally scared of everything but um yeah it's scary enough enough. So it's the uncertainty as well, though, isn't it? And I think, you know, there are a lot of conversations actually about uncertainty at the minute. And, you know, medical practice is uncertain, like you're moving into an uncertain world. But I think there's that. And then there's, you know, understandably, the desire to have certainty around something that's going to influence your progression. Like, I think that's two separate things. You know, you can be thinking that training people to manage uncertainty or kind of become familiar and comfortable with uncertainty is a good thing, but not when it comes to exams. I mean, you know, there's a line, isn't there? And that crosses it, in my view. I think in Judy's case as well, I would feel so demotivated after finding out that I actually wasn't on the Monday. Like, I know me, I would go into panic mode and work, like, 24 hours a day for that weekend, and then I would end up deflated. Yeah, and you know that the timetable's just going to roll forward as normal. There'll be an apology email, right, probably, and then like nothing else. There's not going to be any recovery time for people who've done that, even like you've spent the weekend kind of with no sleep and no food and you're exhausted. And it's, I can't imagine that there would have been any allowance or understanding of that. It's compassion. I don't know. I often think there's just a lack of compassion in systems generally within medicine and medical education, probably because I'm bitter and I've had bad experiences myself. But I think, you know, it's just that lack of compassion and understanding and that kind of human level. There's something dehumanizing about the way that systems work, in my view. Not to be too morbid but yeah I know I I completely agree there are so many reasons that medical school exams are scary I think number one has to be that they are so high stakes you know this is your career like you know medicine is a it's a career that're moving towards. There's a quite a clear career path and you've got to get through these hurdles. And it's all, it feels a lot of the time and in a lot of institutions, it's pinned on these kind of few exams that happen within the space of a couple of weeks in the summer, the culmination of everything that you've been working towards. I think that's really challenging because it's, it's a snapshot of you realistically, isn't it? It's not, I don't know, to me, it hasn't felt like the whole picture of myself through that year and the growth and the progress that you've made. So I think them being so high stakes in a lot of cases, it makes them feel really scary. And then it's the performative thing again, isn't it? I know we've mentioned it previously, but OSCEs, Eva, like I, this is really embarrassing. I had a lucky top when I was at medical school and every single OSCE that I did throughout medical school, every year I wore the same lucky top.
And I was like, right, that's it. This is the recipe to success. And it's that performance. If it was like, I'm putting on my lucky top, it's my costume, right? Like I'm going to go through the Oski and I'm embodying what it is to be a kind of the showcase essentially of a good student. And again, you know, that's scary. We're not, most of us aren't actors, you know, we're not trained like that. And so you have to get yourself in that headspace. And it's almost like stage fright, isn't it? A lot of the time when you're going into these situations. So for me, them being so high stakes and having that performative element to these exams that really, really make them quite scary. That performative side of it that you were talking about has like never rang so true for me I am a chronic OSCE hater OSCE sufferer OSCEs drag my results down every single year I failed my second year OSCE I got I had this amazing GP tutor who told me to think of it like a method acting exam and like literally told me to get method acting classes if I needed it and she was like just think of it like acting and it's actually a tip in a podcast a sharp scratch episode from years ago and it's the only thing that's ever worked for me with OSCEs because honestly I love placement and I love the clinical side of like the degree I could talk to people all day I love like the buzz of the hospital I love real patients but then Orskies I just switch I'm like a different person I'm like a bumbling mess and but isn't that sad though isn't it sad that we're assessing you like not in that way that you're meaningfully connecting with patients on the wards and getting both of you I'm sure getting so much from that interaction but on on this like performative artificial interaction, they're often quite formulaic. You know, there's a checkbox, you know, you have to say if someone's crying, you have to say, oh, I'm so sorry to hear that. Oh, that must be really difficult to you. You know, there are these phrases you can just learn and kind of tick off. And it's, I don't know, like for me, I can't connect with my emotions when it's an actor in the space of five to ten minute station. Charlotte, on the slightly funnier side of OSCE preparation, I know you have a fantastic OSCE story. Could you please share it and lighten the mood? Yeah, please. I've dragged it right down. No, no. I dragged it right down, Megan, not you. We did it together, Eva. Teamwork. So one Christmas Christmas my friend got me this sounds very like irrelevant at the start but one Christmas my friend got me this board game uh it's called like who's the dude or there's the dude or like some something along those lines and it's basically like charades like charades or however you want to however you want to say it with this like massive inflatable doll it is just a ridiculous game like it's hilarious it would scare people so much when they came to our house we were like an all medic house and you'd open the door in the dark and there would just be this like huge like mock oski patient sat in the corner um i i wish i had a giant inflatable person who lived in my house i very kindly got gifted like a like a five foot tall sloth oh wow from my friend and so it's a teddy and so i practice my oskis i put like a hoodie and some like scrubs bottoms on this giant sloth teddy. And he like lives on my bedroom floor for like two to three months a year. And everyone who visits just has to like ignore the fact to have a giant fully clothed sloth. Which kind of links us back to that conversation about identity. Because if it wasn't an all medic house, you wouldn't have an honorary inflatable housemate it's just another like super weird part of medicine but definitely did like lie in the mood around exams and like yeah when we eventually moved out of that house and had to deflate the uh the sad patient it was yeah but yeah i think um you know bits of it can be funny and like definitely the the run-up to exams are funny chaotic moments but they they do feel high risk I failed some exams in second year and when I had to retake them you know my family and friends would be trying to tell me like don't worry too much about it don't don't get yourself so like stressed and worked up about it over the summer and I was kind of like you don't understand if I fail again I think they'll kick me out like that's the rule you fail twice and you're gone and I just found that super super stressful the like high stakes nature definitely like amplifies any fears that you might have kind of at baseline um which is just unhelpful really and I and I think because the degree is so connected to identity as well, like it's not, you know, I think to fail any degree, any exams in any degree is horrible and difficult and challenging. But especially when it's connected to your career, it's not just, you know, you're not taking a degree where there's a kind of multitude of options. I mean, more and more people are talking about what you can do with a medical degree, but that, you know, the usual, the normal, what's seen as the normal path is to move forward into being a doctor. And there's not other ways you can get there and do that. And if you've started to feel like a medical student and a doctor, and then that's taken away from you as well, that's another layer of difficulty, I think. Yeah, completely agree. And I think for me, at least when I did fail those did fail those exams my logical next conclusion is well I'm going to be a terrible doctor now and that's taken a bit of unlearning that you know failing any exams at any stage doesn't ever mean that you're not going to be a good doctor but yeah things like that take some unlearning I guess. I don't know if it was the same where you guys went to medical school but like that whole like two strikes and you're out thing all of the different ways that you can have your studies terminated was told to us on our first ever lecture it was like welcome to med school here's what happens if you fail here's what happens if you misbehave so when I think it's like nearly that positive versus negative reinforcement thing like from the very first day it's like perpetuating that fear of like what might happen if you don't pass you're never like told by all the good things that might happen if you do completely you know what I mean yeah I don't know yeah and it's you know fear people can learn through fear it's not a healthy way to learn and you can learn through fear you can learn through shame but most of the time when that happens and you feel shame you just remember remember the feeling of shame. You don't remember, you know, what the person who shamed you was trying to teach you. You might be motivated to go away. And, you know, I've got so many, I mean, experiences on the ward where, you know, you would be questioned about something that I had absolutely zero clue about and made to feel kind of, you know, this small because you didn't know the answer and you go away and frantically revise it that night and try and bring it back. I can't remember any of that information. I mean, I'm a long way from medical practice now, but all I remember is feeling really shamed, really ashamed. And I think there are so many more better ways to learn than that, where you feel supported, where there's collaboration, where you feel, you you know kind of safe to just kind of contribute and get involved with with the learning as well yourself in a way that's not so like top down and like authoritarian dare I say um in a way that's kind of a bit more collaborative and co-produced with students oh completely but yeah we've touched on like various different hurdles and things that we've kind of had to get through that we found scary during medical school. And we'll come back to off the episode, we've got some clips from previous panellists talking about some of the things that they found difficult or, you know, has taken a bit of getting used to when they started medical school. To start off, we've got a clip from Lily, one of the panellists, talking about dissections.
And it's just the most, it's very disturbing, but it's slightly amusing as well. The loaf of bread just got me. I remember I really struggled with anatomy when I first started at medical school. And I think it's the fear that you attach to going into that environment and not, for me, it was like not wanting to do something wrong, not wanting to, you know, be disrespectful in any way, not wanting to do something that kind of stepped outside the lines of what was acceptable in that environment that I wasn't familiar with. And I was really worried about that smell. I'd heard that story that the smell was going to be very difficult and that it could make you feel hungry and all these kind of horror stories almost that are passed down that are not great. And so I had this like big tub of vapor rub and I figured that if I just like slathered my upper lip in vapor rub that I wouldn't smell anything but the very strong smell of vapor rub so this is something that I did every single time I went into the anatomy lab and I think it you know it's like the power of those messages that are passed down yeah I can see why that was submitted as something that was scary I think it's so hard in that situation because you on the one hand you know it's such a privilege to be there um and it's such a you know massively important thing to be doing and then on the other hand I think some people did learn really well from it but I can't say I ever felt hungry or ever felt like I was learning I just basically constantly felt overwhelmed which is maybe maybe my theme of the podcast but yeah my medical school didn't use like full body dissections to teach anatomy and I am really really grateful actually I think I totally understand how much of a privilege it is for medical students who do do it and I also think it's such a great like admirable thing for people to do to like donate their bodies it's a huge thing for a family to like give up their relative it's a huge thing for a person to do and I think that can be true but at the same time I think I hear more negative stories than I do positive stories I'm 22 now and I still don't think I would feel very comfortable in an anatomy lab never mind like fresh out of school fresh for a 18 year old like learning in that way and that's not to take away from how big a thing it is or how like much of a privilege it is and how grateful that we as a profession should be for people who who do that but yeah not for me it is such a big deal and it is um an incredible act of of donation and service for someone to give their body to science and to medical schools in that way. I think the thing that I struggle with is that we, you know, through medical school and in, you know, your clinical practice, you're mostly interacting with living bodies with with living anatomy um and i appreciate you know the need for an understanding of anatomy and within some specialties in particular a deep understanding of that anatomy and my slightly controversial view is that perhaps some of that could be moved to a postgraduate level and that at medical school becoming comfortable and familiar with surface anatomy, you know, kind of other people's bodies, peer examination or examination of simulated patients. And we did some body painting, not at medical school, but when I was a PhD student, some body painting to kind of get familiar with the anatomical landmarks. They're really great ways because you're also communicating at the same time as doing that. So I think you're completely right, Eva and Charlotte, it's such a gift. But I think it's got to be clear, you know, what you're achieving and what the purpose of that is. And maybe sometimes that's not clear to medical students. Maybe there is evidence that I'm not, I wouldn't want to style myself as an expert in anatomical education um but yeah I think just even kind of communicating what that what that purpose is and why you're engaging and um and having sensitivity around that is obviously really critical as well yeah definitely and then I guess for the final clip of the the episode you mentioned anatomical education there, Megan. And we've got maybe the kind of spookiest or strangest clip of all from Anna here, one of our panellists talking about how they learn anatomy. Hi, everyone. My name's Anna and I am now a specialty trainee in obstetrics and gynecology in the North East. And I don't know if this is like spooky, but like looking back, it was definitely kind of weird. So I went to one of the more like old school traditional medical schools. And one of the things that you could do in first year when you were like learning all your basic anatomy and stuff is they basically had a skeleton library. So you could pay a deposit at the beginning of the year and they literally just went in back, got out a box with a skeleton in it and handed it to you. And you could borrow the skeleton for the whole year and use that to learn all your sort of bony landmarks and things like that. Vaguely spooky. That's how Anna described that. Vaguely spooky. I wouldn't want to know what the definition of horrifying was. Yeah, I was really confused when I heard the clip at first because we also got given like a box. It was just a box of like plastic bones in our first year. Okay, yeah, I get that like a model you know I get that yeah that's quite helpful um and I really thought that she meant the same thing and then I realized at the end she she did not mean the same thing um and yeah it's just so strange isn't it like I like I appreciate what she's saying about having to be respectful and it's really you know it those checks are there in place. But just that idea of renting a skeleton, like an actual real person, like their bones and bringing them into your house to study is just, I don't know. I don't know if the idea itself is respectful like even if the the conduct of the student is you know yeah like I so in my university so after every term you had to move out for like so you had to move out for Christmas you had to move out for Easter and for summer and things um so every term my parents would have to come and get me and kind of cart all my stuff back home which was always a big palaver and this great big box they used to get so frustrated that we had to take this huge box of like bones like plastic bones home every time um and everyone thought that was kind of a strange and interesting concept and an interesting way to learn um so yeah this is this is kind of similar to that I guess but this is another one that's such a far cry from my medical school experience because like I don't know whether it's like this idea of like the traditional mad school like I go to quite like a relatively new mad school my mad school is only about 20 years old whether it's like a like a not that one's better than the other but it's like it seems such a culture shock, even between the two kind of types of medical school that I've literally, until I heard like both of those voice notes, to be honest, from Anna and Lily, I was so like, I cannot believe some people have those experiences because it's such a far cry from my own. Yeah. And I think when you add on top of that, how it feels for like people who aren't studying medicine to hear this, there's an even further level of just our exams are different. Our ways of learning are different. Like there's so many bits about it that are just, yeah, quite unfamiliar, I guess. I would be really interested to know what the evidenced added value is to taking a skeleton home with you like like what is the actual I I am I mean come at me if there are papers please um but like is there any actual evidence that that is helpful for learning yeah I'm not sure well yeah on that note that is all we've got time for but um if anyone does have any any stories about this or anything that you kind of want to share I'm sure we'd all will be really interested to hear it but yeah that that's all we have time for today so uh thanks so much to our panellists Megan and our new host Eva for joining us today and everyone at home for listening to this episode of Sharp Scratch this is my final outro as Eva will be hosting from now on. And I just wanted to say that hosting Sharp Scratch has been such a privilege and it's been a really amazing experience to reflect on all the different parts of medical school with a really wonderful panel and all of our amazing expert guests. Yeah, I'm really sad to be leaving, but hopefully I'll pop up as a panelist now and again. So yeah, for the last time, if you like our show, I'd love it if you could support us by leaving a review wherever you get your podcasts or by sharing it with people you know. Tell your friends about it, that really helps people find the show.
You can find us on social media, we're bmjstudent on Twitter, Facebook and Instagram. If you'd like to hear other episodes, subscribe to Shark Scratch wherever you get your podcasts. And in two weeks time, you'll be notified of our next episode. Until then, goodbye from us. Bye. Bye. Thanks, everyone. Bye.
Hello and welcome to the October edition of In Conversation with The Lancet HIVs podcast. I'm Philippa Harris, the Deputy Editor, and today I'm talking to John Shooter from the Albert Einstein College of Medicine about cigarette smoking and harm reduction for people living with HIV. Before we get to this, I wanted to highlight some of our other October content, which includes the 2019 Global Burden of Disease Study, looking at the global, regional and national sex-specific burden and control of the HIV epidemic. This issue also contains studies looking at pre-term birth in pregnant women living with HIV and cancer risk among adolescents and young adults with HIV in South Africa. And now to speak to John. Thank you, John, for speaking to us today. So we're talking about your viewpoint. So why should clinicians who provide care for people living with HIV be particularly aware of smoking cessation and harm reduction approaches for smoking? Yes. So I'd like to start with the big picture, and that is that cigarette smoking has emerged as the leading killer in individuals living with HIV in the modern antiretroviral era. There are a fair amount of data supporting that view, both in the United States and Western Europe. And that's based on big picture statistics. But not only do you do research, but I've been for decades a clinician who takes care of a fairly sizable panel of people living with HIV. So I like to start all of these sorts of talks about my research with stories that I think can make the issue more real. So we had an unfortunate story, a true story that we're living through right now. I have a patient, she's got well-controlled HIV and she's been pretty healthy in most other ways, but she's been a cigarette smoker and I'm something of an anti-smoking zealot. So I've been trying to get her to quit for the last 25 years unsuccessfully. And she started complaining about a cough to me several months ago. The diagnosis of non-small cell lung cancer was confirmed. It's a terrible story, but it's an all too common story. And we talk a lot about statistics and curves and survival analyses and that sort of thing. And there's a danger in summarizing data in that way that you could forget that those data are the sum total of a whole lot of tragic life stories. And this is one of them. So I always keep that in the forefront of my mind. And that is why it is really, really important for us to do a better job with smoking cessation. And as we argue in this paper, that the approach to tobacco use and smoking cessation maybe should not be all or none, but should expand into the harm reduction realm. And I think we'll talk more about that as the podcast goes on. But the idea of harm reduction is that for people who can't quit, and that's probably 85 to 90% of smokers living with HIV, even those whom we try to get to quit very aggressively, still the vast majority continue to smoke. But maybe we can do some real benefit, almost certainly we could create some real benefit by getting them to at least cut down and to do other things that I think that we'll talk about as the podcast goes on to mitigate other end organ risks of cigarette smoking. So, yeah, you know, you highlight, obviously, that, you know, in an ideal world, everyone would stop smoking, but why can that be particularly challenging for smokers living with HIV? At least where I work, but I think this is representative for sure of the United States and Western Europe, but probably globally also, you know, maybe with different nuances, that people living with HIV have an array of socio-behavioral factors that predispose them to smoke, to start smoking, to continue smoking, and to have a hard time quitting. Those socio-behavioral factors are driven by higher rates of psychiatric comorbidities and substance use. So it is really hard to quit smoking if you are depressed and you don't even really want to go on living. So the message that you should quit smoking so you could live longer might not resonate very well. Or if you have a severe anxiety disorder and you depend on cigarettes to calm you down and get you through the day. Or if you're a user of other substances where cigarette smoking is really tied in with that whole substance use culture, it can be hard to untangle it from other substance uses. And it can be very challenging to quit everything altogether. But I do want to move on to a second point here. And that is a really, really important point that we've discovered both in our qualitative and our quantitative research. And I'm going to state something that I think is obvious, but maybe is not thought about enough, that people with HIV are not a homogeneous group. And different subgroups of them have different challenges pertaining to their tobacco use. So for example, people who use cocaine and heroin and are tobacco users, it is part of the drug using lifestyle and culture. Your friends that also use substances are probably also at very high rates of tobacco use. And there's a thought that tobacco use might sustain or prolong the high associated with these drugs. So those different behaviors are very much entangled. So that is cocaine and heroin users. Methadone maintenance patients work around the corner for a methadone maintenance program. And you see the people going in every day, lined up outside, many of them smoking. Obviously, you can't smoke inside in these centers, at least in the United States. But in order to get there, you have to walk through a tobacco smoke cloud. And it is hard to quit if you're exposing yourself to that every day. Now, that is different from the MSM group that we study. Tobacco use in MSM tends to be a very, very social phenomenon. So you could wind up being an outsider in a group of MSM who are smoking and you are the one who is not smoking. It's a hard stance to take if you want to be part of certain social groups. And that's something that we've discovered in that subset of the population. We've had transgenders tell us it is really hard to quit smoking because the hormones that I take make me moody. And smoking is the only thing that controls that well. And finally, the patients and the individuals with psychiatric comorbidities, I've already alluded to this. It can be very hard to quit smoking if you're in the midst of a severe depression or anxiety or patients with psychosis who smoke at very, very high rates. And the smoking could be a sort of self-medication of their psychiatric morbidity. All of those are distinct factors that make it really hard to quit, but they are more prevalent in different subsets. And I think for any given patient that you're trying to get to quit, you have to explore those things and see why they're smoking and what their social groups are and that sort of thing. And so what sort of evidence-based approaches do we know can work for smoking cessation? And what is the evidence base for their effectiveness in smokers living with HIV? So regrettably, not too much has worked very well, at least in clinical trials, to promote smoking cessation in this group. I think that the people who listen to this podcast will be familiar to some extent with the reality that there's a mountain of evidence for the general population of smokers on what works. And what works in them, what works best is a combination of behavioral therapy in the form of all different kinds of counseling, live counseling, one-on-one counseling, group counseling, web-based counseling, text-based message counseling. All of these things are evidence-based in the general population, and they work best when you combine them with one of the approved pharmacotherapies. When you put those two things together, you can achieve reasonable quit rates. Now, you get used to failure in this business. So people who are involved in tobacco treatment for a career, if they can get 25 or 30% of their candidates to quit smoking, they are rock stars. So under the best of circumstances, we have to accept failure in most cases. But the most effective approaches combine aggressive and intensive behavioral therapy and intensive pharmacotherapy combined. There's a small evidence base for combined behavioral and pharmacotherapy in people with HIV. And just a handful of studies, really three studies so far, that combined those two modalities in different ways and yielded quit rates that were significantly better than control at the six-month mark. More of the therapies were able to achieve three-month quits, but had high relapse rates at six months. And the value of getting someone to quit for a short window of time just to relapse down the road is, I don't know what the long-term benefit of that is. And just another word or two about things that work. We have a suggestion from our data that there is a role for peer support and social support. So when we involve ex-smokers with HIV in the conversation, in the counseling, that seems to promote higher rates of quitting.
So we ask questions, how tempted would you be to smoke in a bar with friends? And after you become depressed over a specific depressing situation, et cetera, et cetera, with the triggers for smoking and ask them how tempted they would be. And then tailor our counseling message based on that. So maybe anticipate that since the bar is going to be a really tempting place for you to light up, maybe you should stay away from the bar for the first few months that you've quit. Avoid those high-risk situations. And finally, when we ask individuals to rate their satisfaction with the messages they've received, they tend to rate high the elements of the intervention that are tailored to them. So, I mean, that's a theme in much of the tobacco use, tobacco treatment literature, that when you tailor the message to the target group, that message resonates better with them. So your viewpoint talks about sort of looking at a more holistic view of harm reduction for smokers. And I wondered if you could expand on that and kind of the key points that you think are worth highlighting. Yes. So I would really like to get away from the very restrictive view of harm reduction that emerged from the original description of harm reduction, where the term was coined in the early 1980s, where we were trying to reduce harm by reducing substance use and sexual risk behaviors. There was a theme in a lot of that literature and the harm reduction approach that you might not be able to extinguish those behaviors. But if you could reduce those behaviors, there would be a mathematical resultant reduction in the amount of HIV transmission in the community. So that's where harm reduction comes from. But the restrictive view is harm reduction is about cutting down in someone who can't quit. And there probably is value in that in cigarette smokers. There's not tons of data about the downstream beneficial effects of say cutting from a pack a day to half a pack a day. I think that it is sensible to believe that it is better to smoke half a pack a day than a full pack a day. And there's an awful lot of evidence that lighter smokers, long run lighter smokers, do better from the standpoint of lung cancer and cardiovascular risk than heavier smokers. So that view is not a matter of debate. That is proven. But the actual effects of getting someone to cut from a pack a day to half a pack a day is probably a good thing to do. And I think most people would accept that, but there's less evidence that you wind up with health benefits by doing that. We do and support the idea of cutting down. Another reason to support cutting down is that oftentimes reducing your daily cigarette smoking winds up being a stepping stone on the way to quitting for good. So that is the reduce to quit approach. And there is a literature supporting that. But your question was about a more expansive, holistic approach to cigarette smoking and to tobacco treatment. So I'm a strong supporter of the idea that we should try to think logically about this. Why is smoking bad? Smoking bad because it has downstream bad health effects that lead to morbidity and mortality. So what kills smokers? It's the same question for what kills smokers who are living with HIV. So the things that kill them are lung cancer and cardiovascular disease, so myocardial infarction and strokes and progressive lung disease. So there are measures that are out there and very well proven in the general population that can mitigate those risks. And in the paper, we argue for more aggressive screening for lung cancer. So there is a robust evidence base to support low-dose CT scan screening for lung cancer. And we should be doing more of that in our population. In more aggressive lipid and blood pressure control, hyperlipidemia and hypertension are much more prevalent in people with HIV, and we can do a much better job of controlling those things. So even if someone continues to smoke, we can lower the lipids and we can lower the blood pressure and hopefully result in a lesser rate of heart attacks and strokes and mortality related to those things. And those are things that are pretty easily done in the clinical setting. And for people who are too busy to do that, appropriate referrals could be made to other subspecialists to try to be more aggressive, particularly about lipid and blood pressure control. So you're based in the States, and obviously a lot of the published data comes from either the States or North America in general. How global do you think this approach should be? So that's a great question. So I think that there's enough evidence to convince us that the United States and Western Europe are similar with regard to most of these issues. But it would be a tremendous leap to say that the same issues apply and pertain in Africa or in Asia or in other areas of the world. We do do some tobacco work in my group in Kenya, and we've done some qualitative research in that area. I'm also involved in some work that's being done in Vietnam. And when you interview individuals with HIV who also smoke and try to understand their beliefs and practices regarding their cigarette smoking, there are differences. I think that it's universal that people understand that smoking does bad things to one's health. But the actual social circumstances that surround the cigarette smoking behaviors in these different areas of the world are very different. So in Kenya, where we have a trial going on, for example, there are a lot lower rates of people scoring in depressed and anxious ranges in depression, anxiety scale. So that might be less of an issue there. In Vietnam, where smoking is restricted almost exclusively to men, there's a lot of disapproval among their wives at home. And that's not something that we've really discovered in our qualitative research in the United States, or at least in New York. So that might be something that one could leverage when one is trying to develop smoking cessation interventions for these populations. So I think that, you know, it's kind of an obvious statement, but it would be foolish to try to impose American or Western European values and beliefs on tobacco cessation initiatives in other areas of the world. In order to do things right, one has to do qualitative and quantitative research in those areas to see what kind of message is the right message to deliver and what would resonate best with the target population. So talking about research, so where do you think the main research gaps are? What information could we have that could really help smokers living with HIV? And is there anything. They don't like to do stuff that doesn't work, and understandably so. And frankly, they don't have time to do that sort of thing. As someone who goes to clinic several times a week and sees many of these patients, I understand how challenging it can be and how complicated the patients are. So I think a real need is not only to find something that works so that we can offer it to the people, but try to structure the clinical visit in a way that fosters this and might potentially promote success. Because in real world terms, what happens with so many of these patients including my own is that you go into the visit you have say a 20 minute block of time to complete that visit and all the paperwork that goes along with it and the patient is in an HIV clinic so your first question all the time is are you taking your medicine you have to delve into adherence you have, you have to go over T-cell counts and viral loads. And then there's generally a multiplicity of other problems that have to be addressed. So your problem one is HIV. And then there's asthma. And then there's hypertension. And then there's cardiac. And then there's the social situation. And, you know, I'm getting evicted from my apartment and I can't pay my rent. And these are all real problems that have to be addressed by the, or at least understood and acknowledged by the doctor and the rest of the providers in clinic. And smoking is one of those things on the list. And you only have a few seconds to deal with each of them. So oftentimes, the smoking cessation item on that problem list is noted. And at most, the plan is encourage smoking cessation. And I don't even know how you do that, but encourage smoking cessation and return to clinic in two or three months. I think that that's a bad and unsuccessful approach. So I push to try to actually have individual visits where I warn the patient that next time you come in, we are going to focus only on cigarette smoking. Or it might not only be that. It might be next time you come in, we're going to focus only on your diabetes. We're going to focus only on your asthma. And that kind of approach, I think, can sometimes be more productive because then you could get a 20-minute block of time to actually talk to that person about the cigarette smoking and try to increase their motivation to quit and give them some strategies and teach them why pharmacotherapy would be a really useful adjunct to the treatment. And I think that that sort of approach really can improve your odds of succeeding.
I think there's room for innovation and innovative research here. So the whole topic of genetic predictors of substance use and cessation is a very, very active field. So we need to understand more about genetic traits that lead one to smoke or to fail to quit so that we have those markers. And that might be off in the future, but there are groups that are actively researching that. And other more innovative approaches like contingency management, exploration of social network aspects of smoking. These are very, very important topics and everyone knows they're important, but not enough research has been done. So those are our future research areas that could produce findings that manifest themselves in a productive way in the clinical setting eventually. So everyone needs to get writing grants. That's the message. Yeah, yeah. Writing and hopefully some of the grants get funded and the research gets done. So yes, I'm all for that. Well, thank you so much for taking the time to speak to us today. Thank you. Thank you for listening. And if you're interested in this topic, The Lancet HIV published a trial in the 2018 March issue on varenicline for smoking cessation in people living with HIV in France. We hope you enjoyed this edition of the podcast and we'll be back next month to continue the conversation.
From the JAMA Network, this is the JAMA Editor's Summary, a review of important research and review articles appearing in the latest JAMA issue. Hello, I'm Dr. Gregory Kerfman, a Deputy Editor of JAMA. In this JAMA issue summary, I'll be presenting synopses of the articles in the February 8, 2022 issue of JAMA, an issue of considerable interest that I believe will be very relevant to your medical practice. I'll begin with three original investigations in this issue. The first original investigation by Dahl and colleagues is titled Effect of Subcutaneous Terzepatide versus Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients with Type 2 Diabetes, the SURPASS-5 Randomized Clinical Trial. Terzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist. In this study of 475 adults with type 2 diabetes, terzepatide administered in conjunction with long-acting insulin glargine was more effective than placebo plus insulin glargine in reducing hemoglobin A1C levels over 40 weeks. Patients also lost weight with terzepatide, but some patients did not tolerate the drug due to diarrhea or nausea. In an accompanying editorial, Chipkin concluded that the study protocol answered questions about the efficacy of terzapatide with respect to both reduction in hemoglobin A1c and weight loss, but left open questions about generalizability and effectiveness in different populations, especially patients with certain complications or comorbid chronic diseases. The second original investigation by Perkins and colleagues is titled Effect of Non-Invasive Respiratory Strategies on Intubation or Mortality Among Patients with Acute Hypoxemic Respiratory Failure and COVID-19, the RECOVERY-RS randomized clinical trial. In this adaptive clinical trial, 1,273 patients with COVID-19 and hypoxemic respiratory failure were randomized to continuous positive airway pressure, or CPAP, high-flow nasal oxygen, or HIFNO, or conventional oxygen therapy. The primary endpoint, death or need for tracheal intubation, occurred significantly less frequently in the CPAP group than in the conventional oxygen therapy group, which was driven primarily by a reduction in the need for tracheal intubation. However, the primary endpoint was not significantly different between the HIFNO group and the conventional oxygen therapy group. Thus, the authors conclude that an initial strategy of CPAP, but not HIFNO, may be beneficial in patients with COVID-19 and hypoxemic respiratory failure. In an accompanying editorial, Zampieri and Ferreira observe that it is reasonable to assume that CPAP is probably beneficial to reduce the need for invasive mechanical ventilation in patients with COVID-19 and acute respiratory failure, whereas the role of HIFNO is far less clear. For the immediate future, CPAP may be recommended as the first-line oxygen therapy in these patients. The third original investigation by Hesachers and colleagues is titled Clinical Outcomes Among Patients with One-Year Survival Following Intensive Care Unit Treatment for COVID-19. This was a prospective multi-center cohort study conducted in 11 Dutch hospitals. Among 246 patients who provided data one year after ICU care for COVID-19, 74.3% reported physical symptoms, which were most often weakened condition, joint stiffness, and muscle weakness. Mental symptoms were reported by 26.2%, and cognitive symptoms were reported by 16.2%. The authors conclude that one year after ICU care for COVID-19, persistent symptoms are common. A review article in this issue by Rigotti and colleagues is titled Treatment of Tobacco Smoking. Approximately 34 million people in the U.S., or 14% of the adult population smoke cigarettes. Both behavioral therapy and pharmacotherapy are known to be effective in smoking cessation. Pharmacotherapy includes nicotine replacement therapy, such as the nicotine patch, varenicline, and bupropion, which may be used individually but are most effective when used in combination. This important article provides an authoritative review of methods of smoking cessation and will serve as a valuable guide for healthcare providers in helping their patients quit smoking. The article is accompanied by a podcast with Dr. Rigotti. In a clinical guideline synopsis by Hamid and colleagues titled Blood Management and High-Risk Surgery, the authors review the following recommendations. The use of synthetic antifibrinolytic agents such as epsilon-aminocoproic acid or tranexamic acid for blood conservation in surgery. A restrictive perioperative allogeneic packed red blood cell transfusion strategy is preferred over a liberal strategy to conserve blood. Goal-directed transfusion algorithms incorporating point-of-care testing to reduce periprocedural bleeding and transfusion, and for elective cases, ticagrelor, clopidogrel, and prazigrel should be withdrawn preoperatively. In a diagnostic test interpretation by Lung and colleagues titled Elevated Serum Aminotransferases, the authors provide a concise and helpful review of the appropriate use of alanine aminotransferase, or ALT, and aspartate aminotransferase, or AST, which are intracellular enzymes in hepatocytes for the diagnosis of various forms of liver injury. Although the magnitude and ratios of serum AST and ALT may suggest certain causes of hepatocyte injury, serum aminotransferase activity alone cannot establish disease etiology, and additional testing is usually necessary. There are four viewpoint articles in this issue. The first viewpoint by Zhao and colleagues is titled, Equity and Quality, Improving Healthcare Delivery Requires Both. In this thoughtful article, the authors make the important point that, quote, there is no quality without equity and there is no equity without quality. As new quality improvement measures and approaches are put into place, they should be planned with equity in mind and monitored to ensure they reduce disparities. The authors also state that equity improvements need to be considered when analyzing quality-based performance payments. The second viewpoint article by Nundi and colleagues is titled The Quintuple Aim of Healthcare Improvement, A New Imperative to Advance Health Equity. The quintuple aim includes improving population health, enhancing the care experience, reducing costs, and preventing burnout among the healthcare workforce. The authors argue that, quote, the pursuit of health equity ought to be elevated as the fifth aim for healthcare improvement, purposefully including with all improvement and innovation efforts, a focus on individuals and communities who need them most. The third viewpoint article by Simon and colleagues, which is part of the Diagnostic Excellence series, is titled At-Home Diagnostics and Diagnostic Excellence, Devices vs. General Wellness Products. Examples of new at-home diagnostics include a smartphone app to detect coughing patterns, a dermatology app that allows patients to photograph skin lesions, and the use of the Apple Watch to detect atrial fibrillation. Of the three devices, only the latter device has undergone any sort of FDA regulatory review. This viewpoint describes the issues raised by products that straddle the line between medical devices and low-risk general wellness products, and also examines the difficulties the line poses for regulation, consumer understanding, physician use and interpretation, and equity. The fourth viewpoint article by Capuro and colleagues is titled Preventing Digital Overdiagnosis. The widespread adoption of digital health technologies, such as smartphones, smartwatches, and social networks, is generating vast amounts of health information. These large data sets, coupled with progress in artificial intelligence and machine learning algorithms, provide opportunities to detect diseases at earlier stages and improve population health. However, these new diagnostic algorithms could precipitate over-diagnosis. The authors discuss how data-driven approaches may be used to prevent over-diagnosis and enhance the value of digital health technologies. There are two research letters in this issue. The first, by Maslow and colleagues, is titled Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron wave compared with previous waves. This study describes the characteristics and clinical outcomes of patients hospitalized in South Africa during the Omicron wave compared with the same variables from earlier COVID-19 waves. The authors observed that the Omicron patients were younger and had fewer comorbidities. There were fewer hospitalizations and respiratory diagnoses and a decrease in severity and mortality. These earlier observations from South Africa appear to be similar to Omicron cases now occurring in the U.S. The second research letter by Chua and colleagues is titled U.S. Insurer Spending on Ivermectin Prescriptions for COVID-19. This study examines insurer coverage of ivermectin prescriptions for COVID-19 in the U.S., the authors found that insurers heavily subsidized the cost of ivermectin prescriptions for COVID-19, even though this therapy is believed to be ineffective. Wasteful insurer spending on ivermectin was estimated to be $129.7 million annually. In a piece of my mind essay titled The Path of Courage, Jacobson describes how walking away from her medical career path was as much of an act of courage as her decision to pursue medicine in the first place.
There is also a patient page by Walter and John on malaria and a medical news and perspective article by Kuhn entitled, Vaccine Development is Charting a New Path in Malaria Control. I hope you will find the February 8th, 2022 issue of JAMA as interesting and informative as I have. This concludes our JAMA issue summary. Today's episode was produced by Shelley Steffens. You can listen to and follow all our shows wherever you get your podcasts and can find the complete set of JAMA Network podcasts online at jamanetworkaudio.com. Once again, I'm Dr. Gregory Kerfman, a deputy editor at JAMA. Thanks for listening.
There's a scene that plays out on chilly winter weekends across Wisconsin. Almost religiously, the TV comes on and legions of fans tune in to their team from Green Bay. One Sunday we were at home, my husband and I watching a Packer game. It's not the norm for me to ask him to help with laundry duties when the Packers are playing. But that day, I was very persistent for him to help me. We walked from our living room to our laundry room. In an instant, the peace of that quiet Sunday was shattered. We thought someone was kicking in our doors to break in. He turned off the lights and was like, hey, stay here, be safe, let me check it out. He crawled upstairs and then he looked, the doors were intact. But we saw glass everywhere. Someone was running through our property, shooting through our home. When the police came out, they recaptured the scene. The officer asked us to sit where we were and took a red light and showed us where the bullet would have went had we stayed there. I have a chair that I sit in. The bullet went through the house, went through the reclining chair and the bullet launched in the wall. Had I been sitting in that chair that bullet would have pierced through my heart. My husband was sitting on the love seat and the bullet launched in the wall. Had I been sitting in that chair, that bullet would have pierced through my heart. My husband was sitting on the love seat, and a bullet went through the side of the house. It would have went through his head. Had we stayed there, this would have been a different kind of scene. Instead of a shooting, it would have been a homicide. There's no question that gun violence is a problem of epic proportions that's plaguing American society. In the United States in 2017, there were just under 40,000 gun deaths. There are only about five other countries that are near the United States rate of gun deaths. In this three-part podcast series, we'll take a look at the gun violence epidemic in the United States and some of the people and organizations that are creating actionable, repeatable change in the dialogues, enforcement, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical practice. Here's your host, Ed Livingston. First, a disclaimer. I spent many years of my life in Texas. I even worked on a ranch for a bit. So I know firsthand the usefulness of guns and understand their importance in some areas of the country, both professionally and culturally. That's not what this podcast series is about. It's not about gun control or blanket gun confiscations. What it is about is figuring out common sense, achievable ways to move the bar forward and to reduce some of the entirely preventable violence that's taking people's lives. My producer, Jesse, and I traveled from the West Coast to the Third Coast to find people that are making a difference and ultimately saving lives. As part of a recent TEDMED conference in Palm Springs, I had a chance to sit down with April Zioli. She's an associate professor at Michigan State University with a background in public health and a focus on criminal justice, and she penned a recent viewpoint in JAMA entitled Firearm Policies That Work. April lays out the scope of the problem. We are not more violent than other countries in the United States. The difference with the United States is that when we are violent and we have access to guns, we kill. And other countries don't have the same kind of access to guns that we do in the United States, meaning when they are violent, they are non-fatally violent. So we have a pretty big gun death problem. One of the main reasons people want guns for protection is because of how lethal they are, because of how effective they are in stopping the assailant, whoever they think they're going to be attacked by. That is exactly what makes guns so dangerous and so deadly. So if you have a gun around and you are angry, you are arguing with somebody, you pick up the gun, they are likely to die, the person that you shoot at. You could be across the room from them. You could be across the street from them. We had a case recently where somebody killed a toddler by shooting through the front door of a home. You don't even have to be in the same room to kill somebody with a gun. That makes guns uniquely dangerous, uniquely deadly in the pantheon of weapons. April Zioli pointed the JAMA clinical reviews team to an area of the country that's been dealing with the specter of gun violence for a long time and is taking innovative steps to tackle the problem. To understand more, JAMA Clinical Reviews went up to Milwaukee to talk with James Cross, known as Freed, who served a nine-year prison sentence beginning at the age of 14. Now he's working to help other men as they transition back into society from incarceration. I jumped off the porch at like 12. Up until then, I was kind of just a regular kid, a little angry, a little frustrated or whatever. But then once I started running the streets, it snowballs quickly. You go from making nothing a day to $10,000 a week really fast, but it all comes crashing down really fast too. I started gangbanging, started selling dope, started carrying pistols, and yeah, it landed me in prison. I was a shooter. I went to prison for shooting someone. The first time I held a gun, one of the big homies gave it to me because he was driving and we were going to 21st and Scott to see if any 2-1's were outside to dump him down. He couldn't shoot and drive so he gave me the gun so I shot while he drove. You feel like Superman when the gun is in your hand, but you feel all type of anxiousness and fear and there's a, I know I'm fucking up aspect of this when you're pulling the trigger, the heartbeat and the heart racing and you know, like, we know we shouldn't be doing this. That's why we run from the scene and things like that. You know, I'm not a sociopath. I knew I was doing wrong. But at the same time, I was getting these affirmations from people who I aspired to be like, people who I seen with, air quotes, economic stability or people who drove flashy cars and wore flashy clothes. And those affirmations were stronger than the condemnations of society. So even though I'm hearts pounding and I'm scared as hell that this is going to be the day that I don't go home, I didn't want to let those guys down. And so I pulled that trigger and I did it over and over. It's sometimes hard to put yourself in the shoes of someone in a gang with a gun in their hand. I really believe firmly that we, as humans, aren't naturally wired to shoot at each other. There's got to be something else happening that ultimately leads to this kind of violence. And I think that once we understand some of those root causes, we'll understand some of the pieces of the puzzle. In order to maintain that viewpoint that you can shoot someone or that selling dope is okay, you have to isolate yourself into the parts of Milwaukee where this is okay and normal. It's the constant reassurance that that's okay. And it sounds so crazy when you don't grow up in it. But when you grow up in it, we're constantly told you're acting like a bitch, you're acting soft, quit crying, things like that. If you show anything other than happiness and anger, then you're being soft. If you show any interest in Chuck Taylors instead of Nikes, you're acting white. And these are things that we hear a lot that automatically put activities, actions, thoughts, ideals, values into a negative box. So I can like whatever I want and all you have to do is say, you soft ass, you like this and I'll never do that again, you know, or you acting white, you think you're white, I'll never do that again you know or you acting white you think you white I'll never do that again you know and so it's really easy to find yourself with no other outlet than slapping dope and then the affirmations on that other end once you are selling dope once you are violent once people do know your name in the streets is where it's like perpetuated it's where it's kept up up. So now you're making $10,000 a week selling heroin and you're considered a success. Everybody wants to be your friend. Everybody wishes they know you. People talk about you. Now you feel like you're doing right. You feel like you're doing good. You feel like you're doing well because, you know, who cares about these addicts? You know, these people don't understand or whatever.
And the idea is that this crime is economic and the crime isn't economic. The crime is an assuasion of desperation. I was desperate for acceptance. Some people are desperate for money and means. Some people are desperate for drugs to fuel their addiction. If we can stop people before they reach that desperation to where they'll do things that they know are wrong in order to achieve that assuasion of that desperation, we can stop crime. It's a point reflected by Becky Redmond Walker, reentry manager for the Alma Center, an organization in Milwaukee that works to support former prisoners as they reintegrate into society. From a human being point of view, I'm not stealing because I'm rich. I'm not robbing because I have wealth. I'm not selling drugs because I live in very nice neighborhoods. I am not doing these things because I went to college and I understand that my education can provide financial wealth for me. I am doing these things because of the trauma I've experienced as a young adult. Because if I live in certain areas, dope dealing is a norm. I have guys tell me, Miss Becky, you're always saying, be a good man. What does a good man look like? Because everybody in my neighborhood sell dope. Everybody in my neighborhood is a gangbanger. Everybody don't have a father in my neighborhood. So please tell me what this good man looks like. Because in my neighborhood, I'm mirroring what I see. All children start off dreaming. Everybody wanted to be a fireman, a policeman, a doctor, a lawyer. What shifted the programs that our organization offers. Most of the individuals that go to prison are from poverty-stricken homes. And to come home or even to be in prison is financially expensive. We try to empower guys to do things different in prison. We've sent books to them to read. We will send envelopes and stamps so they can write home. We realize that a lot of the guys are being sent home with the things that they had in the institution. We then took it upon ourselves to say, leave prison in prison and come home as a community member. And that means, why can't I come home with undergarments that are not prison-issued? So we do what we call a welcome home kit. And the welcome home kit is socks, underwear, T-shirts, wallet, like a book bag, shower gel and deodorant. So they can come home and at that moment rinse off the prison and bring on the community. It's like a transformation from what I was to what I'm going to be. This help comes at a critical crossroads in these individuals' lives. Recidivism is a real danger. The easiest path for these men after going to prison is to go back to their pre-conviction way of life, including picking up a gun. When I came out, the desperation to assimilate really had me right back where I started. I went to where I knew, what was familiar. But the Alma Center supports a different path. When we have certain events, we have people from the community, they share the gun violence. When people start sharing those stories, the impact it has on our guys that are in the program, we call them Alma Brothers, it's amazing. You see a light go off because now we have an 80-year-old woman saying, I'm tired of being afraid in my home where you guys are just shooting. I'm always hearing shots around my window, my bedroom window. And there's this 80-year-old woman with tears in her eyes. And to see the look on the guy's face, basically saying, that could be my grandma. Now they're putting a face with some of the behavior that they're doing, and I don't think they can easily excuse it anymore. Because the impact now is, that could have been my family member. Becky could have been my mom, and you could have shot up her house. And so now that they're putting a face with it, I think it's becoming personal, where they can no longer say, oh, I don't know them, I don't care about them, I don't even know who they are. Now you do. So you can't make excuses anymore. And I think it's causing them to think twice now of how they're using and operating these weapons. Coming home from prison is kind of like quitting drugs. You've built your whole life around these streets for so long that everyone you know is involved with it. They're all either selling dope in toxic, abusive relationships. But in trying to do something different with your life, you have to isolate and build a new community. But man, you know, it sucks being alone. And so akin to addiction, you hit up that one person who's kind of trying, but they drag you down with them or you drag them down with you, whatever. But, you know, you guys are used to the same thing. So they're not the person to help you. And I came here and they taught me all about toxic masculinity and trauma and how all these times when I zigged, when I should have zagged. But that wasn't dynamic. What was dynamic was that I could come before class and stay after. I could go on retreats. I could hang out, drink coffee, bother people. And now I have a new community that isn't full of shooters, that isn't full of drug dealers, that isn't full of gangbangers, that is full of people who encourage and support. And here I am, 11 years later, working for them. The Alma Center is one of many community organizations that come together to be a part of another groundbreaking approach in Milwaukee, a cross-department shoot review that brings together law enforcement and criminal justice components, support organizations, and many other stakeholders to go through all the gun-related violence that happened in the city in the last seven days, case by case. Everyone is in one room at one time and focused on a singular goal, reducing gun violence collaboratively. It was something that nobody had ever done anywhere in the country. No jurisdiction had really tried to put this comprehensive process together. Mallory O'Brien was a driving force to instituting these reviews. These partners weren't coming together on a regular basis. They did not have established relationships. So when we first asked people like the Department of Corrections to come to the table, they're kind of like, well, I don't know, we don't really like it. We know this is a little out of our comfort zone. And what we found over time was that it was really a valuable use of people's resources to come to these reviews because we found lots of issues that just digging a little deeper, we could identify and then come up with a fix and fix it. Captain Daniel Thompson talks about some of the partners involved in these shoot reviews. This is a whole community model. You've got the customer referrals, customer interrupters. We work with our community organizations such as Alma Center, DV Advocates, Sojourner Truth House. We also have the faith-based partnerships as well. We also work on educational opportunities with individuals, federal partners, FBI, you'll have ATF, you'll have U.S. Attorney's Office, State District Attorney's Office, licensing will have corrections, Milwaukee County Sheriff's Department, internally, robberies, property crimes, forensics, violent crimes, homicide unit, the whole row of analysts. Sentence of crimes, I forgot to mention sentencing of crimes from the Bureau. Intelligence in the simplest form is information that provides a decision-making advantage. So when we are talking to each other and we're breaking down the silos, we're building bridges, we're all here in person working together to mitigate whatever the issue is, whether it's a group of individuals, whether it's a domestic issue, whether it is a robbery issue, but we're working all together, integrating into solving this issue or problem. These reviews started in 2005 in Milwaukee, and there was an immediate change in the amount of violence happening in the districts where it was tested. It was soon expanded citywide. When he became the Milwaukee Police Department chief in early 2018, Alfonso Morales took the shoot reviews to a whole new level. Chief Morales had seen the value of doing the reviews, how important it was to have this multidisciplinary response, how important it was to engage the community. And so he has taken the reviews and basically put them on steroids. So instead of doing them once a month, he's actually having the department do them once a week. Morales attends from a seat in the back row, jumping in where necessary, but letting the process unfold. It's a holistic approach at understanding the root causes of the problem and identifying what levers you can pull.
We look at it through three lenses, three components. It's the law enforcement lens, which you saw today. It's the community component and the research component. So when we're addressing these, what you will find is when you bring the law enforcement entity to the table to communicate the seven days of problems, the same names are going to come up, the same groups are going to come up, the same locations are going to come up. So very often you see that a small group of people are a result of 80% of the problems. If you bring your patrol, if you bring your investigations, you bring your special investigations, that being your federal DEA, FBI, U.S. Marshal and ATF partners, you bring in now probation and parole, that's our Department of Corrections, you bring in the prosecutors, both state and federal, chances are more than one person in that room has heard that name. That's where the communication comes in, and everyone holistically knowing that they play an important role in reducing violent crime. The intensity in this room, filled to the brim with police officers, the police chief, federal prosecutors, community partners, and many others, is hard to describe. It's methodical and laser-focused on usingring the 14th of February at 6.14 p.m., five .40 caliber casings and the Glock recovered. Our victim is a . She received a gunshot wound to the back of the neck, left arm, and right arm. We have a suspect. He is on active probation for disorderly conduct, I believe. It looks like the victim is suspect they're dating and's a little jealous of the father of her four children. After the shooting occurred, he does the carjacking, tosses the gun in the flight path so that gun's recovered. I mean, he's on a little bit of a crime spree. Hopefully we're going to have a warrant in the system today. Is that correct? So we're going to wrap things up at the DA's office today. He'll be was on supervision, the agent had given him some travel permits to Chicago. So he's got some family that lives in Chicago, and he has some addresses. As a doctor, this sort of review makes perfect sense. We regularly have cross-specialty conferences called tumor boards when we're collaborating on a patient's care to make sure all the patient's doctors are on the same page. When something goes wrong, there's a rigorous system-wide process that we go through to make sure that mistakes or factors that led to them are corrected. According to Mallory O'Brien, this constant review and reconfiguration is an essential part of these reviews. We have over a thousand recommendations that we've made since 2005. Many of them we've been able to implement. There are certainly some that we haven't. And so for me, it's being able to look across all of the disciplines and figure out what can we do and recognizing that it has to be a cross-discipline response, that it's not any It requires not only attendance, but active involvement from a wide they're down 15% from 2017 and 16% from 2016. So just in that very short period of time, we've seen a substantial decrease in the number of people. Almost 100 fewer people have been shot or killed in 2018 compared to the prior years. That's a significant, significant change, not only from the life lost and the people that are injured, but if you think about it from the financial perspective, the number of people that aren't treated in an emergency department or in a hospital, it's huge. All the families, the community, everything. It makes a big difference. A hundred people. From my perspective, thinking about this more from a public health perspective, identifying the small number of people that we know are involved in the gun violence and trying to get them on a different path. Or in some cases, because they've committed the shooting, you want to remove them. You're removing the contagion. So if you can remove the contagion, you can reduce whatever the disease is that you're trying to prevent. In our case, it's reducing the gun violence that we're seeing in the community. So here we've heard about two approaches to gun violence that can be implemented in any city across the country. A community organization supporting former prisoners as they make the transition back into society, and an innovative cross-departmental approach to intelligent law enforcement. In the next episode on our series on gun violence, we'll take a look at Wisconsin's unique gun hearings, the law behind them, and more of April Zioli's research about getting deadly weapons out of the hands of potential offenders. We'll also go on a ride-along with a Milwaukee police officer and hear the boots-on-the-ground perspective on how a gun confiscation usually goes down. That wraps up this episode of JAMA Clinical Reviews. You can hear this and all of our other great content on Apple Podcasts, Stitcher, Google Play, or wherever you get your podcasts. If you have a minute to review and rate our show, it really helps us know how we're doing and makes it easier for other people to find us. Do you want to get all of our clinical reviews podcasts and CME all in the same place? Check out JNListen in the App Store. It's our app that has all of our clinical reviews podcasts and the ability to get CME from them in the app. You can also find the entire array of JAMA Network podcasts at jamanetworkaudio.com. A very special thanks to today's guests, Chief Alfonso Morales and the officers of the Milwaukee Police Department, Mallory O'Brien, April Zioli, Freed, and Becky Redmond-Walker. By the way, here's how you can support the Alma Center. Please follow us on Facebook. We do need donations because we help families. We have our welcome home for men coming out of prison, which is a huge celebration with the community, family members. We're trying to be that positive reinforcement. Please give me a call at 414-265-0100. I'm extension 216. And we can have a meal together. We can support these brothers and we can make Milwaukee great. Today's episode was produced by Jesse McWhorters. Our audio team here at JAMA includes Michelle Krasinski, Daniel Morrow, and Mike Berkowitz, the Deputy Editor for Electronic Media here at the JAMA Network. Once again, I'm Ed Livingston, Deputy Editor for Clinical Reviews and Education for JAMA. Thanks for listening.
From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical practice. Hello, and welcome to this Women's Health Podcast. I'm Dr. Linda Brubaker, Associate Editor with JAMA. Today, we're joined by two distinguished guests, both of whom have careers in the subspecialty of maternal fetal medicine. Today, we're going to discuss when pregnancy threatens the mother's life. Although we'll be using the term mother frequently throughout this podcast, we want to recognize that this includes the life of any birthing parent, and we encourage our listeners to consider the specific counseling and treatment needs of transgender and gender-diverse individuals. Our two guests today are Dr. William Grobman, who is a professor and vice chair of clinical operations in the Department of Obstetrics and Gynecology at The Ohio State University Wexner Medical Center, and Dr. Cynthia Gianfi-Bannerman is professor and the Samuel Yen Endowed Chair in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego Health Sciences. Welcome to both of you. To begin, I'd like to discuss the overall issue of the rising maternal mortality rates. Dr. Grobman, would you be willing to comment on this problem in our country? Dr. Brubaker, thank you so much for that introduction. The rising rates of maternal mortality in this country are a public health crisis. Over the last two decades, they have increased two to threefold in this country overall. I think it's also important to recognize that they are wildly disparate among people of different groups. And I think it's also really important to realize that among all high income countries, the United States has the very worst, meaning the highest maternal mortality rate among any. And in fact, it's not just a little bit worse than others. It's substantially worse. Depending on the other country that you were to look at, it could be five to 10 times higher. And Dr. Graubman, it's my understanding too that this mortality rate is not headed in the right direction. We're not making progress. In fact, we're slipping. Our rates are rising. Yeah, that's exactly correct. That's been going on for really years at this point. If we were to go back many decades ago, it actually had been falling. But then after stabilizing, it actually has begun to rise again over the last two decades, doubling approximately and continuing to increase year over year. Dr. Chiamphi, Dr. Grauman highlighted some of the disparities by race and ethnic categories. Could you explain a little bit more about that? Thank you, Dr. Brubaker. I can. In fact, as a Black woman, it's very disheartening for me to see that Black women are three times more likely overall to die from causes linked to pregnancy than white women. And when you look at these statistics by education, it's even more harrowing in that a Black woman with a college education is more likely to die than a white woman with less than a high school education. And when you look at college graduates overall, Black women with college degrees are five times more likely to die than their white counterparts. That's very disturbing. I really appreciate you and your colleagues for everything you do to make the best options for patients and safeguard pregnancy outcomes, sometimes in extremely difficult circumstances. But we know that even day one, from even the most healthy patient and the healthiest pregnancy, it simply is a fact that it's more dangerous to be pregnant than not be pregnant. Would you both agree with that? That's a true statement. Undeniably. So that increased risk of death can occur from pregnancy-related phenomenon, but there are also non-pregnancy-related phenomenon. During today's podcast, I'd like to sort of focus on the areas of pregnancy outcomes that you experience in your work as maternal fetal medicine specialists. So Dr. Gianfi, there are catastrophic outcomes even in normal pregnancy and delivery. Could you talk a little bit about some of those that you care for? So there are several catastrophic events, like you mentioned, that are rare, but that could happen in pregnancy. And it's very challenging to predict some of these. One example is an amniotic fluid embolism. In a normal, healthy pregnancy during the time of delivery, for reasons that are not completely understood, a woman can essentially aspirate amniotic fluid within her lungs and suddenly shut down and go into cardiac arrest. And there's really no way to predict this event. And many of these events result in maternal mortality, even with the best drills in place to recognize and treat some of these events. And so those can happen during pregnancy. Similarly, a woman in her mid-trimester who, even in her first pregnancy, who might not realize that she's at risk for breaking her water, might in fact develop an infection in her pregnancy that could be life-threatening and that could necessitate evacuation of the uterus. Thank you. So for this podcast, we'll sort of set aside the morbidity and the mortality from early pregnancy complications such as ectopic pregnancy and miscarriages and abnormal pregnancies such as molar pregnancies and focus a little bit on the pregnant individuals who have serious medical conditions that are pre-existing or acquired during pregnancy. So those without medical training sometimes speak in terms that make it unclear as to what qualifies as having a mother's life in danger. The magnitude of the mortality risk and the imminent risk of death pose heartbreaking situations for the pregnant individuals and their family. Perhaps we could begin talking about some of the cardiovascular risks that patients may face. Dr. Grobman, I'd like to hear some of the more common serious cardiovascular situations that pose some serious mortality risks. Dr. Brubaker, I'm glad you brought this specific topic up because in fact, when you look at the reasons contributing to maternal mortality, cardiovascular reasons are among, if not the most common. And there are a variety of cardiovascular conditions that can lead to an individual's death. And I actually also want to say that although we're focusing here on death, I want to acknowledge that oftentimes the conditions that we're talking about may not lead to death, but may lead to severe morbidity that has life-altering consequences for an individual. And that's incredibly important for us to consider as well. Some of the conditions, for example, and I'll just pick out a few because there really are many. One would be something called an Eisenmenger's physiology, when there is pulmonary hypertension and there is a right-to-left vascular shunt that occurs. And if an individual has that type of physiology, their chance of dying in or around the time of pregnancy is considered to be somewhere on the order of 30 to 50%. There are other conditions such as cardiomyopathy that can actually develop in a given pregnancy, although pre-exist pregnancy as well. And if a person enters a pregnancy having had a cardiomyopathy, for example, in a prior pregnancy, and their cardiac function continues to be decreased, they similarly have a significantly increased risk of dying. And as I implied at the very beginning, even if they don't die, the chance that their heart continues to deteriorate in its function is significantly, significantly increased. And Dr. Grobman, most of these patients seek care from a maternal fetal medicine specialist, but that's not always available for every individual. What kind of care do these patients generally need? As you said, I think it's particularly these patients that we're talking about. It is incredibly important that they receive care with a multidisciplinary team that includes ideally high-risk obstetric specialists, but of course, other individuals who are expert in their condition. That would include cardiology, expert anesthesiologists. So if a person were to have these types of very significant cardiac conditions, I would really encourage them and their providers to make sure that they can access just not only the providers that they need, but also the type of institution that can bring all the resources to bear because their care can be quite complicated. And I think it's important for us to recognize that that can't always be in a local setting. And when it can't be, we need to find a way within our healthcare system structurally to ensure that people can get the care they need and to the places they need to go. And Dr. Goldman, even with all of that care in the best setting, that risk of mortality persists for some of these patients with serious underlying cardiovascular disease. Dr. Brubaker, you bring up an excellent point. I think when I had mentioned getting to the right physicians and getting to the right locations, that in no way was meant to imply if those things were to happen, then the chance of mortality or significant morbidity goes away. And in fact, the rates that I quoted you can be considered to be best case scenarios with all resources and knowledge brought to bear.
Thank you. Dr. Chiamphi, another major category are cancers that are either first diagnosed during pregnancy or recurrent. I recently was discussing an acute leukemia that occurred during pregnancy and the challenges that pose for a patient, her family, and their healthcare team. Would you be willing to talk a little bit about some of the common cancers and scenarios that may occur in your experience may threaten the life of the mother? Yes, thank you. One of the most common cancers that can occur during pregnancy is breast cancer. In fact, about 1 in 3,000 women will have breast cancer during their pregnancies. And either they'll have an early diagnosis of breast cancer during the pregnancy or will come into pregnancy with the diagnosis. And it's challenging for the physician, the patient, and the pregnancy in general to decide what the best kind of treatment program will be. Oftentimes, the mother needs life-saving chemotherapeutic agents, and the trimester of the pregnancy will dictate which chemotherapeutics you can give, certainly, or the timing of these agents. And so in general, you start to time these after the period of organogenesis, so after the period of the initial formation of the organs, and then you want to end it about a month or so before delivery, because you also want to optimize the mom for the complications that potentially could occur during delivery, including bleeding. And so as we know, chemotherapeutic agents tend to decrease the white blood cells and red blood cells. And so for that particular reason, you stop the chemotherapeutic agent early, but this is all in terms of timing and could come at a risk to the mother, particularly if the mother has some advanced disease. So that's a common scenario that I've seen several times in my career, but also some of the more rare cancers like rectal cancer and intestinal cancer, we've also seen, like you mentioned, Dr. Brubaker, leukemia and lymphoma. So these occur during pregnancy and management of this sometimes will benefit the one patient over the other and the maternal child interface. Thank you. Dr. Grobman, are there any other underlying medical conditions, either pre-existing in pregnancy or that occur during pregnancy, that we should briefly discuss before we go on to our next area? I think the list of conditions that can cause significantly increased risk of mortality in pregnancy is long, even if no one condition is particularly frequent. We could, for example, look at a condition like vascular type of Ehlers-Danlos syndrome, in which individuals who are pregnant have a significantly increased risk of rupturing their aorta. That would also be true in someone who has something called Marfan syndrome and has a dilated aortic root. So I think what I'd like to emphasize is that there are actually, even if any given individual isn't likely to have one of these pre-existing conditions, the types of pre-existing conditions and the list of pre-existing conditions that can significantly increase the chance of mortality is quite long. I think we're very fortunate to have maternal fetal medicine specialists who focus in this difficult interface and do the very, very best they can to get good outcomes for these patients. We do have some worrisome trends that are increasing the risks of adverse pregnancy outcomes, especially hypertensive disorders of pregnancy, preterm delivery, or low birth weights. Current estimates say that these adverse pregnancy outcomes now complicate about one out of five live births. And I wanted to just get Dr. Gianfi's opinion about why these hypertensive disorders of pregnancy are rising and why this is so concerning? You know, this is a challenging area for us to study because we look at the demographic of our population and it's hard to understand why we see increases with all of the interventions that we've tried to decrease rates of preeclampsia and gestational hypertension. There still are increases. And whether that's due to body habitus or to the fact that folks come into pregnancy with more preexisting morbidities and get preeclampsia over a chronic hypertensive picture, but we are seeing an increase in these rates. And the problem with that is historically preeclampsia and eclampsia have been in the top three to five causes of maternal mortality worldwide. And so as we try to decrease rates of maternal mortality, that comes with an increasing of one of our more common complications. Thankfully, we do have many learning initiatives, many bundles, many quality initiatives to try to decrease these, identify them and treat them early. But with increasing rates, it's really challenging in the obstetric field to try to decrease the mortality and morbidity that comes from developing these diagnoses. Commonly in the first pregnancy, we see women that develop hypertensive disorders of pregnancy. And sometimes that occurs at term, but it can even occur very preterm. In fact, so preterm that continuing the pregnancy could be life-threatening to the mother. But that can happen in any pregnancy. And certainly once you've had multiple pregnancies, that risk can go up even higher. Dr. Giampi, is it also true that although this is certainly capable of causing mortality, again, there's also a significant morbidity burden that accompanies the hypertensive disorders of pregnancy. That would be correct, Dr. Brubaker, that the morbidity that comes with these, while we're fairly reasonable at preventing the mortality, the morbidity that comes with these complications is very common, much more common, you know, obviously than the mortality. And complications such as pulmonary edema and effects in the liver and kidney are relatively common. And these can lead to adverse outcomes for pregnant people. And so the early identification is key. But sometimes, and we've all seen this as maternal fetal medicine specialists, pregnant people will come in with preeclampsia or HELP syndrome that's so far advanced with very little signs or symptoms before they reach that point. And those are the cases that are devastating to families. Dr. Goldman, you recently participated in a paper about temporal trends in adverse pregnancy outcomes in birthing individuals age 15 to 44. Would you go over the highlights of that to help our listeners understand what the temporal trends reveal to us? Dr. Brubaker, I think it goes back to what you introduced this part of the podcast with, which is that the temporal trends in adverse pregnancy outcomes in general have been, in fact, increasing over time, not only because, for example, the average age of people at delivery has gotten older. In fact, if you were to look at all different age groups, the chance of adverse pregnancy outcomes has risen such that depending on the exact definition that you use, but with ones that are commonly used, such as hypertensive disorders of pregnancy, preterm birth, small for gestational age birth, they're now occurring in approximately one in five people who are pregnant. Much of that increase has been driven by, as we've been discussing, the increase in hypertensive disorders of pregnancy that begin during pregnancy and can occur early even in pregnancy. Those have been increasing at a clip of several percent a year, year over year. And in fact, in the last five or six years, it seems that those have been increasing at rates that are nearly 10% year over year. Dr. Gianfi, this paper highlights the disturbing trends, but it also highlights some of the deepening racial and ethnic inequities that were noted. I'd like you to comment on those disturbing trends a bit as well. Thank you. Yes. So what was found in that paper is that the rate of adverse pregnancy outcomes were higher in non-Hispanic Black birthing people compared to non-Hispanic White, Hispanic, and Asian birthing people without a narrowing of disparities across the study period. And so not only were there increases in adverse pregnancy outcomes, but there was no difference in the disparity, which is very disheartening. The authors were potentially able to look at disparities and maybe inform some strategies to mitigate some of these disparities in morbidity and mortality, but the trends are disturbing in that we're not seeing a difference. I think I'd like to begin to talk a little bit about ways that we can work together to reduce maternal morbidity and mortality. There's clearly much work that needs to be done to make pregnancy safer for more common conditions, such as hypertensive disorders of pregnancy, but also these less common, potentially life-threatening conditions. And I'd like to talk a little bit about why other countries seem to do better with their maternal morbidity and their mortality, and what can we learn from them? Dr. Brubaker, that is a fantastic question and one that I think a lot of us are trying to answer. I think the first step and one of the basic steps is education of all of our providers. Our pregnant people will go to a wide variety of providers for obstetric care.
So education, I think, is the very first step. And then moving from that would also be standardization of care. While you're in school, you learn all of these scenarios for different situations. And it's really important to think outside of the box. But I think when you have very common complications like hypertensive disorders of pregnancy or hemorrhage or sepsis, that there should be a standardized way to care for these women such that they all get the same excellent care that's been described and vetted. And since everyone is using that type of care, in theory, then the decision-making and the biases and all of those elements that come into the care will go away and the patient should have a similar outcome. Thank you, Dr. Giampi. And Dr. Grobman, are there any lessons from other countries that we can use to help reduce inequities across the racial, ethnic, and socioeconomic gaps that we see in our country? I think there are. I think many of the other countries we've spoken about in general have social support systems that seek to optimize maternal health. And conversely, we face many structural and policy issues that work against us in terms of achieving optimal and equitable care. And I think we need to be focused, as Dr. Jomfie had mentioned, on education and standardization within institutions, but we also need to be thinking as a society how our policies can best support pregnant people in general, but also drive toward equity such that the social determinants of health that serve as barriers to accessing any care and achieving equitable care are overcome. I think it's also so important that people who are pregnant or thinking of becoming pregnant at any time, before, early, during, or after their pregnancy can access all aspects of evidence-based medical care. Dr. Grobman, Dr. Gianfi, thank you first for the commitment you've made to the subspecialty of maternal medicine and the work that you're doing to improve pregnancy outcomes. It's very, very important work. We very much appreciate your time with us today and you sharing your expertise. Dr. Groban, we wish you all the best as you continue your work at the Ohio State University Wexner Medical Center. Thank you for joining us today. Thank you so much for having me. And Dr. Gianfi, thank you very much for contributing your expertise and highlighting some of the very important areas of racial and ethnic disparities. We look forward to seeing your continued work in this area as well. Thank you, Dr. Brubaker. Thanks for having me. Thanks for listening to this JAMA Women's Health Podcast. This has been Dr. Linda Brubaker, Associate Editor, JAMA. This episode was produced by Daniel Morrow at the JAMA Network. The audio team here also includes Jesse McCorders, Shelley Steffens, Lisa Hardin, Audrey Foreman, and Marilyn Fricula. Dr. Robert Golub is the JAMA Executive Deputy Editor. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com. Thanks for listening.
From the JAMA Network, this is JAMA Surgery Author Interviews, conversations with authors exploring the latest clinical research, reviews, and opinions featured in JAMA Surgery. Welcome JAMA listeners. This is Amalia Cochran, the web and social media editor for JAMA Surgery. Today I am speaking with Dr. Seema Khan, who's a professor of surgery at for this. I'm very pleased to be here. Thanks for the invitation. I find there's usually a good story behind why investigators pursue a specific line of inquiry. And so I'm curious about why you wanted to pursue this particular work looking at oral versus transdermal tamoxifen in women who have ER-positive or estrogen receptor-positive ductal carcinoma in situ or DCIS? That's a great question. I would just start by saying that the DCIS that we chose to focus on, that entity, was being used in our trial as a model for cancer prevention. So women who have DCIS, this is in-situ disease, the cells are inside the duct, so they cannot travel to other places. And the main purpose of treating DCIS is to prevent invasive cancer in the future. So this is really a prevention model. And our focus has been on breast cancer prevention for quite a while. And one of the sort of main issues in breast cancer prevention implementation over the last 25 years has been that the landmark trial by the National Surgical Adjuvant Breast Group, the P1 trial, which tested oral tamoxifen against placebo and showed a 50% reduction, a halving of the breast cancer risk in women at increased risk. That trial was expected to lead to strong implementation, acceptance by many women because tamoxifen was considered to be a low toxicity, well-tolerated agent. That turned out not to be true. And so 25 years later, we're in a position where oral tamoxifen is being declined by about 85% of women who would benefit from it. So alternatives were needed. And for a variety of reasons that I can't get into now, we had gotten interested in the idea of transdermal delivery of drugs to the breast. And this is based on the fact that we've known for a long time, you know, for the past century or more, that the breast is a skin appendage. And we have learned recently that it has a very well-developed internal lymphatic circulation and that drugs applied to the breast skin reach good concentrations in the breast, but very low concentrations in the circulation. So this seemed to be an approach where one could deliver drug to the breast where it was needed and avoid exposure of the rest of the body and therefore avoid side effects. So that was the reason for wanting to do the trial and DCIS was the perfect model because we expect hormone receptor positive DCIS to respond to tamoxifen. Will you please talk to us about the biomarker that was selected as the endpoint for the study? I am not a specialist in breast cancer by any means, and so I am curious what we already know about KI67 and its importance in DCIS. Right. So it's really important in trials like this, which are short intervention trials where we cannot watch for the occurrence of a new cancer. And we use what's called a surrogate endpoint. So something that will change in the direction that tells us that cancer would likely be prevented. So for that purpose, KI67 is actually very well established in the breast cancer world, more for invasive cancer than for DCIS. But, you know, if something works for invasive cancer, it's very likely it'll work for DCIS. But KI67 measures cell proliferation. So dividing cells express this protein. And so the intent was to measure the rate of cell division in the DCIS lesion and to show that the oral tamoxifen would achieve a reduction in cell proliferation using this marker. That was expected. So that's the positive control arm. And then we were testing against that positive control, this newer approach where we were hoping to see non-inferiority. So we were hoping to see that the effects on KI67 or cell division would be similar between the two treatments. Thank you. for them to miss that. I would, however, love for you, Dr. Khan, to share with our listeners the process that you all worked through with the changes to the trial protocol and trial outcomes. Because when I was reading the supplement, I saw those and I thought, wow, this is not a decision that I know was made lightly by the investigators. So I would love to hear more about that. So that's always a challenging process. So when we design the trial, we try to anticipate the characteristics of the population that we are hoping to enroll in the trial and to make the trial inclusion criteria broad enough that we will have a wide funnel for participants to enter the trial, but to make them selective enough that the results will be scientifically rigorous and that we will not include populations for whom use of the agents that are being tested in the trial will cause a hazard. So it's a question of finding the right line between safety for the participants and scientific rigor and pragmatism in the sense of having a wide open funnel so that most women with the condition would consider participation. So this process that we went through, so that's how we set up the trial. The first thing that we changed was we wanted to do a six-month intervention so we would actually be able to measure a decrease in the size of the DCIS. That did not work out because most women are unwilling to wait that period of time to have their DCIS removed. And we had very low accrual in the first six months of the trial, and it was obvious that we needed to rethink it. So we went to this so-called window design where the treatment is much shorter. We had a treatment of four to 10 weeks. And that was the interval for many patients between the initial surgical consultation and the date of surgery. So that was sort of the natural interval that many women would wait anyway. And so that became a lot more feasible. It meant that we couldn't use the size of the DCIS. We would have to use this surrogate endpoint of KI67 that we've just discussed. And then the second thing was the inclusion of, we had to make various decisions about how we were excluding women who had been on hormones prior to entry into the trial, because withdrawal of hormones, which many women do when they're diagnosed with DCIS, they stop their estrogen medications that they're taking either for contraception or for menopausal symptoms. And that cessation of estrogen will cause a decrease in the KI-67. So we didn't want women to be going off their estrogen treatment and starting the trial treatment at the same time, because that would alter the response. And a lot of the response could be coming from the estrogen cessation. So we had to, you know, try a few different variations of that in order to make it still retain the scientific rigor, but increase the flexibility of the trial. I think those are the two main areas that we had amendments in. The others were mostly, you know, technical feasibility, things like that. But that's always the balance that everyone who does clinical trials is trying to achieve. And it's sort of the art of the clinical trial design. It absolutely is. And that's why I like to ask that question about the process, even though it's something that's not obvious, because I think it's important for investigators who are in the learning phase of how do I do a good clinical trial to understand that even really experienced clinical trialists sometimes have to back up and recalculate the route that they're taking to get somewhere. That's certainly true. Why was it important that you use a non-inferiority design for this study? I love non-inferiority studies. I remember first learning about them a long time ago and thinking, gosh, this is genius. But why was this important for your study in particular? Because oral tamoxifen is the current standard. So anything that is introduced as an alternative to oral tamoxifen should really provide equivalent results. And so it's a challenge, again, with a small trial like this to show non-inferiority. But, you know, we designed it to the most rigorous degree possible with this kind of sample size because this is a phase two trial. We had hoped to go to a phase three trial based on the results from this trial if we could show non-inferiority. So those hopes were dashed, obviously, but showing lack of difference is not the same as showing non-inferiority. The statistical testing is quite different. The goal is to show that the new medication is within a certain range of what the standard medication achieves for the same purpose. Your final evaluable group that you had didn't quite make it to the mark of the 80 patients that you all had calculated that you needed when you did your power calculation at the beginning of the study.
It's not only that that's a small difference between 75 and 80. It's also that we were sadly quite far away from showing non-inferiority. So, you know, if we had been like this close to showing non-inferiority, that might have played a role. But, you know, I think we sometimes clinical trials involve interim analyses for futility. We didn't have an interim analysis for futility. But I think if anyone thinks about doing a larger trial, our study, our results, hopefully would be helpful to them in that, you know, they can at least exclude the sample size required for the final effect that they're hoping to see. Because this was, I think, definitively not non-inferior. Right. I am always really curious to hear from investigators what lesson they learned in a study. And so what for you is the biggest lesson that you learned in either designing or conducting this particular study? We learned several lessons, but I think the most important one is that in this general approach of transdermal drug delivery that we've been interested in quite some time and it's very intuitively attractive to women. So we get a lot of interest from women in wanting to use a drug gel applied to the breast skin rather than taking a pill. So I think that's in line of investigation that will continue. Certainly, we're continuing it and hopefully others will too. But in setting up a comparator to an oral medication, the fact that we did not consider strongly enough is that oral tamoxifen and many other oral medications have several metabolites. So from the gut, drugs travel to the liver, and in the liver, they're broken down into several metabolites. And tamoxifen is actually a prodrug. So when it's taken, when tamoxifen is delivered to a Petri dish, for instance, of cancer cells, or, you know, in a situation where it's not going to be metabolized into its active components, it has very little effect. The activity of tamoxifen really comes from its metabolites, and there are two important ones. One is the 4-hydroxytamoxifen that we used in this trial, and the other was discovered later and is called endoxifen. So we were actually very fortunate in being able to measure tissue concentrations of both 4-hydroxytomoxifen and endoxifen. And what we learned is that the endoxifen generated that ended up in the breasts of these participants was many times larger quantity than the 4-hydroxytomoxifen. So it actually had the dominant effect. And the gel participants received only the 4-OHT, and the 4-OHT concentrations in the two arms were not very different, but the oral tamoxifen group got this extra big whoosh of effect from the endoxifen. And there's been more work. I mean, we designed this trial in 2015, and there's been more work on endoxifen since. It seems like it may actually be a more effective metabolite than 4-OHT. So we are currently engaged in trying to develop an endoxifen gel, and we're hoping that that's something we can test and it'll have better efficacy. There are also theoretical reasons for thinking that endoxyphan will get through the skin better, which will also be an advantage. So I think the next thing we need to do is really use a very potent metabolite and then also be able to deliver it through the skin in larger quantities. I like that. You mentioned that this was essentially a negative study, that the non-inferiority of the transdermal formulation that you all selected for this study could not be established. Where does this point you for your next investigation? Is that going to be going with the more potent metabolite of the drug, or is there something else you're thinking about as well? So we are, as I said, working on developing an endoxyphrine gel using different technology than what has been used so far in the gels that are available. But that'll take a little time to develop. In the interim, we are still focusing on the idea that we have to make tamoxifen more or similar drugs more tolerable to women. And a very important concept in prevention medicine is that we should not keep doing what we've done historically, which is borrow dosing from the therapy trials. So, you know, therapy trials, when drugs are developed for treatment, the general approach is to demonstrate the maximum tolerated dose because the idea always is more is better. And this trial on the transdermal delivery has given us some interesting data. And we actually have just completed a different trial that is also adding data to that is how little is too little. You know, that's the approach to use, not how much can a person tolerate. And so that's minimal effective dose. And actually, big strides have been made in this area by a group in Italy led by Dr. Andrea DeChenzi, who's a medical oncologist. And he has published a couple of years ago a trial on low-dose tamoxifen, where he used five milligrams rather than 20, and found that it was remarkably effective for being a quarter of the usual dose. But that dose was not as effective for premenopausal women. So now the study that we'll be starting hopefully early next year will be a trial where we are trying to find the right dose for premenopausal women. So premenopausal women who would benefit from tamoxifen for prevention will start a five milligram dose. And then six months later, we'll check their breast density because breast density has been very well shown to reduce in women on tamoxifen in many women, not all women, but many women on tamoxifen. And this is particularly true for premenopausal women. So we're going to use, instead of KI-67 as the surrogate endpoint, we're going to use density as the surrogate endpoint. And among women whose density doesn't decrease on the 5 milligram dose, then we will escalate the dose to 10 milligrams and then check again. And if the density still doesn't decrease on 10 milligrams, we'll offer them 20 milligrams. So this is actually a novel concept in cancer prevention is, you know, patients stratified individual-based risk dose escalation using a surrogate endpoint. And so I'm pretty excited about that trial. I think it's breaking new ground in prevention. And many of my colleagues are as well. So we have 10 participating institutions. And everyone I spoke to about the trial was very enthusiastic about being part of it. So we have funding for the trial from the National Cancer Institute, but also from the Breast Cancer Research Foundation. And so, you know, we're just gearing up to launch that study. And hopefully we'll see results from that in two or three years. Sounds like lots of exciting work to come from you and your group yet. Dr. Khan, thank you so much for taking time out to speak with me today. I think this has been a really helpful conversation, both in terms of learning about your science and in terms of hopefully providing some education to folks about clinical trials and why they're not nearly as easy as we want to believe they are. Yeah, well, I enjoyed talking to you. Thank you for inviting me to do this. And I'm really looking forward to the reaction to the study, although disappointing, we did learn some important things. Absolutely. This episode was produced by Daniel Morrow at the JAMA Network. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com. Thanks for listening.
Hello and welcome to JAMA Network Open Conversations. I'm Dr. Angel Desai, Associate Editor for JAMA Network Open. Today we are speaking with Dr. Emily Sturbis and Dr. Premal Trivedi about inferior vena cava filter retrieval rates associated with passive and active surveillance strategies adopted by implanting physicians. Welcome. Thanks for having us. Happy to be here. To start, can I have you both please introduce yourselves? My name is Emily Sturbis. I'm a current radiology resident. I'm one of the integrated IR diagnostic radiology residents at the University of Colorado Hospital, and I was the first author on this paper. And I'm Pramil Trivedi. I'm an interventional radiologist at the University of Colorado where I do health services research. I'm the interim division director for vascular interventional radiology. Can we start by talking a little bit about the background of the study and what prompted your interest in this topic? Yeah, so filters have been around for a while to stop clots from traveling primarily from the legs into the heart. And for a while, there have been filters that have been placed that were really just left in with the thought that if they caused any issues in the future, they could be taken out. However, we've seen that as more filters stayed in for longer, there were more complications. And a lot of the national retrieval rates are actually very, very low with these filters. Some estimates say somewhere between 14 to 24% in the general population. It's even lower, more like 12 to 18% in the Medicare population. So our study was really looking at our experience with our filter retrieval methods and how we've changed things really in 2016 and how that affected our filter retrieval rates. Those are pretty low rates that you mentioned there. What are some of the issues with leaving a filter in too long or past its indicated time frame? You mentioned a few complications. Once you get past around 30 days, they estimate that the rates of complications from having those filters in place really go up. Things that you worry about are increased risk of clots in the legs in the future. Sometimes these filters can fracture, which means that if we try to take them out, you leave metallic objects in place. There's risk of the filters migrating, either going further up in the inferior vena cava than you want them to, potentially going to the heart or the lungs at times. And those rates go up the longer the filters are left in. Now, what did you do in this pre-post study? So we had a follow-up program in place since around 2011. At the time, it was a nurse coordinator who was helping to maintain our filter database and from there occasionally sending patients letters. And in 2016, we decided to take a more active approach to how we followed up these filters and how we encourage patients to get them out. And so we primarily looked at 2011 and 2016 filter rates, how were those, and then from 2016 to 2019, when we started doing our analysis, how did they improve? Were all of the filters placed by interventional radiology specifically, or were there other service lines involved in the study? This was specifically our interventional radiology database, since we had a little bit more control in how we collected which patients were included in the database. Great, and what did you find? So we found that when there was a more active approach from our team, that the filter retrieval rates actually went up. So the annual retrieval rate in our more passive method, which was sending patients letters saying, hey, you have this filter in place. It was placed for this reason, but they should really be removed if you don't need them anymore. That filter retrieval rate was 48.7%. And then when we switched to a more active model where we are more communicating with the physicians taking care of these patients after they left the hospital and communicating with them to determine, has the clot gone away? Are they back on anticoagulation now and this filter can come out? With that more active method, it went to 61.3%. With the filter retrieval rates of those filters that were placed and then had them removed within one year, went from 46.4% to 58.1%. Dr. Treti, I'm just wondering, were there any findings in the paper that were surprising to you or things that you didn't expect? It's a good question. We had some preconceptions, certainly some hypothesis going in, which is that generally speaking, the active approach would yield better retrieval rates. There were a couple of unexpected findings. One is that the retrieval rates increased almost immediately. So there was really no lag time. And it was pretty consistent year after year. It's rare that you see within a pretty complex healthcare system, one intervention yielding a consistent signal. And that's what we saw here is that there was approximately 15% or so jump in retrieval rates. And it didn't really die down over time. The other unexpected finding is we thought that with the active approach, we would have a decreased proportion of patients who were lost to follow-up. That was, in fact, not the case. What we found is that a smaller proportion of patients were deemed requiring permanent filtration. And this is adjusting for underlying patient mix. The more active approach was associated with a greater proportion of filters retrieved. And by contrast, the passive approach was associated with more non-retrieval. And the difference is primarily driven by a much larger proportion of the patients being deemed needing permanent filtration. Based on some of these findings, what advice would you give to patients or maybe ordering providers on filter retrieval? Yeah, that's a great question. So I want to reflect a little bit on why this finding may be driving the difference in retrieval rate. So why is it that we are considering more filters permanent? And it also has to do with our decision to enact a more active surveillance program. So if you go back in time and look at the FDA advisories that came out at the time when we began to understand that filters are in fact associated with a lot of complications, really the gist of the message is we should be thoughtful when we place these devices in patients. We should have long-term follow-up and retrieve them when feasible. And really the implication is that the physicians, care providers who are responsible for the ongoing care of that patient should be following up these devices and adjudicating whether the device should come out or not. The problem that we have seen practically with that approach is that often the physician who requests the IVC filter replace is separate from, of course, the implanting physician, is separate from the doctors who are doing long-term care follow-ups. So there's a structural fragmentation in the follow-up of patients who have these devices. And that leads to issues with the approach where the primary responsibility, if it falls on the physicians who are providing primary care for that patient. They may not be positioned well to have all the necessary information to make an educated decision on filter retrieval. By contrast, implanting physicians, interventional radiologists, we're very aware of the complications associated with these devices. We take care of them and we're highly invested in ensuring that the devices come out in a timely fashion. It's really just about facilitating through the framework of a surveillance program, gathering information that is necessary to make the decision for whether the filter should come out or not. So the two reflections I have is that number one, I think to the extent that having a surveillance program at all is helpful, any passive approach or really any active approach is significantly better than no program at all. And then if it's possible logistically for the implanting physician team to manage an active role in device follow-up and retrieval, that is likely to yield higher retrieval rates in a timely fashion. Makes a lot of sense. Based off of this, what do you think are some of the next important or potentially unanswered questions in the area that maybe you are conducting in the future? I'm glad you asked. We actually have grant funding now to look at what I think is one of the central hurdles remaining. When you look at the national problem of unretrieved or forgotten filters, there are facilities of varying resource across the United States. If you look at the gap between the aggregate retrieval rates and really any facility that has published their experience with filter retrieval, you'll see a big gap. And I think that's reflective of the fact that you have a little bit of a selection bias when facilities publish their experience. In reality, committing more resources to follow filters in patients over time can be difficult. And so we're looking for really pragmatic solutions that can be adopted at facilities of varying resource. What can work at a safety net hospital? What can work at a tertiary, ordinary care academic center? Those solutions are likely a little bit different, but there's probably common denominators.
A lot of really important implications for patients, for sure. Do either of you have any final thoughts regarding the study? There's been other studies previously that have looked at other retrieval rates. And like Dr. Trivedi mentioned, just putting something in place that's realistic for an institution to really work on is, I think, really the key step. If you don't have time necessarily to set up a clinic to follow up these patients routinely, that's okay. It's okay not to have those resources and to instead do something that's a little bit more passive so long as you have some sort of follow-up method in place to make sure that these filters just don't stay in and the patients, you know, have no idea, oh, I have this device and that really should be coming out at some point. I think that's a great thought to end on. Thank you so much to the both of you for speaking with me today about this important topic. This episode was produced by Shelly Steffens at the JAMA Network. The audio team here also includes Daniel Morrow, Lisa Harden, Audrey Foreman, Mary Lynn Furkeluck, Hannah Park, and Dr. Linda Brubaker. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com. I'm Angel Desai. Thanks for listening.
Hey listeners, it's 2024 and we are so excited for everything ahead this year. If you haven't done so already, make sure to check out our Patreon at patreon.com slash curbsiders, where you can get access to bonus episodes. We've already released 18 of them and they come out twice a month. Plus you can get access to ad-free episodes and our private Discord server to hang out with other members of the CashLack community. That's patreon.com slash curbsiders. Hey, Paul, what do you call a Jedi with anxiety? Ooh. Hmm. I don't know. Panic in Skywalker. That's maybe my favorite one that you've done. All right, what do you got? Matt, I don't know if I ever told you this, but I just, I have anxiety all the time. Okay. I'm a walking nervous system. All right. We say these with love. We always like to start the show with a pun. We will be talking about generalized anxiety disorder with a fantastic guest, Dr. Jesse Gold, who is just all over the internet writing, tweeting, just all your... I don't know, Paul. She's all over the place. She's very well known. She's a media mogul. Yeah. Yes. I'm starstruck. In just a second, we will introduce our producer for this episode. But first, could you tell the audience, what is it that we do on Curbsiders? Sure, Matt. As always, we are the Internal Medicine Podcast. We use expert interviews to bring you clinical pearls and practice changing knowledge. And with us today is Edison Eddie Jang. Eddie, it's been a while since you produced a show with us, but you do a lot of our artwork. I'm sure the audience knows your work. They just, they don't know they know your work. How you been, Eddie? Good, good. All right. So we had a great guest, Dr. Jessie Gold. Our guest, Dr. Jessie Gold, is the Chief Wellness Officer of the University of Tennessee and Associate Professor in the Department of Psychiatry at the University of Tennessee Health and Science Center. She writes regularly for the popular press and has been featured, among others, in the New York Times, The Atlantic, and Self. Her first book, How Do You Feel? One Doctor's Search for Humanity in Medicine, will be out in October 2024 from Simon Element. You can find her at Dr. Jesse Goldacross social media platforms. Okay, and a reminder that this and most episodes will be available for CME credit for all health professionals through vcuhealth at curbsiders.vcuhealth.org. And also a reminder, if you want to check out our Patreon, it's patreon.com slash curbsiders, where you can get bonus episodes and ad-free episodes, all sorts of other cool stuff. Check it out, patreon.com slash curbsiders. Okay, Jesse, we've been talking for a while, but time to bring the audience into this. And thank you so much for coming on the show. The first thing they're going to want to know is, do you have a hobby or interest outside of medicine? And can you share it with us? I like this question because it implies we have hobbies. I used to have hobbies and then I went to medical school is how I kind of feel in my life. But, you know, I write a lot and it started as a hobby and a comfort kind of thing and has evolved as actually part of my job now. So I kind of have to fight the urge to write something for the popular press when I'm writing. And I have to be like, this is for you and it makes you feel better. You can do that later. It's a whole thing. But that would be my answer, I think. That's a good one. So you are doing some sort of like journaling or just writing that you're not putting out there into the world. Is that what you're saying? I had to buy a pen and paper and I have to do it that way because otherwise if I do it on my computer, I go right into trying to make it into something else. And it's not what it's supposed to be for. You know, if something I write like ends up there, that's fine. But it's not comforting and like self-care if you're going right to making it work, you know? Yeah. Probably good to take a break from a screen once in a while as well. So, you know. I don't know if you know Neil Gaiman. He wrote American Gods and a bunch of other stuff. He's one of my favorite authors. But he now writes his first draft of his books with pen and paper because it forces him. Like this way, I can't look up words. I don't go down internet rabbit holes. I'm not interrupted by emails. Like it's just me and the page. And what happens, happens. Then I always go back and revise it. But his first draft is now all fountain pen handwritten. I'm sure his editors hate that. Like I have enough post-it notes scattered across my office. I'm like, I have no idea what I'm reminding myself at this point now. So I don't think it would go well for me if I tried it. Paul, anything else you'd like to ask about? I do like the favorite failure question. So if you have one, and it doesn't have to be a medicine-related failure necessarily, but do you have a failure that you learned something from or at least enjoyed? All my failures are my favorite failures. You know, like the same way you would say, do I have hobbies? I don't know, but I certainly have failures. I wish we talked about them more. I think for me, I'm a really bad test taker, like standardized tests and like starting young. That was a big failure for me. Like I threw up in the ACTs and had to cancel my score, which was a whole thing. You know, I started taking it. There were like five minutes left or whatever. I got super anxious. I like made it to the end of that and then just like ran out and then canceled my scores immediately because I was like one, embarrassed, two, like definitely not thinking straight at all. But, you know, I think it it taught me not to put so much pressure on myself ultimately in the long run. But we have tests all the time and it's not like I'm so much better. I'm just a bit better. Yeah, tests aren't fun. I hear you. So let's let's go to our first case from Cashlack. Eddie, do you want to present the case? This is Sophie, right? Sure. So Sophie is a 24-year-old female, past middle history of depression, obesity, hypothyroidism, who's coming to your clinic with six months of increasingly anxious mood. The only medication she's taking right now is levothyroxine. She doesn't smoke or do any other recreational drugs and is just a social drinker. She just moved into town six months ago working in a design firm, which has been kind of stressful since her first job. She said she's felt similar anxiety before in college, coupled with some depression, but she's not currently depressed. And she brings some recent blood work in, which shows that her CBC, CMP, and thyroid studies are all within normal range. So for this patient presenting with anxiety, how should we direct the conversation? This is a good case and a good question. You know, I think the first thing you have to think about, and this is a problem with sort of how we use mental health terminology day to day, is that anxiety is a symptom, not an actual diagnosis every time someone says it. So we use the word so, so much to mean the symptom sometimes, to mean the diagnosis other times, but people just automatically assume that that's what's going on if people use that word. And it's a lot more complicated than that. So it's like any other medical condition and you have to go through all the details to figure out what's going on. You have to roll things out. So big thing for me is mental health diagnoses are diagnoses of exclusion, which is as frustrating as it is, I'm sure, for primary care doctors. But, you know, you really are supposed to make sure that nothing else is going on because it could be a red flag. A lot of medical symptoms present like anxiety. And, you know, we're very quick to be like young person, stressed person, anxiety.
That saves you a lot of time. But you do want to like be careful that you don't just make assumptions, you know, whether she had anxiety in the past or not. But, you know, a lot of people who have it in the past will tell me that things get misdiagnosed as anxiety all the time when something else is going on in there. So that's a big thing. But just like anything else, you know, you got to ask like how long things have been going on, what it's like, rule out other symptoms, do a complete review of some systems in both psych and medical. So I think when something is in a psych box, you also have to add all the psych, you know, asking really thoroughly about depression. Like she said, she's not depressed, but that's the same thing, right? As saying like, I'm not anxious. Like, what does that really mean? So you want to know about sleep. You want to know what's going on in the whole SIGGY caps symptoms of depression, which is like mood, really, have you been depressed? And the second one being anhedonia. So you're asking that anyway, I'm sure. I think for primary care, it helps in particular to have the questionnaires just because your time is so limited. So I'm a psychiatrist. I still get like an hour intake with people, which is probably like shocking to all of you. But you know that I don't necessarily use the screens unless I'm tracking symptoms over time and really feel like I need it. Or if somebody, you know, is really bad at clarifying symptoms for themselves in a way that's helpful. But, you know, that's probably how I practice and it's probably not how most people practice, like just because it can be easier to see change and like subtle change when you do that stuff. Yeah, the questionnaires, tracking them over time, you know, the change in the score for partial response and that sort of thing. Yeah, I find it helpful for time wise. And also sometimes patients like don't notice until they like objectively see that their score has changed or hasn't changed. But I'm just bad. How are you bad? Okay, great. Yeah, yeah. But you're like most of the experts we have on the show, they tend to have internalized a lot of these questionnaires and they don't rely on them the same way a more of a novice primary care would when they're doing them. Well, I have to ask every question anyway. I have an hour. You know, so if you said if you like flagged as depression or anxiety, I'm asking you the whole thing anyway. The only difference being sort of like counting the symptoms and asking it in a way to understand frequency. Right. So like it has more days than not less, you know, so really you just want to understand that part. And that's probably the most helpful aspect of that than anything, because all of us have trouble sleeping and concentrating and sometimes feel sad, you know? Yeah, absolutely. Okay. So Eddie, let's go on to the next part of this and, uh, and dig into it a little more. Yeah, so you kind of ask about the frequency, character, and severity of some of her symptoms. She states that it's been ongoing for six months with anxiety more days in a week than not. It occurs at work, at home, and even when she's out with friends. At work, the anxiety revolves around not being competent. At home, she's anxious about her finances and time to do chores. With her friends, she's anxious about being awkward and annoying. When this happens, she feels really restless and tense in her neck and shoulders and hasn't really found a way to control these symptoms. When you ask her if the anxiety is affecting her performance at work and her relationships with her friends, she says that her supervisor says she's been doing excellent work and that her friends have reassured her that she's not awkward or annoying. When the GAD-7 anxiety scale is performed, she scores a 14, moderate anxiety. So does she have an anxiety disorder? Which type? And does it matter much? I like that she said that her friends would think she's awkward and annoying. That's just like such a classic way of kind of describing anxiety to other people, you know? But, you know, yes, because of she does have an anxiety disorder, but really because of the big things here, which is time frame. So six months is generalized anxiety disorder. You know, I always say to patients, like, not everyone makes it to six months because it interferes in your life before that. So both of those things are measures of severity. And sometimes people can't wait six months to have that. So if you were going to go by strict definition, you might say they don't quite qualify for having generalized anxiety disorder yet, but they just came in earlier because their life was more consumed by it. So it's a little complicated, but you know, in the main things here, like one, you did an objective screen, so she needs criteria that way, but also really like timeframe and severity. And then, you know, if you look at generalized anxiety disorder, it's like time, difficult to control, worry, and then a bunch of symptoms like, and you need three of them. And she has those, you know, I mean, you can ask it. They're all weird symptoms, I think, when you ask people because they don't really like, are you easily tired? Has your sleep changed? Are you feeling like very keyed up? Like these kind of things like happen to people in stressful workplaces and life a lot. So again, like someone might flag on the symptoms, but not on the timeline or not on the severity. She thinks it's not that big of a deal. You know, like work is not interrupted. Her friends say she's fine. But then if you look at the objective measurement, and in this case, that would have been helpful, you know, like she might not be noticing it as much or other people might not be noticing as much because it's just like an extreme version of her baseline personality. And so people might just be like, well, that's her and that's how she is in the end. So I think that in those cases, the objective measure can be helpful. You also said, does it matter what kind is going on? Super complicated. You know, in my personal opinion, there are times where it matters and times where it doesn't. You know, at the core, you probably might do the same treatment no matter what. If you go by FDA approvals, which you can in certain circumstances, and you can also understand that to want an FDA approval for panic instead of anxiety, it just means you paid the money for the trial. You know, then you can, you might alter what you're doing in those circumstances. A lot of them are comorbid. So you're going to get somebody who has like generalized anxiety disorder and panic. So that's confusing. I think the big ones for those are like, I think panic, you might treat a little differently because someone might need a as needed medicine more than somebody who might be just stressed and anxious all the time. You know, but for the most part, it's helpful to know symptoms. And sometimes the diagnosis matters in those circumstances, but sometimes you're going to do the same thing anyway. So, you know, we used to have like anxiety not otherwise specified and we just have like unspecified anxiety. Now, a lot of people fit that because of timeline and because of what's going on is not exactly what the DSM said. So, you know, if you're a strict definition person, you would argue very differently than me, I think. But I'm more of like a spectrum, these things overlap person help alleviate the daily burden of overworked clinicians everywhere. And for Irez, selfishly, it would mean that he could spend more time with Gabby, who is spending nights, weekends, and holidays updating medical documentation. Freed turns clinicians' daily workflow into accurate documentation instantly. There is no training time, no onboarding, and no extra mental burden. All of the magic happens in just a few clicks, so clinicians can spend less energy on charting and more time on doing what they do best. Today, more than 4,000 clinicians and their spouses have fallen in love with Freed. Freed is an AI scribe that does your medical documentation for you. This podcast is brought to you by LocumStory. There's a shortage of doctors in America, and locum tenants physicians help alleviate that strain. Did you know that 72% of healthcare facilities are now seeking locum tenants physicians? That's almost double what it was a decade ago.
They are your source for all things locum tenants. You can find interviews on the advice they want to give others looking to try it. You have questions, they have answers, and you can find them by tuning into the LocumStory podcast on Spotify're like, well, thank you. Like that, you've saved me a lot of time. And other times, as you mentioned, this is part of the differential for a lot of stuff, or maybe just pick up on something. So you go through the diagnostic criteria and they meet them. And those patients are the ones that kind of struggle explaining what generalized anxiety is and sort of how we think about it, because to them, it may just, you know, this is stress. This is how life is. You know, this is, you know, this is a normal response to things. So when I, and I know in your field, maybe the patients are presenting, maybe the diagnosis has already been semi-made, but I guess, how do you talk to patients about the diagnosis and sort of how it's different than just the stress of life? Yeah. experiencing something else. So I often am like, what does worry mean to you? And like, how does that like present in your life, like mentally and physically and try to understand it kind of more conceptually than just to be like, are you sleeping? Are you stressed? Are you keyed up? Like, right. Cause a lot of people might not understand that. That's a first step. If someone uses the word anxious themselves, I do the same thing, which is reflect it back and say, like, what does anxious mean? Because they used it and they must have a concept of it in their head. But then when somebody is actually like, I'm going to say like, so this is what I think is going on. You're right, though, that anxiety is normal, right? So all of us evolved to have anxiety. And I explain it this way because I think it helps people, which is to say when we were like in the wilderness, anxiety was an indication that there was a threat or there could be a threat. And so our body prepared for that in part with like sort of what we can like conceptually think of fight or flight. But if you think about it, if there's a bear, I can't go to sleep. The bear's going to eat me. Like if there's a bear, I can't stop thinking about bears because he might come. Right. So like all of these symptoms that like we evolved to have are actually like helpful. The problem is our detector gets off, right? So you start seeing threats or predicting threats everywhere. So when all of us might see it, when there's like a natural disaster, like these things where like our body's like, oh gosh, that's not good. Somebody who has anxiety disorder is like firing all the time. And their sort of like ability to detect an actual threat or an actual predicted threat is just off. And so because of that, it makes existing in life challenging because you just see threats everywhere and you're prepared to go, right? Or you think, oh, this is where bears sleep. I know this because I've seen a bear in a place like this and I need to keep looking for the bear, right? Like I'm just using bear as a weird example, but I, in my head, I kind of, it's probably like dinosaurs, right? So, but I think, you know, I explain it from an evolutionary perspective a lot because all of the symptoms make sense within that perspective. And just to say, you're just kind of like your triggers too fast. Like it just comes on too quickly for you. The degree to get you to there is too low. So people like, you know, you're seeing it all the time. And what we want to do is get you back to, you know, this state where it's helpful and not a state where it's like in your way and making it so you can't do it takes a while to work. So like, what can they do in the meantime? You also don't have enough time to do a lot of things. So you're not giving yourself credit for that. But I think that there's just the time pressure to really do like some kind of effective intervention is just not fair for you guys. You asked about hobbies in the beginning, and I think that is a really helpful way of conceptualizing what I tell people. So I think coping skills, this is a personal opinion, should be viewed as hobbies instead of prescriptions. So there's evidence on mindfulness. There's evidence on meditation. There's evidence on journaling. But if you hate journaling, you're not going to do it. If you hate mindfulness, you're going to be like me and like lose your actual mind in those settings, right? So you have to pick something you're going to do. That might mean like a hobby, you try out some stuff. So that might mean you say like, hey, here's some stuff that patients have liked. Mindfulness, journaling, whatever you know and can explain quickly. And then you say, or even something you've like enjoyed and liked. Then you say, but the thing is, these things are not a prescription and it only matters if you do it. What is self-care to you is what you will do, right? So it's important that even if these things have evidence that you're doing the one that you actually like and that's comforting to you. The cool thing is there are a lot of things to choose from. You know, there's this whole like pleasant activities list, which can seem cheesy, but in a lot of ways you can hand it out to people and it's just like things that people do that they enjoy, right? So sometimes when you're anxious and sometimes when you're sad, you can't get there. Like it's just like, I got too much. It's like choosing where to go to dinner or like looking at one of those really big menus and you're just like, I can't do anything and you kind of freeze. And so that sort of is like helping you guide the menu. So that can be pretty easy. You know, I also like keep a stress ball on my desk. I keep stress putty on my desk. I think those things can be really helpful for people if they start playing around with it, especially if like the stress is coming from something like work and like you can't see my hands unless I go like this on Zoom, right? So I've played with stress putty while talking to patients before because you can't see it. And I think that's helpful. You know, apps are mixed. I have no problem with people using them. I think there are some good ones. I would not expect you to like memorize which apps are good. But if you've used one or a patient's used one, having a list of them can be helpful to just be like, these are quick. You download them. You can play on them. It's your call, right? But I think the caveat on apps is like, they're not a replacement for therapy, but also some of them can be shady and steal your data and stuff like that, just like any app. So you just have to be aware that like, just because they're for mental health does not mean they're perfect. But, you know, I think a lot of, you know, Headspace and Calm are good apps. The free versions are good. If you're not a person who likes that stuff, like Calm has bedtime stories. They just read you stories before you go to bed, like famous people. Sometimes people like that instead of like a meditation that just doesn't resonate. You know, having you guys like actually work through like what thoughts are coming up and what was going on at that time and how are you feeling? It's like too big of a thing to try to tackle in 15 minutes. Like you're basically explaining how cognitive behavioral therapy works, you know, in like a second, because that's like the basis of it. And I think that also wouldn't work on everyone. And I would only probably recommend something like that if it was super clear that if that person listened to the things they were saying to me, it would make a difference. And I might say, jot down your thoughts when you notice you're anxious and see that what happens, but don't obsess over it. So the other thing people with anxiety is if you give them a skill or you give them a way to track their mental health, sometimes they obsess over it because they become like, this is what I'm supposed to do. The doctor said I had to do it, whatever. And, you know, mood apps and tracking totally helpful once a week for something.
But if you use like a Fitbit or, you know, like an Apple Watch and it tells you you slept like 0.1 less, like what does that mean? Like, does it mean anything? And I can't tell you the number of people who will be like, I have sleeping, I'm sure it happens to you too. Like, I have a sleeping problem because my watch said so. And you're like, well, are you sleeping? You know? And so I think it's just like with these things, you have to do what's easy for you guys. I don't expect you to know everything. Pointing them towards useful resources, even if it's like NAMI or some of these like organizations that have been around and collect resources on their own, like you're able to do stuff like that pretty easily, I think. You know, if you make a handout that you just give to everyone with anxiety that has like a list of apps, a list of pleasant activities thing, you know, and you're like, I realize this is information overload, but like read it and play around with it and see what you like. And next time you come back, we'll talk about it. Right. Like you're not a therapist. What does NAMI stand for? So it stands for National Alliance on Mental Illness. So it's like just a very big organization that really their purpose is to educate like patients and families. And so that can be really helpful as a place to find information and find what works for people. They even have like peer supporters and stuff like that. So if you had a new diagnosis of something like schizophrenia and your family or your self wanted to help around that, they have trained people who can help you. So it's definitely a good, and there's chapters in every state and a lot of cities and stuff. So it's a good place to start if you're just like, it's a good organization, I swear, right? Like you just, sometimes you don't want to point people towards these like big overbearing organizations and they just have tons of stuff and the website itself is like an anxiety stressor. Paul, you were going to say something. Oh, was I? Oh, I was just thinking about the patients who are so good at tracking their symptoms and are so good. Like Matt, you've had the patient who has prediabetes who checks their sugar 14 times a day and they have like the Excel spreadsheet and you're like, this is almost too much self-efficacy. Like I appreciate what you're trying to do, but I guess my, Jesse, my question for you, we'll talk about medications, I think at length, but what kind of calculus, can you just talk us through sort of what you're thinking about and how you decide whether or not to offer medication versus a lot of this sort of other supportive stuff at the initial visit. So for the person who's presenting to you for the first time, what factors play into the decision to start a medication versus really kind of leaning into these non-medication options? So when I, I'll start with the meds part. So I'm a psychiatrist. Usually by the time someone comes to me, they're at least considering medication. You know, there definitely are psychiatrists that just practice psychotherapy or do practice psychotherapy in addition. But in our insurance-based structure, most people are doing med management visits as at least some part of what they're doing. So to come to me, you have to at least have it like in the back of your mind in some capacity. It doesn't mean that I'm going to give it to you, but it means that you might not hate the idea, right? So you're going to not have that because that comes up all the time. So I consider patient preference because meds don't work if you don't take them, right? So I can tell you all you want that like a medication makes sense, but like if you're not ready to do that yet, we might come up with another alternative. If you're like hesitant, I might think about whether there's a PRN or something you could give to sort of start the kind of easily creeping into anxiety management with meds thing. Like I try to get on some plane with them on that. So patient preference is huge for mental health, I think, because placebo or not for some of it, but also just like buy-in really, really matters. I think people will tell you they have a hundred side effects too if they really don't want to be on meds. Past history matters. So she said she had anxiety, depression. If she'd ever been treated before, that would be a big thing because you'd say, well, did it work? And did you get like, did you feel better? And if she says yes, like you actually could just put her on the same thing. She just probably came off because she didn't want to be on meds forever. So having that can be a big thing. You know, severity, right? So anxiety is less concrete and severity sometimes for people than depression. Like there's a point at which, you know, that person is really in a risk to themselves in a way that you're like, you need meds, right? But to me, like anxiety really disrupts people's ability to exist in the workplace and exist in like friends and family interactions. And if they're like sleep is affected, if they're not functioning in the way that they used to, like you might start having a medication conversation then, you know, her objective measurement would imply that you would have that conversation just based on that, because it's high enough that if she wanted to try it and she wasn't like morally opposed, you would do it. I think family history matters too. Like if her mom was like super anxious and has always been on meds, she might not hate meds, first of all, because she sees her mom on them. But also you might be able to be like, you know, some of this stuff is genetic in some capacity. Some of it is environmental because of genetics. But, you know, I think you kind of can, that might raise that to my thought process. You know, I want everybody, like if you've come to me for meds, like I want you in therapy. Does that mean that's going to happen? No, for lots of reasons, like barriers to care, cost, ability to actually like get in with a therapist, time, huge. Like you have to go every week for the most part upfront. And that's really challenging for people like cost and access, not included in that. But I think, you know, most of the studies would say, Yeah. tolerate them. I can make you sleep. I can make you like maybe not feel so on edge all the time. But I, if you have those thoughts, they're still there. If something in particular is triggering you like a fear or a situation, I can't drug that out of you either. You know, I see a lot of healthcare workers and, you know, they want a med so they can just go back to work and they don't want to talk about their feelings. And it's like a very different group because, you know, there's a lot of just medication hesitancy and mental health to begin with. But health care workers are sort of like, just give me the thing and like, let me go back to work. So, you know, I think I would always recommend therapy with the caveat of all the barriers. I don't get mad at people if they don't go, but if we've tried a lot of meds and nothing's working, that's probably why. So at a certain point, like you kind of have to just be like, well, that's the problem. Like that's the missing thing. It feels stressful. It feels time consuming. It feels like woo woo sometimes, but it actually makes a big difference. You know, evidence-based wise, cognitive behavioral therapy probably has the most evidence in anxiety, but it's hard to study all other forms of therapy. They're not manualized in a way that you can do a randomized control trial. So you're not going to see, so I like open-ended sort of psychodynamic psychotherapy personally. And, you know, that's, I go to a therapist that does that or sort of a mix of that. And I think if I was like listening to evidence, I might say that's not good because there's no evidence that works. But again, those aren't, they're very individual. Like the person is the tool. So if you have fit and get along with your therapist, it could work just as much as cognitive behavioral therapy. Some people just don't want to do cognitive behavioral therapy either because it's work, like homework work and like skill practice work. Like it's more like school sometimes than therapy.
So like some people just don't want to do that. Right. And like, it doesn't work if you don't do it. So, you know, keeping that in mind, if you say to someone like the evidence says this, or like, you know, you might consider this kind of therapy, you also might say, but keep in mind, you're going to get homework. They're going to go over skills specifically with you. And it usually is, it's something like eight to 20 sessions that people go to for it. So I was going to ask like there's we don't have to mention brands here, but like there's a couple different online or, you know, all online, all remote like services that you can sign up for. I know some health systems even like provide them for their employees and you can get a therapist there. Yeah. It's almost like Uber for therapy. Like you just like, you know, you throw a line out there and there's a bunch of therapists that like are around that you could choose from. So what do you think about those resources or just like online self-directed CBT or those things that you've seen anyone have success with? I think that is huge, especially because on a good day, a medicine I give you is going to take six to eight weeks, right? Yeah. That's a long time to wait. And then if you're also on a wait list for psychotherapy, like what are you doing, right? Like you asked like how to give people stuff, but even if you are working with them and having them come back and trying to like kind of patch it while they're waiting, it's really just patching it. You're not their therapist. So access wise, it's great. I think it comes with the caveat around quality. So I think even the people who are therapists who might moonlight for some of these places would tell you that too, that it's very hit or miss in the therapy, like who is good. They're underpaid and overworked. So to want that job is a specific kind of person. Sometimes you might be a person who only wants to see a PhD and the chances that you're going to get that on one of these apps is probably almost zero. So that's a training thing, right? So again, as a healthcare worker, sometimes people want the six years of somebody doing the training as opposed to the one to two or something like that. So I think that's a decision you might make. Honestly, I tell people they exist and that they can use them, but that I prefer they use them as a bridge. Like that they use them while they're waiting for whoever they want to see in the community for the long term. That they use it for short-term, quick access. That they ask for a different one if they hate the person or they're really bad. You know, I've had patients say that the therapists on some of them bring up things that they shouldn't, like religion or politics and, you know, like things that are just really wrong. Like if that happens and you're really uncomfortable, you don't feel safe. Like, I hope it doesn't scare you away from getting help, but I hope you know that you can ask to see someone else, you know? So I usually would say stuff like that. But it's very hard to poo-poo an entire thing that makes somebody get in that quickly. But, you know, they are, after all, businesses and people in mental health are vulnerable. People struggling with their mental health are vulnerable, meaning that you want an answer and you want an answer quickly and you want help and you want help quickly and the system isn't built that way and you're not getting a lot of support. And so you're like, well, what can I do and what can I do quickly? And that's how like all these kind of, I don't know, not scientific ways of helping your mental health kind of get chosen. That's how these kind of companies thrive. That's how some of them that actually were psychiatrists just gave drugs to everybody. You know, I think it's a very, very vulnerable population for like the search for answers and answers that don't take years. And it makes me sad a little bit that it's such a hot market for this stuff. This episode is brought to you by Allbirds. Folks, if you're anything like me, you spent the winter cursing the cold, maybe exercising less, maybe not eating as well as you would like. But now as spring is coming, I'm thinking about redefining myself, reengaging with the world, and thinking about what I'm going to do and where I'm going to go. And warmer temperatures also mean new super light styles from Allbirds. Meet the Super Light Collection, Allbirds' lightest ever shoes, now in fresh colors. A lighter-than-air feel and barely-there fit make some of these the most packable styles ever. What can you do in a super light shoe? The better question is, what can't you do? And because they are so packable, the real question is, where are you taking them? Allbirds were nice enough to send me a pair of sneakers. I have to say, they look fantastic and they feel even better. You barely feel like you're wearing anything at all. They're comfy right out of the box. They're great for hiking, for walking, for running, for your day-to-day wear. I've really enjoyed having them. And I will say that now Allbirds is featuring the Super Light Tree Runner, their most breathable lightweight style yet. It is made with ultralight foam, so it's super comfy and packable, which means you can hit the road with less baggage. They have a light as air feel and the lowest carbon footprint yet to support every step all day and all night. They're made from a cushy lightweight foam and they have extra outsole traction to give you the grip to go for it. They also feature breathable eucalyptus fiber and comfy midsole for all-day adventures. Experience how Allbirds redefines comfort. Visit allbirds.com and use the code CURB for a free pair of socks with a purchase of $48 or more. That's A-L-L-B-I-R-D-S dot com slash CURB. I agree with you. The appeal there is the ease of getting into care. That's the issue. It is very hard to get people in rare in my experience as a primary care. So Jesse, let's say Sophie does all the stuff. She's doing things she enjoys. She's practicing relaxation techniques. She's followed your recommendations as much as she's been able to and yet still continues to feel anxious. And so at this point, she says, I think I'm ready to try medication to kind of further help my symptoms. What kind of considerations do you think about when you're actually starting an initial agent? Like, how do you choose for her? Yeah, it's a good question. And I think it has an imperfect answer. And I think that actually frustrates patients a lot because I don't think we have a very good algorithm for medication in psychiatry. So when I'm thinking about it, I definitely just have meds that we almost always start with an SSRI. Let me just say that. Just again, it's an algorithmic thing. Probably 20 years ago, they started with tricyclics, then SSRIs made it easier, right? They're just less side effects. So that's what happened to them being the ones you start with. So I have preferred ones based on patients and seeing them and seeing what people tend to like. And that's some of my thought process. Some of it is, again, like if you have a family member on something, there's a chance it works in you too. So you might as well, right? If a friend's on something and you're really into it because that friend told you it was really helpful, I'm also okay maybe starting that med because you might take it. Side effects come into thought here too. So sertraline sometimes is worse on your stomach. Depending on who you ask, you might have some more activation on some versus others. Some people might argue that something like escitalopram will make them hungrier. You know, it's very varied. But sometimes like if a person's main concern is that they're awake, like I might be more thoughtful about one. Or if somebody has Crohn's, I might not give them something that is known to have more diarrhea up front, right? So that comes into thought. I will also say that I sometimes deviate from starting with an SSRI and sometimes have given probably like the most no-no of all medicines up front, which is Bipropion.
So I actually have seen it be activating in some people and worsen their anxiety. But I also see a population that doesn't want to gain weight and doesn't want sexual side effects. And sometimes the risk that their anxiety gets worse when you weigh it against those things, they don't care. They're like, give it to me. If it makes me worse, I'll stop it and try one of the ones you say I have to try. So I use it a lot as a first agent. And that is not what anyone would teach you. And it also goes against this sort of like bupropion is the devil for anxiety mindset. But I actually think it helps on a lot of people, especially this sort of comorbid anxiety, depression folks. And if you're going to be so mad about weight gain or sexual side effects that you won't take it, you know, your patients are grownups. It's a risk-benefit conversation. And the risk is, you know, it might be a couple weeks of feeling uncomfortable. It depends on when they stop, right? So I have done that before, which I'm sure is a big, big no-no to someone. For a second, the relief that washed over me, I thought you were going to take a left-hand turn and be like, and I start them all presently. I was just ready to be heartbroken. So when you said reprobate, I was like, oh, okay. Yeah, that sounds fine. And Jessie, I was reading that it's a good idea to just start lower doses of medications because people with anxiety disorders are just like increasing suicidality is very hard for people to understand because you're treating the thing and you have the chance of making the thing worse, right? But they both exist. And so, you know, I just kind of, I'm like, it's weird, but this is also possible. And it's about tolerability. It should go away. And if it doesn't, that's a problem. But I will usually start like half the starting dose for like a week, week and a half, because usually you get more anxiety right away. And if it's really bad, it would be really bad. And then I have them go up to starting. I don't rush up as fast either, probably for the same reasons. I mean, it might be better. I would be like, well, it could make your anxiety worse if we go up or it could make you feel better. Like, do you want to hang out and see if you get better in another couple of weeks? Right. Like I might give it more time. But yeah, the data like studies on anxiety have lower doses versus something like OCD, which higher, which is confusing because they're also friends. Like people and OCD is like a different form of an anxiety, you know, in a lot of people. So it's funny or, you know, not funny, but like polar opposite. So if I'm hearing you, you might give escitalopram five milligrams and tell them to take half of that for the first week. And then they could go up to five milligrams after a week or so if it's going okay or sertraline 25 they would take half of that and you know if it's going okay they would go up something so that's hard because those are both like really small doses no matter what right so i think i would probably say like five is actually the half for my experience but i wouldn't go five to ten i'd go five to seven and a half. Um, you know, I would give that as an option. Some people are like, just, I don't want to cut a pill and just give it to me either. Right. But, but I wouldn't maybe not jump that quickly to 10. Um, in the 25 question, those pills are also super cuttable and come in all the different things. So that can also be nice. But I would probably start with 25 and then go to 50. Like that's still low. Most people are going to end up at 100 or more probably on that, even anxiety. If you push the dose too quickly, does that manifest, does the patient come back and tell you I had increased anxiety or does it manifest as treatment, not efficacy? Does that make sense? Both. Now I'm starting to worry if I've like increased the dose too quickly and just didn't give them time to actually acclimate and become less anxious. Is that a possibility? Possible. Cause it takes a long time, right? So the hard thing is it takes a long time and none of us have time. And a patient who is anxious is going to call a lot and they're going to say, I'm not better. What's wrong? And you're going to want to do something. Right. And the same thing if they come to a visit, like you're not going to be like, oh, cool. Like, let's just hang out there. Right. So it's hard. And it's why an inpatient, you know, they if you remember inpatient psychiatry at all, like they rush that stuff up so quickly and then they come out patient. And I'm like, I don't think you need to. I mean, I think we should go down on some of this stuff, right? Like, because I'm not even sure that it like you need this much medication. So, you know, in an ideal world, you would give it time. In a actual world, it might not happen because you might feel like you need to do something and it might be the best option. But I would just say that it's not perfectly linear, that if you had a side effect before, you're going to get it again when you increase the dose, just like on any medicine. But the risk is there again. So, you know, it's a good conversation with the patient where you just say, like, there's a chance if I increase your medicine that you might feel bad. So, you know, that's just something to know, but I'm happy to do it to see if it makes a difference. But I definitely think that we probably increase too fast and like not everybody needs to be on that, but it's not humanly possible to not for the most part. Like if you looked at studies, they're waiting, like they're just, they're waiting and giving it like a full eight weeks or whatever. It's just not feasible in a clinical setting, really, where that's not your parameters to just do nothing for somebody if your tool is medicine. So you are going to push it up fast. And I wouldn't really be worried about that as much as you're just aware that side effects can happen and people might feel more anxious and that maybe you have to go back down, which I've had to do and maybe go slower. Like if you went 25 to 50 and they were like really anxious, you might try the middle, you know, like something like that instead of like completely getting rid of the drug entirely. I also think people don't max out meds as much as they should. You know, like I think we switch a lot. Like I think we're like the same reason, like you need something to do and like the person's already at like a decent dose and you're like, well, is this a failure or not? And I think that's a really hard question to answer and that we probably switch meds more than most, but like when I get someone's med list and they've been on like 15 meds, I try things they've been on before because as long as it didn't give them hives and it didn't make them so miserable that they won't take it, I can't be certain that they gave it a good go. So I want to give you another common scenario with this is if someone sounds like they have generalized anxiety, but they're also having episodes of panic, I try not to prescribe benzos. And one of the articles I was reading said, if you are going to prescribe benzos, you should prescribe them in a fixed dose and tell the patient you're going to stop them after two or four weeks. You shouldn't prescribe them as needed. And I was a little bit like, that's a little counterintuitive to me because usually I give it and I'm like, don't use it unless you're having like a panic attack. What do you think about benzos along with this? Or do you use hydroxyzine as needed? I've seen some people do that. Sure. So there are many reasons to not use benzos in people, including their past history. So that has to come into your thought process, of course.
And so we don't. But some people need benzos because meds take six to eight weeks to work on a good day. And if you're having panic all the time, you're miserable. And whether you take it as needed or you take it scheduled, I think is a frequency question. So if you're having a panic attack every day, you should take it at least once a day for a bit while it kind of settles and try to get yourself to settle. But you have to know that like if you took it consistently, you're going to have to taper it because even on like tiny doses and attending told me this before, like even on tiny doses, if you were consistently taking a tiny dose of like clonazepam or something, you're more likely to seize even if the dose is small because you're taking it consistently if they just pulled it off. And so it's just something to be mindful of. You know, I'll tell patients like, you know, you're having a lot of panic. I think you probably need to take something every day. But this is not a long term everyday med. This is the until we figure out what the other thing is med and we're going to taper you off of it eventually. And that's the goal. Like I'm not planning on you being on this for a long time. I think in some people though, if the frequency was like three times a week, I would probably say take it as needed, but use it as a benchmark for how you're doing. So as-needed meds are fantastic measurement tools, right? If you're taking an as-needed med every day, you need a daily med. So like I have patients who want to start with as-needed meds and I say, if that's all you'll take, I won't start clonazepam probably in those situations. But I will say like if that only thing that you'll take isn't as needed medicine, that's fine. But we have to use it as a barometer for how you're doing. And if you take it every day, we're having this conversation again, you know. But in most people, it's a severity thing for me whether I offer that up front or not. It can be sedating though. The weird thing about benzos, I think is like some of my patients take them and then take a test and some of my patients take them and go to sleep. And sometimes that's the same patient. Yeah. like candy. And I think it's because, so most anxiety meds that are as needed are sedating. And most people can't just sleep all the time. Most of the time when you need to take an as needed med, it's like a work meeting, a test, like whatever is the problem, you cannot be asleep. And a lot of times it's like that physical reaction. That's the problem. Like people can tolerate their thoughts. And propranolol is awesome at the physical reaction. Obviously, biggest risk being dizziness. And if you have low blood pressure, something to begin with. But we're using like 10 milligrams. Like we're not using big doses. So if you think about it like that's a tiny baby medicine and it can really help and isn't sedating, it doesn't have a risk for tolerance. People take it in much higher doses every single day. Like, so I have no qualms telling someone to take it every day. I'm like, okay, take it every day. I can get on board with this, Paul. is the symptoms part, but maybe I was misunderstanding sort of the thought process behind it. But yeah, it's something I've been thinking more about recently as a possible adjunct event, but not something I've been using in the past. I think like because of the patient population I see, it was like, oh, they have data and test-taking anxiety and performance anxiety, et cetera. And I was like, that's basically that on steroids, right? Like that's what I'm seeing so much of. And like, I don't want everybody to be on a benzo for lots of reasons. I'm not like, oh my God, benzos, because I think that's not helpful either. And I think some people need them. And I think that that mentality doesn't help patients, especially if they've been on them before. But propranolol is a nice alternative. I mean, in my mind, there are also other alternatives would be something like hydroxyzine, but keeping in mind, it's really sedating. I usually ask people what Benadryl does to them and have a conversation around that. Like, yes, it's different, but I guess I shouldn't. Diphenhydramine, what diphenhydramine does to them. But, you know, if they feel like it, you know, they have that weird reaction where they get really activated, that's not helpful. And if they feel like they can sleep for 80 hours, that's not helpful either. So I tend to steer clear of hydroxyzine in those situations. I use buciparone sometimes. If you look at an insert, it is not an as-needed medicine. but some people would like to take it as needed, and that's fine with me. I try to prescribe it once daily and once as needed and use the once as needed as a measurement for severity because people don't like twice-a-day meds. It is a twice-a-day med. It is a three times a day med sometimes, but they do not like that. So sometimes if I'm like, you know, someone's not quite ready to be on an SSRI, that can be an option, which is to say, okay, well, there's this like sort of in-between med where you have to take something every day, but it doesn't have the same side effects. You might just like it. But I also describe buciparone as either someone thinks it's the best thing that was ever invented and that was their answer to everything or does absolutely nothing. There's no in between. I have no idea why, but it is not a spectrum. Like it is like, that was the best thing. Why did no one give that to me before? Or why are you giving me tech tax? Like there's literally nothing in between. And so that doesn't scare me from taking it or like, you know, having people take it, but I will say that. And I will say, we will know very quickly if this does absolutely nothing and there's a chance it does absolutely nothing, but it sometimes really works for people. And I'm trying not to like take that opportunity away from you if you want it. And then probably the last one on my like hobble list would be something like abapentin. Again, with sedation being big. But, you know, you can start at 100. And what's the max is like 3,600, like something bonkers. So the space there is like astronomical for some of these concerns that people have around gabapentin. And with boost prone, are you typically using that with an SSRI or using that as sort of monotherapy if the SSRI is not effective for the patient or just kind of depends? Like what are the contexts where you're using buspirone? Because I feel like that's the one, you know, doctor up to date whom I trust in all things who haven't sponsored us yet. I feel like that's sort of their recommended sort of next step in therapy, but I'm never quite sure how to use it in combination with the other medications. So my most go-to use of it is these people who don't want meds yet. It's a good option for people who don't want meds yet. It's like a test of them taking something and it doesn't look as bad if they Google it. In fact, there's like no information really if they Google it. And so for the most part, that's helpful. And so I'll be like, well, here's an in-between and it's not as needed. So you're not chasing it as much, you know, if you have them take it that way. As an adjunct, like to an SSRI, I would say it's only helpful if you are mostly there and you don't want to change the med. Like if somebody's on almost a max dose of something or, and they really like what they're on, they just have like a little bit left that they would like a little help with, then I might try something like that because it's easier than switching and it's probably lower risk than adding another antidepressant or something as she would want.
Like they could take up to two doses a day or up to three doses a day of either of those, something like that? Yeah, I would say if, you know, Sophie said, like, I kind of like it and I feel a bit better, but I'm not perfect. And I, you know, not that anyone ever is, but like I still am pretty anxious and it's still interfering with my life. The question would be how bad and if you should go up above 100, right? That would be your first thing. But if it's like, I don't want to do that, like I am good with this. Is there anything else I can do? Or like you feel like you don't need to do that part, you know, then I might add it in that circumstance. You know, something like gabapentin, if like the problem is that she feels great, but she's not sleeping, it's solving two things. So with something like hydroxyzine, right? Like it's helping with both. Like it's anxious thoughts at night, usually, you know, in that circumstance that you're just putting them to bed. So, you know, I think that in those circumstances, like adding something like that can be helpful because you're like kind of, you know, for lack of a less bad metaphor, killing two birds with one stone. But I think you're sort of like trying to say like, okay, what are the symptoms that are left that are really interfering? And if you can target that with something else, you might. That's why you might sometimes see someone with anxiety who's on like a sleeper and an S-needle because it's like people are trying to kind of put it all together in a way that's helpful for them. So this is a little bit out of order, but I wonder what the thinking is with SNRIs for anxiety. Like for depression, I will usually reach for them if there's some sort of possible secondary benefit like basal motor symptoms of menopause or if there's some sort of chronic neuropathic pain. Like then I might be like, why don't we try this and see if we can't sort of attack both. Is there a role for SNRIs with anxiety or a reason that you would reach for them versus an SSRI as initial therapy or switch to them perhaps? Same reasons for initial. You know, if somebody was like having migraines, I might do the same with like a TCA. You know, so I do still think like that, even though there probably isn't as good of robust evidence in anxiety for thinking like that. You know, there's a lot of sort of chronic pain, overlap with depression and a concern and need to treat that. Right. And so there's been a lot of studies on it. But it's not to say those people aren't anxious, too. So, you know, it will come up in certain situations where it makes sense like that for me. But most of the time it would be one to two SSRI choices. And then at that point, if I sort of was like, eh, like I would look at the propion and I would look at an SNRI, especially if it wasn't like they partially were working and I'm like wanting to add an adjunct. It's like they're just not working because, you know, I think the caveat on all SNRIs is the coming off of it is horrible and skipping doses is horrible, especially for venlafaxine. Venlafaxine is the worst for that. And so, you know, I always give that caveat. Like, I'm going to try a different class of meds, but there's a chance if you skip a dose, you might feel miserable. Even the extended release? That med is hard to come off of if you've ever tapered someone. You know, rule of thumb, I might go down every two weeks or something if I can, if people can tolerate it. But sometimes that one needs a little extra. Sometimes I've had to use a benzo in those circumstances, like trying to come off a med just as much as coming on. So it sounds like part of what we got to with Paula's questions was if someone had no response to like one or two SSRIs or an SNRI, then what would you do then? You know, like if we've tried some of the first line agents, then are you going to TCAs as like, or are you going to antipsychotics? You mentioned whatever, what is it? Aripiprazole or Ketiapine I've seen listed, Risperidone. Some of the articles I was reading said like, if you get to that point, then they should be seeing a psychiatrist because side effects can be much worse with those meds. Yeah. I mean, I wouldn't assume that you guys would be like throwing antipsychotics at people just because there's just a lot of side effects inherently with them and it's complicated. I have used quetiapine in a similar like sleep being the main thing situation, but 25 to 50, we're not talking. 300 or 200. Yeah. You know, I think if you're feeling like you're just adding meds or just throwing darts, they should probably see a psychiatrist because at least if we're throwing darts, we've thrown them a bunch. You know, it's imperfect and we might still be throwing darts. But inherently, like we've probably seen more people like that and that dart worked or that one to the middle. Right. So I think that if you're feeling like that, you know, it's not to say if you feel super comfortable that you don't do something like that, you know, but I do think that it's probably outside of saying that someone should go to therapy or something, what you're going to end up having to do in those situations, because it's not like you even have the capacity to keep being like, okay, let's try something else. Like, okay, let's try something else. And it's really frustrating sometimes. There are very expensive genetic tests that sometimes people will request because they've heard of them. They're correlations, not causations, and they are imperfect too. It's like a percentage, you know, but sometimes in someone with anxiety, it like helps you make an argument or switching or another med or something, right? So sometimes it just gives them something to lay their hat on. Like I describe it like it's expensive. You're not probably getting that covered. It's not really that helpful. But if it would help you to have a list and go off that list based on what the test said, more power to you. You all go off the list. So sometimes that can help. This test is looking at how they might metabolize certain drugs and you might respond better to this one than that one. I actually have come across this and after kind of looking at it, looking it up and discussing with the patient, they decided not to go through it, basically because of what you said. But I could see how in the right person, if they just want to know and it's not cost prohibitive for them, then it might help them do better with a medication if they know physiologically like they're more likely to benefit from it. Yeah, it can be a double-edged sword, of course, like if you give them that knowledge and then you're like, we're out of the green ones. Can we go to yellow? It's like a stoplight. And, you know,, they might get a little bit mad, but you know, I think it can help if you're feeling sort of like spinny with somebody. Um, but they are not, I mean, you know, they're out of pocket, not that cheap. And so that's kind of hard. Okay. Before we get the more exotic stuff, um, I feel like, you know, disorder sleep can be so much part of anxiety and one depression too. But I also, I don't see folks reaching for mirtazapine so much for anxiety specifically. And I, what's the thought about that in terms of when to use it or to use it at all? So weight gain is real. For that, it is not a good long-term drug in most people because sometime in our life, our weight catches up to us or sometime in our life, our weight is already a problem, right? So it can be hard. If people are fine with that, it's not a bad option at all, especially if they want help quicker. So in the hospital, you use ritazapine a lot on like consult psychiatry because it works really fast and it has like no drug interactions.
And it doesn't interact with a lot. So it can be really good in people like that. I think older people, skinny, older people who aren't eating anyway. So that's the other way our bodies can go. So they're fine being on something like that and it might help quicker and it can be great. You know, like it's fine if they're a little hungry. I see college kids who will like murder me in my sleep if I make them gain weight. So it's not an early choice for me just for those reasons. But I, you know, I worked Cygonc for a while. It was like my only option. So I think, you know, it definitely can be helpful. The important thing with mirtazapine is just to remember the dosing is super weird. And at low doses, it is more sedating than at higher doses. So it has to do with like when it hits certain receptors and histamines like lower doses, but that's super strange to patients. So like, you know, like a 30 is actually probably like in the middle, right? So you kind of need to, you sometimes start there because you're like, I don't know if I need to go up or down. So, but it doesn't really make sense that that's the case. So that's just something weird that you probably remember from like a test if you've never used it before. But like that is true about that particular medication. Is the weight gain a problem at all doses though? Yeah. Okay. I thought so. It's like hunger. Again, you can also say to people, if you don't feel more hungry, that's fine, right? Like you can track it. If you feel comfortable tracking that, that's fine. But it's sort of like, I wouldn't say it's as bad as steroids, but it's like, it has a similar thing. Like people eat at night and they just don't get, they just don't get full on like their meals and then they're snacking and they don't realize it. And then they gain a lot of weight just like steroids. Matt, did I tell you this, that my cat is on ritazapine? Are you aware of this? It's transdermal. And this, the part I shouldn't share is that the vet's office, I'm like, do I just put on, like, should I be using a glove or whatever? They're like, you can just wash your hands, I guess. I was like, I don't know. Maybe they're picking up a vibe from me. I'm not really sure. But yeah, so it's being used for appetite for my older cat. So fun side note about mirtazapine. Apparently vets like it. They like trazodone too. And gabapentin and buprenorphine too. Um, all right. I, I know we're sort of coming to the end here of the, cause we, we've got to let you get, get to the rest of your night at some point. So, um, let's, let's say we go back to the beginning. Sophie read in the news that SSRIs don't work, that this theory about how serotonin agents work was incorrect. So how do you address that? Have you come across this? Because this was in the popular press in 2023 that like, oh my God, I had people say, oh my gosh, I heard SSRIs don't even work. It was a total sham. Yes, I have come across it. It gives you a really good opportunity to explain scientific misinformation and how to digest what people are reading. So like, you know, they're not necessarily ever going to go to the original paper. If you go to that original paper, not only will you find out that the people who wrote it hate medication, if you look at all of them, but you'll also note that the paper is just saying that it's not just serotonin, but it never once says meds don't work because that's not the point of the paper. The point is to say it's not just serotonin. But if you ask a psychiatrist, it's like, duh, because SNRIs aren't just serotonin. Mirtazapine isn't, you know, serotonin. Bupropion isn't just serotonin. Like we've always known depression is more complex than that. It's a very simplistic view to assume that the only reason we are not happy is serotonin. It is a part of it, but it is not the only thing. And I think with SSRIs in particular, like they probably do more on precursors and things like that than we can, you know, really, really know. But I think when I talk to patients about it, it's like, let's talk about how articles and headlines come from something that is not what it says. And let's talk about how that's just kind of how science gets conveyed and where the problems with that are. And then I will say things like what I just said about how we've kind of always known it's more complicated than that, but that, you know, what it tells us is that sometimes people need different meds, but sometimes SSRIs still work, right? So it wasn't studying that at all. And we have data that SSRIs work, right? And like, it doesn't negate that because they made some claim about actual kind of gathering of data that says that about serotonin, you know? So I think it's important that we don't make leaps like that to say like, not just serotonin equals meds don't work because that's not what they studied. And that's not what they even said, even though they don't like meds. So, you know, I think it's really important that you have that conversation. I'm a big believer, like, so tons of like, all of us have to deal with this, but TikTok in particular has a lot of like mental health conversations that like encourage people to come in with diagnoses. And I'm a big believer of like wherever you get your information, it's still information. And at least you looked it up and at least you're interested in yourself and at least you care. So instead of going, no, that's a stupid thing. That's not true. I would be like, well, where did you read it? Like, let's, what makes you worried about that? And like, how can I help explain that in a way that would make you feel better about it? If you came in with a diagnosis and we're sure you had it, I would say, well, what about that resonated? And then I would say, don't hate me, but concentration is more complicated than ADHD. Can we talk about that without you hating? All right. Well, thank you for saying that. I felt like we had to address it just since it was like, so at least in the news in 2023. All right. So Paul, any last things that you wanted to ask about? And we'll check in with Eddie as well, but Paul, anything else on your wishlist for this? You know, I'm going to ask about cannabis because it's my favorite topic. Oh, that's right. I forgot. I couldn't let you go without this. And I'm not, certainly not asking for treatment recommendations. I think in Pennsylvania, it's actually one of the certifying conditions where we have medical cannabis, at least, which I, and the data seems sort of dubious to me. But I guess my question to you is sort of how do you counsel patients who are using cannabis to sort of self-medicate for anxiety or the insomnia that comes along with it? Is that something that we endorse? Is it just something we acknowledge? Or is there other counseling that goes for patients who come to us with that? Yeah. Cannabis for mental health reasons is there's no good evidence. In fact, it would probably, if any evidence exists, it's the other way. I don't write medical marijuana cards for that reason because I just don't even want to bother. Like I just am, for the most part, more afraid that someone will become psychotic than I am or like, you know, something else will happen than I am that, you know, it's going to have an amazing effect on their anxiety because I've seen the psychosis more. And so I actually won't do it. But, you know, they are marketed as anxiety medications. If you go into a shop, they will say like this strand is really good for anxiety because it has like blah, blah, blah. And so usually what I'll say is like, see how serious it is that they take that.
It would be really awesome if we didn't have to take both right now just to make sure we figure out what works. And there's nothing like making it more complicated. But if that's like a deal breaker, I will tell them that rebound anxiety is a thing and that they need to just like rebound insomnia with that stuff and that they need to pay attention that like even if they might feel better in the moment, that there's a very good chance that they won't later. And then it'll tell them to take more. And so they just need to like pay attention to that and also be aware that like their mood can be affected and that they could like have other issues as it relates to their mental health when it comes to taking those strands. And that is something to keep in mind. I'll try to do like motivational interviewing around it and like get a cut down. Yeah. where we got. But I actually think that that probably was harm reduction just because in the grand scheme of things, like who knows what's in it? Like they're not really like made like meds are, right? So, you know, I say that to them too, but I'm like, listen, like I don't know how to keep like you took this one and did this. You took this one and did this. Like if we're going to play that game, I'm not switching your meds all the time. So can you just like kind of consistently get the same thing? I also, no one's, I see a lot of young kids. They're going to smoke. They're going to drink. Like nobody's going to listen to me telling them like, no, but they will listen to like some of the risks sometimes. And they will listen to you being like, listen, I'm not trying to like be your mom. I'm not trying to be annoying about this. It's just that like it also does stuff in your brain and I'm also doing stuff in your brain and I'm worried that I'm going to mess something up. And like it would be very helpful to me if you just kind of took that out of the equation. But, you know, it's hard to do in a lot of ways, you know, with drinking on meds, it comes up a lot too, because the bottle says don't do it. But I talk about tolerance really with them because I do think their tolerance is affected. It doesn't, again, a pharmaceutical company might disagree with me. I don't think it makes it not work and it doesn't make alcohol stronger, but it does somehow make it so like you might've been a four drink person and you're a one drink person. So I do think that like, I'll say when you first drink on a medication, please like drink less and wait and see how you feel so that you don't like miss a whole day. Because I just, again, if I could, I could see college students and have them all stop drinking, I would, but it's just no one would ever take a medicine if I had to tell them all to stop drinking. So I'm just very realistic about this stuff. And it probably isn't most people's way of dealing with it. And I think there are probably some psychiatrists, especially who are like, that stuff affects your brain. None of that while we're figuring this out. I'm just not that naive. And I would rather have buy-in from the population that I see. And sometimes that's like being a little bit more real and getting to where you can in a motivational interviewing sense. And like, I had a parent sit in once on something like this when I was having a conversation and I just like could see the parent's face just kind of being like, I don't know that I, that's the conversation I would like you to be having with our kid, you know, because it was just like, well, how can we like limit this? And how can we just get, where are you getting it from? And how, you know, and the parent's face was kind of like, well, that's a tactic, you know, like it was just fine because the kid likes me and she like, they have no say, right? Because they're an adult, but it was just very interesting to me. Well, yeah, I mean, I feel like we've known this for forever that telling someone about a behavior that might have adverse health consequences that they should just stop doing that has worked exactly zero times. Like that is not, it's not going to work for any of them. So it's, I think partnering with the patient is always a good option. Yeah. All right. I think we should move to take-home points because, Paul, we could probably go another hour, but I think that would be cruel to poor Jesse. I work psychiatrist hours, folks. I probably would be asleep. All right. So if you had to pick maybe, I don't know, like two or three take-home points from this discussion we've had for the audience to remember, what would those be? Number one, if you don't feel comfortable doing it, ask a psychiatrist. But, you know, really, if you, I like it when primary care doctors try because it's too hard for everyone to get in and see psychiatry. It's not necessary for everyone to come see psychiatry. And for the most part, there's less stigma seeing you guys. So it's not helpful to just assume everyone who has a mental health condition should see a psychiatrist. But if you start to feel like it's beyond the scope of like what you can do in the time, in your comfort level. Like that's when you refer just like you would for any specialty. The second thing being, you know, mental health is like the reason we get like motivational interviewing training and we know how to do therapy is a lot of it's about the person and like getting on their side. And you don't always have time for that. But remember that when you're rushed, which is to say, like, try to understand how they use terms. Try to understand what brings them and try to understand what's really troubling them or how they describe it. Try to understand, like, how they feel about medicine and why they're so hesitant or why it's causing problems, because they're not going to take it if they don't talk to you about that stuff. And I know it's really hard to do, but it's really important. And mental health, probably like even more than some things, you can kind of think about it as like the way you guys have to talk to people who are taking insulin and stuff and like, you know, struggle with it. And, you know, trying to understand that and get on the same page with them is really important. And then the third thing, just being like, listen, we're healthcare workers. We have our own mental health stuff. And so I, you know, I just like want everybody to know that like being anxious is normal, but being anxious so badly that like you can't do what you want to do and it lasts for a really long time is not right. So there's, it's a spectrum just like anything. And it doesn't need to get to the level where your whole life is affected before you get help. That includes for healthcare workers, but that's the same with your patients. If somebody's in your office and they're mentioning stuff and you might be able to catch it early, that's important because not everybody should get to the point where they have to see me or not everybody should get to the point where they only notice it's a problem because they're failing at school, right? Like our criteria for mental health challenges is like getting A's or like a job performance evaluation, right? Like my boss says I'm fine. Like I'm still getting A's and you're like, well, what did you do today? And they're like, I haven't left my room in weeks and I eat takeout every single day and I have no friends, right? Like that's, there's a lot to life that's not this objective measurement of success that we have. And so it's important that just because someone says like they're doing well in school or work that we ask about the rest of their life and we make them look at the rest of their life. But we also realize that like you can catch this stuff earlier in primary care than I ever could. And asking about it is really critical. I don't expect, you know, I mean, it might end up in this setting where you like people are going to have to screen just like they have to do depression like all the time. But screening is helpful. Most of the time people see general practitioners much more than they would see a mental health professional.
And I think that's a really cool power. Like, I wish I had that. I don't have that because people come so much later, but you know, like it's a cool power to be like, I actually prevented that person from needing a med or like, I actually only needed to use a baby dose and stop it on someone. Like, that's cool. Paul's America's primary care physician. So that's, that's like his day. That's just like a normal day in the office and butter. Yeah. time you can. It is very large amount of mental health. You might prefer trauma, but you're still getting mental health. So, you know, you have to be comfortable enough with it and you have to like it enough to help people because that's what you're seeing. Did you want to plug anything coming out later this year before we let you go? Sure. Anytime people want to find me, I'm at Dr. Jessie Gold on like everything. I annoyingly spell it J-E-S-S-I like Jessica without the C-A. So you can blame my childhood self for that. I have a website. I have a website with the same name where like all my writings and stuff are, you know, sometimes I've had friends say that some of the things that like I've explained in writings have been helpful to give to patients or refer to patients. So that can be a place where if you just want, I do a lot of psycho ed on things for like self or in style. And those are places where it's made for not, you know, academic settings. And then I have a book coming out in October. It's called How Do You Feel? It is really about me and my healthcare worker patients and like what it's like to care for other people and not care for ourselves in the meantime. And all of the barriers in sort of our group of people to really focus on themselves and care about themselves, especially their mental health. And that's in October, but hopefully I'll have pre-orders in like the next month or two. And I'm hopeful that like people in your audience will feel like a little seen by it because it's really the purpose in writing it. And also realize that like, you know, there's caregiving across the board, not just in healthcare. We're just this like horrible microcosm of it. But you know, that other people might understand us a little better if they understood what that's like too. All right. So everyone in the audience, please buy a copy of the book, check out the website, follow her on social. And thank you so much for all your time and all your teaching tonight. This is great. Thanks for having me. This has been another episode of The Curbsiders, bringing you a little knowledge food for your brain hole. Yummy. I wasn't sure if you were going to go for it. Now I'm not sure I'm glad you did. Still hungry for more? Join our Patreon and get all of our episodes ad-free, plus twice-monthly bonus episodes at patreon.com slash curbsiders. You can find our show notes at thecurbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox, which includes our Curbsiders Digest, which recaps the latest practice-changing articles, guidelines, and news in a couple minutes. And we're committed to high-value, practice-changing knowledge. And to do that, we need your feedback. So send an email to askcurbsiders at gmail.com. It also really helps if you subscribe, rate, and review the show on YouTube, Spotify, or Apple Podcasts. And a reminder that this and most episodes are available for CME through vcuhealth at curbsiders.vcuhealth.org. Wanted to give a special thanks to our writer and producer for this episode, Edison Eddie Jang, and to our whole Curbsiders team. Our technical production is done by Podp Jang. And as always, our main Dr. Paul Nelson-Williams. Thank you and goodbye.
From the JAMA Network, this is Conversations with Dr. Bauchner, interviews featuring researchers and thinkers in healthcare about their publications in the latest issue of JAMA. Hello and welcome to Conversations with Dr. Bauchner. Once again, it is Howard Bauchner, Editor-in-Chief of JAMA. I'm joined by three remarkable individuals. Thank you. Florence and Laura Norman, Professor of Public Health, Chair, Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Professor of African and African American Studies and Sociology, Harvard University, and Clyde Yancey, a friend and a colleague, the Magenstrat Professor, Professor of Medicine in Cardiology and Medical Social Sciences, Northwestern Feinberg School of Medicine, where he is Vice Dean for Diversity and Inclusion, Chief of Cardiology in the Department of Medicine. Lisa, David, Clyde, thank you for joining me today. Absolutely. Thank you for having us. This podcast is focused on structural racism in medicine, and I think this particular conversation needs context. On February 24th of this year, JAMA tweeted about a recently posted podcast discussing structural racism in medicine. The language of the tweet, as well as portions of the podcast, do not reflect my commitment as editorial leader of JAMA and the JAMA Network to call out and discuss the adverse effects of injustice, inequity, and racism in medicine and society. I take full responsibility for these lapses and sincerely apologize for both the lapses and the harm caused by both the tweet and aspects of the podcast. Comments made in the podcast were inaccurate, offensive, hurtful, and inconsistent with the standards of JAMA. I want to be clear, racism and structural racism exist in the United States and in healthcare. JAMA will schedule a podcast, and that's exactly what we've done. I wrote on March 4th in the future to further discuss issues of structural racism. David, this is work you've been at for decades. In 2015, you wrote a piece with Ron Wyatt for JAMA entitled Racial Bias in Healthcare and Health. What's the current landscape of structural racism in medicine? How do you think about it? I think of structural racism in medicine in the broader context of structural racism in the United States. And medicine is one institution in American society, but structural racism is pervasive throughout American society. And so the healthcare system, like other social systems, has been shaped by structural racism and sometimes reshapes structural racism in powerful ways. I want to give a concrete example. One of the aspects of structural racism that I have studied is residential segregation. It's a legacy of the past. It started in the late 19th century, was established firmly in the 20th century, and has been in place since 1940. And although it's been illegal since the 1960s, the structure put in place still exists. And you say, well, what does that have to do with health? Well, where you live in these United States determines access to opportunity on so many dimensions, including access to high-quality medical care, but it's access to educational opportunity, access to employment opportunities. I'll tell you how powerful it is. Let me cite empirical evidence. There was a study by David Cutler, an economist at Harvard University, and he showed statistically if we could eliminate residential segregation in the United States, we would completely erase black-white differences in income, in education, in unemployment, and reduce black-white differences in single motherhood by two-thirds. All of these striking differences are driven by opportunity at a neighborhood level. And it didn't just happen. It's not an accident. It's not an act of God. It reflects the successful implementation of social policy. And those neighborhoods that lack access in education and occupation and so on often lack access in high quality medical care as well. Lisa, when you hear David's remarkable analysis of 100 years of structural racism around where less access to a lot of the amenities that other larger institutions might have. People are less likely to be attracted to go and work there. So they have many fewer staff that might have experiences and things like that. And they experience discrimination in who they can refer their patients to. So that would be one manifestation. Another one would just be in the patterns of health care disparities that we see because of where minority patients go for the most part. And then also because of the interpersonal interactions within those systems. But in large part, because of where they get their care, they experience poor health care quality and poor access to health care. Then we look at the structure of the people who are delivering care and the fact that they often don't look like the communities of color that they might serve. So the racial and ethnic diversity of the workforce. And then you just look at other institutional practices and policies and funding for health equity work and so on and so forth. And you see disparities in that. So I see structural racism as manifesting in those ways, in terms of health care, in terms of resources, in terms of the racial and ethnic diversity, and in terms of the funding, which is also part of the resources, but the funding not just for health care, but also for science and for education that leads to better health care for communities of color. Yeah, there's about 100,000 individuals in the U.S. with sickle cell disease. There's about 25,000 with cystic fibrosis. And the stark contrast in funding for those two entities has been well delineated. Clyde, you're a cardiologist. You care for patients. You're at a remarkable institution. When you hear David and Lisa comment about the larger world, living, housing, and then Lisa talks more specifically about healthcare encounters, how do you think about it? To be very clear, there are bookends here that touch the space in which I live and work. One space is the diversity of our physician workforce. 100 years ago or more, the flux in the report deconstructed most of the medical educational opportunities for Blacks. Using David's term, empirical evidence, it's a clear estimate between 30,000 to 50,000 physicians did not evolve because of the consequence of losing those schools. The ultimate toll that that represents with the absence of representation in those who provide care, particularly care to those that are underserved, has been almost incalculable. And so for those who argue about the entity of structural racism, that one act alone of closing all but two minority-serving medical schools at the turn of the 20th century still has consequences in the 21st century that I and others who advocate for diversity in medical education are still trying to overcome. But then, Howard, let's make this more important. Let's fast forward to 2020 and COVID-19. It is very clear that the disproportionate burden that we've seen, well, one out of 600 Blacks in this country is dead due to COVID-19. And as we speak, the risk of death is still nearly threefold higher for Blacks compared to Asians and whites. It really gets localized, as David and Lisa have so carefully and thoughtfully put in place, to place, not race. And it is the marginal the fact that we have to be, and you talked about that. Can you just talk about the relationship? I think people sometimes struggle about the relationship between structural racism in society and in medicine and healthcare disparities. Could you say how you think about that? Sure. When we think about racism that exists on a societal level, it's sort of the way people have been trained to think over like centuries about people of color, particularly about African Americans. And so it influences a lot of the beliefs and attitudes about people on a cultural level. And so when you get into healthcare, healthcare is not a vacuum, right? It's a product of the larger society. So in addition to those structural factors we have, we also have attitudes and behaviors that people within healthcare bring into those interactions that they have with one another and with their patients. And so it's not as if we're immune to those things either. So we, because of those beliefs and stereotypes that exist on a broader societal level, in addition to the hierarchies that exist within our organizations, those kinds of things influence the way we interact with one another. And they influence the power structures, the power differential between those who are in leadership roles and those who are the ones that are providing more of the service and frontline work and those who are actually trying to obtain care. So all those dynamics play a part in our interpersonal relationships. And we've actually studied interpersonal relationships in healthcare and found that patients experience poor communication, patients of color experience poor communication with their physicians, especially when it's a physician of a different race or ethnicity. We found that, you know, physicians of color experience harassment and biased treatment from their colleagues and from their supervisors and higher-ups and even oftentimes from patients.
The structural factors and the broader cultural factors provide the context for which interpersonal relationships can develop and the way they are shaped. David, do you have an idea why the term racism is so charged for white people like me? It's just a charged term, and I don't know how to get to a conversation sometimes. You are absolutely right, Howard. It is a charge term. There is research that indicates that most white Americans believe that racism is a thing of the past, that racism, the problem of racism in America was solved with Martin Luther King in the 1960s, and that we have moved on beyond that. We saw a crescendo of those beliefs when Barack Obama was elected president of the United States, that America had now moved into a post-racial society was the belief. In fact, what research indicates is that white Americans overestimate the degree of racial equality that exists. In other words, the reality of racial inequality, for example, in 2018, African-American households earned 59 cents for every dollar of income white households earned. Identical to the racial gap in 1978. 1978. The P.K. of the narrowing of the black-white gap, we got it to 59 cents, and in 2018, it's 59 cents. Most white Americans believe that there's much more racial equality than actually exists, and strikingly enough, and I'm just reporting a scientific finding, the overestimation is strongest among highly educated whites. So David, let me chime in here because you really bring something to the table that's very important. I went to medical school in 1978. The number of black men who attended medical school in 1978 is the same number of black men who attended medical school in 2019. That is the statement of fact. So how could there not have been a change? How could there not have been some impediment? At a minimum, there should have been secular changes, but none such occurred. So it argues that there are barriers, almost impenetrable, that still exist. I think the other point, Howard, that's important to keep in mind is that most white Americans today endorse the principle of equality. They support, and there is public opinion survey data, one of my colleagues, Larry Bobo, has shown that, that you can see massive trends over time, where in 1958, for example, most whites in America believed that white people should have the first chance at any job, and blacks should just wait in line. That was a belief of the majority of whites in the United States. And by the early 70s, you saw only less than 10% of whites endorsed that view. So the endorsement of the principle of equality is widespread within the white population. At the same time, what the research shows, while there is overwhelming support for the principle of equality, there is much less support for policies that would actually implement equality. So it's almost like, I mean, some call it laissez-faire racism, that if you can have equality on your own, we're not opposed to that, but no sacrifice on my part, no cost to me. It shouldn't affect me or my opportunities in any way. So that endorsement of the principle of equality leads most white people to think, I am not racist because I am supportive of equality for all, even while we live in a very unequal society and we are often unwilling to support the policies that would address the stark inequalities that persist. Lisa, have the events of the last year led us to an inflection point? Is there going to be something different in five years or different in 10 years? I grew up in the 60s and 70s. It's the Black Lives Matter movement, the stark disparities around COVID, only once again magnifying issues around disparities and equity. Have we reached an inflection point? I certainly hope so. You know, I think that we've reached other inflection points in the past. But I would say that in particular, the murder of George Floyd, which was so widely circulated globally and nationally, and the fact that it was such a clear picture of what basically what happens on a much broader scale and maybe on a much not as dramatic of a level. And I think when people are able to see how unjust some of the things are that occur in our society and to empathize with what it would be like to be in that position themselves, I think that does shift attitudes in a dramatic way. But I think that, you know, it's very easy for us to go back to what we typically do in our daily lives and to become outraged about a particular event, but not to really be more self-reflective about how our own decisions and choices and the way the policies we support might affect other people. So I think that's one thing we really have to keep in mind with this is that, yes, this is an opportunity, but it's also a moment for us to remember that it's not only about those episodes that are so blatant and that everyone is able to observe, but it's about the everyday issues that go on. And it's about the way we allow people to have opportunities and to not have opportunities based on who they are or where they were born. And if we continue to do that, then we won't see change. So I think we really have to take this opportunity that is really what it is to really take a closer look and also not to let ourselves off the hook. Each person really needs to look in and see which part am I playing in this? And really not only on our individual behaviors, but the organizations we work within and that we associate with. Hold those leaders accountable for the decisions they make that might impact our communities in a harmful way. So Lisa, let me leverage your concept of each person. I too am a child of the late 50s and the 60s and I have vivid recall of some horrific experiences. But what's different now compared to then is that each person is multiracial, multicultural, multiethnic from all different domains in life. The main reason we're having this discussion today is because there was a righteous uproar from the social community, not just one group, but from many people who said that is not good, that is not okay. And the fact that so many people are able to stand up and say, this is not okay. That is the inflection point about which you're speaking now. It is the path forward. It is the moment in time where there are more people aligned with this thought of, as David said, not just the principle of fairness and equity, but some action that follows. How durable will this moment be? Will policy follow this? Those are the unanswered questions. But I think we're here today because that each person you talked to, Lisa, stepped up in response. And Howard, I want to go back to 1999 when Congress voted to ask the Institute of Medicine, it was called at the time now the National Academy of Medicine, to answer a very simple question. When African Americans and other minorities enter healthcare context in the United States, does your race determine the quality of care that you received? And I was one of the persons who served on that committee that produced the famous unequal treatment report that documented across virtually every therapeutic intervention from the most simple to the most complicated, African-Americans receive poorer quality care than whites. And it's shocking that what's even more shocking is that if you look at recent reviews of the literature, the pattern still persists. And I do not believe that most health care providers wake up every morning and think, how am I going to get my black patients today? But that is what is happening. They are getting poorer quality care so that within the health care system, there's a lot that has to be done in terms of raising awareness levels that this problem exists and then providing the skills and the training and the diversity and so forth that Lisa was talking about to reduce the chances that these inequities would persist in the United States. Otis Brawley wrote a piece for us that actually has gotten a fair amount of traction called Cancer Justice. And he describes the black-white difference in screening for prostate cancer, screening for breast cancer, and screening for colorectal carcinoma. And it's 10 to 20 percentage points between black and white adults. And he said, this isn't complicated. This isn't new science. This isn't new technology. It's a renewed commitment and to measure it. So we know, are we making progress in closing that gap? I have two final questions. Lisa, if you could hone down on one or two things that you think medicine needs to do. David, for you, it's going to be society. But for Lisa, it's medicine. What do you think the one or two things that you think we need to do within the healthcare system? Howard, I would say the first thing would be to really make a clear commitment to this issue and to take some responsibility for our part in it.
So I think making it clear that addressing health equity in communities of color and many of our institutions are situated in the midst of those communities doing world famous research and cutting edge Thank you. raising the health equity work to the level of other issues that we face in healthcare, patient safety, quality, but equity somehow gets shifted somewhere else in that picture. Equity should be raised to the same level, given the same resources. The data ought to be tracked with the same sort of excellence and precision and monitored. People ought to be held accountable for equity, for showing equity or improvements in reductions and disparities in certain populations over time. Those are starting points and I think critically important to work in partnership with our community partners because clearly we're not responsible for everything that happens to our communities and we aren't necessarily even the best equipped to address all of their problems, but we do have partners who can assist in that. So if we can do a good job of understanding our communities, knowing what their needs are, and working with those who are out there to help our patients address those issues that are outside of the realm of healthcare that we know are getting in the way of them being healthy, and also helping people who are out there stay healthy and not have to get sick enough to come and see us. I think those are the starting points. David, the broader society, the broader U.S. society. We need to make a commitment to dismantle the systems of inequality that are producing the inequality that exists. Lisa and I wrote a paper reviewing the evidence of what can be done to address racial inequities in care, and we talk about the need to create what we call communities of opportunity, communities where we eliminate the negative effects of residential segregation. And I think it's important to make the point that the problem of residential segregation is not residential segregation per se. There's nothing negative about living next to people of your own race. So it's not living next to people of your own race. It's the clustering of social ills and the absence of opportunity in these communities, the disinvestment, as Clyde so eloquently talked about earlier. And so what does that mean? We need to have an emphasis on workforce strategies that enable people to earn a living wage to take care of their family. We need place-based solutions that improve the quality of neighborhood and housing environments. And we have high quality scientific evidence that if you just improve neighborhood quality, no health intervention, you lead to improvements in health. From randomized controlled trials shows that that's possible. And what we do for the next generation by creating opportunities, early childhood centers and high quality elementary schools that put individuals on a trajectory for academic success so that they can compete and go to medical school. But if you go to a school where you don't get the background, you don't get the training, you're not prepared to go to medical school. So I think there's a lot that we can do as a society. I sometimes say we need a Marshall Plan in the United States for disadvantaged communities. We need to make that kind of investment. And one important point, the research is also clear that if we only do this, it would save the United States economy billions of dollars a year because we would be creating a more productive workforce. We'd have a more competitive economy in the world. So it's in all of our interest to invest so that every American child can live the American dream. Clyde, when you hear Lisa talk about health care specifically and then David about the broader society, How do you think about it vis-a-vis being a cardiologist and your position at Northwestern? So let me be very clear, Lisa. I want to echo what you just said. Equity should be the new metric of professionalism. That is a takeaway for anyone listening to this podcast. Equity should be a new metric of professionalism. And David, without question, as we are trying to reinvent our society, our economy, a Marshall Plan, which is akin to what we've done to disseminate vaccines, needs to be developed to disseminate appropriate determinants of health that penetrate all communities. Now, Howard, when I think about the broader context of what we discussed and how this intersects cardiovascular care, more importantly, cardiovascular health, we really become the bellwether moment because we represent still the predominant disease that inflicts suffering and even death in our communities. If I have a lifelong commitment to reduce the burden of cardiovascular disease, and I do, I can no longer afford to ignore not only social policy, but public policy, because all policy has a health consequence. If I really do champion best outcomes for cardiovascular diseases, then I can't let one group of patients start off with greater burdens of disease than another group and expect everyone to behave the same. What has become so abundantly clear, especially with cardiovascular disease, is that we cannot deconstruct these very important aspects of social science and public health from cardiovascular physiology and ultimately cardiovascular diseases. It is so clear now that there are intersections between the community, inflammation, and the burden of disease. There are consequences of the life and living circumstances, whether it's population density, access to fresh fruits and vegetables, transportation to facilities, even access to a pharmacy. We now have pharmacy deserts. So if I'm trying to advocate best care for patients and they're not able to, in an approximate location, acquire what's necessary, change the natural history of their disease model, then all the research, all the science, everything we've written is for naught because there's no way to implement it. This increasingly interconnected interfacing world that we have now no longer allows us to take the comfort of science and clinical medicine and stay in that space and say, I need you to do this, this, and this. We have to become expansive thinkers and realize all the different places that in my world, at least, really exercise levers on cardiovascular disease. So I'll finish by saying, yes, ethics is the new metric of professionalism. Yes, we need a Marshall Plan to address the health in our communities. And yes, there is such intersectionality now between cardiovascular medicine, social sciences, and public health that we can no longer afford to work in a silo. Final question for each of you. Lisa, all three of you write for medical journals. You also write for other journals, but you have all written for JAMA. As I said, David wrote a stunning piece with Ron Wyatt in 2015. Clyde, you're on the senior leadership of JAMA Cardiology. Lisa, what can journals do? What can we do better? What can journals do? Journals have to do what we were saying everyone else in society needs to do, is to take a look within, look at yourselves and your practices and policies, look at who's on your editorial boards. Look at what kinds of articles are you actually like reviewing and accepting that are related to this topic. How are you engaging the broader community in this conversation and helping to move not only the science forward, but also changes in health policy and practice forward. So really looking at your portfolio and looking at the people who are submitting to you, you know, and as leaders in the field, really making sure that this issue is front and center and that people don't forget about it. And the fact, you know, holding people accountable for doing the science with the same level of rigor and excellence that we expect for every other topic, and at the same time, really encouraging that work to be done, and engaging in people and asking people to offer their perspectives and opinions on these issues, seeking out experts. Those are the suggestions I have. David? journal, I think 25 years ago, writing a paper on racial discrimination and health, one of the reviewers for a social science journal said, the term racism does not belong in a scientific paper. He or she went on to explain that racism was an ideological concept that cannot be measured. So that was thinking, even among at least some, luckily for me, the editor said, disregard this reviewer's comment, respond to the other issues. But it just illustrates where the field was, even in the social sciences, just less than three decades ago. And so journals can play an enormous role. It's a platform. You can shine a light on important topics. You can have special issues. You can elevate important issues. And I certainly think that in this pandemic, dealing with COVID-19, look at what JAMA has done in terms of raising awareness levels of COVID-19, the social context, the role of race and racism. I mean, Lisa and I have written for you, Clyde has written for you. And I think some of that has happened because we've been invited to write on these topics. So journals can play and have played a powerful, important role. Clyde, you're a deputy editor at JAMA Cardiology. You really live it every week. What's your sense of like the role of JAMA, the role of JAMA cardiology?
And I think the first thing we have to acknowledge is the importance of ownership. What we do as scientists, as clinicians, as editors, is an imperfect discipline. And when we have a misstep, we need to exercise ownership, which we are doing today. Second, acknowledgement. We only get better when we get feedback. Sometimes the feedback is hard to digest. Sometimes it's harshly critical. Sometimes it's praiseworthy. Regardless, we get better when we get feedback and when we accept that feedback and agree to act on it as we're doing right now. But the other part that is so fundamental about what we do is this ethos that you helped to establish, Howard, but that we all share within the JAMA Network. It's our search for ground truth. We hold the data accountable. We hold the authors accountable. We hold ourselves as editors accountable. Our entire current is the ability to publish that which we believe at the time, based on best evidence, is true. If we can continue to do that and really make an unyielding commitment that what we will do is own our experience, have the courage to accept feedback, acknowledge others, thank them for the feedback, and then continue to, without fail, seek the ground truth and publish that for which we have the strongest conviction, then we're executing a very valuable service in helping the community understand the direction that medicine is going and the things we need to do to get to a different place. In closing, I once again want to recognize the tremendous pain that the tweet and the podcast caused. The responsibility is mine. And we're looking at everything that JAMA does, process decisions about who does podcasts to make sure something like that never, ever happens again. Lisa Cooper, Bloomberg Distinguished Professor, Equity in Healthcare, Professor of Medicine, Johns Hopkins. David Williams, Florence and Laura Norman, Professor of Public Health, Chair, Department of Social and Behavioral Sciences, Harvard University. Clyde Yancey, Magertstedt Professor, Vice Dean for Diversity and Inclusion, Chief of Cardiology, Professor of Medicine, Northwestern Feinberg School of Medicine. I just can't thank the three of you enough. It was an education for me. I try to listen. I know I can do a better job, but I really want to thank the three of you. This is Howard Bauchner, Editor-in-Chief of JAMA, and this has been Conversations with Dr. Bauchner, focused on structural racism in society and in medicine. Thank you. Thank you. For more podcasts, visit us at jamanetworkaudio.com. You can subscribe to our podcasts on Stitcher and Apple Podcasts.
From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical practice. Welcome to this JAMA Audio Podcast. I'm Mary McDermott, Deputy Editor of JAMA, and I'm here today with Dr. Johanna Daly. I'm a professor of medicine in infectious diseases at Albert Einstein College of Medicine and Montefiore Medical Center and a professor of medicine in microbiology and immunology. I have been studying malaria since I was an infectious disease fellow, so I was thrilled to get this invitation. So could we start by having you tell us what is malaria, what causes it, and how is it transmitted? Malaria is actually the illness secondary to a plasmodium infection. So malaria is actually fever, chills, and the symptoms. So it's really the syndrome. And malaria is caused by a plasmodium parasite, which you acquire after you get bitten by a female Anopheles mosquito. She needs blood for her eggs. And so she's probing her skin up and down, trying to find some blood. And during that time, she's accidentally injecting just a handful of sporozoites. And these sporozoites somehow, from the dermis, find a blood vessel and are carried to the liver. And so they set up their first major stage of infection in the liver. And these few sporozoites become millions of merozoites. And this occurs in falciparum over one to two weeks. And you have no symptoms. We actually can't detect that you have them in the liver. You're feeling completely fine. And then in falciparum, people typically get symptoms after they return to the U.S., after they leave the endemic area within 30 days. So in falciparum, they're kind of in a hurry. They come out of the liver as little merozoites, which very quickly invade red cells because they want to avoid the immune system. So within the red cell, which is their new home, they're digesting hemoglobin, they're growing and they're dividing maybe one to 32. And 48 hours later, they burst open that red cell, merozoites are released, and they quickly reinvade other red cells. So you could see how quickly you go from a very small number of parasites to many. And so that's falciparum, which is the most important malaria because it's prevalent and deadly. The other malarias, plasmodium vivax, which is about 10%, has an additional stage that stays in the liver. It's a dormant stage. It's called the hypnozoite. And it may stay there for weeks to years later. And so you may have left the endemic area years later, and now you have malaria. So that's true for Vyvax and Ovali. In terms of the other species, Malariae, which is more benign, does not have a liver phase, but can also cause illness weeks to years later. And then Nolesi, which is the recently identified human malaria, identified in the 1990s. It's a true zoonotic infection, which really is restricted to Southeast Asia because you have a reservoir of macaques. So it has to go from macaque, mosquito to person. There's no person, mosquito, person transmission. Nolesi can also cause very severe disease. So this is a mosquito-borne illness, and that's why preventative measures are around controlling the vector. And then, of course, the medications in case you get infected to kill the parasite at these different life cycle stages. Great. Thank you. Can you discuss how common malaria is in the United States and who is at risk? Well, that's one of the problems, Mary. Actually, malaria is an uncommon infectious disease in the United States. Right now, we're sort of averaging about 2,000 cases a year. And because it's so unusual, it is often overlooked or misdiagnosed. The folks who are at risk for malaria are primarily those who visit the 85 countries across the globe that are endemic for malaria. And occasionally we see cases where there's transmission from the mom to the newborn. Occasionally we see cases from blood transfusions. And then there are cases where we can't really figure out where they got malaria. Those are called cryptic malaria, but those are very unusual. Primarily 90% are from patients who return from an endemic area. And which areas of endemic malaria are the most common where a person returning to the U.S. may have been and is diagnosed with malaria? Africa, by far, seems to be the origin for 80 to 90% of our cases that we see in the United States. The level of transmission of malaria in Africa is very high. So even if just a few people visited Africa, their chance of getting infected would be very high, as compared to traveling to another endemic part of the world, such as Latin America, South America, where transmission is not as great. Africa is where there's very high transmission and a very high burden of plasmodium falciparum, which is one of the five malarias. However, you can acquire malaria in Haiti, in the Dominican Republic, parts of the Caribbean, South America, Central America, and parts of Asia. So it really remains widespread across the globe. And with that in mind, can you discuss the general approach to preventing malaria in travelers? Right. And I think, Mary, you're hitting on an incredibly important point. This is a preventative disease. And if people come to our travel clinic, essentially we'll review the itinerary, determine whether they're going to a country where they're at risk for malaria, and you have to get somewhat granular. Are they going to a high altitude in that country where there is no infectious mosquitoes? Are they going to an area where in the city there's no malaria? So parts of Latin America, if you're in the city, you're not going to get malaria. So you have to get granular. What are the exact regions that people are visiting? And then once you decide they may be at risk, I always discuss with my patients preventative measures such as screened accommodations, long-sleeved shirts that are permethrin impregnated, and then we can use chemoprophylaxis, which is taking a pill that has a very high success rate of preventing malaria. And that's chemoprophylaxis. And I would say that's the keystone for our patients who are visiting areas, particularly with falciparum and Vyvax, some of the more deadly species of malaria. I have to ask you, where does one find long sleeve shirts that are impregnated with pyrethrin? Well, I asked that to myself because I go to the field a lot. Actually, if you go to the outdoor stores like REI, EMS, they have beautiful, lightweight, fashionable, long sleeves, long pants, and often they are permethrin impregnated. If they're not, you can apply that yourself. Great. Good to know. So really, patients just feeling unwell. The problem is sometimes they may present with predominantly GI symptoms, diarrhea, belly pain, and that may put you down a different diagnostic thought process. They may come in with pulmonary symptoms. So I would say typically it's fever, and it's really flu-like nonspecific symptoms, and occasionally symptoms that seem to be on a particular organ where you may start thinking about a diarrheal illness or pneumonia. In fact, that could be malaria. And this is the challenge with the misdiagnosis of malaria because patients often look good. Even non-immune patients at the beginning of their presentation look very well. So this is part of the challenge with making the diagnosis. You have to first think about malaria. So when malaria is suspected, what's the diagnostic approach? So the diagnostic approach is to, first of all, have a high degree of concern if malaria is in your differential diagnosis. Most of our patients are non-immunes. Even our patients who were born and raised in endemic areas are at risk for severe disease. So I already have a slight amount of anxiety because I know things can go not well. So I would make sure I can get a malaria diagnostic as soon as I can. And there's two ways that we can make a laboratory diagnosis of malaria. One is the classic way, which is taking a pinprick of blood, finger stick, making a blood smear and examining that to look for intra-erythrocytic parasites. And all clinical labs are certified to do that. There's thick smears and thin smears. Thicks are very sensitive, but take a long time to dry and prepare. Thins, you can prepare very quickly, a little bit less sensitive, but they'll give you the morphology and the parasite load.
The other thing that we can do is utilize a rapid diagnostic test. It is like a dipstick, and it can detect the presence of parasite antigens. You don't really need training for it. You can get it done in 15 minutes. But the downside to the rapid diagnostic is it can detect falciparum, but cannot detect or separate the other three species. Number two, it's not as sensitive. And the non-falsipram species, usually there is a low parasitemia. And number three, it can't tell you what's the parasite burden, because the parasite burden may help prognosticate severe disease in falsipram. So I would say, Mary, the standard for the diagnostics is that we get it readily. And if I don't have it at my hospital, I'm going to put them in an ambulance or tell them to go to the next hospital or find out where they can get a rapid diagnostic test. Gold standard is microscopy, but we could do a rapid diagnostic while we're evaluating those glass slides. The key thing here is to think of it and then to obtain promptly a diagnostic test. So just to clarify, what you do in your practice, you always get the rapid test when you suspect malaria and then do you go right for the thick smear and wait? We do both. So we do thick and thin because it's easy enough to do. So we do both right away. So if the patient's in the emergency room, the rapid diagnostic is sent off. And then in the meantime, they're preparing both the thin and thick smears. What's the most common malaria species diagnosed in the United States? So of the five species, the most common is Plasmodium falciparum, which is too bad because falciparum is the one that really is associated with most fatalities. So I would say 80 to 90% of malaria in this country is falciparum, again, related to Africa. Most of malaria is contracted in Africa, and most of the malaria in Africa is falciparum. However, the other species are there. So the most common malaria is falciparum, which can be deadly. We always admit a patient with falciparum because they can have a downward turn rapidly. After that, the next most common is plasmodium vivax, which is about 10% of malaria, more commonly acquired in Asia or Latin America. In this case, you don't really achieve a very high parasite load because it infects reticulocytes, and we don't have that many reticulocytes in the circulating blood. Vivax is less severe disease, but there are case fatalities. So vivx is also an important illness. After that, there's two other malarias called Plasmodium malariae, Plasmodium ovale. These both result in low-level parasitemia, rarely associated with severe disease. And then there's a true zoonotic malaria called Nolesi, Plasmodium Nolesi. And it's a very interesting fifth human malaria that is really restricted to Southeast Asia because the vector or the reservoir are macaques. And so there's really no mosquito person mosquito. It has to go macaque mosquito person. So it's still restricted. But Nolesi is deadly as well. However, we haven't seen very many cases of Nolesi in the United States. But if we see it, it can also cause severe disease. The other thing to say about these five malarias, I always think of Felsoprum, potentially fatal, typically chloroquine resistant. And then in terms of vivax and ovale, once you treat the blood stage, which I know we'll talk about, it has an additional dormant hypnozoite stage in the liver that we need to provide a second type of therapy. And given there are five types of malaria, can you comment on treatment? Right. This is sort of another complication of malaria. We have five different species. I told you they have different drug sensitivities. They have different risks for severe disease. But let's start with P. falciparum. That's the majority of malaria in this country. It is potentially fatal. So I'm going to admit that patient. And falciparum became chloroquine resistant quite a while ago. So when I see or hear about a falciparum patient, I'm already thinking I'm not going to use chloroquine. And I'm going to use an artemisinin combination therapy. Now, there are still places in the world where falciparum is sensitive to chloroquine, such as Haiti. So that's, you know, something that's sort of special information. But in general, I would be worried about severe illness. I need to hospitalize the patient, and I'm not going to use chloroquine. I'm going to use artemisinin combination therapy. We can also use atovaquone proguanol for that. In terms of the other species, they're generally chloroquine sensitive. So we can use chloroquine with Vivax, Ovale, Malariae, Nolesi. The thing to know is if you can't figure out the species, because sometimes species identification is difficult, Artemis and in combination therapy works beautifully for all the malarias. So if we can't be sure, we should go to ACT. And if we have more than one species, we should consider using ACT. In fact, about 1% of cases of malaria in the United States have two species. The second part, after we treat that illness, which is in the bloodstream and making the patient ill, we have to remember if they have vivax or ovale, they are going to have a second stage that's sitting in their liver that will relapse. Even though you've treated the bloodstream stage, they may relapse. And that's an error people make is they treat 5-Ax or Ovali with chloroquine or ACT, the patient gets better. However, they forget to treat this other stage and the patient relapses weeks to months later. We have two therapies to treat this dormant stage. Primaquin, which we've been using since 1950, you have to give it for two weeks. And recently, Tofenoquin was developed and FDA approved, where you only have to give a single dose. The problem with both of these drugs, Mary, is that you have to test patients G6PD level, because if they're G6PD deficient, these drugs will be more difficult to use. You will not be able to use tefanoquin, and if they're G6 PD deficient, you can still give promaquin, but at a much lower dose, and you're going to observe them for hemolysis. How about severe malaria? Can you comment on what that is and then the treatment? Right. So I think the important thing is recognizing malaria, making the diagnosis, and then determining whether they have severe disease. And I have reviewed some cases where patients haven't done well, and this is where the error is, is that we need to review the criteria of severe malaria. Because once we decide they have severe malaria, the drug of choice is intravenous artesonate. And so severe malaria is defined by WHO and the CDC website, which is really very, very good, as vital organ dysfunction, perhaps pulmonary disease, hypoxia, ARDS, hypotension, change in mental status, and then a series of laboratory abnormalities such as high lactate, severe anemia, renal insufficiency. And as I mentioned earlier, you can see a patient with severe malaria and sitting in front of you, they look non-toxic. They look well. And that's why I think people get fooled. So I think it's very important to then make sure you look at these laboratory criteria as well. They may be a sign that this person actually has severe malaria. Once you decide they have severe malaria, and by the way, any species can do it, although most of them are secondary to falciparum, then we're going to hospitalize them. We're going to obtain IV artesanate, which we can talk more about, provide supportive care, watch as their parasitemia comes down, and we then complete their treatment with, once they're taking orally, the parasitemia is less than 1%. We give them a full course of ACT, which is three days of therapy. The other thing to know about severe malaria is artesonate, which is clearly the drug of choice, can result in hemolysis a couple of weeks after you treated them. So this is called post-artesonate delayed hemolysis. So you just have to keep an eye on their hematocrit for four weeks after giving artesonate. They can have a delayed hemolytic syndrome.
I was just curious, how long do you keep them hospitalized? And when do you know it's okay for them to go home? Right. So we're going to admit all patients. So I first decide whether they have severe disease or not. If they don't have severe disease, they're taking orals. Then I treat them with oral ACT. And the other major point, Mary, is you can admit them, you can write a beautiful note noting why they don't have severe disease, but I have seen patients within 12 hours after admission deteriorate. And if they do, we now have to treat them as severe malaria. So that's the other key thing. Many patients do well. They tolerate their oral medications, their parasitemia declines, and they become clinically well and you can discharge them. So just like any other patient, as patients improve, you can discharge them with follow-up. CDC does say that we should obtain a negative smear upon completion of treatment for all patients with malaria. So you could either do that as inpatient, or if they're doing really well, send them out on orals, and then just make sure we get that negative smear. Got it. Are there any other comments you'd like to make about malaria? thing to know is artesanate is now commercially available. So if you're in a region where you see a lot of malaria cases, it might be important for your pharmacy to stock artesanate because then it's going to be much easier to use the drug. I think in the past, it seemed to be difficult to get the drug. So I think all hospital systems should perhaps stock it. If they're not stocking it, their pharmacy heads should be aware of how they can get it within 24 hours. It's now commercially available. Other major points, I think tofeniquin to prevent relapse in our vivax and ovale patients is a real breakthrough. They only have to take one dose and not the two weeks, which most patients weren't able to do. And again, you have to make sure G6PD is normal. That's pretty much the major breakthroughs I'd say over the last couple of years is tefenoquine and now the availability of IV artesanate commercially. Thank you so much for that really clear and informative summary of malaria in the United States. I've been speaking today with Dr. Johanna Daly from the Albert Einstein College of Medicine on the topic of diagnosis, treatment, and prevention of malaria in the United States. This episode was produced by Jesse McWhorters at the JAMA Network. The audio team here also includes Daniel Morrow, Shelley Steffens, Lisa Hardin, Audrey Foreman, and Mary Lynn Furkeluk. Dr. Robert Golub is the JAMA Executive Deputy Editor. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com. Thanks for listening.
COVID-19 has swept through the world wreaking havoc and disrupting the normal daily lives of hundreds of millions of people. A major problem resulting in so much trouble with this pandemic is that there has not been sufficient capacity to test for the virus. Because in most cases it's not known who does or doesn't have this virus. Widespread lockdowns have been implemented isolating people from one another and shutting down the economy in unprecedented ways. It's hard to understand why testing is not widely available in an era where technology is so advanced and the type of testing performed for COVID-19, the polymerase chain reaction, or PCR testing, is so ubiquitous in research and clinical laboratories. In this special edition of JAMA Clinical Reviews, we discuss COVID-19 PCR testing, how it works, and why it's not as available as it should be. From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical practice. Here's your host, Ed Livingston. Amongst the most affected by COVID-19 and the risks associated with providing care for patients with this disease are resident physicians. So I teamed up with UCLA General Surgery resident, Dr. Joe Hadaya, and an expert in COVID-19 testing. Let's meet the expert. My name is Omai Garner. I am the Laboratory Director for Clinical Microbiology for the UCLA Health System, and it is our laboratory, it's my laboratory that is running the COVID-19 PCR test for the UCLA Health System. Can you explain to us how that test works? Sure. There are a couple of different versions of the tests, but essentially what happens, a sample is collected from the patient to test for COVID-19. And that sample can be a nasopharyngeal swab. That sample could also be lower respiratory for inpatients, including BAL or sputum. And then that sample is transported to my laboratory for testing. The testing process is really two-part. The first part is called nucleic acid extraction. And so what happens is that that sample, all of the viral RNA that may be contained in that sample is extracted out of that sample. And then the second part of the test is called a nucleic acid amplification test or PCR test. And this is a test that looks at that extracted nucleic acid or RNA and sees whether there is any COVID-19 viral RNA in that specimen. And if there is, then the test is positive. And if there's not, then the test is negative. Can you give us a little bit more detail about how PCR works for those who don't understand the technology? Yeah, absolutely. So PCR is an amplification scheme. And what happens is that PCR is a test where there are primers. This is a short nucleic acid sequence that is going to match up against the specific COVID-19 viral sequence. And if that primer then binds to that specific viral sequence, there will be an amplification of that specific sequence. So you can imagine if there's one viral sequence there and the primer binds, then after a certain set of conditions, there will be two viral sequences. Then it'll go from two to four, four to eight, eight to 16. And these are called PCR cycles. As these cycles then continue out, there's a level of fluorescence that's associated with that primer binding. And so when the level of fluorescence reaches a threshold, then there's enough signal there for us to be able to call it positive. The elegance of this type of test is that it is exquisitely sensitive. And so in the analysis of some of the tests that we're running at UCLA, we've discovered that it'll get down to about 500 copies per mil of fluid. So what that means is that if there are 500 viruses in that, which is a very, very small amount of virus, our test is sensitive enough to be able to get a positive signal from that because of the amplified technology. So I'm old enough to remember when PCR was discovered and introduced into the laboratory environment. That was in about the 90s, I guess. And it was a game changer for anyone doing molecular biology work in that you could identify any particular sequence that is characteristic of a gene or a genome and dial it in. In fact, I guess you still do it this way. You could just mail in the sequence that you want the primers made for and they mail them back to you and you're on your way to doing PCR. So conceptually, it's a fairly simple test, a very, very important test and one that everybody's doing. Every research laboratory these days does PCR. So one of the things that I've wondered, given that background, is why is it that when there's this pressing need and a national emergency regarding COVID-19, that research labs or clinical labs or anyone that has PCR technology couldn't just ramp this up and get the tests done? What is the limitation in getting this testing done? Yeah, that's a great question. And we have to get into the intricacies of the FDA and the quality checks around performing patient testing. So when a research laboratory is performing a PCR, because there isn't anything actionally medical that's going to happen from that particular result, there doesn't need to be regulatory control around that. And that regulatory control is in two forms. One is whether or not the reagents are high enough quality reagents and the test itself has been clinically validated so that you can be sure the results are correct. And the other is the licensure around the type of laboratory that can be run in. So patient testing can only be performed in CLIA certified laboratories. And these are laboratories that are connected to hospitals or large scale reference facilities that are licensed to be able to do patient testing. In addition, the person performing the test needs to be licensed and be able to perform diagnostic patient testing. So you see there are these levels of regulations that exist, and this is mainly to protect our patients, right? When a laboratory comes out and just says they can do a test, it doesn't mean that that's going to be high enough quality work to make medical decisions off of. So in the constraints of that, in the very beginning of the outbreak, there just wasn't very many tests that were approved by the FDA for patient testing. All the only tests that was available was the test that was created by the CDC. And it really wasn't until February 28th, which is fairly far down the line of the outbreak, that the FDA even made it available for anybody else to be able to create a test, clinically validate that test, and run that test within a clinical laboratory. So when you say that they made the test available, is it that they provide primers or positive controls? What is it that they are making available? Yeah, that's great. So what they're making available to run in clinical laboratories is the protocol. So laboratories still had to find the primers, buy the primers, and there was one company called IDT, Integrated DNA Technologies, that was selling the CDC test or components of the CDC test. But then the protocol also demanded a certain extraction device. And so you had to use that specific extraction device. It was from QIAGEN. And you had to use a certain PCR platform. It was called the ABI-7500 FAST. If a laboratory didn't have those exact pieces, they couldn't then perform that FDA-approved protocol. And again, this was another layer of challenge is that most laboratories didn't have those pieces or the ability to run what is a highly complex test. My laboratory fortunately did, which is why we were one of the earliest clinical labs to be able to bring on the FDA-approved CDC test, but it really was not a test that was built for mass expansion of testing. We've also heard that there are shortages of reagents. Are the reagents that you just referred to the ones that are in short supply, or are there chemicals that are not available, or what is in short supply? It's actually the reagents that are associated with each extraction kit. And so, for example, Kyogen produces an automated extraction kit that you can run patient samples on and within a short period of time get very high efficiency nucleic acid extraction. That was the original platform that was qualified for the FDA to be used for this patient test, and it was the only platform. And so anybody that then wanted to bring that test on had to unfortunately compete for a very limited resource for QIAGEN to be able to get that single extraction platform. And if a laboratory wanted to validate, which means make clinically available a different extraction platform, they actually had to petition to the FDA for their own emergency use authorization for that change in the approved protocol. So you can see, again, the system has been initially set up to make it very, very difficult and make supply an issue because there were such limited reagents that were available to perform that specific protocol.
So just setting aside COVID for the moment, it seems that this is an extremely powerful and useful technique for clinicians to make very rapid diagnoses of infectious disease for very sick patients. Is that technology being used clinically very often now, or where are we in that development? Yeah, you know, it's a great question, and it really speaks to kind of what's happening now with COVID-19 testing. So it has become commonplace in most hospitals that there are enough manufacturers, diagnostic manufacturers, that are producing these multiplex respiratory pathogen panels. And so these are panels that contain primers that are associated with 18 or 20 different respiratory pathogens, and they can all be run at the exact same time. And the beauty of those platforms is that extraction and PCR is all contained in one unit. And the PCR, these things are done very fast. So you can get a result back in about an hour and a half, which is what makes it rapid, for a PCR result for all of these different pathogens all at one time. And so this has become commonplace now in most hospital systems to be able to offer this for inpatient respiratory viral testing. Is it available for other forms of infections, bacterial sepsis or pneumonia or anything like that? It is. It's starting to come online for those things. So there's a newly approved test for lower respiratory tract infection or pneumonia. There are multiplex panels that are available for diarrheal illness that can cover the spectrum of parasites, viruses, bacteria. So, you know, I think syndromic testing, which is what this is referring to, or multiplex syndromic testing, is becoming more commonplace because it allows a diagnostic laboratory to support a clinician in their decision-making as quickly as possible. Given your central role at UCLA in getting these tests done and negotiating all these problems and your expertise in this particular area, thinking about the future, these epidemics and pandemics are going to continue. They will happen on a cyclic basis. Do you have any thoughts about how testing could be ramped up more quickly in the next epidemic rather than what we've gone through today? Is there a way maybe to recruit research laboratories to get them up to speed to do clinical grade work right away? Or if you could dream about the best possible system or envision what kind of protocols should be put in place on a national level in an emergency, what would they look like? That's a great question. You know, I think fortunately we don't have to dream about that. We actually have a good system that was in place in South Korea that we can then use as an example of perhaps what we should have done in the United States. And so ultimately, diagnostic testing in the United States is driven through diagnostic manufacturers and not this idea that either the CDC or research laboratories should be creating tests. Diagnostic manufacturers have had the expertise for creating these high-throughput tests, just like the multiplex testing that you're talking about for years. And so, you know, what happened in South Korea is that the South Korean equivalent of the FDA, before the outbreak happened, so when it was happening in mainland China, but before it moved to South Korea, actually gathered together all the diagnostic manufacturers across the country and said, we need you to pivot to making high-volume manufactured tests for our clinical laboratories for this new disease. And that really sort of encouragement from that private sector of diagnostic manufacturers really allowed them to expand their testing because ultimately a high-throughput test that I run at UCLA and one that's run at Cedars and one that's run at Harvard Thank you. And we're just starting to see that now in the U.S. And as we all know, we're behind the curve on testing instead of ahead of the curve. So if I'm going to dream of a world where we have the flexibility to do this, it's really, I think, an engagement between the federal government and the regulatory bodies with the known manufacturers as early as possible to get them to pivot so that we can have clinical testing available in all hospitals before an outbreak happens or while an outbreak is just starting instead of two months behind. This may not be a fair question for you given what you do, but there are reports, especially here in California, of rapidly rising numbers of cases of COVID-19. Do you think that the number of cases is actually increasing or is it just that we're catching up on testing and we're doing more testing and finding more people with this disease? I think, unfortunately, we're in the scenario that it's impossible to answer that question because I think one of those two things could be happening. And until we're able to massively expand their numbers of tests performed, we won't know. We don't know what our baseline is. So we don't know what we're growing from. I will say though, that the good news is testing is starting to expand. So some of the major medical centers in Southern California are starting to bring on testing. And I think over the next two to three weeks, especially in our ill population or our symptomatic population that potentially needs to be hospitalized, we will start to see more and more testing in that group and start to get a better number of understanding of where we are on that curve and where we're going. Because right now it's impossible to know. I think that we can assume we are still expanding just because it's been seen in so many other places. But the question really is how rapidly. You know, I think that we've seen in the New York outbreak that things are progressing much further along right now in New York than they potentially are in Los Angeles, despite what's happening in the hospitals. But really getting to know where we are on that curve, it's critical that we increase testing now as much as possible. Does anybody know what the sensitivity and specificity of the tests are? Yeah, that is another great question that I actually tackle with my hospital system on a daily basis. And so from a lab medicine perspective, just to pull apart that question, it's really two questions. The first question is, what's the analytical sensitivity of the test that's being performed? Meaning if you have a test and it's purified form and you spike in virus, this is how we clinically validate these tests. What is the analytical sensitivity? How low a number of virus can your test actually register? And we know from a PCR perspective that our tests are exquisitely sensitive. As I said, the tests that we're running, we believe we can get down to 500 copies of virus per mil to be able to test and recognize that as a positive by PCR. So from an analytical sensitivity perspective, my answer is these tests are very sensitive. The question then comes is really around clinical sensitivity. In what patient population, at what stage of disease, and what sample is taken is the sensitivity of the test. So for example, what we know is that for the acutely ill patient, the patient that is symptomatic and within the first seven days of acute infection, a nasopharyngeal swab has a very, very high clinical sensitivity. The estimation of this can be upward of 90%. That is the population that we know the most about. The questions start to come up with, let's say the population that potentially has much more severe disease and is hospitalized. Is it better to take a nasopharyngeal swab for that particular patient, or is it better to take something lower respiratory? And this is really about the movement of the virus. Is the virus still in the upper respiratory nasopharyngeal area when it's causing severe pneumonia, or has it left that area and now it's all within the lower respiratory tract? And these are the things we're still trying to figure out. You know, I think some articles have come out recently, even in JAMA, that have suggested potentially the lower respiratory tract specimen is better for severe disease versus nasopharyngeal. But those numbers, so the ends on those data were pretty small. And we're still trying to figure this out. I can say anecdotally, for the hospitalized patients that we have at UCLA, even for the ones that were also lower respiratory tract positive, they've all been nasopharyngeal swab positive as well. But again, anecdotes aren't data. And so what we really need is a large data set collected on that severely ill inpatient population to understand what is the best sample. Then in addition, another question comes up with, well, what's the sensitivity in an asymptomatic population, right? We assume there's some level of either asymptomatic or pre-symptomatic viral carriage. Does a nasopharyngeal swab have a good sensitivity there? And we don't know the answer to that at all. The studies haven't been done and surveys haven't been done to understand how our tests work. So it's really this sort of distinction between analytical sensitivity. The tests are very good, but is the virus in the sample that's collected is really the question we have to ask now. And it's a clinical sensitivity question.
Just anecdotally, do you have experience with other body fluids and whether or not the virus is picked up there? This pertains to like in surgery. I'm a surgeon. People are worried about laparoscopic surgery and if there's virus in venting from the abdominal cavity like peritoneal fluid or blood. I know in some of the reports that we've published, it has been found in blood in some cases, but have you seen that? So we haven't at UCLA. So again, we're constrained by the FDA in where we can test and what we can test. So all we have experience on right now is nasopharyngeal swabs, BAL, and sputum. We have seen positivity across the board. Now, I am familiar with data suggesting that you can find the organism in blood by PCR. I haven't seen good studies that suggest that that is something that should be used in a clinical setting to determine whether or not somebody has disease, meaning somebody would be nasopharyngeal swab negative, BAL or sputum negative, but blood positive. But there have been some studies to suggest that rectal swabs, very latent infections, so after a patient is already recovering, may be the best place to find nucleic acid from the virus, so PCR positivity. But I have read a study saying that that virus isn't active and you actually can't culture from that specimen. We have no data on peritoneal fluid. We have no data on pericardial fluid. None of these specimens have been tested. And again, I think this goes back to the overall lack of testing. If we were in an area of testing excess, I would be able to survey these things amongst my UCLA health population. But because testing is so limited and there's such high demand just to be able to diagnose acute disease, we now don't have the ability to answer the very important questions that you're asking. Dr. Hidayah, Joe, do you have any questions? Yeah, I guess a follow-up on that previous question is, is there any value to antibody testing, such as thronalyza or something similar? Yeah, that's a great question. This is something that we're thinking about a lot. You know, I'll answer that kind of in two stages. One, where do I think there's value? So I do think there's value in certain populations of doing antibody testing. One thing that we're thinking about quite a bit at UCLA is, of course, donor screening and recipient screening for transplant. So how can we know, even if somebody is asymptomatic, whether or not they've potentially gone through a coronavirus infection and may still have the virus in their body. So I do think that that's a good area for that. And then also, you know, I saw out of New York, they're potentially going to use passive immunity for treatment. So taking antibody from people who have already had the disease and see if they can use that to treat people who have acute disease. So then serology would be a really good method of finding those particular patients so that they could donate that IgG product. You know, I think there's some epidemiology worth in something like an IgG. We know there's a certain amount of asymptomatic transmission going on. And so screening a large body of population so that we can get an understanding in the community how many people have had COVID-19 infection. And then I think there's some value in healthcare worker screening, right? There's all this question of, well, if a healthcare worker is positive, when can they return back to work? And we're going to see a severe shortage of healthcare workers. This has been seen across the nation if you have an exposure in a healthcare worker setting. And so potentially serology can play a role there. Some of the challenges of serology is that currently there are no FDA approved tests. For IgG or IgM, we are concerned about cross reactivity with our circulating human coronaviruses. So there are four known human coronaviruses that circulate as regular cold viruses. If a serology test is cross-reactive with those, you know, it's not going to be specific for COVID-19. These are things that definitely need to be worked out before we do a large-scale launch of any level of serology testing. I guess another question that I was interested in are what are the potential challenges with developing a point-of-care test for the virus itself? Yeah, that's a great question. So most of our point-of-care testing around respiratory viruses, we really know from flu and RSV, right? And in most physician offices across the country, you can get an influenza antigen test, and it will have a relative equation to the sensitivity of PCR. You know, the best antigen test can be 80, 85% sensitive, which is pretty good. I think part of the challenge of that, though, is that antigen testing usually works on a lateral flow model. And these are the little cartridges that you can find in clinics. And then there are some distinct sensitivity issues around that compared to PCR. And there are antigen tests that are out there that have a sensitivity as low as 60 or 50 percent. And so part of the challenge of point-of-care testing is, can you make an antigen test that is reasonably as sensitive as PCR and then get that out into the community setting? So the first challenge is creating the test. The second challenge is getting it through the FDA. The FDA has some very stringent restrictions on tests that are performed outside of a clinical lab, because in that setting, there's a loss of control on quality. There's a loss of control on test interpretation. And so the test really needs to meet a specific standard, a very, very high standard before it can be released as point of care in a physician's office. So there hasn't been any tests yet that have panned out that way. There have been quite a few manufacturers that have attempted to make antigen tests. And some of these have been compared to PCR in some of our academic medical centers that are doing some of this evaluation work. And as far as I know, we have yet to have an antigen test that has come anywhere close to the necessary sensitivity to be used for patient testing. Because the challenge is if you have somebody acutely ill and you run this particular test and it says a negative, a false negative is really in our COVID-19 outbreak scenario now, something that's really dangerous as far as having that be a result. A lot of, you know, my co-residents and myself are concerned about asymptomatic transmission in the hospital that we could potentially carry on to other patients. I guess in that setting, you know, when there's a moderate risk of exposure or a high risk of exposure, how much can we really rely on even the PCR-based test to tell us, you know, you're negative, you should be able to go back to work versus not going back? This is, again, something we do not have a lot of data around, but some of the studies coming out of China suggest that even in an asymptomatic population, if somebody can move from being asymptomatic to actually having symptomatic illness in two or three days, so not this true asymptomatic carriage, but this idea that you're just kind of a couple of days before you get sick. The nasopharyngeal swab PCR seems to have a good sensitivity in that population. But again, those were small studies. So I can't give you a definitive answer from an asymptomatic perspective, whether or not a nasopharyngeal swab PCR will have enough clinical sensitivity for what you're talking about. We just don't know yet. And I think that we are attempting to rely on that. But what I have heard is that in areas of just sort of mass transmission of virus, so in areas like Northern Italy, there has to be a level of assumption that potentially everybody working in a healthcare setting has been exposed when you have that many COVID-19 patients that are being cared for. And perhaps in settings like that, this is where this idea of universal masking policies come into play. Dr. Gardner, is there anything that we haven't spoken about that you think needs to be covered? I will say that the case for testing is improving. There are now nine or 10 different FDA approved tests, and some of them are very high throughput. So the test that I'm running now only takes an hour and a half, and I can run up to 500 of them a day. And if we could get more reagent or more kits from the manufacturer, we could push that potentially to a thousand. And so things are getting better slowly. You will see more and more testing. And I think with that, we'll get a better idea of where we are, which I think will put us in a better place in this outbreak.
That's really great. Well, I thank you for taking the time to speak with us and to help us understand the issues around COVID testing and where we're headed with it. So this has been extremely helpful. I really appreciate your taking the time. I very much enjoyed it. Thank you for inviting me. I hope it was both research and clinical laboratories. Because regulation of these tests to ensure their quality is stringent, and there's a very limited number of suppliers of basic reagents, in times of emergency there's been an inability to ramp up testing capacity on the scale needed in the current COVID-19 crisis. Much can be learned from South Korea, whose government anticipated a COVID-19 epidemic based on what was occurring in China and asked private industry to ramp up production of COVID-19 testing supplies. They did so, resulting in an enormous capacity to perform testing, which very effectively controlled the spread of COVID-19 and its deadly consequences. This didn't happen in the United States. In the future, we're going to need to review what went wrong in the U.S. and develop plans to ensure that this mistake doesn't happen again. I'd like to thank Drs. Omai Gardner and Joe Hadaya from UCLA for speaking with us about COVID-19 PCR testing. Today's episode was produced by Jesse McWhorters. Our audio team here at JAMA includes Shelley Steffens, Daniel Morrow, Lisa Harden, and Mike Berkowitz, the Deputy Editor for Electronic Media here at the JAMA Network. I'm Ed Livingston, Deputy Editor for Clinical Reviews and Education at JAMA. Thanks for listening.
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. Good morning, good afternoon, good evening, clinical problem solvers. Nice to see everyone. So Valeria, do you want to give us just the chief concern and then we'll go ahead and get started. Yes, so the chief concern is headache and altered mental status. Headache and altered mental status. So Joy, when you hear either one of those concerns and or both of them together, what starts running through your mind? Well, definitely I would first think of primary headache ideology here, being that this is a neuro-VMR, but obviously you have to rule out the systemic causes right like if you know toxins and you know the high the electrolyte imbalances that that could be but you know, my mind goes right away to primary headaches and secondary headaches, obviously, like, and there is also the altered mental status there. And yeah, I would definitely think as far as like, is this something chronic or this is just something abrupt, the chronicity. Excellent. This is great. So just sticking with headache for a moment, you mentioned primary and secondary headache disorders. Just for others who might not be familiar with those terms, Joy, can you define what you mean by primary and secondary headaches? Well, primary headaches are, you know, the most common that brings people to a neurology office would be migraines, right? Like the other ones are cluster, the cluster tension headache, the headaches that obviously not caused by, we can't pinpoint other costs for them. Like if you would say secondary headaches, like trigeminal neuralgia, there is something like you can point to like as a cause of them having the headache. So yeah, that's what we mean by secondary versus primary headaches. Okay, great. That's perfect. Yeah. So the primary headache disorders are the disorders that they must have some cause, but we haven't elucidated it yet. So we call them primary and that includes migraine, tension, cluster, and then cluster is part of a larger umbrella of trigeminal autonomic cephalges that have cluster itself is actually very rare, though it's common on the boards exams. It's not very common. And then there are even less common headaches in that category, sunk and suna and paroxysmal hemicrania and hemicrania continue, all these that have sort of a description but don't have a particular biomarker yet. And it's still important to distinguish one from the other because they respond to different preventative and abortive treatments. And then the secondary, as you said, are headaches where we can identify the cause. And I usually break those down into headaches caused by problems in the head, of the head and neck, or systemic. So in the head, anything that can affect the brain, meninges, vessels, ventricles can cause headache. Anything that is of the head, so anything as mundane as eye strain or sinusitis or, you know, a dental problem to some very serious, you know, orbital cellulitis or glaucoma or any of those structures of the head, right, not in but but of the head. And neck also, right? Because neck pain can be referred to the head. There's so-called cervicogenic headache from cervical degenerative disease, carotid and vertebral dissection pain can be described headache in some cases. So neck pathology and then systemic pathology, right? Those of you who have had or are recovering from or received the vaccine for COVID, right? There's often a headache with it. And I always wonder, what is that headache? Is that just from cytokines floating around or some mild irritation of my meninges? Hopefully not. Or is it just dehydration? Or what is it? But headache can also be caused by systemic conditions. So great. The headache we're thinking primary versus secondary and then the altered mental status and the headache as well to some extent, right? You mentioned the time course, which is very important. Some people like to use mnemonics for this, MIST and others. I always find mnemonics very hard to remember what things stand for unless the mnemonic and the symptom are sort of the same, even then, you know, is the I inflammatory, iatrogenic, idiopathic? You know, what is the I? Is the I the second letter? I find them very difficult. So I like to organize things as you did, Joy, by the time course and ask, is this sudden onset that would make us think of a vascular cause or epileptic cause or trauma or some toxic congestion causing confusion? Is this acute but not sudden, so fast but not instant? Is it some type of neurologic infection or inflammatory process? Is it subacute, making us think maybe of something neoplastic, although some inflammatory or infectious conditions can be subacute as well, such as fungal or TB related or parasitic infections, or as this chronic change in mental status, which might make us think of something degenerative, although these are just rough rules and many exceptions and toxic metabolic etiologies are sort of in the differential for all, as you mentioned with electrolyte dysfunction. So now I'm turning to you, Matthias, as a neurologist here. So we've talked about an approach to headache, just a very broad brushstrokes. We talked about an approach to altered mental status. What's running through your mind when you see these two things together? Yeah, no, excellent discussion. You know, the first thing that the system, one thing, you know, that makes me jump to is kind of, first of all, thinking about what the setting is, right? Because if this were an ED consult, an urgent ED consult, and someone presented with a headache, and then they had some disturbance in their level of arousal that was hyperacute, I would definitely be thinking toward something vascular, like a subarachnoid hemorrhage, for instance, or an ICH. On the other hand, if it was more on the acute side of things, you know, we see this a lot, I would jump toward something like meningitis and cephalitis, but that's more like sort of the type one thinking, right? And this would be a completely different story with regard to whether this would be a patient presenting in my clinic with a chronic headache and, you know, altered mental status. And I think a lot of this, you know, more going more toward the layered and thoughtful approach here. I think a lot of this also has to do with what we mean by altered mental status. And I think that we may mean a bunch of different things. We may mean disorders of arousal, where someone may present with difficulty in rousing. So we may be dealing with someone who is stuporous, or may be dealing with someone who's somnolent. And what that really means is how easy are they to wake up? Are they, first of all, are they awake, alert? Or are they falling asleep and then waking up, which would make us think of drowsiness or somnolence? Or finally, are they arousable only to pain where we're dealing with stupor or are they not arousing to anything, in which case we're dealing with a coma? In that case, really knowing the trajectory of the headache and then a disorder of arousal would make me go toward, you know, if it's hyperacute, again, probably something vascular. And it could be both a bleed, as we said, a trauma, importantly. And finally, of course, an ischemic stroke, although those don't present with the headache commonly, of course, there are plenty of exceptions, especially with, I mean, one can think of plenty of exceptions with a thunderclap headache causing a deception, but that's a whole other conversation. But I think really knowing the time course is key. And again, then going toward other buckets, you know, thinking about acute, thinking about the setting, you know, is this someone who's febrile, you know, which would make us think about meningitis and encephalitis. We know that the Koenig and Brzezinski sign are beloved, but imperfect, of course. And finally, you know, if we were to go toward episodic, subacute and chronic, we'd probably be dealing with something else. We've seen, I don't know your guys' experience, but we've seen patients with very severe migraine who looked confused. And we went down the meningitis rabbit hole. And finally, of course, toxic metabolic is always a mimicker of plenty of things. Now, that's for arousal. If we're dealing with content of consciousness, then we may be dealing with something completely different.
Of course, I kind of didn, so I think HSV and sublitis is also possible, of course. But yeah, I mean, it's really about knowing the time course, I think, knowing about what the trajectory is from the headache, how the headache started, whether it's a thunderclap headache that started within seconds. And of course, knowing what the setting was in terms of is the patient febrile? Is the patient hypertensive? Do we have any risk factors for PRESS? Is the patient immunosuppressed? Those are just some of the thoughts, but it's a really, really rich chief concern. And so just to highlight some key points, right, the Mattia mentioned here, right, how important context is, although context can trick us sometimes. So if this, I think what you mean to say, is this an emergency, the patient is coming and these symptoms have come on suddenly or over days is very different than in the clinic and having coming for months to years, though sometimes patients come to the emergency room for something that's not acute or to the clinic for something that is acute. And I'll sometimes ask my residents who are ordering a lot of studies in the emergency room, well, hold on, if you were seeing this patient in the clinic, would you have sent them to the emergency room and done all these things, right? So sometimes context is helpful. And I think what you mean there is coming back to our friend, the time course, which is going to help us. And also to highlight, when we talk about altered mental status, we get, as Mattia knows as a resident, probably nine out of 10 consults, right, are for this chief concern. And what does it really mean? And you divided that nicely, as I like to do, into level of consciousness and content of consciousness. Is this a patient who is somnolent or having difficulty maintaining their arousal or they're awake or when they are awake, there is some cognitive modality that's affected, right? Is a patient inattentive, which could lead to confusion? Some patients with amnesia seem very confused. And when you tease it apart, you see, oh, this is actually amnesia. And they're confused because they're not recording any new memories, right? And could it be aphasia? Some patients with aphasia, people think they're confused. So again, digging into whether this is a problem with level of consciousness or content of consciousness, by which we mean sort of the cognitive modalities we usually think about most commonly, attention, memory, and language, though there are others that can give the appearance of confusion and then thinking of the venn diagram of these as you said if this happened all of a sudden it's hard for us not to think of something vascular we don't really think of seizure per se causing headache though there can be postictal anything and headache could be part of that there's postictal nose wiping and ictal spitting and ictal crying and all these interesting things that can happen during a seizure. If this is over days and not weeks, as you said, we'd have to be very worried about meningitis and encephalitis. And coming back to what you said, Joy, headache plus the altered mental status already, we have a red flag there, right? And if this is subacute chronic, then we have other things to think about as Mattia's resident reflexes here, right? Are wondering urgently, do I need to do anything, right? If this is the emergency room and this is minutes, hours, or days of symptoms, what tests might I need? But so the time course is going to be very informative here. And I think after this excellent discussion by Joy and Mattia, we are ready Valeriaeria, to hear a little more of the time course. And maybe you can tell us the history and anything else in that first column you'd like to reveal up until the exam and pause there if that works for you. Yes, perfect. So this is the case of a 52-year-old female, right-handed female, that had three months ago the recent diagnosis of not Hodgkin's lymphoma. Since then, she's been having some chronic occipital predominant headache. However, one week before admission, this headache became of her whole head and increased in intensity. Six days before admission, she went to the ED, but they didn't really admit her. So the headache got worse and she started having nausea and vomiting and also some dizziness. And the whole week, her daughter noticed that she started becoming more somnolent, started sleeping more hours during the day, and she eventually could not recognize her daughter, and started talking words that didn't make any sense. So that's why she was admitted. In her past medical history, she had a diagnosis of not Hodgkin's lymphoma, of primary cervical giant B-cell lymphoma with high risk because the bone marrow was infiltrated. She was diagnosed three months before and had three courses of chemo. And the last course ended two weeks before admission. She denied any other diseases and she denies deny any fever any weight loss she was diagnosed just because it was a little weird diagnosis the family said that she had some weakness in her legs and that's how she was diagnosed and she couldn't walk after she was first admitted to the hospital after she was given the lymphoma diagnosis, but we didn't have her records from that admission. So we really couldn't know. And the patient, of course, was not in the best shape to tell us what happened. Family history, it was a remarkable social history, no alcohol, no tobacco. Her related behaviors were not contributory as well, and she had no allergies. Excellent. So let's see. Joy, do you want to tell us what you're thinking now based on some of this new information? Yeah, I'm thinking, I'm inclined to think that this is something secondary, like some sort of adverse effect of the chemo. They just had a round of chemo recently. And it sounds like to me like chemo drugs can cause a lot of neurologic adverse effects, side effects. So that's my first knee jerk here. Yeah, that's an important one. Yeah, so let's put that on the list here as a possibility of something related to the chemotherapy. Mattia, what's coming to mind for you? And then I'll share some thoughts also, and we'll get into the hearing the exam. Yes. I mean, so much in that we have a, so let's talk about the course, right? So we're really talking about the progressive headache, subacute in trajectory that got worse and went on from involving the occipital lobes to then or the occipital region rather to then involve the whole head to then involve a disorder of arousal so I think when I think subacute I mostly think about either subacute infections, which can be fungal, can be something like TB, some viruses can also present their way. And then we have inflammatory disorders. And finally, we have tumors and something, and toxic metabolic too, but something about her history though here is key. We have someone who has non-Lachshman lymphoma. So by definition, they are immunosuppressed. They're also on chemotherapy. So they're even more immunosuppressed. So that I think makes us even more worried about something space occupying, first of all, related to the, to the immune and immunosuppressed state. And by that reasoning, infections come to mind that that would be a big one. And if we're thinking about subacute infections, again, depending on where this region of the world we're at, you know, fungi do come to mind. Then another thought, of course, is also that chemotherapy specifically can lead to, well, both the tumor itself, the budal lymphoma itself and the chemotherapy can lead to a hypercoagulable state. So another thought would be something like CVT, which of course would explain the headache and then would explain a bleed, which would explain a space-occupying lesion. A bit fast, my third thought is a thing that would be a bit fast, but it could be localization of the lymphoma to the brain. I believe that could be possible. And interestingly enough, when I heard originally the occipital headache then leading to a little holocephalic headache kind of made me think about PRESS2, which of course can lead to obtundation in some cases. And of course, we know that it's associated with multiple chemotherapies like tacrolimus.
But I'll stop there. There's so much to say, but I'll stop there to allow some discussion. are the cancer. And yet we have to be careful of being anchored and prematurely closing and saying this is a complication of the cancer because patients can still get other conditions. But gee, I agree with you. It's hard to tear ourselves away from that very important element in the history here. So how can cancer affect the nervous system? I divide that into three broad categories. One is there can be direct involvement of the nervous system, such as a brain tumor or spinal cord tumor or metastases, which are more common to nervous system structures, or tumors in areas that are compressing neurologic structures. So direct involvement is one. The second, as Joy mentioned, is complications related to treatment. So chemotherapy can have all sorts of neurologic complications. Mattia mentioned press. Peripheral neuropathy, obviously not on the table for this case, with headache and altered mental status, very common complication of cancer chemotherapy. There are radiation toxicities to the brain cord, plexus, etc. And then the newer checkpoint inhibitors, CAR T-cell therapy, a whole sort of field of neuroimmunology is evolving around all the complications that can be caused, neurologic complications that can be caused by these treatments. So that's sort of category two, chemotherapy, radiation therapy complications. And then category three are perineoplastic syndromes of which the the list continues to grow, in which some type of immune response to the cancer generates neural autoantibodies. And I would sort of add roughly in that perineoplastic category, something Mattia mentioned is just the hypercoagulable state of cancer, Trousseau's syndrome, which again, one of my mentors, I think some of you have heard Marty Samuel speak about Trousseau syndrome, that it's a true apostrophe S because Trousseau both discovered the syndrome, which again, one of my mentors, I think some of you have heard Marty Samuel speak about Trousseau syndrome, that it's a true apostrophe S because Trousseau both discovered the syndrome and died of his own syndrome that he diagnosed in himself when he developed a DBT related to what was ultimately gastric cancer. So sort of in that field of cancer related, a sort of hypercoagulability. And then you have the additional factor here, as Mattia mentioned, that the cancer itself and the chemotherapy are immunosuppressing this patient, which puts the patient at risk for all kinds of infectious complications. So you were trying to use, Mattia, the time course here, but this is really going on for over a week now. I agree a bacterial meningitis would be less likely, strep or Neisseria, the patient would probably not survive for a week without treatment. So does this patient have a space-occupying lesion that could be infectious, cancerous, or chemotherapy-related? We wouldn't think of PRESS as necessarily space-occupying, though it's edematous, though it can be when severe, or a hemorrhage, or a stroke, or something like that. The course here is sort of progressive, so something vascular seems a little less likely. And I think the other thing to think about in terms of localization is if we'll see on the exam, but if there are really no localizing features, and we just have sort of headache, insomnolence, nausea, and vomiting, whether we're seeing a rise in intracranial pressure here, which I believe we are and has been mentioned. Mattia mentioned the possibility of a space-occupying lesion. Let's just remember that intracranial pressure can rise, one, due to problems in the brain, two, due to problems in the ventricular system, and three, due to problems in the vasculature. Those are the three intracranial compartments, 80% brain, about 10% CSF, and about 10% blood. Mostly that blood is in the venous system. So a mass could raise intracranial pressure. This patient could have hydrocephalus. Maybe they have a meningeal infection. Maybe they have meningeal spread of their lymphoma to the meninges and have developed hydrocephalus. And then a venous sinus thrombosis, I don't think of lymphoma per se as a condition that's going to be causing hypercoagulability and a venous sinus thrombosis per se, but progressive headache, progressive decline in consciousness, that's one of the things one could think of because the patient would develop sort of cerebral ed edema and unless they have a hemorrhage or stroke related to that venous sinus thrombosis, they may not have a focal lesion. So I think one important aspect of the exam is going to be seeing if there's anything focal here, we're dealing sort of with a global encephalopathy, um, and, uh, or if there's anything focal and, um, and so, yeah, so let's, um, hear and so yeah, so let's hear the exam. And yeah, let's hear the exam and go from there. I have lots more thoughts, as I know, Mattia and Joy do too, but we have to get some more data here. So I think we're still wide open. Is this cancer affecting the brain or meninges? Is this some complication of chemotherapy? Is it a sort of second also sort of indirect complication of chemotherapy causing immunosuppression causing some type of infection? And is that in the meningeal compartment? Or is that in the brain parenchyma itself? perineoplastic, this is a little fast for that. And there's a headache, which I don't really associate usually with perineoplastic. So I'd probably put that lower. So we're sort of, I think, leading now with cancer or infection due to immunosuppression as we go into the exam. So let me just ask you, Mattia, since you're in a part of your career where you're examining hundreds, if not maybe close to a thousand patients per year. And so by the time you finish a history, you probably have a hypothesis already. Do you think you're going to find anything on the exam that's going to take you further towards a diagnosis? And we all know that there's going to have to be imaging of the brain in this case. Is this a case where you're sort of doing the exam to make sure, but eager to see the imaging or going into the exam thinking there's clues here that are going to help me figure this out? You know, with the fact that we're suspecting increased intracranial pressure and we have this differential of whether there's something space occupying or not, I think that's definitely something I would be looking for. You know, any kind of suggestion on the exam that there is some focality to this, whether it's just the patient being less briskly reactive to pain on one side. Of course, I'm not still too sure what kind of mental status we're going to see. I think we're going to see something in between obtundation and coma from what I've heard so far. But of course, if we were to see something like a blown pupil, for instance, a compressive cranial nerve 3, right? Or any kind of ocular, and really any kind of cranial nerve, focal cranial nerve deficit that would make me want to lean to one side or the other. And of course, again, any kind of difference in the motoric response. I think that that would really give us a good yield. If we were to see no focality to this, then we'd go in another direction, really. You know, it could be something like meningitis, of course. But then again, you know, I would be really curious to see whether there's anything space-occupying at this point. That's where I would go. Excellent. And what is your... Yeah, go ahead. Sorry. Yeah, and not the last thought is, of course, like looking at the vital signs, right? So if we were to see any specific pattern to the breathing itself, that could make us go toward a specific level in the brainstem, no stick versus ataxic. So I think those are all my thoughts. And let me just push you a little bit, just to ask you sort of your instinct and intuition. Obviously, if you had been taking a history, you'd been looking at the patient the whole time. We don't have that luxury in this exercise, but your intuition, are we going to find something focal here or sort of a non-focally somnolent patient plus or minus papilledema? What's your instinct? Is this going to be a focal exam and revealing or going to be a non-focal and unrevealing exam? I'll say this.
And then with the whole history of someone being, you know, immunosuppressed, I'm more and more going toward this being sort of a subacute meningitis secondary to the immunosuppression. But I usually like to stay pretty broad with my differential, but that's where we go. I agree. Yeah, always good to stay broad. And I think it's helpful to enter the physical exam with some hypotheses and intuitions as also when we look at data, although those can also anchor us, right? And it's hard to pull away from initial system one thinking, as you said, the sort of thinking fast. But I think it's helpful to have these hypotheses, because then when we're testing them, if we get surprised, they have a certain valence, right? If we go in, I'm sort of thinking based on what we've heard, and the things we're considering, that we might not find too much on the exam that helps us further. But if we do find something then, and I have that thought in mind, then it's in a way more striking. Although I'm also putting myself at risk for saying, well, the reflex are a little bit different, but I'm not going to. So it's, I appreciate your metacognition here, right? Saying, well, I'm thinking this, but I have to be careful in case that, but I still like to always push when I'm, you know, on round saying, okay, we're, we all agree to order an MRI. Who thinks it's really going to be abnormal, right? Is it, are you doing it to rule in or rule out? Cause if you have a instinct, um, and you see that your instinct was correct, you get a little point in your temporal lobe of my instinct in this case, um, I learned something. And if you're wrong, you also get a point in your temporal lobe or wherever saying, wow, I have to think next time that I just went down this pathway of thinking this obtunded sick patient is not going to have anything on exam and I'm going to need an image. And then we can talk about the image also. I actually, you know, you get to the point where you think, I'm actually don't think we're going to see anything, but I agree we should get it. And you do see something and say, what, where did I go wrong in my logic? So I think helpful to have these hypotheses as long as we're not attached to them, but that is a tricky dance in our minds, isn't it? Okay, Valeria, so tell us what, if anything, did you find on the exam? Okay, so the vital signs, her blood pressure was 100 over 60. Her heart rate was 65, respiratory rate 20, temperature 37 degrees. She was saturating 98% on womb air. So initially, well, on general appearance, she seemed acutely ill. She was lying down. She had some dehydration and paleness, but otherwise her respiratory and cardiovascular exams were remarkable, as well as her abdominal exam. On her neurological exam, she was somnolent. She was disoriented in time and space. And when I examined her, she was very fluctuant in terms of her orientation and the evolution of her superior cerebral functions, because sometimes she could answer my questions. Sometimes she just would look away and not answer or easy message. She couldn't hear me, but she would come back and apologize. And it was very fluctuating. So when I examined her, so that made really hard to examine her, but her language was okay. She could nominate, repeat. Her language was fluent when she was able to talk and she also could understand what I was saying, but I could not examine a lot of like calculations and judgment. Then on the cranial nerves were normal. She did have some bilateral papilledema on the eyes. Then the motor exam, she did have some generalized weakness, but no focal weakness. All four extremities were four over five and reflexes were plus two throughout. Her muscular atrophism was normal. She didn't seem to be hypotonic or hypertonic. She didn't have any involuntary movements. And she didn't have Babinski or Hoffman or any Babinski-like reflexes. And she didn't have any changes in sensitivity. She did have nocule rigidity when I examined her her and also on admission. I didn't see her on the ID, but they did report that she didn't have Karnik or Brudzinski. She didn't have any signs of frontalization. And when I examined her, she did have some Laseg and Bragaard signs, which were a little off, but I was not so sure about the correlation of that and the classic correlation of those signs. The coordination, she didn't have any dysmetria or diacosynesia, and we couldn't examine her walk or rumburg because she couldn't come out of the bed. And yeah, that's basically the neuro exam. Fantastic detailed neuro exam from Valeria and very wonderfully presented. So Joy, let me ask you the question I asked Mattia to predict before this exam. And now we have a lot of information here. Is this a focal exam, a non-focal exam? Does it lead you in a particular direction, Joy? Well, I was hoping the cranial nerves would, you know, do that for us, but it's normal. Except for the papilledema, which we know already that she should have. We know that she has increasing intracranial pressure. No, the physical exam is equivocal. Yeah, excellent. So in neurology, we love the physical exam and we love to spend a lot of time at the bedside teasing things apart if we're trying to figure out what is the cause of this facial weakness, what is the cause of this diplopia. But in some cases, we have a so-called non-focal exam or an exam that doesn't really tell us the location beyond this is in the brain, right? It's not in the peripheral nerve muscle, neuromuscular junction, spinal cord, cetera. And so that's right. We knew the intracranial pressure was going to be elevated. We've proven that with the papilledema. And that also tells us that it's been there for some time because papilledema takes some time to develop. And we also sort of knew that from the history. So this was a sort of hypothesis confirming exam rather than a hypothesis changing exam. Although we did find some neck stiffness, which is going to increase our concern here for some meningeal process. Now, Mattia mentioned the excellent point earlier. We all learned Koenig and Brudzinski. And I know I said, I don't like mnemonics, but people reminded me to remember that Koenig has K. That's the one where you have the knee flexed and then extended. So K for me and then Brzezinski is bending the neck. And there's a nice JAMA rational clinical exam series. I love these papers where they look at sensitivity and specificity of physical exam signs. And the one for meningitis says that Koenig and Brzezinski signs are something like 5% sensitive, even though they're very highly specific. Why might that be? Well, if you work in a very high resource place where people can get to the clinic emergency room or hospital within a day of their symptoms, and they present very early with bacterial meningitis, they might not have developed these symptoms yet. But if you work in places where it takes people a long time to come to the hospital due to difficult access to a healthcare facility, and in places I've worked like that, oh, you see a lot of Koenig and Brzezinski signs actually, because patients are coming with very advanced disease, either due to limited access or due to their situation that makes it hard for them to get to the hospital until they feel they're very sick and need it. So I suspect in Koenig and Brzezinski signs that not everyone was getting to the hospital within a day of their symptoms. And so these were important signs for Dr. Kernighan-Brasinski whenever and wherever they were practicing, but definitely nothing to hang your hat on now unless it's step one. So we need an image here. And so I'll ask the same question I asked before the exam. What are we going to see on this image? We have now a, well, does one of you want to give a problem representation and then tell us what type of imaging you would get and what you'd be looking for? Either Joy or Mattia can take one or both of those questions. This is, I will try further problem representation here. 52-year-old female known to have a giant basal lymphoma.
That's great. Problem representation. Probably the only thing I would add is with one week of those symptoms, right? Because that tells us the time. So with that in mind, and we might also add with nuchal rigidity on exam if we were including the exam there. But yeah, this is just... Yeah, so Mattia, what imaging study would you order and what are you expecting to see or not see? So I suppose it really depends on what kind of resources we have. Because to be honest with you, if I was in my institution and this was an ED consult, I could get an MRI with and without contrast and an MRB. Now, whether that's the most parsimonious use of resources, I don't know. But the reason to get an MRI brain with and without contrast is to get a good look at the meninges, especially in this setting where we're thinking, could this be some kind of infectious leftomeningitis? And then if that, you know, that would be a way to prove our hypothesis and then also to rule out anything space occupying, although our exam has, in fact, ruled it out already. MRV would be, I've been burnt in the past thinking, you know, oh, increased papilledema without any other symptoms. It's probably IAH, but still we should get an MRV just in case, because you cannot call something idiopathic without ruling out the other causes. And in fact, the gentleman ended up having a CVSD, cerebral venous sinus thrombosis. By the way, not that I'm advocating this is in any way IH, no. But now, if an MRI wasn't an option, then we could go with a head CT. And I think the reason here, correct me if I'm wrong, but the reason here is that we really have someone with increased ICP and altered mental status, which would fall into, which would be a requirement for us to image the patient before doing an LP, which would be our next step. So this combination would be, would demand imaging. So I think in short, if I were to have all my tools, I would want an MRI brain with and without contrast. Yeah, I agree with you. MRI is going to give us more resolution and that contrast is going to help us image the meninges here, which are interesting to us. You said our suspicion for a space occupying lesion is low. I would probably just slightly, I know what you mean, I would say one in an eloquent area of the hemispheres or posterior fossa structures is probably low. There could be a mass lesion in the ventricular system causing hydrocephalus. So there could be space-occupying but not the usual spaces that we think of intraparenchymal. But I agree, I think if I was going to guess, and I always like to do this, not as a game or, but, you know, on rounds to say, we're going to get this MRI, what are we going to see? And, again, both because if you confirm it, you say, okay, my history and exam and hypothesis really led me down the right track here, and you file that away. Or you say, wow, I definitely wasn't expecting to see that. I need to add this one to my sort of developing concept of what one could see in this situation. And as Mattia talked about getting burned, I mean, this venous sinus thrombosis is a good one that you could miss on imaging without contrast or MRV. There are subtle signs you can see even on a non-con CT scan, but they're not always there. And so there are things that by missing them and someone else finding them or finding them in a different way, you know, these help us develop our problem representations going forward. So I agree MRI with contrast. And what do I think we're going to see? I think we are going to see meningeal enhancement and that we are going to see hydrocephalus and that you're right, Mattia, of our four most common tests in neurology, MRI, LP, EEG, and EMG, probably the second one to really make a firm diagnosis here if we think it's safe based on the MRI. We don't have an obvious answer as a lumbar puncture to try to distinguish between infectious and meningitis and leptomeningeal involvement of this lymphoma. Because for infections, this really could be anything I think you've mentioned before, it's a little long for bacterial, but could really be any, you know, fungal cause, depending on the patient's exposure history, could be tubercular as well. And there's not gonna be any real specific imaging findings there. All of those would cause some combination of meningeal enhancement and or hydrocephalus and or small or large ring enhancing lesions, tuberculoma, cryptococoma, and or infarcts because the basilar meningitis affects the vessels. And so we're probably ultimately going to do a lumbar puncture to make a firm diagnosis here, whether that's filled with B cells that through flow cytometry match the patient's cancer, or whether we see an infectious profile and we're able to grow something or have antigen or PCR testing come back positive. So what did you find on the imaging, Blair? Are we on the right track? Are we in for a big surprise that's going to shift the course in the last two minutes here and show how my time budgeting skills continue to be poor as goes with the history of BMR? And we'll go over for another hour based on what you're going to show me. No, you're right on track. I think I'm going to give you just everything I've got. But I think, I mean, you totally got the imaging right, but I think the LP may be a little bit of a discussion point. So yeah, as you totally got right, we got an MRI because our CT machine broke. So we had to decide a CT or an MRI to ask the family for. And so they got an MRI and indeed it showed a lot of leptomeningeal enhancement. However, the LP that we got was a little confusing for us. So the CSF was transparent. We found 140 leukocytes, 65% were mononuclear, and there were 15 red blood cells, 51 proteins, and glucose was 20. Leptomeningeal enhancement on the MRI. Was there hydrocephalus or no? No, there was just a diffuse cerebral edema. Edema. Okay. So we were pretty close there and nothing else on the scan, just the leptomeningeal enhancement and cerebral edema. Fantastic. Well, not fantastic for the patient, but fantastic for your concise summary of the imaging. And then do you have a serum glucose to go with that CSF glucose by chance? Or it's a low number, but if the serum is based also hypoglycemic, it might not be that low. Yeah. Yeah. It was 96. 96. Okay. Great. So just quickly, since we're getting, well, we're past the end of the hour here, Joy, what do you make of this CSF? We're sort of down to trying to figure out now, is this an infection or involvement of the cancer? Does this profile lead you in any particular direction? Not really, but I'm going to think that investigate for would think for infectious here, even like the 140 leukocytes, like what you said, fungal, definitely fungal with a chronicity of their um presentation and um um the uh 15 rbcs that's more within the range of normal um the the glucose 20 glucose that's i that i would think that's low right right? So it could be. Usually we would think of that as like a bacterial etiology. So I'm not sure. I'm thinking definitely infectious or inflammatory, something like that. Yeah. Yeah. Excellent. So yeah, we see meningitis on the scan as we expected, but it doesn't tell us if it's infectious inflammatory neoplastic and the CSF profile. So we tend to think of low glucose in bacterial fungal and tubercular meningitis and low meaning usually less than 40 or less than about less than 40 or 30% of the serum glucose. So this is quite low. But you can actually see low glucose in some viral infections. You can see it in leptomeningeal disease. You can even see it, I believe, in sarcoid, if I'm not mistaken. So all these things we learn in medical school, you know, have their exceptions. The rest of the profile, what's interesting to me is if, well, if this was the patient's lymphoma, presumably we would have heard lymphocytes or atypical cells. And we're seeing monocytes here. Am I right, Valeria?
Oh, no, no, no. They're just not PMNs. They're not PMNs. I see. So we don't know if they're lymphocytes, monos, EOs or otherwise. Okay. Okay. So it's a lymphocytic predominance with a hypoglyco-rachea, low CSF glucose. As you said, this could be anything infectious, inflammatory, or neoplastic. And those could be the patient's cancer. I corrected, I said, these are mononuclear, but not monocytes. That was my misreading. And this could be infectious also. And this is a common scenario we end up in. So what are the next tests you would be ordering, Mattia, to try to sort this out? And we're obviously trying to get to a diagnosis, but is there any treatment you would start while awaiting these tests coming back? Well, it's complex. I mean, I would definitely want to start some kind of empiric therapy. I would have started empiric therapy in the ED. Now, whether this is sort of a mixed bag of NLP, so I don't know that I would stop my empiric therapy. I wouldn't. Now, in terms of where we are going with this, I definitely would want to see a flow. I would definitely want to add bacterial cultures. Given the high risk of this patient having some kind of fungal etiology, I definitely want, at the very least, to know about Cryptococcus and other environmental fungi. I was also curious, what was the opening pressure on this patient? I'm going to guess high. Sorry. Oh, well, it was 25. Yeah. Because of course, Cryptococcus can be associated with very high opening pressures. TB for sure. So an acid-fast stain. And then again, both flow and cytometry, I think those would be key to have. Because then again, with a low glucose and a lymphocyte predominance i think fungi are still on the table here um absolutely yeah excellent so that's right so we're going in our usual order here of you know uh history exam labs imaging but as matthias said as soon as you examine this patient and maybe even over the phone while you're going to the ed this is a treat first ask questions later situation because there's studies that show that if this is bacterial meningitis for every hour you wait the patient's going to do worse and you're not changing your lp results that's a myth the biochemical and and culture changes last probably days. So get your antibiotics going, get some blood cultures, because a lot of bacterial meningitis cases, the blood cultures would be positive. Also, I don't remember the exact percent, but I think well over 50% at least. So right. And this patient's immunocompromised and over 50. So we'd be looking at vancomycin, ceftriaxone, ampicillin. Before you had the imaging, a lot of people would throw on acyclovir just in case this patient has HSV. Probably after that scan, you probably don't need the acyclovir anymore. But I agree, this would not be a typical bacterial profile or a bacterial course, but I think most people would be hesitant to stop antibiotics until we see cultures. So we do want bacterial cultures. We do want cytology, someone to actually look at the cells under the microscope and say, hey, hey, these really are very atypical. This looks like lymphoma. And then flow cytometry, where actually they're measuring based on the CD profiles on the cell surface, what types of cells these are in case they are lymphoma, although CSF studies are actually not that sensitive. And we say it takes up to three lumbar punctures to get into a reasonable sensitivity range to diagnose primary CNS lymphoma, although probably a little higher if it's invading the meninges as it is here. And then for infections, I agree we're probably more in the fungal and TB category. So what are the most sensitive tests for crypto? It's actually the crag or cryptococcal antigen. Fungal culture takes a long time to come back. What is called India ink here, though my colleagues in French-speaking countries say encre de chine. So some places it's Chinese ink and some places it's India ink. I think Valeria, you've told me before, it's also ink of China in Spanish-speaking countries. Is that right? This is on the boards, but very insensitive. You really want that CRAG study, depending where you are in the world. If you're where I am in California, I'm learning that people are looking for coxioid. So it's antigen antibody testing in the CSF. I haven't seen my first case yet, but I'm waiting for it. And then TB, again, we learn about acid fast and zeal, Nielsen and culture. The diagnostics are very insensitive for TB culture is very sensitive, but takes a long time to come back acid fast, not very sensitive. So you really want the gene expert, which is a DNA PCR for TB. And even that is imperfect in its sensitivity. Is this, so let's take our final votes. Is this infectious or is this cancer? Just in one word, Mattia, in one word, Joy, and I'll go last so I get to hear what you think first. Infectious or cancer? I'll go with infectious. I guess it was my first thought. I guess I'm having a bad case of anchoring. No, that's okay. Sometimes the anchor is in the right port. Yeah. And Joy, infectious or cancer? Okay. So we'll just cover everything. So I would think cancer or something inflammatory. Okay. So a vote for infection and vote for cancer. It really could be either. I think I'm on the infectious side of the coin. I can't really give you a good reason for that. Maybe this is a little fast for leptomeningeal lymphoma, but maybe not. Your ICP is not elevated until it is, and then things can go down quickly. The glucose can be low in neoplastic invasion of the meninges, but it's really low compared to the serum there. It's not kind of on the border. But it could be anything. And if it is an infection, what infection is it? I don't think we could say without further data. I don't know. Valeria spent a lot of time in the US recently doing rotations. I don't know where this case is from, if it's from Peru or from the US. If it's in a TB endemic area, I think it'd be hard for us not to start covering that if the patient's getting worse on bacterial treatment and we don't have data back. Yet, if not, would you add amphotericin and some of these very toxic antifungals while awaiting those tests? Probably depend on if the patient's getting worse in front of your eyes on just antibacterials. So where is this case from, Valeria? From here. I said that our CT machine broke. Your CT, yes, that was a clue, although this can happen and you still had an MRI, so I wasn't. So, well, in that case, I have my valerian bias. I think it's been in several different versions of TB over the course of years, but that's just a morning report gamesmanship and not clinical reasoning. This could be either, and we'd be probably adding a lot of empiric stuff while we waited for our pathology lab to tell us what's going on here. So what came back positive? I'm going to, I'm going to go with infection and I'm, I, this feels a little fast for TB, but I don't know. Would listeria present with this? Listeria is more abrupt, right? I would, I've actually never seen a case of listeria. Could do. Could do this. Yeah, I would think bacterial in general, the patient's not going to be still able to wake up enough to answer Valeria's questions with normal speech after one week. But I don't have an experiential illness script for listeria just because I haven't seen my own case. But yeah, it feels a little bit, it's fast, but it's a little bit leisurely for bacterial, for me, especially in someone with hardly any immune system to fight it. So I think if it's infectious as TB or fungal and just going with a Bayesian approach, I'm going to say TB, but tell us what you found. Yes, we were right there with you thinking this could be TB because of where we are. The glucose really threw us off.
We did get a repeat gene expert. So gene expert negative two times, crypto and digital negative twice as well. Gram didn't show anything, sorry. And glucose cultures didn't grow anything either. And then we got some pap and cytology samples, but they were not very good. And pathology suggested flow cytometry and also the immunohistochemistry. So we did that and flow cytometry showed phenotypic findings compatible with meningoencephalic infiltration by lymphoproliferative disorder, chronic B lymphoproliferative disorder. So yeah. Plexomeningeal lymphoma. Yeah. Yes. So yeah. Looking back, anything that would have led us to or from that versus infection? Sounds like you and your colleagues are in the same place as us. This is either infection or malignancy. And it's very hard to tell the CSF profile by itself could really be either glucose is maybe a little low for you might say for neoplasm, but important teaching point here that you can see that and that doesn't rule it out. The negative gene expert doesn't rule out TB, right? Valeria has a lot of experience with this. I think it's only 60 to 80% sensitive on the CSF or something that's worse. Don't quote me on that, but it's, it's not as nice, as good as we would hope it would be, but negative twice, I guess. And did you start TB therapy while awaiting all this pathology to come back, Valeria? Or just curious how you practiced there? No, we started, as you said, empiric bacterial coverage, as well as listeria coverage. And oncology started at a cyclover, but we weren't really sure if that was the best thing to do because I think Icyclobate has some neurotoxicity properties or risks. And that's what the team mentioned. Nephrotoxicity, I think. But yeah. Okay. Okay. I may have to look that up. But so, but, and then, no, we didn't start any anti-TV coverage. We were pretty convinced with low glucose that this could be TB, but just because it's a great commitment to start TB therapy, we waited. And the flow cytometry and the repeat LP were pretty quickly to come back, thankfully. So we had those answers. And at some teaching points, I have a lot of leeningeal carcinomatosis just quickly because we did learn a lot. It was my first case. And I think for some of the people in my team as well. So it usually it's associated with some cancers like breast, lung, melanoma, and hematologic malignancies. And it can be a complication in up to 8% of solid tumors and up to 15% of hematological cancers, but it's still very rare. It can cause Bink-Meal syndrome, which is caused by, I believe, meloproliferative, like it's a variant of multiple myeloma. Bink-ing mule syndrome when there's leptomeningeal carcinomatosis due to a variant of uh multiple myeloma but it just has an eponym and then it's a very bad prognosis and what i learned that was really important in this case was that false negatives are really common, especially when samples are refrigerated for 48 hours or more. And false negatives can happen up to 36% if this takes a while. So, you know, to take that in mind, because it was a case of this patient, because we had to do the studies outside of the hospital. We didn't have the best conditions. So of course we did see some problems with the cytology at the beginning. And CSF studies usually show myoclosis hypoglycolic, usually less than 60 and elevated protein, which was a case of this patient as well. So yeah, thank you for this amazing discussion. Excellent teaching points. And Valeria, how did you treat this patient and how did they do? Yeah, so the patient is still with us in the hospital. Oncology started in tracheal chemotherapy. However, when we talked with them, this lymphoma has very bad prognosis. And I think what could have made a difference probably would have been to diagnose it earlier because usually the time from like the life expectancy when you are diagnosed with this cancer is usually three months. So this patient had a three-month history of headache. So she's probably going to pass away pretty soon, sadly. However, I think oncology didn't pick on this headache concern early on. And given the lymphoma and the type of lymphoma she had, I think this was something that could have changed maybe the course of the disease, because it was something that the family did say that was happening for a while. Thanks again Valeria for bringing us this very instructional case. We all learned a lot from the case and from your presentation and Joy and Mattia thanks again for your discussions. We all learned a lot from those as well and we will do this again sometime soon. That's a wrap.
Alright, so we've said that in this country, cystic fibrosis is the most common cause of bronchiectasis, and TB in third world countries. There are many other causes of bronchiectasis, and one that they like we've already mentioned, that's the immotile cilia syndrome. Another name is Cartagena syndrome. Remember the 9 plus 2 configuration in terms of microtubules and cilia? The problem with emotile cilia syndrome is an absent dynine arm. And those 9 that are on the outside of the cilia, those 9 microtubules out there, they have little arms off of them. They should have little arms off of them to kind of keep them together. Those are missing. And so when those little arms are missing, those di-9 arms, the cilia can't move. And so those places that have cilia that aren't moving are going to be affected. So those would be sinuses, and so that's why sinusitis is a problem. Bronchiectasis, because there is cilia, you know, pseudostratified columnar epithelium that has cilia, so that's affected. Males and females are infertile mainly because the tail of the sperm is a modified cilia. So the head is willing but the tail is weak. Did you get that? Do you want to move? This is a sperm. Can you move? Why? Because the tail is a modified cilia and it can't. So I was saying, the head is willing, but the tail is weak. It doesn't move. Okay, so that means you're infertile. I thought that was pretty clever. Most of you didn't get that or you didn't think it was funny. I don't know what the other was, but I thought that was pretty clever, actually. Women are infertile, too. Why? Why should you be infertile? Because your fallopian tube needs cilia to carry that fertilized egg down. So if it doesn't move, you're infertile. So bronchiectasis, infertility, male-female, sinusitis, and then organs being located on the opposite side, dextral cardia. Remember, that's not complete transposition. It's just a normal heart on the other side. And sometimes even organ shifts is part of that syndrome. Famous question because it gets into histology. It's a histology correlation. Okay, before we do cancer, in terms of asthma, bronchial asthma, remember it can be extrinsic, which is type 1 hypersensitivity, and intrinsic, which involves chemicals oftentimes. Many times people in the workplace get wheezing when they come in contact with a certain chemical. We already know one cause of that would be triad asthma related to taking nonsteroidals, okay, as an example. A lot of people, especially athletes, when they run, develop wheezing, exertional asthma. That's where chromal and sodium is the absolute drug of choice for that, for exertional asthma, you know, that type of thing. Sometimes cold temperatures, you know, cause asthma. Those things have absolutely nothing to do with type 1 hypersensitivity. The wheezing is due to inflammation in the terminal bronchioles, okay, except it's going to be from a different cause. It's not going to be from smoking irritating it and causing goblets or metaplasias. It's coming because of factors like LTC4, D4, and E4, okay, and prostaglandins that are causing inflammation are producing the inflammation and narrowing of those airways, okay, and ending up with the wheezing, okay? That's pretty much it. Cancer. And I remember on my exam, but honestly, I'm not kidding you. I remember on my exam, it wasn't this picture, it was a schematic. And the schematic had this over here, and they labeled that A, and they had this over here, and they labeled that D, and then they ask all kinds of questions about cancer. Because what it's getting at is peripherally located versus centrally located cancers in the lung. The centrally located cancers in the lungs are the ones that have the highest association with smoking, and they would include squamous cell carcinoma and small cell. So those are generally centrally located, which means main stem bronchus types of locations. Adenocarcinomas, which are the more common cancer now, primary cancer, they beat squamous out about two or three years ago. It's kind of like 40% versus 30%. It's very, very close, but adenocarcinoma is a little bit more common. They have a tendency of being more peripheral, as opposed to snatching. Want to know why it shifted? This will just blow you away. It shifted to the periphery because of filters in cigarettes. When the cigarette industry put filters in cigarettes, it took out the large carcinogens, but allowed the small ones to go through, so they were able now not to be trapped in the main stem. They were getting trapped in the periphery. So filters in cigarettes is responsible for the increase in peripherally located adenocarcinoma. Isn't that fascinating? I got that from a pulmonologist from his literature. You can't win with the cigarette industry in any way, shape, or form. Everything they say that say that they're going to do that's going to help you, you know, not get bad things is actually making it worse. Okay, so that's that. So centrally located squamous cell, small cell carcinoma, squamous more common, and small cell peripherally located adenocarcinomas. But remember, there's at least three, maybe four different types of adenocarcinoma. One obviously does have a smoking relationship, but actually the other three don't. And they include things like bronchioloalveolar carcinoma, nothing to do with smoking at all. Large cell carcinoma, the lung tends to be adenocarcinoma. Scar cancers tend to be adenocarcinoma. They have really no relationship to smoking at all. But obviously, the one that is producing cancer does because it is related to smoking. I'm going to show you some cytology, guys, because they think that all second year medical students should know what squamous cancer looks like with a pap smear. Now, a lot of people think that the papanicola stain is only done for cervical smears. No, no, no. It's the famous stain that we use on all cytologic specimens from whatever organ we get it from. And the beauty of the stain is that it stains keratin bright red. So please look at this slide, please. Okay, this, let's say I give you a history. It's a patient that's a smoker. He's got a centrally located mass. And this is a sputum sample with stain with tapanicolostain. Is that red? Yes or no? Yes or no? It's squamousylcarcinoma. That's all you need to know. Okay? If I said this is a cervical pap smear from a woman that's 40 years of age, what's the answer? Squamous cell carcinoma. It's in the stain, keratin in the stain, bright red. So it's very easy. You're not colorblind. You will never miss this. It's very, very straightforward. Bright red cells, cytoplasm, squamous because it's keratin. And I would expect you to be expert psychologists and know, well, that's an irregular hyperchromatic. No, no, no, no. They're not interested in making you pathologists. They just want you to have this understanding that a papenicolostane stays keratin a bright red. And that's going to be to your advantage. Look at the bottom one over here. And here we can see these small cells that kind of look like lymphocytes, don't they? Okay? That's why it's called small cell carcinoma, because they're small cells. And it's a little bit more difficult, actually, to diagnose because of the fact that it's sometimes hard to tell them from lymphocytes. Okay? But these are malignant cells. Small cell cancers are the most malignant cancers of the lung. There's No doubt about that. In fact, you don't do surgery on them. You just do radiation and chemotherapy and they're going to be dead in three months. Don't do surgery. Whereas the other ones you do if they fit a certain criteria. So these are the small cell cancers. Remember these are output tumors with neural secretory granules in them.
They can make ADH, ACTH. A slightly less malignant type of output tumor that's also in the lung is called a bronchial carcinoid. It's a low-grade malignancy of the same kinds of cells that produce small cell carcinoma. So they can invade, they can even metastasize, they can produce carcinoid syndrome if they make increased amounts of serotonin. They don't even have to metastasize to do it, it just goes right into the bloodstream. But it's very uncommon, and that's all I have to say about it, actually. The actual most common cancer of the lung is metastasis. Okay? We're seeing here a lung. This is the pleural surface of the lung. And look at all these metastatic nodules in here. We can see a little bit of cancer in here. A lot of this is around bronchi. Some of it's probably in lymphatics. But this is metastatic cancer to lung. If you played odds, what would you say? Breast. Breast is the most common. Cancer, a cancer of the lung. Of the lung. Okay, so metastasis is the most common cancer. Primary adenocarcinoma is the most common primary cancer, followed by squamous and small cell carcinoma. The worst prognosis of all of them, small cell carcinoma. Okay. Horner syndrome or pancoast or superior sulcus tumor. Okay. These are tumors that are usually in the upper lobe posteriorly. So that's usually in the posterior medius sinum. High.. The use most commonly is caused by squamous cancer in that area. And you remember what's happening here is that the tumor is locally invading into the lower part, the lower trunk of the brachial plexus, so you can get some lower trunk brachial plexus types of findings. But then you also could knock off that superior cervical ganglion. That's in the posterior medius thymum. And so you can end up with Horner's syndrome. You're basically knocking off sympathetic activity. And so instead of having your lids up, you lift your legs. And I think you can see it's subtle. Admittedly, it's subtle. You can see that the lid is lower on this side than it is that. You, of course, can't tell that he's not sweating. They'll have anhidrosis on that side. And since sympathetic stimulation of the pupil produces medriasis, it dilates the pupil. And the purpose of that is fight or flight. Remember, you want a dilated pupil to make taking as much light as you can. So if you're destroying the sympathetic, then you get not medriasis, you get meiosis, which is not the same thing as the meiosis in germ cells. It's a different meiosis. You get pinpoint pupils. See, I have problems between meiosis and midriasis, which one's dilated, which one isn't. But then some students said, midriasis, D, D, dilate. So I haven't had a problem since. That's the one I remember. Midriasis, D, dilate them. It's the other one, it's the other one. Works for me, guys. You might think it's crazy, but it actually works. And every student that I teach my students that, right off the bat, boy, I get comments later on. I say, you know, that has really, really, really helped me to remember. Just remember one of two things that always confuses me, and the other one's the other one. I remember P. Anka, polyautorhidus. I mean, C. Anka's Wagoners. Okay, that helps me. I don't fiddle with the, you may like the fact that you treat it with cyclophosphamide, and that goes with C. Wagoners. That's fine. If that works for you, great. That means the other one's the other one. Okay, whatever. All right? Okay, you can't really, if you came up here later, you can probably see. I'll show you how the pupil here is about this big. The pupil here is about that big on that side. So this is Hornet's syndrome. Pancose tumor, superior sulcus tumor. This is the one they like for the obvious reason, neuroanatomy tie-in. Okay, with the brachial plexus stuff and then the superior cervical ganglia. They like that. Do not confuse it with superior vena cava syndrome. That's just blocking off the superior vena cava. Okay, in terms of mediastinum, things I don't have a whole lot to say about it. When we do a little muscle, I'll talk about myasthenia gravis because it does have something to do with the entry mediastinum and that is thymoma and B-cell hyperplasia of the thymus. So we'll save that for then. Otherwise, mediastinal things are worthless. In terms of pleural fluid, you know the difference between an exudate and a transudate. Transudate is less than three grams, hardly any cells in it. Most common cause for pleural effusion due to transidase, heart failure. And then an exudase is a protein greater than 3 grams and has, you know, cells in it. Okay, so things like pneumonias, pulmonary infarctions with effusions, those are exudases. So you already knew that. No reason to go through them again. GI. GI is simple. There is absolutely nothing difficult in GI. Not one thing is conceptually difficult. Well, maybe malabsorption, but that shouldn't be. So it's going to be a picture show. It's going to be just purely a picture show. There's a couple comments here, a couple comments there. We should be able to get through this. All of these things you've heard before. Most of them you could probably get up here and tell me a little bit about them yourself, so it's not hard. Let's start in the mouth and work our way down to the butt. I think that's a good way to go. No, I want to go up on the butt and work in the mouth. Well, that's fine for you. But I'm the one that's controlling things. And I'm a dictator. Okay? And there's no negative feedback on me. Might as well make it a teaching experience. Alright. Diagnosis. Herpes simplex. Okay? Now remember, primary herpes is a systemic infection. You have viremia the whole bit. You have fever. You have lymphadenopathy. Generalized. But then it goes away and stays late in the sensory ganglia. Forever. It's dormant in that sensory ganglia. And every now and then it can come out with stress, menses, whatever. Okay? And will come out and form vesicles in the same spot, but no more systemic. There's no more fever. There's no more lymphadenopathy with recurrent herpes. Don't forget that. Remember, there's other viruses that remain latent. Herpes zoster remains latent also in sensory ganglia, and it can recur from there. So it's always there. It's always there. It can come out any time it wants, involve a dermatome, or in this particular case, the lips, sometimes in the mouth. Okay, so primary herpes is systemic. Recurrent herpes is not. No fever, no liteninopathy. If we unroofed one of these things and scraped it and did a stain, that's called a tank prep. We would see inclusions, which I will show you when we do GYN tomorrow. I will show you what the inclusions of herpes look like. It's a multinucleated cell with internuclear inclusions. Why? Because it's on boards. In fact, they put it in the esophagus, as a matter of fact. They gave a picture of a multinucleated cell that they said was a biopsy from the esophagus from an ulcerated lesion in the patient HIV, and it had multiple internuclear inclusions. So it was herpes esophagitis. That's how they did it. No problem. This is not an AIDS-defining lesion, guys, but it is a pre-AIDS type of infection, as is thrush, as is shingles.
This has nothing to do with dysplasia. This is an infection due to Epstein-Barr virus. Okay, so it's really a horrible choice of words for this because it gives the idea that this is a pre-neoplastic lesion and it's an Epstein-Barr virus infection of the tongue. It can be treated with acyclovir. It is not AIDS-defining, but start seeing this maybe a couple months before their helper T cell count gets to be 200. So we see that commonly as well. This is the real thing. This is thrush. You can see that this is adult, so you know automatically this would have to be an immunocompromised patient with a defect in cellular immunity. There is no way in God's green earth that this is an adult, that this is normal. No way. Kids, of course, very old newborns, commonly get this because if mommy has candida on the way out, the baby picks it up. And, of course, that's not a sign of immunodeficiency. They just picked it up on the way out. You see it in an adult, immunocompromised. It is not an AIDS-defining lesion, but like herilukukaplasia, it occurs with it. This is exudated tonsillitis. Okay, what's the percent chance that this is group A beta hemolytic strep? 30%. 70% chance it's a virus. That's good. You should have that honed into your head big time. Because many physicians, maybe yourselves, when you see exudated tonsillitis, just assume it's group A strep and give them penicillin. Bad, bad, boys will just eat you alive with stuff like that. You've got to prove that's group A strep. You can do it by a latex agglutination test or by culture. You just don't arbitrarily give penicillin thinking that all exudated tonsillitis is group A strep. 70% of the time it's a virus. Adenovirus, F-stombovirus. So most pus tonsils are not bacteria. Now, if this was group A strep, and let's say three weeks later a patient went into a bibasal arrails that had polyarthritis and had a pancestolic mermen apex radiating into the axilla,heumatic fever. Very good. And if I did a blood culture, what would I find? Nothing. Because it's not an infective endocarditis. Okay, this exact picture. These two right up there on the boards, and it was a very unfair question. I couldn't believe it when the student said that was on my test. I said, really? These two tongues are on your test? Yes. I said, what did they want to know? They wanted to know which was invasive cancer. I said, that was bad. That was not good. That would require someone that has a little bit of experience with looking at things like pathologists. That was not fair, but part one. Okay, this fits the concept of leukoplakia. I see a white lesion, okay, it's plaque-like. I would try to scrape it off, and it doesn't come off. That fits the clinical diagnosis of leukoplakia. Boards will always say, what's your first step in management? The answer is always biopsy. That's true in the vulva area or the penis area. You see a white plaque-like or even reddish-white plaque-like lesion on those areas, and it doesn't scrape off. Now, a second-year medical student can get anything scraped off, but, of course, the whole penis would fall off and every other thing. I mean, see, I got it all, so this can't be really bad. Nah, look at that mass of bleeding down there. No, no. I mean, it's just gentle. It doesn't come off. First step in management, biopsy. Why? To rule out dysplasia and or invasive cancer. Okay. The most common cause of squamous dysplasia and cancer, you already know. Smoking, second most common cause. Alcohol, you do both. You increase your risk. This is fun. Okay? Up, down on this one. Okay? Which of these two do you think is invasive squamous cancer? Now, the best thing to do is look at the midline and see if there's any color changes or any shits or anything like that. What is this? Is that just squamous dysplasia? Do you think that's invasive squamous or do you think this is just just squamous dysplasia and not invasive squamous? Which one? What is this? That's invasive squamous cancer. You can see there's a color change. It's red here and it's pale there. Okay, and you can see if you follow the midline, it's curved. It doesn't go straight down there, so you know it's infiltrated. This one has a pretty reasonable straight line, has color changes the same. This was squamous dysplasia. That was invasive cancer. And that's what they wanted you to know on part one. So it's the one on the left. Okay. All right. Okay, this is the lower lip, guys. Diagnosis. Squamous. Let's put this on the upper lip. Diagnosis. Basal cells. Very good. Is chewing tobacco cause cancer? Sure. Verrucus carcinoma. And for crazy reason, it seems to have a human papillomavirus relationship, too. We had an 18-year-old in Oklahoma that died of disseminated squamous cancer because he was chewing tobacco at six years of age. We're redneck country in Oklahoma. That chewing tobacco was like chewing gum. I mean, it's just spitting all over the place, out the windows, on your windshield. It's just unbelievable. We call them rednecks. You always know a redneck when you have a pickup truck and in the window in the back you see a compound bow and a gun. That's a redneck. That's a redneck. Compound, you know, fighting. Okay? If you checked inside, there'd be knives and all the kinds of things in there. Never stop a redneck. Because you'll get an arrow through your head and there was something like that. I mean, they are big time something. And they go 90 miles an hour this far away from each other. Cars. And you just kind of stay out of the way and let them kill themselves. That's all you do. All right. Hyperpigmentation, hyperpigmentation, diagnosis. Addison's disease. Addison's disease. That's diffuse pigmentation in there. That would be Addison's disease. Low cortisol levels, ACTH. ACTH has melanocyte stimulating properties. The very first place you see the hyperpigmentation is buccal mucosa. You got it right there. What's this place? Puchetakers. Notice that the hyperpigmentation here is just splotchy, splotchy. Just little areas of hyperpigmentation. Not diffuse. not diffuse. This is Puch-Jakers right here. Puch-Jakers. Now, where are the polyps? Tell me where the polyps are. Exactly. Small intestine. That's actually one of the exceptions to the rule for polyps in the small intestine colon. Most polyps in the entire GI tract are located in the sigmoid colon. But the polyps of the Puch-Jagers in the small intestine and their hematomas, which means they're not neoplastic, which means that their ability to change into cancer is about zero. So there is no cancer relationship with Puch-Jagers. This picture's been on many, many exams, as has this one. Of course, it'll give you a little bit more history than just me saying, what is it? Diagnosis. Mumps. Mixed tumor. Another name for a mixed tumor is a pleomorphic adenoma. Is this a teratoma? No, it's a mixed tumor. It's got two different types of tissue, same cell layer. It's the most common salivary gland tumor overall, and it's in its most common location, parotid. This is mumps, okay, paramexovirus. I want you to tell me what enzymes elevated, please. Amylase, very good. Is the incidence of orchitis high? No.
No. It's because it's unilateral most of the time. If it was bilateral, then it would be a much greater chance, but it's unilateral. Usually in older, like teenagers or adults, men, that get mumps, they're more likely to get orchitis. Can women, can you get oophoritis with mumps? Yes, you can. And just like in males, it's more commonly unilateral than bilateral. Okay, so infertility is not usually a problem with mumps. Although they will put it down oftentimes in an infertility question in terms of, you know, risk factors. That would be way down the list. Way down the list. All right, I want to make sure you understand the term dysphagia. Okay? And odynophagia. Now, they don't actually use this term dysphagia on the stem of the question because it's kind of giving it away. They'll just say difficulty with swallowing. And that's what it means. Now, listen carefully. I'm telling you, and I mean it, because I've studied sample board questions for years to see clues. And I circle things and I say, I already know what the answer is based on this. Okay, most of the time, on one side of the long, there's at least five to six clues on what the answer is. And so it's just a question of which one it is. Okay? They give the answer away, guys, if you know these kinds of things I'm telling you right now. If they say that a patient has a problem with swallowing foods, what is it to? Solids and or liquids. If it's just solids and not liquids, it's an obstructive lesion. Something is obstructing the food from going down. What? Esophageal web, Plummer-Vincent syndrome. That's an iron deficiency anemia with chelosis, glossitis, and an esophageal web. That would be dysphagia for solids but not liquids. Cancer. If you have an esophageal cancer, you will have dysphagia for solids but not liquids. But if they say that the patient has problems in swallowing solids and liquids, it's a peristalsis problem, guys. It's a peristalsis problem. That's very bad. Of course, everything's bad, pretty much. If it's up here, then it's myasthenia gravis. Because as you know, myasthenia gravis affects striated muscle, and you know that the upper one-third of the esophagus is striated muscle. Okay, and then the middle one-third, combination of the two, lower one-third, pure smooth muscle. And so the lower causes of dysphagia for solids and liquids are things like scleroderma, which is better termed as progressive systemic sclerosis and Kress syndrome, and achalasia. So right off the bat, they will tell you basically what the answer is by telling you that this patient can't swallow liquids and solids. I mean, it's clearly a peristalsis problem. It's just a question. Is it up here that it's getting stuck or further on down? Up here, myasthenia. Down here, PSS, Crest Syndrome, or achalasia. How are you going to separate them? An achalasia, when they go to bed at night, they vomit up the food they ate. Classic history. You don't have that with scleroderma, Crest Syndrome. It will give you the you the other things like rainouts and other things. That will tell you it's that. It's very important. You can differentiate things. Boom. Right on down there. Palpable purpure. Small vessel vasculitis. Immune complex. Type 3. OBS and not sure why it's purpure. Most common. That's the one they're going to do. These just think boom. Epistaxis. Platelet problem. I'm not going to think hemophilia. Are you following me? Giveaways. Absolute giveaways. Physical diagnostic findings. Say the pan-systolic murmur increases intensity on inspiration. That makes it tricuspid regurg. Okay? Expiration. That makes it mitral regurg. Simple little things like that. They put in there that you kind of breeze over with the breath of your life and you say, well, okay, that has nothing to do with it. Oh, yes, it does. It just gave you the diagnosis. Okay. Odinophagia means painful swallowing. That's always abnormal. What's the most common cause of odinophagia in an HIV- patient? Please. Candida esophagitis. Is it AIDS defining? Yes. Candida is the most common fungal infection in HIV. And when it gets in the esophagus, that's AIDS defining. When it just produces thrush, that's a pre-AIDS lesion. That's not AIDS defining. Candida esophagitis is the most common. So adenophagia means painful swallowing. Now I'll just show you pictures. Can someone focus this? I don't know where it's at. It's a little out of focus over here on this side. If you can make that clear, then I think everything will be clear. There we go. Thanks. Well, it's close, I guess. This was a piece of paper, so it got folded a little bit. Key fistula, tracheoesophageal fistula, always asked, always asked, always asked, some embryology type of thing. You don't need all four types, you just need to know the most common one. So in the tracheoesophageal fistula, what happens, you have a blindly ending esophagus. And the proximal esophagus ends blindly. Okay? But the distal esophagus arises from the trachea. That's weird. What does mommy have? Talk to me, because that's a board question. Polyhydramnios. Now remember, amniotic fluid is baby urine. They have to pee just like you do right now. Okay? So they have to pee. That is what amniotic fluid is predominantly. It's baby pee. Okay? So you have to have some way of recycling it or mommy's going to have a pretty big belly there. Okay? And so they swallow it. And it's reabsorbed in your small intestine. So if you have obstruction in your esophagus or proximal portions of your duodenum, you will have, mommy will have polyhydramnios. So of course you know the two answers. One is TE fistula, and the other one is duodenal atresia and Down syndrome. Those are the two associated with polyhydramnios. Because they would block the ability to reabsorb the amniotic fluid polyhydramnios. See? Also these kids, when they eat, when they have a drink for the first time, the food gets in here, and they can't go any further, and it refluxes out, gets in the trachea, they cough and sputter. Because of distal esophagus, it rises from the trachea, they have distension of their stomach. It's a very, very characteristic thing. Part 2 deals with Vater syndrome, V-A-T-E-R, part of which has tracheal esophageal fistula. They get into the syndromes on Part 2, not 1. This is the Zanker's diverticulum, right over here. What chord is this, please? False. What about this? True. What's that? Epiglottis. What's this? Diverticulum. What's the area of weakness there that causes diverticulum? The cricopharyngeus muscle. There's a little slit in between the fibers of it. And so mucosa and submucosa. Not the whole thing. That's a true diverticulum. This is a false diverticulum. It goes out and you get this pouch. And of course you collect things in this thing. You get halitosis. You probably go like this. And everyone would die with that. It would be so bad. They have a tendency of regurgitating things and when they do it comes out the nose. That's horrible. So it would be this undigested food coming out of their nose.
You run. You just run. You just run. Now I would like this.. Now, I'm going to tell you why. Because you can control it, too, because you know that you can control the food that's in there. So let's say you have a delicious breakfast. And so you just shunted some of the food into there, okay? You're hungry, and you need a little bit of a snack, okay? So you can just go, and it just comes out, and you have food. Okay, nice and warm. What do you think about that? That got some of you awake with this hot temperature. Okay. Only pathologists can think of things like that, because we think that that's extremely funny. Achalasia. Achalasia. Achalasia, remember, is a peristalsis problem. It's a problem with the failure of relaxation of the lower esophageal sphincter. Okay. So it's a spasm all the time. Is that correct? Why? Because if you biopsy that area, you see that the ganglion cells are missing. Does that remind you of some other disease? Hirsch-Bruns. Ooh, that's interesting. And what was in those ganglion cells? Vaso-intestinal peptide. Ooh, maybe that you didn't know. Because you probably thought VIP was a very important person when they discussed that in GI physiology, didn't you? No, that's vaso-intestinal peptide. And guess what its function is? To relax your lower esophageal sphincter. And so when you destroy those ganglion cells, not only do you destroy the movement of the lower esophagus, but you also reduce the VIP levels, and so you have constant constriction of the lower esophageal sphincter. And so what happens is you get a bird's beak type, and this almost looks like a bird's beak. Maybe it rammed into a wall and it's kind of a little flattened, the beak. But whatever, it kind of comes down like this, the esophagus, like that when you do a barium study. Okay, and the proximal portion is dilated, and you get this beak-like appearance. And that's classic achalasia. Okay? So it's the peristalsis problem, the stage of the solids and liquids. Okay, I'm going to play a game with you and see if your parasitologist did a good job. There's a disease in South America where the leishmanial forms can invade the ganglion cells of the lower esophageal sphincter and the rectum and produce acquired achalasia and acquired hearth sprungs. Name me. Chagas' disease. Vector, please. Redubit bug. Another name. Kissing bug. Very good. What's that swelling of the eye sign? Romanos. Okay, what does it do in the heart? It produces myocarditis and chronic heart failure. In fact, congestive cardiomyopathy. I left that one out. and it's one of the more common causes of heart failure in South America, shock assist disease. Okay. You've seen this already, okay? Did you? You did. When we talked about what? Barrett's esophagus, okay, this is all ulcerated, mucosa in the distal esophagus here. This is not. Little tongue, little island. Here's Long Island. This is the ocean. Okay, that's all the areas of ulceration. We biopsy along there. What do we see? We see metaplasia. We see glanular metaplasia. We see goblet cells and mucous cells, which shouldn't be there. But they're there because the esophagus can't protect itself from acid injury. Okay, and then what risk do we run? Adenocarcinoma. Of what? The mid-esophagus or distal? So they're talking about a lesion. They're talking about the stage of a solace but not liquids. Okay? And they say that a lesion is noted in the distal esophagus. Don't pick squamous cell carcinoma as a cause of that, guys, because that's an admitted esophagus. If it's distal, what is it? It's an adenocarcinoma. What's the precursor lesion? Barrett's esophagus. Very good. All right. Excellent. Okay. Esophagus. What is that? Veins, guys. Veins, guys. Veins, guys. Veins, guys. What is it? Esophageal varices. So who's the patient? Cirrhotic. Who was? Who has? Cirrhosis and? Portal hypertension. I don't want to know the name of the vein. Left gastric vein. Left gastric vein. Now, if you didn't know that, you better go back to your anatomy notes that Seiden wrote and check the portal vein out. You'll find out that one of the branches right of the portal vein, right before it goes into the liver, is the left gastric vein. You'll find out that that drained the distal esophagus and the proximal stomach. What drained into the left gastric vein? The azagus vein. That comes from further on up, drained into the left gastric vein, which drained into the portal vein. But because of cirrhosis, the portal vein can't empty as blood as efficiently into it, the hydrostatic pressure increases and you reverse blood flow into the left gastric vein, splenic vein, and other veins, and you end up producing varices, which rupture. What's hematemesis? Vomiting blood. What's hemoptysis? Coughing up blood. What's hematocysia? Blood. Blood. Pouring out of your anus. That's not the same thing as blood-coating stool. That's internal hemorrhoids. It's actual dripping of blood coming out. Anybody happen to know the most common cause of that? Diverticulosis. Not itis. Osis. Why not itis? Because the vessel was right next to the diverticulose sac. So if it was itis, it would be scarred off. But osis, it's intact. So all you've got to do is erode it. Voila, 600 ml bleed. Make sure you know those terms. Okay, so that's esophageal varices. What's this? It's a tear right at the esophagogastric junction. What's that called? Tear. Mallory Weiss. Let's say this is a young lady. Play odds. Not anorexia. Come on. Bulimia. There you go. Bulimia. Okay? But, you know, usually the classic thing that we all learned in pathology was the alcoholic with retching. Now, you know what retching is? Retching is beyond vomiting. Retching is when you go, and nothing's coming out. Tremendous pressures. So you can tear, have hematemesis, or you can puncture. Borchardt syndrome. That's when the air starts getting into and all the crap gets into your pleural cavity. It starts dissecting up the air, and get Hammond's crunch and the intermediate Stein, that's Borhoff's. So you can see this in bulimia and I believe that's the route they're going now because of the eating disorder thing being so high. They're going to do Borhoff's in the context of a bulimic more so than a retching alcoholic because they know that that would give you a tip-off. You may not necessarily be thinking about a bulimic. Okay. Can we just focus this back? I think we made a little... I know that this does better than that. That's worse. Do it the other direction. How about there? Okay. This is esophageal cancer. This is squamous. Okay? That's not the distal esophagus. That's the metasophagus there. In fact, the distal esophagus would be down here. This is squamous cancer. Okay? Over here. And so what would the most common cause of that be, please? Smoking, second? Alcohol. Very, very good. What do you think the dysphagia would be initially?
So here's your board question. 50-year-old man who's an alcoholic has problems with swallowing food but not liquids. Okay? And they say that he has weight loss. Diagnosis? Esophageal cancer. Playing odds, squamous cell carcinoma, and menosophagus. That's the exact question. Straightforward, no problema. That means no problem. Boy, you really know your Spanish. I do. I'm just very good at it. Uno, two-oh, three-oh. See, I'm very good at it. Four-oh, five-oh. It's funny. I did that one. I just did it without explaining it. I'm goofing around. I had a whole pile of Spanish-speaking people. Now, Dr. Goy, this is the way it is. Uno, whatever. I don't even know what it is. Dos, tres. And I said, I know. They thought I really thought that that was speaking Spanish. It's really funny, actually. Now, they like this, guys. You want to know why? Because it's kind of like the CT MRI thing that they're going to get. I know one person, and I don't, you know, students have a tendency of exaggerating when they take this test. And I had 50 CTs, MRIs, and schematics for my anatomy questions. I think that's probably pushing it. But, you know, they like cross-sections and stuff like that and identifying structures structures. So if I were going to do esophageal cancer, I wouldn't use this one. I'd use this slide. Why would I do that? Because I want to see if you know what's what. What's that? That's the, what is it? It's the trachea. You can see the cartilage rings right there. Okay? So what's this? That's the esophagus, and what's this? That's an elastic artery. Okay? So the esophagus is right in that middle between the two, and you can see that's completely surrounded by white-looking stuff that seems to be going out there, going out there. It's esophageal cancer. That's the one I've used on boards. This picture is a known pathology slide, and this picture has been on boards. This one's too easy. This is the one they do. Okay. This kid, and this is not the treatment for this. This kid is a male, and at three weeks of age, started vomiting non-biostain fluid. You palpated the abdomen. You felt a little knot in the right upper quadrant area. And you looked kind of at the, looked across and looked and you could see hyperperistalsis. What's your diagnosis? Congenital pyloric stenosis. Now notice I said non-biostain vomit. Notice I said three weeks. Now whatever was due to an atresia and a Down's kid? Okay, that would be at birth, vomiting of bile-stained fluid. Okay, and then you have the so-called double bubble, son. You ever wonder what that double bubble was? I did for a while. Double bubble, what does that mean? Well, the atresia, the lack of development of the lumen, is distal to where the bile duct comes in. It's distal to it. And so, in other words, bile can still empty into that proximal portion of the duodenum. So that's why it's bile-stained. And because there's no movement of anything, there'll be air trapped in there, and then, of course, there'll be air trapped in the stomach. Okay, and so that will look like a bubble in the stomach and a bubble in that proximal duodenum double bubble sign. So one's in the stomach, one's in the proximal duodenum compendiae. And also mommy will have polyhydrandials. Okay, so don't confuse duodenal atresia. It's not even remotely the same as the history of congenital pyloric stenosis, which has no relationship to Down's. It does have multifactorial inheritance, so it can be increased in future children, yes. Here's the pyloric stenosis right here. You can see how thick the muscle is. What they usually do is they put a little slit in the belly button, go in there, and just split the muscle. It's called pyloroplasty. That's the end of it. It just opens up. These are what nonsteroidal ulcers look like, or NSAID ulcers, which our friend Trevor probably talked to you about. Remember, the nonsteroid ulcer will block PGE2, which is responsible for the mucus barrier of the stomach. Ulcer is responsible for vasodilatation of the vessels, mucus secretion, and the secretion of bicarbonate into that mucus barrier. So when you take nonsteroidals for any period of time, that whole thing is destroyed. Okay, destroyed. And so you are just sitting duck for ulceration to occur. Okay, and these are little multiple ulcers. Over time, you can get significant blood loss from these things. Now, these ulcers are usually not very deep, maybe just a little bit through the mucosa, maybe a little bit into the lamina propria, but they're nice punched out things all over the place and they can cause some bleeding over time. This is our little friend Helicobacter pylori. Notice that that's a silver stain, so here's another silver stain. So we have Deedle-E silver stain, Legionella, silver stain, pneumocystis, silver stain, Bartonella hensleyi. Okay, now we have silver stain H. pylori. Now a good pathologist doesn't need one because they can kind of, they're good at picking up things and they can see them without any special stains. Just a plain old H&E. But you can see they're little comma-shaped organisms. That's why they initially thought they were campylobacter, because campylobacter is, you know, a comma-shaped organism. But later they turned out that they really didn't have the same cell wall stuff, so now they call them helicobacter pylori, as opposed to campylobacter pylori. These are nasty, nasty little dudes. Why? They make urease and lots of cytokines. The urease, of course, is going to convert urea to ammonia, and that's one of the main reasons they can burrow through that mucus layer. Ammonia is very toxic, as you know, and that's because it's a urease producer. And that's the way, that's the test that we make use of when a GI person takes a biopsy of the mucosal stomach, we do a urease test on it. And if it's positive, then we know helicobacter is present. Also, you can use serological tests, but that only works the first time. Okay? Serologic tests are outstanding. The antibody is against it, but they don't go away, the antibody, so you can't diagnose recurrent disease. It's great for the first time, but after that, it's useless because if you already know they had previous infection, of course it's going to be positive, so it doesn't tell you dork. Now, we want to make sure that you understand where H. pylori is working. That's why I made a big deal about the parietal cells when we're talking about pernicious anemia and telling you that it was pylorus and fundus, body, not pylorus, fundus and... Body and fundus. That's where the parietal cells, they're getting destroyed by the autoantibodies against them, an intrinsic factor, and you get an atrophic gastritis in the body and fundus. That's not H. pylori country. H. pylori country is pylorus antrum. Okay, and it destroys that mucosa, produces an atrophic gastritis of the pylorus and antrum. And that's where cancers are. Remember, most cancers are along the lesser curvature of the pylorus and antrum. That's the exact same place where gastric ulcers are. It's the exact same place where gastric ulcers are. Exact same place where gastric ulcers are located, the lesser curvature in the pylorus and antrum. So this is today's pylori over here, notice it's living in the mucous barrier.
Not the most common cause, but it can do it. But it's low-grade. I'm going to show you two ulcers here, guys. Gastric duodenal. Why don't we ever biopsy a duodenal ulcer? Because they're never malignant. So I'm going to ask you a question. Is that benign or malignant? How many say it's benign? Nobody. How many say it's malignant? Nobody. I guess you don't think it's a gastric ulcer. You think I'm lying. You think I'm kidding, don't you? What I wanted you to say is that it's benign. Okay, then I would say, how do you know? See, the only reason they biopsy a gastric ulcer, guys, is because they're trying to rule out whether it's cancer or not. They know it's an ulcer, so they don't have to prove that it's an ulcer. They just basically biopsy it because an ulcer like that has a 3% chance of being a malignant ulcer. So the only purpose of biopsying a gastric ulcer is to see if it's malignant versus benign. But you never have to biopsy a duodenal ulcer because it's never malignant. So you just leave them alone. Why run the risk of a bleed? The more common association of helicobacter pylori with peptic ulcer disease is duodenal ulcers more so than gastric. Why do you get melanoma with upper GI bleeds? Upper GI bleed, by the way, means anything that's a bleed from the ligament atrites. That's where the duodenum hits the jejunum up. It's considered upper GI. Why is it black? Answer. Acid acts on hemoglobin and converts it to hematin. And hematin is a black pigment. So that's why you get melanin. That's why it's so important to know that because if you have black tarry stools, then you have a 95% chance it's an upper GI bleed. And if you play odds, it's duodenal ulcer or gastric ulcer. Understand? Okay, so melanin, I mean not melanin, the black tarry stools is due to the conversion of hemoglobin from the bleeding by acid into hematin, which is the black pigment. Don't forget that. That's a board question. You ever hear of vomiting of coffee ground material? What that basically is is blood clots that have been acted upon by acid changing into hematins, so it does look like coffee grounds. But it ain't. I tried it. It was very, very terrible. That was a joke. I guess that was not good, some of you. I got only people that laughed, probably pathologists. Okay. I have nothing more to say about these ulcers, septic ulcer disease. Oh, yes, I do. Got a patient, executive, under great stress, has some onset of severe epigastric pain, which radiates into the left shoulder. First step in workup, the patient, please. Flat plate of the abdomen, because he has a perforated ulcer. Odds, duodenal. Why do they have shoulder pain? Because air got out, it settled under the diaphragm, irritated it, which is the fourth nerve, and you got referred pain to the shoulder, which shares the same dermatome. Classic board question. So your first step in management is to do a flat plate because 85% of the time you will see air under the diaphragm. That's a part one and part two board question because they wanted to get into that referred pain thing, knowing about dermatomes and phrenic nerves, C4, and dermatomes and where it can spread. Okay? All right, let's break.
From the JAMA Network, this is the JAMA Medical News Podcast, discussing timely topics in clinical medicine, biomedical sciences, public health, and health policy, featured in the Medical News section of JAMA. Welcome to the JAMA Medical News Podcast for September 2021. I'm Becky Voecker, Director of Medical News, and joining me today are two of my colleagues. I'm Jenna Bossy, Associate Managing News Editor. And I'm Rita Rubin. I'm a senior writer. Today, we're going to talk about three stories that we've published in the medical news section during September. The first one is very timely as we're heading into October now and an optimal time to get flu shots. This story deals with what we might expect for the coming flu season. This is one of Rita's stories. So, Rita, fill us in, please. Sure. Well, it was about a year ago that I wrote a story about people's concerns that we were going to have a twindemic flu season wrapped up in a COVID-19 pandemic. It never materialized. In fact, deaths and illness from influenza worldwide plummeted. I mean, influenza flew out the window instead of in the window. I mean, just for comparison, the previous flu season before the pandemic started, 22,000 Americans died of influenza, according to CDC estimates, 22,000. This past flu season, 748 deaths were coded as influenza. Both those numbers are probably underreported, but still you can see the dramatic difference between the two. A lot of people theorize that we had basically no influenza this past flu season because of all the mitigation measures for COVID-19. And so there's concern that, oh, things are loosening up, kids are going back to school, international travel's resuming to an extent. It's going to be a bad flu season. The problem with that is it's not clear how much those mitigation measures contributed to the practically non-existent flu season. In Japan and some other Asian countries, people have traditionally worn masks out in public. Usually they wear them because they're sick and they don't want to infect other people. But you know what? I talked to an epidemiologist in Hong Kong who said there's really no evidence that Japan has had less influenza because of the mask wearing. So it's a puzzle. Rita, if we had hardly any flu last year, could that affect the severity of flu in the coming season? Really, no one is sure. You know, on the one hand, flu basically wasn't circulating. And, you know, and again, you know, in Australia is already into the or near the end of its second flu season during the pandemic, and again, saw little influenza. So it could end up like that in the US, or there are concerns that, okay, the mitigation measures have really been relaxed compared to this past winter. That could mean a worse flu season. You know, another factor that could mean we're going to get a bad flu season. Anything would be worse than this past flu season. But the fact that there is basically no herd immunity, no one was exposed to influenza during the past year. And so it's unclear whether that means we're going to be more susceptible. I think the bottom line is it means we to manufacture all the millions and millions and millions doses of influenza vaccine. It could mean that the vaccine is not going to be a good match. I mean, even the WHO pointed out that it had, obviously it had less data to go on. There just wasn't as much influenza circulating in the southern hemisphere, anywhere in the world. And so they just didn't know, okay, so are these the strains that are going to be affecting the northern hemisphere? I mean, on the other hand, one person I talked to for this story said, well, there's also the possibility because there was so little flu circulating, we may have just identified all the strains that were circulating. And even the WHO, I think, pointed out that there were some new influenza A strains identified. And so it's not like the flu shot for this coming flu season is exactly the same as it was for the previous season. It was updated. Even in like the years where influenza vaccine is not a good match, because it happens, the vaccine still prevented millions of cases of the disease. Thanks, Rita. Our next story is by one of our freelance writers, Bridget Keene, and it has to deal with farm workers who are exposed to outdoor temperatures that are rising because of climate change. And these workers are experiencing heat stress and other problems because of their exposure to the extreme temperatures. Some efforts are underway now to have OSHA, the Occupational Safety and Health Administration, develop a rule for farm owners to take measures to protect these workers. Jen, tell us about some of this story. Yeah, so Bridget's piece, as you mentioned, is about those growing risks to farm workers and potential legislation and workplace solutions to mitigate those risks. So some background. Heat-related worker illness, injury, and death are rising as the U.S. increasingly faces higher than normal average temperatures and more extreme heat waves. So between 1992 and 2019, more than 900 U.S. workers died and almost 80,000 were seriously injured because of extreme heat exposures. And during that period, the three-year average number of worker deaths from heat doubled. Without mitigation, the number of days workers are exposed to extreme heat could double by the middle of the century, according to projections, and they could triple by the end of the century. Now, as some of our listeners may remember, temperatures in Oregon reached 117 degrees this summer during record-breaking heat waves. And by mid-July, there were already more than 100 heat wave-related deaths in Oregon. That state enacted a temporary rule that focuses on access to water, shade, and rest, as you mentioned. And Oregon and other states are also working to pass permanent heat protections for workers. Washington State, California, and Minnesota have already done that. There is an act called the Asuncion Valdivia Heat Illness and Fatality Prevention Act, proposed in May, that would create a national standard requiring paid breaks in cool spaces, access to water, time limits on heat exposure, and emergency care for workers with heat illness, which is something that the farm worker the act is named after did not receive. And a coalition of advocacy organizations and legislators is pushing OSHA to adopt a national heat standard for workplaces. Some good news is that OSHA will begin seeking information next month as a first step towards that sort of rulemaking. It's essential, though, that the process for developing a standard moves quickly and that the standard is enforceable. Thanks, Jen. Besides the obvious illnesses that workers develop like heat stress and heat stroke, the piece also mentions a link between these long, hot days and kidney function. Could you tell us a little bit about that? So heat stress and dehydration have been linked with acute kidney injury in farm workers. A study found that 12% of 283 summer agricultural workers in California developed acute kidney injury over the course of just a single day's work. And then also in a report about agricultural workers in El Salvador, the Pan American Health Organization linked kidney dysfunction with heat stress. But it's too early to say definitively that a similar phenomenon is affecting U.S. workers. The report did cite evidence that interventions to provide water, rest, and shade could prevent kidney damage. Now, physicians can do their part to prevent heat-related health problems by asking patients about the kind of work they do and discussing risk factors and strategies for preventing heat stress for those who work in hot conditions. And arriving to work hydrated is one simple piece of advice that physicians protecting the migrant workers. That's right. So a study in California found that about 7% of workers on farms that met California's standard still had an elevated core body temperature at the end of their shift. So there are lots of ideas of what more can be done. For example, employers should be monitoring workers for heat stress, helping them acclimate to the climate and advising them about how to dress appropriately for the heat. Some farms are experimenting with things like having shorter work days, earlier starts, or harvesting at night. But it's also important to change the way workers are paid to provide a minimum wage and overtime. Some workers are paid by each piece of fruit they pick, which incentivizes them to work harder, skip breaks, and to work on scorchingly hot days. And then there's some other interesting ideas like if bathrooms are too far away, workers may drink less water to reduce the time they're spending going to and from the bathroom. So some growers have tried to solve that problem by having a mobile toilet that travels with them as they move. And then other growers in California are using a slow-moving shaded trailer to protect workers from the sun, which seems like a neat idea.
So researchers have also looked at interventions to improve housing for them so they can cool down in the evening. And of course, these protections are super important, but the elephant in the room is that larger structural changes are ultimately needed. And of course, that means mitigating climate change. Thanks, Jen. This is such an important issue. These are the workers who provide food for the country, and they deserve much better working conditions. Absolutely. Our next story is one of Rita Rubin's. It deals with some of the after effects that patients in the intensive care unit may experience. These symptoms result from some of the traditional ways that patients are cared for in the ICU. Rita, tell us about this. Yes, Becky, I had the pleasure of talking with Dr. Wes Ely from Vanderbilt, who's really been a pioneer in helping to improve ICU care. And what I found so fascinating talking with him was about how the COVID-19 pandemic really set back progress that had been made in ICU care and in reducing patients' risk of suffering long-term effects from being in the ICU. We've all seen the stories and seen videos of ICUs, especially at the beginning of the pandemic, when no visitors were allowed, a lot of patients were heavily sedated, they were on ventilators, and those are factors that really can contribute to the likelihood of long-term mental health and physical health problems related to being hospitalized in the ICU. Rita, have the experts estimated about how many patients in the ICU will develop PICS? Well, yes. And let me explain what PICS is. It's P-I-C-S. It stands for post-intensive care syndrome. And, you know, it's just a whole constellation of problems. Dr. Ely told me that at least a third to more than half of patients will end up with PICS. And that consists of such problems as dementia, post-traumatic stress disorder, and depression. But not only that, because they're lying in bed, often on a ventilator, they're not getting up and moving around. They also can be left with long-term muscle and nerve disease. So that makes them unable to even climb the stairs. So it's pretty tragic. So Dr. Ely and colleagues developed a protocol for ICU patients. Can you tell us more about that protocol? And I was particularly interested in the family component and why that's so important. Yeah, Dr. Ely helped develop what's called the A2F bundle. And that stands for the six components, A, B, C, D, E, F. And they each stand for a different area of managing people in the ICU to prevent long-term problems from their stay there. For example, A refers to assess, prevent, and manage pain. C is choice of analgesia and sedation. And F is maybe what, you know, he considers to be the most important, and that's family engagement and empowerment. And that's why he viewed, especially in the early months of the pandemic, that COVID-19 really set back progress that had been made. Dr. Ely said the ICU can be the great depersonalization zone because these patients are admitted, they may be sedated immediately and their wishes aren't known. Or even who they are as a person can't be known because there's no family member there to talk about the patient with the people providing their care. Thanks, Rita. It's good to know that there are experts working on this area. Just a special note, Jenna Bossy and Shelley Steffens produced a terrific two-part podcast about the health problems that firefighters and others who volunteered at the World Trade Center after 9-11 are still experiencing. The firefighters, the volunteers, and everyone who contributed to cleaning up the site was exposed to a toxic stew of dust and dirt and chemicals, and they have had health effects because of it. This is a very moving podcast, both parts. And in addition to our 9-11 podcast, there is also a podcast from Rita's discussion with Dr. Ely. So please tune into that one too. You can find these podcasts and all of our others at jamanetworkaudio.com. Again, I'm Becky Voecker for JAMA Medical News. I'm Jenna Bossy. And I'm Rita Rubin. Thanks for joining us and please tune in again next month for our stories in October.
I'm Rachel Gottbaum, and I'm interviewing Dr. Michael Osterholm. He's director of the Center for Infectious Disease Research and Policy at the University of Minnesota. He's written a prospective article in this week's issue of the New England Journal of Medicine about preparing for the next flu pandemic. Dr. Osterholm, why do you say that another flu pandemic is inevitable? Influenza pandemics among humans are like the seasons. They come and they go. For example, over the past 300 years, there have been at least 10 pandemics of influenza, or the situation where a new influenza virus emerges out of the bird population, gets into humans, and spreads around the world. So it's inevitable that we'll have more pandemics in the future as we've done nothing to change that basic system of the influenza virus moving from birds to humans. Now, you talk about this H5N1 virus, and I'm wondering what are the similarities between this strain and the strain that killed millions of people in 1918? The H5N1 virus is one that emerged into Hong Kong around 1997 out of the bird population, likely in the adjoining Gundong province in China. Over the past eight years, that virus has continued to emerge in the animal population. And when I mean by emerge, it has continued to change. And now the way this virus is actually affecting birds and humans is one where it actually not only attacks the human lung cells and other cells in the body, but that it also induces an immune response of the host that is almost what we call an autoimmune-type disease. This is exactly what we saw in 1918. In 1918, 1919, the pandemic that swept around the world killed about half of its victims in the age group of 18 to 40. And this is what is the so-called cytokine storm? A cytokine storm occurs when some agent, usually an infectious agent, basically induces this out-of-whack response. What happens with the cytokine storm is that the body's immune system overreacts. It sets off the immune system in a very robust way, and that in itself is what ends up attacking the host and causing the actual cell damage and ultimately the death. The initial data that we have from Southeast Asia, both clinically, epidemiologically, and laboratory-wise, all support that this virus is killing its victims, in many instances, from a cytokine-type-like storm, and that, in addition, the number of cases that are occurring, particularly in young, healthy adults, where they have this very rapid onset of what we call acute respiratory distress syndrome, or ARDS, which is the result of that cytokine storm, parallels very much what we saw in 1918, 1919. Well, you talk about this worldwide Manhattan Project to deal with a pandemic. Are we seeing examples of this Manhattan Project happening? Unfortunately, in a period of roughly the last 20 years, we've only made a very limited impact on really increasing international production capabilities. Yes, we're vaccinating more people in this country. We're vaccinating more people in Canada. We're vaccinating more people in Europe. But it still is a very, very small amount. On an annual basis right now, we can produce, with all of the equipment running at high speed, about 330 million doses of the current influenza vaccine. That is far short of what we'd need to vaccinate the 6.5 billion people on the face of the earth. And unlike certain vaccine problems like we see with HIV, where the technology is just not there yet to actually create a vaccine that is effective against the HIV virus because of a lot of unique characteristics of that virus. We believe that we can actually technologically make a very efficacious vaccine for influenza that can be very different than the one we use today. We just haven't invested in that. This has basically been, you might say, the stepchild of all the vaccines of the world. And yet, ironically, this particular risk of pandemic influenza poses, I think, the single greatest infectious disease catastrophic potential of anything that we could imagine. Why are we still using a 1950s technology to make this vaccine? People have not seen it as a lucrative market in the private sector pharmaceutical industry. We have to change that. Even if it means public resources, we have to pay for this surge capacity. What company is going to build multiple plants for suddenly making 6.5 billion vaccinations for the world when on an annual basis they may only sell 500 million to a billion? They won't use that excess capacity year in and year out, and so it's a waste of their money. It's part of the global just-in-time economy, the idea of minimizing any kind of capacity that's not routinely used. Now this takes more of what I would call a public issue concern. We've got to invest with the private sector in this kind of capacity, even if it means we have to pay for plants that never operate but once or twice in a decade. Should we be stockpiling antivirals? And if so, which ones? Is that the same idea there? We clearly need to stockpile much more in the way of antivirals for influenza. We today have a limited number of treatment doses of the antiviral that would be hopefully effective against this virus sitting in a stockpile in our federal government. We don't have a plan yet for who's going to get that. It'll be a very small number of people. When will they get it? Why will they get it? I don't want to wait until we're in the middle of the crisis to figure out who should get that limited amount of antiviral drug. We need those plans now. But if we were able to one day get to the point of having a safe and effective vaccine that could be actually supplied quickly to the world's population, that would begin to mitigate a lot of the other concerns that we have. If we look at what happened in 1918, and there are reasons to believe that it could happen all over again, we could see a 1918-like situation. And there, if you look at today's population, based on the number of people that died in 1918, we could expect to see up to 1.7 million Americans die of influenza. Remember, half of them healthy people, 18 to 40 years of age. And on a worldwide basis, that number could rival anything we've seen anywhere before, and well up into 180 to 360 million. Remember that HIV-AIDS, as horrible as it has been, has killed only 40 million people in the last 25 years. So you talk about the Manhattan Project, you talk about this blueprint. What needs to happen so that we don't see this worst-case scenario that you're talking about? Well, first of all, we have to again take a step back and say it may be too late. We may already see this scenario unfold. If tonight, next week, next month, next year, the next few years, we see a pandemic emerge, we're just basically going to try to get through. Our hope is that if we can still buy some more time, and given the current H5N1 situation in Asia, that's a real critical question. Can we? But if we can, we need to have the international leadership, bold and decisive leadership, that says we're going to invest in this, much as our country did in the Manhattan Project in World War II, to say we will work with other developing world countries, we will work with private sector organizations, and we are, as our goal, going to set the standard that we want to be able to make 6.5 billion doses of an effective vaccine within a very short period of time, and we want to have a way to distribute it to the world. Now, that seems like a very, very overwhelming task, but the consequences of not doing that are so significant that any investment we make in that type of project will pay back in millions and millions later on when we actually preempt a world pandemic. Well, thank you very much. Thank you. Dr. Michael Osterholm is Director of the Center for Infectious Disease Research and Policy and a Professor of Public Health at the University of Minnesota.
Thank you. unless so identified. All relevant financial relationships have been mitigated. Information contained herein should never be used as a substitute for clinical judgment. For more episodes, links to CME and MOC, or to viewine-based, it is no more predictive of that outcomes of end-stage renal disease or death compared to someone who has a GFR of 80. Welcome to Annals on Call, a podcast based upon articles from the Annals of 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 Animals on Call features an article titled, Association of Local Merit Filtration Rate with Adverse Outcomes at Older Age in a Large Population with Routinely Measured Cystatin C. Joining us on the podcast is Dr. Joel Toff, who is a renowned medical educator and in private practice in Detroit. There, he works with and teaches medical students, residents, and fellows at the St. John Providence Hospital. We hope that you learn a little bit more about estimating GFR and when to be concerned about GFR. Thank you for coming to our podcast. Joel, thank you for joining us again on the podcast. I thought this article raised some very interesting problems that we have with estimated GFR. And I've heard you talk about the controversy over whether CKD stage 3A really is kidney disease in people over 65. And maybe you could explain what that controversy is. You know, if you take a look at how predictive different CKD stages are for outcomes like kidney failure or death, you know, in general, as you go from CKD stage 3 to 4 to five, it becomes more and more predictive of these outcomes. But if you index it by age, something kind of unusual happens. At age, you know, young people, if they get stage three and four, it is highly predictive of those patients getting, progressing to more advanced kidney disease and needing a transplant or dialysis. As you get over age 65, if you're using an estimated GFR with solely creatinine based, it is no more predictive. It's just not predictive of that outcomes of end-stage renal disease or death compared to someone who has a GFR of 80. And that's in people that are elderly. And you start to question, well, maybe we're not, this is not nearly as specific as we would like to be. And maybe what we're actually mixing up are patients who just have normal physiologic deterioration of kidney function as they get older. We know as people advance, they get older than age 40, they lose about 1% of kidney function per year. And so this overlaps, you get this overlap of people have normal physiologic deterioration of kidney function of aging. Those patients don't progress to end-stage renal disease and people that may have more accelerated deterioration of kidney function due to diabetes or some other sort of kidney disease. And those patients are much more problematic. And at one point early on, they're going to overlap in the CKD stage three position. And we need to be able to separate those out. That's the concern here, and that's the debate. Right now, we think we're catching way too many patients, especially the elderly patients that just have kind of normal physiologic deterioration of kidney function and are not going to progress, and it's no longer predictive, and we're not capturing the people that we need to see. And we're investing resources. We're scaring a lot of people, having them be referred to kidney doctors and such and getting a lot of over-testing with just normal physiologic gauging. How much of this is a problem of the estimation equations and of the difference in muscle mass of five different people who are 70 years old? we assume they all have the same muscle mass with that estimation equation. Right. I mean, the estimation equation right now only allows you to, it estimates that muscle mass based on age and gender. That's the only variables it has to try to make that guess. And we, you know, you can just use your eyes and you walk around the wards or see patients in your clinic and you have wildly different variations there. So that is clearly part of that. And that is one of the concerns. One of the things they've actually seen with creatinine-based GFRs is that patients with very high GFRs, you know, the little old lady that comes in as a GFR of 80 or 90 milliliters per minute, estimated GFR of 80 or 90 milliliters per minute. And you look at her and she's frail and small. And you're like, how could that possibly be? It's exactly what you're describing. Somebody who's very low muscle mass has a very low creatinine. And so according to the equation, they're doing great. And according to your eyes, during the eyeball test, you're like, this patient's very frail and they're not going to do well. And in fact, they don't. And we get, and in some of these, in fact, in the article we're going to talk about, they actually demonstrate a U-shaped curve worth increased mortality with the highest GFRs. And that's exactly what you're describing. As estimated by? As estimated by creatinine alone. So that brings up the whole cystatin C thing, which finally is part of the guidelines that we should be thinking about. So maybe you could explain Cystatin C and why it might be a little bit better predictor in these people. Right. So Cystatin C is just going to be another marker. It's secreted by every nucleated cell in the body. It is cleared by the kidney. It's handled slightly different than creatinine. I don't think that's important for the internist to understand. The one thing that's brilliant about it that makes it so easy to interpret is the normal levels of a cystatin C are roughly the same as creatinine. So when you see a cystatin C of 1.2 and your mind just translates that to a creatinine of 1.2 and you'll get it, that's about what, it's pretty darn close within about 10%, which makes it real easy to just eyeball and say, hey, what's that cystatin C like? But where it really comes into its own is you plug it into the same type of formula that we have been doing for EGFRs with creatinine. And in 2021, there was a new cystatin C plus creatinine calculation. That is the recommended formula that comes out. It uses age, it uses gender, no race component. And it'll, it'll get you a more accurate GFR than creatinine alone. And it is resistant to some of the problems that we've been talking with creatinine in terms of, in terms of muscle mass. Now it has its own weaknesses, right? So it'll be inflated with obesity. So obesity can be one thing that throws it off. And the other thing that can throw it off is inflammation. And so I have some of my patients that have lupus and their cystatin C's are always elevated. And it's kind of interesting. It's kind of a good question of like, is that really a problem? Because it's part of the reason that cystatin C is actually pretty good at predicting outcomes, right? Because patients that have a lot of inflammation are going to have not, you know, obviously they're going to have more of those adverse outcomes that we're really trying to detect. And so it may push it away from being a purely accurate measure of GFR, but in the end, you know, sometimes we want to know GFR, but more often we just kind of want to get a sense of the patient's risk of an adverse outcome. And this one just helps there. So this study, which is a Swedish study, they measured both creatinine and cystatin C, and they calculated the estimated GFR with creatinine alone versus the estimated GFR with this newer formula of creatinine plus cystatin C. And they had pretty long-term follow-up. And I think they looked at like eight different markers. And maybe you could talk about the gist of what the study, it's a very complicated study, and there's so much data that we're not going to get into all the data on this study, but it does have an interesting bottom line. Right. So I think the first thing you've got to understand is that we've seen a lot of these studies come in and they say, how good does this formula? The study is not trying, and there's no component of the study where they did measured GFRs and they compared the estimate to the measured GFR.
This study is saying, oh, well, we would expect patients with GFRs to have worse outcomes. And it's interesting because they didn't choose, you know, the obvious choice here is to choose a kidney failure, acute kidney injury, and total mortality. And they, just like you said, they went beyond that. They looked at cardiovascular disease, cardiovascular mortality, heart attacks, strokes, hospitalization. Am I missing something? There may have been another one, but kind of a broad scope of outcomes. And they just said, hey, do patients with worse GFRs by these two different equations, either creatinine or a cystatin plus creatinine estimated GFR, do worse as their GFR falls? And they wanted to see if there's a separation there. And so, you know, the first thing that we talked about, we talked earlier about the little old lady, the frail lady who has a very high GFR, has bad outcomes, and you wouldn't expect that from the high GFR. That is eliminated by using this formula. So this formula kind of avoids some of the pitfalls that we get with the creatinine-only thing. One of the things we also found is almost everybody's GFR got pushed down about eight or 9% on average. And that recategorized a lot of patients in this study from a CKD stage two to a CKD stage three or a 3A to a 3B. A lot of people got pushed down in their CKD staging. And appropriately pushed down. And appropriately pushed down. We do believe, and in fact, we actually have good data, not in this study, but in other studies, that it is a better estimate of measured kidney function. And in this study, it shows it's a better predictor of adverse outcomes. What are most practicing nephrologists doing at this time? And is this study going to change what practicing nephrologists do? You know, I've been using, I've been using Cystentancy for two or three years now, kind of incorporated in, you know, in 2021 when the new guidelines came out and it was available in my, in my hospital. And I started, I started ordering it mostly my outpatient units. People are using it for acute kidney injury. It's pretty interesting. And, you know, these estimates of GFR, they're just estimates. And, you know, occasionally you'll have an outlier where it really explains, you know, you have a patient who has an amputation or a wildly different muscle mass than predicted. I've had some, you know, young people that are bodybuilders coming in with an elevatedannies 1.6. And everybody's freaking out about that they have CKD and you do a cystatin C and everything lines up as you'd expect that they're healthy, not sick. But those exceptions have been relatively rare. And usually the change in GFR of eight or 10%, it doesn't change a lot of what I do. That I find that very few of my decisions are dependent on a specific GFR measurement. And again, I might be in a slightly different position. I'm a person who deals with these numbers all the time. I'm pretty comfortable with understanding the kind of the uncertainty. And I think my decision-making might be different than a busy outpatient clinic where you're having to make that call, is this patient need a referral or not? So for me, I have not found Cystatin C as a super game changer for me. Occasionally, I find a patient where it really, really helps. And I'm thinking, I have a patient actually I saw recently, and they have a wide difference between their Cystatin C and their EGFR by creatinine and their creatinine GFR is in the 40s. And when you look at that, you're like, all of a sudden there's all these mysteries. Why is their phosphorus so high? Why do they have all this metabolic acidosis? Why are we having trouble with their hyperkalemia? Usually GFRs are 40. We're not seeing that. You check their cystatin C and their GFR is 18 and everything makes sense. Oh, now with a GFR of 18, I understand why they have hyperphosphatemia. I understand why we're having trouble with hyperkalemia. The case makes a lot of sense. And, you know, the patient and I tussle back and forth because they don't want to believe that their kidney function is so low. And I'm like, well, you know, I think it really is this low. And, you know, we kind of go back and forth on that. But it does, it clarified thing in that one case. But in general, I don't think it's a huge game changer for me. But I think if you're making these decisions about, hey, do I need to refer this patient? You're going to get a more accurate measure. You're going to avoid some of the pitfalls that you get with a creatinine-based GFR. Robert, are you using SysAdnC? Yes, we have it in our, we've had it in our hospital now for a year and a half. And I use it to give me a better estimate of GFR. And someone said, we have a lot of patients with amputations. Anytime the muscle mass is going to be off, we see cord injury patients. You can't use the cranium based in cord injury patients. Patients who come in very cachectic. I was telling you earlier, I had a patient with type 4 RTA and estimated GFR above 60 from the cranium model. I got a cystatin C and it was down to low 30s. And now I understood why the patient had that. And I understood that there was really significant kidney disease. I don't get to see very many bodybuilders on my service, but I do see a lot of cachectic patients. And I think it's useful, especially if we're going to be dosing antibiotics to get a more accurate estimation of GFR. But in those patients, I pretty much use just the cystatin C, not the combination. Don't use the combination. If their muscle mass is off. One of the things that we're going to be seeing shortly is the GLP-1 receptor agonists. There's a number of studies that are going to be looking at kidney outcomes in those patients that some of them do measure GFR studies, but if they don't do measure GFR, I've already kind of looked at their protocols. They're doing a lot of cystatin C, which reassures me because that's a group that's going to have wildly different weight changes throughout the test, throughout the study, right? You wouldn't want to misinterpret an improvement in GFR just because they had lost the muscle mass. Exactly, because GLP-1s do cause loss of muscle mass. So from the nephrology side, you've dealt with this intellectually in the past, and now you have this as another tool. For the primary care physician or the hospitalist, some of us believe that EGFR is a number. It's not a number, it's an estimate. But plenty of my interns and residents think it's a number until I berate them. What advice would you give to a primary care physician or a hospitalist who's listening to this podcast about when they should consider also getting a Cystatin C? Okay. So anytime that the GFR is going to be critical for making a decision. So you pointed out antibiotic dosing. That's a good one. If you're on the fence of whether you can, you're going to refer this patient for a nephrology or transplant or fistula, getting a cystatin C for a little added accuracy would be helpful. Anytime that you are unsure of the muscle mass, this is a patient who doesn't fit your standard body type, whether it's amputation, whether it's cachexia, whether it's bodybuilding, that would be another time to do that. Areas where you have some question there. And I think you could flip that around. You could say someone who has a tremendous amount of inflammation, they have lupus flare, they're in the middle of some other type of infection. Maybe cystentancy is not going to be as accurate as you hope it's going to be, because you're going to have some errors on both sides of this. And I kind of think that's one of the nice things about the equation that uses both of these variables, is you're going to kind of neutralize some of the effect from both of them and kind of get a happy medium. Will this help you?
Might this have an impact from a nephrology point of view in terms of how you looked at that problem? Yeah, I mean, I think once I'm seeing a patient, I'm less concerned about the specific EGFR, right? I'm going to follow their creatinine over time. And I'm less concerned about how that creatinine translates into an EGFR and more concerned about, is that creating progressively rising? Okay. Or is that cystatin C progressively rising? The one that I find to be more important and is a better multiplier risk rather than the EGFR is the albumin to creatinine ratio. And so honestly, if you're going to add one additional test on top of that creatinine-based EGFR, get an albumin to creatinine ratio. That is going to be more helpful and is going to better identify the patients that have true kidney disease. I don't think there's any nephrologist in the world that says you've got a patient who's got a GFR of 50. We'll argue all day whether that patient has kidney disease or not. But if you say they have an EGFR of 50 and they get an albumin to creatinine ratio of 120, everybody's going to agree they have kidney disease, right? It takes away, there's no controversy once you've identified that albuminuria. Now that same patient with an albuminuria of five or 10, all bets are off. Probably, I would say probably no kidney disease. What I hear you adopting is the same thing that the guidelines say for GFRs above 90 or GFRs from 60 to 90 that, let's say you have a patient with type 2 diabetes for 12 years, their estimated GFR still looks good, but you still should check that albumin and creatinine because you want to catch them as early as possible so that you could, you have quite a few options of how to take care of their kidney disease now. A hundred percent. And remember that the early finding in diabetic kidney disease is hyperfiltration. Their GFR may go up to 80 or 90 milliliters per minute early in that kidney disease as they're hyperfiltering, you can't be reassured by that, right? You talk to a nephrologist and we say, we're much more concerned about the diabetic patient who's got a GFR of 120 than the diabetic patient who has a GFR of 70. So this study is, well, not a perfect study. And in the editorial, they mentioned it would be nice to have similar data with measured GFR as opposed to just the creatinine, cystatin C. But the exact number is not as important as sort of these trends. And what I hear you saying is this might be a clue that if I hadn't already thought of getting an albumin-creatinine ratio, I better get an album-cratinine ratio because that's going to be a better predictor of what I can do to help the patient. Yeah, and I want to add that one thing that's interesting. Just last month, the new version of the KDGO CKD guidelines came out. And there's one of the new things that we hadn't seen before is they are recommending risk-based approaches to decisions like referral and decisions like fistula placement. And what this means is this means taking their GFR, taking their albuminuria, taking their gender and their age and plugging it into the kidney failure risk equation. And then they say, I think if it's greater than 3% risk of kidney failure in five years, that's when you refer. I love that because that's going to decrease our referrals of very old people. And it's going to increase our referrals of those younger people that we may have been missing otherwise. It's a new way of thinking about this. I think it's better than the heat map, which we've been using before. It does address some of the other issues that people have been looking for. And I think it's a start you know, we're just getting more sophisticated with the data. It used to be just based on the GFR. And now we're saying, hey, actually, we can get more additional information and people can use that. And I think, I think, you know, we've seen it with the decisions for cholesterol treatment for a long time. Let's do a 10-year risk and we'll use that to make the decision. I think we're going the same way, the same kind of direction in nephrology. Well, Joel, thank you so much for putting this complex but important article into context. Yeah, absolutely. I'm delighted to be here. Thanks for the invitation. Now it's time for Bob's Pearls. First, this article reminds us that EGFR is an estimate and an estimate that it becomes less accurate when muscle mass is not average. It's especially important to not ignore people with decreased muscle mass. Cystan-C plus creatinine gives a better measure of estimated GFR in previous studies. What this study shows is that this does a better job of showing what kind of outcome someone's likely to get as the eGFR decreases using the combination of creatinine, cystatin C, the more likely they are to have negative outcomes. As Dr. Toff reminds us, please don't forget the urine albumin creatinine ratio as another marker of kidney disease. And finally, he mentions the kidney risk failure calculator, which I quickly found on MDCalc. This can be useful for deciding whether or not you need to refer a patient to a neph clinical judgment. For more episodes, links to CME and MOC, or to view disclosures, visit go.annals.org slash on-call.
This is the New England Journal of Medicine COVID-19 update for January 13th, 2021. I'm Stephen Morrissey, Managing Editor of the journal, and I'm talking to Eric Rubin, Editor-in-Chief, and Lindsay Baden, Deputy Editor. Today, we're also joined by Dr. Salim Abdul-Karim, who's been central to efforts to control the COVID-19 outbreak in South Africa. Salim's a clinical infectious disease epidemiologist who has been central in the past to work in South Africa on HIV. He's based in Durban. His work has brought him many international awards, including most recently the Canada Gardner Global Health Award, which he shared with his wife, Horatia. In the past, he's led the South African Medical Research Council, which is the equivalent of our NIH, and he's a member of the British Royal Society, the U.S. National Academy of Medicine. With the COVID-19 epidemic, he has again taken a central role. He is leading the Ministerial Advisory Committee for the Government of South Africa. But before we talk about South Africa and the new viral variant that was first recognized in Durban, let's look at some of the work we've published on the use of the anti-IL-6 receptor antibody tocilizumab. Why has there been such interest in this therapy? We've discussed many times in the past the fact that inflammation appears to play an important role in COVID-19, particularly during the later stages of disease when people develop manifestations like ARDS. While the driver or drivers of this inflammatory response aren't really known, it's certainly true that many patients have elevated levels of IL-6. So starting early in the outbreak, there was a good deal of interest in using agents such as tocilizumab in severe illness. In fact, at some hospitals, it became the standard of care even before we had any data supporting it. But the early RCTs haven't been very encouraging. However, there are conflicting studies out there, including a preprint, which has gotten a lot of attention. So what's different about the study that we published? This was a multicenter randomized controlled trial, which enrolled patients who were hospitalized but didn't yet require a mechanical ventilation. Like the earlier study that we published, the primary endpoint was intubation or death. This study was somewhat larger with 389 patients randomized two to one to Tussilizumab or placebo. Unlike the previous trial, however, this group met their primary outcome with 12% of patients in the Tussilizumab group dying or requiring mechanical ventilation as compared to 19.3% in the placebo group. This resulted in a hazard ratio that didn't quite overlap with one. Thus, a much better looking result than in the previous trial. And most of the secondary outcomes also favored the tocilizumab group, except one, and that's a pretty important one. Remember that the primary outcome was a composite of intubation and death. But when death was considered alone, there was actually a slightly increased rate in the tocilizumab group. So how do we interpret this finding? It's not entirely clear. There are many differences in patient care among the Tuxelizumab trials, all of which were performed as a standard of care evolved over the course of the outbreak. And the patients recruited into each trial had different baseline severities of disease, different ethnicities, different races, and all of these might account for their differing outcomes. But I'd keep two important points in mind. First, there certainly is a value in ensuring that patients don't require mechanical ventilation, even if the agent doesn't end up preventing them from going on to die. However, neither Tocilizabab nor remdesivir, which is being widely used, has been shown to save lives. And in fact, the evidence suggests that they have little effect on mortality. And second, it's difficult to know the place of agents like tocilizumab and baricitinib, which we published on recently, in an era where another anti-inflammatory drug, dexamethasone, actually has been shown to decrease death rates. Eric, what I've learned is that when a result from a study is straightforward, the description of what it means can be simple. And as you've tried to help us understand where TOSI fits in, given the conflicting data, it makes me come back to a refrain that we've had over the last many months. Clinical research is hard to do. It just is. There's a changing baseline of treatment. There are different contexts where treatments are given. There are different comorbidities and backgrounds that may influence outcome. And there are different values as to which outcomes matter, such as shortening hospital stay versus having an impact on mortality. And there's also a changing virus with viral evolution, something we'll get to a little bit later. And as these factors all change over the last six months, then new observations are that much more challenging to fit into practice, particularly when multiple therapies along the same pathway are emerging, such as the anti-inflammatory pathway, as you pointed out. So my hat's off to the investigators, but it's a challenge for us at the bedside to know where these treatments may fit in. Things are happening so quickly in this area in COVID-19 that we get overlapping results. We get the results of studies that were done months ago showing up now at the time when the standard of care already has changed. And I agree with you, even with these well-done studies, and this is another well-done study, it's so tough to know how to implement what we're learning. Slim, in South Africa, are these types of therapies being used and is there a sense of where they fit in? Thanks, Lindsay. As we look at the way in which we are managing patients here in South Africa, the focus has been on dexamethasone oxygen support and focus on ensuring that patients maintain their saturations. All of the additional pharmaceutical interventions are really secondary and are individualized, and we are not routinely using POSI in South Africa. And remdesivir, where has that emerged as a potential therapy? Remdesivir is available in South Africa. It's used in the private sector and much less so in the public sector. I think the big concern is the fact that it's injectable, places a huge burden on the healthcare service, the cost, and also the modest benefit in terms of mortality and hospital stay reduction. I think all of that combined makes it a drug that doesn't have a pride of place in our first-line management of patients with COVID-19 in South Africa. It'll come as no surprise that the U.S. healthcare system isn't set up for efficiency. And there's no question that right now we're using a lot of interventions which aren't necessarily very cost-effective. In fact, we haven't really seen cost-effectiveness analysis for anything that we're using. Nevertheless, I think as Lindsay has pointed out, people who are treating patients with COVID-19 want to do the best for them. And there's a move to implement things very early, perhaps earlier than the benefits have been thought fully through. Perhaps I'll just add that in managing our patients, we do provide a range of additional therapies. But one of the things we found that's been particularly important is the inclusion of low-weight molecular heparin. I think that when we look at all of those combined, our outcomes have been quite reasonable in terms of pretty low case fatality rate compared to many of the other countries. And so I feel sometimes that keeping it simple is a pretty good way to manage patients. And along those lines, Eric, what you said before about when we're taking care of patients and at the bedside, the temptation is always to do more and to do more with whatever is the latest treatment that people are suggesting might have a benefit. And we all struggled with this with hydroxychloroquine and the chloroquine compounds, you know, eight, nine months ago. And finally, after study after study after study failed to show any evidence of benefit, were we as a community able to move on? And I think we're struggling with that currently. You know, when we have a sick patient in front of us, the temptation is to do something, even if the evidence does not support it or does not support it for the outcomes that we care about most. And Slim, your point about low molecular weight heparin is the complications of COVID are just as important, if not more important. And it's defining that pathogenesis and then using interventions that we have on the shelf in ways that we know how to use may turn out to be some of the most important interventions that we do. I want to ask about an article that we're publishing today, the early phase results of an adenovirus-based vaccine. What did we learn in that study?
It's an inactivated adenovirus that is used as a vector to deliver the gene for the viral spike protein. So the antigen is the same, but the delivery method is different. The concept is very similar to other vaccines out there, such as COVID Shield, which has already received the equivalent of an EUA in the UK, India, and Argentina, and Sputnik V, the Russian vaccine, which is being widely distributed, and a Chinese vaccine, 6185.HK, which is being used, as I understand it, in the Chinese military already, even though it hasn't had a report in phase three study. In the case of the vaccine that we published, AD26-CoV-2S, the serotype being used is AD26, which is relatively rare in human populations, suggesting that there's not a lot of pre-existing immunity to the viral vector, and therefore perhaps a vaccine is more likely to take than one for which there is a pre-existing immune response. The trial we published is a phase two trial, which used different doses and regimens to look at safety and immune response. I'm going to summarize a good deal of data across several arms of the study, which used different dosages and different schedules. Safety appeared broadly similar to other reported adenoviral vector vaccines. As seen with the other vaccines, the most common side effects were local injection site pain was the major one. Several recipients also developed the usual array of systemic effects such as fatigue, headache, myalgia, and fever. Almost all the recipients developed neutralizing antibody responses, and these persisted through at base 57 in the study. Most also had evidence of an appropriate T-cell response. And importantly, even the recipients who received a single dose of vaccine developed antibody responses that looked broadly similar to those who received two doses. More is better, and having another vaccine will be vital for the control of the epidemic. We don't know how well this one will work yet, but the finding that a single dose can produce lasting immunity, at least lasting for a couple of months, led the investigators to start a phase three trial of this using only a single dose of vaccine. That trial is underway, and we hope to have the results over the next several weeks. I mean, I think that, as you suggest, Eric, these data are very encouraging. They are early clinical phase data, no endpoints in terms of prevention of illness, but those studies are ongoing. I think this work overall is incredibly elegant in how the preclinical, the NHP model, the non-human primate model, and the early phase human data are highly choreographed by the investigators to allow a better understanding of how the immune responses elicited may behave. Ultimately, we need the data from the efficacy trials, the two of which are going on globally currently, to tell us whether or not it actually works. But the preclinical and early clinical work do work very synergistically to give us a good sense of how this may work. You know, one of the issues that we've had all along is it's not clear what an effective immune response looks like. And when we get to the point of understanding that better, these data will mean even more because it may not be so important to do a very large study to measure efficacy. It's, of course, will be important for safety reasons to follow a large group of patients for a longer time. But these sorts of responses do look broadly similar to the responses that do produce protection in the vaccines that have been studied more heavily. And therefore, I think, once again, I think we can be pretty optimistic about vaccines like this being effective. Eric, what I think you're getting at, which is one of the most important questions in my view, is identifying a correlate of protection. I think that can only occur from the human efficacy studies, but the supportive data from the preclinical models will be helpful to better understand that. But once we have a correlative protection, then the ability to do bridging studies to other populations such as children or perhaps to other vaccine constructs if we need to evolve the insert based upon viral changes becomes possible. And so I think the pursuit of a correlative protection is incredibly important, hopefully will come out of the large-scale phase three efficacy trials, and then with these preclinical data, hopefully will make sense scientifically. Let's turn back to South Africa. Slim, before we talk about new viral strains, what's the overall situation in the country? Thanks, Stephen. It's great to be here with you. When we look at the epidemic in South Africa, shortly after we had our first case on the 5th of March last year, South Africa took very early and decisive action to prohibit mass gatherings, close schools, close borders, and institute a lockdown. And this led to a slowing of viral transmission in the community, and it postponed a peak that we were expecting in April, pushed it all the way back to July. And that gave us a bit of time to prepare, put up field hospitals, secure adequate oxygen supplies and all of the things that helped us deal with the peak when it arrived in July. But we always knew that the lockdown and the restrictions were really not sustainable, not sustainable beyond a few weeks. And so we always were expecting that viral transmission would come back and come back quite rapidly. And so as we increased into this peak in July and dealt with it, we were a bit surprised, actually, that it wasn't that bad. And I think partly it was the case because we had empty field hospital beds and the number of cases that we had anticipated through mathematical modelings just didn't pan out. I mean, we did have a severe epidemic. We're not anywhere near as bad as we thought. And I think partly that created a bit of complacency because we didn't anticipate what was to come next. The original thought was, okay, we're going to see a second wave. We'll see it after our summer vacation when everybody moves around and goes back after vacation. So we were anticipating it would probably be somewhere in early January. Well, two things happened. The first is that when university and high school students finished their final examinations in October and November, it was party time. Difficult to control. We ended up with a situation with several super spreading events where thousands got infected. And we didn't know at the time that we had in our midst a new variant, a variant that could spread more efficiently. And so that combination of a more efficient variant together with super spreading events ended up in a situation where it seeded community transmission. And we went into our second wave somewhere in the middle or latter part of November. Right now, we have just over 1.2 million reported cases and just over 34,000 deaths. Hospitals are straining. We today in South Africa have more cases and more deaths than we ever had during the first week. I had never imagined how much more severe the epidemic would be. And it's really about the speed with which the cases have increased and the burden that they have placed and the pressure that they have placed on our hospitals. But on the plus side, it's been important also as an opportunity to come together, where in the midst of the frustration and the pandemic fatigue, people are now realizing and coming together to deal with this. Because almost everyone knows somebody who's got this disease or who has died. It has served as an important opportunity to rededicate ourselves to prevention, not just for ourselves, but for our families, our work colleagues, our neighbors, and our community. In a sad way, this coronavirus has helped us re-identify our interconnectedness and our interdependence and how prevention is for all of us to do for everyone. Slim, may I ask what is the impact on day-to-day life as of now? What's open? What's closed? What can people do? We have a five-tiered alert system and we are now at restrictions called adjusted level three. Adjusted level three involves no mass gatherings. Funerals are restricted to only 50 people. Beaches and parks are closed. There's no stay at home order. So, you know, shops are open and there's no restrictions as that is concerned. But there is one major issue and that is that alcohol sales is banned. Because we learned from our first wave that when we banned alcohol and cigarettes, that it had a huge impact. It basically cleared out our emergency rooms, our ICUs, all of those motor vehicle accidents, interpersonal violence, those cases of pancreatitis, all gone. So we had to implement restrictions on alcohol in order to ease the burden on the healthcare services and to make space in the ICUs and the ventilators to allow for the COVID patients. So right now, you can't buy alcohol in South Africa. Wow. I mean, that's pretty tough. And Durban, which is known for beautiful beaches, no one getting out there. How well do people comply with these restrictions? We have generally had good compliance in the early stages of this epidemic.
And it is well described, you know, as we eased our restrictions, the masks got lower and lower below the nose and then below the mouth. And now they're pretty much on the neck. So we saw that. We saw a case of people just reaching a point of tired and just irritated and frustrated with having to put these restrictions. But now that we are in the second wave, we've actually seen much better compliance. One of the important aspects of our prevention measures is to enhance enforcement. And while mask wearing, for example, is compulsory, as is sanitizing when you go into a building, it hasn't been a criminal offense. And so because of the big concerns about pandemic fatigue and the need for greater enforcement, mask wearing has for a short period now become a matter that's amenable to law enforcement. And I think that that's just part and parcel of trying to regain momentum for social distancing, mask wearing, and hand hygiene. So Slim, you've described a remarkable series of interventions in South Africa. We hear a lot less about the rest of the continent. Do you have a sense of how things are going elsewhere in Africa? As I serve on the African Task Force for Coronavirus, we've been monitoring the situation at a continental level. It's largely being coordinated by the African CDC, which has assumed a much larger role in supporting individual countries. And their leadership has been central to the response in Africa. As of now, there are just over 3 million reported cases in Africa. And it accounts for about 3.5% or so of the global cases, much lower than the proportion of the population. There have been about 73,000 deaths that have been reported, a case fatality rate of around 2.4%. Just five countries out of the 55 on the continent account for just over 70% of all cases. They are South Africa, Morocco, Tunisia, Egypt, Ethiopia, and Libya. But what's important is that the entire continent at this stage is in the grip of a second wave, not just South Africa. Anything that's happening in the Southern African region is also being mirrored in West Africa, Central Africa, East Africa, and Northern Africa. So we are grappling with this problem. Now, some have said to me, oh, you know, it's just bad reporting. It's true, there is underreporting. And we have seen that in many countries in Africa. But it's not true that that underreporting is so severe that it gives us a completely skewed picture because our colleagues across the continent are not describing hospitals and healthcare services where there are queues of acute respiratory distress waiting to get in. We're not seeing that. So I think on the whole, the underreporting is there, but we are seeing an epidemic that is much less severe than we had anticipated and that had been predicted in Africa. That's very interesting. As you said, I think a lot of people have attributed the low numbers to both underreporting and a lack of availability of testing in some countries. But it is interesting that when you look at highly urbanized countries like Nigeria, Nigeria is not on this list of the top countries. And it makes you wonder what the cultural differences are that are leading to very, very different rates of disease. Yes, Eric, it's been quite an enigma actually to try and understand why the epidemic hasn't taken hold as was predicted. And I think one of the important features or explanations is the age makeup of the population in Africa. We have a predominantly young population. If you look at our population curve, the large proportion of our population is under 30. I think so. Besides age, I think that there are other things as well. One of the things that was done very early, for example, in the entire Southern African region, was they instituted lockdowns. So just the interventions at country level also contributed to slowing the transmission. And then there are many other hypotheses, too many to name here, but they include things like the limited international travel to Africa was also contributing to less seeding of the virus within the communities. And so there are other explanations that add to it. But I think overall, we don't fully really understand why Africa hasn't been impacted as we anticipated beyond the age factor. Slim, I mean, do you think testing is adequate across the continent to understand transmission? Because if you're waiting for disease to be the marker of transmission, as you pointed out, there may be population stratification issues that might decrease the detection through that mechanism. Yeah, and that's been noted now in a few countries where they have done ser prevalence surveys. So, for example, in a recent survey in Kenya, they found that about 5 to 7 percent of the population was infected, whereas they have such a small proportion of actually reported cases. In South Africa, similarly, if we look at just the data in South Africa, for every reported case we have, we have nine more individuals who have antibodies. So, I mean, you can imagine that if that's what we're dealing with, and in a country like ours where we test a lot, you know, we don't even know about 90% of the epidemic. So our ability to control the spread of this virus is very limited. I mean, the traditional way in which you would go in, test, isolate, quarantine, and so on, when you don't even know most of the cases, even if you can pick up half of the cases you don't know, you still have several cases that you just don't know, and they will keep spreading. And as you know, asymptomatic and pre-symptomatic spread is really critical. So we've had real challenges in Africa trying to control the spread of this virus, because the methods that have been very successful in much of Southeast Asia are difficult to implement to the same level in Africa. Slim, a new variant of SARS-CoV-2 was found in your hometown, Durban, and it's become increasingly clear that related viruses are being found all around the world. What can you tell us about the mutations in the South African variant? The new variant of SARS-CoV-2 that was found in South Africa is called the 501Y.V2 variant. And it's really named after the position of the key mutation within the receptor binding domain. So what's unusual about this variant? We've been monitoring the phylogenerics, the genetic sequences of our SARS-CoV-2 in South Africa every month. Once a month, I get to look at all of the sequences. And essentially, we've been seeing about one to two mutations a month on average. I mean, generally, it's been quite underwhelming in terms of the genetic variability in this virus. Suddenly, in November, we see the emergence of a new variant. This one has 23 mutations, of which 20 lead to amino acid changes. In other words, the protein structure is changing, not just the gene sequence. And of those, the most important are three mutations that are in the receptor binding domain. And I'll give you their positions just so that you are aware of where they are. They are positions 417, 484, and 501. We also have in this variant a cluster of five mutations and three amino acid deletions in the N-terminal domain of the spike protein. Now, each of these three receptor binding domain mutations is associated with immune escape on their own. But what's interesting is that if you look at just the mutation at position 501, it results in a change in both charge and shape. And that, as a result of that, the virus, when the spike protein is coming to attach to the ACE2, it is rotated by 20 degrees. And in the course of that rotation, it's able to bind deeper to the ACE2. So the binding of the spike protein to the ACE2 receptor is enhanced by that mutation. That binding is even further enhanced by the mutation at position 484. So 484 is normally negatively charged. The ACE2 receptor at that point is also negatively charged. So there's a bit of a flap there. The position at 484, the spike protein is not quite attached. It's just flapping around. But what happens with the mutation is that the minor acid at position 484 is now positively charged. And so the positive charge is now attracted to the negative charge. And so the binding between the spike protein and the ACE2 receptor on the human cell, there's much more affinity. The binding is stronger. So that means that it's now more efficient in the way it's being transmitted. Slim, the basic science that you're describing, the mechanistic understanding of the interaction between the virus and its receptor, has that been borne out with epidemiologic observations in Quisalunatal? So what we are now seeing as a result of what we've observed biologically is now being correlated epidemiologically. What we are seeing in South Africa is a virus that is spreading faster.
If you look at the province of the Western Cape, the amount of time it took to reach 100,000 cases was 50% faster in the second wave with the new variant than it was in the first wave. Now, there are many things that influence the speed at which the virus is transmitted, behavior, restrictions, and so on. But the variant is contributing to that as well. If one looks at my own province, it took about 40% faster to get to 100,000 cases in my province under the current variant than it did in the first wave. And the net effect of this is that the evidence we have is that the new variant is not causing more severe disease. The disease is not any worse. The clinical features are not any worse. But the pressure on the hospital is much worse. The cases are arriving at a very rapid rate, and they're putting enormous pressure in a short period in the health care system. So the health care system struggles. And that's what we've been seeing. And it correlates well with what we've seen with the B.1.1.7 variant that's common in the UK and in many other countries. In the UK, that variant was shown to be 56% faster in the way in which it transmits. So it's in keeping with what we've been seeing with variants that these viruses are able to transmit more efficiently. And you would expect that because viruses generally evolve to become more transmissible and usually less pathogenic. Why did this viral variant or really many viral, emerge in South Africa? And I'm not even sure we know that it emerged in South Africa versus it was detected by those who were in a position to detect it. Either there is tremendous transmission allowing the chance events, or there's some kind of selective pressure, selective environment, perhaps cofactors like HIV, TB, nutrition. Why do you think the viral variants emerged in your neighborhood? What pressures do you think facilitated that? When we look at the way in which viruses evolve over time, in the particular case of the coronavirus, we sort of look towards four different ways in which new variants emerge. The first is just by natural variation. The second is by replication errors. But then the other two become important, which is cross-species transmission. In other words, did the virus go into some animal and then come back into humans? That might explain why you got 23 mutations in one go from a virus that's otherwise very stable. Or is there immune pressure? Is it replicating in somebody where there is convalescent antibodies putting immune pressure on the virus to mutate in this way. I guess all of these are important hypotheses. We can't answer the question right now. It's an important question because I think knowing how this variant has come about is going to be important so that we can predict where it's going to happen again. And if it's happened here already in South Africa, it can happen anywhere. And it could happen in a way that we could predict if we knew how it was emerging. What proportion of the community isolates now is the new variant? Within the three coastal provinces, we have now sequenced a few hundred of the viruses. And in all three of the coastal provinces, the Western Cape, Eastern Cape, and KwaZulu-Natal, they account for up to about 90% of all the isolates. So from a variant that was barely present a month ago to one where it's so dominant, it just indicates how rapidly it is spreading. What are the implications of these variants for immune escape, both for reinfection and for the efficacy of the vaccines that we're currently using? There have now been three or four published papers, either as preprints or in journals, that have looked at this question. In particular, a most recent paper found that nine out of 11 convalescent sera were not neutralizing the variant that has a mutation at position 484. It seems that the mutation at 484 is particularly important for immune escape in natural immunity. So the implications of that is that we are now running a risk that there may be more cases of reinfection with the new variant among those who've previously acquired the disease. And that escape from natural immunity, it's not only from 484. 484 is the most important, but actually the mutations at 417, 501, and at the N-terminal are all contributing. The studies that have been done have looked at each of their contributions, and in combination, they have quite a substantial amount of human escape, as I pointed out. So that is a concern. Are we seeing reinfection because antibodies from past infection are not protecting against the new variant? That is a question we don't have an answer to right now. There are anecdotal accounts, there are clinical cases, but we had clinical cases even in the first wave. So this needs a very careful study. And so several studies are underway to answer that question exactly, but we don't have the answer yet. Similarly, we do not yet have any evidence that looks at the ability of vaccine-induced immune responses in utilizing this variant. I'm very hopeful that we're going to see those results soon because those studies are well underway. But at this point, we have no evidence to show whether any of the currently available vaccines are able to neutralize the 501Y V2 variant. So in regard to vaccination, what are the plans in South Africa and in the rest of the African continent? South Africa is securing vaccines through three mechanisms. We are part of the COVAX facility. Also, there is an African procurement mechanism that is procuring about 2 billion doses for the whole of the continent. And we also have individual bilateral arrangements with certain manufacturers. Using those three mechanisms, we're hoping to secure an adequate number of doses. At this point, our target in terms of our vaccination strategy is to achieve 67% immune protection. That is considered herd immunity, and it's actually based on an R0 of 3 with several assumptions, but we chose to go with a higher level for herd immunity because of our variant. Our variant might actually have a higher R0 than the previous variants. The plan is to vaccinate in three phases. Phase one is healthcare workers. And at this point, we've secured doses of the AstraZeneca vaccine to initiate vaccination in healthcare workers within the next two to three weeks. The next phase is moving on to elderly people, those with comorbidities, essential workers, and those in congregate settings like schools. The phase three is then the remaining population, adult population, and then phase four is the remainder of our country. So our goal is to vaccinate 40 million people. The challenges are enormous, the hurdles abound, from procurement of enough doses, to storage challenges, to distribution challenges, to documentation challenges, just the logistics of doing all of this. The president of our country on national television, he calls them our family meetings. He articulated it better than I can. He said that this is a challenge beyond any other that we have faced in health. It is even bigger and more complex than hosting an election or scaling up antiretroviral therapy. Thank you, Slim, for joining us today. And as usual, thank you, Eric, and thank you, Lindsay.
Welcome. My name is Devine. I am a fourth year medical student. This is the 20th episode of the Devine Intervention Podcast. Today we're going to continue with autonomic pharmacology. So let's get right into it. Okay, so one thing I forgot to mention at the last podcast where I talked about Alpha-1 agents was high yield use of prazosin. So prazosin is an alpha-1 blocker. It can actually be used to treat the flashbacks that accompany PTSD, post-traumatic stress disorder. Remember your DSM-5, you need one month to make that diagnosis. If it's less than a month, that's acute stress disorder. Okay, so let's jump to the alpha-2 receptors. The alpha-2 receptors, they are GI-coupled receptors, okay? So they're inhibitory receptors, so they inhibit adenylate cyclase, so you ultimately get less activation of protein kinase A. And these receptors, it so happens that they are found on the presynaptic adrenergic receptor, so it's sort of a negative feedback system for the sympathetic nervous system. So let's talk about agonists. So the goal of an agonist will be to help you release less norepinephrine, again, because it's a GI-coupled receptor. So the big drug I'll talk about here is clonidine. Clonidine is an alpha-2 agonist. It's used to treat hypertension. It actually works extremely well. the only problem is once you stop the drug you get rebound hypertension and it's actually made a name nationally as a straight drug because it makes opioid withdrawal symptoms feel better right because if you really think about this opioids their mechanism of action is the decrease the release of catecholamines like norepinephrine at the adrenergic synapse, right? So clonidine being an alpha-2 agonist also decreases the release of catecholamines at the adrenergic synapse. So that it basically works as an opioid. It just uses a slightly different mechanism, okay? So it will sort of temper the hyperadrenergic symptoms that accompany opioid withdrawal. Now, the next alpha-2 agonist I'll talk about is alpha-methyl dopa, okay? The big thing you want to know about this is it's an antihypertensive that is safe in pregnancy, okay? It's kind of big, so it doesn't cross the blood placental barrier very well. Now, with regards to the alpha-2 antagonists, right, so if you're inhibiting an inhibitor, right, that will ultimately make you release more norepinephrine at the adrenergic synapse, right? So we know one of these diseases, according to the monoamine theory, that's associated with a decrease in norepinephrine, that's depression, right? So if you increase norepinephrine, you could potentially relieve symptoms. So that's the mechanism of action of a drug like mirtazapine. Mirtazapine is an antidepressant that works as an alpha-2 antagonist. It increases the release of norepinephrine at synapses, so it makes depression symptoms better. One big side effect you want to know is obesity with this drug. It spurs up a person's appetite. So it's probably a good choice on an exam in an anorexic patient that has depression. Or if they give you a question about an old lady that is not eating, that is sort of depressed, you can also give amortazapine. That'll be a nice agent for that. So now we're done with the alpha receptors. Let's jump to the beta okay uh so start with the beta 1 receptors remember these are found in the heart okay the positive uh it's a receptor where if it's activated you can increase heart rate right so positive chronotropy you could also increase contractility that's a positive inotropy okay and um in the juxtaglomerular cells that comprise the afrin arteriole, if you activate beta 1 receptors at that spot, you increase the release of renin. So the first thing I want to establish here is that beta blockers, right? So beta blockers that start with the letters A through M, M as in Mandy, okay, they're all beta-1 selective, but beta blockers that start from the letter N, like Nancy, through Z, they're beta-1 and 2, okay, so they are non-selective. In general, you want to avoid the non-selective beta blockers in asthmatics, because remember, if you block beta-2 receptors, you'll cause bronchoconstriction, and that can trigger airway compromise. So the beta-1 selective blockers, right? So we have drugs like atenolol, okay? Esmolol. Propranolol is non-selective, okay? And one other thing I will say with these beta blockers, there's three beta blockers that have been shown to improve survival in heart failure or improve survival in like an ischemic cardiomyopathy after a person has a myocardial infarction. Okay. The easy way to remember them is just remember biochemistry, like the B, the C and the M in biochemistry. Okay. So the drugs here are Bisoprolol. Okay. There's Carvedilol. It's an alpha beta blocker. And then there is Metoprolol, which is also a beta 1 selective agent. So these drugs, the improved survival, they actually slow down remodeling of the heart. Because norepinephrine can actually induce a cardiac remodeling that can make a person's heart failure worse. But one thing you want to remember is, yes, these drugs are good for heart failure. But you do not want to give a beta blocker in the setting of an acute heart failure exacerbation, right? Because you don't want to cardio depress these people even more. You also probably want to avoid a non-dihydropyridine calcium channel blocker under this scenario. Okay, now some other words with the beta blockers, right? So Carvedilol, Labetalol, they are alpha beta blockers. One special thing you want to know about Labidolol is that it is in fact safe in pregnancy, okay? Remember that mnemonic for the drugs that are safe in pregnancy, the antihypertensives that are safe in pregnancy. The mnemonic here is hypertensive moms love nifedipine, okay? So the H stands for hydralazine, the M stands for alpha-methyl-dopa, L stands for labetalol. And the N stands for nifedipine. So labetalol is safe in pregnancy. Another good thing about labetalol is that it's a great drug that can be given in a hypertensive emergency. There are some other drugs you could also give. Drugs like nitroprusside. Be careful with your cyanide toxicity with that. And you can also give like nifedipine or nicardipine. And Carvedilol, Labidolol. They are also nice drugs that you can give in the setting of a cocaine overdose. Because you don't want to have the unopposed alpha-1 vasoconstrictive effect that can cause hypertension. So you can give Labidolol under those circumstances. Although the first-line drug for the treatment of a cocaine overdose or cocaine intoxication, if a person is severely hypertensive, is a benzodiazepine, right? So like lorazepam or diazepam or anything like that. Now, another special set of beta blockers, we have acebutolol and pindolol, okay? These drugs are partial beta agonists, okay so yes they're agonists but they have partial activity so they in fact present with um beta blocking actions okay because if you think about it if you have norepinephrine around you will get the full effect from activating that receptor okay so drugs like acebutolol and pindol by taking over those receptors, they are giving you less than a full effect. So they're basically exerting an antagonist effect, if you may. So again, think of those drugs as partial beta agonists, but they're classically described as being beta blockers. Now, another special beta blocker here is an ibivolol. One, okay? One special thing about Nibivolol is it actually increases the release of nitric oxide in endothelial cells, okay? And remember, nitric oxide is a potent vasodilator, okay? So it can actually lower your total peripheral resistance. So an unusual step one question will be a patient that should avoid, they could give you like some extra drugs and say, oh, which of the following is contraindicated with Nibivolol administration, right?
Remember, it's a PDE5 inhibitor that's used to treat pulmonary hypertension, and it's also used to treat the erectile dysfunction. And you also probably want to avoid this in a person that's taking a nitrate. Okay. Now, beta blockers, they do act as class two antiarrhythmics, right? So you can use them in AFib, okay? Remember, AFib classically shows up on exams as an arrhythmia that has an irregularly irregular interval okay um you can also use beta blockers for an svt right so supraventricular tachycardia remember again the classic description of this kind of arrhythmia is a narrow complex regular tachyarrhythmia okay so it's originating above the av node right so you have very narrow qrs complexes with that uh you can also use beta blockers in heart failure, okay? So they do decrease myocardial oxygen demand because they somewhat cardio depress the heart, okay? And by slowing down the heart, right, they increase the astolic filling time. So your end-astolic volume actually increases, so you could potentially take advantage of the Frank-Stalin relationship. And it also, again, because the antiarrhythmics, they decrease the risk of dangerous arrhythmias that could cause death okay alternatively you could also use beta blockers in the setting of a thyroid storm okay usually you resort to non-selective beta blockers like propranolol okay the first thing propranolol does is it dumps down the hyperadrenergic state that accompanies a thyroid storm. But in addition, it inhibits an enzyme known as a 5'-diiodinase. The 5'-diiodinase converts T4 to T3, okay? So by inhibiting that 5'-diiodinase, you decrease the formation of T3, okay? Which again can dump down the responses of your body in the setting of a thyroid storm. Other things you can use in a thyroid storm besides propranolol, right? You also want to use PTU, right? So PTU, propylthiouracil, it inhibits thyroid peroxidase, okay? Which is the rate-limiting enzyme of thyroid hormone synthesis, but it also inhibits the 5-prangioiodinase that converts T4 to T3, PTU, one quick thing I'll just slot in here is that it's actually the preferred antithyroid medication in the first trimester of pregnancy. But once you get to the second or third trimesters, you want to switch to methimazole. Because PTU has some nasty hepatotoxicity that you want to avoid. Okay, so in a thyroid storm, you can also give steroids. Okay, so steroids also inhibit the magic 5' diagenes that converts T4 to T3. But in addition to that, steroids can also spruce up your adrenal axis, right? Because there's been some reports that show that people that are in thyroid storm actually have some kind of adrenal suppression. Another use for beta blockers, you can actually use them in the setting of esophageal varices. You use them for prophylactic treatment in esophageal varices. You don't necessarily use them under acute circumstances. If a person is having an acute variceal bleed, the first-line drug you give is octreotide. No one really knows how octreotide works for this purpose, but studies have shown that it reduces splanchnic blood flow. But if you want to prophylax in the long term against esophageal varices, you want to go ahead and give a non-selective beta blocker like propranolol. Other things you can use for the prophylactic treatment of esophageal varices, right? So you can give spironolactone, okay? Spironolactone is an aldosterone receptor antagonist, okay? It does reduce our portal pressures. And in general, there is an antibiotic you usually add on in patients that have a history of esophageal varices as prophylaxis against something known as spontaneous bacterial peritonitis, which actually has a pretty high mortality rate. The classic antibiotics that are administered are fluoroquinolones, right? So you can give like norfloxacin or ofloxacin or ciprofloxacin, okay? They're good prophylaxis against spontaneous bacterial peritonitis. Now, if a person overdoses on a beta blocker, how do you rescue those people? You rescue them with glucagon. Right. So what's the mechanism behind that? The thing is, if a person takes a beta blocker, right, so beta 1 receptors, for example, are GS coupled. Right. So when you block them, you have low levels of cyclic AMP. So if a person has beta blocker toxicity, what you try to do is you're like, OK, wait, a beta blocker dumps down cyclic AMP. Let me try to raise that person's cyclic AMP in a different fashion. So you could potentially give an agent that has activating activity, if you may, at a GS coupled receptor, right? That GS coupled receptor will increase the activity of adenylate cyclase and increase the conversion of ATP to cyclic AMP, okay? So it so happens that glucagon works through a GS coupled receptor. So you can raise your cyclic AMP through a different receptor as compared with a beta receptor that has already been blocked with a beta blocker. Another useful thing you should also think about with glucagon is you can actually use it as a rescue agent in severe hypoglycemia. It raises a person's blood glucose really fast. Another thing you could also use glucagon for, but this is more for a third year, is if a person has something stuck in their esophagus, the administration of glucagon can actually cause smooth muscle relaxation in the esophagus transiently, and that can help that item pass. okay? And it's one of those bizarre things that may just pop up on an exam out of the blue. And another high-yield thing with glucagon is glucagonoma, right? So glucagonoma, right, as the term says, right? It's a tumor that secretes glucagon. It's classically associated on exams with the MEN1 syndrome, okay? Remember, in MEN1, you have parathyroid problems, you have pancreatic problems like a glucagonoma, and you also have pituitary problems, classically a pituitary adenoma that secretes prolactin. So glucagonoma, the classic thing you want to know with that is these patients classically have diabetes. Because remember, glucagon's job is to raise your blood glucose levels and they also have a skin rash right so the classic the skin rash is uh classically termed on exams as a necrolytic migratory erythema okay so again remember the association man1 so if you get an exam question about a person that has new onset diabetes and they have a skin rash, okay, and they potentially give you like hypercalcemia from a parathyroid problem, think about a glucagonoma with that. That's probably the first thing your mind should jump to on an exam. Now, let's go on to the beta-1 receptor agonists, okay? The big one I'll talk about here is dobutamine, okay? You can give it in the setting of a CHF exacerbation right because in those cases the heart is not pumping very well right so by activating those beta-1 receptors you provide some positive inotropy to the heart okay you could potentially get that person over the hump of an acute chf exacerbation you could actually also use dobutamine for a cardiac stress test okay so if a patient cannot go on a treadmill uh you can try to stress out the heart pharmacologically by giving a beta-1 agonist like dobutamine okay now a quick detour here you can use dobutamine for a pharmacologic stress test but another thing you could actually take advantage of is a principle known as the coronary steel principle, okay? The coronary steel principle. And it also takes advantage of pharmacology. They use a different kind of pharmacology to stress out the heart or to induce ischemia, if you may. So what's the coronary steel principle? In the coronary steel principle, when a person has a thrombus, right? So let's say they have a thrombus that's largely occluding one of their coronary vessels. The body tries to respond by maximally dilating that vessel, okay? Now, the thing is that vessel that's maximally dilated, it's great, right? It's helping you provide more perfusion to that ischemic region of the heart. But that vessel that has been maximally dilated essentially loses its response to the administration of a vasodilator.
Because, I mean, if you sort of think about it teleologically, you don't want that person's blood vessel to, that coronary vessel to pop, okay? So, if that vessel is maximally dilated and you give a coronary vasodilator like dipyridamol, it's a phosphodiesterase inhibitor, I believe I talked about that in a previous podcast on hematologic pharmacology. Or celostazole, which is also a phosphodiesterase inhibitor. Or regadenosine. Regadenosine is an adenosine analog. Remember, adenosine is a very powerful coronary vasodilator. So if you give these drugs, you will dilate all the other normal coronary vessels, but you will not be able to dilate the stenosed vessel. And when the other coronary vessels are dilated, you will increase blood flow through those vessels. And if you sort of think about it this way, if you're increasing blood flow through those vessels, those vessels are effectively stealing blood away from the stenosis vessel because the resistance in those newly dilated vessels from the administration of the vasodilator causes more blood flow through them. So because you're ultimately having less blood flow through the stenosis vessel, you begin to induce ischemic symptoms in the region of the heart that is supplied by those stenosis vessels. That's the principle behind the coronary steel, or I guess the physiology behind the coronary steel principle. This is probably a rare scenario, but a weird thing they can give on an exam potentially is to say, oh, what if a person has like three coronary vessels and all of them are stenosed and maximally dilated? You would not have a positive coronary steel test with those people, right? Because all those vessels are all dilated. But that would be a super, super, super unusual scenario. As long as there is differential stenosis of coronary vessels, you would almost certainly have inducible ischemia with the administration of a vasodilator when you're trying to apply the coronary steel principle. Now, next drug I'll jump to here is isoproteranol. Isoproteranol is a beta-1 and 2 agonist, okay? It decreases systemic vascular resistance, right? Because by activating beta-2 receptors, you increase the synthesis of cyclic AMP, you cause smooth muscle relaxation, and you cause a vasodilation. But it also increases cardiac output, okay? Because it's a beta-1 activator, okay? So one very nice thing they love to do on these USMLE exams is to try to test your knowledge of cardiovascular parameters like blood pressure and systolic blood pressure and diastolic blood pressure and pulse pressure and all that fun stuff when you administer certain Cardioactive agents. I'll talk about that with me or you know in a few in a few minutes. Okay, so isoproterian only increases cardiac output because it's a beta 1 agonist,, but it also decreases your total peripheral resistance because it's a beta-2 agonist. Now, for the beta-2 agents, remember again, your beta-2 receptors, the GS couple, so they increase the QKMP, so they cause smooth muscle relaxation, right? So you could potentially use your beta-2 agonists in the treatment of asthma, okay? So those are your terol drugs, right? So like albuterol, salmeterol, famoterol. Albuterol is a short-acting beta-2 agonist, okay? Salmeterol and famoterol are long-acting beta-2 agonists, okay? You could also use these drugs to relax the smooth muscle in the uterus, right? So like the myometrium. You can use drugs like Ritodrine, R-I-T-O-D-R-I-N-E, or Tributaline, okay? These are both beta-2 agonists that can relax the myometrium of the uterus, okay? You could use them as tocolytics, right? So if you want to delay delivery, right, by stopping contractions for like 24 to 48 hours, you can use a beta-2 agonist like a rhododrine or terbutaline for that purpose. Now, one other thing you want to keep track of is that when you activate beta-2 receptors around the ciliary body of the eye, you actually increase the synthesis of aqueous humor, right? So if a person has a disorder like glaucoma, where they have increased intraocular pressures from too much aqueous humor, you potentially want to give something that blocks those beta receptors, okay? So you want to give a beta blocker like acebutolol or pindolol or nidolol or timolol, okay? These are all beta blockers that by blocking those beta receptors that you find around the ciliary body, you do in fact decrease the synthesis of aqueous humor. You could also treat glaucoma with an alpha-2 agonist, right? Because again, let's reason through this physiologically. If you activate an alpha-2 receptor, you release less norepinephrine. And by releasing less norepinephrine, you release less of an activator of the beta receptors on the ciliary body. So you ultimately make less aqueous humor. That's how drugs like apriclonidine and brimonidine work. They are alpha-2 agonists that can be used to treat glaucoma. Now, let's take a small detour and talk about myurinone. So myurinone is a phosphodiesterase inhibitor it's classically used in icus is a phosphodiesterase 3 inhibitor okay and remember that the job of phosphodiesterase is to break down cyclic amp to amp okay so you're basically inactivating cyclic amp so if you inhibited phosphodi. So if you inhibited phosphodiesterase, you would have less breakdown of cyclic AMP. And like we said, cyclic AMP does different things depending on the kind of muscle we're concerned with. So if you're dealing with cardiac muscle, cyclic AMP leads to the activation of protein kinase A, okay? And when protein kinase A is activated, it phosphorylates phospholamban. And when phospholamban is activated, I mean, when phospholamban is phosphorylated, it becomes inactive. So by inactivating phospholamban, you have less inhibition of a circopump. The circopump is something that actively brings calcium into the sarcoplasmic reticulum of cardiac muscle. So phospholamban inhibits the circopump. So if you phosphorylate phospholamban with protein kinase A under the activity of cyclic AMP, phospholamban becomes inactive. Your circopump becomes active. You put more calcium in the sarcoplasmic reticulum and as more calcium goes into the sarcoplasmic reticulum more calcium can also be released which can ultimately aid in the contraction of cardiac muscle okay so myelinone by inhibiting phosphodiesterase 3 boosts cyclic E AMP levels in cardiac muscle and causes cardiac muscle contraction. But in smooth muscle, when you inhibit phosphodiesterase, you increase your levels of cyclic AMP, you actually have an inhibition of myosin light chain kinase. Myosin light chain kinase. And when myosin light chain kinase is inactivated, you have less phosphorylation of your actin and myosin filaments, and that causes smooth muscle relaxation. So the big takeaway here is high levels of cyclic AMP increase contraction of cardiac muscle. High levels of cyclic AMP cause relaxation of smooth muscle. So let's talk about some cardiovascular parameters in the context of myelin. So myelin, we know it increases cyclic AMP. So if you understood the spiel, I just went on for the last two minutes, you should be able to answer all these questions. So what should cardiac output, what should happen to cardiac output if a patient is placed on myine? It should increase, right? Because again, your cardiac contractility is going up. Now, what should happen to your end diastolic volume? What do you think? What should happen to your end diastolic volume? Well, I hope you're saying nothing, okay? Because your end diastolic volume really has nothing to do with contractility, okay? So your end diastolic volume basically stays the same with murine administration. Now, what happens to your end systolic volume? Well, it should decrease, right? Because when you have better contractility of the heart, your stroke volume increases, right? And if your stroke volume increases, the volume of blood that's left in the heart at the end of systole or contraction, which is your end systolic volume, should go down, okay? So if your heart contractility is increasing, what's happening to your stroke volume on Murino? It should go up, right?
It should increase as well. Right. Because remember, your cardiac output is a proxy for your systolic blood pressure. If your cardiac output increases, your systolic blood pressure increases. OK. Your cardiac output is the primary determinant of your systolic blood pressure. OK, contrast that with systemic vascular resistance. That is determinant of your diastolic blood pressure. OK, so myo-renone increases your cardiac output because it increases cardiac contractility. So it does, in fact, increase your systolic blood pressure. OK, now, what does myo-renone do to the systemic vascular resistance? Right. So think of, again, think about, work with me here. Your cyclic AMP levels go up in smooth muscle. Smooth muscle constitutes your blood vessels, right? So you should have a decrease in your systemic vascular resistance, right? And if your systemic vascular resistance is going down, what should then happen to your diastolic blood pressure? It should go down as well, right? So we've already deduced that milrinone increases systolic blood pressure and decreases your diastolic blood pressure. So if milrinone is increasing your SBP and decreasing your DBP, what should happen to your pulse pressure? It should become wider. It should increase, right? Remember, pulse pressure is the difference between the systolic and the diastolic blood pressure, okay? So your pulse pressure widens or increases in the setting of myo-renone administration, okay? And again, don't forget, again, myo-renone, by decreasing your SVR, your afterload is going down, your inotropy is going up again because it's improving our cardiac contractility. Okay, so let's so i will see we are basically done with the sympathetic agent so let's go ahead and jump to the parasympathetic agents okay the parasympathetic agents so the first thing i will say is if you want to synthesize acetylcholine at a cholinergic synapse okay the first thing that happens is that sodium right remember sodium is primarily an extracellular ion. So as it goes down its gradient into a cell, you can use that gradient energy to pump things against their concentration gradient. So how is this relevant to our acetylcholine synthesis story? Its relevance here is that the first step in the synthesis of acetylcholine is that sodium, as it goes down its gradient into a neuron, it can also drag choline alongside. So there's a sodium choline symporter that brings choline into the cell. There's a drug known as hemicholinium that inhibits that transporter. The next thing that happens is that the choline combines with acetylcholine under the action of choline acetyltransferase or CHAT to make acetylcholine okay and then that acetylcholine is ultimately packaged into vesicles okay there's a transporter that actually makes that happen that transporter can be inhibited by a drug known as vesamico okay vesamico vesicle inhib if you may. And then as an action potential travels down that neuron, right, you change the voltage of the neuron, okay, and as you change that voltage, a voltage-gated calcium channel opens. Remember, that's the channel that's blocked by autoantibodies in the setting of Lambert-Eton-Myasthenic syndrome, okay? So calcium comes into the cell, okay? And that triggers the exocytosis of acetylcholine at the synapse from vesicles, okay? Now, the turn-off mechanism for acetylcholine, right, is acetylcholinesterase, right? So acetylcholinesterase can break down acetylcholine into choline and acetate, right? So you can repeat the cycle all over again. Now, some high-yield pathological integrations here. First is botulism, okay? So remember, the botulinum toxin cleaves the SNAP proteins, like your V and T SNARES, that help you bring the vesicles to the membrane of the neuron to cause exocytosis and release of neurotransmitters. So theulinum toxin its mechanism of action is it cleaves those snare proteins okay and by so by doing that you decrease the release of acetylcholine okay so um how do people get botulism right so uh there are two ways you can get botulism they love to test this on exams to see if you can differentiate between how a neonate gets botulism and how an adult gets botulism. So how does a neonate get botulism? They contract botulism if, for example, they take honey. So that's why pediatricians say, oh, don't give your kids that are less than a year old honey. because honey can contain a botulinum spores okay and those spores uh they can actually germinate in the gi tract of neonates because neonates they don't have a very robust gi flora so those spores can germinate okay as those spores germinate they release the botulinum toxin and then that can cause a lot of trouble for the neon need like a flaccid paralysis if you may but an adult has a robust gi flora okay so in general botulinum spores cannot germinate in the gi tract of an adult so how does an adult get botulism they can get botulism if they consume the pre-formed toxin not the spores the pre-formed toxin okay and the classic exam scenario here is when an adult consumes uh home-canned goods okay they can get botulism with that okay and again remember ultimately with botulism you have decreased release of acetylcholine at the cholinergic synapse so you get flaccid paralysis okay another pathological integration here is myasthenia gravis. Okay. In myasthenia gravis, you essentially form autoantibodies against the nicotinic acetylcholine receptor. Okay. Or I guess just think of primarily acetylcholine receptors. And when you make those autoantibodies, right, acetylcholine cannot bind anymore. Okay. Because again, you're making a competitive inhibitor of its receptor. And if you really think about that, they can actually test that very easily in the context of Michaelis-Menthen kinetics. OK, so if a person has myasthenia gravis, right, their acetylcholine receptors are operating under competitive inhibition physiology. Right. So under those circumstances, your Vmax does not necessarily change, but your Km goes up. So that signals decreased affinity of acetylcholine for the acetylcholine receptor. And in myasthenia gravis, right, the classic testing, I'll say right now, like clinically, the first line test in the diagnosis of myasthenia gravis is to get anti-acetylcholine receptor antibodies, okay? But occasionally on exams, you'll hear about the Tencelin test, okay? How does the Tencelin test work? The Tencelin test is basically a test that involves the administration of a drug known as edrophonium, okay? Edrophonium is an acetylcholinesterase inhibitor. Okay. So when you administer edrophonium, you inhibit acetylcholinesterase, your levels of acetylcholine build up, and those can outcompete the autoantibodies that are parked on the surface of the acetylcholine receptor. Okay. So edrophonium will improve the symptoms of myasthenia gravis transiently. It's a short-acting acetylcholinesterase inhibitor. So most times for myasthenia gravis, you just go ahead and give pyreidostigmine. Pyreidostigmine is a longer-acting acetylcholinesterase inhibitor that also has the ability to cross the blood-brain barrier. Now, one weird thing they can do on the USMLEs is to say that, wait, a person has flaccid paralysis, right? They have like a myasthenic presentation, but you administer edrophonium and those people's symptoms fail to improve. What could be the reasoning behind that? I'll let you think for a second. So think more upstream. What's the rate limit? What's the enzyme that helps you synthesize acetylcholine? That's CHAT, choline acetyltransferase. If you have a CHAT deficiency, you will never be able to make acetylcholine. If you don't make acetylcholine, there is nothing that you can put in the cholinergic synapse that you will try to boost levels off by inhibiting acetylcholine esterase. So if you get a question about a person that has a myasthenic presentation, but their symptoms do not improve with the administration of endrophonium, the very first thing you probably want to think about on the exam is a CHATS deficiency or choline acetyltransferase deficiency.
So they may frame this as a bioterrorism question or they may frame this as a question about a kid that played in a farm that was recently sprayed with pesticides because pesticides, a lot of them contain organophosphates. Organophosphates, they inhibit acetylcholinesterase, right? So by inhibiting acetylcholinesterase, you have a very high buildup of acetylcholine and that can cause a cholinergic toxidrome, okay? So a person will be like hypotensive, they'll be bradycardic because remember, acetylcholine slows conduction through the AV node. If you have enough slowing of conduction through the AV node, you can actually have like a heart block, okay? Those people will sweat a lot, because remember, your sweat glands are responsive to acetylcholine through muscarinic receptors, although remember that that entire system is under the control of your sympathetic nervous system, right? Remember, that's one of those oddities about a sympathetic nervous system where it actually works with acetylcholine through muscarinic receptors. Now, you could also have like urination, right? Because your parasympathetic nervous system wants you to urinate. You could have like fecal incontinence. You would have lacrimation. So like these people are like leaky from everywhere. If you see that, think about a cholinergic toxidrome. OK, another thing that can cause that cholinergic toxidrome is nerve gas. Right. So like sarin. Sarin works by inhibiting acetylcholinesterase. Right. So real quick, how do you treat a cholinergic toxidrome? Right. You treat a cholinergic toxidrome by giving something that blocks muscarinic receptors, right? So you can give a drug like atropine. Atropine is a muscarinic receptor antagonist that can be used in the acute treatment or I guess as a rescue agent in a cholinergic toxidrome. In addition, you also want to give a drug like pralidoxine. Pralidoxine helps you regenerate it's in the hospital i believe it's known as tupam it helps you regenerate acetylcholinesterase right so that you can break down that excess acetylcholine right because there is not many um i should probably not talk about this uh i have some ideas in my head about nicotinic acetylcholine receptors, but that's more anesthesia domain. So I think I'll just sort of let go of that. I'll make some mention of that when we get to anesthesia pharmacology. I'll make a podcast on that. Okay. So I think we should probably go ahead and stop here. I will continue autonomic pharmacology in our next podcast, and we'll just go through it step by step. If you're listening to all these podcasts, you should become an expert in autonomic pharmacology by the end, and you'll probably know all you need for your USMLE exams. So I wish you all the best. Have a wonderful evening, and God bless. Thank you.
Hello and welcome to the Lancet Oncology podcast. I'm Richard Lane and this month we're focusing on a review in the February issue of the Lancet Oncology concerning new and updated guidelines for the use of opioids in the management of cancer pain. Earlier I spoke to one of the authors of the paper, Dr. Augusto Caraceni from the National Cancer Institute in Milan, Italy. Dr. Caraceni, many thanks indeed for talking to the Lancet Oncology. You're one of the authors of a very important paper published by the Lancet Oncology, and this concerns the management of cancer pain. This is clearly a very important issue. Give us some background to your work here, because basically the paper you publish are a series of guidelines, aren't they? So tell us about the background to it. Thank you for giving me this opportunity. The paper actually focuses on the use of opioids in the management of cancer pain. You should position this paper in the history of cancer pain guidelines, which goes back to the WHO analgesic letter and the WHO recommendations guidelines, first published in 1986. And you have to think that this publication and the following dissemination and education campaign was a major change worldwide to implement appropriate use of opioids in particular in this patient population, both because there was no availability of opioids in many countries at that time, but also because the use of the easy, simple method of pharmacological therapy for these patients found a strong professional and public opposition at that time. I think that after that, the European Association of Palliative Care guidelines and recommendations, which were published in 1996 and 2001, were also very important, and they elaborated on those guidelines, and they've been used quite widely for educational tools as a reference for professional associations and patients, and to provide an updated framework of the available evidence on opioid pharmacotherapy for cancer pain. And these goals, the same topics are now updated and developed in this new effort. And I think it's also important to offer a framework for health care policy makers. Last but not least I think these guidelines are very general and flexible to local needs and I think they should be also used for an inter-societal approach to cancer pain management. Can you go on and give us a little bit more detail about the process involved, about how do you actually come up with these new and updated guidelines? Yeah, I think this is interesting because if you compare this with the previous EAPC guidelines, I think we certainly achieved some degree of technical and scientific improvement. This project was made possible by sixth EU framework funding in a project called EPCRC with the specific aim of updating the previous EAPC guidelines. And the process took three years and included a large number of people because besides the 25 final authors of the Lancet Oncology paper, you have to think that at least 100 more people were directly involved from the beginning to developing the final guidelines in several steps. Just to mention briefly, we had a review of the available guidelines and of their content. We identified the topics to be included by an international formal consensus of experts. We identified the best methodology, which is the grade, actually, for guided development, and we published this methodological process. Afterwards, we had a number of authors and groups performing 18 independent systematic reviews. All of these were peer-reviewed and published in Palliative Medicine in July 2011. Finally, the final summary paper published by the Lancet Oncology is therefore a synthetic piece of work based on a much wider analysis of knowledge and also allowing the possibility for the reader to get in touch with this knowledge in further steps. So I think it's a sort of interesting framework for re-addressing more modern way the whole issue of opioids in cancer pain. Are there any particular recommendations? There are many, of course, in the paper, and I would urge everyone listening to this podcast to read the paper. But are there any particular recommendations that you would like to highlight here? Yes, just to summarize, we can say we have 16 topics and a few more recommendations because some of the topics, they lead to more than one recommendation. But just to give to the people interested some flavor of what it is in there, I think it's interesting to see that in our second recommendation, we re-evaluated the so-called opioid of first choice for the WHO Step 3 opioids that are the opioids that are indicated for severe cancer pain. And that all the guidelines and some guidelines still report as morphine being the only first-choice opioid to be recommended. In our guidelines, based on the available evidence, we are saying that morphine, oxycodone, and hydromorphone by oral route, they are all considered potential first-choice step three opioid for moderate to severe cancer pain. So this is already an interesting aspect. And the other one which I would like to recall is, for different reasons, is the one about the use of specific drugs, opioid drugs, for breakthrough pain. As somebody can know or may have noticed, there is some pressure from new drugs coming in the market now for this specific indication. And I would like to make it short, but the recommendation as it reads is very finely balanced in maintaining a role for the less expensive and well-known immediate release oral morphine while also giving the right potential indication for the more modern, fast-acting, potent transmucosal fentanyl preparations that are now quite popular and may be under the attention of many specialists and non-specialist physicians and non-physicians as a potential effective drug for breakthrough cancer pain. And a final thought, guidelines are always essential, up-to-date guidelines, whatever the field of medicine. What do you think clinicians should do now? And also more broadly, do you think now that we have these updated guidelines, is it fair to say that really cancer pain, whether it's early stage or late stage, really ought to be managed properly now because we have the knowledge to ensure that patients are not in pain? Well, for sure there is a part of cancer pain which is not managed appropriately because available guidelines are not appropriately implemented. This is part of the problem. It is also true that I don't believe that after reading our guidelines, everybody will go out and begin to treat every patient in the best way. But I think that guidelines and our guidelines, they have a role. They have an interesting role in many ways. First of all, I think from the point of view of specialists, but also non-specialists, I think they should use them. I mean, try to use them. I would encourage people to use them in their clinical experience. I would encourage specialists to compare their practice with what the guidelines are saying. I would think that they could be used in policy, in education. I think that people around should criticize our guidelines and should participate next, for those who are interested and are in the field, in the process of updating them. Because guidelines are not a finished business. They are making a picture of a situation which is already old when we publish the picture, in a way. So they're dynamic, aren't they? Guidelines should evolve all the time. Absolutely, dynamic process and getting more people involved. And I think another way to use them is to identify potential research questions coming from the guidelines. I will just underline that we are using the GRADE system, so we are giving a weak or strong recommendation depending on what is the evidence. And most of our guidelines, most of our recommendations are weak recommendations based on relatively limited quality and quantity of evidence. So if I may make a plea to the reader, I think that we have not enough research in cancer pain and in palliative care. And I would also ask people interested to join the European Association of Palliative Care Research Network Thank you. And thank you all for listening. See you next time.
Welcome back to Run the List, a medical education podcast in partnership with McG first, I'll introduce the one and only Dr. Naveen Kumar, our gastroenterologist extraordinaire, RTL founder, and an attending GI at Brigham and Women's Hospital, associate medicine clerkship director at the Brigham and also at Harvard Medical School. Without further ado, Naveen, are you ready to run the list? Thanks so much, Blake. So happy to be back. I think I'm now on eight episodes in a row. So I'm going to try to finish strong today and then take a little holiday from run the list. That's OK with us. So I'll begin our case today. It is the case of a 58-year-old female in the emergency department who's presenting with a three-day history of right upper quadrant pain, nausea, and vomiting following meals. She has a history of hypertension and recalled one prior episode of self-resolved afebrile right upper quadrant pain a couple of years ago. Her vitals are 99 degrees Fahrenheit, heart rate of 112, blood pressure of 135 over 85. She's satting 99% on room air and a respiratory rate of 18. She takes lisinopril daily but has had no recent medication changes and no significant dietary changes or recent travel history or illness. There are no notes in the EMR. She previously never had any hospitalizations. And on exam, the EM resident noted that the patient's afebrile. She has tenderness to palpation in the right upper quadrant with a positive Murphy's sign. She appeared dry on exam with dry mucosa and some skin pallor, and she has icteric sclerae. Her labs were notable. She had a normal CRP of 8, ESR of 10, and mild white blood cell count of 10,000. But LFT showed a mild elevation in ALT of 60, AST of 55, and market elevation in ALKFOS at 295 units per liter, the upward limit of normal here being 130, and a total bilirubin elevated at 4.2 milligrams per deciliter. Her lipase was normal and urinalysis was positive for urobilinogen. So that is a lot, Naveen, but I'll pause there. Can you tell us how you start thinking about a common presentation such as right upper quadrant pain? Yeah, absolutely. So with any acute abdominal pain complaint, I like to use the framework from an anatomical standpoint. So with this being right upper quadrant pain, I like to think what organs are in the right upper quadrant of the abdomen. And the two main organs I think about are the liver and then the gallbladder slash biliary tree. So thinking within those two major organs, we can start with the biliary system. I need to think about how can something in the biliary tract cause pain. And so we usually think about pain from the biliary system from a gallstone. And then it depends on where that gallstone is in terms of what kind of diagnosis we're dealing with and what kind of presentation we'll see. So the first type of gallstone that can cause pain is a gallstone in the gallbladder where it is transiently blocking the cystic duct or the passage from the gallbladder into the common bile duct, but it's transient. And so the stone comes up into the cystic duct, causes symptoms for a few hours, and then it falls off. And so those patients have what we describe as biliary colic, or this really intense right upper quadrant pain, usually with nausea, vomiting. And I think the hallmark feature is if you see a patient having biliary colic, you'll see that they just can't get comfortable. They're moving around. They're not staying stationary. They're just, they're very uncomfortable. So that would be symptomatic cholelithiasis or biliary colic. Now, if that same gallstone gets lodged in the cystic duct and does not fall off, then you deal with the issue of acute cholecystitis where the patient will again have the right upper quadrant pain, but this will be constant. And they'll also have oftentimes fever as well as leukocytosis because behind that blockage of the stone and the cystic duct, you're now getting an inflamed gallbladder wall. So that's how I distinguish cholecystitis from cholelithiasis. Honestly, it's a lot more of looking for a systemic inflammatory responses in the colocystitis, which you don't see in the biliary colic patients. And then kind of just traveling down the biliary tree, if that stone, let's say it gets through the cystic duct, but it gets stuck in the common bile duct, then honestly, the presentation may be very similar to someone having biliary colic. They have the pain. They may have some nausea, vomiting, but they don't have the inflammation. And so they generally don't have fever or elevated white count, but they will have elevated liver enzymes because they're actually blocking the passage of bile from the liver. So that's one way to distinguish that from gallbladder disease. And then on top of that stone, if they have inflammation behind the stone, so ascending cholangitis, then you start thinking about things like Reynolds-Pentad, where you have fever, right at required pain and jaundice. And then that's from Charcot's triad. Blake, let me put you on the spot. Do you remember the two others for Reynolds-Pentad? Oh, I might get you here. I think you did. I remember that there were neurologic symptoms as well. Awesome. Yeah. So there's altermental status and then hypotension is the fifth one. And so when they have any of the conglomeration of those symptoms, you can start thinking about, could this patient have cholangitis? But essentially, so with the biliary system, you're thinking about, could there be a stone? If there's a stone, where is it? And is there anything happening approximately to it from an inflammatory standpoint? So that's one major category of causes of right upper carton pain are the biliary causes. And then the other main organ, as I mentioned, is the liver. And so the liver can cause pain, usually in the setting of acute hepatitis, where you have inflammation of the actual capsule surrounding the liver, and that will cause pain. And of those, there's many different causes. There can be toxic, metabolic, they're infectious, there's autoimmune processes. So the differential is very wide for hepatitides. But certainly I'm thinking basically basically let's use the anatomical framework. Let's think about the biliary tree and the liver. And then don't forget, sometimes patients have a very deep right basilar pneumonia that can then cause pleuritis of that area. And sometimes those patients really present with right upper quadrant pain, even though the disease process is in their lung parenchyma. Yeah, I like that because in med school, we learn right upper quadrant pain, we immediately think gallbladder, but there are other anatomical organs in that quadrant of the abdomen. So it's good to think broadly, especially at this stage of working up the patient. So Naveen, as you're further evaluating this patient, what else do you prioritize in your history taking and or labs? And I'm willing to give you the labs again if you need them. No, that's great, Blake. And I think you already did it initially in your presentation. So one thing I always want to ask about if I'm seeing abnormal liver enzymes, which we do in this patient, is was this patient recently started on a new medication? Medication is often a cause for change in liver enzymes. And so I'll always ask that. You mentioned that this patient only takes lisinopril and then gave the permanent negative that there were no recent medication changes. So that's very helpful. You also want to ask about non-prescription based medications. Are they taking any supplements, herbal supplements, things over the counter or even off the counter that you would not normally ask about, that will be very helpful when looking at a patient with abnormal liver enzymes. And so with our patient, I'll just remind our listeners. So you mentioned they had a mild elevation of ALT of 60 and an AST of 55. And so I always think about the ALT and AST together because those are our hepatocellular liver enzymes. So if those are elevated, that indicates that there is some inflammation damage happening at the hepatocellular level. And then you gave us correctly the alkaline phosphatase next, which was notably elevated at 295 units per liter, where our upper limit of normal is 130. So more than twofold rise in the alkaline phosphatase.
So a different pattern of liver injury compared to hepatocellular. And then we finished with the T-billy being elevated at 4.2 milligrams per deciliter. And although I think there is this tendency to use tolybilirubin in conjunction with the alkaline phosphatase, you really should think about it separately because the T-billy can be elevated in either hepatocellular or cholestatic processes. So I think the key thing here is to think about AST, ALTs, or hepatocellular enzymes, ALK-FOS as your cholestatic, and then recognize that T-bill can go up in either case. So once I've gone through that process, which we just did here, right, we said mild hepatocellular injury, but more significant cholestatic injury based on the alkaline phosphatase being over twofold upper limit of normal. I also like to objectively make sure that I am making the correct liver enzyme abnormality classification. And so to do that, there is a helpful calculation you can do called the R factor, which essentially differentiates between a cholestatic versus a patocellular versus a mixed liver injury process. And so the actual calculation is taking the ALT over the upper limit of normal ALT and then dividing that by the ALK-FOS over the upper limit of normal of ALK-FOS. And so what you're essentially doing is you're comparing the ratio of the rise in the ALT to the ratio of the rise in the ALK-FOS. So if you think about it that way, your numerator being the rise of the ALT, your denominator being the rise of the ALK-FOS, you can kind of actually just figure out which one will lead to hepatocellular and which one will lead to cholestatic process. The actual numbers, the way they work out for this R factor is that if that R factor is above five, then that's indicative of a hepatocellular injury. Basically, that's saying that the proportion of the ALT rise is significantly more than the proportion of the ALK-FOS rise. If it's less than two, then that's a colostatic liver injury, basically showing that the alkaline phosphatase rise is proportionally higher than the rise of the ALT. And then if it's between two and five, then it's a mixed picture. And so we do that in this case, and the R factor comes back at 0.66. So less than two kind of confirms our initial feeling that this was a cholestatic liver injury. And then when you think about, okay, so we got a cholestatic liver injury, we got right upper quadrant pain, but no evidence of systemic inflammation, no fevers, no leukocytosis. At this point, I'd be most concerned for a common bile duct stone. Thanks for that, Naveen. I feel like every specialty has their own calculator and we love incorporating math and run the list. So thanks for walking us through your initial kind of diagnostic approach and really talking about how the numerator of ALT and the denominator of ALKFOS are kind of competing in these acute injuries and to think more of a hepatocellular injury or more of a cholestatic injury and using this R factor to differentiate them. So now that you're thinking about an acute biliary blockage, a CBD stone potentially causing cholestasis without the classic Charcot's triad or Reynolds-Pentad, as you like to point out before, what additional workup would you send at this point for this patient? Exactly. So we've kind of honed in on this being an acute biliary blockage, and now we're trying to figure out where is that blockage. So what I would first start out with is an ultrasound. An ultrasound be readily available. There's no radiation exposure. And it very well may confirm our diagnosis. We generally at least want to see gallstones because it'd be surprising to see a gallbladder empty of stones, even if they had a CBD stone. Generally, you see stones in the gallbladder, and then hopefully some evidence that there is a stone in the common bile duct to confirm our diagnosis. Now, you could consider getting a CT scan after, but let's start with the ultrasound. Why don't you tell us what we see in the ultrasound, then we can think about if we need any further imaging. Yeah, definitely. So the right upper quadrant ultrasound demonstrated numerous gallstones within the gallbladder and a dilated common bile duct of one centimeter, but no obvious CBD stone. So would you order further imaging in this case? Yeah, exactly. So we see this presentation, honestly, quite a bit where clinically the patient is presenting with an acute biliary obstruction. We see gallstones when we do the ultrasound, but we don't see a stone in the common bile duct. So imaging wise, we don't confirm the presence of choledocholithiasis with the ultrasound. And so oftentimes I think the next reflex is to get some cross-sectional imaging, be that either CT scan or MRI. But there's a very helpful prediction score that honestly, I think this is probably more readily appreciated within the GI field. But there's an American Society of Gastrointestinal Endoscopy, ASGE, and they have this really helpful algorithm for working up a patient with possible common bile duct stone. And part of that algorithm is that if they have one of these three predictors of the CBD stone, the chance that they have a CBD stone is so high that you basically treat them as such and you go directly to the intervention to relieve the CBD stone. So those three predictors are either seeing a CBD stone on ultrasound, so that's obvious. If they're presenting with ascending cholangitis, so they have the features of biliary obstruction, but also those other systemic features that we went through, the Reynolds-Pentad, that suggest that they're cholangitic, then you're going to directly go to the procedure needed to relieve the biliary obstruction. Or the third one, which is honestly the one that we most commonly see in these patients, is a total bilirubin above four milligrams per deciliter. And so I remember, Blake, you said that her total bilirubin was 4.2. So that gives her a very strong predictor of having an underlying CBD stone. And so with that taken together, we would actually go straight to an ERCP to relieve that CBD stone rather than obtain more imaging before. Awesome. Thanks for that AGSC recommendation. And again, here, since we didn't see any CBD stones on ultrasound, but we did see a dilated CBD, we were kind of tipped off to the potential of this choledocholithiasis and using the T-billy, which in this case is above 4.0. Based on your recommendations, the patient does go directly to ERCP or endoscopic retrograde cholangiopancreatography. Got that. And so the ERCP indeed shows several CBD stones found in the distal comorbial duct, which are cleared via balloon sweep of the duct. And then a sphincterotomy is performed to prevent recurrence of those CBD stones. In addition to monitoring her post-ERCP for any complications, what else should be done before discharge? Yeah, so you mentioned in the ERCP, they do a sphincterotomy. So that's basically where they're making a cut through the ampulla so that it's for two reasons. One, it gives easier access to remove the stones when they do their balloon sweep of the common bile duct. But two, because now they've actually made the ampulla, they've essentially dilated the ampulla by cutting it. If more stones were to form, they will come out more easily. They won't as readily get stuck. But the key thing to do for these patients before they go home is that you need to consult surgery to remove their gallbladder. Because if you leave the gallbladder in place, they're just at higher risk for forming more gallstones that can lead to future episodes of choledocholithiasis. But then also with the gallbladder still in place, they're still at high risk for complications related to the gallbladder. They can still get cholecystitis from formation of future gallstones. I mean, one thing to mention is that even if you take the gallbladder out, what then starts to happen is the common bile duct itself will start dilating in response to no longer having a gallbladder to hold bile. And so with that common bile duct dilating, you still can form stones in the common bile duct even without a gallbladder. So that's a good, important point to remember for patients post-cholestectomy who you're seeing with right upper quadrant pain. There still is the possibility that they formed a stone in their biliary tree. And then also a good reminder for oftentimes we get consults for dilated common bile duct.
So just remember that after the gallbladder is removed, the common bile duct does tend to dilate a bit. But having that sphincterotomy is going to prevent recurrence, hopefully, of another, if a stone were to form, of it getting stuck in the common bile duct. And I just want to mention one thing. This case was nice and clean, and the patient had that very strong predictor of a CBD stone with a T-billy above four. But oftentimes, you don't have that very strong predictor. And so they end up being in this intermediate risk category. And so generally, the patients with intermediate risk, they have a total bilirubin of 1.8 to 4, or they have a dilated CBD like our patient did without that T-billy above four. And in these patients, when you have a clinical suspicion of them having a CBD stone, but not enough to go straight to ERCP, that's when you get imaging. And the best imaging to get is either an MRCP, which is basically an MRI with a dedicated protocol to look at the biliary tree very carefully for a CBD stone, or an invasive approach would be an endoscopic ultrasound. So sometimes for these patients, what they end up doing just to save time is that they go for an EUS or an endoscopic ultrasound to look for the stone. And if it's there, then right in that same procedure, you can convert and add on an ERCP. But if the EUS is negative, then the patient is all set and they're essentially done with their workup for a CBD stone. That was awesome. Thanks for describing, again, some of the complications post-ERCP and potentially post-cholestestectomy and really discussing that intermediate case in patients that don't have one of these three diagnostic criteria for doing an ERCP. So we talked a lot today about how to approach a set of abnormal liver function test labs in a patient who is afebrile with right upper quadrant pain. And we use that to really interpret how to guide patient care in this case. So before you go, Naveen, can you leave us with a few pearls? Yeah, absolutely. So number one is with any patient presenting with abnormal liver enzymes, really spend a lot of time with the history. Think about were they exposed to any potential hepatotoxins? Are they recently started on any new medications? And also, do they have any associated symptoms that could explain their liver enzyme rise? I mean, certainly in our patient, having right upper quadrant pain definitely pointed us towards the biliary tree. Although, as we mentioned before, hepatitis can cause right upper quadrant pain as well. So use your history to first start narrowing your differential. The next pearl is once you see liver enzyme abnormalities, try to put them into one of three categories, right? The hepatocellular liver injury, the cholestatic, or the mixed. Because once you get into one of these three buckets, you can further narrow your differential and your workup from there. I really think the R factor can be a more objective measure of the injury type. I think we all do a kind of gestalt about is the AST ALT most elevated or is it the ALKFOS? But to really kind of clinch it objectively, you can use the R factor, which is again, the ALT over the upper limit of normal ALT, and then divide that by the ALK-FOS over the upper limit of normal of ALK-FOS. And then lastly, for patients like ours who had a very high risk of CBD stone, remember those ASG guidelines, the high risk, very strong predictors are either having a CBD stone seen in ultrasound, having ascending cholangitis, or having a T-billy above four, the next step is to go directly to ERCP, have the ERCP advanced endoscopist sweep the common bile duct, perform a sphincterotomy, and then consult surgery for a cholecystectomy before discharge to prevent future episodes of gallbladder-related stone disease. Awesome. That was so much. Thanks, Naveen, for that and for reminding us about these calculators like R-Factor, these guidelines, the classic signs of right upper quadrant pain. And we hope that you guys enjoyed this episode. I know I did as the host on this. And hopefully you will join us again on another episode of Run the List. Awesome. Thanks, Blake.
This Curbsiders episode is sponsored by the American College of Physicians all-new CME 100 video package. Order now to earn CME at your convenience at acponline.org forward slash 100 curb and use the code 100 curb. Thank you. Okay. These are on. Hey, guys. Hi. Hi, Matt. Welcome back. This feels totally natural. I'm totally at ease right now. What about you, Stuart? Absolutely. That's probably true. Actually, it is. I feel more at ease talking in front of a group of people than I do talking to my computer screen in my office with my door closed and my kids screaming on the outside and cats scratching on the door and then dogs barking in the background and my wife asking when we're going to be done. Well, today we do have a show. I promise we'll get to it. We have a wonderful guest, Dr. Mary Quack, and we're going to be talking about some abnormalities in the CBC and a couple cases. But before we do that, Paul, why don't you tell the audience what we do on this show? Thank you. So sorry in advance, but for anyone who may be listening to this later, you should be ashamed of yourself if you skip past the good parts, which are at the very beginning. I should also mention that this is being recorded as a joint Grand Rounds between Walter Reed and Uniformed Services University, aka USU. But in case, for whatever reason, when they preview this, they decide we can't release it, we'll just say this is at Cashlack Memorial, and I'll bleep all that out. So I think we've covered all our bases. At this point, Paul, you should probably tell them about our wonderful guest. We have a wonderful guest. We are fortunate and lucky to have Dr. Mary Klock, and I will now tell you about her without stumbling through her biography. She attended undergraduate at University of Washington with a BS in biochemistry and a BA in anthropology in Seattle, Washington. Attended medical school at Uniformed Services University of the Health Sciences. And this is where I pause for applause. Do you guys do that? There we go. And her internal medicine residency and hematology oncology fellowship at Walter Reed Army Medical Center. Thank you. Dr. Clark was also a research fellow in multiple myeloma at the National Cancer Institute and currently is the program director for the hematology oncology fellowship Program at Walter Reed National Military Medical Center. And with that, can we present Dr. Mary Kwok. Well, Dr. Kwok, we'll call you Mary from here on out if that's okay. Please do. Yes, thank you. So we are always going to start off our show with this easy question. Can you give the audience a one-liner about yourself? Include something outside medicine. Of course. Okay, so let's see. I am an Army oncologist, hematologist oncologist, here working currently at Walter Reed National Military Medical Center, which is in Bethesda, Maryland. I am currently the program director of the Hematology oncology fellowship, but probably more accurate to think of me as a PGY-12, because the truth is I'm constantly learning new things, not only in hematology and oncology, but learning from the house staff here, from things in general medicine. Outside of the hospital, I am married to a gastroenterologist, so that's kind of inside the hospital too. And I'm a mom to three girls, ages 3, 6, and 10. On the side, I like to try to cultivate a garden, but it's probably a good thing we're not dependent on it for our food. Okay, so that's an aspirational goal. Absolutely, Yeah. What are you growing? Snap peas, little peppers, and then, you know, like other things, but the rabbits or something keep eating them. This keeps coming up on the show that many guests have said that they're gardeners. And I keep saying I'm going to start a garden, still have not started a garden. But I, you know, maybe now this is like the fourth or fifth time I've probably got to do it. I keep saying it publicly too. So. So Dr. Kwok, is it Uniformed Services University or is it Uniformed Services University of the Health Sciences now? Uniformed Services University of the Health Sciences. Okay. All right. So that's wrong. Got it. Incisive. Good stuff. So is there, in your estimation, is there a favorite book, you can't get that anymore, Paul, that you think every physician or learner should read? Yes. Yes. Okay. So for our hematology oncology fellows, we've wanted them to read Emperor of All Maladies by Siddhartha Mukherjee. It's an amazing history, the story of cancer and where we are today with cancer therapies. I sent all our incoming fellows an advanced copy for them to read and hopefully they've read it before they arrive. But really, I think there's this quote by like Sir Isaac Newton that says something like, if we see further now, it's because we stand on the shoulder of giants. And I think that reading this history and knowing where we came from makes us better oncologists now because of all the work that was done before. But if I could give a second book, I think all doctors should probably read When Breath Becomes Air. So this is a book that outlines a story. It's actually written by a physician, a neurosurgeon, I believe, who was diagnosed with metastatic lung cancer. And the book was, I think, finished by his wife after he passed away. And maybe it was because I read this during a period of just personal burnout that it really reminded me like, oh, this is why I went into medicine. This is why I went into oncology and has really encouraged me to think about the patient's perspective. And so I think that would be a great book for all physicians to read. Just FYI, in case you pick it up, I read it like while I was seated on the aisle seat of an airplane. Nobody told me that I needed tissues or should have chosen a window seat because there were like tears streaming down my eyes. And so just for future reference. I'm sure the people in your row were super comfortable during that flight. It's just the turbulence. My seatmate's having a nervous breakdown right now. Yeah, the flight attendant, I'm sure, appreciated it. I'm generally, but we've talked about that book before. And I read it. I generally don't like to read stuff like that. My father actually died complications of cancer therapy. But I actually found that book helped me more than hurt me emotionally, if that's a thing to say. But I really enjoyed it. So even for someone who generally I never read stuff like that, I really liked it too. Let's punt it to Paul. Yeah, no, I was going to ask about best advice, but it sounds like bring Kleenex. But I guess more specifically, your best advice you've received, either as a learner or as a teacher, so more specific to medical education, what sort of wisdom can you pass on for us? Yeah, so maybe I'll say as both, is to set goals for whatever you're learning. And so right now I'm rotating on the wards. It's probably been my umpteenth time rotating on the wards with health staff. And so it could become very, very routine. But I think that if I set goals for myself or if the health staff are setting goals for themselves, within two weeks, I think we could accomplish something. And so that's been the most, I think, tangible and measurable type growth as a learner and as a teacher. Can people up in the back hear us when we're just talking? Okay. So we won't worry about the house system. I can see it's still picking up on my recorder here. So we should be okay. What are you? Okay. All right. Let's get on. Did that work? I don't know. Did it? I don't know. No. All right. Let's just forget about that. We're getting distracted. You're the king of distractions for me. But it's working. How's Grand Rounds? All right. It was great. They spent 20 minutes pushing a dial. It was fantastic. I learned a ton. So this is the part of the show where we like to just spend a lot of time on a technical difficulty. But actually, we wanted to bring some picks of the week to you. And I'll throw it to Paul first.
Thank you. Yeah, no, I wish I hadn't. I've got to be honest with you guys. I find you to be a really intimidating crowd. I feel like a worse person in front of you, is I guess what I'm saying. And so my pick of the week was initially, I think, going to be John Wick 3, but then I felt really just uncomfortable recommending that. But guys, there's a scene where they're using display knives and they're just hucking them at each other. So if you like that kind of thing, John Wick 3. But you're better than that. You probably would not be interested in that. So I think I'm going to recommend a movie-related podcast. It's the movies that made me. And it's Joe Dante who actually directed Gremlins and this guy Josh Olson, the screenwriter. And they bring in this third guy. And basically, it's just three lunatics Thank you. and really, really passionate about something, unlike us three. So it's nice to sort of listen and hear experts discuss something that they really, really enjoy. So even if you're not a huge movie fan, I got a lot out of it. So it's the movies that made me. Or John Wick 3. I definitely want to see John Wick 3 now. I would like to recommend an episode of the Tim Ferriss podcast. I'm a big fan of that podcast. He recently had an episode where he interviewed Julie Rice, who's one of the co-founders of SoulCycle. And in general, I'm obsessed with listening to people that have founded things and built things talk about how they did it. What I thought was most usable from what she said is that she had a partner, a co-founder, and they actually saw a therapist kind preventively, like when they first formed their partnership, they didn't know each other that well. And they were seeing like a therapist slash coach. And from that partnership, they learned how to like work together, how to negotiate with each other. And they actually founded their whole company's culture based on that. And it's sort of built into the culture from the top down that way. I think it's a very inspiring interview. And just as someone who works in a big team on this show, and then just she also even talked about partnerships in her marriage. I thought it was really useful for any of you who are interested to listen. So I thought we were going to be passing up on the picks of the week. One of the ones I wanted to recommend, one of the ones I wanted to briefly talk about is a Travis Malloy film called Infinity Chamber. It's kind of like a sci-fi Groundhog Day where this individual is put into prison and then essentially lives the same day over and over and over again as they're trying to glean information from him. It's actually quite poignant, in fact. The ending is a little bit surprising. You've got to look for a couple of very subtle findings. But what I found interesting is that the individual who directed this film is the same individual who had written the script for another film that I really liked called Pandorum. So if you know anything about sci-fi and you know anything about the first film,, 2021 lectures, and associated Q&A, plus an exclusive 25 bonus CME sessions. You can stream the sessions, answer brief multiple choice quizzes, and earn CME credit and mock points anytime, anywhere. Our team attended the American College of Physicians internal medicine meeting this year, and it was fantastic. There were so many great clinical sessions, and as hard as we try to keep up with the literature, we still learn so much practice-changing knowledge. So definitely check out this video package. Order ACP CME 100 now and start earning CME at your own pace. Visit acponline.org forward slash 100 curb and use the code 100 curb. That's acponline.org forward slash 100 curb and use the code 100 curb. We definitely want some time to talk about medicine. Let's move into a case here. And I think we have some clever names. Yeah, I'm not proud of this one. So we're going to start with Lucas Aitosis. And again, I'm sorry. He's a 55-year-old male. He's presenting for primary care. He has no complaints. He's here at the behest of his wife. Hopefully our information matches up with what's on the screen. It does not. Fantastic. Why don't I actually see what we're looking at here? There you go. It's there now. Great. So where are we at? He's presenting. He has no complaints. His wife has made him show up. And then his past history seems good for some tobacco use. He's a little bit overweight. He uses Tums for heartburn. He takes ibuprofen for shoulder pain. His vital signs and exam are grossly normal. In a moment of weakness, you let your resident order a screening CBC, you know, just to get a baseline. And then you're stuck with it because the white blood cell count comes back at 13.1. And it's 60% neutrophils, 25.6% lymphocytes, 2.6% EOs, 0.7% basophils, 11.1% monocytes, and no bands. The remainder of the CBC is normal. And here we are. So we're going to use that as a launching point. Just from the start, knowing that I'm an inherently lazy person and I'm presenting this to you as someone I don't know what to do with, what information is important to you and sort of where should we start with this case? Yeah, so in the CBC, the white count, generally hemoglobin platelets, the MCV and the diff are probably the parts of the CBC that we look at regularly. The rest are there and may play a role sometimes, but not usually. So we want to do calculations of the absolute neutrophil count, absolute lymphocyte count, etc. And so knowing the absolute counts is the most helpful. Now, you gave us some history that the patient is here, and it sounds like he's coming in just for routine care. And so this is a CBC for someone who's totally asymptomatic. Correct. Okay. As one does. Right. I mean, I love my CBC. Like, I love my morning coffee. So I don't know about you all. But now you have an abnormality and you have to figure it out, right? So probably the biggest abnormality on this gentleman is that he has a white count that's elevated. Excuse me, a white count, a neutrophil count that's elevated 7,800 and a monocyte count that's elevated at 1,300-ish. Yeah. So those are the two that jump out at me. I wanted to just go back to what you said. I've always was initially taught to look at the differential, but it sounds like you like to look at the absolute counts. Is that more useful for us? Because they usually report it out, differential, like the percentages at the top and then the absolute counts at the bottom. Sometimes they don't always match up with like what's normal, what's abnormal. Right, right. So we generally skip over the percentages or make a quick calculation and pay attention to the absolutes. So what is, when someone comes in with like, you know, in primary care or whether you're in the hospital wards, I think like most CBCs are abnormal if you're seeing a patient that's worthy of internal medicine. Like they almost always have abnormal CBC. I just don't waste my time. Yeah. I'm just like, oh, normal CBC, get out of my office. What are some immediate red flags that might just be like automatic hematology oncology consult? So specifically with the white count, is that what you're asking? Yeah. So this has to do with the diff, right? So anytime you see blasts on the peripheral blood smear, we want a consult like ASAP, right? But the rest of them really depend on the clinical scenario, right? So neutrophilia, maybe think of an infection. And then this person is a smoker, right? And so smoking is probably a very common cause for neutrophilia without any other reason. If they have a lymphocytosis, then we start thinking, you know, could they have a lymphoproliferative disorder? And then certainly for a monocytosis, particularly if they're older, you know, we think of maybe CMML, chronic myelomonic... Just CMML. Yeah. Sorry. We got you.
And so these would be things that we would want to work up eventually. But probably blasts or super high counts we would want to see right away. Oh, I'm sorry. I left out one. Basophilia. Basophilia. Yeah. This is never normal. And so basophilia raises our suspicion for a myeloproliferative neoplasm, and we'd want to see them right away as well. And when you get the, I just tend to see a lot of people with like a eosinophil count in the 5% to 10% range, and I'm like, oh, there's that. And then I'm just like, you know, if it's like 30%, and then obviously the absolute count's going to be really high, and I'm going to be... Has absolutely nothing to do with their diarrhea there, Matt. So actually, an absolute eosinophil count of over 1,500 gets our attention. Less than that, you know, maybe it's an allergic reaction, maybe it's medications or something like that. And as an internist, I think for me, the favorite thing to do with lab abnormalities is just keep repeating them until they go away. I'm wondering, in this particular patient, is that a reasonable approach? Is there anything that sort of warrants immediate referral just based on what you know? Or would it be reasonable just to say, huh, that's weird, and just recheck it first? I would repeat it first. I think that's generally a good rule of thumb. But if you repeat it and find the same thing, probably the next thing I would do is ask him to stop smoking and then repeat it. That's a hard thing to do. Did you guys ever want me to advance the slides? I mean, we do have some, like, tables and stuff. That's okay. Okay, cool. Yeah, you can advance the slides. That's, uh... Advance. I'll let you have fun with that. Mine's not working anymore still. Again. And again. Perfect. And this is the part of the show where Stuart brings us back to the technical difficulties we've been having. For five sweet minutes, it looked like a professional operation, and then it just went off the rails. Mary, we talked about this a little bit before we started recording. The peripheral smear, when we order that, what exactly happens, and who's looking at that, and how confident are you when you send one? Do you always look at it yourself? You're probably qualified to. I don't think I am anymore, nor was I ever. So a peripheral smear is typically created and read by the hematology tech at the bench. If they see any abnormalities, they'll typically ask a pathologist to take a look at it before they certify the thing. And so sometimes it'll read uncertified until it is certified. Here, what we would typically do is ask them to make a peripheral smear and then look at it ourselves. And if there's something that looks a little bit funny, we have very willing hematopathologists who would look through it with us. And so we're fortunate in that way. Okay. Yeah. It just, for all these cases, it just kept, you know, coming up. Peripheral smear. Yeah. And then when I get them in my hospital, I'm like, you know, who's looking at this? How much do I need to, you know, I cash back. We have a lot of sketchy personnel. So it's just like, I'm never sure what's quite going on. All right. And I wanted to ask you a little bit about like, just in general, the leukomoid reaction that people mention all the time. Is there a certain cutoff for that? Or how do you, is that ever worrisome? Yeah. So generally a leukomoid reaction means that you have a high neutrophil count without a malignant etiology. So a benign etiology for a high neutrophil count. I can't say that I've used that word since medical school. And so, um, I, yeah, the reason it's come up like a couple of times recently is just someone has like a really high count and we're just like, all right, it's, it's, we do this thing called a pro cal now. A pro cal. I don't know, Stuart, teach me something. You don't know what a pro cal stonin is? No, I do. I do. But I, I mean, I, that wasn't on my like pathway. So I mean, the way that I would approach it in this case is that if they have elevated neutrophil count, I'm going to check a pro-cal because that's going to determine to me, do I treat this as an infection? Do I look for something else that's going on that I'm missing potentially? Or do I consider sending this to my hematopathologist in order to do potentially a bone marrow biopsy and look at a plate, a smear, whatever. Is this expert opinion or guideline-derived? This is Stuart-driven opinion. And do you mind me asking, in this particular patient, just because I do like the physical examination, are there certain areas other than, I'm not sure I've ever actually felt a spleen tip, if I'm being completely honest, but are there certain, what sort of physical examination features are specifically important for leukocytosis or this type of patient? Right. So a spleen exam is really important, and then also a lymph node exam. And then if they have any other signs of infection, you know, you want to be looking for that, right? So when do we get to the big test that I don't know how to interpret, the bone marrow biopsy and the flow cytometry? Is that at all part of this pathway for someone with leukocytosis? So, yes and no. So I think that in someone that comes in with a neutrophilia, probably not our first go-to test, but if someone has an elevated lymphocytosis, so an absolute lymphocyte count over 5,000, or sometimes even if it's less than that, or if they have lymphadenopathy or anything else that makes you concerned for a lymphoproliferative disorder, this is where flow cytometry can be really, really helpful. So flow cytometry, can I talk about it for just a second? Please do. Oh, okay. So what it is, is you take someone's, you know, blood and then it's tagged with all these different markers and then run through a machine. Like millions of cells are read individually at a time and then they're put out on a scatter plot. And essentially what, you know, what the pathologist will identify is normal populations of cells. And then what they're really looking for is an abnormal population of cells. So these might help us identify like maybe a clonal disorder, a clonal, typically B cell process or T cell process. But you can also pick up blasts this way, myeloid or lymphoid blasts as well. I usually involve a hematologist before I order that. Is that good practice or should I just be like, do you want me to do that before I send this person to you with their, with their lymphos, absolute lymphocyte count that's elevated? If they have an absolute elevated lymphocyte count, I actually think it would be okay to send it. And if they had like smudge cells on a peripheral blood smear or something like that. I like to impress my consultants. I think Paul, Stuart, you guys probably feel the same way, right? Sure. I have not done it yet, but that's the dream. So how does this case end, Paul? I'm curious to know. I think we follow my approach. We repeat the labs until he's better. Okay. Yeah. So he got better. Yeah. He came down. Hey, everyone. You know I love my Birch mattress. I've had this thing for about six months now, and I am sleeping great. It is soft. It is comfortable. And I'm now realizing that my old mattress, which was like 10 years old, was too firm and very uncomfortable. My Birch mattress is organic, non-toxic, it's made right here in America, shipped right to your door. Birch offers free shipping, free returns, they have a 25-year warranty on their mattresses, and a 100-night sleep trial, so there's really no risk. They're made with just three materials, organic latex, New Zealand wool, and American steel springs, and they donate 1% of all sales to the National Forest Foundation.
So visit birchliving.com slash curb and check them out. And Birch is giving $200 off all mattresses and two free eco-rest pillows at birchliving.com slash curb. That's $200 off all mattresses and two free eco-rest pillows at birchliving.com slash curb. He's presenting just for a work physical. Minimal history other than he had maybe a sinusitis a couple weeks ago. He was treated at an urgent care with a medication that maybe started with the letter A. Takes occasional ibuprofen for joint pain in his hands. Mom had arthritis from a young age. Father's history is not entirely known. Denies any drug, alcohol, or tobacco use. He's sexually active with three female partners and usually uses barrier protection. And so you decide to fire your intern because you do a screening CBC. And it comes back with 28% PM&Ns, ANC of 1,100. The remainder of his counts are normal. The remainder of his labs are stone cold normal. And now, again, you're stuck with this healthy patient without really any kind of complaints who's now here with this sort of wonky white blood cell count and an ANC that's low. So now what? Yeah, this is commonly seen as well, actually. So I'd want to know historically if he had access to his previous CBCs, what his white count was before. Can we go through both scenarios? So let's say this is we're meeting him for the very first time and we got nothing. So then how would you approach it? So we don't know if this is new or if it's old. And also in the setting of a recent infection where he might have gotten some sort of medication, that would be my first thought. Could it be a medication effect or somehow related to whatever his infection was? Maybe it was bacterial, but maybe it was viral, right? We don't know. So then the first step would actually be to repeat the CBC. I love it. You're speaking Paul's language. Are you a hematologist? Are you trained? I do flow cytometry on him. I'll see what happens. But say, you know, you had access to his labs before. And I'm sorry, staying on this case. So say it was not associated with a one-time infection. Maybe he's had chronic sinusitis, and maybe this is something that is now a problem for him. He's symptomatic, right? Then we want to find out what's going on, right? So I would repeat it. If it's still low, then look for other causes. If he doesn't get better, then you want to know, you know, what else could be driving this. And so this is where you look at the rest of the CBC. You know, you don't want to miss any blasts on the peripheral smear. You don't want to miss any other cytopenias that might be directing you more toward a bone marrow problem. And if you went back and you get old records miraculously, I'm not sure how well you guys do, but I feel like I'd never get them. But it actually turns out his counts have been consistently like this for, say, the past three years. How does that sort of change? Yeah, so we actually have an amazing EMR. That's very nice. Congratulations to all of you. And so we could potentially get some historical data. If it looks like that he's had neutropenia for a long time, right, but asymptomatic, meaning no problems with recurrent infections, then I would be thinking, could this be what we call benign ethnic neutropenia? And so I'd be interested to know, first of all, what's his ethnicity? And then there's actually a lab test that we could obtain to confirm benign ethnic neutropenia. And so one way that we could do this is by obtaining a phenotype of the RBC to see if there's the presence or absence of Duffy antigen. And if someone is Duffy null, meaning they're negative for the Duffy A and Duffy B, then that would be Duffy null and consistent with benign ethnic neutropenia. Once you confirm that and they're asymptomatic, send them back to their PCM and they don't have to follow up with you. You look so happy right now. Part of this case was, as I was just doing a little bit of pre-reading, which very occasionally I do, I tried to give this case kind of a flavor of maybe an underlying rheumatologic issue of some kind. How often is sort of a neutropenia sort of a harbinger of an occult or maybe not so occult rheumatologic process? I actually don't know if it's like a harbinger. Usually it's seen concomitantly, right? So if someone has, you know, symptoms of say a rheumatologic process or their ferritin sky high, then certainly that can be associated, say like in Felty's syndrome or something like that. To recap, it basically sounds like you look for drugs that might have caused it, look for some infections. If they have an obvious autoimmune process of some sort, that might explain it. Otherwise, we might check a Duffy. See if they're Duffy Null. Am I using the lingo right? That's correct. I want to sound cool. Is that one word or two? It's stuffy antigen. Yeah. Two words. Got it. Are we back to the technical difficulty show, Stuart? Why don't we go on to, are we done with this case, Paul? I think so. Why don't we move on to Coach Tony? All right. So we've got Coach Tony here. Go ahead and advance one more slide there. So just like our prior gentleman, this is a 55-year-old gentleman who's coming in. He's requesting actually that we start testosterone replacement on him. This is not infrequent in some of the clinics that I work in, unfortunately. So a quick peek, however, at his last CBC and prior CBC suggests that his hemoglobin has really been 16 to 18 range, give or take, for at least the past few years. He denies a history of chest pain, of any DVT-PE, or unexplained weight loss. Past medical history is significant for obstructive sleep apnea. Not surprising considering where I typically practice medicine. Medications include chlorthalidone and past surgical history. He is a non-smoker and he drinks about one to two alcoholic beverages per week. Go ahead and advance it one more there. But unfortunately, he says he's half the man he used to be. He really wants that testosterone replacement. So first off, before we go to the physical examination, what are some things that you're thinking about right now? Just... I've seen the picture up there. Don't look at that. So that's a pretty high hemoglobin, right? So for a man, if the hemoglobin is over 16.5, that certainly gets their attention. Right. One, we want to know again, is this new or is it something that he's had lifelong? Oh, this is definitely not new. No, no, no. So he's had it for a while. He has. And, you know, is he symptomatic? Has he had any complications related to this? No, he pretty much denies everything because he really wants a testosterone. Right. Okay. So then the next question becomes, you know, what's driving this? So he has some personal risk factors, but then it's possible that this could be a bone marrow process, another myeloproliferative neoplasm. So what are some things that we should be looking for in examination before we even start to take a look at them? Right. So the MPN or the myeloproliferative neoplasm that I'm thinking of is polycythemia vera. And so generally for P vera, what you want to see is do they have an enlarged spleen? So on physical exam, I'd specifically look for that. And then you'd want to see if they have any symptoms related or physical exam findings related to the erythrocytosis. Right. Go ahead and advance it one more there. So you've got the gist of his exam, which is probably about as good as I'll get it when they consult me for who knows what. So his pulse ox is a little bit low, but it's not really significantly low. He has a ruddy appearance to his face. He's a little bit red when he comes and sees you, but he says he just rushed in from outside and it's about 105 degrees outside, not here, but where I typically practice medicine.
With his MCV being normal, the RDW is not elevated. So what else would you want to know at this point? So I think the first step for this would be to check an EPO level. I would want to know, is this erythropoietin level elevated or is it low? So it's like a feedback loop. If it was low, that would mean that these RBCs are being produced without any stimulation. And that would make me think more of a primary erythrocytosis like polycythemia vera. But if his EPO level is like normal, inappropriately normal, or even elevated, then it would make me think there's something else driving this. For instance, like hypoxia, maybe related to his OSA, or maybe he has some underlying lung disease. You know, possibly also something stimulating the kidneys. So renal cell carcinoma, certainly, but also renal cysts, renal artery stenosis, things like this can also stimulate EPO production. And then lastly, there's some tumors that could do this too. Okay. So even before that, is this a patient that you would want me to send to you or you think that I should be working this patient up before I send them to you? So if you could check an EPO level on your way with your referral, I think that would be probably the most helpful because that impacts our immediate decision-making when we first see them in our clinic. Should I just immediately order a JAK2 mutation? Okay, so it might not be unreasonable, but it might be a better use of resources, maybe if you started with an EPO level and then did the JAK2 later. Excellent. I will not wear the JAK2 next time. All right. I don't know if we can advance. We'll try again. Oh, my gosh, it's working for one slide. Okay, great. I think we have it on record, Stuart, that Mary told you not to order a Jack 2. I did on this patient already. So, unfortunately. Let's see. We already talked about that one. This is amazing. All right. So, other things about him. So, his EPO was elevated. Jack 2 was negative. All right, guys? It was negative. So, we don't have to worry about that, so to speak. But there's some concerning findings on him. So he does not like his APAP. How often does sleep apnea actually cause a secondary polycythemia? Is that a common thing? Is that uncommon? I don't know. Yeah. I think it's a hard thing because then you're hoping the patient's actually going to be compliant. And they're not. I'll start off with that. I don't want to sound like I'm just saying they won't ever be compliant, but anecdotally, it's southward of 50%. I would say most of the patients that I've seen with this sort of thing, they're smoking and they probably have sleep apnea and it seems like it's a multiple hit situation. But if you tell them that if they're compliant with their CPAP and they're smoking, and they probably have sleep apnea. And it seems like it's a multiple hit situation. But if you tell them that if they're compliant with their CPAP and they're not having any significant blood discredits, that you're going to give them testosterone, I kid you not, their compliance report is almost 100% all the time. But that's only for 30 days. We did want to ask you with this case about some of the fancy terms, aquagenic pruritus and erythromelalgia. Can you tell us about those a little bit? Yeah, sure. So aquagenic pruritus is kind of just what it sounds like, right? So that's like itching or maybe like burning or stinging that's triggered by exposure to water, right? That's weird. Sometimes patients will describe like, you know, with a bath or shower that they get itching. And so why it happens, I don't really know. Maybe some sort of histamine release, but it's a real thing. And then the erythromelalgia is actually really interesting. It's erythema. There's a great picture here that seems to happen in the hands and feet that seems to be associated with polycythemia vera specifically. So this, Stuart, your patient, his quest was to get you to prescribe testosterone. How did you hack this situation? Not very well, as you already know, right? So this specific patient, his hemoglobin was actually not that high initially. So we're talking years ago. I've had the same patient for a very, very long time. So anywhere from like 14 to 15. His testosterone level was less than 65. It was very, very low. Had a history of anabolic steroid usage. So had secondary hypogonadism with other things going on at that point. Not compliant initially on his CPAP. Came back with a compliance report that was 30 days, looked great. Ended up putting him on testosterone after being fairly convinced that we'd be okay. But then after being on testosterone for a period of time, his blood counts shot back up. So not shot back up, but started to shoot up. So initially, the hematocrit was less than 50%, but came back within a period of a couple of years. And yeah, his hemoglobin was 19.2. So the next question they gave me, and one that I don't even know how to approach, I was like, look, guy, I'm not going to give you your testosterone at this point. He's like, well, can I just go donate blood? I don't know. What do you think? Yeah, I don't know either, but I don't think that would probably hurt him. I don't know that that's a great long-term solution either. Just tell him to put some leeches on his fingers and walk away. Right, yeah. I think it's a reasonable option. The leeches? The phlebotomy. In a similar patient at Cashlack, I did convince a hematologist to, because the patient had such great responses to prior testosterone and was so insistent about it and compliant in every other way. We did him a solid and we would do therapeutic phlebotomy and he was put back on testosterone once the level had dropped down. Do not try this at home without the approval of your local hematologist. Right. So the concern is that if someone has a really high erythrocyte count that they would be at risk for thrombosis, right? So that's like the big thing to look out for. It's, I think, way better understood in the setting of a myeloproliferative neoplasm like P. vera. In other settings that are secondary, you know, is it as strong? Not so sure, but probably it's a good idea to bring the numbers down a little. I knew it. So I hope everyone in the back can hear us all okay still. So our final case is a case of Lola Platelets. She's a 47-year-old female. You're right to groan. That is correct. It's the little things in life. I mean, I know it bothers Paul so much that we just had to go with this. This is the one time I didn't go along with him, and I should have. Yeah. So Lola Platelets is a 47-year-old female. She comes in as a new patient. She's complaining of fatigue. She's got a history of multiple sclerosis, some neuropathy. She used to smoke, doesn't smoke anymore. She's on some meds, duloxetine, pantoprazole, vitamin D, B12, pretty normal physical exam. On her lab, she has a hemoglobin of 11.2, platelets of 96,000, white blood cell count 9.5, the MCV is 90, the RDW is 15. So with this patient, I mean, what jumps out at you about it and how might you approach this? So this is a patient that comes in with mild thrombocytopenia, right? So a normal platelet count being somewhere between 150 and 450. She's in the 90s, right? Yeah, 96. Okay. And then otherwise, she's having mild symptoms of fatigue. So you wonder if that could be related or not either. Looking at the rest of the CBC, however, she doesn't really have an abnormal white count.

Subsets and Splits

No community queries yet

The top public SQL queries from the community will appear here once available.