Think Fungus Early: Preventing Angioinvasion Via Early Detection With Gary Procop

Hi and welcome to Meet the Microbiologist, the podcast about the people who discover, innovate and advance the field of microbiology. I'm your host, Ashley Hagan, and today I'm joined by Dr. Gary Prokop, CEO of the American Board of Pathology and Professor of Pathology at the Cleveland Clinic Learner School of Medicine. Welcome to the show, Gary. Thanks so much for having me. Excited to be here. Yeah, we're so excited to speak with you today. I'd love to know more about your background and how you became interested in clinical pathology. Well, you know, I've always been interested in microbiology. I remember probably started back in an eighth grade science class, which I think, you know, probably speaks to the importance of, you know, a good science education. And I remember watching the old black and white films of individuals, you know, going off to the heart of Africa and, you know, fighting strange and exotic diseases. So that probably was the seed that was planted many years ago. How cool. I love hearing that that started so young. And so if your interest began when you were really in junior high, how did you facilitate moving forward in your career? You know, what were some of the steps at that early age that allowed you to get involved with science and then how did that translate to microbiology? You know, I think always interested in science classes and, you know, then, you know, having experienced them through high school and going through all the high school science classes started to give you a taste of which type you'd like. And, you know, in the beginning, I was interested in being a high school biology teacher and then became more and more interested in microbiology, which got me more and more interested in medicine. And, you know, really didn't know that much about clinical microbiology until, you know, I discovered it through a, you know, through a friend in class and then took that route to a profession. Very cool. And where did mycology come in? Is there something in particular about this group of microorganisms, the fungi, that's captured your attention? You know, I have to say, I really like all different types of infectious diseases. But I had a very good mycology professor in undergrad and I think that's probably another important point to underscore and we've noticed that we've studied individuals that go into pathology because a lot of people that finish medical school don't go into pathology. So we've studied those people that have and most of them you can draw, you can connect the dots back to a mentor. So I think having somebody really important early in life that demonstrates how interesting a certain field of microbiology could be, that probably is what got me interested in medical mycology. Yeah. That makes sense. And what was it that this particular mentor showed you that made pathology so interesting after medical school? Yeah, you know, I think, you know, just all the variety of different types of diseases that these organisms cause, in some ways, they're a little bit underrepresented. You know, we have important molecular diagnostic tests for, you know, transplant associated viruses, CMV, BKEBV, but we still have transplant patients that are succumbing to invasive fungal infections. And the types of tests that we have are really limited, often limited to culture, antigen detection tests, those types of things, some histopathology, you know, we really haven't yet exploited the power of molecular diagnostics in a routine way for mycosis. And why do you think that is? That's really interesting. I think that, you know, often, you know, underrepresented or less frequently encountered organisms may be one of the issues. The other issue is there's such a great variety of different types of fungi that can cause infections in these patients that, you know, you can't build one single assay, or it's difficult to do that, surely it's proven difficult to do that, but, you know, with the advent of next generation sequencing, you know, kind of broad range PCR, there's hope on the horizon for advanced diagnostics for early detection. And the real key is early detection of fungal infections in immunocompromised patients. Absolutely. And why is that early detection so important? Well, you know, once, so many of these organisms are what we call angiotropic, they actually grow towards blood vessels, and they grow into blood vessels. And once the fungus has penetrated into the blood vessel, the blood essentially clots, right? And so once you have a blood clot, then the tissues downstream from that blood clot are going to die. That's called an infarction. And so now you have not just an invasive fungal infection, but you have dead tissue beyond the site of angioinvasion, and you can't deliver antifungal drugs to those areas because the blood supply is stopped. So in those really invasive infections, like a mucormicosis, for example, you really have to take a combined surgical and medical approach if you're going to save those patients. Which is really just so invasive all the way around. Right. So, you know, I'm sorry, just circle back. So if you catch them early, that's why the early detection is so important. If you could catch them early, then you could initiate appropriate antifungal therapy and hopefully avert those bad outcomes. Yeah. That definitely makes sense. So what is classified as early? Do we have kind of a time frame for diagnosis? Well, you know, I mean, from a purely pathophysiologic standpoint, it's once the fungus breaches an area where it shouldn't be, right? So, for example, I mean, we all have candida, if you will, and candida albicans and other candida species in our gastrointestinal tract. But they're not causing an infection, they're just part of our microbiome. But if you had someone who had a breakdown in the mucosa and those organisms started to invade, that would be the earliest form of invasion once they start to breach that mucosal barrier. So once an organism gets into an area where it shouldn't be, that would be the earliest phase of infection. So you know, of course, it's always number one is do our best to maintain host defenses, which of course is not always possible. But and then after that, you know, understand how, you know, we can treat these organisms the most effectively. Absolutely. Okay. So what would be some of the early signs then because you mentioned, and I think many of our listeners are aware that fungal infections are not the pathogen that is first thought of in the differential. So what would be some of those early signs that might key you into the fact that a fungal infection is taking place? Well, you know, the problem with our responses to, you know, injury or infection is they're often nonspecific. So, you know, we have swelling and redness and fever, you know, and so those things are are common to bacterial infections, fungal infections, you know, a variety of different types of injury. So they're really quite nonspecific, somebody getting a fever, it could be anything. And you know, you bring up an important point, often it's fungi are not the number one cause. So folks are going after the number one cause with regards to treatment, and it's kind of quite far down the line when treatment isn't, or the patient isn't responding to treatment, you know, the light bulb goes off. Well, maybe it's not a, maybe it's not a bacterial infection after all, could this be fungal? And they start thinking fungal and now it's, you know, two weeks into antibacterial antimicrobial therapy and, you know, the fungal, the fungus has been invading that whole time. So I think fungus early, it's not always going to be, but that's why we need, you know, advanced diagnostic tests that can actually tell us. So it's not just guessing. And who knows, I mean, it could be, it may not be a test that detects the fungus itself. It may be a human immunologic profile, you know, an RNA profile or something like that that actually gives us the right answer. I know individuals have studied RNA profiles that will help differentiate bacterial pneumonia from viral pneumonia. So you know, there are, you know, fortunately a lot of some art people working in these spaces. So I'm just waiting for that breakthrough wherein we'll have a diagnostic test that will help signal early fungal infection because we do have some, you know, very effective antifungal drugs. And again, if we can get those antifungal drugs on board prior to the organism being deeply invasive. And again, once it's deeply invasive, you run into, you know, really the pharmacologic issues of can you deliver a drug to that infected site? And that becomes very problematic. Do we have a deep knowledge of what it is about those tissues that is causing that trophism? Why is the fungi so anti-invasive? You know, not to my knowledge, there may be somebody out there and you know, probably is who's, you know, kind of studied this, this further life work. But I know, you know, when we look at this histopathologically under the microscope and the tissues have been excised, you know, we'll see those, you know, hyphal elements streaming towards or invading through the wall of the blood vessel. And then again, once the clot forms actually being in the center of the blood vessel where there should just be blood. That's so interesting. So we've talked about the need for advanced diagnostics. I'm curious, can you give our listeners a little bit of a breakdown about what is available now and kind of how the field of diagnostic mycology has evolved throughout your career? Right. So, you know, kind of begin in the beginning and old tests don't mean that they're bad tests, right? So, you know, we have direct examination. So a specimen is taken to the laboratory and we look at it on the microscope. Usually after it's been treated with often KOH and calcophora white, that's a very common way to do a direct exam and the potassium hydroxide breaks down human cells to make it easier to see the fungal elements. And then the calcophora white will use that with fluorescent microscopy and be able to see the organism much easier. And so what's important here is, as we talked about, you know, you've got major categories bacterial, fungal, viral, parasitic, et cetera, or inflammatory but non-infectious. And so what's key is that simple direct examination. Once you see those hyphal elements and then hopefully you have, you know, medical laboratory scientists at the bench that are going to correctly characterize those, butting yeast and pseudohyphae, you know, taking down, you down some of the roots like, you know, candidate species versus broad, posiseptate hyphae, taking down the roots of amucorallace. So that becomes very important because, you know, days before the culture is positive, you've now told the physician out of all the possibilities, all the different kingdoms, this is a fungal issue. And so automatically they can tailor therapy to what they think that might be. If it's amucorellis, they know don't use voriconazole because they're inherently resistant to those. And so again, extremely old test, inexpensive test, very useful test. Of course, we're going to culture these out and culture is still extremely important for traditional identification. And then if we need to do susceptibility testing, you have a live organism that you can do susceptibility testing for. So those would be the mycology side of this. And then again, we also want to send tissue to the histopathology laboratory because we would like to see, is this organism real? Is it an invading tissue and eliciting an inflammatory response? Or could it have been a spore that fell into the specimen and just happens to be a contaminant? So mycology and histopathology really work hand in hand. And you know, this is honestly sometimes a difficult concept. It doesn't seem like it should be. But to get across to some of our surgeons, when they remove potentially infected tissues, you need to make sure that part of it goes to mycology laboratory and that it doesn't all get put into formalin and sent to pathology. I really think this is honestly a national quality metric that could be pushed forward because talk to any microbiologist and you'll get a rise out of them when you talk about how many times does the tissue all get dumped into formalin. Somebody finds a microorganism in the tissue and now we have nothing growing in microbiology. So really a quality issue that again, I think this would be a great opportunity for ASM and other organizations to put forward as a national quality metric. So those would be our traditional tests. That's such an important point and thank you for raising it. In that case then, is that kind of been the arsenal that you've been working with, those quality metrics throughout your career and what are some of the specific, you've kind of hinted at some of them, but specific developments that you see kind of in the pipeline as far as fungal diagnostics goes. Right. So, you know, probably, you know, then during my career, things that came out were antigen tests for specific fungi like histoplasma urinary antigen, et cetera. And then antigen tests that have broader applications, you know, beta-glucan, for example, glactomanin. So those are great. Those are good tests. You're looking for fungal antigens, they're in the patient's blood. So those have been advances. When you get it, do you know exactly which one it is? We know there's some cross reactivity. Is it already late in the game? So good, but not perfect. Nothing's perfect, I know. And you know, then I think we really had the explosion of PCR and then rapid cycle PCR, real-time PCR. And, you know, over the years have, you know, developed specific tests, specific, there's a histoplasma PCR, et cetera. But again, you're really asking one specific question, and the question is, you know, does this patient have histoplasmosis? And you know, if you have the right specimen and you have a, you know, highly sensitive PCR, then you'll probably get the right answer. But you know, if the patient has another organism, your histoplasma PCR will be appropriately negative, but you still won't have an answer. So you know, that opens the door to, you know, what's been described as broad-range PCR. So using primer sets for PCR that will really pick up anything in the fungal kingdom, you know, it's a two-edged sword, right? So the beauty of that is it picks up anything in the fungal kingdom. The problem with that is it picks up anything in the fungal kingdom, and there's a lot of spores floating around. Canadian and the like, so, you know, you can get a PCR that's positive, but not clinically meaningful. Thus, the importance of correlating that in context. So what I mean is, you know, if you had a aspergillus PCR, and the histopathology showed an adenocarcinoma, it's likely a contaminant, right? If you have aspergillus PCR and you see invasive highland septate hyphae, you've got your answer. So broad-range PCR will amplify any fungi, and then the question becomes, how do you differentiate which fungus is it? And there's a lot of post-amplification techniques that can be used. The most common, of course, being sanger sequencing. And so you can sequence that amplicon and get the name of the organism if you've chosen your primer sets appropriately. Now other people have looked at this and, you know, used limited microarrays and things like that. You know, a lot of ways to skin that cat. But getting those into routine use has, you know, really not happened as far as using them up front. Usually what has happened is somebody will see an organism in tissue, and again, they forgot to send anything to the mycology laboratory, and they will then send it off for broad-range PCR. So, you know, those are some of the, you know, current advanced diagnostics that are available now. It's exciting, but it makes sense. You did a very eloquent job of explaining the importance of context, and I think that is just a really important point across the board. That interpretation of the results is so key. So I would love to ask you, I'm shifting gears a little bit here, but I'd love to ask you if there are any particular cases that have stood out to you throughout your career, either they were especially interesting or impactful or unique or unexpected? You know, I'm trying to think about, you know, any ones in particular. You always remember the ones that you messed up on, right? But that's how we learn, and we always hope when we do mess up, nobody gets hurt by it. But you know, I think that's probably one of the most exciting things about our field, you know, being in clinical microbiology, you know, pathology, and the like is, and it's probably what I miss the most about my old job. So you know, my first, you know, my 22 years of practice at the Cleveland Clinic, you know, knee deep with the clinicians, challenging patients and, you know, their infections, et cetera. You know, I tell you, when you can reach the diagnosis that everybody's been grasping at, that just is, it kind of makes you feel like that's why I'm doing this. So, you know, the, I don't think any particular cases, you know, stand out right away. But you know, that's probably the most rewarding you can, you can feel like even though I may not have ever met that patient at the bedside, that patient is getting better because you know, either, you know, you with your microscope or your team in the laboratory, et cetera, were able to make the diagnosis when no one else could. Yeah. Absolutely. What a good feeling. And what an important impactful part of your career. So let's talk a little about antimicrobial resistance and how that pertains to fungi. What are some of the factors that we see driving antifungal resistance? I know you mentioned that there are quite a few antifungals that are still very effective once the diagnosis has been made. I know this is something, there's a global threat that we are all concerned about. So yeah, what are the factors driving it? So, you know, antifungal resistance is very different from, you know, antibacterial resistance. I mean, these really are apples and oranges. And you know, the reason is that we have, you know, eukaryotic organisms with fungi and we have prokaryotic organisms with bacteria and, you know, prokaryotic organisms are pretty promiscuous in the exchange of genetic material. And so there's, you know, many different ways that they exchange it, et cetera. And it's just not the same for eukaryotes. So, you know, we did a study years ago looking at cryptococcus and CDC did a similar study. We both had the same finding, I'll tell you a little bit about our study. You know, we looked at three different, we got cryptococcal isolates from three different areas of the globe, U.S. where you could only get antifungals with a prescription, one site where you could get antifungals over the counter, and one site where, you know, it was not too difficult to get antifungals. Not as readily easy as over the counter, et cetera, but, you know, not terribly difficult. And we looked at the antifungal resistance to cryptococcus in those three areas and there was no statistically significant difference. Now, we did that same study when ESBL's extended spectrum beta-lactamases were just coming out in gram negatives. We did the exact same study except in two sites. One site where it was antibacterial antibiotics were available over the counter and the U.S. And of course there was a statistically significant difference. So of course where there was more antibiotics, there was more resistance. So, you know, that just shows you the acquisition of resistance is very different in fungi. So fungi being eukaryotic, not as promiscuous with DNA exchange, although, you know, of course it does occur. So that being said, you know, the genome of fungi is much more stable. And so we'll often say, if you can get to the identification, you've got some good information about the likelihood of responses to certain drugs. And so, in my mind anyway, identification becomes priority to antifungal susceptibility testing. Now, that doesn't hold true for all organisms. We know there are some that you can't predict their profiles like fusarium, et cetera. But the, you know, CLSI, antifungal susceptibility subcommittee has been working on and publishes what's called epidemiologic cutoff value, ZCVs. And essentially what they've done is they've gotten these less common fungi, usually ones that we won't have enough in clinical trials to get breakpoints for. And they test them in numerous laboratories and they look at what is the normal distribution of these fungi with respect to MICs against different antifungals. And so from that, you can kind of see how are these fungi probably going to act. And from that, as well as clinical trials, I know that group has also worked on lists of groups that have intrinsic resistance. So for example, you always know that Canada cruzii is intrinsically resistant to fluconazole. So I think knowing what the intrinsic resistance profile is is very important. And then if you have an identification, that can be used to help guide therapy. Speaking of therapy, what is it about, you've kind of already touched on this, I think, but what is it about fungi that makes developing therapies unique? Well, again, these are eukaryotic organisms, so we're eukaryotic organisms too, right? So usually when drugs are developed, the idea is kill the bad thing, don't kill the host. And so if they have a physical property that's very similar to our physical property and a drug is targeted towards that, we'll probably have human toxicity. So that's why most drugs are trying to target things that are different about the microorganism and the host. For example, we have cholesterol in our cell membranes, fungi I have are gastro. So there you go, there's a target for something different. They have chitin in their cell wall, we don't have cell walls, so we can target things in the cell walls. So I think one of the challenges is we're both eukaryotic, so you want to be careful of toxicity. And again, you hate to say it, but money drives a lot of things, right? And so if there's a lot more UTIs in the US than there are invasive fungal infections, drug companies are going to be making those drugs, not that we don't want drugs for that. But they're wanting to get a bigger market share, etc., and then it comes down to business. So I appreciate that there are new drugs coming out and new drugs that have come out not long ago, and so that's really great and really needed by our immunocompromised patients who are at risk for these infections. Absolutely. And what do you see in terms of vaccine, like a future of vaccine? So obviously we have a lot of the same challenges there, but want to pick your brain on that. Do you see that coming anytime in the near future? You know, I do not know of any vaccine trials, but you know, I would not count it out. Because folks who, let's say, if they know that they're in queue for a liver transplant or in queue for a renal transplant, if there's a possibility to build the immune system in some kind of way that would help protect them against invasive fungal infections, pretty interesting thought. And you know, these things I know from a researcher kind of close to our laboratory at Cleveland Clinic, you know, big breast cancer vaccine being worked on there. I mean, kind of who would have thought that? And you know, with some really encouraging results. So you know, maybe there will be a vaccine in the future. So you recently co-authored an upcoming seventh edition of Lerone's Medically Important Fungi, which is a guide to identification. And if I'm not mistaken, that is going to be published by ASM and Wiley this month, so July 2023. Can you tell me why you were interested in participating in this effort to write the new edition? Well, first of all, it was an amazing honor to be asked to, you know, first of all, you know, I've known Dr. Lerone for many, many years and we've given presentations together and just an amazing lady. And so we've used that book and I've seen how the, you know, medical laboratory scientists at the bench have used it and it's what you can tell when a book is good, when it's falling apart, right? People are using it so much and that's that kind of book. And so first of all, it was just an honor to be able to try to contribute to it. You know, the other portion is, you know, look at these co-authors I was asked to be with. It's as if I was a, you know, rhythm guitar player and they asked me if I wanted to sit in with the Beatles. So the, you know, the other authors are just superstars and, you know, just really an honor to be with them. You know, I will say we really worked hard on this book, really worked hard updating it. You know, I really hope the users will be pleased and I know as soon as we finished it, we started talking about, you know, what we would do next time. And so I think that this will continue on and on and I sure hope it does. Oh, that's awesome. And are there any particular updates that you want to highlight, some of the things that you were most excited about in this edition? Yeah, you know, I really tried to update the histopathology section with regards to descriptions of fungi and tissue, et cetera. You know, I think fungal nomenclature changes quickly and I think, you know, we took a very reasonable middle of the road approach to that and that's well described in there and it will, you know, really be in sync with, you know, other documents that are out or coming out. So really trying to make sure that the, even if the name has changed, the important information is conveyed appropriately to the clinician so they know what's going on since, you know, they don't live in the microbiology space all the time. And then really looking at all of the, you know, newly described organisms, et cetera, or like I said, important name changes. So it really is an up to date text. Awesome. Is this a, is this a textbook that you use while you're teaching? Yeah, absolutely. You know, in the beginning of our conversation, you mentioned how impactful it is to have a good mentor to shape your education and career trajectory. Is there any advice that you would give to young students and the next generation of scientists how to develop their career or be successful in this space? Yeah, I think a couple of things is one is, you know, be active in seeking out a mentor. You know, folks are, everybody's busy. We're all too busy and, you know, establish individuals, you know, I think probably if they're in academics, that's why they're there. And they would love to be a mentor. Sometimes they don't really know your interest, et cetera. So no matter what you're interested in, kind of scope out the faculty, find somebody that you think would be great to work with, and, you know, introduce yourself to them. So I think, you know, take an active role in finding a mentor, I think would be important, of course, to all of our established people. Be a mentor. If somebody asks you, you know, say yes and help them along, it's all about paying it forward. So I think those are the, you know, that would be primary with regards to finding a mentor. The other thing I've told my residents for this year, you know, you really got to follow your heart, you know, do what you love and, you know, 20 years from now when you're still doing it, you know, a lot of it will have become work, but you'll still love major pieces of it. So follow your heart and do what you really love. That's awesome. Do you still love it? I still love it. I'm loving it even more. Awesome. What do you find most enjoyable? You kind of mentioned that you, what you miss about your old job when you were kind of in the thick of it, working with the clinical team. What do you love most about what you do today in your day to day job? Yeah. So it's really a, you know, it's a sea change, right? And so, you know, we give certification exams. I mean, that's what a board is known for, right? But you know, our board has, you know, is really taking a, you know, significant change. And, you know, I'm really proud of the way that they're going. And we'll still give, you know, the highest quality certification examination. We have a continuing certification program that makes sure individuals who have our certificates stay up to date. And we're, we've really taken some important steps to help trainees while they're in training and to be more transparent about what you need to know to be a board certified pathologist. So we don't make people guess we're, you know, putting it down in black and white. So I think really helping those students along the way and then helping people as they, you know, as they go through their career. And, you know, I've just got done saying this at a meeting that, you know, we're really your partner in lifelong learning. And you know, we take that really seriously. So we're really trying to do our best to, you know, help anybody who, you know, is, you know, in our program to, you know, they may not have seen something in a journal and, you know, so hopefully we can help present that in our continuing certification program. And you know, maybe there are students that are at programs that don't have access like people that have access at really rich programs, if you will, well, how can we level that playing field and maybe provide content for free that would be available to all students. And so I think in one of the things I've kind of preached a bit about is that really helps address what I think are educational inequities because not all training programs are created the same. And so if you can provide some of that content and again, free because we're providing the students who don't have any money anyway, you're really helping the world. I mean, that's another great way that we can help the world, you know, through continuing education. Absolutely. Is this primarily U.S. centric or are you talking on a global sense? You know, we've, you know, we're working right now. One of the things that we've discovered not relevant to microbiology, but there'll probably be a microbiology piece that follows is individuals coming out of medical school. There's good evidence that the new curriculum is not teaching histology, what are tissues look like under the microscope, normal tissues, and you got to know normal if you're going to know abnormal. And so for example, by the end of this year, we will have a histology primer that will be available to everyone and that's everyone throughout the world. And so, you know, anybody who wants to, you know, study in that space can log in and use it. And it's, you know, it has a written text, it has a mini lecture, it has virtual microscopy and then it has a voluntary quiz if you want to see how you do. So you know, we could do things like that in microbiology for people who are, you know, choosing this as a field. It just happened to be, you know, kind of low hanging fruit and something that we knew was extremely relevant to, you know, some of our diplomats. So that's why we chose it, but I just presented this at the Association for Pathology's chairs meeting and one of the questions was, you know, what are you going to do for clinical pathology, of course, which includes microbiology. So I'm sure that ask is coming. So you know, I mean, it could be a Gramstein interpretation primer, something like that. So a direct exam for the identification of fungi primer. So I think a lot of things that high level organizations can do that are free and, you know, free for students, but you know, then make them free for everybody. I mean, we all want a world that's better and these are some ways that we can make it better. I love that. And if, you know, if COVID-19 has taught us anything about how connected we all are building these resources and like you said, making us better in ways that count and that don't cost much, it's brilliant. I mean, it's just such a way to prepare, I think, for the future. Thinking on the level of a global scale, when it comes to outbreak detection and surveillance efforts, what's the status of that when it comes to fungal pathology? Well, you know, I think it's, it's probably poor with everything. I mean, you saw what happened with, you know, COVID-19. I mean, we have countries wherein things are going on and they're supposed to be sharing and they're not sharing. And, you know, so, you know, I think it's, it probably unfortunately is know which countries you can trust and really will share with you. And the ones that won't, you also just know that, I mean, it's, it's what you know. And you know, I think continue to bolster CDC efforts, you know, as we talk about an ounce of prevention being worth a pound of cure, you know, we can only, you know, kind of hypothesize what we could have known, what we could have done, maybe lives that we could have saved, you know, had we predicted, you know, six months earlier that, you know, this was going to be a pandemic. So of course, you know, studying what has happened, we as pathologists like to call that a postmortem, right? Or an after action review, what happened, how can, and not to place blame, you know, not a time to place blame, but to actually say, how can we improve on this? And so, you know, I think it really goes for all microorganisms. You know, I saw that, I'm sure you, you asked Dr. Lockhart about Candida Orris, since he's an expert in it, you know, we saw that, you know, pandemics can occur with fungi too. So, you know, I think learning from the past to make sure that we have in place and having, you know, opportunities in place requires funding. I mean, you know, you have to, if you don't fund your fire department, you're out of luck when a fire occurs. We all hope a fire doesn't occur, but when the fire occurs, you want there to be a fire department. Well, you've got to fund it. And you've got to fund it when your house is not on fire. And so, same story here, you know, we have to have appropriate governmental funding for early, early detection of potential pandemics. The other thing that became absolutely clear from the COVID-19 pandemic, and I was running the clinical virology laboratory at Cleveland Clinic when this occurred, is it was, you know, absolutely ridiculous that early in the pandemic, our public health infrastructure was expected to do all the testing. You know, we have an underfunded public health system. Those people are real soldiers that work there. I mean, I have the highest respect for all of our public health workers. So, this is not on them. This is on funding for them, you know. But when you see exactly the scale of testing that was required, I think no matter what, unless we change to complete public health healthcare, which I don't see the US doing in the foresee future, we've got to know it's going to be a partnership in testing between public health and hospitals, and, you know, reference type laboratories. And honestly, that's how we tackle this in real time. Once we got the approval from the federal government that we could, you know, submit emergency youth authorization for tests for COVID-19, then you could actually hear the bugle of the cavalry and the bugle of the cavalry were all the hospital laboratories that were doing, you know, rapid cycle PCR that they do every single day. We were allowed to come in and help and develop, validate, et cetera, tests for COVID-19. So again, I know there's a lot of efforts to make this how it works in the future, and it's good. To look at what didn't work and any wide scale, particularly, you know, respiratory, because respiratory infections are so easily spread, you know, pandemic type situation, there's no way public health can handle it alone. So we have to have an infrastructure wherein, you know, hospitals can work in concert with public health. They can provide the primer sequences, et cetera, and, you know, give us the protocols to use, et cetera. I mean, that's what we did. The first assay we brought up was the CDC assay. So, you know, again, learning from things, not pointing fingers, not assigning blame, but figuring out what a better future looks like for these responses. Absolutely. So important. For our listeners, if you are wondering, you'd like to learn more about Canada Oris and wondering about who Gary referenced, Sean Lockhart, we recorded an episode with Sean last week and he is another of the co-authors for Lerone's medically important fungi. And you can find that on ASM.org or on any podcast app, and you can learn more from him as well. Well, Gary, I want to thank you so much for speaking with me today and for taking the time to discuss clinical mycologies with a specific slant toward diagnostics and fungal identification. I've really enjoyed our conversation and learned so much today. Same, Ashley. It's been a pleasure working with you and your team and thanks so much. That's it for today's show. If you enjoyed this episode, please share it with someone else who might enjoy it. I'd like to thank Ray Ortega for our podcast production. I'm Ashley Hagan and I'll be with you next time with a new microbiologist for you to meet. [BLANK_AUDIO]