Podcasts about vzv

With the arrival of Eyezirgan (commercial available topical ganciclovir), we now have a more readily accessible preservative-free option for treatment of HSV.  So why is Eyezirgan a potentially important new player on the market?  How does one decide between oral or topical treatments for HSV, and is there a longer-term role for antivirals in the treatment of Zoster, in addition to just HSV? Dr. Parwez Hossain joins the podcast. This episode is sponsored by Thea Pharma Canada - https://www.theapharma.caBecome a supporter of this podcast: https://www.spreaker.com/podcast/blind-spot-the-eye-doctor-s-podcast--5819306/support.

Welcome to Research Renaissance presented by the Karen Toffler Charitable Trust. In this episode, host Deborah Westphal dives into the fascinating world of neurovirology with Dr. Maria Nagel, a renowned professor, clinician, and scientist from the Department of Neurology at the University of Colorado. Dr. Nagel shares her insights on how viruses affect the nervous system, focusing on the varicella zoster virus (VZV) and its implications for diseases such as stroke and shingles.Dr. Maria Nagel is a distinguished neurovirologist specializing in the study of how viruses impact the brain, spinal cord, and peripheral nerves. With a particular focus on VZV, Dr. Nagel's work explores the virus's ability to remain latent and later reactivate, leading to various neurological diseases. Her research has significant implications for understanding and potentially preventing conditions like stroke and dementia.Key Discussion Points:Understanding Neurovirology:Dr. Nagel explains her role as a neurovirologist, studying viruses that affect the nervous system.Her primary focus is on VZV, one of the eight human herpes viruses that remain latent and can reactivate later in life.Impact of VZV:VZV causes chickenpox in initial infections and can later reactivate as shingles.The virus's reactivation can lead to serious conditions like stroke, known as VZV vasculopathy, without necessarily presenting with a rash.Mechanisms of Virus Reactivation:Factors that weaken the immune system, such as aging, cancer, immunosuppressive drugs, trauma, and chronic stress, can trigger viral reactivation.Dr. Nagel discusses how these reactivations can cause different diseases depending on the location of the virus's latent residence.Association with Neurological Diseases:Dr. Nagel shares findings on the link between VZV and stroke, as well as potential connections to dementia and Alzheimer's disease.Her lab's research indicates that viral reactivation may contribute to amyloid accumulation, neuroinflammation, and cognitive deficits.Current and Future Research:The episode highlights ongoing research efforts to understand the intersection between VZV reactivation and neurodegenerative diseases.Dr. Nagel emphasizes the importance of multidisciplinary collaborations in advancing this field.Prevention and Treatment:The discussion includes recommendations for the shingles vaccine, particularly for individuals over 50, and its potential benefits beyond preventing the rash, such as reducing the risk of stroke and possibly dementia.Thank you for joining us on this episode of Research Renaissance. We hope you found Dr. Maria Nagel's insights into neurovirology and the impact of viruses on the nervous system both enlightening and thought-provoking. Stay tuned for more episodes as we continue to explore the forefront of brain science and its implications for our understanding and treatment of neurological diseases. Until next time, onward and upward!To learn more about the breakthroughs discussed in this episode and to support ongoing research, visit our website at tofflertrust.org. Technical Podcast Support by Jon Keur at Wayfare Recording Co.

If there's one person you'd want to talk to about immunology, the immune system and Covid, holes in our knowledge base about the complex immune system, and where the field is headed, it would be Professor Iwasaki. And add to that the topic of Women in Science. Here's our wide-ranging conversation.A snippet of the video, Full length Ground Truths videos are posted here and you can subscribe. Ground Truths is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Transcript with many external link and links to the audio, recorded 30 April 2024 Eric Topol (00:06):Hello, it's Eric Topol and I'm really thrilled to have my friend Akiko Iwasaki from Yale, and before I start talking with Akiko, I just want to mention there aren't too many silver linings of the pandemic, but one for me was getting to know Professor Iwasaki. She is my go-to immunologist. I've learned so much from her over the last four years and she's amazing. She just, as you may know, she was just recently named one of the most influential people in the world by TIME100. [and also recognized this week in TIME 100 Health]. And besides that, she's been elected to the National Academy of Medicine, National Academy of Sciences. She's the president of the American Association of Immunologists and she's a Howard Hughes principal investigator. So Akiko, it's wonderful to have you to join into an extended discussion of things that we have of mutual interest.Akiko Iwasaki (01:04):Thank you so much, Eric, for having me. I equally appreciate all of what you do, and I follow your blog and tweets and everything. So thank you Eric.Eric Topol (01:14):Well, you are a phenom. I mean just, that's all I can say because I think it was so appropriate that TIME recognize your contributions, not just over the pandemic, but of course throughout your career, a brilliant career in immunology. I thought we'd start out with our topic of great interest on Long Covid. You've done seminal work here and this is an evolving topic obviously. I wonder what your latest thoughts are on the pathogenesis and where things are headed.Long CovidAkiko Iwasaki (01:55):Yeah, so as I have been saying throughout the pandemic, I think that Long Covid is not one disease. It's a collection of multiple diseases and that are sort of ending up in similar sets of symptoms. Obviously, there are over 200 symptoms and not everyone has the same set of symptoms, but what we are going for is trying to understand the disease drivers, so persistent viral infection is one of them. There are overwhelming evidence for that theory now, all the way from autopsy and biopsy studies to looking at peripheral blood RNA signatures as well as circulating spike protein and nucleocapsid proteins that are detected in people with Long Covid. Now whether that persistent virus or remnants of virus is driving the disease itself is unclear still. And that's why trials like the one that we are engaging with Harlan Krumholz on Paxlovid should tell us what percentage of the people are suffering from that type of driver and whether antivirals like Paxlovid might be able to mitigate those. If I may, I'd like to talk about three other hypotheses.Eric Topol (03:15):Yeah, I'd love for you to do that.Akiko Iwasaki (03:18):Okay, great. So the second hypothesis that we've been working on is autoimmune disease. And so, this is clearly happening in a subset of people, again, it's a heterogeneous disease, but we can actually not only look at reactogenicity of antibodies from people with Long Covid where we can transfer IgG from patients with Long Covid into an animal, a healthy animal, and really measure outcomes of a pathogenesis. So that's a functional evidence that antibodies in some people with Long Covid is really actually causing some of the damages that are occurring in vivo. And the third hypothesis is the reactivation of herpes viruses. So many of us adults have multiple latent herpes virus family members that are just dormant and are not really causing any pathologies. But in people with Long Covid, we're seeing elevated reactivation of viruses like Epstein-Barr virus (EBV) or Varicella-zoster virus (VZV) and that may again be just a signature of Long Covid, but it may also be driving some of the symptoms that people are suffering from.(04:32):So that's again, we see the signature over and over, not just our group, but multiple other groups, Michael Peluso's group, Jim Heath, and many others. So that's also an emerging evidence from multiple groups showing that. And finally, we think that inflammation that occurs during the acute phase can sort of chronically change some tissue tone. For instance, in the brain with Michelle Monje's team, we developed a sort of localized mild Covid model of infection and showed that changes in microglia can be seen seven weeks post infection even though the virus is completely gone. So that means that inflammation that's established as a result of this initial infection can have prolonged sequence and sequela within the person and that may also be driving disease. And Eric, the reason we need to understand these diseases separately is because not only for diagnostic purposes, but for therapeutic purposes because to target a persistent virus is very different approach from targeting autoantibodies, for example.Eric Topol (05:49):Well, that's great. There's a lot to unpack there as you laid out four distinct paths that could result in the clinical syndrome and sequelae. I think you know I had the chance to have a really fun conversation with Michelle about their joint work that you've done, and she reminded me how she made a cold call to you to start as a collaboration, which I thought was fantastic. Look what that yielded. But yeah, this is fascinating because as I think you're getting at is that it may not be the same pathogenesis in any given individual so that all these, and even others might be operative. I guess maybe I first delve into the antibody story as you're well aware, we see after people get Covid a higher rate of autoimmune diseases crop up, which is really interesting because it seems to rev up self-directed immune response. And this I think many people haven't really noted yet, although obviously you're well aware of this, it's across all the different autoimmune diseases, connective tissue disease, not just one in particular. And it's, as you say, the idea that you could take the blood from a person suffering from Long Covid and give it to an experimental animal model and be able to recapitulate some of the abnormalities, it's really pretty striking. So the question I guess is if you were to do plasmapheresis and try to basically expunge these autoantibodies, wouldn't you expect people to have some symptomatic benefit pretty rapidly or is it just that the process is already far from the initiating step?Akiko Iwasaki (07:54):That's a great question. Plasmapheresis may be able to transiently improve the person if they're suffering from these autoantibody mediated diseases. People have reported, for example, IVIG treatment has dramatically improved their symptoms, but not in everybody. So it's really critical to understand who's suffering from this particular driver and appropriately treat those people. And there are many other very effective therapies in autoimmune disease field that can be repurposed for treating these patients as well.Eric Topol (08:34):The only clinical trial that has clicked so far, interestingly, came out of Hong Kong with different types of ways to manipulate the gut microbiome, which again, you know better than me is a major modulator of our immune system response. What are your thoughts about taking advantage of that way to somehow modulate this untoward immune response in people with this condition?Akiko Iwasaki (09:07):Yeah, so that is an exciting sort of development, and I don't mean to discount the importance of microbiome at all. It's just the drivers that are mentioning are something that can be directly linked to disease, but certainly dysbiosis and translocation of metabolites and microbiome itself could trigger Long Covid as well. So it's something that we're definitely keeping our eyes on. And as you say, Eric, the immune system is in intimate contact with the gut microbiome and also the gut is intimate contact with the brain. So there's a lot of connections that we really need to be paying attention to. So yeah, absolutely. This is a very exciting development.Eric Topol (09:57):And it is intriguing of course, the reactivation of viruses. I mean, we've learned in recent years how important EBV is in multiple sclerosis (MS). The question I have for you on that pathway, is this just an epiphenomena or do you actually think that could be a driving force in some people?Akiko Iwasaki (10:19):Yeah, so that's really hard to untangle in people. I mean, David Putrino and my team we're planning a clinical trial using Truvada. Truvada obviously is an HIV drug, but it has reported antiviral activity to Epstein-Barr virus (EBV) and others. So potentially we can try to interrogate that in people, but we're also developing mouse models that can sort of recapitulate EBV like viral reactivation and to see whether there's any sort of causal link between the reactivation and disease process.Eric Topol (10:57):Right now, recently there's been a bunch of anecdotes of people who get the glucagon-like peptide one (GLP-1) drugs which have a potent anti-inflammatory, both systemic and in the brain. I'd love to test these drugs, but of course these companies that make them or have other interests outside of Long Covid, do you think there's potential for a drug like that?Akiko Iwasaki (11:23):Yeah, so those drugs seem to have a lot of miraculous effects on every disease. So obviously it has to be used carefully because many people with Long Covid have issues with liver functions and other existing conditions that may or may not be conducive to taking those types of GLP-1 agonists. But in subset of people, maybe this can be tried, especially due to the anti-inflammatory properties, it may benefit again, a subset of people. I don't expect a single drug to cure everyone. That would be pretty amazing, but unlikely.Eric Topol (12:09):Absolutely. And it's unfortunate we are not further along in this whole story of clinical trials, testing treatments and applauding your efforts with my friend Harlan there to get into the testing which we had hoped RECOVER was going to do with their more than billion dollars or allocation, which didn't get us too far in that. Now before we leave Long Covid, which we could speak about for hours, I mean it's so darn important because so many people are really out there disabled or suffering on a daily basis or periodically they get better and then get worse again. There's been this whole idea that, oh, it's going away and that reinfections don't pose a threat. Maybe you could straighten that story out because I think there seems to be some miscues about the risk of Long Covid even as we go along with the continued circulating virus.Akiko Iwasaki (13:11):Right, so when you look at the epidemiological evidence of Long Covid, clearly in the beginning when we had no vaccines, no antivirals, no real good measure against Covid, the incident of developing Long Covid per infection was higher than a current date where we do have vaccines and Omicron may have changed its property significantly. So if you compare, let's say the Delta period versus Omicron period, there seems to be a reduced risk per infection of Long Covid. However, Omicron is super infectious. It's infected millions of people, and if you look at the total number of people suffering from Long Covid, we're not seeing a huge decline there at all because of the transmissibility of Omicron. So I think it's too early for us to say, okay, the rates are declining, we don't need to worry about it. Not at all, I think we still have to be vigilant.(14:14):We need to be up to date on vaccines and boosters because those seem to reduce the risk for Long Covid and whether Paxlovid can reduce the rate of Long Covid at the acute phase for the high risk individual, it seems to be yes, but for people who are not at high risk may or may not be very effective. So again, we just need to be very cautious. It's difficult obviously, to be completely avoiding virus at this time point, but I think masking and anything you can do, vaccination boosters is going to be helpful. And a reinfection does carry risk for developing Long Covid. So that prior infection is not going to prevent Long Covid altogether, even though the risk may be slightly reduced in the first infection. So when you think about these risks, again we need to be cognizant that reinfection and some people have multiple infections and then eventually get Long Covid, so we're just not safe from Long Covid yet.Nasal Vaccines and Mucosal ImmunityEric Topol (15:24):Right. No, I think that's the problem is that people have not acknowledged that there's an ongoing risk and that we should continue to keep our guard up. I want to applaud you and your colleagues. You recently put out [Yale School of Public Health] this multi-panel about Covid, which we'll post with this podcast that gave a lot of the facts straight and simple diagrams, and I think this is what you need is this is kind of like all your threads on Twitter. . They're always such great educational ways to get across important information. So now let's go onto a second topic of great mutual interest where you've also been a leader and that's in the mucosal nasal vaccine story. I had the privilege of writing with you a nice article in Science Immunology back in 2022 about Operation Nasal Vaccine, and unfortunately we don't have a nasal vaccine. We need a nasal vaccine against Covid. Where do we stand with this now?Akiko Iwasaki (16:31):Yeah, so you're right. I mean nasal vaccines, I don't really know what the barrier is because I think the preclinical models all support the effectiveness against transmission and infection and obviously disease. And there is a White House initiative to support rapid development of next generation vaccine, which includes mucosal vaccine, so perhaps that's sort of pushing some of these vaccine candidates forward. You're probably more familiar than me about those kinds of events that are happening. But yeah, it's unfortunate that we don't have an approved mucosal booster vaccine yet, and our research has shown that as simple as a spray of recombinant spike protein without any adjuvants are able to restimulate immune response and then establish mucosal immunity in the nasal cavity, which goes a long way in preventing infection as well as transmission. So yeah, I mean I'm equally frustrated that things like that don't exist yet.The Neomycin and Neosporin SurpriseEric Topol (17:52):Well, I mean the work that you and many other groups around the world have published on this is so compelling and this is the main thing that we don't have now, which is a way to prevent infection. And I think most of us would be very happy to have a spray that every three or four months and gave us much higher levels of protection than we're ever going to get from shots. And your whole concept of prime and spike, I mean this is something that we could have had years ago if there was a priority, and unfortunately there never has been. Now, the other day you came with a surprise in a paper on Neomycin as an alternate or Neosporin ointment. Can you tell us about that? Because that one wasn't expected. This was to use an antibiotic in a way to reduce Covid and other respiratory virus.Akiko Iwasaki (18:50):Right. So yeah, that's a little known fact. I mean, of course widespread use of antibiotics has caused some significant issues with resistance and so on. However, when you look at the literature of different types of antibiotics, we have reported in 2018 that certain types of antibiotics known as aminoglycoside, which includes Neosporin or neomycin, has this sort of unintended antiviral property by triggering Toll-like receptor 3 in specialized cell types known as conventional dendritic cell type 1. And we published that for a genital herpes model that we were working on at the time. But because it's acting on the host, the Toll-like receptor 3 on the host cell to induce interferon and interferon stimulated genes to prevent the replication of the virus, we knew that it could be pan-viral. It doesn't really matter what the virus is. So we basically leverage that discovery that was made by a postdoc Smita Gopinath when she was in the lab to see if we can use that in the nasal cavity.(20:07):And that's what Tianyang Mao, a former graduate student did, in fact. And yeah, little spray of neomycin in the nose of the mice reduce this infection as well as disease and can even be used to treat shortly after the infection disease progress and using hamster models we also showed that hamsters that are pretreated with neomycin when they were caged with infected hamsters, the transmission rate was much reduced. And we also did with Dr. Charles Dela Cruz, a small clinical trial, randomized though into placebo and Neosporin arms of healthy volunteers. We asked them to put in a pea size amount of Neosporin on a cotton swab into the nose, and they were doing that twice a day for seven days. We measured the RNA from the nose of these people and indeed see that more than half the participants in the Neosporin group had elevated interferon stimulated genes, whereas the control group, which were given Vaseline had no response. So this sort of shows the promise of using something as generic and cheap as Neosporin to trigger antiviral state in the nose. Now it does require a much larger trial making sure that the safety profiles there and effectiveness against viral infection, but it's just a beginning of a story that could develop into something useful.New Frontiers in Immunology and Tx CellsEric Topol (21:51):Yeah, I thought it was fascinating, and it does bring up, which I think has also been underdeveloped, is our approaches for interferon a frontline defense where augmenting that, just getting that exploiting the nasal mucosa, the entry site, whether it be through that means or of course through even more potent a nasal vaccine, it's like a missing, it's a hole in our whole defense of against this virus that's led to millions of people not just dying, but of course also sick and also with Long Covid around the world. So I hope that we'll see some progress, but I thought that was a really fascinating hint of something to come that could be very helpful in the meantime while we're waiting for specific nasal vaccines. Now added to all these things recently, like last week you published a paper in Cell with your husband who's in the same department, I think at Yale. Is that right? Can you tell us about that and this paper about the whole new perspectives in immunology?Akiko Iwasaki (23:05):Yeah, so my husband Ruslan Medzhitov is a very famous immunologist who's in the same department, and we've written four or five review and opinion pieces together over the years. This new one is in Cell and it's really exploring new perspectives in immunology. We were asked by the editors to celebrate the 50th anniversary of the Cell journal with a perspective on the immune system. And the immune response is just a beautiful system that is triggered in response to specific pathogens and can really provide long-term or even sometimes lifelong immunity and resistance against pathogens and it really saves our lives. Much has been learned throughout the last 20, 30 years about the innate and adaptive immune system and how they're linked. In this new perspective, we are trying to raise some issues that the current paradigm cannot explain properly, some of the mysteries that are still remaining in the immune system.(24:22):And we try to come up with new concepts about even the role of the immune system in general. For instance, is the immune system only good for fighting pathogens or can it be repurposed for conducting normal physiology in the host? And we came up with a new subset of T-cells known as, or we call it Tx cells, which basically is an interoceptive type of T-cells that monitor homeostasis in different tissues and are helping with the normal process of biology as opposed to fighting viruses or bacteria or fungi. But these cells, when they are not appropriately regulated, they are also the source of autoimmune diseases because they are by design reactive against auto antigens. And so, this is a whole new framework to think about, a different arm of the immune function, which is really looking inside of our body and not really fighting against pathogens, but we believe these cells exist, and we know that the counterpart of Tx cells, which is the T regulatory cells, are indeed well known for its physiological functions. So we're hoping that this new perspective will trigger a new set of approaches in the field to try to understand this interceptive property of T-cells.Eric Topol (25:59):Yeah, well, I thought it was fascinating, of course, and I wanted to get into that more because I think what we're learning is this immune system not only obviously is for cancer whole. We're only starting to get warmed up with immunotherapy where checkpoint inhibitors were just the beginning and now obviously with vaccines and all these different ways that we can take the CAR-T cells, engineered T-cells, take the immune system to fight cancer and potentially to even use it as a way to prevent cancer. If you have these, whether it's Tx or Tregs or whatever T-cells can do this. But even bigger than that is the idea that it's tied in with the aging process. So as you know, again, much more than I do, our senescent immune cells are not good for us. And the whole idea is that we could build immune resilience if we could somehow figure out these mysteries that you're getting at, whereby we get vulnerable just as we were with Covid. And as we get older, we get vulnerable to not just infections, but everything going wrong, whether it's the walls of our arteries or whether it's the cancer or the immunity that's going on in our brain for Alzheimer's and neurodegenerative diseases. How can we fix the immune system so that we age more healthilyThe Immune System and Healthy Aging Akiko Iwasaki (27:37):Oh yeah. A lot of billionaires are also interested in that question and are pouring money into this question. It's interesting, but when you think about the sort of evolutionary perspective, we humans are only living so long. In the very recent decades, our life expectancy used to be much shorter and all we had to survive was to reproduce and generate the next progeny. But nowadays, because of this amazing wealth and health interventions and food and everything else, we're just living so much longer than even our grandparents. The immune system didn't evolve to deal with such one to begin with. So we were doing fine living up to 30 years of age or whatever. But now that we're living up to a hundred years, the immune system isn't really designed to keep up with this kind of stressors. But I think you're getting at a very important kind of more engineering questions of how do we manipulate the immune system or rejuvenate it so that we can remain healthy into the later decades? And it is well known that the immune system itself ages and that our ability to produce new lymphocytes, for example, decline over time and thymus that is important for T-cell development shrinks over time. And so anatomically it's impossible to help stop that process. However, is there a way of, for example, transferring some factors or engineering the immune cells to remain healthy and even like hematopoiesis itself can be manipulated to perhaps rejuvenate the whole immune system in their recent papers showing that. So this is a new frontier.Eric Topol (29:50):Do you think that some point in the future, we'll ex vivo inject Yamanaka factors into these cell lines and instead of this idea that you know get young plasma to old folks, and I mean since we don't know what's in there and it doesn't specifically have an effect on immune cells, who knows how it's working, but do you foresee that that might be a potential avenue going forward or even an in vivo delivery of this?Akiko Iwasaki (30:22):Yeah, it's not impossible, right? There are really rapidly evolving technologies and gene therapies that are becoming online. So it's not impossible to think about engineering in situ as you're suggesting, but we also have to be certain that we are living longer, but also healthy. So we do have to not only just deal with the aging immune system, but preventing neurodegenerative diseases and so on. And the immune system may have a role to play there as well. So there's a lot of, I mean, I can't think of a non-genetically mediated disease that doesn't involve the immune system.Eric Topol (31:03):Sure. No, I mean, it's just, when I think about this, people keep talking about the digital era of digital biology, but I actually think of it more as digital immunobiology, which is driving this because it's center stage and in more and more over time. And the idea that I'm concerned about is that we could rejuvenate the relevant immune cells or the whole immune response, but then it's such a delicate balance that we could actually wind up with untoward, whether it's autoimmune or overly stimulated immune system. It's not such a simple matter, as I'm sure you would agree. Now, this gets me to a broader thing which you've done, which is a profound contribution in life science and medicine, which is being an advocate for women in science. And I wonder if you could speak to that because you have been such a phenomenal force propelling the importance of women in science and not just doing that passively, but also standing up for women, which is being an activist is how you get things to change. So can you tell us about your thoughts there?An Activist for Women in ScienceAkiko Iwasaki (32:22):Yeah, so I grew up in Japan, and part of the reason I left Japan at the age of 16 was that I felt very stifled because of the societal norm and expectation of what a woman should be. And I felt like I didn't have the opportunity to develop my skills as a scientist remaining in Japan. And maybe things have changed over the years, but at the time when I was growing up, that's how I felt. And so, I was very cognizant of biases in society. And so, in the US and in Canada where I also trained, there's a lot less barrier to success, and we are able to do pretty much anything we want, which is wonderful, and that's why I think I'm here. But at the same time, the inequity still exists, even in pay gaps and things like that that are easy to fix but are still kind of insidious and it's there.(33:32):And Yale School of Medicine has done a great job partly because of the efforts of women who spoke up and who actually started to collect evidence for pay gap. And now there's very little pay gap because there's active sort of involvement of the dean and everyone else to ensure equity in the medical school. But it's just a small segment of the society. We really need to expand this to other schools and making sure that women are getting paid equally as men in the same ranks. And also, I see still some sexual harassment or more just toxic environment for people in general in academia. Some PIs get away with a lot of behavior that's not conducive to a healthy environment, so I have written about that as well and how we can have antidotes for such toxic environments. And it really does require the whole village to act on it. It's not just one person speaking up. And there should be measures placed to make sure that those people who does have this tendency of abusive behavior that they can get training and just being aware of these situations and corrective behavior. So I think there's still a lot of work left in academia, but things have obviously improved dramatically over the last few decades, and we are in a very, very good place, but we just have to keep working to achieve true equity.Why Don't We Have Immunome Check-Ups?Eric Topol (35:25):Well applauding your efforts for that, and I'm still in touch with that. We got a ways to go, and I hope that we'll see steady and even more accelerated and improvement to get to parity, which is what it should be. And I really think you've been a model for doing this. It isn't like you aren't busy with everything else, so to fit that in is wonderful. In closing up, one of the things that I wonder about is our ability to assess back to the immune system for a moment isn't what it should be. That is we do a CBC and we have how many lymphocytes, how many this, why don't we have an immunome, why doesn't everybody serially have an immune system checkup? Because that would tell us if we're starting to go haywire and then maybe hunt for reactivated viruses or what's going on. Do you foresee that we could ever get to a practical immunome as we go forward? Because it seems like it's a big missing link right now.Akiko Iwasaki (36:33):Yeah, I think that's a great idea. I mean, I'll be the first one to sign up for the immunome.Eric Topol (36:40):But I'm depending on you to make it happen.Akiko Iwasaki (36:44):Well, interestingly, Eric, there are lots of amazing technologies that are developed even during the pandemic, which is monitoring everything from antibody reactivity to reactivated viruses to the cytokines to every cell marker you can imagine. So the technologies out there, it's just I think a matter of having the right set of panels that are relatively affordable because some of these things are thousands of dollars per sample to analyze, and then of course clinical validation, something that's CLIA approved, and then we can start to, I guess the insurance company needs to also cover this, right? So we need to demonstrate the benefit to health in the long run to be able to afford this kind of immunome analysis. But I think that very wealthy people can already get this done.Eric Topol (37:43):Yeah, well, we want to make it so it's a health equity story, not of course, only for the crazy ones that are out there that are taking 112 supplements a day and whatnot. But it's intriguing because I think we might be able to get ahead of things if we had such an easy means. And as you said during the pandemic, for example, my friends here in La Jolla at La Jolla Immunology did all kinds of T-cell studies that were really insightful and of course done with you and others around the country and elsewhere to give us insights that you didn't get just from neutralizing antibodies. But it isn't something that you can get done easily. Now, I think this immunome hopefully will get us to another level in the future. One of the most striking things I've seen in our space clinically before wrapping up is to take the CD19 CAR T therapies to deplete the B cells of people with lupus, systemic sclerosis and other conditions, and completely stop their autoimmune condition. And when the B cells come back, they're not fighting themselves. They're not self-directed anymore. Would you have predicted this? This seems really striking and it may be a clue to the kind of mastering approaches to autoimmune diseases in the future.Akiko Iwasaki (39:19):Yeah, absolutely. So for multiple sclerosis, for example, where B cells weren't thought to be a key player by doing anti-CD20 depletion, there's this remarkable clinical effects. So I think we can only find the answer experimentally in people when they do these clinical trials and show this remarkable effects. That's when we say, aha, we don't really understand immunology. You know what I mean? That's when we have to be humble about what we think we understand. We really don't know until we try it. So that's a really good lesson learned. And these may be also applicable to people with autoimmune phenotype in Long Covid, right? We may be able to benefit from similar kinds of depletion therapy. So I think we have a lot to learn still.Eric Topol (40:14):Yeah, that's why, again, going back to the paper you just had in Cell about the mysteries and about some new ideas and challenging the dogma is so important. I still consider the immune system most complex one in the body by far, and I'm depending on you Akiko to unravel it, not to put any weight on your shoulders. Anyway, this has been so much fun. You are such a gem and always learning from you, and I can't thank you enough for all the work. And the fact is that you've got decades ahead of you to keep building on this. You've already done enough for many people, many scientists in your career, and I know you'll keep going. So we're all going to be following you with great interest in learning from you on a frequent basis. And I hope we'll build on some of the things we've talked about like a Long Covid treatment, treatments that are effective nasal vaccines, maybe even some dab of Neosporin, and keep on the momentum we've had with the understanding of the immune system, and finally, someday achieving the true parity of gender and science. And so, thank you for all that you do.Akiko Iwasaki (41:35):Thank you so much, Eric.************************CreditsHeadshot photo credits by Robert Lisak, Yale School of MedicineMy producer for Ground Truths is Jessica Nguyen, Scripps Research and our technical support for audio/video is by SInjun Balabanoff at Scripps Research.I hope you found the spot informative. Please share itThe Ground Truths newsletters and podcasts are all free, open-access, without ads.Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in.Comments are welcome from all subscribers. Get full access to Ground Truths at erictopol.substack.com/subscribe

Episode 168: UTI in MalesFuture Dr. Tran gives a summary of UTIs in Males, including epididymitis, orchitis, urethritis, prostatitis, and pyelonephritis. Diagnosis and treatment were briefly described and some differences with female patients were mentioned by Dr. Arreaza.  Written by Di Tran, MS-3, Ross University School of Medicine. Editing and comments by Hector Arreaza, MD.You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.WHAT ARE URINARY TRACT INFECTIONS?Urinary Tract Infection (UTI) is an infection of any part of the urinary tract system. It may involve any part of the renal system, the kidneys, the ureters, the bladder, the prostate, and the urethra.  Different from men, a woman may get a UTI more easily due to their anatomical difference. A woman's urethra is shorter and lies close in proximity to both the vagina and the anus, which allows easy access for bacteria to travel up to the bladder.UTI is further subdivided into two different categories, depending on where the infection takes place within the urinary tract:Lower Tract Infection – cystitis and urethritis when the infection occurs on the bladder and the urethra, respectively.  Common infections are a result of bacteria migrating from the skin (and also from sexual organs) to the urethra and ending up in the bladder.In males, other forms of lower tract infection can result in prostatitis, epididymitis, and orchitis.Upper Tract Infection - aka pyelonephritis, is a more concerning infection that involves the upper parts of the urinary system, in other words, the ureters, and kidneys.AGE DIFFERENCES IN UTI FOR MEN:For men, the incidence of UTI increases with age. Dr. John Brusch reports UTI rarely develops in young males and the prevalence of bacteriuria is 0.1% or less.  Men who are 15-50 years of age often have urethritis due to sexually transmitted infection (STI), mainly by Neisseria gonorrhoeae and Chlamydia trachomatis.  Symptoms include frequency, urgency, and dysuria (most common).Men who are 50 years or older, especially those with prostatic hyperplasia, will have signs and symptoms of incomplete bladder emptying, hesitancy, slow stream, difficulty initiating urination, and dribbling after urinating. Due to the enlargement of the prostate gland, there will be partial blockage of urine flow from the bladder, which in turn, creates a reservoir where bacteria can grow and cause an infection. The most common offending microorganism for this age group is Escherichia coli.Interestingly, while UTIs are rare among men under 60, by the age of 80, both women and men have similar incidence rates. The bladder tends to have a higher residual volume in older males because the prostate grows no matter what, it´s just a part of aging for males. Some may end up with more or less lower urinary tract symptoms, but the prostate is enlarged in general.Other risk factors for UTI in males are men who are not circumcised, urethral strictures, fistulas, hydronephrosis (or dilated ureters overfilled with urine due to failure of drainage to the bladder), and the use of urinary catheters. DIFFERENT TYPES OF UTIs IN MALES:EPIDIDYMITIS:The infection starts from the retrograde ascending route from the prostatic urethra, backing up to the vas deferens, and eventually ending in the epididymis.In men who are younger than 35 years of age, the usual pathogens are C. trachomatis and N. gonorrhoeae (sexually transmitted).In men who are older than 35 years of age, the usual offending agents are Enterobacteriaceae and gram-positive cocci (E. coli as mentioned previously).ORCHITIS:This unique UTI is caused by viral pathogens, such as mumps, coxsackie B, Epstein-Barr (EBV), and varicella (VZV) viruses.  Several studies have shown that patients having orchitis have a history of epididymitis. Fortunately, this infection is uncommon, and it was the main reason to develop the MMR vaccine. It is caused by viruses other than mumps, so you can still have orchitis even if you are vaccinated. Antibiotics are not prescribed for viral orchitis.BACTERIAL CYSTITIS:Having a similar pathophysiology of ascending infection mechanism, male patients in this category often present frequency, urgency, dysuria, nocturia, and suprapubic pain. On a side note, having hematuria is concerning, especially without symptoms, because it's automatically a red flag that should prompt an immediate evaluation in search of other causes besides infection, such as underlying malignancy. Possible etiologies are calculi, glomerulonephritis, and even schistosomiasis infection that can ultimately result in squamous cell carcinoma of the bladder. Arreaza: Let me share a little anecdote about hematuria. One Sunday when I was a resident I woke up with hematuria. Of course, I immediately went to urgent care, knowing hematuria means trouble in men. I had a urine dipstick test, which was normal. The first thing the nurse practitioner asked me was, “Did you eat any beets?”, and I never eat beets, but that day I had a full bag of beet chips. So, yes, that was the cause of my pseudo-hematuria. Lesson learned: Always ask about beets when you have a patient with painless hematuria with a normal dipstick. PROSTATITIS:This is an infection of the prostate gland. The most common offending agent is E. coli. Acute prostatitis will present with signs of “acute” infection, such as fever, chills, and suprapubic pain. On rectal exam, we will find a prostate that is warm, swollen, boggy, and very tender. Make sure you perform a gentle prostate exam as you may spread bacteria to the blood and cause bacteremia and potentially sepsis. Patients are normally very sick and it is not your typical cystitis, but it is more severe. Chronic Prostatitis can arise from different causes, ranging from retrograde ascending infection, “chronic” exposure to urinary pathogens, and even autoimmune etiologies. The majority of patients often are asymptomatic.   URETHRITIS:This infection is further classified into two groups, gonococcal and non-gonococcal. For gonococcal urethritis, N. gonorrhoeae is the most common pathogen. Agents of non-gonococcal urethritis include C. trachomatis, Ureaplasma, trichomonas, and Herpes Simplex Virus (HSV).  Patients often present symptoms of dysuria, pruritus, and purulent penile discharge.PYELONEPHRITIS:Following a retrograde ascending mechanism, an infection may travel from the bladder and make its way to the kidney, causing damage and inflammation to the renal parenchyma. According to Dr. John Brusch, E. coli is responsible for approximately 25% of cases in males. Pyelonephritis presents with chills, fever, nausea/vomiting, flank pain/costovertebral angle tenderness, and dysuria.  Other findings include pyuria and bacteriuria.  Pyelonephritis is a common cause of sepsis. Diagnosis of UTIs.URINE STUDIES: Urine culture remains the gold standard for diagnosis of UTI. Other studies include suprapubic aspiration, catheterization, midstream clean catch, and Gram stain. Imaging studies are not always needed, but you may order plain films, ultrasonography, CT scans, and MRIs.  It will depend on the severity of your case and your clinical judgment.UTIs in women: In males, we should perform urine culture and susceptibility studies. However, in women, urine studies are not needed all the time, they should be reserved for women with recurrent infection, treatment failure, history of resistant isolates, or atypical presentation. This is done to confirm the diagnosis and guide antibiotic selection.Interestingly, in a recent evidence review, published in the American Family Physician journal, women can self-diagnose their uncomplicated cystitis. All that is needed is having typical symptoms (frequency, urgency, dysuria/burning sensation, nocturia, suprapubic pain), without vaginal discharge. If you have those elements, you have enough information to diagnose, or even the patient can self-diagnose, an uncomplicated UTI without further testing, but in males, you should ALWAYS perform urine studies.TREATMENTS:Men with UTI should ALWAYS receive antibiotics, with urine culture and susceptibility results guiding the antibiotic choice. Laboratory results will help us determine the best treatment plan. UTIs are often treated with a variety of antibiotics.  Dr. Robert Shmerling, of Harvard Medical School, states that most uncomplicated lower tract infections can be eradicated with a week of treatment with antibiotics. Common antibiotics for UTI are fluoroquinolones, trimethoprim-sulfamethoxazole (TMP-SMZ), minocycline, or nitrofurantoin.On another hand, if it's an upper tract infection or prostatitis, the course of treatment can be extended for longer periods. For those patients who are hemodynamically unstable or have severe upper UTI, hospital admission is required to monitor for complications and IV antibiotics.UTIs in males are less frequent than UTIs in females, except when patients are 80 years and older when the incidence is similar in both sexes. UTIs in males must prompt further evaluation because if left untreated, they can have detrimental effects on your patients' health. As a take-home point, UTI in males is less common than in females, and it requires urine studies or other studies to identify the etiology and guide treatment. Antibiotics are always used, and you may guide your treatment depending on the results. Imaging is not always needed, but use your clinical judgment to make a more specific diagnosis and detect complications promptly. __________Conclusion: Now we conclude episode number 168, “UTI is Males.” Future Dr. Tran described the different anatomical areas that can be infected in males with UTI. She reminded us that UTIs in males always need to be treated with antibiotics and urine cultures are done to guide treatment. Dr. Arreaza mentioned a few differences in the diagnosis and treatment of UTIs in females. For example, women can self-diagnose an uncomplicated cystitis, and urine studies or antibiotics are not always needed in women. This week we thank Hector Arreaza and Di Tran. Audio editing by Adrianne Silva.Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week! _____________________References:Shmerling, R. H. (2022, December 5). Urinary tract infection in men. Harvard Health Publishing. https://www.health.harvard.edu/a_to_z/urinary-tract-infection-in-men-a-to-z.Brusch, J. L. (2023a, March 27). Urinary tract infection (UTI) in males. emedicine.medscpae.com. https://emedicine.medscape.com/article/231574-overview.Kurotschka PK, Gágyor I, Ebell MH. Acute Uncomplicated UTIs in Adults: Rapid Evidence Review. Am Fam Physician. 2024;109(2):167-174. https://www.aafp.org/pubs/afp/issues/2024/0200/acute-uncomplicated-utis-adults.htmlRoyalty-free music used for this episode: Tropicality by Gushito, downloaded on July 20, 2023, from https://www.videvo.net/royalty-free-music/

Ginkgo biloba, known for its distinctive fan-shaped leaves, has been used in traditional medicine for centuries, particularly in Asia. Ginkgo biloba is often touted as an herb for brain health, such as improving memory and cognition. This reputation does a great disservice to the most versatile herb in the world. Ginkgo biloba can be used as a potent antiviral agent for a variety of viruses. Ginkgo biloba has some key bioactive antiviral components: Flavonoids and Terpenoids: Ginkgo leaves contain high levels of flavonoids and terpenoids, compounds known for their antioxidant properties. These substances contribute to the antiviral activity of the plant. Ginkgolides and Bilobalides: These are unique terpene trilactones found in Ginkgo biloba, which have specific antiviral activities. Ginkgo Biloba's Mechanisms of Antiviral Action The antiviral properties of Ginkgo biloba are multi-faceted, involving multiple mechanisms: Inhibition of the fusions and synthesis of proteins in the viruses herpes simplex 1 and 2 (HSV-1 and HSV-2). Inhibition of genome replication in cytomegalovirus (HCMV) and Zika virus (ZIKV). Inhibition of viral fusion proteins in HIV, Ebola virus (EBOV), influenza A virus (IAV), and Epstein-Barr virus (EBV). Inhibition of the targeting protein and DNA of coronoviruses (SARS-CoV-2), varicella zoster virus (VZV), and measles virus. Inhibition of Viral Entry and Replication: Some studies suggest that Ginkgo biloba extracts can interfere with the ability of viruses to enter host cells or replicate. This is a key step in preventing the spread of viral infections. Immune System Modulation: Ginkgo biloba might enhance the body's immune response against viral infections. By modulating immune functions, it could help in controlling viral spread and severity. Anti-inflammatory Effects: The anti-inflammatory properties of Ginkgo biloba can be beneficial in reducing the severity of symptoms associated with viral infections. Research on Ginkgo Biloba's Antiviral Properties Anti-MERS-CoV and Anti-HCoV-229E Properties: A study focused on the antiviral activities of Ginkgo biloba leaf extracts against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Human Coronavirus 229E (HCoV-229E). Inhibition of Enveloped Viruses: Research published in Scientific Reports discussed how ginkgolic acid, a component of Ginkgo biloba, inhibits the fusion of enveloped viruses. The study found that ginkgolic acid had a strong inhibitory effect on Human Cytomegalovirus (HCMV) and also tested its effects on Herpes Simplex Virus-1 (HSV-1) and Zika Virus (ZIKV). Researchers also found broad spectrum inhibition by ginkgolic acid of all three classes of fusion proteins including HIV, Ebola virus (EBOV), influenza A virus (IAV) and Epstein Barr virus (EBV). In addition, inhibition was found of a non-enveloped adenovirus. The authors conclude that ginkolic acids may potentially be used to treat acute infections (e.g. Coronavirus, EBOV, ZIKV, IAV and measles), and also topically for the successful treatment of active lesions (e.g. HSV-1, HSV-2 and varicella-zoster virus (VZV)). It was observed that ginkgolic acid could inhibit the entry of these viruses into cells, thereby blocking viral replication. Another study entitled, “Ginkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay” found that ginkgolic acids from ginkgo biloba inhibited the SARS-CoV-2 virus from binding to the ACE2 receptor and thus could potentially be helpful in acute COVID-19 infections. I use VascuSelect from Moss Nutrition which contains 120 mg of ginkgo biloba, 100 mg of grape seed extract, and 100 mg of mango fruit powder per capsule for acute and chronic viruses dosed 1 capsule once or twice a day with or without food. Grape seed extract and mango fruit powder have also been shown to have antiviral properties. This trio of herbs not only has antiviral prop...

The World Health Organization estimates 3.7 billion people under age 50 (67%) globally have herpes simplex virus type 1 (HSV-1) infection, the main cause of oral herpes, and 491 million people aged 15–49 (13%) worldwide have a herpes simplex virus type 2 (HSV-2) infection, the main cause of genital herpes.  Although treatable, most HSV infections are often asymptomatic or unrecognized.  Moreover, management of HSV infections is complicated by overlapping clinical presentation of unrelated herpesvirus infections, such as varicella-zoster virus (VZV), requiring differential diagnosis.  Innovations in molecular diagnostics continue to play a critical role in the diagnosis and management of these diseases.   About Our Speaker:    Lori Henderson earned a bachelor's degree in biology from Bucknell University. She began her career in the laboratory working on drug discovery and then transitioned into commercial roles within the biopharma and diagnostics sectors of the life science industry. Lori has direct experience in multiple disease and therapeutic areas and currently focuses on sexually transmitted diseases and women's health. Within the molecular business unit at QuidelOrtho, Lori is responsible for identifying and helping drive the development of products to meet clinical and patient needs.

TRANSCRIPTEric Topol (00:00):Hello, this is Eric Topol, and it's really a delight for me to welcome Hannah Davis who was the primary author of our recent review on Long Covid and is a co-founder of the Patient-Led Research Collaborative. And we're going to get into some really important topics about citizen science, Long Covid and related matters. So, Hannah, welcome.Hannah Davis (00:27):Thank you so much for having me.Eric Topol (00:29):Well, Hannah, before we get into it I thought because you had a very interesting background before you got into the patient led research collaborative organization with graphics and AI and data science. Maybe you could tell us a bit about that.Hannah Davis (00:45):Sure. Yeah. Before I got sick, I was working in machine learning with a particular focus on generative models for art and music. so I did some projects like translating data sets of landscapes into emotional landscapes. I did a project called The Laughing Room, where there was a room and you went in and the room would listen to you and laugh if it thought you said something funny, . and then I did a lot of generative music based on sentiment. So I, I did a big project where I was generating music from the sentiment of novels and a lot of kind of like critical projects, looking at biases in data sets, and also curating data sets to create desired outcomes in these generative models.Eric Topol (01:30):So, I mean, in a way again, you were ahead of your time because that was before ChatGPT in November last year, and you were ahead of the generative AI curve. And here again, you're way ahead in in the citizen science era as it particularly relates to the pandemic. So, I, I wonder if you could just tell us a bit I think it was back, we go back to March, 2020. Is that when you were hit with Covid?Hannah Davis (01:59):Yes.Eric Topol (02:00):And when did you realize that it wasn't just an acute phase illness?Hannah Davis (02:06): for me, honestly, I was not worried at all. I, my first symptom was that I couldn't parse a text message. I just couldn't read it, thought I was tired. an hour later, took my temperature, realized I had a fever, so that's when I kind of knew I was sick. but I really just truly believed the narrative I was going to get better. I was 32 at the time. I had no pre-existing conditions. I just was, you know, laying around doing music stuff, not concerned at all. And I put a calendar note to donate plasma two weeks out, and I was like, you know, I'm going to hit that mark. I'm going to donate plasma, contribute, it'll be fine. And that day came and went. I was still, you know, pretty sick with a mild case. You know, I didn't have to be hospitalized.(02:49):I didn't have severe respiratory symptoms. but my neurological symptoms were substantial and did increase kind of over time. And so I, I was getting concerned. Three weeks went by, still wasn't better. And then I read Fiona Lowenstein's op-ed in the New York Times. They were also very young. They were 26 at the time, they had been hospitalized, and they had this prolonged recovery, which we now know as Long Covid. and they started the Body Politic Support Group joined that saw thousands of people with the same kind of debilitating brain fog, the same complete executive functioning loss, inability to drive, forgetting your family members' names who were all extremely young, who all had mild cases. and that's kind of when I got concerned because I realized, you know, this was not just happening to me. This was happening to so many people, and no one understood what was happening.Eric Topol (03:49):Right. extraordinary. And, and was a precursor, foreshadowing of what was to come. Now, here it is, well over three years later. And you're still affected by all this, right?Hannah Davis (04:02):Yes. Pretty severely.Eric Topol (04:04):Yeah. And I learned about that when I had the chance to work with you on the review. You were the main driver of this review, and I remember asking you, because I, I didn't know anyone in the world that was tracking Long Covid like you and to be the primary author. And then you sent this outline, and I had never seen an outline in all my years in academic medicine. I never saw an outline like this of the review. I said, oh my God, this is incredible. So I know that during that time when we worked on the review together, along with Lisa McCorkell and Julia Moore Vogel, that, you know, there, there were times when you couldn't work on it right there, there were just absolutely, you would have some good days or bad days. And, and that's the kind of, is that kind of the way is, how it goes in any given unit time?Hannah Davis (04:55):I think generally, I, I communicated as like 40% of my function is gone. So, like, I used to be able to have very, very full days, 12 hour days would work, would socialize, would do music, whatever. you know, I, I have solidly four functional hours a day. on a good day, maybe that will be six. On a bad day, that's zero. And when I push myself by accident, I can get into a crash that can be three to seven days easily. Hmm. and then I'm, then I'm just not, you know, able to be present. I don't feel here. I don't feel cognitively able, I can't drive. And then I'm just completely out of the world for a bit of time.Eric Topol (05:35):Yeah. Wow. So back in the early days of when you were first got sick and realized that this was not going to just go away, you worked with others to form this Patient -Led Research Collaborative organization, and here you are, you didn't have a medical background. You certainly had a data science and computing backgrounds. But what were your thoughts? I mean, citizen science has taken on more of a life in recent years, certainly in the last decade. And here there's a group of you that are kind of been leading the charge. we'll get to, you know, working with RECOVER and NIH in just a moment. But what were your thoughts as to whether this could have an impact at working with these, the other co-founders?Hannah Davis (06:27):I think at first we really didn't realize how much of an impact we were going to have. The reason we started collecting data in the first place really was to get answers for ourselves as patients. You know, we saw all these kind of anecdotes happening in the support group. We wanted to get a sense of which were happening the most at what frequency, et cetera. and it really wasn't until after that when like the CDC and WHO started reaching out, asking for that data, which was gray literature at the time that we kind of realized we needed to formalize this and, and put out an official paper which was what ended up being the second paper. But the group that we formed really is magical, I think like, because the primary motivator to join the group was being sick and wanting to understand what was happening. And because everyone in the group only has the kind of shared experience of, of living with Long Covid, we ended up with a very, very diverse group. Many, many different and I think that really contributed to our success in both creating this data, but also communicating and, and doing actionable policy and advocacy work with it.Eric Topol (07:42):Did you know the folks before? Or did you all come together because of digital synapses?Hannah Davis (07:47):Digital synapses? I love that. Absolutely. No, we didn't know each other at all. they're now all, you know, they're my best friends by far. you know, we've been through this, this huge thing together. but no, we didn't meet in person until just last September, actually. And many of them we still haven't even met in person. which makes it even more magical to me.Eric Topol (08:13):Well, that's actually pretty extraordinary. So together you've built a formidable force to stand up for the millions and millions of people. As you wrote in the review, 65 million people around the world who are suffering in one way or another from Long Covid. So just to comment about the review --you know, I've been working in writing papers for too long, 35 years. I've never, in my entire career, over 1300 peer reviewed papers on varied topics, ever had one that's already had 900,000 downloads, is the fourth most cited paper and Altmetric since published the same timeframe in January of all 500,000 peer-reviewed papers. Did you ever think that the, the work that, that you did and our, you know, along with Lisa and doing, and I would ever have this type of level of interest?Hannah Davis (09:16):No, and honestly, it's so encouraging. Our, our second paper to me did very well. and, you know, was, was widely viewed and widely cited, and this one just surpassed that by miles. And I think that it's encouraging because it communicates that, that people are interested, right? People, even if they don't understand what long covid is, there is a huge desire to know. And I think that putting this out in this form, focusing on the biomedical side of things really gives people a, a tool to start to understand it. And from the patient side of things, more than any other paper I've heard we, we get so many comments that are like, oh, I brought this to my doctor and, you know, the course of my care change. Like he believed me and he started X treatment. and that, that's the kind of stuff that just makes us so, so meaningful. and I'm so, so grateful that, that we were able to do this.Eric Topol (10:16):Yeah. And as you aptly put it, you know, a work of love, and it was not easy because the reviewers were not not all of them were supportive about the real impact, the profound impact of long covid. So when you now every day you're keeping track of what's going on in this field, and there's something every single day. one of the things, of course is that we haven't really seen a validated treatment all this time, and you've put together a list of candidates, of course, it was in the review, and it constantly gets revised. What are some of the things that you think are alluring from preliminary data or mechanisms that might be the greatest unmet need right now of, of getting some relief, some remedy for this? What, what, what's your sense about that?Hannah Davis (11:13):I think the one I'm most excited about right now are JAK/STAT inhibitors. And this is because one of the leading researchers in viral onset illness Ron Davis and that group believe that basically they're, they have a shunt hypothesis, and that means they, they basically think there's a switch that happens in the body after you've, you've had a viral illness like this, and that that switch can actually be unswitched. And that, to me, as a patient, that's very exciting because, you know, that that's what I imagine a cure kind of looks like. and they did some computational modeling and, and identified JAK/STAT inhibitors as one of the promising candidates. so that's from like the, like hypothetical side that needs to be tested. And then from the patient community, from some things we're seeing I think really easily accessed ones include chromolyn sodium.(12:14):So these are prescription antihistamines. they're both systemic. So Coen has been seeming to work for patients with brain fog and sleep disorders. And chromolyn sodium particularly works in, in patients with gastrointestinal mast cell issues. People are going on to kind of address the micro clots. I, for me personally, has been one of the biggest changers game changers for my brain fog and kind of cognitive impairment type things. but there's so many others. I mean, I think we, we really wanna see trials of anticoagulants. I'm personally really excited to start on ivabradine which is next up in my queue. And, and seems to have been a, a game changer for a lot of patients too. I V I G has worked for patients who are, have been able to get it, I think for both I V I G and ivabradine. Those are medications that are challenging to get covered by insurance. And so we're seeing a lot of those difficulties in, in access with a couple of these meds. But yeah, just part of, part of the battle, I guess,Eric Topol (13:32):You know, one of the leading of many mechanisms that in this mosaic of long covid is the persistence of virus or virus components. And there have been at least some attempts to get some Paxlovid trials going. Do you see any hope for just dealing, trying to inactivate the virus as  a way forward?Hannah Davis (13:54):Absolutely. Definitely believe in the viral persistence theory. I think not only Paxlovid, but other a covid antivirals. I know that Steve deas and Michael Paluso at U C S F are starting a couple long covid trials with other covid antivirals that yeah, for sure. I think they all obviously need to be trialed A S A P. And then I also think on the viral persistence lens, ev like almost everyone I know has viral reactivation of some sort like EBV, CMV,  VZV, you know, we obviously see a lot of chickenpox or shingles reactivations and antivirals targeting those as well I think are really important.Eric Topol (14:41):Yeah. Well, and I also, just the way you're coming out with a lot of this, you know terminology and, you know science stuff like I V I G for intravenous immunoglobulin and for those who are not, you know, just remember, this is a non-life science expert who now has become one. And that goes back again to the review, which was this hybrid of people who had long covid with me who didn't to try to come up with the right kind of balance as to, you know, what synthesizing what, what we know. And I think this is something the medical profession has never truly understood, is getting people who are actually affected and, and becoming, you know, the real experts. I mean, I, I look to you as one of the world's leading authorities, and I learn from you all the time.(15:35):So that goes to RECOVER. So there was a long delay in the US to recognize the importance of long covid. Even the UK was talking to patients well before they ever had a meeting here in the us, but eventually, somehow or other they allocated a billion dollars towards long covid research at the NIH. And originally, you know, fortunately Francis Collins, when he was director, saw the importance, and he, I learned bequeathed that 2 of the NIH institutes, one of the directors, Gary Gibbons visited me recently because of a negative comment I made about RECOVER. But before I go over my comment, you've been as he said, you, and Lisa McCorkell ,among others from the Patient-led Collaborative have had a seat at the table. That's a quote from Gary. Can you tell us your impression about RECOVER you know, in terms of at least they are including Patient-Led research folks with long covid as to are they taking your input seriously? And what about the billion dollars ?Hannah Davis (16:46):Oh, boy. tricky question. I don't even know where to start. Well, I mean, so I think recover really messed up by not putting experts in the field in charge, right? Like we are, we have from the beginning have needed to do medical provider education at the same time that all these studies started getting underway. And that was just a massive amount of work to try to include the right test to convince medical professionals why they weren't necessary. all that could have been avoided by putting the right people in charge. And unfortunately, that didn't happen. unfortunately recovers our, our best hope still or at least the, the best funded hope. so I really want to see it succeed. I think that they, they have a long way to go in terms of, of really understanding why patient representation matters and, and patient engagement matters.(17:51):I, you know, it's been a couple years. It's, it's still very hard to do engagement with them. it's kind of a gamble when you get placed on a, a committee if they are going to respect you or not. And, and that's kind of hard as people Yeah. Who are experts now, you know, I've been in the field of Long Covid research more than anyone really I'm working with there. I, I really hope that they improve the research process, improve the publication process. the, a lot of the engagement right now is, is just tokenization. you know, they, they have patient reps that are kind of like just a couple of the patient reps are kind of yes men you know, they, they get put on higher kind of positions and things like that. but they're, I think there's 57 patient reps in total spread across committees. we don't have a good organizing structure. We don't know who each other are. We don't really talk to each other. there, there's room for a lot of improvement, I would say, well,Eric Topol (18:59):The way I would put it is, you know, you kind of remember it like when you have gatherings where there's an adult table, and then there's the kiddie's table. Absolutely. Folks are at the kiddy table. I mean, yeah. And it's really unfortunate. So they had their first kind of major publication last week, and it's led to all sorts of confusion. you wrote about it, what did we, what did we glean from that, from that paper that was reported as a 10% of people with covid go on to Long Covid, and there were clearly a risk with reinfections. Can you kind of review that and also what have we seen with respect to the different strains as we go on from, from the Wuhan ancestral all the way through to the  various lineages of omicron. Has that led to differences in what we've seen with Long Covid?Hannah Davis (19:56):Yeah, that's a great question and one that I think a lot of people ask just because it, you know, speaks to the impact of long covid on our future. I think not just this paper, but many other papers at this point, also, the, the ONS data have shown that that Long Covid after omicron is, is very common. I think the last ONS data that came out showed of everyone living with Long Covid in the UK. After Omicron, which was the highest group of all of them. we certainly saw that in the support groups also, just, just so many people. but people are still getting it. I think it's because it, most cases of Long Covid happen after a mild infection, 75 to 90%. And when you get covid, now, it is a mild infection, but whatever the pathophysiology is, it doesn't require severe infection.(20:50):And you know, where I think we hopefully have seen decreases in like the, the pulmonary and the cardiovascular like organ damage types we're not seeing real improvements at all in kind of the long term and the neurological and the ones that end up lasting, you know, for years. And that's really disappointing. in terms of the paper, you know, I think there were two parts of the paper. There were those, those items you mentioned, which I think are really meaningful, right? The, the fact that re infections have a higher rate of long covid is like ha needs to have a substantial impact on how we treat Covid going forward. that one in 10 people get it after Omicron is something we've been, you know, shouting for, for over a year now. and I think this is the first time that will be taken seriously.(21:42): but at the same time, the way RECOVER communicated about this paper and the way that you talked to the press about this paper shows how little they understand the post-viral history right, of, of like thinking about a definition.  Why wouldn't they know that would upset patients? You know, that and the fact that they, in my opinion you know, let patients take the brunt of that anger and upset you know, where they should have been at the forefront, they should have been engaging with the patient community on Twitter is really upsetting as well. Yeah.Eric Topol (22:20):Yeah. And you know, I, when I did sit down with Gary Gibbons recently, and he was in a way wanting to listen about how could recover fulfill its goals. And I said, well, firstly, you got to communicate and you got to take the people very seriously not just as I say, put 'em at the Kiddie table, but, you know, and then really importantly is why isn't there a clinical trial testing any treatment? Still today, not even a single trial has been mounted. There's been some that have been, you know, kind of in the design phase, but still not for the billion dollars. All that's been done is, is basically following people with symptoms as already had been done for years previously. So it's, it's just so vexing to see this waste and basically confusion that's been the main product of RECOVER to date and exemplified by this paper, which is apparently going to go through some correction phases and stuff. I mean, I don't know, but whether that's going to the two institutes that it's, it's N H L B I, the National heart, lung and Blood, and the Neurologic Institute, NINDS, that are the two now in charge of making sure that RECOVER recovers from where it's, it's at right now. And yeah, so lack of treatments, and then the first intervention study that was launched incredibly was exercise. Can you comment about that?Hannah Davis (23:56):It's unreal. You know, it's, it, it just speaks to the lack of understanding the existing research that's in this space. Exercise is not a treatment for people with hem. It has made people bedbound for life. The risks is are not, the risks are substantial. that there was no discussion about it, that there was no understanding about it. That, you know, even patients who don't have pem who wouldn't necessarily be harmed by this trial deserve better, right? They still deserve a trial on anticoagulants or literally anything else than exercise. And there's, it just, it, it's extremely frustrating to see it, it would have been so much better if it was led by people who already had the space, who didn't have to be educated in post exertional malaise and the, the underlying underpinnings of it. and just had a sense of, of how to continue forward and, you know, patients deserve better.(24:55):And I think we're, we're really struggling because yeah, there's, there's going to be five trials as I understand it, and that's not enough. And none of them should be behavioral or lifestyle interventions at all. you know, I think it also communicates just the, the not understanding how severe this is. And I get that it's hard. I get that when you see patients on the screen, you think that they're fine and that's just how they must look all the time. But recover doesn't understand that for every hour they're asking patients to engage in something that's an hour, they're in bed, you know, that, that they're, they take so much time away from patients without really understanding like the, the minimum they should be able to do is, is understand the scope and the severity of the condition, and that we need to be trialing substantially more serious me treatments than, than exercise. right,Eric Topol (25:54):Right, right. And also the recognition, of course, as you know very well about the subtypes of long covid. So, you know, for example, the postural orthostatic tachycardia syndrome pots and how, you know, there's a device, so you don't have to always think about drugs where you put it in the back of your ear and it's neuromodulator to turn down your vagus nerve and not have the dizziness and rapid heart rate when you stand and all the other symptoms. And, you know, it costs like a dollar to make this thing. And why don't you do a trial with that? I mean, that was one of the things, it doesn't have to always be drugs, and it doesn't have to, it certainly shouldn't be exercise. But you know, maybe at some point this will get on on track. Although I'm worried that so much of the billion dollars has already been spent and no less the loss of time here, I people are suffering. Now, that gets me to this lack of respect lack of every single day we are confronted with people who don't even believe there's such a thing as long covid after all this time, after all these people who've had their lives profoundly disrupted.(27:04):What, what can you say about this?Hannah Davis (27:07):It's just a staggering, staggering lack of empathy. And I think it's also fear and a defense mechanism, right? People want to believe that they have more control over their lives than they do, and they want to believe that, that it's not possible for them personally to get a virus and then never recover and have their life changed so substantially. I really genuinely believe the people who don't believe long covid is real at this point you know, have their own things going on. And just, yeah,Eric Topol (27:38):It's kinda like how Covid was a hoax, and now this is, I mean, the, you, you just, ofHannah Davis (27:44):Course, but it's true, like it's happened with, it happened with me, CF s it happened with HIV AIDS. Mm-hmm. someone just showed me a brochure of, of a 10 week lifestyle exercise intervention for aids, you know, saying that you could positively think your way out of it. All that is, is, is defense mechanism, just, yeah. You know, it's repeating the same history over and over.Eric Topol (28:07):Well, I think you nailed it. And of course, you know, it was perhaps easier with Myalgic encephalomyelitis when it weren't as many people affected as the tens of millions here, but to be in denial. the other thing is the young people perfectly healthy that are those who are the most commonly affected. a lot of the people who I know who have been hit are like you, you know, very young and, and you know like Julia in my group who, you know, was a big runner and, you know, can't even go blocks at times without being breathless. And this is the typical, I mean, I saw in clinic just yesterday, an older fellow who had been in the hospital for a few weeks and has terrible long covid. And yes, the severity of covid can correlate with the sequela, but because of just numbers, most people are more your phenotype. Right, Hannah.Hannah Davis (29:08):Right, exactly. It's a weird like math thing for people to wrap their head around. Like, yes, if you're hospitalized, the chance of getting long covid is much, much higher than if you were not hospitalized. But because the vast number of cases were not hospitalized, the vast number of long cases, long covid cases were not hospitalized. but I think like all of these things are interesting clues into the pathophysiology. You know, we also see people who were hospitalized who recover faster than some of these, the neurocognitive mild, my mild encephalomyelitis subtypes for sure. I think all of that is, is really interesting and can point to clues about kind of what is, what is happening at the core.Eric Topol (29:54):Yeah. And that I wanted to get into before I wrap up some of the things that are new or added since our review in published in January. so I just recently reviewed the brain in long covid with these two German studies, one of which showed the spike protein was lighting up in the reservoir, the kind of initial reservoir, the brain, the skull, and the meninges. the, the, basically the layers covering the brain, the, particularly the skull bone marrow. And that's where all these immune cells are in high density that are patrolling the brain. And so it really implicated spike protein per se, in people who've had covid. and then the other German study, which was so striking in mild covid, the majority of people where they had it 10 months later, all this signature by m r i, quantitative, m r i of major inflammation with free water and this so-called mean diffusivity, which is basically the leaking and you know, the inflammation of the brain.(31:01):And so, and that's as long as they follow the people, you know, if they followed 'em three years, they'd probably still see this. And so there's a lot of brain inflammation that is linked to the symptoms as you've described. You know, the brain fog, the memory executive function. But we have no remedy. We have no way, how can we stop the process? How can we turn it around like, as you mentioned, like a jak stat inhibitor in other ways that we desperately need to get into testing. so that was one thing I, I wonder, I mean, I think people who have had the symptoms of cognitive effects know there's something going wrong in their brain, but here is, you know, kind of living proof that what there's sensing is now you can see it. thoughts about that?Hannah Davis (31:52):I mean, I think the research is just staggering. It's so, so validating as someone, you know, who was living this and living the severity of it, you know, without research for years, it's, it's wonderful to finally see so many things come out. but it's overwhelming research. And I, I don't understand kind of the lack of urgency. Those are two huge, huge studies with huge implications. you know, that the, that the spike would still be in the skull like that in the, in the bone marrow like that. and the neuroinflammation I think, you know, feels very obvious in terms of what, like the symptoms end up presenting. why aren't we trialing things like the, the, this is just destroying people's lives. Even if you don't care about people's lives, like it will destroy the economy. Like people are still getting this, this is not decreasing. these are really, really substantial tangible injuries that are happening.Eric Topol (32:52):Yeah, I know. And, and there's not enough respect for preventing this. The only way we know to prevented it for sure is just not to get covid, of course. Right. And then, you know, things like vaccines help to some extent. The magnitude, we don't know for sure, you know, maybe metformin helps but, you know, prevention and everyone's guard, not everyone, but you know, vast majority, you know, really let down at this point when there's not as much circulating virus as there has been. Now, another area where it has really been lit up since our review was autoimmune diseases. So we know there's this common link in some people with long covid. There's lots of auto antibodies and self-destruction that's ongoing. The immune system has gone haywire. But now we've learned, you know, this much higher incidence of rheumatoid arthritis and lupus and across, you know, every one of the autoimmune diseases.(33:44):So the impact besides the brain autoimmune diseases and then the one that just blows me away at the beginning of the pandemic, even in the first year there were starting to see more people showing up with type two diabetes and say, ah, well it must be a coincidence. And now there are 12 large studies, every single one goes through of a significant increase in type two diabetes and, and possibly even autoimmune diabetes, which makes sense. So this is the thing I wanted to clarify cuz a lot of people get mixed up about this, Hannah, there's the symptoms of long covid, some of which we reviewed, many of the long lists we haven't. But then there's also the sequela to organ hits like the diabetes and immune system and the brain and you know, also obviously kidney and heart and on and on. Can you help differentiate? Cause a lot of people get mixed up by all this stuff.Hannah Davis (34:46):Yeah, I mean I think, you know, we started out with symptoms because that's what we knew, that's what we were talking about. but I do think it's helpful to start, and I, I do think it would be helpful to do a big review on conditions and that does include ME/CFS and Diso but also includes diabetes, includes heart attacks and strokes are includes dementia risks. and yeah, I think the, the difficulty with kind of figuring out what, what percent of long covid are each of these conditions is really biased by the fact that for that, doctors can't recognize me CFS and dysautonomia that it doesn't end up in the EHR data. And so we can't really do these large scale like figuring out the percentage of what is what. but I think like, I, I saw someone describe long covid recently as like a, a large scale neurocognitive impairment emergency, a a large scale cardiovascular event emergency. I think those are extremely accurate. the immune system dysfunction is really severe. I really would like to see the conversation start moving more toward the, the conditions and the pathophysiologies based on what we're finding yeah, more than, more than just the symptoms.Eric Topol (36:15):Right. And then, you know, there's this other aspect of the known unknown, so with two other viruses. So for example, back in 1918 with influenza, it, it took 15 years to see or more that this would lead to a significant increased risk of Parkinson's disease. And then with polio, the post-polio syndrome showed up up to 30 years later with profound progressive muscular atrophy and, you know, falls and all sorts of major neurologic hits that were due for from the original polio virus. And so, yeah, some of the things that we're learning here with long covid hopefully will spill over to all these other post-infectious processes. But I think what's emphasizing in our discussion is how much more we, we really do need to learn how we desperately need some treatments, how we desperately need to have the respect for this syndrome that it deserves which still isn't there, it's just, it's unfathomable to me that we still have people dissing it on a daily basis and, and not, you know, a small minority, but actually a pretty strident group that's, that's not so small.(37:35):Now, before you wrap up, what have I missed here? Hannah with you, because this is a rarefied opportunity to have a sit down with you about what's going on in long covid and also to emphasize citizen science here because this is, if there's anything I've ever seen in my career to show the importance of citizen science, it's been the long covid story. you as one of the leaders of it. So have I missed something?Hannah Davis (38:05):I feel like we actually covered a pretty good bit. I would say maybe just for people listening, emphasizing that long covid is still happening. I think, you know, so many people that we see recently got long covid after getting vaccinated or having a prior infection and just kind of relaxing all their precautions and they're, they're angry. You know, the, the newer group of long Covid folks are angry because they were lied to that they were safe, and that's completely reasonable. you know, that it's still happening in, in one in 10 vaccinated omicron infections is a huge deal. and, and I think yeah, just re-emphasizing that, but overall that, yeah, you know, this is very serious. I think there's my, my MO for Twitter, really, honestly, despite all the, the accusations of fear mon mongering, I really don't put extreme stuff online, but I really do believe that this is this is currently leading to, you know, higher rates of, of heart attacks.(39:08):I do believe that we will see a, a wave of early onset dementia that is honestly is happening already you know, happening in my friend group already. and like you said there, there's a lot of unknowns that can be speculated about the fact that we see E P V reactivation in so many people. Are we gonna see a lot of onset multiple sclerosis mm-hmm. you know, lymphomas other E B V sequelae, like the danger's not over the danger's actually, like pretty solidly. there's pretty solidly evidence for some, some pretty serious things to come and you know, I keep saying we gotta get on top of it now, butEric Topol (39:55):Well, I, I always the, unfortunately, some, some people don't realize it, but the eternal optimist that we will get there, it's taking too long, but we got to ratchet up the heat, get projects like RECOVER  and elsewhere in the world to go in high gear and, you know, really get to testing the promising candidates. You so have aptly outlined here and in your writings. you know, I think this has been an incredible relationship that I've been able to develop with you and your colleagues and I've learned so much from you and I will continue to be following you. I hope everyone listening that if they don't already follow you and, and others that are trying to keep us up to speed, which you know, just this week again, there was a Swiss study, two year follow up showing that the number of people that were still affected significantly with long covid symptoms at two years was 18%.(40:58):That's a lot of folks, and they were unvaccinated, but still, I mean, they, in order to have two year follow up, you're going to see a lot of people who before the advent of vaccines. So this, if you look at the data, the research carefully and it gets better quality as time goes on, because we have control groups, we have matched controls, we have, you know, hopefully the beginning of randomized trials of treatment. we'll hopefully get some light. And part of the reason we're going to get there is because of you and others, getting us fully aware, keeping track of things, getting the research committee to be accountable and not just pass off the same old stuff, which is not really understanding the condition. I mean, how can you start to really improve it if you don't even understand it? And who are you going turn to to understand it? you don't, you don't just look at, you know, MRI brain studies or immune lab studies. You got to talk to the folks who, who know it and know it so well.. All right, well this has been hopefully one of many more conversations we'll have in the future and at some point to celebrate some progress, which is what we so desperately need. Thank you so much, Hannah.Hannah Davis (42:19):Thank you so much. Absolute pleasure.LinksOur Long Covid review with Lisa McCorkell and Julia Moore-Vogelhttps://www.nature.com/articles/s41579-022-00846-2The Brain and Long Covidhttps://erictopol.substack.com/p/the-brain-and-long-covidHeightened Risk of Autoimmune Diseaseshttps://erictopol.substack.com/p/the-heightened-risk-of-autoimmuneCovid and the Risk of Type 2 Diabeteshttps://erictopol.substack.com/p/new-diabetes-post-acute-covid-pascThanks for listening and reading Ground Truths.Please share if you found this informative.Your free subscription denotes your support of this work. Should you decide to become a paid subscriber you should know that all proceeds go to support Scripps Research. That has already helped to bring on several of our summer high school and college interns. Get full access to Ground Truths at erictopol.substack.com/subscribe

In Radio HI van maandag 17 oktober: Alles over de uitnederlaag van de Oranjemannen in Griekenland. Niels Versteijnen legt de vinger op de zege plek. Verder: Ruben de Bok over de competitiestart van eredivisiekoploper Houten, Europees succes voor Quintus en VZV en de eerste veertien namen van de EK-selectie van de Oranjedames. Zie het privacybeleid op https://art19.com/privacy en de privacyverklaring van Californië op https://art19.com/privacy#do-not-sell-my-info.

In Radio HI van maandag 3 oktober: Een tweede plaats voor de Oranjedames tijdens de Golden League. Afgelopen weekend debuteerde Pipy Wolfs voor de A-ploeg en wist zelfs al te scoren. Verder: Aalsmeer en LIONS op één en twee in de BENE-League, rechterhoekspeler van HSG Nordhorn-Lingen Sander Visser over zijn goals tegen Rostock, de derbyzege van Hellas op Quintus en VZV van de nul af.

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Mike Gershon is a Professor of Pathology and Cell Biology at Columbia University and has been at the forefront of studying neural control of the gut for the past 60 years. In this episode, Mike gives a tour de force on the pathways of gut-brain communication but first sets the stage with an overview of gastrointestinal tract development and anatomy. He then explains how the gut communicates with the brain and vice versa, from early observations in physiology and anatomy up to our present understanding of what makes the GI tract so unique and complex relative to other organs. He talks about how the gut responds to meals of different food qualities and how that affects satiety signaling to the brain. Additionally, he explains how antidepressants and other drugs impact digestion through effects on serotonin signaling, and he discusses the effects of antibiotics, and what's really going on with “leaky gut.” Finally, Mike offers his thoughts on the utility—or lack thereof—of gut microbiome diagnostic tests, and wraps up the discussion by considering how diet, probiotics, and prebiotics impact the microbiome and GI tract. We discuss: The basics of the gastrointestinal (GI) system [3:45]; The very early development of the GI system [9:30]; The unique properties of the blood supply and portal system in the GI tract [12:45]; An overview of gut anatomy and innervation [16:30]; Turnover of the epithelial lining and why cancer rarely develops in the small intestine [26:45]; Nutrient and water absorption in the small and large intestine [30:30]; Ways in which the gut and brain communicate [34:30]; The gut's role in the regulation of appetite [43:30]; The impact of gastric bypass surgery on satiety signals [51:15]; How varicella-zoster virus (VZV) can infect neurons in the gut and create issues later in life [54:30]; The relationship between autism and gastrointestinal illness [1:02:45]; The important role of serotonin in the gut, and the impact of SSRIs on serotonin in the gut [1:09:45]; Defining “leaky gut” and its most common causes [1:16:45]; The gut microbiome [1:30:45]; Fecal transplants: use cases, limitations, and how they illustrate the importance of gut microbes [1:40:45]; Gut microbiome diagnostic tests: why they aren't useful outside of special cases such as cancer detection [1:50:30]; Nutritional approaches to a maintain optimal flora in the gut [1:55:00]; Prebiotics and probiotics, and getting your GI system back on track after a course of antibiotics [2:02:30]; More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Dr. Carole Keim MD takes listeners through vaccines in today's episode. She explains everything from how vaccines are created to common myths and misconceptions about them. She then details each baby and childhood vaccine, and what disease each prevents.Dr. Keim breaks down how vaccines work and what criteria they must meet in disease to be effective. She explains the four main types of vaccines and lays each vaccination out in a clear manner, covering what age your baby or child will be when they receive the vaccine and how the immune response works. These vaccines are proven to protect your baby against everything from tetanus to mumps to pertussis and more.This episode will cover: How vaccines workCriteria to create a vaccineThe 4 different types of vaccinesCommon myths or misconceptions about vaccinesSpecific vaccines (all routine childhood vaccines)Total number of vaccinesCommon side effects and red flags, how to treat How vaccines work: 00:44The purpose of vaccines is to trigger an immune response faster and with less harm than the original disease.The immune system is a lot like a microscopic team of superheroes, made up of white blood cells, antibodies, the complement system, and a few others.  These superheroes fight villains such as bacteria, viruses, and other pathogens.  If they cannot fight them fast enough, the villains will multiply and cause symptoms of disease.  Vaccines give your superhero team information about what the villains look like, so they can recognize them as soon as they enter the body, and fight them off quicker and easier.Vaccine criteria: 01:26In order to make a vaccine, certain conditions must be metIt has to be effective.  We must be able to become immune to the pathogen; diseases like RSV and HFM are ones we can catch multiple times.  Chickenpox is one that you become immune to after catching it once.The pathogen must not be able to mutate faster than the vaccine can be given - we do flu boosters annually because the flu virus mutates about that often.  HIV and common cold mutate too fast for a vaccine to be developed.The vaccine must be cost-effective; it has to be cheaper to prevent the disease than to treat itThere are 4 main types of vaccines: 02:31Inactivated (killed pathogens)Live attenuated (weakened pathogens)Toxoid (a piece of what's inside the pathogen)mRNA vaccines Inactivated vaccines 03:44Most common typeThe bacteria or viruses in the vaccine are killed, so your immune system can safely learn to recognize the pathogen that it is trying to fight off.  These vaccines do not have the potential to cause actual disease.  What they do is cause the immune system superheroes to practice fighting the villains, kind of like practicing on dummies, which may cause mild signs of illness - fever, sore muscles, crankiness, or other symptoms.  Examples: IPV (polio), HPV (human papillomavirus), HiB (Haemophilus influenzae B), pneumococcus (Streptococcus pneumoniae), meningococcus (Neisseria meningitidis), and Hepatitis A and B vaccines.Live attenuated vaccines 04:02Made from bacteria or viruses that have been exposed to chemicals that make them weaker than the natural or “wild type” bacteria or virus.  Since these pathogens are not killed completely, your superheroes aren't just practicing on dummies, they are actually fighting the weakened villains.  So it is possible to have symptoms of the disease, but milder.  Some people with weakened immune systems may not be able to fight them off, and can get the actual disease.  People taking steroid medications or immune suppressants, or who have HIV or other immune deficiencies should consult a doctor about whether it is safe to receive these vaccines.  Examples: oral polio vaccine, MMR (measles, mumps, and rubella), Varicella zoster (chickenpox), and rotavirus vaccines.Toxoid vaccines 04:55Made from just part of the pathogen, and protect against the kinds of bacteria that cause symptoms after the toxins inside them are released.  These toxin-carrying bacteria are like villains carrying around a bottle of poison, and the toxoid vaccine gives the superheroes the poison to sample and build up resistance to it.  Example: DTaP (diphtheria, tetanus, and acellular pertussis).MRNA vaccines 05:23Newest typemRNA is like a copy of instructions. These give your immune system something like a sewing pattern to print out and make the dummies for your body to fightExample: some COVID vaccinesMyths and misconceptions about vaccines: 05:45Many parents have concerns about vaccinating their children.  It only takes one serious reaction to call into question the safety of vaccines.  And it has been so long since the vaccine-preventable diseases have run rampant that we in the United States don't fully understand the scope of what is being prevented.  Here are some of the top concerns that I have heard from parents, and the truth behind them.Aluminum.  There is aluminum in vaccines, but the amount is far less than babies get from other sources.  The total amount of aluminum that babies get from vaccines in the first 6 months is 4.4mg.  Breastfed babies consume 7mg, formula-fed babies consume 38mg, and babies on soy formula consume 114mg of aluminum in the first 6 months of life.  Consuming aluminum vs. having it injected in a vaccine looks the same to the body, so the tiny amount of aluminum in vaccines will not harm your babyAntigens.  An antigen is any microscopic substance that has the possibility to elicit an immune response.  Babies are exposed to over a trillion antigens in the first year that naturally occur in the environment.  The entire vaccine series that children receive today contains just over 150 antigens.  A young baby's immune system can easily recognize these few antigens and make antibodies to the diseases without getting sick.Autism.  It has been proven that vaccines do NOT cause autism.  The age that children first start showing signs and can be tested for autism is 15-24 months.  This is the same age that children receive booster vaccines, so it is understandable that some parents think they are related. Long-term protection.  Vaccines will protect a person for just as long as if they got the original disease.  So a person who had chickenpox as a child is just as protected from getting it again as a person who has received the chickenpox vaccine.  Some people do not seroconvert (develop antibodies to that disease) - that depends on their immune system and is not a failure of the vaccine itself.Mercury.  There used to be a preservative called thimerosal in vaccines.  That preservative (which contains mercury) has been removed from all vaccines in the US that children receive.  The only vaccine that still contains thimerosal is the adult flu vaccine.Unnatural exposure.  Some people worry that getting exposed to a disease through an injection is not the same as getting it “naturally” by being exposed to a sick person.  This is not true; any disease will get into your bloodstream, which is where it is recognized by the body, and once in there the body has no idea how it got in.  So getting an injection looks exactly the same to your immune system as getting the disease from a sick person.Doctors DO NOT get paid to vaccinate childrenVaccines are NOT a punishment for children who are behaving badlySpecific vaccines: 10:47Hep B - 0, 2, 6 mos.  Hepatitis B is a viral infection that can be passed from mom to baby through the placenta or during delivery.  90% of babies born with HepB will develop chronic infection and are at risk of liver cancer later in life.DTaP - 2, 4, 6, 15 mos, 4 years.  Tdap - age 11, every 10 years.  DTaP has more diphtheria, Tdap has more tetanus. Bacterial infections.  Diphtheria causes severe sore throat and enlarged tonsils, and can block the airway from swelling/tonsils being so enlarged.  Tetanus makes spores that live in soil; any penetrating wound could have tetanus in it (nail/thumbtack, dog or cat bite) and tetanus is not killed by antibiotics so it must be prevented.  Pertussis is whooping cough and causes babies less than a year old to stop breathing.  Everyone who takes care of the baby should be current on their TDaP (within 10 years).  Polio - 2, 4, 6 mos, 4 years.  Polio is a virus that attacks nerves and causes paralysis.  Sometimes it's minor, and sometimes it's the diaphragm that's affected and they stop  breathing.  There is no specific treatment for polio.HiB - 2, 4, 6, 12-18 mos.  HiB (haemophilus influenzae B) bacterial infection that affects children less than 5 years, and especially those under 1 year of age.  It used to cause severe infections like epiglottitis, sepsis, pneumonia, and meningitis.  PCV - 2, 4, 6, 12-18 mos.  PCV = pneumococcal conjugate vaccine, pneumococcus is another name for streptococcus pneumonia, which is a kind of strep that gets into the bloodstream and causes sepsis, pneumonia, and meningitis.  PCV has 13 strains of strep in it right now.Rotavirus - 2, 4, 6 mos. Viral infection that causes severe diarrhea and dehydration in babies. Hep A - 12 and 18 mos. Hep A is a type of food poisoning, there's no specific treatment.  MMR - 1 and 4 years.  Measles causes high fever, rash, and can cause brain damage, hearing loss, and death.  Mumps causes parotitis (infection of salivary glands), but in boys also causes orchitis (inflammation of testicles) and can lead to sterility.  Rubella is a fever and rash; more dangerous to unborn babies, causes miscarriages and birth defects.VZV - 1 and 4 years.  Varicella Zoster virus (chickenpox) causes cold symptoms, fever, and an itchy and painful rash in children, and shingles in adults.  VZV in pregnancy causes miscarriages and birth defects.MCV - 11 and 16 years.  Meningitis A, C, W, Y are viruses that cause inflammation around the brain that develops quickly and can be fatal.  HPV - 11 years.  Human papilloma virus causes warts and dysplasia and can lead to cancer of the mouth, throat, anus, cervix, and penis.  Currently 9 strains of HPV in the vaccine.  Flu: recommended annually COVID: recommendations are still evolvingVaccines that are available but not given routinely: MenB, PPSV23, Dengue, Typhoid, japanese encephalitis, yellow fever, rabiesTotal numbers of vaccines: 22:351 at birth (Hep B)2 mos: DTaP, polio, HiB, Hep B, PCV, rotavirus - 1 or 2 combo vaccines, PCV and rota = 2 or 3 shots plus an oral vaccine4 mos: DTaP, polio, HiB, PCV, rotavirus - 1 combo plus PCV and rota = 2 shots and one oral6 mos: DTaP, polio, HiB, Hep B, PCV, rotavirus - 1 or 2 combo vaccines, PCV and rota = 2 or 3 shots plus an oral vaccine6+ mos: flu vaccine annually12-18 mos: 2 doses Hep A, 1 of DTaP, HiB, PCV, MMR, VZV.  5-7 shots depending on combos.4-6 years: DTaP, polio, MMR, VZV, typically given as 2 combo vaccines11 years: Tdap, MCV, 2 doses HPV16 years: MCV21+ years: Tdap every 10 years; booster if you have a wound and it's been less than 5 years, booster while pregnant9 shots and 3 oral before 1 year of age, 5-7 shots from age 1-2, 2 shots age 4-6, 4 at age 11, 1 at age 16 = 21-23 total shots before adulthood.  18 flu shots.  Common vaccine reactions: 23:53Birth: nothing; sometimes redness/swelling2-6 mos: redness and swelling (local reaction), can be as much as the entire thigh and still be considered normal.  Low grade fevers.12-18 mos and 4-6 years: muscle soreness, MMR and VZV cause fevers, VZV sometimes causes rash, other vaccines can cause local reactions11yrs: muscle soreness, local reaction with Tdap and MCV, fainting with HPV16 yrs: local reaction from MCVTdap boosters: muscle sorenessFlu, COVID: flu-like symptomsIt is NOT normal to have a body rash or vomiting after vaccines; those are signs of allergyLarge local reactions and muscle soreness can be treated with cool compresses (wet washcloth) and/or acetaminophen or ibuprofen.  Fever or flu-like symptoms: acetaminophen or ibuprofenI DON'T recommend pre-medicating your child before vaccinesIf your child has an adverse reaction to a vaccine, you should report it to VAERS (vaccine adverse event reporting system).  Remember that VAERS is like Yelp for vaccines, so take that about as seriously as you would a Yelp review.All of this information is also in The Baby Manual book, which is available for purchase. Remember it is always okay to call your doctor or emergency services if you have concerns about your baby's health.  Resources discussed in this episode:The Baby Manual - Available on AmazonVAERS--Dr. Carole Keim MD: linktree | tiktok | instagram

近期於歐洲、美洲及大洋洲等非屬猴痘流行國家爆發疫情，因此來整理一下重點吧。 先說在前面：這個病主要是密切接觸傳染。他也可以透過人傳人飛沫傳染，但應該不是很有效率的傳染方式，因此應該算是相對好防範的疾病。本次傳染到非洲外的地方，可能主要是透過性行為傳播，這是之前沒有發現過的傳染途徑，但性行為當然也是密切接觸的一種。實際上的確切傳染途徑還在調查中。 1.猴痘（monkeypox）是一種由猴痘病毒引起的罕見傳染病，主要在非洲囓齒類動物中傳播，猴痘偶爾也會感染靈長類（多種猴類和人類）。猴痘是人畜共通傳染病，主要通過接觸受猴痘病毒感染的動物、人類或受病毒污染的物體傳染給人類。人與人之間的傳播比較少見。 2.傳播途徑：猴痘主要通過與傳染性個體的密切接觸傳播。可以是接觸到帶病動物或是病人，或是被病毒汙染的物品。病毒會從受傷的皮膚（也有可能是看不見的），呼吸道，或是眼鼻口的黏膜進入人體。動物傳人可以透過咬傷或抓傷，人吃動物，直接接觸動物的體液或是皮疹處，或是被動物汙染的物品，比方說床鋪。人傳人並不容易發生，可以透過飛沫傳染，或是接觸傳染，比方說使用到被汙染的床或是毛巾，或是直接碰到病人的皮疹。在2022年本次非洲之外的疫情發生之前，猴痘不被認為是性傳播疾病。然而，病毒在本次非洲外疫情中發現透過狂歡和性行為相關的快速傳播，引發了性行為可能也是猴痘傳播途徑的猜測。 3.猴痘病毒與天花病毒同屬正痘病毒屬（Orthopoxvirus），但他不是天花的子孫，也不是天花的祖先。其症狀與天花非常相似，但較爲輕微。傳染力也遠低於空氣傳染的天花。 4.症狀：前面1~3天會有發燒、發冷、頭痛、肌肉疼痛、背痛、淋巴結腫大和感覺疲倦。之後疹子出現，通常從臉部開始，然後到身體其他部位，包括生殖器。會從紅疹、丘疹、水泡進展到膿疱，最後結痂。整個症狀持續時間通常為2至4週。和天花一個主要不同的地方是天花不會有淋巴結腫大。可由此做鑑別診斷。 5.致死率：一般會自然好轉，但嚴重時也可以致死，死亡率在1%到10%。猴痘分兩個演化支，分別為剛果盆地（中非）支和西非支，地理分布、嚴重程度、傳染特徵區別都很大。前者致死率高達10%；後者致死率不足1%。 6.潛伏期：7~14天。但從5~21天都有可能。 7.治療：目前沒有非常確認有效的治療藥物。有幾個抗病毒藥物可能有效。 8.預防：避免與帶病動物或是病人密切接觸。 避免接觸可能攜帶病毒的動物（包括在猴痘發生地區生病或被發現死亡的動物） 避免接觸與生病動物接觸過的任何物品（例如被褥） 將受感染的患者隔離 與受感染的動物或人類接觸後保持良好的手部衛生（例如用肥皂和水洗手或使用含酒精的洗手液） 照顧患者時使用個人防護裝備 (PPE) 根據美國CDC的建議，一種減毒活病毒疫苗JYNNEOS（也稱為 Imvamune 或 Imvanex），已被美國食品和藥物管理局批准用於預防猴痘。雖然過去已證明接種天花疫苗可預防猴痘，有效率為85%，但在天花絕跡之後，天花疫苗已不再供一般公眾使用。以前接種過天花疫苗可能會減輕猴痘病症，但保護力並非終身有效。 9.猴痘的第一例人類病例發生在1970年的剛果民主共和國，此後非洲平均每年發現幾千例病例，但在非洲以外地區很少發現。2022年猴痘疫情標誌著非洲以外地區首次發生廣泛的社區傳播，該疫情約2022年5月在英國開始傳播，隨後在歐洲和澳大利亞都出現了確診病例。實驗室於5月6日通過對水泡拭子進行PCR確認從奈及利亞回來的患者感染了猴痘的西非演化支，是兩種變種中致死率較低的一種，致死率約為1%。 近期歐美及大洋洲多國爆發猴痘疫情，我國尚無報告病例，將持續監測疫情發展 https://www.cdc.gov.tw/Bulletin/Detail/n27ENsv3uCSM2hKvfqKMww?typeid=9 近期於歐洲、美洲及大洋洲等非屬猴痘流行國家爆發疫情，今年5月1日到21日已累計11國新增87例確定，28例疑似病例，確定病例中以英國29例、葡萄牙及西班牙各23例為多，且不排除當地發生罕見本土傳播疫情。依據世界衛生組織(WHO)資料顯示病例多屬感染西非分支猴痘病毒，出現發燒、皮疹、頭痛等症狀，部分亦出現生殖器感染情形，於兒童或免疫低下族群可能導致重症。 疾管署指出，過去猴痘疫情多發生於西部及中部非洲地區，其他國家偶發零星的境外移入病例，而今年與以往不同，迄今除剛果民主共和國、奈及利亞、中非共和國等仍持續報告病例外，包括比利時、德國、法國、義大利、瑞典、美國、加拿大及澳洲等國陸續報告1至3例病例。 疾管署進一步指出，國內迄今尚未曾出現猴痘病例及相關通報，將持續監測國內疫情發展，必要時，將研議強化相關防疫措施。 疾管署說明，猴痘臨床症狀與天花類似，但傳染力較弱，嚴重度較輕微。常見症狀可用目前天花臨床條件進行通報，如醫師診治到病患有突然發燒 38.3°C（101°F）以上，接著會依序出現不同型態及進展一致的皮膚病灶如紅疹、丘疹、水泡或膿疱，且無其他明顯病因，並須特別與水痘（VZV）做鑑別診斷，臨床醫師對該等疑似病例可以於傳染病通報系統選擇天花通報項目，並於備註中填寫「疑似猴痘」，檢體採檢與送驗方式同天花，送疾病管制署昆陽實驗室進行檢驗。 疾管署提醒，近期歐美國家陸續發生疫情，呼籲出國民眾返國入境時如出現上述症狀，應主動告知航空公司人員及機場港口之檢疫人員，儘速就醫，並告知醫師旅遊接觸史。 Wiki百科 猴痘 2022年猴痘疫情 WHO主頁面 https://www.who.int/health-topics/monkeypox#tab=tab_1 FAQ https://www.who.int/news-room/fact-sheets/detail/monkeypox Multi-country monkeypox outbreak in non-endemic countries https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON385 英國UKHSA https://www.gov.uk/government/news/monkeypox-cases-confirmed-in-england-latest-updates 美國CDC https://www.cdc.gov/poxvirus/monkeypox/index.html 歡迎追蹤前台大感染科醫師。04b的發聲管道！ 我的電子名片 https://lit.link/linshibi 希望大家當我的種子教師，推廣正確的新冠衛教。科學防疫，不要只以恐懼防疫！ 歡迎贊助林氏璧孔醫師喝咖啡，讓我可以在這個紛亂的時代，繼續分享知識努力做正確新冠相關衛教。 https://pay.firstory.me/user/linshibi Powered by Firstory Hosting

In this episode, Dalilah Restrepo, MD, discusses barriers to shingles vaccination and strategies to increase routine vaccine uptake in the COVID-19 era.Using the latest data and expert guidance, this podcast covers topics such as:Shingles disease burden and increasing incidence over timeDecline in shingles vaccination rates in the COVID-19 eraNational Vaccine Advisory Committee standards of careCDC guidance catching up after RZV dosing delaysStrategies to increase shingles vaccine uptakePresenter:Dalilah Restrepo, MDInfectious Diseases SpecialistFountain Valley HospitalFountain Valley, CaliforniaContent based on a CME program supported by an educational grant from GlaxoSmithKlineFollow along with the downloadable slides at:https://bit.ly/3pW7Bl8Link to full program:https://bit.ly/3o4PB8N

In this episode, Dalilah Restrepo, MD, discusses expert guidance on vaccination for the prevention of shingles complications in the COVID-19 era.Contributor:Dalilah Restrepo, MDInfectious Diseases SpecialistFountain Valley HospitalFountain Valley, CaliforniaUsing a case study and the latest expert guidance, this podcast covers topics such as: Expert guidance on maintenance of routine vaccination during the COVID-19 eraCommon shingles complications in immunocompetent patientsAdditional shingles complications in immunocompromised patientsGuidance on safe shingles vaccine delivery during the COVID-19 pandemicCDC guidance catching up after RZV dosing delaysContent based on a CME program supported by an educational grant from GlaxoSmithKline.Follow along with the downloadable slides at: https://bit.ly/3r3AKx1Link to full program:https://bit.ly/3o4PB8N  

In this episode, Tracy Zivin-Tutela, MD, discusses expert guidance on vaccination against shingles.Tracy Zivin-Tutela, MDInfectious Diseases SpecialistDepartment of Infectious DiseasesFountain Valley Regional HospitalLos Alamitos Medical CenterFountain Valley, CaliforniaUsing a case study and the latest expert guidance, this podcast covers topics such as: Counseling patients on benefits and efficacy of vaccination against shinglesVaccine safetyVaccination guidelines for adults with or without previous vaccination with zoster vaccine live or recalled childhood chickenpoxAdministration of vaccination with consideration for other routine vaccines for flu, pneumonia, COVID-19Content based on a CME program supported by an educational grant from GlaxoSmithKlineFollow along with the downloadable slides at: https://bit.ly/3kunxJrLink to full program: https://bit.ly/3o4PB8N

An interview with Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews neurologic toxicities in patients receiving ICPis, such as myasthenia gravis, Guillain-Barre Syndrome, peripheral neuropathy, aseptic meningitis & encephalitis in Part 9 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey. And today, we're continuing our series on the management of immune related adverse events. I am joined by Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center in New York, New York, author on Management of Immune Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy ASCO Guideline Update and Management of Immune Related Adverse Events in patients Treated with Chimeric Antigen Receptor T Cell Therapy ASCO Guideline. And today, we're focusing on nervous system toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Santomasso. BIANCA SANTOMASSO: Thank you for having me. BRITTANY HARVEY: Then I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Santomasso, do you have any relevant disclosures that are directly related to these guidelines? BIANCA SANTOMASSO: Yes, I'd like to disclose that I've served as a paid consultant for Celgene, Janssen Pharmaceutical, and Legend Biotech for advising them on the topics of T cell therapy side effects. BRITTANY HARVEY: Thank you. Then getting into the content of this guideline, what are the immune related nervous system toxicities addressed in this guideline? And what are the overarching recommendations for evaluation of these neurologic immune related adverse events? BIANCA SANTOMASSO: So neurologic immune related adverse events actually encompass a very diverse spectrum of neurologic syndromes that can occur as a complication of treatment with checkpoint inhibitors. So the spectrum that is covered by this guideline includes myasthenia gravis, Guillain-Barre syndrome, polyneuropathy, aseptic meningitis, and encephalitis. And although these are rarer than many of the other immune related adverse event types affecting other organ systems, they're increasingly being encountered due to more patients being treated with novel combinations of immunotherapies. And they're important to recognize, because along with myocarditis, they have generally more morbidity and even more mortality than irAEs affecting other organ systems. So it's important for clinical care providers to have a high index of suspicion for these events. Studies have suggested that these tend to occur in about 3% to 12% of patients, probably between 1% and 2% of patients developing severe events. So they're rare. But again, the events are probably more commonly seen in patients treated with combination checkpoint blockade. And we're increasingly seeing more combinations. So we should be on the lookout for these. Neurologic immune related adverse events can be divided into syndromes that affect the peripheral nervous system, so meaning the peripheral nerves, the neuromuscular junction, and muscle. So that would be Guillain-Barre syndrome, myasthenia gravis, and myositis. And those that affect the central nervous system, such as the brain, spinal cord, or leptomeninges. So those would be aseptic meningitis and encephalitis. The peripheral nervous system irAE appear to be more common than those affecting the central nervous system. And patients can present with a number of different symptoms that kind of relate to these syndromes. That can be as diverse as a headache to numbness, tingling, or focal weakness, such as a foot drop or facial weakness. You may see patients with severe altered mental status or personality changes or gait difficulty, walking difficulty, which could actually mean any number of syndromes. It's generally important to be aware that the timing of onset is generally early, a median of four weeks after the start of treatment, but can range anywhere from one week after the start of treatment to greater than a year. And because we know that cancer can spread to many parts of the nervous system, neurologic toxicity should be considered a diagnosis of exclusion. So that means that as part of the workup for neurologic immune related adverse events, it's imperative to rule out nervous system metastasis, stroke, and infection, which we know can occur at higher rates in patients with cancer. So for most neurologic immune related adverse events, diagnostic workup is similar. It should include MRI brain and/or of the spine, with and without contrast, and often a lumbar puncture for cerebrospinal fluid analysis, including cytology to rule out leptomeningeal metastasis. BRITTANY HARVEY: Thank you for that overview. In addition to those points for evaluation for all nervous system toxicities, what are the key recommendations for identification, evaluation, and management of myasthenia gravis? BIANCA SANTOMASSO: So for myasthenia gravis, presenting symptoms usually include fatiguable or fluctuating muscle weakness. It's generally more proximal than distal. And there's frequently ocular and/or bulbar involvement. So that means either ptosis, like a droopy eyelid, diplopia, or double vision, difficulty swallowing, dysarthria, facial muscle weakness, and/or head drop or neck weakness. Again, for any patient with new neurologic symptoms, an MRI of the brain or spine should be performed depending upon the symptoms to rule out central nervous system involvement by disease or some alternative diagnosis. And similar to idiopathic myasthenia gravis, acetylcholine receptor antibodies can be positive. So these should be checked. This is a blood test. But it's important to note that while these antibodies may be confirmatory, their absence does not rule out the syndrome. The rate of acetylcholine receptor antibody positivity in immune related myasthenia gravis has not been definitively established. So depending on the presentation, one might also consider sending a paraneoplastic panel for Lambert-Eaton myasthenic syndrome. The single most important point I'd like to make regarding suspected immune related myasthenia gravis is that orbital myositis and generalized myositis from immune checkpoint inhibitors can present similarly. For this reason, early neurology consultation and electrodiagnostic testing with repetitive stimulation or single fiber EMG becomes important and helpful to distinguish the two. And to make matters even more complicated, we've learned that there's an overlap syndrome, where patients may develop not only myasthenia gravis, but also myositis and/or myocarditis at the same time. So basically, the neuromuscular junction is affected. But the local muscle and myocardium, which is heart muscle that's kind of related, may be affected all at once. And this overlap of syndromes may increase disease severity and mortality. So they're important to recognize. So what this means is that when you encounter a patient with suspected myasthenia gravis, you should also be checking CPK, muscle enzymes, aldolase to evaluate for myositis, and troponin and electrocardiogram to evaluate for myocarditis. And this should be done even if there are no obvious symptoms. So onto the treatment of myasthenia gravis, this is similar to the management of the idiopathic form. Therefore, it's helpful to have the involvement of a neurologist. The immune checkpoint inhibitor therapy should be held. And patients with mild symptoms are often started on pyridostigmine and corticosteroids. And patients with more severe symptoms should initiate IVIG or plasmapheresis. And patients with more severe symptoms may need to be admitted to the hospital. So that their neurologic and pulmonary status can be monitored closely for improvement. Some patients may require ICU level of monitoring. And considering adding rituximab if symptoms are refractory, and often, as symptoms improve, the steroids can be de-escalated. BRITTANY HARVEY: Understood. Those are all very important points for clinicians to consider. So then following that, what are the key recommendations for identification, evaluation, and management of Guillain-Barre syndrome? BIANCA SANTOMASSO: So Guillain-Barre syndrome, like myasthenia gravis, also presents with weakness. Most often, patients present with a progressive ascending muscle weakness. The syndrome can start with sensory symptoms or neuropathic pain that can be localized to the lower back and thighs. In addition to the classic ascending weakness, there may be facial weakness, double vision, numbness or tingling in the hands or feet, loss of balance, and coordination. And shortness of breath may occur due to respiratory muscle weakness. The autonomic nerves can also be affected and can present as new severe constipation or nausea, urinary problems, or orthostatic hypotension. The reflexes are often reduced or absent, deep tendon reflexes. So again, as for all of the syndromes, early involvement by a neurologist is recommended, if possible. Usually, MRI imaging of the spine is important to rule out spinal cord compression. And it also may show cauda nerve thickening or enhancement, which can occur with this syndrome. And the second aspect is cerebrospinal fluid analysis is important for diagnosis. This is important really for ruling out leptomeningeal metastasis, since that could present similarly. And often, what can be seen in GBS is an elevated protein level in the cerebrospinal fluid. In addition, unlike idiopathic GBS, there can be an elevated white blood cell count in the cerebrospinal fluid. Electrode diagnostic testing can also be helpful for confirmation, and serum tests for antiganglioside antibodies, and a paraneoplastic antibody workup may also be considered. Bedside pulmonary function test and swallowing evaluation should be performed if there's a concern for respiratory or swallowing dysfunction. And some patients do need to have inpatient admission and monitoring if symptoms are severe or if they appear to be progressing from mild. For management, the checkpoint inhibitor therapy should be held. And patients are most often treated with IVIG or plasmapheresis. Corticosteroids can be added to the IVIG or plasmapheresis. These are not usually recommended for idiopathic Guillain-Barre syndrome. However, in immune checkpoint inhibitor related forms, a trial is reasonable. And steroids are usually given at a higher dose for five days and then tapered over several weeks. BRITTANY HARVEY: Understood. I appreciate that overview. So then what are the key recommendations for identification, evaluation, and management of peripheral neuropathy? BIANCA SANTOMASSO: So peripheral neuropathy, or polyneuropathy, is a rare but likely underreported complication of immune checkpoint inhibitor therapy. So in the large databases and meta-analyses, those have really focused on Guillain-Barre syndrome for reporting. But other types of neuropathies, such as painful length dependent sensory and motor axonal neuropathies, or polyradiculopathies or sensory neuropathies do occur after immune checkpoint inhibitors and are probably under-recognized. So evaluation of immune related neuropathy should include neurology consultation to guide the neurology phenotype determination and also the workup. The evaluation primarily relies on a combination of electrodiagnostic studies, serologic tests, and MRI neuroimaging. Because peripheral nervous syndromes can overlap, screening for neuromuscular junction dysfunction with electrodiagnostic testing and myopathy is recommended for any patient who presents with at least motor symptoms that are thought to be peripheral. Serum testing can be helpful for ruling out reversible causes of neuropathy. Spinal imaging is recommended to exclude metastatic disease. And for management, it usually involves holding the checkpoint inhibitor in mild cases, using neuropathic pain medication or steroids in more severe cases. And very severe cases that kind of resembled GBS would be managed as per the GBS algorithm with IVIG or plasmapheresis. BRITTANY HARVEY: Understood. And it's key to look out for those overlapping adverse events. So then following that, what are the key recommendations for aseptic meningitis? BIANCA SANTOMASSO: Right, so now we're getting into the central nervous system toxicity. So aseptic meningitis is an inflammation of the meninges. And it can present with headache, photophobia, neck stiffness. Patients can have nausea, and vomiting, and occasionally fever. The mental status is usually normal. And in patients presenting with headache, which in isolation, could suggest an aseptic meningitis, it's important to evaluate if they have any confusion or altered behavior, which might suggest an encephalitis. And this distinction is important, because suspected encephalitis triggers a different workup, which we'll be discussing later, and also even different management. So the workup for aseptic meningitis includes neuroimaging, usually an MRI of the brain. And on that imaging, we sometimes see abnormal leptomeningeal enhancement. It's important not to assume that this is cancer and to do a lumbar puncture to evaluate cerebrospinal fluid both for inflammation and to exclude other causes of meningeal disease, particularly neoplastic and infectious causes. So cytology, Gram stain, and culture, and other infectious studies should be negative. And it's recommended that empiric antibiotics or antiviral therapy be considered to cover for infectious meningitis until the cerebrospinal fluid results return negative. What's seen in the cerebrospinal fluid in aseptic meningitis is typically reactive lymphocytes, but also neutrophils or histiocytes may be prominent on the cytology. And while the symptoms can be severe, sometimes requiring hospitalization, the management of this entity, these are usually quite treatable. Aseptic meningitis generally responds very well to corticosteroids. So management involves holding the checkpoint inhibitor. And you can often get away with starting a fairly modest dose of corticosteroids, such as oral prednisone, 0.5 to 1 milligram per kilogram or the equivalent. And steroids can usually be tapered over two to four weeks. BRITTANY HARVEY: Great, thank you for reviewing those recommendations. So then you just mentioned the distinction of aseptic meningitis and encephalitis. So what are those key recommendations for identification, evaluation, and management of encephalitis? BIANCA SANTOMASSO: So in encephalitis, the mental status is not normal. It's characterized by, really, an acute or subacute confusion, altered mental status, altered behavior, memory deficits, including working memory and short-term memory. There can be, as associated symptoms, headaches, new onset seizures, psychiatric symptoms, which can include delusions or hallucinations. There could be weakness, sensory changes, imbalance, or gait instability, along with the mental status changes. And so similar to aseptic meningitis, the other central nervous system toxicity, it's important to distinguish encephalitis from other causes of altered mental status, such as CNS metastases, stroke, or infection. And as for the other syndromes, it's very helpful to have neurologic consultation early, if possible. An MRI of the brain is critical. And in addition, MRI of the spine may be obtained to evaluate for inflammatory demyelinating ischemic or metastatic lesions. In immune related encephalitis, MRI brain imaging may reveal T2 flare changes, typical of what can be seen in idiopathic autoimmune or limbic encephalitis. But most often, the MRI imaging is normal. So in this situation, a lumbar puncture for CSF studies to evaluate for evidence of inflammation can be very helpful. You can expect to see either a lymphocytic pleocytosis or an elevated protein, or CSF restricted oligoclonal bands. CSF analysis is also helpful for excluding other causes of encephalitis, particularly viral encephalitis. So HSV, Herpes Simplex Virus, or varicella zoster virus encephalitis should be ruled out and treated with antivirals while the tests are pending. So typically, these entities can be excluded by PCR testing for HSV and VZV. Electroencephalogram, or EEG, can also be helpful for revealing subclinical seizures or status epilepticus, which can occur as a complication of encephalitis or as a cause of persistently depressed sensorium. But these are not specific to encephalitis. Other testing that's done includes screening metabolic tests to look for alternative etiologies. And for this entity, serum and CSF autoimmune antibody evaluation should be sent to assess for malignancy associated neurologic syndromes. And your neurologist can help you with the workup and management, in particular which tests to send. There have been reported cases of antibody positive checkpoint inhibitor related encephalitis. For management, in contrast to aseptic meningitis, these are generally not as steroid sensitive. So you often have to treat with either higher steroid doses, even pulsed steroid doses, along with IVIG or plasmapheresis. If no improvement, escalation to rituximab and cyclophosphamide can be considered, with the assistance of neurology. This management guidance is taken from how to treat autoimmune encephalitities that are not related to checkpoint inhibitors. Unfortunately, these can be difficult to treat. The response may only be partial. So this is one area in need of better understanding of best therapeutics. BRITTANY HARVEY: OK, thank you for reviewing that and pointing out where there's future research needed as well. And I appreciate your reviewing the recommendations for each of these neurologic immune related adverse events. So then to wrap us up, in your view, how will these recommendations for the management of nervous system toxicities impact both clinicians and patients? BIANCA SANTOMASSO: Yeah, so I think this is a daunting list of toxicities. But I'll say that in most situations, the immune checkpoint inhibitor side effects are often manageable and reversible with proper supportive care. They can be serious, and they require close vigilance and prompt treatment and identification. But by knowing what to look for in early identification, that allows early intervention, which is really the key to reversibility and the best outcomes. So having these toxicities on your differential diagnosis is critical. And I think these guidelines really help inform both clinicians, and care providers, and patients on what the possible manifestations are. So we believe this guideline and its recommendations will help members of clinical teams with the recognition and the management of these unique toxicities. And again, it's timely recognition and early intervention that helps patients, really, by increasing their safety with early management. BRITTANY HARVEY: Great, well, thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Santomasso. BIANCA SANTOMASSO: My pleasure. Thank you so much. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. Stay tuned for additional episodes on the management of immune related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe. So you never miss an episode. [MUSIC PLAYING]

In part one of this two-part ASCO Education Podcast episode, Dr. Sonali Smith (University of Chicago Medicine) and Dr. Paolo Strati (MD Anderson Cancer Center) discuss the application of recently approved therapies for diffuse large B-cell lymphoma through examination of challenging patient cases. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 10/20/21   TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] SONALI SMITH: Hello, and welcome to this episode of the ASCO Education Podcast highlighting new therapies for lymphoma. My name is Dr. Sonali Smith, and I'm a hematologist and medical oncologist specializing in lymphoma and clinical investigation in lymphoma. I'm also the Elwood V. Jensen Professor and chief of the hematology/oncology section at the University of Chicago, and very excited to be joined by my colleague, Dr. Paolo Strati. PAOLO STRATI: Good morning to everybody. My name is Paolo Strati. I'm a hematologist and medical oncologist and an assistant professor in the Department of Lymphoma/Myeloma, and in the Department of Translational Molecular Pathology at MD Anderson Cancer Center, Houston, Texas. And I'm also the clinical director for the Lymphma Tissue Bank. In part one of this podcast episode, we will discuss the adoption of recently approved therapies for diffuse large B-cell lymphoma, such as selinexor, tafasitamab, Liso-Cel, and Lonca-T. These therapies have transformed care for patients with this disease. And we'll start our conversation today with a patient case. SONALI SMITH: Great. Well, I'll go ahead and present a patient to you, Paulo. So this is a 78-year-old man with diffuse large B-cell lymphoma that is the germinal center-derived subtype. It is not double expressor, it is not double-hit. He has advanced stage disease with a high IPI, as well as the high CNS IPI. Luckily, his performance status is zero and he has no significant comorbidities or other health conditions. He received frontline dose-adjusted EPOC-R with intrathecal methotrexate for six cycles. But at the end, he had a partial remission. So how do you select your salvage therapy in this situation? Are you concerned about using agents targeting CD19 in the second line, given the potential need to use anti-CD19 cellular therapy, or CAR-T in the third line? PAOLO STRATI: This is a very interesting and unfortunately not uncommon case. And thank you, Sonali, for asking these very important questions. Technically, a platinum-based regimen followed by autologous transplant will be a standard answer and may be feasible. Because as you mentioned, this patient has a good performance status and non-meaningful comorbid health conditions. However, patients who are refractory to a frontline anthracycline-based regimen, such as in this case, with achievement only of partial remission at the end of frontline dose-adjusted EPOC, can potentially experience a suboptimal outcome following the standard approach with a platinum-based second line regimen. And as such, alternative strategies may be needed. To this regard, the combination of tafasitamab that, as you know, is a monoclonal antibody targeting CD19, and lenalidomide, an oral immunomodulatory agent, a combination which is currently approved by the FDA in the United States as a standard second line option for transplant ineligible patients, would be a great option in this case. Data from the three year follow-up of the phase II study that has brought to the FDA approval this combination, the L-MIND had been recently presented and have showed the complete remission rate of 40% and immediate duration of response of 44 months, including patients who received this regimen as a third line or beyond. So there is, of course, a biological concern by targeting CD19 in second line. These may potentially impact a third line use of an autologous anti-CD19 CAR-T, because CD19 downregulation may potentially be a mechanism of escape to tafasitamab. And recent data has shown the CD19 levels are strongly associated with the efficacy of CAR-T cell therapy in patients with large B-cell lymphoma. Small retrospective studies have shown that autologous anti-CD19 CAR-T can be safely and effectively used after antibodies or antibody drug conjugate targeting CD19. But we need a significantly larger and prospective data, including serial tissue biopsy in these patients before considering this combination as a standard practice in patients for whom we plan to use CAR-T as a third line. Until then, I would be cautious in using second line tafasitamab in patients, again, for whom there is a potential plan for anti-CD19 autologous CAR-T in third line. And if necessary, limited to very selective cases. Finally, recent press releases have anticipated the two autologous anti-CD19 CAR-T products, Axi-Cel and Liso-Cel, are superior to autologous settings transplanted in second line. And so in the near future, CAR-T cell therapy may become a standard second line option. And that would be an ideal option in primary chemorefractory patients as the case that you presented here. SONALI SMITH: Yeah, I agree. There are a tremendous number of options. And having anti-CD19 products as well as autologous stem cell transplant, the sequencing will be an evolution. So going back to this patient, he received tafasitamab and lenalidomide for two cycles with no significant toxicity, but unfortunately, he had further progression after two cycles based on a PET/CT scan. So what are your next steps? Would you move directly to an autologous anti-CD19 CAR-T cell therapy now? Would you re-biopsy before that? And how would you select among the three available CAR-T products? PAOLO STRATI: These are not easy questions, particularly the selection of one out of three available CAR-T products. As you said, there are currently three autologous anti-CD19 CAR-T products approved by the FDA in the United States for the treatment of large B-cell lymphoma in third line or beyond. And these are Axi-Cel, Tisa-Cel, and Liso-Cel. For all of them, the best outcome is observed for patients who have a low turmor burden at time of CAR-T infusion. And they need to either select patients with no bulky disease or to decrease it through bridging therapy. And as we define bridging therapy given between leukapharesis and CAR-T infusion. Unfortunately, there is currently no standard bridging therapy and all FDA products approved in third line can potentially be used in this specific scenario that you described, including polatuzumab with bendamustine/rituximab, selinexor, and Lonca-T, of course, beyond tafasitamab and len that has already been used in this case. Of course, when selecting a bridging therapy, there are many disease-related and patient-related factors to take into consideration, including the need to preserve the host immune microenvironment that we all know is crucial for the subsequent activity of CAR-T cells. And also, we need to give into consideration the need to preserve as much as possible, as we discussed previously, in CD19 expression. To this regard, and going back to one of your questions, I strongly recommend to re-biopsy patients if any bridging therapy is used between bridging therapy and CAR-T infusion in order to document CD19 expression before CAR-T infusion. When it comes to CAR-T product selection, as I said, it's a really difficult decision to do. And we don't have at this time randomized trials in third line. And as such, the decision is really left to the treating physician based on multiple factors. But all of the limitations of inter-study comparison, efficacy seems to be pretty much the same for the two products, maybe slightly higher based on the recent second line data. But Axi-Cel and Liso-Cel as compared to Tisa-Cel, and also as suggested by recent press release. However, due to the fact that Liso-Cel and Tisa-Cel have less potent co-stimulatory domain for 1BB instead of CD28, the rate of CRS and ICANS, the two main toxicities associated with CAR-T cell therapy, is usually lower with this to the point that some centers are able to infuse them in the outpatient setting, whereas Axi-Cel is almost always infused in the inpatient setting so the toxicity can be monitored more closely. So with older patients or those who have comorbid health condition, Tisa-Cel and Liso-Cel may be a safer option, though there's a lot of research going on trying to mitigate toxicities associated with Axi-Cel. Finally, it's important to keep in mind manufacturing time. Axi-Cel is manufactured in an average of 17 days, whereas Tisa-Cel and Liso-Cel take typically longer than three to four weeks. This can be itself a determining factor, particularly for patients who are quickly progressing and where immediate treatment is needed. SONALI SMITH: Yeah, I agree. I think there are going to be many patient product and disease-based factors that will impact both the effectiveness as well as the toxicity. And you did a really great job of explaining the role of the co-stimulatory domain potentially in some of that, as well as all of the products that are out there. It's definitely a complicated area. Going back to our patient, so he did undergo leukapharesis for Liso-Cel and received third line polatuzumab and rituximab without bendamustine. The restaging PET/CT after two cycles showed a PR with a significant decrease in tumor burden, and repeated biopsy showed high expression of CD19 by flow cytometry. He then proceeded with Liso-Cel, which was relatively well tolerated. There was only grade 1 cytokine release syndrome and no ICANS, so no neurotoxicity. And his day 30 PET/CT showed a complete remission. Unfortunately, the 90 day PET/CT showed progression. So Dr. Strati what is the outcome for patients who relapse after CAR-T? Do you recommend to re-biopsy? And what are the efficacy data for FDA approved agents for these patients? And I know this is a long question, but is there any role for repeated CAR-T or allogeneic transplant now? PAOLO STRATI: Unfortunately, currently, the outcome of patients with large B-cell lymphoma relapse or progress after autologous anti-CD19 CAR-T is suboptimal, with a life expectancy, unfortunately, shorter than six months. Hence, the need to be creative and customize treatment based on biological data. To this regard, I think it's crucial to repeat a tissue biopsy to guide subsequent therapy. As mentioned previously, there are currently four products approved by the FDA for patients with large B-cell lymphoma in third line and beyond. Two of these target CD19, tafasitamab plus lenalidomide and Lonca-T One targets CD79B, polatuzumab combined with bendamustine and rituximab. And one is an SPO1 inhibitor, selinexor. While we have no data for selinexor in patients who relapse or progress after CAR-T cell therapy, limited prospective data showed that a progression-free survival in the order of weeks is usually observed for patients who receive polatuzumab with or without bendamustine and rituximab after CAR-T cell therapy. So I would not recommend that. However, there's some interesting activity in the post-CAR-T setting for Lonca-T and for tafasitamab/len is limited to patients who still express CD19 in time of relapse. And of course, it needs to be largely and prospectively further investigated before becoming a standard approach for patients who relapse or progress after CAR-T cell therapy. When it comes to cellular therapy, repeated anti-CD19 CAR-T infusion is not shown to be successful in the original registration studies. So it is not currently something that I would recommend and is not definitely a common practice. And very limited retrospective studies have shown the use of allogeneic stem cell transplants in the post-CAR-T setting may be associated with quite elevated treatment-related mortality. So I don't suggest this as a standard practice in large B-cell lymphoma at this time. This is different from B acute lymphoblastic leukemia, where instead, allogeneic stem cell transplant is becoming progressively a standard approach. And we definitely need more data before using this consistently. While we strive to identify the optimal cell batch therapy for large B-cell lymphoma patients who relapse or progress after CAR-T cell therapy. I think the priority should be given to clinical trials, including CAR-T targeting molecules other than CD19, such as CD20, CD22, CD79B, allogeneic CAR-T there are immediately available, so without the need to wait for manufacturing times. And K-CAR, that may be less toxic than CAR-T and other non-cellular therapy biological agents. So definitely, clinical trials are, at this time, the best approach in patients who relapse after CAR-T cell therapy, as the case that you described. SONALI SMITH: Thank you Dr. Strati. As an update, this patient had repeated biopsy showing a CD19 positive relapse. He consented for a clinical trial with a novel NK-CAR targeting CD19, achieving CR which is still ongoing at nine months. And this case really does represent some of the most exciting advances that we've had for this disease for patients who can tolerate aggressive therapies and have access to clinical trials. PAOLO STRATI: Dr. Smith, I'd like to hear your opinion about another patient with diffuse large B-cell lymphoma. This patient is an 81-year-old man with a history of coronary artery disease and well-controlled diabetes mellitus, who noticed a right cervical lymph node while shaving that seemed to have popped up. He was evaluated by his primary care physician and given a course of antimicrobials. 10 days later, the lymphoma seems to be enlarging and he is referred to ENT pharyngeal biopsy. The specimen is small but shows follicular lymphoma in a portion of the sample. However, there is also concern for larger cells and possible transformation. The patient is also beginning to note night sweats and a decreased appetite. And labs are notable for elevated LDH, 500, and thrombocytopenia with a platelet count of 110. So Dr. Smith, in your opinion, is this specimen sufficient to start treatment? Or should treatment be delayed to get a larger and maybe excisional biopsy? SONALI SMITH: Yeah, thank you for this question. I think this is a challenge we have in the clinic all the time, which is what is a sufficient biopsy specimen to make a diagnosis that allows us to subtype lymphoma? As we know, every lymphoma subtype, the treatment is really guided by the histology and not so much the stage or some other factors. So having a needle biopsy is unfortunately often insufficient. In this case, we have a very strong concern for a possible transformation. And as we know, both follicular lymphoma and diffuse large B-cell lymphoma can mark very similarly when it comes to immunophenotype. Certainly, the germinal center type of diffuse large B-cell lymphoma or any transformed follicular lymphoma will be CD20 positive, CD10 positive, and it really requires architecture to be able to tell whether or not there are sheets of large cells. So the ideal outcome for this patient would be to have a biopsy that is done promptly that allows us not only to confirm whether or not there is histologic evidence of transformation, but also to conduct FISH studies to determine if there's acquisition of a MYC rearrangement. At its core, all follicular lymphoma patients essentially have a transformation of 14;18, leading to BCL2 rearrangement and BCL2 overexpression. During the transformation process, there can be an acquisition of a MYC rearrangement, which would then make this a double-hit lymphoma and certainly has a much worse prognosis and may also prompt a change in treatment if the patient can tolerate more intensive therapy. So my recommendation would be to have a biopsy. Now one other aspect is that sometimes, we don't really have the time to proceed with a biopsy, or the lymph node may be in an inaccessible area. And in that case, there are some other criteria that we can use to assume that somebody has a transformation. Symptoms such as profound B symptoms and elevated LDH, and sometimes, a PET scan with multiple areas of very high avidity, can lead you to feel or suggest that this person has a transformation. There is some controversy over the use of PET and we know it does not confirm a diagnosis of transformation. But in my opinion, this is very suggestive if there are many areas of high SUV. PAOLO STRATI: Thank you, Dr. Smith. I agree completely about the importance, when time allows, to perform either a larger core biopsy or an excisional biopsy, because as you very well-outlined, this has not just a mere diagnostic purpose, but can meaningfully affect treatment planning for patients. And actually, in this case, as you suggested, the patient eventually had multiple core biopsy that showed transformed follicular lymphoma with very evident areas of diffuse large B-cell lymphoma. FISH, as expected for follicular lymphoma, was positive for translocation for TN18, but luckily negative for MYC rearrangement. So fortunately, we didn't have to deal with a double-hit lymphoma. The remainder of his staging showed he had diffuse lymphadenopathy. And PET scan, as you mentioned, has a controversial role in the diagnosis of transformation. So there's some areas that had high avidity with an uptake with an SUV of 1215, whereas other areas were less intense with SUV 618. And usually, heterogeneity in SUV actually helps further supporting diagnosis or transformation. While meta-maps showed follicular lymphoma, no large cells. So movement was isolated in the B-cell lymphoma. So Dr. Smith, at this point, based on the provided information, what's your treatment approach in this older patient and also a patient with comorbid health conditions, but with diffuse large B-cell lymphoma? SONALI SMITH: Yes. The goal of treating any aggressive lymphoma is to obtain remission, and if the remission lasts, to hopefully offer cure to the patient. And when somebody has a transformed lymphoma, of course, there is a dual concern, which is that the aggressive component can potentially be put into remission in a durable way achieving cure. But the indolent component will always need to be monitored, although hopefully, will not be life threatening the way the aggressive component can be. Treating an octogenarian is really challenging, particularly due to comorbidities in this age group and the potential toxicity of chemotherapy. So the standard of care for diffuse large B-cell lymphoma is anthracycline-based chemotherapy. But this, of course, can have significant toxicity in older patients. And in addition, the vincristine can aggravate neuropathy. And I've personally found that the high dose steroids that are part of CHOP can also cause toxicity in older patients and patients who are frail. So unfortunately, the literature is somewhat sparse. But we do have several data sets that can guide management in this particular patient situation. The French published, over a decade ago, the development of R mini CHOP, that includes an attenuated dose of cyclophosphamide, doxorubicin, and vincristine, and leads to some durable remissions and cure. Unfortunately, the long-term overall survival is less than 50% with R mini CHOP. And so although this is an appropriate backbone, there's certainly a lot of room for improvement. And there's also toxicity even with R mini CHOP. So in their initial phase II trial, there was actual deaths related to the R mini CHOP, particularly in the first cycle or two, really necessitating some type of pre-phase help ease patients into the chemotherapy. One of the challenges that we face in the clinic is that when we meet an older patient, we both want to maximize our chance for cure, but also minimize the toxicity that is particularly pronounced. And there is very little data in terms of how to guide this at the bedside. I'm excited that SWOG, with the US Intergroup, is conducting a trial, S1918, which prospectively includes a frailty assessment tool that was developed by the Italian group in lymphoma, and then also includes serial comprehensive geriatric assessment so that we can get a better idea about quality of life both during and after treatment. So there is no great standard of care right now, but I would say that R mini CHOP, outside of a trial, is a very reasonable way to proceed. PAOLO STRATI: Dr. Smith, thank you for outlining so well what we can do to minimize toxicity and to better select patients for this type of treatment. And as an Italian practitioner in the United States, I am very excited that the Italian frailty tool will be used in this SWOG trial. Are there any other ways to further improve safety when we use chemo immunotherapy in older patients or patients with comorbid health conditions? In particular, there is a lot of concern about potentially infectious complications in these patients. And so I'm wondering if there's any routine antimicrobial prophylaxis that you recommend. SONALI SMITH: Yes. I think it's really important to maximize supportive care for our older patients with aggressive lymphomas getting intensive therapy. I did mention the pre-phase, and I would just like to mention that one more time because I do think there's data that providing a brief pre-phase can minimize toxicity with the first cycle. And how this pre-phase is given is highly variable. Again, the data is somewhat limited, but it typically includes steroids given for five to seven days with or without a dose of vincristine. And steroids themselves can have toxicity. And the dose of the steroids, I think, is somewhat controversial. In my personal practice, I use somewhere between 40 to 60 milligrams per day for five to seven days. And I do not typically use vincristine, although a prospective French trial recently did and showed that this significantly improved toxicity. Other complications that can occur really are related to infection. And so, of course, all patients should have growth factor support as per ASCO guidelines. But I also routinely give VZV prophylaxis with acyclovir or valacyclovir. And for the first cycle in particular, I have patients come back to clinic after the first dose one week later to ensure that the counts are stable and that they are doing well. This is really where our team of nurses and other providers who are part of the care team are so important and communication is also very important. PAOLO STRATI: So Dr. Smith, as you suggested, also, this patient actually received mini R-CHOP without any complications. And end-of-treatment PET/CT can showed a VL score of 3, so a complete metabolic remission, potentially. How do you interpret these findings? SONALI SMITH: So response criteria in clinical trials, and then of course, extrapolated to the clinic, have evolved in lymphoma. And the Deauville or the International Prognostic Scoring System that has been used typically defines a uptake relative to liver and mediastinal blood pool. And those patients who have a Deauville 1 to 2, which is less than that bar, is considered negative. And 4 to 5 is positive, with five being the emergence of new sites of adenopathy. The interpretation of a Deauville 3 can be somewhat more complicated, but this really outlines the limitations of just using the SUV or the PET scan uptake to measure response. For my patient and for this patient, the lymph nodes all substantially decreased in size. And having some type of combined interpretation of the uptake, as well as the size that has decreased, I think is going to be a very important part of how we approach patients going forward. So for this patient, I opted for close observation after the completion of therapy and felt that his Deauville 3, along with the decrease in the size of the lymph nodes, was very significant. PAOLO STRATI: I completely agree with that. Where PET scan is an extremely helpful tool, particularly for the management of aggressive B-cell lymphoma, can also become a major challenge when it comes to its interpretation for these borderline scenarios. And as you said, it's very important to add into the equation multiple parameters, including CT findings and overall patient performance status symptoms. So that's all we have for today. Thank you, Dr. Smith. This was a great conversation. We have learned and discussed a lot about diffuse large B-cell lymphoma, including novel biological agents, CAR-T cell therapy, management of elderly patients, and patients with comorbid health conditions and interpretation of PET/CT scan. I think this will be very helpful. And the conversation will continue beyond this podcast. In part 2 of this episode, airing in November, we will discuss new therapies for mantle cell lymphoma and for follicular lymphoma. Thank you so much to all the listeners tuning into this episode of the ASCO Educational Podcast. SONALI SMITH: Thank you. It's been a pleasure to speak with you today. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO e-learning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

In this episode, Tracy Zivin-Tutela, MD, discusses factors that put your patients at risk for shingles and its complications.Tracy Zivin-Tutela, MDInfectious Diseases SpecialistDepartment of Infectious DiseasesFountain Valley Regional HospitalLos Alamitos Medical CenterFountain Valley, CaliforniaUsing a case study and the latest data, this podcast covers topics such as: Pathophysiology and epidemiologyDisease burden and potential complications in older patients, including postherpetic neuralgiaRisk factors, including age, immunosenescence, chronic diseases, unvaccinated statusContent based on a CME program supported by an educational grant from GlaxoSmithKlineFollow along with the downloadable slides at:https://bit.ly/3ENbcbPLink to full program:https://bit.ly/3o4PB8N

Shaken by a shortage of shingles savvy? Vexed by varicella-zoster imposters? Perplexed by post-herpetic neuralgia? Get ready to sharpen your expertise in varicella vaccines, learn how to tell a zoster from a zebra, and administer infection interventions with an eye towards prevention. We are joined today by special guest and returning Curbsiders expert, Dr. Boghuma Kabisen Titanji MD, M.Sc., DTM&H, PhD. (@Boghuma on Twitter!). Unfortunately, CE credit is NOT YET available for this episode : ( Episodes | Subscribe | Spotify | Swag! | Top Picks | Mailing List | thecurbsiders@gmail.com | Free CME! Credits Written and Produced by: Sarah Phoebe Roberts, MPH Show Notes by: Sarah Phoebe Roberts MPH, Kate GrantMBChB MRCGP DipGUMed Cover Art: Kate Grant MBChB MRCGP DipGUMed  Infographic: Sarah Phoebe Roberts  Hosts: Matthew Watto MD, FACP; Sarah Phoebe Roberts MPH   Reviewer: Paul Williams MD, FACP   Editor: Kate Grant MD, Matthew Watto MD (written materials); Clair Morgan of nodderly.com Guest: Dr. Boghuma Titanji, MD, M.Sc., DTM&H, PhD Sponsor: BetterHelp betterhelp.com/curb Special offer for listeners: get 10% off your first month at betterhelp.com/curb Sponsor: Grammarly grammarly.com/curb Get 20% off Grammarly Premium by signing up at Grammarly.com/curb CME Partner: VCU Health CE The Curbsiders are partnering with VCU Health Continuing Education to offer FREE continuing education credits for physicians and other healthcare professionals. Visit curbsiders.vcuhealth.org . Show Segments Intro, disclaimer Guest bio and one-liner First Kashlak case: Diagnosis of varicella-zoster virus (VZV, aka shingles)  Mimics and atypical presentations Treatment for uncomplicated shingles cases  Second Kashlak case: Post-herpetic neuralgia (PHN) PHN treatment options  Management of complicated shingles cases  VZV prophylaxis and infection control Third Kashlak case: Immunization guidelines for older adults VZV vaccine efficacy, live attenuated vs. recombinant vaccine Varicella (chickenpox) vaccine guidelines Final pearls and Outro 

Episode 58: Transaminitis.  Elevated aminotransferases can be caused by intrahepatic and extrahepatic causes, Dr Martinez and Dr Civelli explain the workup of transaminitis, distribution of Chantix was stopped by Pfizer, smoking cessation updates Introduction: Smoking Cessation UpdatesBy Hector Arreaza, MD, Valeri Civelli, and Yosbel Martinez, MD On June 25, 2021, Pfizer stopped distribution of some badges of Chantix(r) after high levels of the carcinogen N-nitroso-di-methyl-amine (NDMA) were found in some lots of the pills. “Pfizer told Reuters the distribution pause was ordered out of abundance of caution while further testing is conducted.”The FDA approved Varenicline in 2006, and there is evidence that Chantix is the most effective anti-smoking medication.USPSTF Grade A recommendations:1. All adults should be asked about their tobacco use. Then, if determined to be smokers or tobacco users, advise them to quit, and provide behavioral interventions and FDA-approved medications for cessation. This applies to all adults who are not pregnant and use tobacco.2. All pregnant patients should be asked about their tobacco use, advised to quit using tobacco, and offer behavioral interventions for cessation. USPSTF Grade I (I stands for “I don't know”):1. The USPSTF does not endorse or discourages the use of pharmacotherapy for smoking cessation in pregnant patients because there is insufficient evidence.2. E-cigarettes have insufficient evidence to be recommended as an effective way to stop smoking in adults. This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it's sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home.___________________________Transaminitis. By Yosbel Martinez, MDTransaminitis (Also known as Elevated Aminotransferases). “itis” normally means inflammation in medical terms, and for that reason transaminitis is not etymologically correct, but it's easy to use and everyone understands what it means. What are aminotransferases?Aminotransferases are intracellular enzymes are sensitive indicator of liver cell injury (necrosis vs inflammation) ALT (alanine aminotransferase) more specific measure of liver injury because AST (aspartate aminotransferase) also found in striate muscle, heart, brain, kidney and Red and white blood cells.-There is poor correlation between degree of liver cell damage and level of aminotransferases. General Approach of Chronic Transaminitis Chronic > 6 months (Often asymptomatic patient)Initial evaluation for most common liver conditions.-Drugs (herbal or recreational drugs) or medications (acetaminophen, INH, amiodarone, statins)-Hepatitis A, B, C-Alcohol Hepatitis AST/ALT ratio above 2:1-Fatty Liver AST/ALT < 1, RUQ Ultrasound- Hemochromatosis Iron/TIBC > 45% Hereditary hemochromatosis is an autosomal recessive disorder that disrupts the body's regulation of iron. It is the most common genetic disease in whites. Men have a higher risk of iron-overload disease compared with women. Hemochromatosis symptoms are absent in the early stages. If present, symptoms may include weakness, lethargy, arthralgias, and impotence. Later manifestations include arthralgias, osteoporosis, cirrhosis, hepatocellular cancer, cardiomyopathy, dysrhythmia, diabetes mellitus, and hypogonadism. Diagnosis requires confirmation of increased serum ferritin levels and transferrin saturation, with or without symptoms. Treatment of hereditary hemochromatosis requires phlebotomy, and the frequency is guided by serial measurements of serum ferritin levels and transferrin saturation. Dietary modification is generally unnecessary. Screen: Testing should be performed in first-degree relatives of patients with classical HFE-related hemochromatosis, those with evidence of active liver disease, and patients with abnormal iron study results. Screening for hepatocellular carcinoma is reserved for those with hereditary hemochromatosis and cirrhosis. Statins: Statins are very important in prevention of treatment of cardiovascular disease. They are safe.“The risk of hepatic injury caused by statins is estimated to be about 1 percent, similar to that of patients taking a placebo.”Patients with transaminase levels no more than three times the upper limit of normal can continue taking statins; often the elevations will resolve spontaneously. Coexisting elevations of transaminase levels from nonalcoholic fatty liver disease and stable hepatitis B and C viral infections are not contraindications to statin use Dosing: Hepatic Impairment: AdultContraindicated in active liver disease or in patients with unexplained persistent elevations of serum transaminases. Further evaluations to Determine likely source-Hepatic source (less common liver conditions)-Autoimmune Hepatitis (women, SPEP, ANA, ASMA)-Wilson disease (ceruloplasmin, slip lamp exam for Kayser- Fleischer rings)-Alfa 1- antitrypsin deficiency (emphysema out of proportion, obtain AA-1 level)-Other viral Hepatitis D, E, CMV, EBV, HSV,VZV. Non-Hepatic source.-Muscle disorder (CK, aldolase)-Thyroid disease (FT4, TSH)-Celiac/IBD (IgA anti-tissue transglutaminase, Calprotectin,CRP, P-ANCA, MRCP/ERCP.-Adrenal insufficiency (8 am cortisol level and plasma ACTH)-Anorexia nervosa (Psychiatric evaluation, BMI, electrolytes and Echo or TTE) Final step of evaluation.Liver biopsy (for diagnostic, staging and grading of liver disease)Now we conclude our episode number 58 “Transaminitis”. Dr Martinez and Dr Civelli explained what to do when we find elevated aminotransferases. Remember you can have intra-hepatic and extra-hepatic causes. If you cannot determine what's causing transaminitis, you may need to ask for a liver biopsy.  Even without trying, every night you go to bed being a little wiser.Thanks for listening to Rio Bravo qWeek. If you have any feedback about this podcast, contact us by email RBresidency@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. This podcast was created with educational purposes only. Visit your primary care physician for additional medical advice. This week we thank Hector Arreaza, Yosbel Martinez, and Valerie Civelli. Audio edition: Suraj Amrutia. See you next week!_____________________References:Pfizer Halts Distribution of Stop-Smoking Pill Chantix, WebMD, webmd.com, accessed on Jul 6, 2021. https://www.webmd.com/smoking-cessation/news/20210625/chantix-distribution-halted-pfizer. Tobacco Smoking Cessation in Adults, Including Pregnant Persons: Interventions, United States Preventive Services Taskforce, uspreventiveservicestaskforce.org, accessed on Jul 6, 2021. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/tobacco-use-in-adults-and-pregnant-women-counseling-and-interventions Uworld Boards Family Medicine Qbank.Harrison's Manual of Medicine 20th Edition.Pocket Medicine 7th Edition by Marc S. Sabatine.      

Cranberry Powder Attenuates Benign Prostatic Hyperplasia University of Suwon (South Korea), June 21, 2021   Cranberry powder (CR) is reported to be effective against lower urinary tract symptoms (LUTS) and recurrent urinary tract infections. Benign prostatic hyperplasia (BPH) in men older than 50 years is a common cause of LUTS. Here, we attempted to evaluate if CR is also effective for treating BPH using a BPH-induced rat model, which was orally administered CR. Male Sprague-Dawley rats weighing 200–250 g were randomly divided into the following six groups (n = 9): noncastration group; castration group; BPH group; BPH and cranberry for 8-week (CR8W) group; BPH and cranberry for 4-week (CR4W) group; and BPH and saw palmetto group (saw palmetto). Compared with the BPH group, the CR8W group showed a significant decrease in prostate weight (by 33%), dihydrotestosterone (DHT) levels (by 18% in serum and 28% in prostate), 5-alpha reductase levels (18% reduction of type 1 and 35% of type 2), and histological changes. These results indicate that CR could attenuate BPH by inhibiting 5-alpha reductase and by reducing other biomarkers such as prostate weight and DHT levels. Thus, CR may be an effective candidate for the development of a functional food for BPH treatment. IACUC (USW-IACUC-R-2015-004).   In our investigation, the administration of CP significantly prevented the progression of BPH by reducing the 5AR levels, and consequently reducing DHT levels in the serum and prostate, along with reduction of the prostate size. This study demonstrated that CR exerts positive effects against BPH, based on biochemical and histological changes in BPH-induced rats. Although further investigation and validation is required, our study provides evidence, for developing a potential treatment for BPH from natural products.     Psychedelic spurs growth of neural connections lost in depression Yale University, July 5, 2021 The psychedelic drug psilocybin, a naturally occurring compound found in some mushrooms, has been studied as a potential treatment for depression for years. But exactly how it works in the brain and how long beneficial results might last is still unclear. In a new study, Yale researchers show that a single dose of psilocybin given to mice prompted an immediate and long-lasting increase in connections between neurons. The findings are published July 5 in the journal Neuron. "We not only saw a 10% increase in the number of neuronal connections, but also they were on average about 10% larger, so the connections were stronger as well," said Yale's Alex Kwan, associate professor of psychiatry and of neuroscience and senior author of the paper. Previous laboratory experiments had shown promise that psilocybin, as well as the anesthetic ketamine, can decrease depression. The new Yale research found that these compounds increase the density of dendritic spines, small protrusions found on nerve cells which aid in the transmission of information between neurons. Chronic stress and depression are known to reduce the number of these neuronal connections. Using a laser-scanning microscope, Kwan and first author Ling-Xiao Shao, a postdoctoral associate in the Yale School of Medicine, imaged dendritic spines in high resolution and tracked them for multiple days in living mice. They found increases in the number of dendritic spines and in their size within 24 hours of administration of psilocybin. These changes were still present a month later. Also, mice subjected to stress showed behavioral improvements and increased neurotransmitter activity after being given psilocybin. For some people, psilocybin, an active compound in "magic mushrooms," can produce a profound mystical experience. The psychedelic was a staple of religious ceremonies among indigenous populations of the New World and is also a popular recreational drug. It may be the novel psychological effects of psilocybin itself that spurs the growth of neuronal connections, Kwan said. "It was a real surprise to see such enduring changes from just one dose of psilocybin," he said. "These new connections may be the structural changes the brain uses to store new experiences."   How long can a person live? The 21st century may see a record-breaker University of Washington, July 2, 2021 The number of people who live past the age of 100 has been on the rise for decades, up to nearly half a million people worldwide. There are, however, far fewer "supercentenarians," people who live to age 110 or even longer. The oldest living person, Jeanne Calment of France, was 122 when she died in 1997; currently, the world's oldest person is 118-year-old Kane Tanaka of Japan. Such extreme longevity, according to new research by the University of Washington, likely will continue to rise slowly by the end of this century, and estimates show that a lifespan of 125 years, or even 130 years, is possible. "People are fascinated by the extremes of humanity, whether it's going to the moon, how fast someone can run in the Olympics, or even how long someone can live," said lead author Michael Pearce, a UW doctoral student in statistics. "With this work, we quantify how likely we believe it is that some individual will reach various extreme ages this century." Longevity has ramifications for government and economic policies, as well as individuals' own health care and lifestyle decisions, rendering what's probable, or even possible, relevant at all levels of society. The new study, published June 30 in Demographic Research, uses statistical modeling to examine the extremes of human life. With ongoing research into aging, the prospects of future medical and scientific discoveries and the relatively small number of people to have verifiably reached age 110 or older, experts have debated the possible limits to what is referred to as the maximum reported age at death. While some scientists argue that disease and basic cell deterioration lead to a natural limit on human lifespan, others maintain there is no cap, as evidenced by record-breaking supercentenarians. Pearce and Adrian Raftery, a professor of sociology and of statistics at the UW, took a different approach. They asked what the longest individual human lifespan could be anywhere in the world by the year 2100. Using Bayesian statistics, a common tool in modern statistics, the researchers estimated that the world record of 122 years almost certainly will be broken, with a strong likelihood of at least one person living to anywhere between 125 and 132 years. To calculate the probability of living past 110 -- and to what age -- Raftery and Pearce turned to the most recent iteration of the International Database on Longevity, created by the Max Planck Institute for Demographic Research. That database tracks supercentenarians from 10 European countries, plus Canada, Japan and the United States. Using a Bayesian approach to estimate probability, the UW team created projections for the maximum reported age at death in all 13 countries from 2020 through 2100. Among their findings: Researchers estimated near 100% probability that the current record of maximum reported age at death -- Calment's 122 years, 164 days -- will be broken; The probability remains strong of a person living longer, to 124 years old (99% probability) and even to 127 years old (68% probability); An even longer lifespan is possible but much less likely, with a 13% probability of someone living to age 130; It is "extremely unlikely" that someone would live to 135 in this century. As it is, supercentenarians are outliers, and the likelihood of breaking the current age record increases only if the number of supercentenarians grows significantly. With a continually expanding global population, that's not impossible, researchers say. People who achieve extreme longevity are still rare enough that they represent a select population, Raftery said. Even with population growth and advances in health care, there is a flattening of the mortality rate after a certain age. In other words, someone who lives to be 110 has about the same probability of living another year as, say, someone who lives to 114, which is about one-half. "It doesn't matter how old they are, once they reach 110, they still die at the same rate," Raftery said. "They've gotten past all the various things life throws at you, such as disease. They die for reasons that are somewhat independent of what affects younger people. "This is a very select group of very robust people."     Dried Plum Consumption Improves Total Cholesterol and Antioxidant Capacity and Reduces Inflammation in Healthy Postmenopausal Women San Diego State University, June 27, 2021 Dried plums contain bioactive components that have demonstrated antioxidant and anti-inflammatory effects. The objective of this study was to determine if dried plum consumption reduces the risk factors for cardiovascular disease (CVD) in postmenopausal women, specifically examining lipid profiles, oxidative stress, antioxidant capacity, and inflammation in a dose-dependent manner. We conducted a 6-month, parallel-design controlled clinical trial, where 48 postmenopausal women were randomly assigned to consume 0, 50, or 100 g of dried plum each day. After 6 months of intervention, total cholesterol (TC) in the 100 g/day treatment group (P = .002) and high-density lipoprotein cholesterol in the 50 g/day treatment group (P = .005) improved significantly compared to baseline. Inflammatory biomarkers interleukin-6 (P = .044) and tumor necrosis factor-α (P = .040) were significantly lower after 6 months within the 50 g/day dried plum group compared to baseline. Moreover, total antioxidant capacity increased significantly within the 50 g/day group (P = .046), and superoxide dismutase activity increased significantly within both 50 and 100 g/day groups (P = .044 and P = .027, respectively) after 6 months compared to baseline. In addition, plasma activities of alanine transaminase (P = .046), lactate dehydrogenase (P = .039), and creatine kinase (P = .030) were significantly lower after 6 months in the 50 g/day dried plum group. These findings suggest that daily consumption of 50–100 g dried plum improves CVD risk factors in postmenopausal women as exhibited by lower TC, oxidative stress, and inflammatory markers with no clear dose dependence.     Regular physical activity linked to more 'fit' preteen brains   Childrens Hospital Boston, July 2, 2021 We know exercise has many health benefits. A new study from Boston Children's Hospital adds another benefit: Physical activity appears to help organize children's developing brains. The study, led by Dr. Caterina Stamoulis, analyzed brain imaging data from nearly 6,000 9- and 10-year-olds. It found that physical activity was associated with more efficiently organized, robust, and flexible brain networks. The more physical activity, the more "fit" the brain. "It didn't matter what kind of physical activity children were involved in," says Dr. Stamoulis, who directs the Computational Neuroscience Laboratory at Boston Children's. "It only mattered that they were active." Crunching the data Dr. Stamoulis and her trainees, Skylar Brooks and Sean Parks, tapped brain imaging data from the Adolescent Brain Cognitive Development (ABCD) study, a long-running study sponsored by the National Institutes of Health. They used functional magnetic resonance imaging (fMRI) data to estimate the strength and organizational properties of the children's brain circuits. These measures determine how efficiently the brain functions and how readily it can adapt to changes in the environment. "The preteen years are a very important time in brain development," notes Dr. Stamoulis. "They are associated with a lot of changes in the brain's functional circuits, particularly those supporting higher-level thought processes. Unhealthy changes in these areas can lead to risky behaviors and long-lasting deficits in the skills needed for learning and reasoning." The team combined these data with information on the children's physical activity and sports involvement, supplied by the families, as well as body mass index (BMI). Finally, they adjusted the data for other factors that might affect brain development, such as being born before 40 weeks of gestation, puberty status, sex, and family income. Healthy brain networks Being active multiple times per week for at least 60 minutes had a widespread positive effect on brain circuitry. Children who engaged in high levels of physical activity showed beneficial effects on brain circuits in multiple areas essential to learning and reasoning. These included attention, sensory and motor processing, memory, decision making, and executive control (the ability to plan, coordinate, and control actions and behaviors). In contrast, increased BMI tended to have detrimental effects on the same brain circuitry. However, regular physical activity reduced these negative effects. "We think physical activity affects brain organization directly, but also indirectly by reducing BMI," Dr. Stamoulis says. Analyzing brain effects In the analyses, the brain was represented mathematically as a network of "nodes": a set of brain regions linked by connections of varying strength. Physical activity had two kinds of positive effects: on the efficiency and robustness of the network as a whole, and on more local properties such as the number and clustering of node connections. "Highly connected local brain networks that communicate with each other through relatively few but strong long-range connections optimizes information processing and transmission in the brain," explains Dr. Stamoulis. "In preteens, a number of brain functions are still developing, and they can be altered by a number of risk factors. Our results suggest that physical activity has a positive protective effect across brain regions."   Could Sumac Be Effective on COVID-19 Treatment? Fırat University Medicine Faculty (Turkey), June 11, 2021 Sumac is an herbal product, commonly consumed as a spice and was used for medical treatment for centuries. The phytochemical structure of Sumac was studied extensively, and it was established that the herb contained tannins, polyphenols, flavonoids, organic acids, and essential oils. Various scientific studies demonstrated that Sumac had a free oxygen radical-scavenging effect, a protective effect against liver damage, antihemolytic, leukopenia, and antifibrogenic effects, along with its antiviral, antimicrobial, anti-inflammatory, and antioxidant properties. Recently, several scientific studies described the pathophysiology, clinical course, and the treatment of COVID-19 infection. The examination of the characteristics of COVID-19 infection revealed via the clinical studies suggests that Sumac extract could be useful in the treatment of COVID-19. Given the scientific studies focusing on the beneficial effects of Sumac, the present review aims to provide an encouraging viewpoint to investigate whether Sumac is effective in treating COVID-19 infection. Antiviral Effect SARS-CoV2 virus, which causes COVID-19 infection, is a highly infectious RNA virus. There are no scientific studies on whether Sumac is effective against the SARS-CoV2 virus. On the contrary, the medications currently being used for treatment were directly administered in clinics, without scrutinizing whether they were effective against the novel coronavirus. Subsequently, several medications were identified to be useful during the clinical course of the disease. Yet, there are scientific in vitro and in vivo studies that investigated the antiviral effects of Sumac against several viruses. In a study, bioflavonoids isolated from Sumac were evaluated for their antiviral activities. Sumac presented inhibitory activities against respiratory viruses (influenza A, influenza B, and measles) and herpes viruses (HSV-1, HSV-2, and varicella zoster virus [VZV]).2 Another study found that Sumac extract exhibited significant antiviral activity against fish pathogenic infectious hematopoietic necrosis virus, and viral hemorrhagic septicemia virus. Furthermore, it was considered that Sumac was a potential antiviral therapeutic against fish viral diseases.3 In a study conducted in 2015, it was established that urushiol obtained from Sumac exhibited reverse transcriptase inhibitory activity for human immunodeficiency virus type 1 (HIV-1). It was specified that Sumac could be used as a biological resource due to such inhibitory activity.4 Another study focusing on HIV found that Sumac extracts exhibited anti-HIV activity due to inhibiting the HIV-1 reverse transcriptase and protease activity. It was also demonstrated that Sumac inhibited the viral load in HIV-infected CEM-GFP (a CD4+ T-lymphocytic reporter cell line expressing green fluorescent protein [GFP] under HIV-1 LTR promoter) cells and human peripheral blood lymphocytes.5 Another study reported that Sumac extract presented strong antiviral activity against HSV-1 and HSV-2. The study also revealed that Sumac extract did not only interact with the viral envelope but also interacted with the surface of the host cells of the viruses, thus, disrupted the ability of the virus to adsorb and penetrate the host cells.6 The above-mentioned studies indicated the antiviral effects of Sumac extracts. The review of the viruses, on which Sumac is effective, such as influenza, HSV-1, HSV-2, VZV, and HIV-1 demonstrated that the common point between these viruses was the fact that they are all enveloped viruses, contain dense lipids in their envelopes, and are sensitive to ether.7 Coronaviruses share the same common features.7 Sumac is likely to affect the lipid layer in the virus envelope, disrupting the adsorption to the host cell and preventing the virus from penetrating the host cell, positively contributing to the infection. Naturally, this hypothesis should be evidenced in future studies. However, its effectiveness on the novel coronavirus (SARS-CoV2) should be clarified first through animal testing and subsequently should be tested through human subjects. Conclusion An evaluation of the up to date knowledge, revealed by the clinical studies, on the characteristics of COVID-19 infection, its pathophysiology, clinic, and treatment, suggests that the use of Sumac extracts could be beneficial. Based on the beneficial effects indicated by the scientific studies on Sumac extracts, the present review could be encouraging to investigate its effectiveness for COVID-19 treatment. The authors of the present study believe that the benefits of Sumac extract can be tested by adding the adverse-effect-free Sumac extract to treatment and protecting the existing treatment protocols.   Sugar intake during pregnancy is associated with allergy and allergic asthma in children University of Bristol (UK), July 5, 2021 High maternal sugar intake during pregnancy may increase the risk of allergy and allergic asthma in the offspring, according to an early study led by Queen Mary University of London (QMUL) involving almost 9,000 mother-child pairs. While some research has reported an association between a high consumption of sugar-containing beverages and asthma in children, the relation between maternal sugar intake during pregnancy and allergy and asthma in the offspring has been little studied. The team, which included researchers from University of Bristol, used data from a world-leading birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC), also known as 'Children of the 90s'. The cohort recruited mothers who were pregnant in the 1990s and has been following up their offspring ever since. The current study, which is published in the European Respiratory Journal, analysed associations between maternal intake of free sugars in pregnancy and allergy (defined by positive skin tests to common allergens, namely dust mite, cat and grass) and asthma at seven years of age. While there was only weak evidence for a link between free sugar intake in pregnancy and asthma overall, there were strong positive associations with allergy and allergic asthma (where the child was diagnosed with asthma and had positive skin tests to allergens). When comparing the 20 per cent of mothers with the highest sugar intake versus the 20 per cent of mothers with the lowest sugar intake, there was an increased risk of 38 per cent for allergy in the offspring (73 per cent for allergy to two or more allergens) and 101 per cent for allergic asthma. The team found no association with eczema or hay fever. Lead researcher Professor Seif Shaheen from QMUL said: "We cannot say on the basis of these observations that a high intake of sugar by mothers in pregnancy is definitely causing allergy and allergic asthma in their offspring. However, given the extremely high consumption of sugar in the West, we will certainly be investigating this hypothesis further with some urgency. "The first step is to see whether we can replicate these findings in a different cohort of mothers and children. If we can, then we will design a trial to test whether we can prevent childhood allergy and allergic asthma by reducing the consumption of sugar by mothers during pregnancy. In the meantime, we would recommend that pregnant women follow current guidelines and avoid excessive sugar consumption." The team speculate that the associations may be explained by a high maternal intake of fructose causing a persistent postnatal allergic immune response leading to allergic inflammation in the developing lung. The researchers controlled for numerous potential confounders in their analyses, such as background maternal characteristics, social factors and other aspects of maternal diet, including foods and nutrients that have been previously linked to childhood asthma and allergy. Importantly, the offspring's free sugar intake in early childhood was found to have no association with the outcomes seen in the analysis. As the study is observational, it does not prove a causal link between maternal sugar intake and allergies or asthma. A randomised controlled trial would be needed to definitively test causality.

Episode content: 1. Snellen chart 2. Standard pediatric immunization in US 3. Strength training in children 4. Sturge-Weber syndrome 5. SIDS 6. Suspected foreign body ingestion 7. Timeline of infant nutrition 8. Transient hypogammaglobulinemia of infancy 9. Transient tachypnea of newborn 10. Type II osteogenesis imperfecta 11. Types of plagiocephaly 12. UTI in children and infants 13. Vascular ring 14. VZV reactivation --- Send in a voice message: https://anchor.fm/zusmle/message

Episode 32: VertigoThe sun rises over the San Joaquin Valley, California, today is October 20, 2020.It’s time to talk about vaccines again. The ACIP (Advisory Committee on Immunization Practices) posted new recommendations for meningococcal vaccinations on September 25, 2020. There are two kinds of meningococcal vaccines in the US: 1. Meningococcal conjugate or MenACWY vaccines (Menactra®, Menveo®, and MenQuadfi®)2. Serogroup B meningococcal or MenB vaccines (Bexsero® and Trumenba®). Let’s discuss how they are given.MenACWY: Menactra (MenACWY-D), Menveo (MenACWY-CRW), and MenQuadfi (MenACWY-TT) MenACWY routine: The meningococcal conjugate vaccine should be given to ALL PATIENTS at 11 to 12 years old, with a booster dose at age 16. Remember, it’s a two-dose series, the booster dose at age 16 is important to provide protection during the ages of highest risk of infection. So, that was easy. The hardest part is for patients younger than 10 years old because only patients who are at risk receive routine meningococcal conjugate vaccines before age 11. MenACWY in special groups: This vaccine is given to patients older than 2 months old only if they are at increased risk for meningitis (i.e., persistent complement component deficiencies; persons receiving a complement inhibitor such as eculizumab [Soliris] or ravulizumab [Ultomiris]); persons who have anatomic or functional asplenia; persons with HIV infection; microbiologists routinely exposed to Neisseria meningitidis; persons at increased risk in an outbreak; persons who travel to or live in hyperendemic or epidemic areas; unvaccinated or incompletely vaccinated first-year college students living in residence halls; and military recruits.) I invite you to consult ACIP recommendations regarding vaccination in special groups. MenB: Trumenba (MenB-FHbp), Bexsero (MenB-4C)  MenB shared decision: MenB vaccination is not routinely recommended for all adolescents. It may be given to adolescents and young adults (16 through 23 years old, preferred age is 16-18 years old) on the basis of shared clinical decision. Those who decide to receive MenB vaccine, receive two doses 1-6 months apart depending on the brand name you use. MenB vaccines are not recommended before age 10 in any case. Adults older than 24 and older don’t need MenB unless they are at increased risk.MenB in special groups:Patients with certain medical conditions (persons with persistent complement component deficiencies; receiving a complement inhibitor; with anatomic or functional asplenia; microbiologists exposed to isolates of N. meningitidis; and persons at risk in outbreaks) should receive MenB vaccine. These recommendations will be included in the updated 2021 immunization schedules, and the AAFP will review changes to the schedules once they are available (1).This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program, from Bakersfield, California. Sponsored by Clinica Sierra Vista, Providing compassionate and affordable care since 1971.____________________________“A man is who he thinks about all day long” –Waldo Emerson.If you think you are not good enough, you may not reach your goals. So, think positive about yourself all day long, and you will become that person you think you are and will reach your goals.Hi, this is Dr Carranza, I’m a PGY3, and today I will interview a special guest.Question Number 1: Who are you? Hello, I’m Jagdeep Sandhu. I’m a 4th year medical student from Ross University, currently doing a sub-internship in family medicine. I’m originally from Seattle, Washington. I have an Indian ancestry, so I enjoy meditating and cooking Indian dishes.Question number 2: What did you learn this week? Lightheadedness vs VertigoThis week we learned about dizziness and its differentials. It is important to differentiate dizziness vs lightheaded because a lot of patients will say they are dizzy when they are truly lightheaded. To be honest dizziness (at least for me) is one of the toughest complaints to get from a patient as it is hard to pinpoint its etiology.Important questions to ask the patient are:Do you feel like you’re going to pass out? Do you experience a sense of darkness in front of your eyes? (points to syncope)Is the room spinning? Are you having nausea or vomiting? Ringing in your ears? (points to vertigo)  Peripheral VertigoPeripheral refers to vertigo originated from the ear structures, whereas central from the brainstem. Differentials of peripheral vertigo include:Benign paroxysmal positional vertigo: Transient episodes of vertigo caused by stimulation of vestibular sense organs, this is most commonly due to calcium debris within the posterior semicircular canal, known as canalithiasis. It affects middle-age and older patients; and twice as many women than men. Classically, patients describe a brief spinning sensation brought on when turning in bed or tilting the head backward to look up. The dizziness is quite brief, usually seconds, rarely minutes.The way to Evaluate/diagnose BPPV is with Dix-Hallpike maneuver (turn the patient’s head 45 degrees to one side, then you help you lie back quickly so their head hangs slightly over the edge of the table. If horizontal or rotation nystagmus is noted, the patient has BPPV) and can be cured with Epley’s maneuver.Vestibular neuritis: This is inflammation of the vestibular nerve, which is usually caused by a viral infection. It’s characterized by rapid onset of severe, persistent vertigo, nausea, vomiting, and gait instability. Hearing is preserved but if there is hearing loss(unilateral), then it is diagnosed as labrynthitis.  You can Evaluate/diagnose with a positive head impulse (or head thrust) test and gait instability but know that the patient is still able to ambulate. (lasts a few days and resolves spontaneously) Herpes zoster oticus: It is also known as Ramsay Hunt syndrome when it causes facial paralysis; it occurs due to latent VZV virus in the geniculate ganglion.  The patient will complain of ear pain and vertigo. On exam, you will find vesicles in the auditory canal and auricle along with ipsilateral facial palsy. You can treat with Acyclovir or Corticosteroids. Meniere disease: Itoccursdue to excess endolymphatic fluid pressure, which causes episodic inner ear dysfunctionresulting in the classic triad of vertigo lasting for minutes to hours, usually associated with unilateral tinnitus and hearing loss. Unfortunately, the hearing loss can sometimes be permanent. It usually affects one ear and although it can occur at any age, most cases start between young adults and middle age adults. Evaluate and diagnose clinical features, get an audiogram for hearing loss. Patients go into remission spontaneously but it can reoccur. Other causes of peripheral vertigo: Labyrinthine concussion (traumatic peripheral vestibular injury)Perilymphatic fistula (complication of head injury, barotrauma, or heavy lifting in which a fistula develops at the otic capsule)Aminoglycoside toxicityVestibular schwannoma (unilateral hearing loss associated with neurofibromatosis type 2) Central VertigoVestibular migraine: The mechanism is unknown, so you have to rely on the patient's history of vertigo associated with migraine headache and classic migraine symptoms such as visual aura, photophobia, or phonophobia.Brainstem ischemia: which is due to embolic, atherosclerotic occlusions of the vertebra-basilar arterial system. A few things fall under this category such as TIA, Wallenberg syndrome (lateral medullary infarction), Labyrinthine infarction (Anterior Inferior cerebellar artery) etc. Evaluate and diagnose with Imaging of the head and treat according to diagnosis.  Question number 3: Why is that knowledge important for you and your patients? It is important for when we are working at both the clinic and at the hospital as recognizing serious vertigo can help us plan for intervention. For example, if a patient presents with vertigo and on exam you find vesicles on their ear and facial paralysis then you can immediately begin therapy with a combination of Valacyclovir and Prednisone but if it is a severe case then the patient might need IV treatment.Also, if the patient has vascular risk factors then it is important to keep ischemia as part of your differential when your patient presents with acute sustained vertigo. Remember that for any stroke time of onset is KEY! CT should be done if MRI is not available but MRI is more sensitive for cerebellar infarctions.Question number 4: How did you get that knowledge? (learning habits)I did an ENT rotation in my 3rd yeard of medical school and learned from Dr Trang. I recommend that rotation to all medical students. I also searched in UpToDate, FP notebook app, AAFP and my attendings. See details below.____________________________Speaking Medical: Otolith by Gina Cha, MDStones are located in many unsuspected places in the body. Such is the case of otoliths. An otolith is a calcium carbonate structure in the saccule or utricle of the inner ear, specifically in the vestibular system of vertebrates. The saccule and utricle, in turn, together make the otolith organs. An otolith can cause great trouble if it’s out of its regular place. When otoliths are dislodged from their usual position within the utricle, and migrate into one of the semicircular canals (most commonly the posterior canal), moving the head causes movement of the heavier otolith debris in the affected canal causing abnormal endolymph fluid displacement and a resultant sensation of vertigo.____________________________Espanish Por Favor: Serenoby Claudia Carranza, MD, and Hector Arreaza, MDHi! This is Dr Carranza with our section “Espanish Por Favor”. The word of the week is SERENO (maybe we can have beach waves crushing in the background). SERENO is a state of mind, a peaceful feeling. To be SERENO means to be calm, peaceful, untroubled, tranquil. Sometimes when people are frustrated or too excited you can say: “Sereno, no te preocupes,” which you can loosely translate as “chill, don’t worry.”Sometimes you might ask someone how they are doing and they can say: “Sereno, sin preocupaciones,” which means “calm, without worries.” Nowadays not many people might actually feel that way but you can always remind them to lay back, relax, and take a deep breath “SERENO!”Another meanings of the word sereno includes “humidity on the atmosphere at night.” In some Latin American countries, sereno can make you sick if you, for example, shower and go outside at night, or you can get worse if you are sick and go outside. The sereno can also be used in folk medicine to “macerate” some herbal teas or remedies giving it a special property to cure illnesses. This may not be used in all countries but at least I know it’s true in Mexico and Venezuela.____________________________For your Sanity: Supermanby Tana Parker, MD Friend 1: Do you want to hear a really good Batman impression?Friend 2: Sure, go on. Friend 1: NOT THE KRYPTONITE!Friend 2: That’s Superman.Friend 1: Thanks, man, I've been practicing. “eBay is so useless. I tried to look up lighters and all they had was 13,749 matches.”“I just saw my wife trip and fall while carrying a laundry basket full of ironed clothes. I watched it all unfold.”I made a playlist for hiking. It has music from Peanuts , the Cranberries, and Eminem. I call it my trail mix._________________________Conclusion: Now we conclude our episode number 32 “Vertigo.” Dr Carranza and Jagdeep had an entertaining conversation about the differential diagnosis of peripheral and central vertigo. Don’t forget to practice the Dix-Hallpike and Epley’s maneuvers for BPPV. Otolith is a tiny stone located in the inner ear that can cause vertigo when it gets stuck in the semicircular canals. The word sereno (pronounced (say-RAY-noe) as an adjective is pretty much the same as the English serene, however, Dr Arreaza explained that sereno as a noun refers to the humidity on the air thought to be the “cause” of many ailments in some Latin cultures. Thanks for listening to Rio Bravo qWeek. If you have any feedback about this podcast, contact us by email RBresidency@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. This podcast was created with educational purposes only. Visit your primary care physician for additional medical advice. This week we thank Hector Arreaza, Arianna Lundquist, Claudia Carranza, Jagdeep Sandhu, Gina Cha, and Tana Parker. Audio edition: Suraj Amrutia. See you next week!     _____________________References:Meningococcal vaccine updates: https://www.aafp.org/news/health-of-the-public/20201007meningococcalvacc.html. Review full article at: https://www.cdc.gov/mmwr/volumes/69/rr/rr6909a1.htm?s_cid=rr6909a1_w Labuguen, Ronald H., M.D., University of Southern California, Los Angeles, California, Initial Evaluation of Vertigo, Am Fam Physician. 2006 Jan 15;73(2):244-251. https://www.aafp.org/afp/2006/0115/p244.html Furman, Joseph M, MD, PhD, and Jason JS Barton, MD, PhD, FRCPC, Evaluation of the patient with vertigo, UptoDate, last updated: Feb 11, 2020. https://www.uptodate.com/contents/causes-of-vertigo?search=vertigo§ionRank=1&usage_type=default&anchor=H5&source=machineLearning&selectedTitle=3~150&display_rank=3#H20 

Dr. Toney reviews the epidemiology and management of Varicella Zoster infections. He first discusses the prevalence and clinical presentation of this herpesvirus family infection. He points out the importance of recognizing the prodrome in patients before the complete outbreak occurs. He goes on to discuss the clinical complications of VZV disease, including ophthalmologic, multi-dermatomal, and disseminated infections. He next discusses the treatment options available to manage Zoster infections. The subject of available Zoster vaccines is then discussed, with a focus on the newer Recombinant Zoster Vaccine (RZV). Lastly, Dr. Toney presents a couple of photo case-studies.

Tussen 45 Duitsers in een hotel in Osnabruck ontmoeten redactieleden Bobby Schagen en Stijn Steenhuis elkaar voor de tiende aflevering van het tweede seizoen van Spielmacher: de podcast van Handbal Inside. Schagen is terug van het historische EK en daar wil Steenhuis natuurlijk alles van weten. Wat deed de zege op Letland met de nationale ploeg? Ook alle aandacht voor de nationale competities. Zo voelt VOC de hete adem in de nek. HandbaL Venlo en VZV mengen zich nadrukkelijk in de titelstrijd. Smullen voor de neutrale kijker. Voordat de BENE-League aan de beurt is, klinkt het muziekje van de Half Time Show. In het ontspannende onderdeel van Spielmacher praten Schagen en Steenhuis over carnaval, Alberto Stegeman en de tweede divisie.

In this episode, Charles Vega, MD, Professor of Family Medicine at UC Irvine, will address the clinical impact of herpes zoster, the efficacy, tolerability, and safety of available vaccines for prevention, and strategies to promote adherence to national vaccine guidelines.Herpes zoster, or shingles, results from reactivation of the varicella-zoster virus (VZV) that lies dormant on the dorsal horn nerve cells of the spinal cord. The annual incidence increases with age, from five cases per 1,000 population in adults aged 50-59 years to 11 cases per 1,000 population in persons aged ≥80 years. Approximately 99.5% of people aged ≥40 years born in the United States have been infected with wild-type VZV and are therefore at risk for herpes zoster. Vaccination can reduce the risk of herpes zoster and postherpetic neuralgia (PHN), and a newer vaccine with greater effectiveness is now available. However, various barriers to vaccination exist, and vaccination coverage is suboptimal.This educational activity is supported by an educational grant from GlaxoSmithKline.This activity is not certified for CME/CE credit.

If you don’t have herpes then hearing that everyone has  herpes virus probably just freaked you out! Well, it’s true that everyone has a herpes virus and it’s nothing to be worried about. You’re going to be just fine. Promise.  We’ve been living with these dang herpes viruses for as long as humans have been walking on this earth. The herpes virus want to survive as much as we do and they’ve done a pretty good job at it.  Let me explain.   There are more than 100 known herpes viruses out there! Yep 100! The good news is that there are really only 8 that infects us as humans. Here’s the list and I’d bet you have more than one of them: herpes simplex virus type 1 (HSV) or commonly known as cold sores or fever blisters herpes simplex virus type  2 (HSV) commonly known as genital herpes Varicella-zoster virus (VZV) or commonly known as chickenpox or shingles cytomegalovirus is very common and doesn’t really have any symptoms Epstein-Barr virus or commonly known as mononucleosis or mono and the Symptoms include fatigue, fever, rash, and swollen glands.  human herpesvirus 6 or commonly known as HHV and infects nearly 100% of human beings, typically before the age of three and often results in fever, diarrhea, sometimes with a rash known as roseola. human herpesvirus 7 or commonly known as HHV has symptoms including acute febrile respiratory disease, fever, rash, vomiting, diarrhea, low lymphocyte counts, and febrile seizures, though most often no symptoms present at all. Kaposi's sarcoma virus or human herpesvirus 8 include symptoms that are lesions on the skin: flat, painless spots that are red or purple on white skin and bluish, brownish, or black on dark skin.    Ok so heres the deal. You have 1 or 2 or 3 or many of the herpes virus that are living with us humans. The only one that causes us to freak out or make us believe that we did something wrong is herpes or HSV 1 or 2. So why is it that getting chicken pox or mono doesn’t make us feel like we’re a leper? My guess it’s all a marketing stunt that was put into place to sell the antiviral, valtrex. The pharma companies need a compelling story to convince people that then needed this antiviral in order to continue to live a normal life. And yes, it’s 100% BS. You don’t need the antiviral to live a normal life, yes it helps heal the outbreaks faster but thats really it.    But back to the 8 herpes viruses and how we all have many of them and we all freak out about getting genital herpes or oral herpes.  It really does get me going when you hear people cringe or have an eww attitude towards people with herpes when I know that they have herpes viruses too. Oh and 80% of the people with HSV don’t even know they have it.    The reason why this is important to you, someone living with either oral or genital herpes, is that you can educate the person who stereotypes you or calls you names. Ask them if they have ever had mono or the chicken pox or cold sores. I can guarantee you they’ve had one or all of them.    The truth is you have herpes viruses and that’s just fine. Chickenpox or mono doesn’t define you’re life so why should you let HSV 1 or 2 define your life. What? It’s because you feel like nobody else has it or nobody will date you? It’s total BS and all that it is is a stupid virus that gives you some blisters here and there. That’s it! Life With Herpes Details: Join the Secret Society  HerpAlert (use promo code: lifewithherpes and get 10% off) Shop the LWH Essentials Shop the Secret Society CBD Lip Balm  Oh yea, remember to subscribe to the Life With Herpes newsletter and get The 5 things  I wished she knew before I was diagnosed with herpes sent directly to your inbox + weekly updates.    Xoxo, Alexandra Just in case… Learn about the Herpes Outbreak Toolkit: Need to talk confidentially about herpes?  Oh Yea and in case you need Herpes Outbreak Essentials   Are you social?  Instagram Facebook  

Półpasiec to choroba zakaźna wywoływaną przez wirusa VZV (ang. varicella zoster virus). Najczęściej chorują na niego osoby, które wcześniej przebyły ospę wietrzną, jednak nie zawsze! O tym jak rozpoznać i leczyć półpaśca oraz czym grozi brak odpowiedniego leczenia rozmawiamy z dr hab. n. med. Ireną Walecką, kierownikiem Kliniki Dermatologii Centralnego Szpitala Klinicznego MSWiA w Warszawie, prof. CMKP, MBA, konsultantem wojewódzkim w dziedzinie dermatologii i wenerologii dla województwa mazowieckiego.

Credits: 0.25 AMA PRA Category 1 Credit™ Claim CME/CE credit: https://www.pri-med.com/online-education/podcast/taking-aim-at-shingles-strategies-for-success-pt-3  Overview: Shingles, or herpes zoster (HZ), is a common secondary infection. More than 95% of immunocompetent individuals aged > 50 years are seropositive for the varicella zoster virus (VZV) and are at risk of developing shingles. This podcast series will address the pathophysiology, clinical presentation, and complications of shingles, in addition to the strategies to prevent it.  Guest: Susan Burke, MD, FACP 

Credits: 0.25 AMA PRA Category 1 Credit™ Claim CME/CE credit: https://www.pri-med.com/online-education/podcast/taking-aim-at-shingles-strategies-for-success-pt-2  Overview: Shingles, or herpes zoster (HZ), is a common secondary infection. More than 95% of immunocompetent individuals aged > 50 years are seropositive for the varicella zoster virus (VZV) and are at risk of developing shingles. This podcast series will address the pathophysiology, clinical presentation, and complications of shingles, in addition to the strategies to prevent it.  Guest: Susan Burke, MD, FACP 

Credits: 0.25 AMA PRA Category 1 Credit™ Claim CME/CE credit: https://www.pri-med.com/online-education/podcast/taking-aim-at-shingles-strategies-for-success  Overview: Shingles, or herpes zoster (HZ), is a common secondary infection. More than 95% of immunocompetent individuals aged > 50 years are seropositive for the varicella zoster virus (VZV) and are at risk of developing shingles. This podcast series will address the pathophysiology, clinical presentation, and complications of shingles, in addition to the strategies to prevent it.  Guest: Susan Burke, MD, FACP 

En el episodio de esta semana hablamos sobre Herpes Zoster: importancia, epidemiologia, clínica, tratamiento y prevención. Referencias:  Charles Grose Pangaea and the Out-of-Africa Model of Varicella-Zoster Virus Evolution and Phylogeography. J Virol. 2012 Sep; 86(18): 9558–9565. Paul R Kinchington y colaboradores.  Herpes simplex virus and varicella zoster virus, the house gu https://herpesviridae.biomedcentral.com/track/pdf/10.1186/2042-4280-3-5ests who never leave.  Herpesviridae 2012, 3:5    Thomas Harder, Anette Siedler. Systematic review and meta-analysis of chickenpox vaccination and risk of herpes zoster: a quantitative view on the “exogenous boosting hypothesis”. Clin Infect Dis . Dec 24, 2018.   Frase de la Semana:  La tomamos de Carl Gustav Jung. 26 de julio de 1875 - 6 de junio de 1961) fue un psiquiatra y psicoanalista suizo que fundó la psicología analítica. La frase dice: “Pensar es difícil, por eso la mayoría de la gente prefiere juzgar”        

Recent reports show that varicella zoster virus (VZV) antigen is found in temporal artery (TA) biopsies in patients with giant cell arteritis (GCA). Two experts (Drs Liao and Kedar) debate whether anti-viral therapy should be used routinely in patients with GCA.

Today's topic is hot with 3 major papers in the last few months, that is the viral hypothesis of Alzheimer's disease. Alzheimer's disease (AD) was estimated to affect 35.5 million people worldwide in 2010 and is expected to affect 115.4 million people by 2050. Four members of the Human Herpes Virus family have been associated with development of Alzheimer's disease; HSV-1, VZV, HHV-6A, and HHV-7. My guest today says its time to put it to the test. Joining today is infectious disease physician, Steven LaRosa, MD.

Shingles is caused by the varicella zoster virus (VZV), which is the same virus that causes chickenpox and it can cause a painful rash and many other uncomfortable symptoms. The only way to prevent and protect yourself from shingles is by getting vaccinated. Elizabeth Wright, MD, discusses the new two-dose shingles vaccine, Shingrix and why it might be a more effective vaccine.

The October 2017’s Archimedes podcast includes answers to “Have you ever wondered if it might be worth trying to do an Archi?” and “What came first, the ‘brufen or the necrotic flesh?” along with cerebrospinal fluid (CSF) analysis and musings on the nature of evidence-based medicine. Read more about varicella-zoster virus (VZV) and non-steroidal anti-inflammatories here - http://adc.bmj.com/content/102/10/988.1 - and how to interpret delayed CSF results here - http://adc.bmj.com/content/102/10/990. The ADC Archimedes podcast, home of the best evidence-paediatrics chat, is presented by Bob Phillips, the Social Media and Archimedes Editor.

Brianne joins the TWiVMasters to explain how mutations in genes encoding RNA polymerase III predispose children to severe varicella, and detection of an RNA virus by a DNA sensor. Hosts: Vincent Racaniello and Rich Condit Guest: Brianne Barker Become a patron of TWiV! Links for this episode RNA pol III mutations underlie severe varicella (J Clin Inves) Dengue virus activates cGAS by release of mitochondrial DNA (Sci Rep) Dengue virus NS2B protein targets cGAS for degradation (Nat Micr) Image credit Letters read on TWiV 456 This episode is brought to you by the Defense Threat Reduction Agency. Part of the U.S. Department of Defense, the Agency’s Chemical and Biological Technologies Department hosts the 2017 Chemical and Biological Defense Science & Technology Conference to exchange information on the latest and most dynamic developments for countering chemical and biological weapons of mass destruction. Find out more at http://www.cbdstconference.com Weekly Science Picks Brianne - Up-Goer Five Challenge (related to Thing Explainer) Rich - The Farthest: Voyager in Space and Vipassana Momma: Science Vincent - Episode of Revisionist History: The Basement Tapes Listener Pick Jennie - What Piece of Lab Equipment Are You? Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

1) Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis and 2) Topic of the month: Immune-mediated necrotizing myopathy. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Jennifer Bickel interviews Dr. Don Gilden about his paper on the prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. Dr. Adam Numis is reading our e-Pearl of the week about unresponsive CIDP: Is it POEMS? In the next part of the podcast Dr. Ted Burns interviews Dr. Andy Mammen about the topic of dermatomyositis. The participants had nothing to disclose except Drs. Gilden, Numis, Burns and Mammen.Dr. Gilden serves as an Senior Associate Editor for Journal of NeuroVirology; serves as an editorial board member of In Vivo, Journal of Virology, Scientific American Medicine, Virus Genes, Neurology and Journal of the Neurological Sciences; and receives research support from the NIH.Dr. Numis serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Ted Burns serves as Podcast Editor for Neurology®; and has received research support for consulting activities with CSL Behring and Alexion Pharmaceuticals, Inc.Dr. Mammen serves on the scientific advisory boards of aTYR Pharmaceuticals Inc. and Biogen Idec; serves as an editorial board member of Experimental Neurology and Arthritis and Rheumatism; receives license fee payments, royalties and revenue for a patent from INOVA Diagnostics Inc. for licensed test for anti-HMGCR antibodies; and research support from the NIH.

Herpes simplex virus type 1 (HSV-1) is a double-stranded DNA virus that infects humans and, after a primary lytic infection, establishes lifelong latency in the sensory neurons of the trigeminal ganglia (TG). HSV 1 latency is accompanied by a chronic immune cell infiltration of the TG, the infiltrate being mainly composed of CD8+ T cells. These T cells are believed to control viral latency, but cellular and viral factors like viral microRNAs are also considered to play a crucial role in the establishment and maintenance of viral latency. In the present work, it was investigated whether the tissue-infiltrating T cells are clonally expanded, which would indicate that these T cells are activated by antigen. By applying complementarity determining region 3 (CDR3) spectratyping and immunohistochemistry, several clonal expansions were identified in the TG-resident T cells. In addition, several T cells were present that seemed to be unspecific bystander T cells. Strikingly, some expanded T cell clones were present in the right and left TG of the same individual. This strongly suggests that similar antigens are present in both TG and that the infiltration of immune cells to the TG is driven by antigen. The morphology of the TG was investigated by immunohistochemistry and in situ hybridiza¬tion. Analysis of the distribution of T cells throughout the TG provided puzzling results: unexpectedly, most neurons surrounded by T cells did not harbour the only known prominent transcript during latency, the latency associated transcript (LAT). Whether these neurons do actually harbour latent virus was addressed by a combination of LAT in situ hybridisation, T cell immunohistochemistry, and single cell analysis of laser microdissected sensory neurons by PCR. This analysis revealed that only LAT+ neurons were harbouring HSV 1 DNA and viral microRNAs. Also, mRNA for a viral gene product was only detected in LAT+ neurons. All analysed LAT– neurons were devoid of viral microRNAs and DNA of HSV 1. DNA of HSV 2 or varicella-zoster virus (VZV) was not detected in any of the excised neurons. Alto¬gether this indicates that in the vast majority of infected human neurons, HSV 1 latency is not directly controlled by T cells, but rather by cellular or viral factors like the miRNAs. Our data suggest that CD8+ T cells only come into action if these mechanisms are overrun.

The herpesviruses, like most other DNA viruses, replicate in the host cell nucleus. Subnuclear domains known as promyelocytic leukemia protein nuclear bodies (PML-NBs), or ND10 bodies, have been implicated in restricting early herpesviral gene expression. These viruses have evolved countermeasures to disperse PML-NBs, as shown in cells infected in vitro, but information about the fate of PML-NBs and their functions in herpesvirus infected cells in vivo is limited. Varicella-zoster virus (VZV) is an alphaherpesvirus with tropism for skin, lymphocytes and sensory ganglia, where it establishes latency. Here, we identify large PML-NBs that sequester newly assembled nucleocapsids (NC) in neurons and satellite cells of human dorsal root ganglia (DRG) and skin cells infected with VZV in vivo. Quantitative immuno-electron microscopy revealed that these distinctive nuclear bodies consisted of PML fibers forming spherical cages that enclosed mature and immature VZV NCs. Of six PML isoforms, only PML IV promoted the sequestration of NCs. PML IV significantly inhibited viral infection and interacted with the ORF23 capsid surface protein, which was identified as a target for PML-mediated NC sequestration. The unique PML IV C-terminal domain was required for both capsid entrapment and antiviral activity. Similar large PML-NBs, termed clastosomes, sequester aberrant polyglutamine (polyQ) proteins, such as Huntingtin (Htt), in several neurodegenerative disorders. We found that PML IV cages co-sequester HttQ72 and ORF23 protein in VZV infected cells. Our data show that PML cages contribute to the intrinsic antiviral defense by sensing and entrapping VZV nucleocapsids, thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The efficient sequestration of virion capsids in PML cages appears to be the outcome of a basic cytoprotective function of this distinctive category of PML-NBs in sensing and safely containing nuclear aggregates of aberrant proteins.

Varicella zoster virus (VZV) is a member of the alphaherpesvirus subfamily and with a genome encoding 70 proteins the smallest of all human herpesviruses. Upon primary infection it causes varicella also called chickenpox in children. As a consequence, it reaches sensory nerve ganglia where latency is established. Upon reactivation it causes a secondary disease called Herpes zoster mostly in adults. Todate, VZV is the least studied human herpesvirus due to the lack of cell-free virus in culture, of virus-specific tools and an effective animal model. Therefore, many aspects of the VZV infection cycle, of latency and reactivation are poorly characterized. Moreover, the function of many proteins specific to VZV has not been identified. The goal of this research was to generate hybridoma clones as a permanent source of VZV specific antibodies and to use the antibodies produced to study the localisation of VZV proteins in the viral context on a proteome-wide level. To this end, a VZV ORFeome entry library was constructed using the Gateway® recombinational cloning technology. For VZV protein expression in E. coli, the entry library was subcloned into four different pET derived expression vectors providing either an N-terminal His6, a C-terminal His6, an N-terminal MBP, or an N-terminal GST tag. Following purification of 64 VZV proteins, mice were immunised and subsequently used to generate antibody producing hybridoma clones. So far, our clone collection contains 218 mother clones producing antibodies to 61 (87%) VZV proteins. In this clone collection 190 clones were identified as positive in Western blotting covering 57 VZV ORFs while 123 antibodies were tested positive in immunofluorescence covering 52 VZV ORFs. Using this novel antibody collection, the localisation of 52 (74%) proteins could be determined in the context of VZV infection 22 of which were analysed for the first time. In total, 20 ORFs were localised in the nucleus, 16 ORFs were present in the cytoplasm and 16 ORFs were found in both the nucleus and cytoplasm. Comparison of 41 core proteins present in HSV-1, VZV, CMV, EBV as well as KSHV showed excellent agreement in localisation of conserved glycoproteins, capsid and tegument proteins. Several immunodominant regions on the viral glycoproteins gK, gB, gL, gI, gE and the membrane associated phosphoprotein ORF24 were identified using the pepscan technique. This precious antibody collection gives access to various experimental approaches and will allow to unveil biological secrets in the field of Herpesvirology.

Here we report the case of a 54-year old, immunocompetent German patient with primary varicella whose Varicella-Zoster Virus (VZV)-specific T-cell responses could be detected early in infection and before the onset of seroconversion. This case demonstrates that the detection of VZV-specific T-cells may under certain circumstances support the diagnosis of a primary varicella infection, as for example in cases of atypical or subclinical varicella or in the absence of detectable VZV DNA in plasma.

Herpesviruses constitute a family of large DNA viruses widely spread in vertebrates and causing a variety of different diseases. They possess dsDNA genomes ranging from 120 to 240 kbp encoding between 70 to 170 open reading frames. We previously reported the protein interaction networks of two herpesviruses, varicella-zoster virus (VZV) and Kaposi's sarcoma-associated herpesvirus (KSHV). In this study, we systematically tested three additional herpesvirus species, herpes simplex virus 1 (HSV-1), murine cytomegalovirus and Epstein-Barr virus, for protein interactions in order to be able to perform a comparative analysis of all three herpesvirus subfamilies. We identified 735 interactions by genome-wide yeast-two-hybrid screens (Y2H), and, together with the interactomes of VZV and KSHV, included a total of 1,007 intraviral protein interactions in the analysis. Whereas a large number of interactions have not been reported previously, we were able to identify a core set of highly conserved protein interactions, like the interaction between HSV-1 UL33 with the nuclear egress proteins UL31/UL34. Interactions were conserved between orthologous proteins despite generally low sequence similarity, suggesting that function may be more conserved than sequence. By combining interactomes of different species we were able to systematically address the low coverage of the Y2H system and to extract biologically relevant interactions which were not evident from single species.

This Podcast for the Neurology Journal begins with Dr. John H. Noseworthy, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Aman A. Savani and Dr. Thomas Wingo interview Dr. Donald H. Gilden from the University of Colorado about his paper on VZV vasculopathy. The podcast concludes with Dr. Michael Brooke introducing the Humanities section of the journal and then reading three poems by Nina F. Schor published in January 22, 2008 issue. Podcast participants had nothing to disclose.