Dr. Benedict Michael discusses the clinical spectrum of COVID neurological complications.
we have um have Dr Benedict Michael who is a senior clinician scientist fellow at the NIH our Health Protection research unit for emerging and zoonotic infection and an honorary consultant neurologist at the Walton center. He completed postdoctoral training at the Center for immunology and inflammatory disease, massachusetts General Hospital and Harvard Medical School. He received the Liversedge award for neurology and the british Medical Association varied down award for neuroscience. His advice chair of the Encephalitis Society scientific advisory panel and a scientific advisor to the Meningitis Research Foundation. He is currently co chairing the W. H. O. Commissioned Covid \u20AC19 Research Coalition Task force on acute clinical care for neurological complications of covid 19 and also sits on the W. H. O. Global Forum On neurology and COVID 19. He is currently leading the National Surveillance Program for neurological complications of Covid 19 and the Covid clinical neuroscientist study. Thank you very much. Uh Dr Michael. Yeah. Yes. So hello, my name is Dr Benedict Michael. I'm a senior clinician scientists and a consultant neurologist here at the NIH Health Protection research unit for emerging and zoonotic infection in the UK. And it's an absolute pleasure to talk to you now about spectrum risk factors and outcomes of neurological and psychiatric complications of COVID-19. So I've been giving presentations on this topic for well over a year now and I think it's still appropriate that everyone, I begin with two wonderful photos of Constantin von economy of course, did such fantastic work on neurological complications of the 1918 pandemic. Um and I do so because I feel that uh much like his work, much of ours has raised more questions than it answered, but I hope that this will be of interest to those on the meeting. Now. I was fortunate enough to work help leave the H1N1 influenza pandemic surveillance group for neurological manifestations of disease. Um, this was a prospective study over two years across the whole of the UK and we only identified 25 cases, 21 in Children, all were positive by PCR for respiratory samples, but none in the CSF. There are predominantly Children within careful apathy or in cattle itis, and also a couple of cases of adults within careful apathy in a movement disorder, one of them cattle itis, someone with Guillain Barre syndrome And some of the patients have these very characteristic mari changes here. You can see a T2 showing acute necrotizing encephalopathy with restricted diffusion. So I think it's fair to say that when we found out what was happening in Wuhan and then Italy and the US, most of us in the neurological infection community, we're expecting that there would be at least proportion of patients would have brain complications of the virus. We now know that maybe 70-80% of people hospitalized with COVID-19 have neurological symptoms such as headache and my algebra Up to 10% may have a neurological syndrome such as encephalopathy. And maybe up to 1% of hospitalized patients have a neurological diagnosis. We've really seen this spanning different path of physiological processes. In some cases we think about a leaky blood brain barrier from very miA allowing the virus to enter the central nervous system. But this seems to be relatively rare. We've certainly seen cases of parrot infectious cytokine storms, such as acute necrotizing encephalopathy and post infectious antibody mediated disorders like Guillain Barre syndrome. But what has been striking is that in addition to these processes, we've also seen vascular apathy or vasculitis in multiple organs, including the brain. And it's been the subject of a great amount of work. But of course when we identify an organism and a cute brain complication or needs to establish whether it is an epi phenomena or whether we really think the virus actually playing a role. And there are two approaches we take to this. The first is the hierarchy of diagnostic tests and the second is the Bradford Hill epidemiological criteria. With regard to the hierarchy. We've seen evidence of the organism within the central nervous system or a specific interest equal immune response very rarely with SARS COV two infection. Uh we what we've seen much more of is organism carriage from nasopharyngeal swabs which are tested by PcR or other respiratory samples But evidence of a specific immune response to those patients. Uh zero converts to the virus at all around the time of brain complications. When we apply epidemiological criteria, there are arguments for and against SARS cov two being causal. It's certainly the arguments for that. This is consistent with what we know from other viruses like H one N one. Many of these manifestations occur in a temporal association with the respiratory disease, certainly biologically plausible and coherent with our understanding. And there's some early experimental evidence and it's certainly analogous to other processes in which infection initiates a brain response or an immune response with secondary brain effects. But there are many arguments against it being causal. Certainly it's not a strong relationship when many millions of people have been infected and so few have had a brain complication. It's definitely not specific. We've seen it with other pathogens And it doesn't seem to conform to a biological gradient. I eat not always those with the worst COVID-19 disease that have the most severe brain complications. An experimental evidences in both columns, because the experimental models are not ideally replicated of disease in humans are often requiring mice with various genetic alterations, such as to the ace two receptor, and often requiring uh inducing infection in the brain, which is a very rare complication in humans if it occurs at all. Okay, so very early on in the study in the pandemic, I realized we really needed a whole multidisciplinary team of people if we were going to study this. So the coroner studies group that I helped lead, it is a group in which we convened basically all the UK's major professional neuroscience clinical bodies, including the Association of british neurologists and their pediatric counterparts, the british Association of stroke Physicians, the neuro anesthesia, critical care societies, the Royal College of Psychiatrists and other consortia. We set up a rapid recruitment portal through which anonymized patient data could be submitted within about three minutes by busy frontline clinicians. Uh and you may have seen our first publication just about this time last year, of the 1st 153 patients protective prospectively recruited through this UK-wide surveillance study. And if not the manuscript, you may have seen some of the coverage Which was in some of the us media as well as as the British and others. Uh this shows our cases geographically dispersed across the country in purple, largely corresponding to General COVID-19 cases reported public health bodies. We mobilized early and we were actually able to recruit our patients here at scene on the graph in red. Uh During the exponential phase of the first wave of the pandemic shown in blue. Uh 153 patients which I won't go through in detail. About two thirds or so had cerebral vascular events. About the remaining third had alterations in mental status. And what was really striking was that by june cerebrovascular events were well recognized. But what our study showed was that actually these alterations in mental status fell into diagnoses. Typically thought of as neurological like cattle itis, but also diagnosis typically thought of as psychiatric or neuropsychiatric, including cases of psychosis and catatonia. When we looked at the age breakdown of these patients, they brought in red, they broadly were similar to hospitalized patients with COVID-19 during the same timeframe, although we perhaps skewed to slightly older population. But what was really striking was that whilst cerebrovascular events occurred at all age groups, they tended to predominate in the older age group in blue, whereas those with alterations in mental status and neuropsychiatric manifestations again whilst occurring at all ages, had this predominated predominance of occurring in younger people with about half of the cases in our cohort being under the age of 60 and just over a quarter in their twenties thirties and forties. We've gone on to continue to collect notifications through the various ways of the UK pandemic. We're now out about 800 or so of which we've looked in detail at the 1st 511 identifying cases of encephalitis and meningitis. Um I won't go through it in detail because we've got better data coming through now. But what the notifications did show us was that when we mapped this against the first wave? So the light gray dotted line is just hospitalized covid patients. Um Daily across the UK you see this exponential rise and then the tail of the first wave. When we compare that time frame to cases reported through the portal, we saw that the vast majority of cases early on was stroke or other cerebrovascular events and that the reporting of these cases seemed to decline as the first wave decline. And conversely in the dots and dash line the proportion of cases with alterations in mental status that seemed to rise being the vast majority of reported cases by the end of the first wave of the pandemic. This may of course reflect reporting bias, but it may also point towards path of physiological mechanisms at play and with some growing evidence for why that might be the case in some of our more detailed data. But what these data did show was that neurological complications and psychiatric complications really do span the brain. Mind interface. Uh We found the occasional case of virus in the cerebrospinal fluid. Uh we saw patients with cytokine storms. We saw antibody mediated disease, but what this really highlighted was also the psychological and psychiatric impacts of the pandemic, which may be at play and driving some of these uh manifestations and of course what we do not know yet, although it is seeming hopeful, at least thus far, that there doesn't seem to be altered neuro development due to maternal immune activation. But of course that's something we're all alert to. Uh we'll be studying in detail. So here's the most recent paper because of course all represented thus far is really kind of big epidemiological data but not granular clinical data. Is this paper which has just been accepted in brain communications and should be out soon. It is available as a pre print in which he went back to all of those who notified cases and ask them to complete a really detailed case record for on the patient's symptoms, signs, demographics, risk factors. So we could evaluate not just the spectrum but the risk factors and the predictors of outcome of these complications. We had a detailed complete case record forms on 267 cases. About a third with female and about 1/5 were from Black Asian and minority ethnic groups uh and about 42% well below the age of 60 years. And the covid 19 diagnosis was confirmed or probable by W. H. O. Criteria. In 90% of the patients they were all hospitalist and they all presented with the classical symptoms of cough and fever etcetera that you would expect. So we define them you're anatomically and then path of physiologically. In terms of the neuron anatomical classification, the vast majority of our cases, 226 were central. A. C. N. S. Case is only 41 were peripheral even though we in this study included the british peripheral nerve society. What we found in the original surveillance study held up with the majority being due to cerebral vascular events. But then this other group of cns inflammation, delirium and primary psyche psychiatric disorders. And when we look at the time from respiratory symptom onset to neurological symptom onset, we saw this really interesting pattern which was that cerebrovascular events tended to occur at all around the time of respiratory symptom onset. Whereas central inflammatory, psychiatric and peripheral neuropathic presentations presented statistically significantly later with a median of approximately two weeks after the onset of respiratory symptoms. What we also found was about a quarter of patients actually presented with their neurological or psychiatric manifestation after their respiratory symptoms had improved. A similar percentage actually presented with neurological or psychiatric symptoms and signs that predated respiratory symptom onset. And these data have gone on to help inform the W. H. O. Covid neurological checklist and pathway that I've helped with in which we we flag up during the pandemic which patients presenting with neurological symptoms uh warrant covid testing. So this uh corresponds with what we found at the epidemiological level which was that perhaps there is a different path of physiological process at play for inflammation, psychiatric and peripheral nerve manifestations as opposed to the majority of cerebral vascular cases. When we look at the cases in detail, I will highlight three groups firstly that of the psychiatric diagnoses. Whilst some were exacerbations of existing psychiatric conditions, the majority were actually new psychiatric diagnoses including psychosis, catatonia, mania and neurocognitive syndromes. And it wasn't just that patients fell into one of our a priori clinical case definition criteria actually for many of these patients. They actually were overlapping syndromes. So here are some of the cases with the central disorder also had a peripheral disorder. Here we have patients with cerebrovascular events that also had uh central inflammatory disorders. So, those are, for example, cases acute hemorrhagic leukoencephalopathy. Their patients with cerebrovascular events were delirious and we had some delirium presentations which appeared to meet the criteria for psychiatric manifestations. But really this interesting group here which had neither had central cns inflammation nor peripheral parameters which would explain delirium, but actually had a primary psychiatric presentation. When we compared the cerebral vascular events. There were some ischemic, some mixed scheme and hemorrhagic events and some cerebral venous sinus thrombosis with hemorrhage also. And sometimes patients would have multi vessel disease with or without vasculitis affecting large vessels or small vessels with or without CVS. T. S with without hemorrhage. And what was important was when we compared these patients that met more than one clinical case definition with those that only met one. These were vastly more likely to require intensive care, two thirds as opposed to 26% requiring intensive care and even more likely to require ventilation. With the majority requiring ventilation as opposed to just a singular diagnostic criteria are met. Uh I'd like to focus clinically just on this two groups, severe and careful apathy because they're important and I think increasingly recognized now and the cerebrovascular events because they are most common. We had 13 cases of really profound and catholic Kathy, which would not meet the 10 societies criteria for delirium because there was severely reduced levels of arousal um with without cardiac or renal complications, including cardiac arrest in adults, and then patients presenting with seizures, which fell broadly into two categories seizures occurring in older adults with preexisting neurological comorbidities, but also a group with seizures and status epileptic asAR, often younger who had no pre morbid conditions. And there have been the occasional case of NMDA and other autoantibodies in some of these patients. It's tempting at least a hypothesis that those patients with presenting with Lenovo status and seizures may well have an antibody mediated condition driven by covid. Overall, this group of men careful empathic patients beyond delirium were younger and had higher in hospital resource utilization, requiring longer durations of ventilation and time in intensive care. And this is a group that really requires further study, but it may well be that many of these patients are actually having a leuco encephalopathy or perhaps actually in cattle itis. We know there's been in many senses, not just in the UK, but around the world. Real challenges with scanning patients during the covid pandemic and certainly during the worst waves, due to respiratory difficulties, making the scan not safe and due to logistical difficulties of the infection control. But we know from some studies where they have performed mris on patients who have either not woken up off the ventilator or have had clinical features suggestive of encephalitis. But some of them have a leuco encephalopathy, which could have multiple path of physiological processes, including microvascular ones. And also in this large study from the Covid group in europe, they found that about half of the patients that didn't wake up off the ventilator actually have neuro imaging changes of either acute necrotizing encephalopathy, acute disseminated encephalomyelitis, limbic encephalitis or other inflammatory appearances on the MRI scan, suggesting that actually beyond delirium. Then there this this encephalopathy of Covid, it is a real phenomena which with potentially multiple path of physiological processes underlying it. Okay With regard to the cerebrovascular events, 35 cases, so a quarter were under the age of 60. Really interestingly, when you compare the younger group to the older group, the mean duration of symptom onset of respiratory symptoms prior to stroke was 10 days in the younger group. Whereas in the older group they tended to present with their stroke at or around the time of covid symptoms, suggesting that perhaps in the younger patients there may be a more inflammatory process at play. Where as in the older patients, perhaps it's the virus itself, perhaps an end of the neuropathy perhaps disrupting areas of existing a vascular disease. Uh we saw a large M. C. A. Infarct. Due to dissections. We saw multi territory in fox and also by hemispheric lacuna in fox. Uh In addition to frank cases of cns vasculitis here shows the contrast enhancement. Uh the M. C. A. Which resolves according to steroid treatment. What was important was whether we talk about the younger group, all the older group, many of them had comorbidities, although they were more common in the older patients as you would expect, interestingly, the younger patients were twice as likely to have multi vessel cerebrovascular disease than the older patients and they were also much more likely to have a thrombosis outside of the brain. Yeah, so rather than just comparing older covid strokes to younger covid strokes, what we went on to do was then compare our national stroke audit from the same months. But in 2000 and 19 were all stroke data is captured from from across the UK. And if we compare those sort of non covid stroke cases in gray to the covid 19 strokes, what you can see is that by age actually, the covid strokes were twice as common as non covid strokes to be under the age of 60 years and they were also again more likely to have non for robotic complications occurring in 11% versus 5% of non covid strokes and these included pulmonary cardiac and renal thrombosis, but beyond them being younger and presenting later, essentially having multi organ and multi vessel disease. What was really important was that conventional cardiac risk factors often which are modifiable or controllable, such as hypertension, diabetes in atrial fibrillation, were all common not just in the non covid strokes, but even in our covid stroke cases with around about 80% having hypertension. And if this is borne out in further studies, this has potentially huge public health implications. We look then at predictors of poor outcome as measured by the modified ranking school and actually whether we adjusted to the diagnostic variable or we didn't by far and away. The most statistically significant predictors of a poor outcome. Uh We're Age in 10 year increments with an odds ratio of 1.6 1.67. Um And pre morbid clinical frailty school with there being 1.481 point 51 in terms of the odds ratio when we looked at the Nadia. So the worst M. R. S. Score during the admission and compared that to the M. R. S. Score and discharge. Uh So a red line would be um you know a patient as unwell as they are at their worst is as as well as unwell as they are at discharge. And we saw fortunately that for almost all the conditions including central inflammatory causes, the psychiatric causes, they tended actually to be by and large uh have a better M. R. Escort discharge than they when they were at their most unwell. But as we might expect for those cases, patients with a cerebral vascular event, unfortunately many of them at discharge where as disabled as they had been at their worst. Of course our work and the work of others is now really I think established that severe acute neurological and psychiatric complications do occur in patients with COVID-19 often in those who have previously healthy. But really the bio mechanisms are driving all of this are unresolved and the role of clinical biomarkers are undefined and clearly we need to understand this and these underlying mechanisms that we're going to direct clinical practice and ultimately prevent lifelong disability. And that's why I'm delighted that the Covid clinical neuroscience study, which I'm co principal investigator on has been funded by our UK funding body um uh roughly about $3.3 million in this study. We are going to establish the detailed clinical characteristics and underlying disease mechanisms of these acute neurological and psychiatric complications of COVID-19 establish who's at risk and what the medium terms of where they are. And uh we want to look at routine biomarkers, were using biological immunological techniques to get the pathogenesis and we're also determining the role of serum and brain biomarkers of cNS injury, both acutely and follow up and determining whether is similar but milder complications existing community cases through an existing funded study with the overarching hypothesis is that if we combine markets of cns inflammation injury and genetic risk, we will identify mechanisms of these acute complications and they're so quickly providing targets so that patients can be mechanistic lee stratified to existing and novel therapies. So in conclusion, I think it's clear now that COVID-19 is associated with a broad spectrum of complications throughout the central and peripheral nervous system, although predominantly the former outcomes vary between disease groups and crucially pre covid status. There's this cohort with a severe and careful apathy, often requiring intensive care and ventilation. There's a group with large and often multi vessel stroke offering young people and often with thrombosis outside of the brain, and both of these groups desperately require further study. It looks like potentially conventional and modifiable risk factors are associated with stroke, including young stroke. And this is, as I say, a huge potential for public health interventions here for the many countries which are still suffering so greatly with with Covid God and we will bring together clinical data biomarkers and structural and functional neuroimaging so that we'll be able to mechanistic stratify patients to target a novel therapies and just like in von Economos Day to end, where we began to remain a great many unanswered questions. But working together across the Neurosciences and with our wh partners and partners around the world, we might finally answer them. Thanks to the research assistance Postdocs and PhD fellows in the Covid cns study. Thanks to my postdocs, phds and academic clinical fellows that work on all the brain infections work here. Thanks to the new Axis narrow places team. And thanks to the coroner study group within this all got off the ground over a year ago now and finally, thank you all for your time. Thank you for the invite. And I'd be delighted. Take any questions. Thank you. Yeah, Well, thank you very much. Uh dr Michael, um I know where uh where we're still, I think we're still yet getting all the information and I'm sure a lot of stuff is going to be uh you know, more information will be coming as you know, we even look back and, um, and then also with some of these long collars and the effect on on them. Um, I, there's a question here. Uh, there are a number of patients with lack residual lack of ability to taste and smell for several months. Uh, don't these symptoms indicate neurological effects of COVID-19 when those symptoms disappear, does that indicate no neurological problem existed or that it simply disappeared? Yes, Thank you. Thanks for the question. And firstly to agree, dr Jeff, there's very little rehab in my presentation because there's a lot to learn, certainly before we can plan rehab. But yes, so, and asthma and a geisha have been interesting from the outset. And people that work in the new infection world like myself, were very interested very early on that there might be a neurotrophic effects of the virus. Perhaps to the olfactory bulb to the crew performed plate. But actually postmortem studies even from patients who died first. The covid 19 was so severe show that covid 19 what the stars Kobe to the virus is effective at replicating in the epithelium of the old factory track. Perhaps in the olfactory bulb but not necessarily in the brain. So actually these might not be neurological deficits as much as peripheral deficits and may. In fact it seems that some of the patients some of the worst brain effects. For example huge M. C. A. In Farc's leave them unable to move one side of their body or speak. Actually have no problems with smell or taste. And other people have huge problems with smell or taste but are otherwise neurologically intact. So I don't think the two things are corollaries. Okay. Um you know, one of the things that it seems like noticing in acute rehab is dealing with some of the patients who have had, you know, for example, they had a stroke from the proto robotic um you know, issues in or an anoxic brain injury related to the respiratory compromise. And they seem to present kind of similar to the non covid related causes um with, you know, similar stroke or similar, you know, anoxic um, injury. But then there's also some patients that present with the inflammatory presentations or like with the delirium and things. And and they seem to be um it's uh almost like a different beast. And um are are you sure are you seeing that as well? Um Yeah, absolutely. And I think, I mean that's hitting the nail on the head really. Uh There probably is actually nothing unique about SARS Kobe to as a virus beyond the fact that the common interfere, geography, the but there are two things, firstly, as you mentioned, we've just had such a high number for people affected that we've seen an awful lot of hypoxia and metabolic derangement and renal failure and other things which can adequately causing cattle apathy and cause huge rehabilitation complications and challenges to management. But but to the, to the more nuanced point, the it may well be actually that there is nothing unique to SARS Kobe to in terms of its capacity to induce inflammatory syndromes of the central nervous system. But just that with the huge denominator of the number of people infected, we actually finally, even rare complications become common enough that we can actually study them and to study them is some combination of one's pre morbid genetic makeup, but also one's pre morbid host immune prime ng based on the previous viruses and pathogens that with other pathogens that we've seen. Um one of the one of the things that we've kind of anecdotally been um noticing was uh patients in the rehab unit that there um Mhm. You know, there uh there's a lot of psychological effects of the infection. Um there's we've had patients who have had family members who have died from it and they've survived, you know, there's maybe some survivor guilt and things like that. And so um what it's uh do we have an idea of how um is that one of the things looked at it as far as the effect on the psychological, which may also impact some of these other Uh huh. You know, the other effects of. Absolutely, absolutely. And as a resident of the UK, I appreciate the UK almost always gets everything wrong Brexit being a recent memorable example. But 11 of the few things that I think we've done a moderately decent job of in the study of the effects of Covid on the nervous system is that we've actually brought together neurology, neuro psychiatry, psychiatry, psychology, occupational health physiotherapy across the full Neurosciences spectrum because I think, you know, if there's any silver lining to the awful cloud of Covid, maybe one of them can be that actually realized that the brain mind distinction is an arbitrary one. And if you have a stroke, it has psychological implications if you have a severe respiratory illness that that you or a loved one in intensive care, it has psychological implications for for the family and for yourself and actually all of those things, whether we consider them organic or inorganic, the kind of brain mind interface are nevertheless real and have implications for not just the nature of the complication with which we suffer, but also our rehabilitation needs uh we have another question which is, I'm glad somebody asked this because I was gonna ask to you anyway, but um uh it says, what do we know about covid and those with autoimmune conditions that include inflammatory symptoms such as joint inflammation and its effects on the brain. One of the things that we've noticed is a lot of patients who have had other inflammatory disorders that don't even gout or something like that, that you wouldn't think is has its effect, that they seem to be hit harder. Yeah, so it's it's a it's a real complex question and I'll answer it as succinctly as possible. Um so interesting that we've done a community study of 77, maybe 78,000 now, people who have been affected by COVID in the community. And we've actually found people with preexisting conditions, actually, many of them got better on their self reported schools because there was a pulling together. This may be a sort of I think there may be geographic elements there to do with kind of pulling together and and what that means. But with regard to the autoimmune community, um we've been very, very actively looking for both SARS Kobe to infection, initiating relapses of known autoimmune phenomena and also known autumn in patients on immunotherapy in whom I a transgenic complications might occur. And we've seen very little of either. Actually there are clinics and our hospitals at their worst were completely full and that includes at a national surveillance level uh full with people who had who are otherwise generally neurologically well. Um and one other last briefing on that point to flag up is that I think we recognize increasingly both with with with Covid 19 disease, but also with the Covid vaccines that functional neurological disorders, i. E. Disorders in which the subconscious results in physical manifestations, which often neurological symptom pathology is something that is going to at least already in fact is becoming a part of clinical care. So it may be that people with autoimmune phenomena are primed to be to have a a physiological hypervigilance to their symptoms and to present early. But it doesn't seem that after physiologically we're finding that these patients are particularly at risk either from the infection or from the vaccine. Um What about patients that have had re infections or infections after after the vaccine? Are we seeing differences in the neurological manifestations in those patients? So, I mean the big question we get asked is, look, I think I've had Covid, should I get the vaccine? And I think what at least you can say from our surveillance studies are that having had the vaccine puts one at no greater risk currently to a neurological manifestation once vaccinated. But one thing we have at least anecdotally seen is people who have had the vaccine and then as a consequence of being vaccinated have changed their behavior and become infected in a priority infection during that window that 1st 20 to 30 day window where depending on which vaccine you received, one is 60 to 90% immune. And so so vaccine then changing behavior and then subsequent a covid infection related neurological manifestation regard without without the vaccine actually playing a path of physiological role but more a role in how uh society has behaved once vaccinated. And um again since I have you on here uh the has there been a difference in the different variants? Have you seen a difference in the manifest neurological manifestations for patients of different variants of Covid? Thank you. Yeah, that's really important. Uh I mean at the wh two weekly and we hear from people from all over the world, neurologists from all over the world and it seems to be very similar in terms of the potential clinical complications. The question will come as to what extent it's the variant, or actually perhaps even more importantly, to what extent it's the host immune response, whether that's genetic or driven by prior pathogen exposure, which is what drives this relatively small proportion of the population to develop a neurological complication from a common infection. Well, thank you very much. I appreciate you taking, taking your time and uh you know, being able to have you from all the way across the ocean uh and yet still being able to share your insights on this. I really appreciate it. Thank you very much. You know, honestly thank you very much for having me. Thanks to the team that have organized, you know, all the guys front and, but you know, behind the scenes that have been organizing it and making it work. And uh, you know, we look forward to doing a similar conference and we have many of these answers and clear rehabilitation plans, uh, you know, in person in SAn Diego. And of course, you're always welcome here in, in Sunny England as well. Thank you. I appreciate it. Thanks everybody.