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And I'm just going to introduce our first speaker. So first increase, Professor Craze Hman. So Craig is impressive stroke medicine at the University of Manchester. It's kind of work Basic Manchester Center within in the Neurosciences of Confusion. He studied medicine at the University of Manchester with an insulated BFC in biomedical sciences, followed by postgraduate training in the north west of England, which included a Stroke Association clinical training, hardship in stroke medicine Sociology. He received an MD from the University of Manchester following a period of research in the field of information and cerebrovascular disease. He has said research, leadership roles including a stroke research theme lead the Jeffrey Jefferson brain research center, his research fans experimental stroke and infection, clinical cohort studies, mixed methods, meta analyses and clinical trials. He currently needs a stroke impact clinical cohort study in Manchester and the multi center chosen trial. So you can just hit the ground. Of course, the great thing. Uh huh. Okay. So thanks Natasha and the organizers, the very kind invitation to help me come and speak today. So as Natasha said, um well, she didn't quite tell you the detail. I arrived in 1989 to study medicine here and I've never left, which is quite an interesting for really. So I'm half clinical and half academic. And what I'm going to do today is give you a journey really through my research and the reception been involved in over a period of many years. I'm going to do that not so much chronologically but from a clinical and biological perspective to try and tell you a story. Um I'm going to start by giving you an overview of stroke as to why stroke is so important and then going to talk uh immune system very briefly. Um And then going to talk about the Jefferson, Jefferson Brain Research Center and the facilities that we have here to do straight research and a little bit about the methods that we have to study this field. And then I'm gonna talk about research. So there are going to be figures, there are gonna be graphs, there are gonna be pictures of immune cells. I hope that's all okay. So the first thing to pick up on really is what is a stroke. So a stroke really is an area of localized injury within the brain which relates to an incline vascular cause. And by that, we mean blockage an artery that supplies that area of brain that infected hemorrhage. So blood entering the brain or the surrounding structures such as the Suboxone of spaces. It's very much a clinical diagnosis still and it's supplement it was supported by brain imaging such as CT sounds and our scans have been here a little bit more about that. So this is what stroke looks like in the acute phase when somebody's died. Unfortunately. So, a big area of injury and closest swelling and so on. And this is what common stroked subtypes of like um brain imaging. So, um here you can see some swelling on the right hand side of the brain hands, they're pushing the frontal hall. This is looking actually up through the patient's head in that direction. All those on CT sound, here's wide, similar to bone densities races a bleeding rain and this is leaving around the base of the brain and so called ceratin would hemorrhage. So I'm going to focus almost exclusively on ST mix trickle sterile infraction. And so the infarction is caused broadly by two main types of etiology or mechanism. One is an embolism and this is where a small pot originates, maybe an artery proximal to the brain that supplies the brain. Such is in this case, the protocol queue here or look like that originates in the heart. So in this case, the left atrium lists and from the seven left atrium on an echocardiogram, which is an entre sound of the heart. This is very commonly associated with atrial fibrillation, which is the regular heartbeat, which is seeing an increasing frequency as people get older. So that's a more it's stroke and this is an MRI scans. This shows a white area on this particular type of sequence. And I get confused with the hemorrhage on the west side and it shows an area infarction in the cortex. The other time is what we call small vessel disease in the brain. And this is thickening a deep Perth raise for arteries at the base of the brain. And it causes these small a coumarin parts which very strategic, very important parts of the brain can be plants vada. And on top of that, it causes these changes on slightly different sequence. Them are caused black matter hyperintensities. And this is where the way battling brain gets systemic over time. So how do we go about trying to treat stroke? Well, not surprisingly, the first thing to do is try and prevent stroke from happening in the first place. That would be amazing if we could do that. Population level is very challenging. It's all about getting people to stop smoking a little more healthy lifestyles, get the book, manage the diabetes and so on. However, about 20% of people that have an asemic stroke don't have an underlying cause and this is where inflammation and infection starts to come in because around 20% of people have had a stroke will have had an infection the week preceding the stroke. So once you have a stroke there, then approach is to try and limit the damage caused by the stroke. That's obviously very logical thing to do. And I'll just show an example that one of the things that happens, actress rating about one in 10 people is that they get infection after the stroke and that is something again we'll pick up on. And that also needs either preventing or treating once the dust is settled really within a day or two, we start rehabilitation, which is physical therapy approach is trying to improve function and restoration of activity. And the other thing is that we then look at what the risk factors or causation of the straight water, try and address that to them, recurrent strokes and more laterally. In modern times, we've been trying to think about chronic stroke treatment. So what about treating straight many years or months down the line? And could that potentially influence the development of complications that strips which is dementia? So is really the problem. Yes, strength is a huge problem worldwide. So every uh five minutes in the UK, somebody has a stroke, a new stroke. If you look at this in worlds, there are 12.2 million new strokes every single year. Um One of the big problems with stroke, even though in case fatality, there's been decreasing. So less people have been dying that then leads to a problem. People accumulating deficits and morbidity longer term because a spy stroke, this means more people will develop dementia, vascular epilepsy, fatigue, compression, recurrent straight ongoing coronary artery disease and so on. And the consequences of this is that straight is unfortunately incredibly expensive disease. Mainly because the health and social care costs of looking after people under consequences stroke. So this is something that I'm involved in on a day or weekly basis. And this is treating acute stroke caused by a large vessel occlusion. This is where the thrombus has hit a major cerebral vessel. In this case, middle cerebral artery, this is again looking up through the brain and this is the ct angiogram where blood is represented by contrast here, this is it's a certain race of the basis. So whether little arrow is, is a blocked and all terrible on tree, this is a devastating type of stroke, 20% of people will die and those that survive before for met me, which is what we can now show you before from let's mean as majorities, patient's did early article getting hospital for weeks or months and I don't think that that care hopes. So the big game changer and this is I'm going to actually tell you is the most cost effective treatment in medicine. So if you get cancer to get heart disease, this is the most cost effective treatment that we have in medicine. So what we do is interventional neuroradiologist as an angiogram like this identifies inclusion, puts in a guidewire through the femoral artery, feeds all way through heart into the brain. And then using in this case, a stent retriever, Denyce removes from this and then you can see this restoration of blood flow. And what happens to this individual is at the end of a very limited area of infarction on the CT scan, which is hugely different to what would have happened without the front. Excellent. So you might say, okay, brilliant. We conquer stroke. That's normal to the next thing. Unfortunately, haven't because probably less than 10% currently in the UK patient's are actually eligible for from Etame. And less than that I get from it to me. And that's largely because you have to have a large vessel occlusion and you need to go to a sense that does thrombectomy and you need to be eligible for the reasons. Even if we do treat the complex mean one in three people, one in three will make an excellent recovery, but the other two went so they will then accumulate significant morbidity and disability. So unfortunately, despite these advances, we haven't yet cracked stroke and actually stroke is a massive killer. So it's the second leading cause of death. So still about 15% of people with a stroke that hospitalized don't make it. I'm afraid. So, if you survived your stroke and I've already sort of implied the big problems can often begin their after say, assuming you don't have a recurrent stroke or heart attack. Aled uh ask your epilepsy. Unfortunately, a big problem in straight saliva is this development, these things here. So, cognitive problems. This is an umbrella term which encompasses several different problems such problem in solving fatigue planning, concentration, language, spatial orientation. And this gonna be to dementia. In fact, one in 321 in four people that have a stroke. Unfortunately, over months or years will dementia. This is top rated priority for clinical and they're need and research by stroke survivors and the stroke association. So I'm going to move on to inflammation and immunity and I'm going to start by saying what is it? And I apologize for those of you that may know something about this. So the immune system responds to a chronic insults to the body such as smoking exposure or air pollution, all effects of diabetes. And it also responds to a huge insults to the body such as an infection like a million. And what happens is the immune response, inflammatory responses mounted. And the idea is that it gets rid of the offending stimulus. So it kills off the books that might cause the infection, it destroys dead unusable tissue contains the injury and then sets the audio for restoration of recovery and repair. Normally, this is a very cool mechanism that means that we get better after we have injuries or infections. But if the information is abnormally dysregulated, so if the information is allowed to continue and the immune cells can be reprogrammed abnormally, then this is a bad thing and it leads to most diseases in modern terms. So inflammatory our disease ruined to arthritis, multiple sclerosis, even depression and mental health disorders. Huge number of diseases are related to abnormal disregulation and inflammation. So I'm not going to go to detail. Gay butt. Surprised to say there are lots of different flavours of immune cells that are myeloid cells and these tends to be ones that are associated with looking after the initial immune response. Then our look for your cells and lymphocytes. And these are the cells that orchestrate what we call the active immune response. And this is specializing in response, which also provides a longer term memory against injury, uh injuries, agents or infection. So you may, may not know that the nervous system. So the brain and its its surroundings has its own immune system. And this was something that wasn't known about until in my lifetime. So I didn't actually know much about the immune system in the brain, but it has its own immune system because the brain is so important and it's by far the most important thing in our body. So it has these cells called micro clear. And these are a bit like macrophages and they control the brain environment and they are responsible for looking after doing the housekeeping. But they're also respond to any problems in the brain environment amounts the new response cells that live in the blood or in the lymph point organs like the scheme organ lymph nodes. They can also go into the brain if that's the problem, so it can be instructed to go into the brain and help out. So again, no detail. Here, we have the innate immune system and the adaptive innate immune system is largely orchestrated by itself and eat debris and bad things like bacteria and then produce Kathleen gun machine gun response, which is fairly generic and they have generic recognition of Athens that they encounter and it's all very nonspecific, but it actually is what gets us through most infections of Easter initial phase of infections and it happens very quickly. So if you start without the chest infection, then these guys are on the case really very quickly. Indeed, the other arm of the immune response is the adaptive response. As I said, emphasize, it's these are much more clever because they are very specific recognition patterns. They can produce very specific responses to very specific continents and these can be uh interacting with the in a system. So the innate system presents antigen. So these lymphocytes and it instructs them what to do and then the sites going on with the job. So they produce antibodies and they can directly kill schools such as viruses. This takes days and weeks and months. And then over time, we have memory in both systems, which is very useful. Obviously, it could come across infections end. So how does all this relate to stroke disease? So really, we're living a picture now, over many years that inflammation, infection, immune system is responsible for process is that legal to frustrate. For example, developments, atherosclerosis, which is the disease that causes the majority of strokes and heart attacks. And this is an inflammatory process where the plaque within the artery stuffed full of immune cells are very active. They produce lots of mediators. They can rupture the plaque, they can activate thrombosis factors and plate, that's tell them to stick to the artery or the plaque. And then we get stroke or a heart attack. So this is the inflammatory process. Once the stroke occurs. On top of this proceeding, inflammation comes immune response, there is now a response to the stroke itself. So injury within the brain microglia say this is a normal big inflammatory response that then communicates with the periphery and instructs the blood cells and lymphoid organs to they're also amount of confirmatory response. So this all happens within minutes, certainly progresses over days, hours and it can be activation or suppression puff rays. And as I say, it, it kind of leads to the stroke being contained, recovery mechanisms being stretched on that tissue being sorted out. But in the process of that, the immune system, as I said earlier can be dysregulated. And we're just beginning to understand that that the immune system becomes district created for weeks, months and even years from the initial stroke. And this has to be relevant. This is not random, this has to be relevant and we think it's relevant because it's an abnormal response that is contributing to a longer term problem tree in the brain such as dementia. So this is a slide I put together. It's really er straight my research paradigm. This is, are we trying to bring all this together? So just bear with me. So we have chronic disease, smoking, hypertension, diabetes, chronic infection, the most prevalent in the world is carrying onto disease. That's when you get done. Destructive gum disease is caused by bacterial inflammation. So these things will lead to a progressive inflammatory state within the body. You then might go proceeding pneumonia that provokes the stroke. Here's the stroke, you get activation of the immune system within the brain. And after three, after I spoke the mouth, health deteriorates very rapidly, the flora changes. So there's a uh an increased chance of bad organisms if these aspirated because of swallowing problems, economical stroke associated pneumonia. All of this drives further information, it makes all of the peripheral things worse over time. And then it activates inflammation long term in the brain, which is a destructive process that kills brain cells, destroys or disrupts the blood brain barrier and then we develop dementia. So this is the paradigm. It's a kind of conceptual framework which I'm working too. So here are the research questions we time trying to address before I retire. So how the infection information of immunity contributes a straight risk. How does stroke modify the inflammatory immune response. And how does that relate to development of relevant things that happen to the patient? And then of course, as a medical doctor, for me, what are the opportunities to get patient's better or prevent the problems in the first place? So broadly speaking, in this research thing, there are two main approaches, not strictly speaking, true, but two main approaches the first. So we can use another models. This is a really important part of research. Okay. I don't work myself on another models anymore, but I work with lots of people that do and these are integral to understanding what's very long. So we have mouse models, we can choose stroke, we can introduce infection. We can do an ask almonds in nice. We can do behavioral tests where we try and look and see how they're behaving similar to fatigue or dementia features. And then of course, we can harvest tissue from, from animal models which we cannot really do. Patient's very, very difficult. This is really something that shouldn't be standalone from what we do clinically. So we can recruit patient's into clinical studies or trials. We can have some questions, we can have the data, we can take blood CSF urine, whatever samples we can do drug trials, we can do cognitive tests, very assess people's cognitive function, we can do brain scans. And on top part of that, we can pull all of this together with routinely collected data that happens in primary care or in hospitals to kind of massive healthcare data tests. And this is a relatively new research approach in my generation, massive healthcare data. On top of that, we can then do evidence synthesis, which is where we put evidence together to try and come up with a conclusion. So inject rejection Brain Research Center which is a research center within which I sits highly destroyed the classic adventure. We have a truly translational NGE to bed size, full patient journey research program. This is unique in the United Kingdom. So we have basic and discovery science. So fundamental biological sciences, it's mechanisms, immunology, cellular biology. Basically colleagues as Scott Food and the Eddie Hill, we have experimental medicine where we study patient's in great detail by taking samples. We have clinical trials, you know, implement this into practice. And this is something which goes in line with imaging immune inflammatory by Markis health in thematic sort, big data, patient and public involvement, which is key and we contribute to guidelines and hopefully we contribute to patient benefit. So what about the environment? So I work at a Sulfa drug which is where Manchester Center for Clinical Neurosciences base. It is the largest stroke center into the country by a very large margin. You see oh 2000 confirmed strikes every year and we are the brains monster torment me service the whole region which is best part three million people. We have laboratory facilities on site and we have very well established pipelines with the campus here with my trouble to colleagues for doing basic science work. And we also translate that into trials as you will see as well. So the first question is, how is infection information immunity constitutes a straight risk. So it's been known for many, many years like decades that infection can relate to stroke or you can perceive straight and this can be denied it into different concepts. We can either really CNS infection. So if you get meningitis or toxoplasmosis and the brand new may not come as a big surprise that you might not have straight. There's lots of inflammation going on in the brain. So CNS versus peripheral. So lungs, heart periodontal disease to men have got a few and there are scores of organisms that have been implicated in these infections that can relate to stroke. So that infection can also be acute, they can be sub acute or they can be chronic. So for example, HIV is responsible for a very large proportion of strokes still in place is my sub Saharan Africa. Whereas in this country as well, see acute respiratory tract infections are a major contributor. So if you remember the dark days of the early pandemic, this was some of the news headlines in 2020 I was faced with as a professional straight medicine who told everybody that he was interested in infection straight adults global pandemic on my hands along with everybody else. And this is what we're hearing from the States who were hit before we were. So the press went mad that this terrible new viruses causing straights in young people and they were buying it was awful and there's a lot of sensation is um but we were all really scared. So as an example, one example of collaborative approaches to pandemic, we teamed both across the country with a very, very impressive collaborative effort where we looked at the risk of stroke and other vascular events in people have failed it versus those that didn't in 2020. And this was in 48 million adults. This is power of big data is this is linking data sets from the country. And what we found in this really important paper involved North. A lot of people was that you can see here on the X axis. This is weeks after COVID diagnosis and this is hazard ratio of having a stroke at and ischemic stroke left or hemorrhagic stroke on the right. And what these graphs show is the higher hazard ratio, the higher risk of having a stroke. And you can see that there is indeed for both hemorrhagic and ischemic stroke, a definite increased risk of stroke. And this is really within the first for ischemic stroke, maybe the first one, of course, a hemorrhagic stroke is a much more brief list period. But you can see if the hazard ratio is one that means anything at one means that there's no additional hazard or additional risk. But the worrying thing is that the risk of stroke is maintained above the normal rebel. There is no additional risk for those types of stroke and this goes on for many, many weeks. So getting on towards a year. So there is a very early but also a less than an ounce more prolonging this stroke in absolute terms, this is actually a small number of strokes. That's the thing's bear in mind. So I would say every 100 cases of COVID that hospitalized, maybe one person might have a stroke and that's certainly changed now all the time. So we tried to look and understand biologically why an infection might be associated with the straight. How could that happen? And this is where that's done by one of our very talented colleagues. Care in South is the scientists, works with myself and Stewart Allen. And what we did here was we gave nice pneumonia and then we looked to see how the pneumonia alters information in the brain and inflammation in the blood. Now could be a value because if inflammation in the brain and the blood was changed, that might explain why there's more the risk of stroke. So these are in our scans and what they're really showing is this is our Willebrand factor, which is a robotic molecule that also has an anti inflammatory for inflammatory effects. This is uh the molecule that platelets used to bind, going to connected eight and form cloth. And this is a molecule that black something granular sites. So this is a type of an our imaging. When you've got mock infection strengthening on the ear infection, these animals didn't come bestrode. And what you can see here is that there's a huge intensity signal change for all of these differences that from the inflammation and the animals that has pneumonia compared to those that didn't. This is represented here. So these are the marks and use the pneumonia animals. So what this would suggest is that when an animal or maybe a person has a pneumonia by some mechanism that immune response that's happening in the body communicates with the brain and causes cerebrovascular activation, which could be really bad news. We do not want our cerebro vascular system activated with lots of unhappy uh immune cells stuck to the blood vessels. We do not want that. That could be something it contributes to dementia or it could be something that contributes to institute thrombosis and stroke. When Kieran looked in the blood vessels in the brain, this is a large platelet club. So large, massive activated play that's, that's stuck within one of the blood vessels and this was only seen in the animals would be many years. So this suggests maybe there's actually from this that happened in the blood vessels and the animals that had pneumonia have very high levels of Babylon factor in the blood as well. So this is very interesting, but we don't know exactly what is reinjecting patient's. But we did have the opportunity, of course, with the pandemic to a limited extent. And I was part of the major different cavity where we looked at trying to understand relationship between COVID 19 and stroke. And what we did here was we just collected close data on patient's admitted during the pandemic. Very, very difficult thing to do what we managed to do it. And so we had data on quite a few 100 patient's, obviously, most of them didn't have COVID. And what we saw was his uh the NIH score, which is will be used to measure how steri stroke is once from the consul structural higher, the NIH the worst the stroke. And what you can see is bread for that wants to COVID and blue the ones without, there's a peak of stroke severity here, the patient's that have COVID. So what we demonstrated robustly is that people have a stroke associated with COVID have a worse stroke, that's for sure. Maybe it's because of all of that activation in the blood cerebrovascular activation that was falling a nice, who knows what we also found is yes. If you have COVID on a stroke, then you were worse in terms of your outcome. You're more ex guy, you're more excited about the outcome. And this is a table that shows what we would call regression analysis. And this is where we look at factors that might be of interest and how they relate to somebody dying during the hospital admission. And we do a statistical analysis. And you can see here that for example, having histories, you know, heart disease, many double t risk of death after a stroke. In this study, having COVID when you were admitted to the hospital with a stroke, okay with, with all the stroke double, too risky back. So there's something really hard going on here with COVID and straight. So you'll see that many of these questions are unfinished symphonies, but I'll come back to that. And the next one is how does stroke modified inflammatory immune response? And I was like, really expand comes. So a lot of what we do at the moment is we spend time taking a lot of patients that have stroke and looking at what's going on with the immune system. And what we can do is we have various tubes, were looking at immune cells. I really isolations such as monocytes or we're looking at the complete the merriment of immune system in the blood. And we can look at what happens to immunotherapy populations, how they change. We can look at how they're functioning. We can look at molecules that released into the wood and we can look at genes are being expressed by these different cells and hopefully try and put it altogether and understand what it means so many of these lines. Now we'll have pictures and the pictures of all the people that are involved in these studies or leading on them. And this Pope theorist rates the fact that this is team sciences. It's not about me necessary. This is not having a team of people. So we have several studies um funded by the MRC which looking at how an immune system changes an acute stroke. So very early after stroke in the first hours or days and scheming stroke, her magic stroke and stroke called COVID. And this was very, very difficult to do indeed, because all of my research resources were diverted way. They're now asking me towards looking for acute treatments, which was supposed is fair enough. So these are all the people that are involved and these are some of the remarks that we get. So you remember, I said antibodies were produced by lymphocytes very important to find infection, very important, potentially because they can lead to tissue destruction as well. And this is, this is really just shows this on where access here is concentration of my GM, which is an antibody release, very early an infection. So it's important about I G and so I G N is the fairest antibody that this release. And what you can see here compared to controls who have not had a stroke and people that have had a stroke is that even up to the first five days antibody production or mention on in the blood is reduced. So his patient's are producing less antibody, which is a bit of a worry to me because these people get infections straight associated with many. Um And what you can actually see is that when we looked at people that had an infection compared to didn't have an infection during the time where we're sampling than the GM levels were actually lower. Anything has an infection. So it might be that having lever levels of an antibody put you at higher risk of infection. That's what you think is going on. So that might mean that we could treat patient's the antibody and like the antibody concoction that we could give them earlier to strip. So this is slightly more sophisticated and this is close cytometry analysis. I won't go into any details, very complicated, but it's very jazzy technique that separate cells are out labels than identifies a very, very imprecise, whether it's subtypes. So not just monocytes, but different types of months. France, for example, or dentate itself. And you don't need to really read too much into this. This is again, patient's versus control. These are patients that have sampled within six hours for onset of stroke, even within six hours. We see very profound changes in the innate systems. You can see for all sorts of different types of cells, the stars on top of the lining that it's a significant difference between the two groups So, for example, classical monocytes which are very improved inflammatory, the levels in stroke and much higher than they are in controls. And LifeWise intermediate monocytes, the levels are much higher people who have had a stroke. Where does this particular type of dangerous itself? The numbers of those heart is reduced compared to hi controls. So what does this mean? We don't really know what it could mean is that certain types of cells that are important in antigen presentation and amplifying the immune response are switched off or reduced in the number or dampen down in stroke, which might then mean the ability of the patient and to fight infection or to normalize the immune response is different. So that's why it might be important. So the big piece of work around the mall, but now is the straight impact study, which is an international large network study which front research and network. And the aim of this study is to try and understand how even from basis but great barrier leakage and cognitive trajectory, interest rates are linked together. And this is a massive initiative between several sites in the world including Manchester's major European site. And we are recruiting patient's into a very large family. So this is terrible to take patients'. And as they come into hospital after a stray within the first sort of 2 to 4 days, we take blood, we do an MRI just having the majority of them, we bring them back at 6 to 9 months, do another MRI scan much more fancy and ask them. And then every year after that, we assess them, assess their cognition and we do a blood sample every time going. We also compare this to controls just in terms of the blood results and also controls that happened under trade but still have the same assessments as the straight patient. So their cognitive assessments on their mask hands. So one of the clinical assessments um if you're putting medics or existing medics, then we do comprehensive memory spatial awareness processing, language, fatigue, negotiate balance assessments and these are done. It's taking probably a good hour to two hours to go a lot of engagement, education. I'm not going to really talk much about our think one of your speakers is a radiologist. We'll be able to tell you what more than I will. Um But we do very, very advanced tamar. This is contrast tomorrow. When we look at all sorts of different sequences, here's the original stroke in this patient's that Lacuna stroke, if you remember from earlier and we do lots of different sequences. And this is the blood brain barrier imaging. And you can see that the brain areas broken down around Australia, that's only six, that's still at six months after Australia, the blood brain barrier is broken down still what this means. I don't know what I think it means is that the empowerment of the blood brain barrier leads to toxic substances, being able to get into the brain which she passed and that could lead to dementia. So how do you think it's going to help our patient's? Well, these are the things that I tell patients when we meet with them. So, understanding how the immune system relates to cognitive trajectory, can we develop biomarkers predict who's going to get all these things? And can we develop treatments? So what about routine collected healthcare data? So we have two big studies but one is enormous. It's over 500,000 patient System National Registry um in collaboration Wilkins in London and every single patient in the country that gets submitted with Australia has stayed to collect on them. So very high case ascertainment and I'm interested in the data that's collected on post stroke infection. We also have a local data set called soul sample salted with 500 patients' all with post strep pneumonia and we can do much deeper dive analysis because we have laboratory variables, imaging, we have their drug history, antibiotics and so on. So this is some recent studies we published with one of my phd students, Marco and these are statisticians. So I worked with a lot of statisticians and what we looked at here is how variable you know your stroke across, across the UK and stroke units meeting, see that some units have got hardly any pneumonia down here and then other units have got massive amounts of pneumonia and this was not necessarily related to the case mixed. So excited about how um some units are treating their patients', perhaps or not treating this data shows survive all the patient's who've got pneumonia compared to those that haven't got pneumonia. You can see right from the onset of stroke, huge separation and you can see a massive difference. So the M R S is what we use to measure out come from stroke. And if you've got MRSA of six, which is this box in, you can see that 40% of the people with no, I'm only a guide after the stroke. And that was compared probably to about 15%. And we also get another study looking at pools data to see whether the type of antibiotic that's given for people with dementia actor outcome. So what we're saying here is our or antibiotics, the saying that we treat patient's with pneumonia clear that started to know many antibiotics have anti inflammatory effects, which is interesting, maybe there's something else that they do just apart from killing or not killing books. So again, a large collaboration of European uh workers in a group having called Pisces, which is a um Iranian Stroke Consortium. And what we found here is this is a forest plot where he looks for ranking on our trial of NIH three months. These three political outcome measures. And you can see over here and macrolide antibiotics for every outcome measure. With the only type of drug that let's sort of favorable outcome. So that's right. Mom left worse outcome. All right. So this is not randomized trial data. But what it suggests to me is that giving people that prides with all your enzymatic said that it's associated with better and we need to test this and run the last trial which hopefully will be able to do so. Just finishing up now with therapeutic opportunities, as I've said. So remember we talked about periodontal disease, so bad mouth and brisket, nine million. So with dental colleagues here and nursing colleagues in stroke, I need a clinical trial called, chosen where we're looking at different approaches to mouth care in acute straight to see whether that can prevent pneumonia. And the idea here is that if we can get rid of that bacteria and cleaning our foot, it leads less substrate that you're aspirating, see lungs and therefore less Snowdonia. So this is a clinical trial. It's only early stage and hopefully we'll get funding for a full trial and we've got four groups. So course of ill, which is for hexedine, which brought broads with an antiseptic type of gel or to paste with power brushing or manual brushing with course pill versus normal to brushing. So we just finished this study. So it isn't really very much to say other than watch this space. So the other thing is including one, this is a scientific in which was really propelled into, into the limelight and into the world of stroke. Nancy Rothwell, useful thing you may know as the outgoing Vice President's at the university. And she was one of my uh research supervisors when I started and Stuart Islands on my colleagues who's a basic science system, Stuart has um done huge amount of work. Some of the real nancy in investigating blocking interleukin William stroke by using interleukin one receptor, which is a naturally occurring molecules blocks interleukin one interleukin one is very upstream site of time and information, which means that as a result of being released, it leads to a lot more about things. So activation all aspects, but it may also have a role in neuro genesis and repair that we're just starting to understand. So um this is some um animal data which I wasn't involved in which shows um implant volumes. So I can't get the stroke was. And you can see this is L0 R A which blocks higher one versus placebo. As you can see that even in age and animals or animals that are obese all young animals and even when we look at 24 hours or seven days that the implant bomb is definitely reduced by including one etcetera tactics. So, could this be a treatment Australia? And this brings me back to my original mentor, professor pick material who unfortunately helps to retire because of your health. And what I will say to you is you need a mentor right from the beginning, simulators come championing you, inspire you, root for you and push forward you all the way and get a restore this for me. I will be eternally grateful and Pippa sort of orchestrated the translation of these initial Roman studies hours of research, Harrow African a day. And this is where now two studies and subarachnoid hemorrhage if terrible hemorrhage and steaming stroke where we give very early on in the acute phase three randomized patient's either to include Monistat protagonist or placebo. And what these graphs show here is that this is received over dark boxes are are a great boxes. And basically you can see that if you get A R A in saluting, six levels are reduced compared to placebo and Syrians of protein, which mother inflammatory molecules also reduced. So we know that these molecules are associated with worse outcomes. So maybe this treatment could be beneficial. And this is similar side of graphs in a subarachnoid hemorrhage where the treatment goes on for a bit longer. So it's certainly, I think I'm pretty much on the edge of time. Throw medicine is undoubtedly exciting field with evolving treatments. Remember, this is the field that has got the most cost effective treatment. So just remember and forget everything else. So there are enormous opportunities particularly Manchester to improve the life of people with stroke and there are lots of other areas of research in much. But I haven't been able to cover. So my area infection information strongly located, as you've seen massive opportunities to modulate inflammation and infection and make things out of the patient's I would say, and if people want to talk to me about this clinical academic career, Australia research brings absolutely the best of both worlds. So loads of interactions with patient's and groundbreaking research. So please, if you're interested, talk to us, join us. We offer projects at all levels. We can offer placements, sixth formers in the lab. Much easier than clinical setting. Phds and these on the gradual projects, a perhaps perhaps the whole lot. So lots of people's thank uh research. As I said, it's a massive deal. It's not my individuals trying to claim the glory. This is about teams. So you've got to be able to work in teams and you've got to be able to collaborate and without all of these people, all these things that I've been telling you about women's, it happens. Um And I think if I can just do the last time that we go, these are current stroke impacts um students. So you can see how big stroke impact is. So we have going to graduate, these are phd students and graduate students working on area suspects. And finally, I just like some people for listening. I know it's been a long talk, but hopefully you enjoyed it. I'm not saying all of the patient's that we see all of our assistants, they're helping students search because we didn't have them for what you're able to do. So, thank you very much. Thanks. Great. That's pretty good. Does that work? Does this look? Thanks Craig. That was really interesting. And they have an absolute agree. Um Does anybody have any questions to pray? No, no one. But I think that nobody had any online questions I had. Yeah, we do, we do if you want to, I would say I'll hang around a bit. Uh People want to come and chapter and if that feels less, you know, scary history. Um Wow, this is quite a long question we've got. So why are Duac drugs contra indicated in those have lupus anticoagulants and if they have a check every relation and an A F patient for severe renal impairment for a high meaning risk, what are the prospects replacing vitamin K antagonist, warfarin with inhibitors of clotting factor E G? Uh Factor 12. Uh um It's a long question to reduce incidence of from a politics, rebel strikes. Am I doing on the mic? Uh So yes, that is a long question. It's kind of peripherally related because I'm not really talked much about thrombosis and there's a huge amount of interest in clotting because atrial fibrillation from ever I mentioned before, what we tend to treat people with atrial fibrillation with his um anticoagulant drugs like warfarin or the newer generation of drugs like picks about or Rivaroxaban, which are called direct all anticoagulants and they tend to work on factor 10 on the clotting cascade. So the question is asking why our dough ax contraindicated with, in people with Lupus. And yes, they are. So Lupus anticoagulant is a scenario where people have an increased tendency to clot. So, Lupus anticoagulant, it was historically associated with systemic this arithmetic osis or sle which is an inflammatory disorder of joint, skin tissues, blood vessels and so on. It's a bit of a hematology question as to why it's contraindicated in Lupus. I'm not entirely sure against that is I'm gonna admit there are prospects of cause for new um anti coagulum drug. So this is a busy area of farmer in terms of stroke and cardiology. We have a patented new drug at University monster that steward and care in South leading um uncle which modulates Von Willebrand Factor, which you heard about before and that's called Adam T S 13. Um And there are several drugs that are novel in terms of their actions on the clotting cascade that are currently being trialed in stroke as we speak around the world. I hope that's, I think that's a great answer for a very good question. OK, guys. So now it's just a break. So Faisel will need you guys out of the room while we're having food. See, coffee and pastries sounds just like refreshes out. Um And then we'll directly from there, but we just give a big round of applause. The Craig. Okay.