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we're going to be having a Q and A A the end of the morning. So we're gonna move through swiftly now, living on to invite our next speaker, Doctor Toby Human, who's from UCLA cheerleaders. Long covert service. Their consultant, Respiratory general, Internal medicine. Speaking about a, said the long private, multi systemic involvement. Welcome. Thank you very much. I'm can people hear me? I know, but it's good. So and thank you very much for inviting me to be able to talk about Well, I suppose, the journey of discovery that we've gone on in the last couple of years since we started following people up that had history of coated on. Then I will have a brief mention of some of those sort of the ti respiratory red flags which we see in the clinic on barking that people are aware off to avoid So a very quick history of the world. I have to tell you about my declaration of interest. So I sat on the nice expert panel postcode care and continue to do so. I received a small amount of money for giving talks. I'm a member of a large consorting trial, which is hopefully opening in next week or so. Looking at treatments for non coated, I have experience off some symptoms of long coat bit, but otherwise I don't have any other interests in relation to this talk. So going back to the beginning, this is our clinic. In May, when we opened on the street behind, you still itch in a van because all of the outpatient space is being used for storing equipment for the ward's. On day was our follow up clinic, and we had an X ray in there. We had a couple of consulting spaces. We were doing spyrometry on the street on D. It was a fascinating time on DWI had set up the service really to look for respiratory complications following what was at that point intended to be a respiratory illness. We were expecting that we had seen post viral post pneumonia ARDS or fibrosis. We would assess people, make sure they were safe and then refer the moment of the relevant service. And then we would shut up shop in six months on. But the reality, of course, was very different. So thinking about the multi system effects of cobalt and why long covert. It's such a multi various disease, just looking at some of the research. It came out early on in the pandemic, looking at the way in which Kobe effects body systems 82 receptor. It's special. Which, of course, is the way that code it gets into cells to infect the replicate. We can see the eighties to this receptor is expressed throughout the body, So perhaps it's not so surprising that there is multi system involvement in the secretion of, on importantly on this bit of the bottom here, the parasites and vascular smooth muscle. Expressing a stone strongly is vitally important because those tissues and system where perhaps we don't see ah, high incidence of base two expression within the organ parenchyma the actual tissue of the organs. We do see that the support cells which exists throughout the body, are susceptible to cope with infection. This is the data that we published one year on from our cohort. Hopefully, some of you have seen it, but really what? This is not to sort of discussing great detail, but just a highlight that actually we had Mawr business, more sort of cases coming to the clinic from those and weren't hospitalized in terms of their Covili this on. So that's important to keep in mind when we look at the population to the serving with long. But those that we did see just reiterating these symptoms significant amounts of fatigue, cough from breathlessness on, then these other symptoms and importantly, yeah, we have 8% of people coming through with orthostatic intolerance of postural symptoms as we describe them, looking on a bigger scale because we saw 1300 patients in our first our first year. This is a paper published in nature and 2021 looking at the incidents of new diagnoses following a covert infection. The veterans bears health system in the US and you can see so it's a bit of a complicated chart in it. But these are the yellow spikes, um, are the new diagnosis, which is statistically significant on. They also went on to compare with influenza a infections which confirmed in the same period. And there's a significant difference between the incidents of new conditions affecting all systems following coated rather than fluid. So Covidien is different, and that's kind of the message on this again is from millions of patients, I think, rather than rather than just a 15 on Ben, the multi system nature of the symptoms. So I'm sure lots of you will be aware of Athena Economies Paper, which identified more than 200 is to have the three symptoms which have been reported by patients that were experiencing long term symptoms of Cove it on. So again, it's just a high like that. The symptoms which people are getting or not related to this military disease on do that's have a significant impact on my education. Over the last couple of years ago, we heard that long Kobe it is a patient described term and it was certainly a term which patients were able to rally around on social media, organized and recognize Other people were having similar experiences because certainly at the beginning of the pandemic, it was not clear that, really, the medical profession understood that there was this syndrome, that there was this set of symptoms which were affecting people following coded on. It's important that patients have continued to be involved in things like the nice panel, the research and lot of the studies, such a being set up on a very strong patient involvement and the reason why that's so important as we saw with the cardinal. Symptoms of co bit of things like loss of taste and smell came out and then became one of those key identifies, a coated which had not being picked up or defined by the medical profession but instead had come through the through the use of social media and other types of communication. Yeah, so to prove if you like that, there are multi system pathologies. We have some helpful studies which allow us to look back. And we're now finding pathology, which is not a system rather than perhaps just symptoms on, because, of course, symptoms are what's described by patients. It's very hard to test for symptoms on does a great deal of skepticism amongst the medical profession, which ensure patients will recall an experience. And so we have information from imaging studies that this is the cover scan results and you can see that on the whole body, MRI scans have picked up dysfunction using their protocol in a number of different body systems. So we have an increasing amount of evidence that there is multi system disease just taking you through some of the things that we've observed in all Planica Dennis of feeds slightly into the red flags. Abnormal exercise physiology is certainly a future off Long Cove. It in a significant proportion of our patients we found in our early cohort of this is probably the first of the 100 patients, or so that around and eighth of them were de saturating on a simple sit to stand test. That's a minute of standing up and sitting down. It's a simple as that and and we didn't really know why that waas, because three courses of them had entirely normal tests. And I'm sure that's a familiar narrative as well. Well, the tests are normal, so you can't be anything wrong on yet. We found some very abnormal results when we started to do a slightly different tests, and so we are continuing to investigate this and again we'll talk about some of the potential mechanisms, but just highlight again. The pathology is really if you like. This is probably one of my favorite slides to take two medical audiences in particular on, but just to run you through it. This is a 28 year olds resting blood gas, um, pre tests. And this is before six minute walk test. This is normal. This is the carbon dioxide level, which is normal. It's a normal walks gyn level, and everything else is normal. Where out after they had walked for six minutes in the six minute walk test isn't a stroll, but equally. It's not running up every store, Anything like that, we can see that the pH has gone down to 7.27. And for any non medics that would usually if that was persistent, land you in the intensive care unit or I dependence of unit. The oxygen has remained the same, although we saw the saturation peripherally on this test Onda again. The other thing, which is strikingly abnormal, this lactate. We know that people put their like states up when they're exercising and Olympic sort of athletes a move the high lactate that they can tolerate when they're training to become superficial. And yet this is not entirely normal in a fit working 28 year old person after what is considered moderate exercise. So we knew that something was going on. But the question is why and so I want to sort of take you through a rapid sort of review of what's really the current thinking and the current state of sort of where we think the pathology is may like on day think this is probably where I need to say that Long Cove It is a very useful term for patients to recognize what they haven't understand, that there are other patients, other people who are living with similar problems. Um, it is a unhelpful term when it comes to researching things. I don't believe there is one Long Cove it I think there are probably going to be a multiple of mechanisms on almost your presentation may rely on those which you picked off. The small was bored, potentially duty or genetic potentially do to your initial illness? We don't know, but I suspect that your presentation will be related to the mechanisms you have picked up on. But when we look at literature on long coverted, I think we just need to be mindful of the fact that there are probably there is probably not going to be one answer on. I think that's important when we think about emergent treatment as well So this is from the rhyme of the ancient Mariner, was stuck on a boat on, didn't have any water drink despite being surrounded by it. And that's how we feeling clinical. Lot of the time they're steris everywhere, but nothing really that we can sort of to on make you swollen and turn into a treatment which is successful on Dwell recognized on. So I'm going to take you to a lot of things which are promising things which we need to sort of critically appraise, but which may well explain, as I said, a portion of what we see from from our patient. So there is a lot of this is ah, 2021 paper looking at ideas around postcode syndrome and you can see that it's sort of looking at chronic inflammation. What immunity Got this Bio cysts, a pulmonary long term tissue damage. So this covers the whole sort of gamut. But this was a theoretical patient paper. This is a thought experiment. If you like on DSO we're now getting into sort of thing studies which look at this now This is ah, paper from think it was nature and afraid. I have lost the reference off this slide of viral persistence and this is in gut mucosa. Missus have found up to four months after on acute covert infection, not necessarily with primary. Yeah, it's presentation symptoms, but it was possible to find viable remnants within the small bowel biopsies following code it up to four months later. So viral persistence is certainly a possibility. You don't know our president matter. You don't know how long it lasts for, but the may well be a reservoir of proteins which are continuing some form of reaction to the virus. Andare are abnormal. Immunological responses s Oh, there are. There is evidence off ongoing inflammation dysregulated chemotactic on but of, uh, chemicals, uh, dysregulated myeloid responses lymphocyte impairment in can see that there are sort of impaired and persistently in bed. Immunological responses encoded as well. So we are some certainly seeing this sort of multi system effect because, of course, these sorts of responses don't stay in one organ. So thinking about the multi system effect again, just need to keep in mind that this is not a respiratory specific virus on Grissom or detailed work which has been done. And again, this is taken from acute covert patients rather than necessarily long patients. But in terms of thinking about how a Cuco bit effects people these tender to be people who were in i t you, rather than necessarily the nonhospitalized cohort, which, as I've said, constitutes the majority of our patients. But what we can see is that there is a detectable signal in terms of ongoing inflammatory cited kinds on Be attentional e If we look at it, other signatures potentially looking at where it can be associated with particular symptoms. So this is looking at leukocytes recruitment within the lung. Epithelium, which contributes to some of the over pneumonitis with in the acute phase on some of that, is persisting in patients with ongoing spiritually symptoms following Cove It Again, I'll remind you, this is severe cases rather than necessary nonhospitalized cases and again cell shifts. So this relates to that sort of mild disregulation, or production of somewhat different cell lines following cove it on. We see some sort of interesting signals and interesting differences between those who have mild and severe disease. I'm sure a lot of you will be familiar with this picture. This is from Danny Altman's group at Imperial on This is looking at autoantigen. So they did a high through pass a fishing expedition, if you like. But on looking at 4000 proteins, they found that there was a definite difference between patients reporting long coated on those who are putting full recovery between the number of the proteins. Now we don't know exactly what these are, but it is a promising signal that there is potentially a detectable biomarker or a detectable alteration in immune response, which would allow us to identify potential treatments or potential sort of biomarkers to recognize those who be affected by long coded in a particular way. Blood clots on the lungs is an important part of the security of CO. That we know that acute covert is an incredibly strong, a cardiogenic disease. About 50% of people who are you have being a strong lumbalis disease. When we study those populations on, we know that there is certainly at evidence that plasma exchange with juices thumb out of sort of hypercoagulable itty in patients with again acute severe coded on. These are patients that were studied by memory scallions. You see, a late there's an ongoing study looking at platter exchange in those patients who were really failing on tradition therapy a while, the emerging therapy adding in those agents from the recovery trial. But we can see that plasma exchange made a difference to their caregiver. Ah, pretty. And that seemed to relate. Oh, a clinical improvement as well. But what about Post could be cracking up with your long? There's a paper which I'm sure anybody who's interested in on Kobe will have been able to see The Pretorius paper looking in South Africa on that paper was looking. The initial paper, which has been published, was looking at 11 patients had had coded on. There was in terms of the lot nonhospitalized long covert patients. We're about five, which fitted that definition. But they identified these persistent amyloid micro clots is they're described through fluorescent microscopy on, but they were able to demonstrate this in in patients with long code on. This has led on to a third observation all study, which is in pre print form, looking at 70 patients with Cobra. Then they found 100% of their patients had these micro clots on day treated 24 patients in again as Professor Crabby was relating to a non randomized, normal controlled fashion on, there was some improvement in symptoms. So there is emerging evidence that a continuing activation of coagulation may be a problem. And again, if we think back to that patient that went on their walk and had a high lactate. Perhaps there is something in terms of muscle perfusion during exercise, which converts people from an aerobic to an anaerobic form of respiration leading to that high lactate and metabolic acidosis. So there is a there is a a tract iveness. Soon this steering it remains a theory, but again, we've been studying slightly different measure off coagulopathy in our long Kobe. It clinically, we found that for those who had an abnormal exercise test, there is a round of odds ratio four that you will have an abnormal marker of coagulopathy using the one willebrand on willebrand cleaning Prochnow 13 ratio. So there's something in this collection up. The question is a clinically relevant. Can it be clinically applied? At the moment, it's difficult to control that that is possible, but clearly there are many patients stories which support the idea of some form of anti coagulation being helpful, but really the high quality data. Is there a moment to allow us to put that into a routine clinical practice, referring back to the stimulator. ICP Trial. Low Dose with Rocks Man is one of the arms of treatment on, So that's for a walk covers with long Kobe coming through the clinic. So hopefully we'll have some evidence of that with in clinical practice Suit might calm your dysfunction is a potential problem on If we look at this paper, which is from March this year, we can see again. This is from more of the acute severe patients. But we can see that there are some markers off mitochondrion dysfunction. And again, is that going to be the answer in terms of how people are, um, altering their response to exercise their ability to respond to increasing demands in in their in their on their physiology. On That's leading to the fatigue. The muscle cramps on the difficulty being able to sustain activity over time on the results and fatigue. So this is again another than mitochondrion exists in a while. Cells on their four. This is therefore going to be a multi system problem. Now. This is not relating toe multi system disorders, but just in terms of being able to relate to different systems, which perhaps people don't think about all of the time. This just got my ears picked up When I looked at this. This was presented at the winter BTS last year on Does a fascinating paper not necessary, terribly relevant to my clinical practice but just doesn't idea was fascinating. So this is to do with the small hairs within the upper respiratory tract, which usually workers a sort of an escalator. Travel a turn for mucus out of the Sinuses on move mucus around and up to a year. Post Cove it patients were able to have samples of their respiratory epithelium taken examined by electron microscope on. There were structural differences in the way that those hairs were being generated by the body on deed when they looked at the motion studies instead of waving to, um pro, which is what they meant to do to provide this sort of moving carpet Instead, they were kind of waiting around and around, and we're no longer as efficient of performing their job Now. This doesn't necessarily mean that all cilia in a lot of the body affected. But in terms of the long term effects of coding, it's clear that this is not something you're going to pick up on a blood test. This is not something that you're going to pick up on clinical examination when you see somebody face to face in a consultation. But there are important, long lasting effects of cove it in multiple areas. And perhaps this is some of the reason why people struggle to get their smell back. Perhaps it's why they get recurrent sinusitis. That's sort of the underwater feel in their ears if they have a new station two dysfunction. So there's a number of things on again. It's this sort of idea that if you do old tests for a new disease, you may were will not get the answers that you're looking for. I'm and again looking at something else, which effects all of the body. Red blood cells, as we know, have to travel around the whole body to deliver oxygen on the Max Planck. It's that you publish something last year looking at the side and shape of red blood cells, then we can see again. This is the details, a pact less relevant. But you can see that the wider spread of shapes on more followed geez off blood cells for covert 19 and then those who have recovered on healthy controls. This's an incredibly difficult area to study on the very few places that look at it. But again, it's a Tzemach off the systemic effects of coded on how that could be producing these long term symptoms. It's just important to keep in mind that there is evidence out there on it's not. It's not simply sort of something that's being imagined or generated, Um, and then this is a slide just to demonstrate a little bit of sort of water after and And I So I was still in this from a picture that I remember from medical school about poster from medical school where somebody had done just this on the physiology office on This is just a reminder that what we're studying is a new disease that is affecting physiology, and this is intracellular physiology. This is not sort of necessarily everything on get We're trying to find an answer, so don't be too surprised if during Q and A. I say a lot of I don't know on don't be too surprised if it takes some time for us to be able to define what's going on with. Finally and importantly, there is the psychological element into disease relating back to measure his case. It is important for us to recognize that long term conditions have significant psychological effects. It would be unreasonable to expect a little aged successful mother has got household duties looking after Children trying to work, perhaps running their own business, but finds that they can no longer the form lose rolls. It would be unfair on be entirely wrong to anticipate that there would be no psychological effects of that loss of role, that loss of just self esteem, that loss of efficacy on. So whilst there is a North, a lot of resistance, understandably from from patient groups about the psychology that's associated long term conditions. If we try to treat the physical without considering the psychological, we are really going into battle with one hand tied behind our back. It is impossible to treat one or the other exclusively I believe on, so it's just important to keep in mind that, of course, our response to long term conditions can exacerbate, can applica eye and can prolong symptoms on being able to have a therapeutic relationship with patients. Being able to hold some of the uncertainty around long covert is an important part off the clinician's role in assessing and treating expensive. So I'll get on to the next section of my talk on which is risperidone every red flags. So a lot of patients that, as we've heard in in the case study present with a wide range of symptoms on. But it is important that patients aren't just told. Well, this is long. This is related to your lung code with it sort of seems we don't know anything about you Can't really help you because, uh, normal diseases that you like those things we know about that are well described are presenting in common ways, as they always used to on that may be presenting in there. 3% of the population that's got long term symptoms from Kobe it so we shouldn't be ignoring what we would consider normal respiratory red flags. So that would be a new cough. It would be Espace. It would be significant restlessness, new lease all of these things, which normally would take somebody to see their GP or to see a respiratory physician. But in terms of thing is related specifically to cover it, there are a few things which I think are important to mention on high. So the first thing is clinical experience and clinical judgment. We This's a slide which regenerated back in June 2020 actually, and it stood, stood the test of time. To a certain extent, trajectory was very, very important in the way in which we were managing patients in 19 phase when we really nobody had a clue what was going on, we were reacting to what we saw every day. We were having long discussions, every even going well, I heard yesterday. What does that mean? And so if this happened again and then we have no idea, what should we do next? What tests we do? And we found that there's a goodly proportion of people who follow in expected recovery. That's great. 90 95% of people so brilliant people are getting better. Then we're people who were getting better. But getting stuck on perhaps, uh, this is in proportion, but it makes my slide because you could read the labels, but people who improve a little bit but then bubble along and don't necessarily get any better than that point at which they recover or or stay at following their acute illness. But then, one of the things which caused us great concern was what we what we call the meringue patient on. They were patients who were getting along nicely. They perhaps being too in a in in department and have been sent home because yes, they had covert. They unwell, but they could go away. They weren't needing to come into hospital and take up more of the oxygen supply, which of course, was in a very short survive. Remember back to the dark old days of the first wave. That's the pandemic. But then, having started to get better, they suddenly crashed on crashed. Sometimes in really dramatic ways on, being able to respond to that was very important in the first 100 or so patients that came through a A PSA on acute, any follow up program we found. I think it was six patients with significant on the Enbrel. I had been discharged from A and B because they were well. But during their follow up phone calls, I was concerned they were brought in and then the diagnostics revealed significant problem. We embolize You didn't find that further out than six weeks, but it was an important thing. So and still in the patients that we have with long coated who are now gradually recovering or managing their symptoms themselves at home if they suddenly have a deterioration, it is a warning sign that you need to look at something on. Of course, that doesn't relate only to the spirit tree symptoms, but it's just important notes that understanding the trajectories of long coded in patients is really important. You know that it's fluctuating, so people do have crashes after they've had significant. It's either further real nurse Aleve made a change in their lifestyle, But being aware of the building, lying's is really, really important for keeping patient safe, um, another of the lessons that we learned in the first pandemic, in particular first wave of a pandemic in particular, perhaps less so now, but still something very important for us to be aware of. Um, is that this This'll was the message. Stay out. Don't go out, Don't see a help. Stay at home and get through it effectively. On day shift took Mr Heart. They saw the images on the news of patients stacked up in corridors and any they saw. You know, the story about sort of hospital being a couple of hours from completely running out of oxygen on. So, uh, certainly a large segment population who sort of have a public service attitude said, Well, okay, I'm ill with Kobe, but I'm going to stay home. And I still remember a a chap that we met who said, Yeah, I had a really hard time at home and I only noticed that I was ill in terms of not recovering when I just got back to trying to do my exercise in my own house on the on a stationary bike and I couldn't do the same. So I was before I came in, and we found that he had interstitial lung disease, um, related to coded, and he had done the right thing. It stayed at home, and it was only a chance conversation with a friend which automate the hospital for a review in the outpatient department on so critical illness was happening at home and still patients. When they see the news they read about Kobe going around in hospitals, particularly with sort of recent headlines of increasing numbers of cases, people don't want to be in the hospital. We sort of almost moved back to the sort of 18th century view of hospitals that their places to be avoided because there's bugs running around them and they're going to sort of make you sicker on so people will still be experiencing what would normally lead to an admission and care in hospital. They might be tolerating that at home. So that's one of the key things is that taking a history understanding what's happened to patients is really, really important? Because whilst somebody might have seen a Nonhospitalized case on manage that happened, they may still have had what would traditionally be considered a critical illness. This is, Ah, a quote, which I quite enjoy eso if you listen to your patient, they're telling you the diagnosis, and this is from William Osler. He was a great medical educator, informed medical education in the United States to a huge degree. But if it looks like a dunk, walks like a duck. But sounds like a cow. It's probably not a duck on disses. Something that's really important in clinical practice is, well, I'm a respiratory position. One of my pet hates is his diagnoses of asthma. Um, on some nonsense, partly because the treatment Crestor is simple. It's cheap. It's easy to do. It takes the stroke of a pen. The click of a button on somebody is treated on you, yet it may not be asked. Now, if they respond to that treatment, they get better. That's brilliant. You've you sold the case. You've got the manage the patient to be better. But if they're not feeling better after you initiated treatment, Krassner and then you keep on adding in more asthma medication, and you keep on adding in more acid medication and you're on tablet. But you've had several courses of steroids on. Yes, you feel better when you've taken your course of steroids because they make you your for IC and you're quite happy bouncing around on debt. You're still walking like a duck sand, looking like a duck that sounded like a cow. It's probably not going to be the thing of thought it was. And this is what we're dealing with a lot. So this has taken pre hope it. But it's a good picture on what you can see here is a tricky else stenosis. We're seeing a huge amount of subglottic stenosis in patient to be intubated. Often they not recovered on. This is sort of a stuck on fluctuating group, for those have been in critical care. If anybody being on I t you, you're seeing that nurses work tonight, you'll see that nurses are all process if we check the pressures of the cuffs of their independent tequila and track your ostomy tubes on. The reason for that is that if the pressure is too high in the balloon, that sealing the airway, then you can cause tissue damage on the trickier. Now, when we were having medical student rolling patients to keep them safe, when we had orthopedic surgeons doing extra duties on TV, you performing the role of slides and medical sort of opinions. I mean, almost one of the last things that was being paid attention to was the balloon pressure cuff pressure. People just didn't really know about. It wasn't part of their usual work your pediatric nurse and suddenly looking after critical care patient. You may not appreciate importance, and so this, commonly, particularly it's subglottic, and it's slightly higher up presents is weeds Onda course. What is, well, what we disastrous. So you haven't had any? Have steroids and you have another inhaler and you have a tablet on. But you could go up a little, and none of that is gonna make a difference to a structural problem caused by a scar on your back here. So it is vitally important again that you listen to patients and the red flag, I would say for this is if you have ways on breathing in, it's unlikely to be asthma. Asthma is an experience tree leaves, so if you haven't inspiratory weans on, patients will describe it as the weeds because they can hear it because it's obvious because other people comment it's on it. But if it's an inspiratory means it is unlikely to be asked. Start looking for the cows amongst your ducks. On the other thing, which happens is vocal cord dysfunction where it's caused inducible laryngeal obstruction again, difficulty breathing in on were there. Some talks later about dysfunctional breathing but breathing pattern disorders. But if you have again patients that described difficulty breathing in and they have voice change it that doesn't fit the textbook definitions of asthma. Now the two thing concurrences physicians to talk about talk about what comes razor, which is that will be one diagnosis explains everything. There is a flip side of that, which is Hickam's dictum, which says that the patient can have asthma, any diseases. Is he down? Well pleases on. So, uh, you know, watch out for the co existence off asthma with disorder Really asthma with, uh, inducible allergy of obstruction. Be that one exercise on talking so big. Careful with these things on, then. Finally, I think finally I've got this'll. I'd which, if anybody's appropriate, the age will recognize that it's from back to the future on day one of the things and it's sort of almost, I hope not stealing everybody standard. But we see patients with multi system complaints. Patients coming to us who had COPD, diabetes, heart disease, peripheral vascular disease, asthma, other lung, COPD before they got coded andare experience in clinic and what is recognizable. Too many patients is that you say? Well, the clocks being turned four words by 10 years on those diseases. But you already had, and they get, I guess that makes sense, or the volumes been turned up to 11 on the symptoms that you already had on those. Those phrases really strike a cord with people on. Actually, we're seeing an awful lot of what's going on before coming back and being worse on go. We shouldn't forget that again on this Is this again. It's one of those really difficult areas with long covert, because if you've got COPD and then you're more breathless after your cable infection, well, it's long, Long might not be. It might be your COPD getting worse. Let's treat the COPD probably on. Then you might improve on. Actually, it's not necessarily a lot this inexplicable or call the understand that thing. It's just that we haven't really treated your underlying disease as appropriately as we could. So just be aware of those prior prior problems on then. Finally, this is thank you. It was only my name on the front of the slides, but you can see that there's a huge number of people on ever growing list who weren't there when we did Those slide with the photos of people who are involved in in the clinic in New Zealand have contributed time and effort on but, uh, thank you to them. So that's it for my talk. But I've been allowed to take some questions. Lincoln's I have to run up from afraid, so I won't be here. How old discussion, Right. So is a slight deviation to the plan. I guess the biggest reason we are going to take some questions there are some that have come through online, but perhaps if we open that to the floor, But just probably like some practice so much for such a compensatory. That was absolutely super. And, um, I don't know. I think a lot of our patients have the experience that if they come to finish in with multiple symptoms, they could get sort of this against assumed that they want the making himself for that, you know that there are other not taken seriously with the results, to thank you for speaking back complexity. And so to normalize mental health fast that it's not as well thank you so much, Mr that sort of the trip and old curve it cleared processor for primary care referrals. How sensitive it specific is the election decentration test in picking up Oh, going long disease, whether it's inflammatory lung disease, away cracked piece in practice so I can't give you a A a percentage. What I can say is that a D saturation shouldn't be ignored on it through the looked at in terms of looking for those things which you you mentioned. But in addition, what we have found on as you saw on the slide earlier patients with preferably saturations sometimes really very worrying peripherally saturations when we test their central saturations, if you like, in terms of measuring their arterial oxygen levels when we do our six minute walk. But we don't see Central Hypoc senior, but we are seeing peripherally saturation now, whether that relates to pour capillary blood flow when that relates to mitochondrion dysfunction in terms of not being a extracting more oxygen than you need in the peripheries, I don't know, I I said they'll be lots of I don't know. So some veggies and requests. Yep. And Okay, guys, well, we missed you. So, um so we repeated your chronic problem. Bolic disease can have a normal transfer factor, but you would then be looking at other signs of harmony. Hypertension. So clinical science can be helpful, but really, the echocardiogram is probably the most useful aspect of that. In terms of looking at transfer factor, that was, that is important, and it will pick up the chronic lung disease. It can pick up intracardiac shunts and things like that. So so transfer factor is important. Interpreting in night of prior disease is important, and if you've got anything before, well, that's just a gift. But certainly, transfer factor is a useful test in identifying a problem. It doesn't necessarily tell where or what the problem is on, but certainly if you have so what we are principales in our practice. If you find that the saturation go looking for an answer, and then once you've reassure yourself that this is a a signal problem, not necessarily a probe problem, but instead, actually the reads a peripheral decentration. But perhaps it's not dangerous in terms of causing problem. Essentially, then you can be reassured, but otherwise keep looking for why that person has hypoc senior induced on exercise. We had went to the questions online about the increased off a big women on impact on the reproductive system. Is that something you could speak? Yeah, I haven't dedicated myself to understanding the sort of too much as the sort of gynecological side of things in terms of management off perimenopause on which is around. Because, of course, when you look at the median age of the patients that are coming through the clinic, visit preponderance of female patients on. That's a very live issue on. So it's something we discuss. It's something we look for in terms of the potential for peri menopausal symptoms or hormone disregulation providing a background or a driver to some of the basic motor symptoms that people get on. It's entirely relevant to try and manage that I tend to. I wouldn't pretend to be an expert in into a contraception or hormone management, but some of my colleagues and the clinic have been developing increasing knowledge in that area on, but certainly something recognized regular periods. Ultimate still cycle amenorrhea is Elise. Things are reported by patients with long Tobin on particularly psychical symptoms in terms of worsening in the in the pre menstrual period is a is incredibly, well, incredibly so frequently reported. And it may well be something to do with the vascular stiffness muscular permeability which goes around on these hormone. You're infected. So there is a clear pathological pattern physiological basis for some of that cycle symptoms associated with the mental cycle. But I I'm going to claim a degree of ignorance on that. You're getting a really, really detail. You want to take one from another one from the whole. I think that's probably one, uh, and some GPS. I just have to be interesting and other things we just want to write. Amazing. Well, I don't do much right. I have moments, pain, brightness. It's no yes, And she's a juice to get another scan. Yeah, I just wanted up Wheat. What is that, By the way? Also, scans should be doing you know what helps? That's never Yes, So I think I'm in terms of so if I just sort of summarize you've got somebody with persistent breathlessness with normal lung structure, if you like, but impaired gas transfer Is that still the scenario so echocardiograms looking for the potential for family hypertension because that may not be visible on a CT or CDP, a sort of surrogate markers. But it's not necessarily that means leave acceptable of the new scan can be helpful. And that's showing some small profusion defects in some people s. So that may be contributing to reduce gas tank on, making sure that the technical aspect of that test of being done properly and it's been adjusted to Amenia was seen quite a lot of sort of slight, non specific in union. That can happen in fact, on transfer factories well. And then, really, once you've got to the end of not medical sciences, we know it. But in terms of the diagnostic pathway, it gets into the realms of trying to manage that patient as best you can. And a lot of that is around the same self management which goes with protein. The transfer fact is important, but if you have somebody who's breast us again, we can think of things like metabolic causes of breathlessness which are aren't easily picked up unless you do a dynamic test with some form of blood gas analysis. So I think it's it's about to the testing patients in the situation in which they find their symptoms are worse. Card up on the exercise test has been helpful in some patients, but really, if everything is normal, really need to be looking at patient's getting recruited into trials, I think we're at that point. There are lots of ideas, as I showed you on. A number of those could be contributing to spin Tums, which on those signs that you describe. But the numbers are small studies, a slow to get started on it. It's really difficult, and a lot of it is holding that uncertainty in treating what you can. And it's sort of it's a way I describe it to, Not to people. Is that sort of British Olympic cycling of sort of marginal gains. Let's improve your weight if we can. Let's improve your stamina. Let's improve, Uh, you know, diabetes, control of these things that you can do to help improve some of these fitness and and wellbeing. But we need to hold that certainty. That's tough, really difficult, but it's an important part of the role of somebody is looking after these description patient. We had a 60 be able to address them. Some of them are several spiritually things. Do you like something that we could feel crossed? You're on eight a day I will again can be active with them. That might be a lot of I don't know. That's finally one question it came through with. Do you have a sense of what's given this multi system in involvement is what's long. Hold it in. It's need to look like an infusion. Uh oh, excellent question. I I think that long hold the clinics require the rebirth of the general physician. The patients need some where they can get where they will know, be categorized in a single stream of thinking and then sent somewhere else for somebody else to think about something else. The multi system nature of this means that you have to understand how each of the bits the system might have together now the amount I have learned in the last two years about hematology and do chronology gastroenterology Diabetologia cardiology is well beyond what a simple respiratory position anticipates in their later career. So, you know, I'm slightly disappointed on did you turn it to really difficult because you have to think on you, and and so actually a general physician is really important. We need specialists to be able to look and push forward to the understanding of things like well, here in a moment about sort of cardiac in the like. It's no way I'm gonna be cardiac MRI's, and yet there are. They can be a very useful diagnostic tool, so we need those specialists. But I think a a general clinic, which is able to sort of hold on bringin specialist knowledge from elsewhere. And we're very lucky. We have a weekly ended tea with coverted interested cardiologists in urologists on, We call in human apologists, and you cannot just would be needed. But we hold the patients in the general clinic, and I think it's, uh it is that which helps in specialist clinics. That's not to say that patients can't be held in primary care lead clinics as well, But it's it's that guest out view of a person which is important and not dividing them up into little chance and fragmenting them through a tertiary care or secondly care system. Because otherwise it's incredibly confusing on the multiple different opinions that we keep people get in until certain disease is really unhelpful. For the sort of the understanding of for the patient