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Right. So, good morning or good afternoon. Sure. At the time difference is, but uh it's a pleasure to speak to you today. My name is David Jackson. I'm a professor of Respiratory Medicine at King's College London, uh and adult respiratory physician prom in ologist, specializing in uh severe asthma care. Really. So, what I wanted to speak to you about today is the management of asthma, both from an acute perspective and chronic perspective. Asthma is probably the most common chronic respiratory condition in the western world. Uh So it's a very, very important condition to understand and know how to manage because all of you will see it many, many times uh throughout your career. Um Fortunately, it's quite a straightforward disease to understand. Um just to go through, you know, some of the background, it's fundamentally a clinical diagnosis. There is relevant history of respiratory symptoms. We use shortness of breath, chest tightness and cough. And importantly, these are symptoms that will vary over time and in intensity. Um and these symptoms are there in the context of having some evidence of Xperia Torrey airflow limitation. So this is unlike, for example, COPD where there is not so much different day to day in the level of symptoms, because a lot of that effort, obstruction is more fixed. Uh Similarly, it would be different from other respiratory conditions, like interstitial lung disease where there's fibrosis, uh and sort of scarring of the lungs. Because again, that's more consistent in terms of the daily impairment to lung function, in terms of the daily symptoms. Now, these variations we see in asthma are triggered by a variety of things. Um and the most common of which we're going to come on to shortly is respiratory viruses. Uh like the common cold Rhinovirus being the most common. Now, what there is is there's airway hyper responsiveness, which is sort of the twitchiness of the airways and airways inflammation. Um but you can't use these alone to make the diagnosis. So this is the sort of the lung function. What we see this is a flow volume curve of the F E V one, which is the expiry Torrey volume that the patient blows out. In the 1st 2nd, you can see what's the normal level in green and then you see blue and red, red is before you give the Bronco Dilator. So a drug to open up the airways to relax the bronchial smooth muscle and blue is after and you can see sort of a closer to normal level after give a Bronco Dilator. Um And what is important to notice is, you know, below the X axis. Here, you can see a normal inspiratory loops. This is in spiritually the big sort of semicircle underneath and then you expire, you breathe out fast to give that expiry Torrey Loop. There. In this flow volume loop. As I mentioned, there are many triggers and respiratory infections are the most common but irritants just sort of that aggravate the area like a sudden change in temperature or exercise, cold air or emotion and cause the sort of tightness in the airwaves because of this area, hyper responsiveness. And what's important to remember is this area, hyper responsiveness relates to actually the underlying areas, inflammation. So the more inflammation areas, the more airy responsiveness there is to these different factors. So the other patient where the areas inflammation is very well controlled, then they won't respond in the same way, too cold air and exercise and all these other factors. Viruses are by far the most common cause. And here are three pie charts for infants or very young kids, lesson too. And the normal Children age from 16, 17 and then adults. What you can see is that when you look at the trigger for exacerbations, um viruses, Rhinovirus in particular is the most common influenza in adults is also a very common cause. Uh the reason uh this happens is because of worsening t two inflammation type two areas, inflammation for come onto a minute. This is showing a relationship between the frequency of hospitalizations for asthma and the time of the year. And what you can see over this 10 year period is that every year, there's a spike in exacerbations in the autumn months, in the cooler months. And this is when the viruses are most prevalent, then there's a smaller peak sort of in spring months there. But there's always this one spike and this happens in about September time approximately, actually shortly after Children go back to school after a summer holiday where they start interacting with each other, share in each other's viruses and so on. So the main reason why patients with asthma have exacerbations of their asthma, the virus. Whereas if you don't have asthma, you simply get a runny nose and a bit of a sore throat, but you don't get an asthma attack is because of two issues in asthma immunology. The first is that there is an exaggerated what we call type two inflammatory response. If we think about what the way the immune system is made, we have what we call type one inflammation, a type one th one pathway. And this is really what from an evolutionary perspective, protects us against infections or fights infections. But in asthma rather than this being activated in the normal way, this part is deficient, we call it the deficient antiviral immune response. And the type two response, which is not really there for protecting us against viruses and bacteria is exaggerated in its response. And this is specific to um asthma. And what we now know is that the level of teeter inflammation is th two areas, inflammation at the time of catching a virus directly relates to how exaggerated that inflammatory responses, how impaired the antiviral immune responses and how exaggerated the type two responses. And these two things correlate and relate to each other. So here we have the normal airway on the left, we have the asthmatic area in the middle. And on the right, we have the asthmatic area during an asthma attack during an exacerbation. The main difference, firstly, in the middle is you can see that the airway wall is thickened compared to normal. So the caliber of the airway itself is narrowed. And on the right, what you see is number one, that inflammation is even more exaggerated. So the lumen of the area, the caliber of the areas narrowed further, there's mucus in the area now, and the muscle, the smooth muscle around the airways suddenly becomes tightened, constricting the airway further. So the airway is narrowed both from the smooth muscle, squeezing it from the outside and also the inflammation in the lining of the airway itself. And for mucus in the airway causing a limitation air flow again. Now, this inflammation, the most important cell is the eosinophil for this inflammation in asthma. Normally, in terms of the blood cells, it's very, very few in number. But in asthma, when you look at the airway and look at the cells in the area. The sniffle count has gone up a lot and these cells have many different Granules that produce different cytokines and growth factors and enzymes and they damage the area war and they cause mucus hyper secretion as well. And this is what the sinful looks like. Under the microscope. You can see these tiny little Granules that stain red um with, with person stain that is a characteristic of a cinephiles. And what we know in asthma is it the number your blood eosinophil count directly relates to the risk of the patient having an asthma attack in the future, which is what you see on the left here. What we're looking at is a very large number of patients with asthma and their blood is sinful count and the risk, the odds ratio, which is this oh are at the bottom. The risk of them developing an asthma exacerbation in the following 12 months. And what you can see is the higher the blood thinner for count, the greater that risk of developing an exacerbation are the right. You can look at the same thing, but for symptoms, the higher the eosinophil count, the worst, the asthma control asthma control is essentially asthma symptoms, the breathlessness, the weeds, the chest tightness, how often the patient wakes up at night because of asthma. So there's a very clear relationship. It's a fantastic biomarker in the same way as BP or cholesterol is for heart disease. The eosinophil count in asthma is an excellent biomarker that tells us as clinicians about the risk to the patient, the likelihood that patient's going to have an asthma attack and whether their symptoms are due to asthma. And this is not a new finding. This is now coming up to 50 years ago, almost 1975. Um in the New England Journal of Medicine and Barry Horne wrote that the total eosinophil count reflects asthmatic activity. It's useful for regulating the steroid dose because steroids only work if there's a synthetic inflammation and it's the sinful count is usual for the early detection of exacerbations. So again, telling you about the risk of an exacerbation developing. So what's a normal, listen if account, well, this is data from the healthy population in Austria, 11,000 healthy people. And you can see what the normal range is. The geometric mean of the normal population is 128 cells. But microliter to the 95th percentile is up at 330 cells for micro to and most patients with asthma, poorly controlled asthma have a blood isn't account of more than 300. So we're really looking at numbers in that range where you can see in the higher the number, the greater risk. Now this access only goes up to 850 sulfa microliter. But many times we'll see patient's with the set of accounts of 1005 hund 2000 sultan microliter and it is just due to their asthma. Once it goes beyond 2000 cells, microliter, then you have to think about other conditions like uh synophylate vasculitis and conditions like that. So how did these arsenals get into the airway? Well, it's important you understand the basic immunology of asthma because this will help you be able to treat your patience and understand what's going on here. We have the airway epithelium. Okay. So this is the barrier to the outside world. It lines the airways. And if you are an allergic person, you breathe in different allergens, then the epithelium becomes activated. And these are three cytokines, chemical messengers that are really important that the airway produces the lining of the area. The area epithelium produces I'll 33 interleukin, 33 interleukin 25 T slp. At the same time, there are dendritic cells that sample the environment present the antigen, the allergen, too naive T cells. And these become polarized to th two cells and these cells produce three really important cytokines. One is I L4 which tells B cells to make I G E. The second is I'll 13, that is very important for every hyper responsiveness and mucus hyper secretion. And the third is I'll five, which is what makes a sinful is um a bone marrow. Now, this whole side of the graph of the figure is what we call um the allergic pathway to eosinophilic inflammation in asthma. But we also know that many patients with asthma actually don't have any allergy whatsoever. They're not allergic, they develop asthma in later life and they can have very severe eosinophilic inflammation without any allergy at all. And exacerbations can be triggered by pollution or by viruses or that's just intrinsic, which means there is nothing external that's making the asthma unstable. It is acting like an autoimmune disease where the inflammation is just very, very active. And we know there is another cell or the I L C to call the the type two innate lymphoid cell, which like the TH T cell is also a very important producer of I L5 and I L 13. And we therefore see patient's with very significant eosinophilic airway information without any evidence of allergy. So you have the allergic and the non allergic part of asthma. In both cases, cinephiles are coming into the airway causing exacerbations. So sometimes that first part type two or eosinophilic arrays, inflammation is the dominant inflammatory pathway of asthma. The blood of Singapore counter is a very good biomarker of eosinophilic areas. Inflammation level's relate to symptom control decline in lung function over time and asthma attack risk, exacerbation risk, asthma can be driven by allergic triggers like error, allergens, pollen or house dust mite or non allergic triggers like respiratory viruses. And it can also be intrinsic without any external trigger. Patient with asthma can develop an asthma attack. And this is due to impaired antiviral responses, what's called the interferon response and an exaggerated type two response to the virus. And this is different from the normal response to non asthmatic people where the normal response to viruses A T H one type one response. So moving on to treatment now that I've set the scene in terms of the background to asthma immunology, because the treatment essentially follows on from that. The main goals of course, are to reduce impairment, reducing symptoms, allowing patient's to live a normal life without a day to day symptoms and then minimizing the risk, the risk of having a severe exacerbation, the risk of side effects from systemic steroids. So in many ways, you can think about it, like with cardiology, you're trying to reduce, you know, a patient with a skeptic heart disease, you don't want to have angina and those that chest pain on a day to day basis. And you also want to stop them from having an asthma attack next year, the year after or a stroke and so on. So asthma's like that you're trying to reduce day to day symptoms and you're trying to prevent future risk. Going back to this graph. Essentially the drugs. Then when we use medicines and asthma, autumn, firstly, relax the titans smooth muscle, the broncos smooth muscle and secondly, to reduce the areas of inflammation. So the short term benefit of drugs is to really relax the smooth muscle, the longer term drugs that don't work in, you know, a few minutes are there to reduce inflammation. Now, this there is an asthma. There's a step wise approach to treatment, like with many other diseases, it's sort of like a as treatment ladder where you started essentially step one, step two and you work your way up depending on whether the patient responds adequately. It used to be that step one, which is the first step was only salbutamol, only beta agonist therapy for relief of symptoms. But what we appreciate about asthma is that it is an inflammatory disease. And beta agonists don't offer any anti inflammatory treatment. So you don't stop a patient getting worse, don't stop patient losing on function or developing asthma attacks by using salbutamol by using a beta agonist. What you therefore need to do is right at the beginning, introduced an inhaled corticosteroid, which if the patient does have mild asthma can be used infrequently. But if they have more regular symptoms should be used absolutely every day. The question then is, you know, you add in a the ideal situation is you adding a beta agonist in the same inhaler in the same device. So you have an inhaled cortical steroid and, and that's made in combination with a beta agonist here in Formoterol for step two, which is a beta agonist that lasts about 12 hours and why it's useful if possible to prescribe a drug and an inhaler that has both of the inhaled steroid and the beta agonist inside the same inhaler is because the patient will feel better very, very quickly because it's got a beta agonist. But at the same time, you're delivering the inhaled steroid, which therefore reduces the inflammation and the risk to the patient. If you only had an inhaled steroid on its own, the patient doesn't feel better straight away. And so it's less likely to use it unless you've really explained to them properly. You have to use it every day. It's very important. This is the thing that works the best. But unless use it every day, you're not going to get that benefit in the same way as you brush your teeth every day to prevent tooth decay in the future. Uh And you've really got to sort of explain it. It's not about only brushing your teeth when you get toothache. So you've got to make sure the patient understands the importance of using the inhaled steroids every day. And then the other steps are really just to increase the dose of the inhaled steroid because fundamentally, if the patient doesn't respond to the lower dose and they're actually using it every day and their inhaler technique is good, going to come back to the importance of checking that in a moment, then it is usually their symptoms due to ongoing inflammation, which there needs to be treated by an increasing dose of inhaled steroid. So, Broncho dilators fundamentally, there's two groups of them. The first of the beta agonists debated two agonists in the second group of the anti cholinergic drugs or the muscarinic receptor antagonists, they're given by the inhaled route. They can also be given by the nebulized route. Uh Salbutamol is the most common short acting version and there are longer acting versions. Now, some working for 12 hours like Formoterol, some working for more than 24 hours like real enteral. The short acting anti cholinergic is ipratropium and this can go in the nebulizer if you're in the emergency setting. But the normal longer acting versions now are called long acting muscarinic. So these at LAMAs L A M A and tiotropium is the most common one there. It'll again lost about 24 hours. So, salbutamol stimulates the beta two receptor, which is the main receptor in bronchial smooth muscle stimulation leads to activation of the enzyme adrenal cyclists, which leads the formation of cyclic amp, high levels of cyclic amp, relax the bronchial smooth muscle. Um and it works very quickly. It actually in 3 to 5 minutes with a peak of 15 to 20 minutes. And our administration, it's not, it's not good. You shouldn't be giving self usual via as a tablet. It's a very, very old practice. You should be giving it via the inhaled route. The onset of the the overall duration of sub vitamin is around 46 hours. So on the right here is basically what I mentioned about the, the adrenal psych lays converting ATP into two cy click amp. And this then leads to smooth muscle relaxation. On the left is uh showing the anti muscarinic which act on um the M three receptor on bronchio smooth muscle as well. So it works by a different mechanism to the beta agonists. So they're good together if you have the opportunity to use both. And this is the impact on lung function on the left, using one of the long acting beta agonists tiotropium. You can see there's an improvement there with a tia Tropea um compared to placebo in the F U V one. And this is very quick by half an hour, by the half an hour. You can see there's already a significant improvement and they also reduce exacerbation risk not by a huge amount. You can see here, the risk reduction is 21% compared to placebo, but it nonetheless does reduce the likelihood of having a severe exacerbation. By far, the most important treatment are inhaled cortical steroids. And this is because if the patient is actually having asthma attacks, this is the only thing that's going to stop them and reduce the risk long term unless of course, they have very severe asthma where they need systemic steroids and something else. So in health steroids have been shown to improve symptoms, lung function quality of life, they reduced exacerbations. The reason they work in asthma is because they fundamentally stop signific inflammation, th two inflammation. And you can see the impact on the blood eosinophil count here of going from a medium dose, inhaled cortical steroid to a higher dose, inhaled corticate steroid. There's also another way we measure inflammation in the airways noninvasively. And this is called FENO which stands for fractional exhaled nitric oxide. It's, it's a different lung function test um that you may not have uh widely available in Ukraine or many other countries, but it will come in time. And it's a very good way. It directly relates essentially to type two areas, inflammation, asthma. And you can see the impact here of starting a patient, starting patient's on inhaled cortico steroids are two different doses on the level of Fiona and how quickly it works. So really a normal Fiona is about 25. So you can see you're basically reaching a normal level within about a week of starting inhaled cortical steroids. And this is why they are so effective. What's really important to remember is inhale steroids are only effective if the patient actually uses them. And unfortunately, most patient's don't use them every day. And the way they're using them is not right. They're trying to, some of them who try to use the inhaler technique is so poor that actually very little of the drug gets into the lungs. And this is data from America from almost 20 years ago now. But what it showed was in a large number of patient's that most patient's who prescribed, this is an inhaled corticate steroid with a beta agonist. In combination only used it about 20% of the time. So it's very, very important to check. And the reason it's so important to check as well is because the more patient's use it, the less the risk of death from asthma. So this is data from 2000 published in the New England Journal of Medicine showing at the direct relationship between how many canisters of the inhaled corticosteroid. How many inhalers, the patient's who died of asthma had had in the previous year. When they look, they could easily, they could see quite simply that the more regular the patient's using the hell cutting of steroids, the less the risk of dying from asthma. So it's very, very important. This is data building on this idea. Now, on the left is this is data from the Netherlands from Holland showing that 24% of the whole population who have asthma are on a medium to high dose inhaled cortical steroid gina is the sort of the the global organization called the Global initiative for asthma. And step 4 to 5 basically means a medium to a high dose, inhaled cortical steroid. Now, 24% of the population have this have with asthma who prescribed this level of treatment, 17% was still symptomatic, difficult to control despite that when they actually optimized inhaler technique and made sure that the patient's were using the inhaled steroids properly. This dropped by 80% it dropped from 17 all the way down to 3.7% of patient's who were still poorly controlled, who were still symptomatic because of their asthma, even though they were taking it every day and their inhaler technique was good. And this is what we think of as the, the percent of patient's who genuinely have severe asthma. Why do I say genuinely? Because many patients who appear to have severe asthma actually don't. The only reason they're still symptomatic is because they're not using the treatment every day for these 3.7% is very difficult because systemic steroids are needed to control this. Their asthma traditionally, but systemic steroids are associated with significant side effects and this is data showing the cumulative systemic steroid exposure. So, prednisoLONE exposure um per you know, uh with the risk of developing these four complications, heart phone Michot and function cataracts and osteoporosis. And you can clearly see the higher the exposure to systemic steroids and this is a lifetime exposure, the greater the risk of developing these complications. Now, unfortunately, if you don't have access to what we call a monoclonal antibodies or biologic therapies, um which many countries don't have. This is the only option to control patient with severe asthma, giving them systemic steroids. And you just have to do your best to try and reduce the risk of the complications. You know, making sure that on protection for their bones with calcium and vitamin D, making sure they have I checks, making sure there other cardiovascular risk factors are controlled to reduce the likelihood of developing heart failure. And my cardio infarction, systemic steroids. But there is a new generation of drugs called monoclonal antibodies or biologic therapies. And they have been developed to control severe asthma and severe asthma inflammation without systemic steroids. And there's a whole multitude of them, which I'm showing you here. You don't need to remember them all. Um pretty important you're aware of them because increasingly these are being used and these sort of the latest development in severe asthma, many of them like these three drugs here, Benralizumab, mepolizumab, mepolizumab in one way or another target the eosinophil um and Mepolizumab reslizumab target the isle five cytokine. Remember this is the cytokine I mentioned earlier, uh which is the most important cytokine for cinephiles and asthma and worse sniffles generally. And Benralizumab targets the isle five receptor which is expressed on the sniffles. And this causes the very rapid apoptosis of the eosinophil, the death of the eosinophil. Um You can see that on the right, the eosinophil is read the natural killer cell which comes to kill the cell is green. And when you give somebody Benralizumab, that monoclonal antibody basically puts a flag on the eosinophil that says come and kill me because I'm bad and then they never kills outcomes, essentially kills the cell. And we see the effect of this on the blood eosinophil account. So, Benralizumab, which is the orange. Here, you can see how quickly the sniffle count drops in patients with asthma with severe asthma. Uh Mepolizumab works more slowly, which is the one that targets the L5 cytokine. Uh, but they both reduce the sniff accountant. This is log arrhythmic scale and this, these drugs are very, very effective in severe asthma. And this is showing the relationship between the blood sniffle count and the exacerbation rate. Placebo is great. This is the point I was making earlier about the high the eosinophil count, the greater the risk of having an exacerbation of asthma. So this is what happened when the patient's were given placebo when they weren't treated and in purple, what happened when the patient's were treated by blocking the eosinophil. If you take away the eosinophil like you do in Benralizumab, patient's essentially stop having asthma attacks. The first monoclonal antibody was called omalizumab and it targeted I G E I'm not going to go through this in detail, but it's here for you to if you're interested. One of the things that omalizumab does is it actually helps with the antiviral immune response. As I mentioned earlier. One of the reasons why respiratory viruses are the main trigger for asthma attacks is because there was the immune response of patient with asthma. When you have a virus is abnormal. There is a lower level of interferon produced and some of the cells, some of the key cells that produce interfere on type one interfere. One are these plasma site loaded in British cells. And these cells express the IgE receptor called FC epsilon are one alpha and essentially by giving somebody omalizumab by giving them anti I G E. You normalize some of the antiviral response. And you can see that here when you look at the difference between omalizumab and placebo, you see that the the autumn peak in exacerbations in September, October is reduced when you give somebody omalizumab as shown here. What about acute asthma? So this is a um uh the summary of the kind of clinical signs that you should be looking for and you should be assessing and what the difference in those clinical signs mean in terms of the severity of the aspirin, how the patient is sitting, whether the patient able to talk, you know, in words or whole sentences or not at all. What the respiratory rate is, what the heart rate is. Remember, the heart rate is often going to be high from salbutamol. So you have to interpret the heart rate before they've had the salbutamol. It is to be really meaningful. Um the oxygen saturation rate clearly uh and the peak flow rate, what their area color. It is. The initial treatment is the same for everybody which is giving them the beta agonist to try and relax the bronchial smooth muscle, uh and you give high dose, you know, 10 puffs of the inhaler or a nebulizer just to try and open up the airway and that needs to be repeated regularly. It's very important. You give prednisoLONE as soon as possible, the systemic steroids. So they can start working and start reducing the inflammation while you continue to give the salbutamol. This is a pathway of, of what you would do if you were in. For an example, in emergency department. There, you do the initial assessment, the ABC, which I'm sure you're all familiar with and you assess whether there's confusion or drowsiness or silent chest, which are very dangerous signs. And uh I'm going to go through this, this section here. So again, like I mentioned before, you assess whether the patient's able to speak, whether they prefer sitting or lying, what their respiratory rate is, whether they're using accessory muscles, the oxygen saturations to determine, is this asthma attack mild to moderate or is it severe? The treatment initially? Fundamentally is the same. You give oxygen. If the saturations are low, you give beta agonists and uh anti cholinergics to Broncodilator as much as possible. And you give systemic stones, the difference, the only difference here really is if they're very severe, then you know, you don't want to take their mask off to give them tablets, you just give them intravenous steroids, impossible, hydrocortisone. You could also give magnesium. There's the data for magnesium is moderate. Um uh but it's, it's very low risk. So it's worth giving if you haven't. And then you reassess the patient obviously and determine, you know how severe the patient is. Uh And then you need to decide whether you to keep the patient in hospital or whether they potentially can go home and carry on using the sub you tomorrow at home, carry on taking the prednisoLONE at home. It's very important that you appreciate risk in asthma and identify patient's at risk of asthma related death. And these are patient's who have had a history of a very severe dissipation before patient's who have needed to stay in hospital for asthma in the previous year. All of these are really identifying patients who have the who's asthma is bad enough to need to have severe attacks and therefore, if it's happened before it could happen again, unless you've made a significant change to their treatment. One of the key risks and this is what I mentioned earlier is about inhale steroids and patient's not getting inhaled steroids when they leave the department or not understanding they need to use the inhaled steroids on a daily basis. The other connected to this is the overuse of salbutamol, the overuse of short acting beta agonists um for each cannister of salbutamol, which is the blue inhaler, it has 200 actuations. So when you're using more than one of those every month, you're clearly using, you know, six puffs, seven puffs per day of it, which highlights you, you must be very symptomatic. If you must be very symptomatic, then you must have a lot of inflammation. You have lots of inflammation, you're at risk of a severe asthma attack and potentially dying of asthma. So it really relates to the idea usually in most cases that they're not using their own health steroids every day or although they're trying to use it, inhaler technique is really, really poor. So when you see the patient's the time of the exacerbation or follow up, which is really important to see them after the asthma attack, especially if they're, for example, they've seen, they've been seen in the emergency department but not by a physician rhythm with, you understand, asthma properly. It's important you make the effort to see them after their discharge to make sure they have understood the importance of taking inhale steroids every day. You confirm their inhaler technique is good. It's very important that all of you learn how to do inhaler technique properly because there's no point you teaching bad habits to somebody else. And many doctors don't know how to do inhaler technique for inhalers and asthma and COPD. There's very good videos on youtube to show you how to use a metered dose inhaler properly and you must check, don't assume that the patient understands how to use it. You must check, you must watch them and correct them. Let them show you how they use it because this is the most important thing, the inhale steroids every day and their inhaler technique. So I'm going to stop there. Um And of course, happy to take any questions, pieces on mute or put them in the chat and I can ask, uh Austin. Yes, I can see a hand raised, please. But is there a genetic factor? Uh having some people are more susceptible to that the estern attacks regardless of its cellars use. Like as you said, some, some people have asked them persistently there. Uh No uh no irritant. Nothing. But does that have to do a little a genetic? I'm sorry, I can't, I can't really hear you very clearly close. Okay. I'll try it again. Uh You said one of the uh some, some patient's have the persistent person regardless like they're allergic or they're not allergic, but they have extra mind their entire life and they have to treat, we have to treat them. They can't because, but is there any genetic factor to it? Its intentions that they will have this system attack? Yeah. So, so genetically, so heritage like, so like all diseases, um there is always a genetic predisposition and so, you know, many people who have, who developed asthma in childhood, they will have that genetic predisposition. But even a patient who developed asthma adulthood will have had that genetic predisposition. But the trigger for the genes to be switched on only comes later from a different environmental trigger, a specific virus, something else that's happened that in some way interact through the genes for that gene to suddenly be switched on and now the patient has the disease. So there's definitely genetic factors, there's genes that have been shown to be associated with asthma risk. Um There's nothing we can do about the genes. Uh And you know, even if you have the gene, it doesn't mean 100% are going to develop asthma. It just means that you are increased risk of developing asthma. Is there something as uh the order of a child? This for a bit of Children are born also picks because I don't know whether I'm service tried, but I read in some in German or article in which uh used to say that the first point child are more susceptible of having the estimate compared to the competitive siblings who will come after. And uh the ruler areas, the first one child might have a submit. Uh is that the opposite in the urban? It was, I don't know, I can't even remember what is the proper order, the proper. Uh So the opposite, what do you say the opposite? What? Sorry, like in a ruler area, the first born child is not prone to have. Uh and it's maybe the siblings will going after the first born child may be more prone to estimate and it's quite opposite in the urban areas in which the first born child. Yeah. So, so in terms of allergy and asthma, there's data to suggest that the lack of pathogen exposure is associated with increased risk of allergy asthma potentially. So where a child as siblings, they are more likely to have more infections where a child goes to a school, as opposed to home schooled, or if they live on a farm where there's animals and different pathogens exposure and triggering the immune system, they are less likely to develop asthma and allergies. And this, this is what sort of underpinned the hygiene hypothesis. The idea that in a world that's to clean your immune system doesn't get triggered enough and you don't and and therefore you start developing exaggerated immune responses like allergy and asthma. Any other questions about meant adapting? So rather of the fittest or evolutionary adapting that music. So I, I didn't hear that. That was, that was another question. I didn't hear it. Sorry. No, no, it's, you know, I was saying that it's like the. So I will look the fittest stories whether one doesn't gives you mean so strong that it's, it's the, the, the the immune system has evolved over many, many tens of thousands of years and all of a sudden in some places, it's not being utilized in the normal way and it would appear that there is increased at levels of allergy as a consequence uh of that, any other comments or questions at all or is it a dog barking in the background? I know you've got another, you've got an interesting mix today. You had uh ophthalmology and looking back you've got cardiology uh, this afternoon, um, with no other questions, I'll leave it there. But thank you very much and I hope it was helpful and best of luck with everything. Thank you.