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Um okay. Good morning, everyone. My name is Caroline Delahanty. I've been doing regular sessions, uh, since October, twice a week with you. Last week I talked about asthma, so I thought I would keep with the respiratory theme this week and talk about cystic, cystic fibrosis and then more chronic lung disease and chronic lung problems on Thursday. So let's start with cystic fibrosis. Okay? I'm going to give you an overview. I'm going to talk about how we diagnosed in the clinical presentation, but I'm also going to go on to talk about the new developments, which are probably very interesting because we are improving survival of Children and adults. Facist, ick, fibrosis. Uh, this is our hospital, but basically, I wanted to highlight that there are two consultants supported by a full multidisciplinary team. And we've been running cystic fibrosis service. I'm not part of that team, actually, but I'm just talking about it since 2011. I think what's important is that it is a multidisciplinary team to get optimal care. Does not only medical, you require specialist nursing support. Physiotherapy support is extremely important. Dietetic support to manage the pancreatic enzyme replacement and optimal nutrition. Make sure they're getting adequate fat soluble vitamins because remember, they don't absorb fat without Creon replacement, you need the support. The pharmacist. You need respiratory physiologists to measure lung function frequently to make sure that they're not having subclinical dips in lung function, which would make you think of looking for secondary infection. Looking at the physiotherapy technique, we use clinical psychologists because it is a lifelong illness and it can have profound psychosocial effects on the family. And actually, data management and secretarial support is very important. Do we currently have We sit in between about 40 Children. It is the most common autosomal recessive condition in Caucasian people. Um, the the current age ranges can they can present we pick them up at birth if they have the common genotype. Because we do screening on immunoreactive trips in, I'll come to talk about all these things so they can present at any age, we don't detect everyone through national newborn screening services. You will miss the less common genotypes. And actually, we find that for some reason it's quite often in a socially deprived population. I'm not quite sure why that is. Okay, so what is it? It's the most common, serious inherited condition in Caucasians. It's also so more recessive. We say that across Europe, one in 25 people are carriers, and it is one in 25,000 live births. It's a mutate genetic mutation around chromosome seven, but there's thousands of different mutations, and that's one of the problems. The most common mutation in 75% cases is Delta F 508, which is the one that most of you will hear about. What it leads to is an absence defect in the chloride channel. So the cystic fibrosis trans membrane conductor regulator, which then leads on because chloride can't move and sodium moves with chloride. You have faulty chloride and water transport, which leads to the thick so sticky secretions and the multi system problems. Okay, let's talk about the pathophysiology. So on the right hand side, my screen I have a normal chloride, a sorry cystic fibrosis transmembrane, regulator of the chloride channel, with nice folding and normal folding, which is allowing the chloride irons to move from inside the cell to outside the cell and water will move with that. If you don't move your chloride you don't get the water movement, and therefore you have lack of water on the surface, which leads to thick, sticky mucus building up on the outside of the cell. Okay, so the defect is all about chloride iron transmission across epithelial cells. And that's not only respiratory lung cells. That can be the liver. It is the GI tract. It is the pancreas. It is everywhere. So you get dehydration of surface fluids. Everyone thinks about the sweat test or licking the child to see if you think they're salty. No one ever goes around licking the child anymore, I hope, but certainly the sweat test is abnormal. Salty sweat. So the water sodium balance is incorrect, and you get this dehydrated surface, and you have thick mucus that's clogging tubes, tubules and dots. The problem with this disease is it's life shortening. We are getting better. In the 19 fifties, the life expectancy was two years. Now, with the current average life expectancy is 47 years. But it's improving over the last decade or certainly over the last five years. We have the genetic modification drugs that are coming into play. They are very expensive, and there is still ongoing research. Otherwise, you are heading for a cardiac lung, heart lung transplant. But you have to take in the nutrition, the liver, everything else. So what is the path of physiology? Sorry, I'm probably repeating myself, but let's think again about it. You can't excrete chloride in your airway. Epithelial cells from the cells into the loom loom in through cyclic A M A M MP mediated CFTR channels, so chloride is trapped inside the cell. Sodium follows chloride and water follows sodium. So your sodium your chloride and your water are inside the cell are not providing that lubrication on the extracellular wall. So secretions in the Lumen become viscous elastic. They're harder to clear. They're retained, and we're talking specifically about lung here, but they obstruct the airway, but they would equally obstruct the the liver and cause cirrhosis is the classic one that we think about. So the airways, um, the liver get obstructed. The exocrine pancreas gets obstructed, so this is all coded from being remember. Genes have d n A. They translate. They dictate what proteins are produced by the body through messenger R N a. And then the protein coding being produced. If there is a defect in that d n a code, an abnormal protein is produced, which is what the problem is here. This chloride transporter protein regulator, cystic fibrosis transmembrane conductance regulator is abnormal on the cell surface. There's multiple types of effects. That's the problem. It's not just one fits all, and therefore one genetic manipulation will cure all, so we'd classify it into several classes. This is split over two slides. Class one is obviously there's no functional protein created, so they'll present with quite severe symptoms. Class two. So that's 22% class to the protein is created, but it miss folds, which doesn't allow it doesn't move to the cell surface, and it doesn't traffic up to the cell. We call it a trafficking defect. Class three is when the protein is created. It does move up to that cell surface, but that channel gate and if you think about it, is a gate to open to allow the chloride to go through doesn't open open, and that's defective channel regulation. So the protein is there, the proteins on the cell surface, but it can't open its gate, so there's lots of different genetic modifications past four. Again, it's created. It moves to the cell surface, but the channel function is faulty. And again, you can't get the get the channel conductance of the chloride iron. And there are other forms. We can have reduced sensitive synthesis in Class four, and we can have it's there, but it just doesn't work properly. So you almost need more of the protein for it to work. But it is there. These the Class Six is, are the ones that tend to present later in adulthood because it is there. But they just don't quite have enough of it. So it's slow progression of the disease. Okay, let's talk about the organs affected. I've mentioned some of them, uh, shouldn't have showed you this slide. Actually, I should have asked you. So we have the lungs. We also have the Sinuses, which is why we here in screen young Children to make sure that they don't become death from glue, ear and mucus. Plug in. You can have the pancreatic problems. We think of it as an X, a crime disease, that we can't secrete the pancreatic enzymes because of the mucus difficulties. But it can also lead to diabetes in that you will get scarring as a result of the inflammatory burden that set up liver. We get cola Stasis. We get portal hypertension and Children and adults may need liver transplants. We have the gut problem with malabsorption from the pancreatic lack of exit cry. Nine enzymes. They can't re absorb fat so they fail to thrive. But more but equally importantly, they don't absorb the fat soluble vitamins, which are important, obviously, for vitamin D and your bones. They're at risk of osteoporosis, so you have to think about their fat absorption. It can affect the reproductive glands again. You need moist mucous to allow production and travel of those ovary in, oh, eggs. Sorry into the correct place. Travel of the semen into the correct place the sperm. So all these things and you can have a sweat. You can have excessive salts losing, Um, your sweat glands can become locked, so you're not excessive salt losing. But your sweat glands can become so so we have reduced surface water in the lungs leading. Everyone thinks of it mainly as a lung disease, but it is multi system, as I've just said, but as a result of that thick, sticky mucus, Children cannot. The cilia can't beat properly, and the mucus and bacteria cannot be swept up. And ex expectorated, you cannot clear your mucous. You can't have an effective cough because you're sillier are not brushing and naturally sweeping. We keep our lungs clean and clear by the sillier, moving everything all the time. We don't even realize we're doing it so bacteria can get stuck in the lungs. Mucus can get stuck in the lungs, causing bronchiectasis, causing scarring. And obviously you can have exacerbations of pulmonary infection. You can get bronchi. X issue can get hemoptysis from the inflammation. And overall, you will get poor lung function if you do nothing and you will eventually get respiratory failure requiring that lung transplant one of the problems we have in Children if they're not very good at coughing up sputum for us. So what we have to do is put a swab at the back of their throat and actually make them cough. So we get cough swabs because they won't cough and spit it out. They will cough and swallow, so we use regular cough swabs, so they these Children are seen every three months, and every three months they will get a cough swab as a minimum if we want a better sample. If we get mixed growth and we're not quite sure are we hitting Flora at the back of the mouth, we may have to do some induced sputum. We would give them concentrated sodium nebulizers to make them cough to make them to get more mucus moving. We may, in fact, even go to bronchio al viola lavage. So we actually send all the sputum's to our microbiology. And obviously they're appropriately labeled to make sure they look in detail at them as we want to know things like aspergillus as well. And there will be a weekly meeting to discuss the results to make sure you do not miss adverse microbiology developing. Okay, during the first year of life, you often see Staphylococcus aureus developed, which is why the Children are given prophylactic flu clocks is selling to try to prevent this. If we see him awfulest, we may go on and give them prophylactic antibiotics to prevent or treat haemophilus. Obviously we don't like Pseudomonas very difficult to eradicate once it gets in there, and we don't like a lot of these other bacteria that get in and it comes into segregation. So if you have a cohort of Children that have sued ammonia's you must or MRSA, you must keep them away from the other CF group because you don't want them cross colonizing and share in in the clinical waiting room. We don't allow them to sit in a waiting room. They come into clinic, they go into a room on their own and people go. The team goes to the child and family. That child doesn't move around because we don't have time to clean the rooms that often. So we put them in one room, and then that room is cleaned when they leave, in case they have developed one of these adverse bacteria, such as the Pseudomonas Group that we don't want spread to the other Children. Ideally, what you do is you have Pseudomonas colonized Children clinics and you have non pseudomonas colonized Children clinics. You need to think about Mycobacterium the atypical mycobacterium because you will get abscesses forming and aspergillus. If the child gets it is very difficult to eradicate again, but it is something that we look for and it will deteriorate lung function, and we will need to put them on to antifungal treatment. We advise the families about avoiding high risk environments for acquiring bugs. And that's not major lifestyle, isn't it? You're you're basically telling them you don't want them to go into a busy area. You don't want them waiting around a busy waiting room, a crowd ID room. You want to think about their schooling. You don't want them in high risk environment, so you are sort of semi isolating them a little bit. This a lot of the voiding of higher of and separating in hospitals and making sure that you don't mix. The patient's came after there was an outbreak. It was in Glasgow, actually, and like obviously, I'm speaking from a Scottish hospital. But there was an outbreak in 1992 where pseudomonas basically spread amongst the CF Patient's, and that was because at that point they weren't separating them in clinics and they were allowing them to mix. And obviously, if you're a family and you meet someone else with another with the same disease, you tend to get together. But you have to watch your only mixing with the people that don't that have the same bacteria flora that you have. So degradation was then introduced after 2000 when it became clear what was happening. And we saw that the incidents of Pseudomonas spread in the group dropped dramatically, as opposed to, you know, 20% of the Children sitting with pseudomonas in their cough swaps. In this beauty, um, we can have it by separation, so in practical, it's designated clinics. The waiting rooms aren't used. They walk into a clinic room. We don't allow them to mix when we send them for X rays, and there's strict policies for in patient's there. In single rooms, they're not allowed to come out to the playroom. They're not allowed to go down to the coffee shops and the canteen, and we try to minimize mixing outside the hospital. It's absolutely awful when you think about it. So if you wanted to go to the cinema, you've got to really think about that because that's mixing and is that recommended? We would say no, that we would say, Well, can you buy the film in and have a family night in? It's very difficult. We do keep. There's always a debate about should you give Children intravenous antibiotics, bringing them into hospital, or teach them to give themselves intravenous keftab 13 and to prom izing at home. So every three months as a rule, these Children, particularly if we find they are susceptible to polleny exacerbations. But we actually do it in the first year of life, actually, almost as a preventer, you bring them in to hospital for two weeks and you give them intravenous antibiotics. Obviously we need to have. We tend to use long lines as much as possible, so we put them in. We remove them at the end of the two weeks. But if access becomes an issue, eventually these Children will go on to have permanent central venous catheters placed, and the family will need to be taught how to do that. We do try to still send the Children to school, so they're coming in basically for intensive antibiotics and intensive physiotherapy. But we send them to school so a taxi takes them to school every day. Or sometimes what happens is we keep them in hospital for the first week. Then, if the parents are competent and intravenous antibiotics. And the lung function is reasonable. We allow them to have their home intravenous antibiotics at home the second week. Zero therapy is the most important thing, So yeah, and I'm showing you pictures of our physiotherapist, but at the top, we actually have a picture of a mum doing it. These Children are breathing into masks. The masks look a little bit unusual because they've actually got a positive end xperia Torrey Pressure valve on which is making them harder to breathe I/O of. So we we are forcing them to take deeper breaths to try it to improve and open up the LVO lie at the at the basis we're making them breathe harder. This isn't normal breathing. They've got to breathe out and click that machine, which is a valve, and it will have five centimeters of pressure on it. So their breathing out against normal air plus five centimeters. But activity is important because if you exercise people by boxing jumping on a trampoline, you know the little the toddlers like going on a tramp, it they like, jump in. If you get them to jump, you can actually get them to, you know, work up. Breathe deeper because exercise makes you breathe deeper, and then you're likely to cough and clear and have an effective clearing of mucus session. Okay, I'm going to go on to liver. So 5% of the pediatric population will have significant liver disease, so they will develop thick mucus, sticky secretions that block the billary and hepatic dots. You don't drain by you. Don't drain your parasites, and that will then lead to scarring and inflammation. Initially cholestasis so bile salts being stuck You So you're going to get bile salt malabsorption, But eventually you'll go on to get cirrhosis, portal, hypertension and viruses. And at the point you develop portal, hypertension and viruses. We're discussing transplant because you're at risk of hemorrhagic death. Basically, aren't you if your virus is burst, so once you've got portal, hypertension and viruses will be saying we need to list you for transplant X. A Quran, obviously, to go back to liver. Actually, you'll support liver with nutrition. You'll give them er see deoxycholic acid as a bile salt thinner to try to move the bile salts, and you will give them fat soluble vitamin replacement which they're already on, anyway, to make sure that they have adequate fat soluble vitamins. Because once you can't get that Bilin, you're not gonna You're fat. Absorption gets even worse if you go into the pancreas. Obviously pancreatic. Uh, Stuart, we measure stool khaimah trips in. So there's a lot more to this topic than what the slides suggests, but you always have to limit. So we measure fecal chymotrypsin as a measure of the enzyme excretion, and you actually give Children pancreatic enzyme replacement. The brand we uses Creon, but basically you're given them pancreatic enzyme replacement because it can't. The enzymes are not excreted because the thick mucus you've given them replacements so that they can absorb the fat in their diet. So you want them on a normal diet, basically or a high fat diet, but only a high fat diet to match their Creon replacement. So you have to match it. You know, you look at their their diet, their menu, and you match how much fat is in that meal and therefore, how much enzyme replacement they need for that particular meal. How many capsules they have to take. It's not a liquid. It is a capsule, Um, they have to take so they have to start calculating, because if they under do it, the fat will be excreted and fatty stools are very offensive. The Children won't want to go to and use a school toilet. If they've got very mallow due to fatty stools, they float. They don't flush away. Remember, it's steatorrhea. They're very offensive, and they're floating and difficult to flush. And these are questions you're going to be asking in clinic. Are you seeing fatty stools? Do your poos flush away normally? And if they're not, you know, let's look again at your diet. You're taking enough. Creon, do we need to up it? You know all these things, but remember, it's the digestion and absorption, and if you've got problems with that, you're not going to thrive. You're not going to grow. Growth is so important. The diabetes side is interesting attics. It doesn't present the way classic diabetes presents with polyuria polydipsia Weight loss is more insidious on onset, um, again, it's the sticky mucus, scarring the pancreas and damaging the islet cells. But it's, uh, insulin is still being produced. It's not that they can't produce insulin at the beginning. Obviously, eventually they may scar so much that they won't. But at the beginning, insulin is being produced. It's just it's not actually getting out of the pancreas because the sticky pathway it's getting stuck there so they get slow release. So we do an annual oral glucose tolerance test to pick them up early. Because remember, you don't want the side effects of insulin of diabetes as well. You've got enough on your plate without putting yourself at risk of renal disease and retinopathy. This is an interesting one. This X ray is showing you fluid levels, which is telling you that this bowel is obstructed so the child would have come in with abdominal pain. Vomiting because they're obstructed are not passing stool, okay, and they've probably got a distended abdomen as well. They can progress to complete obstruction and perforation, so it is an emergency to get this disimpacted. The problem is, what you've got in there is not only feces. You've got a lot of sticky mucus that isn't traveling down the looming of the bowel, so it's quite difficult to wash out that mu mucus, so we tend to use gastrograph in Actually and wash. They have to drink liters of a washout solution in addition to intravenous fluids to make sure they're hydrate well hydrated and get the bowel hydrated. So fluids, laxatives, But they can need to go to proper, um, radiological washout with gastrograph in, but very painful. Do you want to do an annual review? Do you know, I've suddenly realized I've not got video on, but never mind. Okay. Okay, So you want to do an annual review? And in that annual review, you take the opportunity to reassess where you are with investigations. Obviously, you go through all the clinic questions, but you're doing that every three months. How are their lungs? If they had any cough, if they had any chest infections, you know, have they got all their vaccinations up to date? If they had their annual flu jab their annual coronavirus job at the moment, um, you know, how are their bowels? Any pale stools? Are they okay? Any steatorrhea? Any pain? Any intermittent constipation? Because you don't want them to be constipated. You want to keep it moving, but then you're going to go on and do they get a chest X ray every year, and they also get an abdominal ultrasound to look at the liver and the spleen. You're looking for cirrhosis. You're looking for portal hypertension. So that ultrasound has to have Dopplers done with it because you want to measure the pressures in the portal venous tract system. You're going to do formal spyrometry. We do that every three months anyway. But you absolutely want to do detailed lung function. You're going to review all the microbiology, and at this point, you do induced sputum for acid fast acid fast bacteria. So you you screen for TB and atypical mycobacteria. You must do all your bloods, including your liver, your vitamin levels, and look for us but jealous in the lungs. Through looking at a specialist teachers we screened for diabetes. With the new oral glucose tolerance test, we do a bone scam, a dexa scan to make sure that they're not developing vitamin D osteopenia because that's a fat soluble vitamin. And there's a formal review of all the medication. Is there anything that we can stop? Do we need to add nebulizers to the chest? What about their prophylactic antibiotics? Are they correct? And you go back over there. Physiotherapy and exercise regime in addition to the clinical examination. Uh, no. And so I put here on it. Doesn't seem to want to let me move my slide. Oh, no. Oh, right. Sorry. OK, there's then a discussion and the parents receive a written written review. Let's pause and go on to talk about diagnosis. Gosh, I'm going to run over, aren't I right? Okay, so the clinical presentation can be with meconium ileus in the newborn period. Any neonate coming in with meconium ileus, you will go on to do a formal sweat test and full genotyping. You will not just do our newborn screening because you remember the newborn Skilling in can miss some of them. You can fail to thrive if it's the exocrine pancreatic function bank reat ick enzymes impede in fat malabsorption, child presenting with significant recurrent chest infections. You would think about it clubbing you would absolutely screen is on our list. And in the UK, we seem to have a high incidence In Caucasian Children, there's a high incidence nasal polyps. I'm showing you a picture of a nasal polyp child presenting with steatorrhea or rectal prolapse rectal prolapse, which is significant, automatically goes to cystic fibrosis screening. It is pathological. Since 2003, however, we have been screening. We've been doing immunoreactive trips in on the heel prick Guthrie test. So the routine national screening, which includes things like hypothyroidism, also includes, uh, cystic fibrosis. And you'll we get about 25 new new Children a year nationally in Scotland. On that basis, it's sensitive. If you're an early diagnosis, early treatment and therefore better long term outcome. A disadvantage is, uh, it's not a perfect test. You are going to potentially pick up some carriers. And if you're not symptomatic, you're telling the parents that their child may die as a young adult and has a lifelong illness when they're looking at this beautiful baby thinking these doctors really right, and it can affect maternal bonding and cause a lot of psychological stress for the families. Okay, the definitive test is a sweat test, so you induce sweating with pillar car pine. You have to correct, you have to collect a volume of sweat, and then you measure the sodium, and if the sodium concentration is too high, then they have cystic fibrosis, and that sodium. Concentration is too high because the water balance isn't right, so it's concentrated. Okay, we would go for a sweat test if we are clinically suspicious, even though they will have had screening. But we also confirm screening diagnosis with the sweat test and full genetic mapping. Uh, as I said, the sweat test isn't perfect. I'm going to skip on to this, actually, because it the sweat the problem with the sweat test, it can pick up carriers single CF gene identification. Okay, let's talk about the new development because this is interesting. So we've been trying to genetically modify cystic fibrosis for years. So we want to replace the faulty genes with normal ones. Okay. And the initial focus was actually on doing nebulized medication to use nebulizer as as a rector to carry the gene to the lungs where it's really needed. But actually, we've now moved on to gene therapy modifiers, and they're listed down the side. I'm going to talk about them in turn a little bit, which are oral medication that the Children can take. What we're trying to do is obviously correct that defect in the chloride channel. The three types the modulators, ones that the one most commonly used is either capital. It's been around the longest. None of these been around very long, actually. So they're making the Cicis fibrosis transmembrane regulator more powerful. They keeping the gate open to allow the chloride to move through. Okay. Or we can have a gene modifier, which is correct in the protein production. So it's helping the protein form the right shape and move to the surface wall. And I've listed Lumacaftor, Tezacaftor and Ellis sick after. Or we can try to modulate by amplifying and increasing the amount of protein if you're not producing enough. So if you produce the correct protein, but you just don't produce enough. If we can amplify your production, that will help you. So it depends on what type of CF gene defect you have, of which drugs and which ways you want to. Jeanne. Improve them to either want to open the gates because the chloride channel regulator protein is in the correct place. It's on the surface war, but the gate shut. Open it, or the chloride channel doesn't want to move to the surface wall, so you want to make it form the correct shape so it can insert itself in the correct folded way into that surface wall. And sometimes then you need to give them a gatekeeper to make it open as well. Or you want to increase the amount of protein produced if they're produced in the right amount. But just not enough. Okay, Have a catheter is probably the one that's most commonly used around Europe. Very expensive, so I'm keeping an eye on time. It is the mutation G 551 d, 5% of the cf population. So not a huge amount. The gating mutation. So the chloride channel regulated protein regulator is at the wall, but not opening it opens it. But look how much it costs. 100 and 68,000 per patient per year. 250 lbs a tablet. So I'm showing you the proteins here, the regulator, there at the wall, we're opening that gate, which is shut. We're opening these gates to allow chloride to move through, so that's what you're trying to do. The evidence base came from strive. It was a 12 year study, so 80 for Children have the study group. 78 people had a placebo for 48 weeks, and they measured their lung function and showed they gained 10%. But 55% of them were less likely to have a mild pulmonary exacerbation. They gained weight. They thrived. They had an improved quality of life measure. And actually, when you did a sweat chloride measurement, a sweat test, it was reduced. Okay, then they looked at the younger Children, saying, Well, is it useful when the disease is established, or should we get in early? But they looked at very small numbers but showed the same results. So actually there now enroll in 2 to 6 year olds as well to see if it should even be given under the age of six. Okay, we then have other drugs. Either capture, loom, a cattle combination or Camby is what it's called, So this is quite a popular one in theory, so it's bringing the protein channel to the cell surface, and it's assisting the opening of the gate. So the group is these Delta F 508 and remember, 75% of CF Children have Delta five F 08, so they have this combination problem. The evidence is less compelling, though. There was a 2.5 to 3% increase in FPV one, but there was a 30% reduction in pulmonary exacerbations. They didn't report on sweat chloride, and this early concerns about side effect profile and it's expensive. Then other drugs. The combinations again your Delta F 508 if they're heterozygous so they will have a second gene for CF, so they're not pure Delta F 508. So same kv ivacaftor and Tezacaftor or or Caprio is the best yet, which is a triple combination drug. Again, it's helping the Heterozygote. It's costing 230,000, but it has been rolled out in the UK um, greater than 12 year olds later, 2019, but greater than six since 2 February 2022. So it's a moving market at the moment and moving intervention on being therapy. But if we bring this in perspective, this is what our poor Children were doing. The boy at the top, sitting on a hospital bed, is trying to do some induced sputum. That's what this is. He's trying to suck out, um, induced sputum, us. Spit it into that jar. He has multitudes of medication to take as a minimum Creon. But he will have his chest medication. He has multiple hospital appointments. You can see he's got a port. A cath in for his intravenous antibiotics. He's having regular nebulizers in his life and they are doing physiotherapy at least twice a day. So his life is not normal. He has to think about his diet. This is our dietician. They have to think about what do I eat? What am I allowed to eat? And when I eat, how much fat is in it? Because I don't upset Upset my stomach with diarrhea if we can cure it. This is going to be a day in your life, isn't it? You are at school regularly. You don't miss it. You can play football and you can dance. I'm actually going to stop there and I'm going to stop caring and I'm going to come back to see if there's any questions. Hi, Doctor. No questions at the moment. If anyone has any questions, please feel free to a mute or right in the chat. Nope, no questions. Okay. I've obviously bamboozled. Dual with cystic fibrosis. Okay. Well, thank you, Doctor. That was pretty clear anyway. I mean, there's a lot of information to take in. In the UK, we would always have cystic fibrosis. Children on the ward. They are because they're planned. Admission's. So they have to You almost wait for two of them to leave, and then you bring another two in for the They're sort of intravenous antibiotics. And there pulmonary exacerbation. Okay, I shall leave you then and go. Thank you, Doctor. Thank you for your explanation and your time. And if anyone has any dying questions before we end the meeting, please do ask, but yes. The feedback link is in the chat, and I will post a certificate. E. Thank you, Doctor. I have to see you soon. Thank you. Bye bye bye.