 to the Brian Drowns this morning. Can you hear me? Yes. So it is a great joy for us to welcome Caroline Klaver this morning. Caroline is professor of thermology, epidemiology, Erasmus Medical Center Rotterdam, and at the Red Bound University Medical Center in Wagen, both in Netherlands, and as well at the Institute of Molecular and Clinical Ophthalmology in Basel, Switzerland. Caroline studied medicine and clinical epidemiology at Erasmus University in Rotterdam, and she received her PhD with honors and took several years of research at the University of Iowa and Columbia University in the US. Caroline is known to be multi-talented. In addition to conducting fundamental experimental research, she leads large-scale epidemiological studies and consortiums on eye diseases, but it is also a clinician. With such a broad interest, she really builds bridges between fundamental and epidemiological research and clinical practice. Right now, as a clinical principal investigator and research principal investigator, she leads a group of 40 persons performing genetic epidemiological and clinical and functional studies on various eye disorders. Caroline is actually fundamental in establishing and conducting several consortia to name the European Eye Epidemiology Consortium and the Iris Consortium. Her research lines cover myopia, age-related macular degeneration, glaucoma, and retinal dystrophies. And Caroline and her group have discovered multiple eye genes and environmental exposures, developed prediction tools for blindness, and is now performing functional studies, lifestyle studies, and imaging studies. Caroline, unfortunately, we cannot have you here in person today. I can say that you are not only an impressive scientist, but also a very funny and enjoyable person. And we are now looking very much forward to your lecture on myopia, and we cannot wait to hopefully meet you in person again soon. So take it away. Thank you for being here, Caroline. It should be better. Thank you very much for your kind words. And so we are used to meeting each other everywhere in the world. But right now, we will have to do it. You being in Utah and me being here. So I feel a bit envious because I hear that you could go outside and have vaccinations. And we are just hearing that we have to stay inside in the evening. And things are really a little bit grim here. So yeah, would like to visit Utah another time. But right now, I will talk about our progression in myopia. And I'm happy that you give me such a long time to talk so I can cover quite a broad field in this sense. These are my disclosures. So we are located in the Netherlands, so quite close to Germany. I'm actually located at several places. But most of my research work comes from Rotterdam. And this is actually the Christmas card of my research team, who I haven't seen for a year, but just on teams like everybody else probably. So indeed, we do cover quite a lot of research lines. I started doing myopia research in 2008 because we had many refractive aerodate and we were just beginning to look at genes. And we have some more cohorts. So what are we covering? We actually have quite a lot of studies looking at genes finding. And now we're doing some functional studies. We also have quite a bit of lifestyle data in our older people, but also in the younger ones. And we are starting clinical trials and going to the clinic to perform myopia control. In Rotterdam, we indeed have many cohorts. The Rotterdam study started in 1989 already. We now have three cohorts finished. We are working on a fourth cohort. And we have follow-up on the longest one, about 30 years. And refractive error was already one of the first variables that we collected. We also have a long-running children's cohort study, which we call Generation R. And that started in 2000, 2004. The children are right now 17. And we have been collecting refractive error data and OCT data, actual length data on all of them since the beginning. We also collected a high myopia case control study. So myopes, who most of them are more than minus 10 diopters. And we are right now looking into their families. And we started treatments at European about 10 years ago. And I will tell you a bit about that. So we also do a lot of collaboration work, mostly to look at genes. We started the cream consortium more than 10 years ago. And we indeed are involved in E3, the 3CC in iris. And we also work with companies in the UK Biobank. So what I will talk to you about today is about the growing problem of myopia. Why is it clinically so bad to have myopia or severe myopia? What can we do to prevent the onset? And what can we do to treat progression? And specifically, I will focus on who to treat, when to treat, how to treat, and when to stop. So in 2019, the beginning, we worked with the International Myopia Institute to come up with a set of rules for myopia, myopia research, but also for myopia clinics. And we, excuse me. So we came up with a set of classifications. So myopia is more than minus 0.5. High myopia is minus 6 or more. And pathological myopia is you do have to have structural retinal changes. We know that refractive error is very closely related to actual length, particularly in the higher degrees. And mild myopia would be around 24 millimeters or more. High myopia is 26 millimeters or more. So of course, I don't need to tell you this. We know that the problem in Asia is really significant. 80 to 90% of the 20-year-olds have myopia nowadays. About 10% to 15% have high myopia in that population. We in Europe have 50% myopia in 20-year-olds. And we are right now approaching 5% to 10% high myopia. We know from the extrapolation studies that in 2050, half of the world will be myopic and 10% will have high myopia. And this paper we recently wrote as an editorial to a Chinese paper showing that during the Chinese confinement, which was really, really strict, there was an increase in the myopia onset among the very young children, 6, 7, and 8-year-old. And no doubt, we're going to see the similar trends. So the onset of myopia is shifting a bit. It used to be, and this is actually an old study, around 13 years was the medium age. And we know that when you have an onset under the age of 10, you are much more likely to develop high myopia as an adult than when you have a later onset. So it's really the school age that we should be worried about. And this paper we wrote some time ago. We looked at the visual consequences of refractive errors and we did this in the Rotterdam study. And what it comes down to is that one in three high myopes will develop severe visual impairment in both eyes. Severe visual impairment would be 20, 70 or worse. And it's really very much related to the actual length of these people. So here in different colors, we have the actual length. So the red line is actual length of more than 30 millimeters. And you see this really goes up after the age of 50 and it actually goes up to 95% as a lifetime risk, both high severe visually impaired. When you see that the lower refractive error do not lead to such severe visual impairment, but anything beyond 26 millimeters does. So 26 millimeters is actually the threshold for severe visual impairment both eyes. And why is that appearing with age? We know that the collagen disappears with aging and when your sclera is already that thin at the back of the eye, it's much more vulnerable to these aging changes and you develop your staphylomas. And this can be look really horrific in the very severe highly myopic. And you know, when you develop these staphylomas, you don't have enough retina to cover it all. That's most of the reason why they are being of becoming severely visually impaired, but also the, you know, the well-known causes as glaucoma, retinal detachment and combined mechanisms were important causes. And a bit to my surprise, actually cataract in this population was too because a lot of ophthalmologists were a bit scared to operate the cataract on them. And the myopic macular degeneration can have all kinds of forms, the more focal atrophy, more diffuse atrophy, you can have retinal scises, retinal cysts, retinal holes, CNVs. And what you can see here is that it really is related to your actual length and it is related to your age. So does that actually mean if that occurs in high myopia that the lower refractive errors are off the hook? So we looked at the complete literature that was out there and we did a meta analysis to see what are the risks for all the different degrees of myopia. And here we are looking at the risk of myopic macular degeneration. And you can see actually that, how is this? So that it actually also happens in the lower degrees of myopia that it doesn't lead to severe visual impairment on both eyes yet. So here a moderate myopia minus three to minus six already has a 34 times increase of developing these changes. And even low myopia actually has some chance. We know that particularly a CNV, often in the end you cannot really find the Fuchs-Fleck and everything turned into atrophy. Other complications are retinal detachment. I think we all know that. How high are the risks? For low myopia it's actually already three times increased. Moderate myopia minus three to minus six, it's almost nine times increased. And high myopia it's 12.6 times increased. So significant numbers. And I think the people that do VR probably are already seeing some increased trends because we are in the Netherlands. So we looked at retinal detachment prevalence and in 2009 and then we compared that to the prevalence in 2019 and these are data from the different clinics. And you can see over that time period, of course also the people change during that age time but you can look at population, total population and do trends and do expected trends. And here I'm showing you this in the dotted lines. This is observed in 2009 and from the population frequency we have an expected line also with the little stripes. And then the solid line is the actual frequency of retinal detachment in that time. And you can see it's actually much more than expected. It's an increase of 44% and I'm quite sure people all over the world are seeing this and it's mostly due to myopia. So what about the risk of glaucoma? That has been around. I think most people know it's still very hard to diagnose real glaucoma progression in a myopia because the optic disc already looks so different. But when you look at course over time usually you can pick this up. Low myopia increases the risk of glaucoma 1.6 times and moderate and high myopia are actually kind of similar. They increase the risk of glaucoma three times. What about cataract? Cortical cataract does not have an association with myopia. Nuclear cataract increases the risk about three times to three times and the subcaptular cataract increases it in high myopia up to 4.6 times. Now I thought at this important day that you are changing presidents, let's put in some president statements. And this one is from the founding, one of your founding fathers in the United States. I think of a clever man because with all these severe consequences that we have not much, we don't have much to offer these patients. I would agree with him an ounce of prevention is worth a pound of cure. So what is that the view on recent presidents? So some presidents have some different views on prevention and there are coming presidents that would like to more stick to science. So hopefully the prevention, particularly for these kinds of traits will have more attention. So what about near work, the lifestyles? And this is a quite a recent paper. So it was quite clear from the beginning that outdoor exposure was protective, but there was always something iffy about near work and what the data were really significant. And to measure near work adequately is actually quite hard. And people have done it with questionnaires, parents fielding questionnaires, children fielding questionnaires. And it was not very reliable data. And I think this study, very large study from China shows more significance because of the large numbers. Continuous reading, watching TV within a meter and having a reading distance very close within 30 centimeters are significant risk factors in this cohort. And we did the same children's study. And I will come down to the conclusion of this slide. We found that already at the age of six, the children that are becoming myopic are more indoors. They have lower vitamin D levels. They spend more hours on screens and they indeed hold their near work at close. So what exactly is that relationship between reading, computer use, reading distance? So this is a bit of a comprehensive graph that we made from our own data in generation R. And you can see the computer use at nine here at the access right here. Reading time and distance over here. And we had less than five hours, more than five hours and then less than 30 centimeters or further away than 30 centimeters. What it shows is that it is basically the children that read a lot and do it up close and then have computer use more than seven hours per week are the ones that are most vulnerable to develop myopia. So what about outdoor exposure? The data is pretty convincing. And I often get questions from parents. So how long should the child be outside? And there's not really very good data from one study. So people put all the studies together and looked at the outdoor exposure in the different studies. And they came up with about two hours per day that is needed to be on the protective side. We also looked at this in our generation R study and we see when you have two hours per day or more, you grow like an emitrop. So we know that serum vitamin D is a good proxy. It's a good measurement for outdoor exposure. So we just looked at our vitamin D levels in our children. And we actually see that the children at six are only outside enough in the summertime. The rest of the year actually they don't come up with the right recommended levels for vitamin D. So particularly in Asia, they've done intervention with outdoor exposure at schools. And here you can see that it works. So 40 minutes per day extra outside their regular scheme and their regular scheme in China was usually less than an hour outside. It actually helped. So the intervention group had a lower incidence of myopia and they had a lower progression rate. So I see patients, I often have to come up with the practical rule. And so we have come up with the 2022 rule because we know near work is a positive factor, but it's actually the continuous close work that is most risky. So we tell the parents and the children do close work but don't do it more than 20 minutes after a continuously and have a break and look at the distance for at least 20 seconds. And then most importantly, be outside two hours per day. So I'll switch to myopia control because I wanna talk to you about that. Yeah, these were the papers from the IMI focusing on the guidelines for myopia control. What should you do? And basically this was a summary. When you do myopia control, you really should focus on actual length. That should be your target, not just spherical equivalent. Age is most suitable for intervention is between eight and 16. You should look at the children every six months for randomized control trials. They should have at least three year followup. Every trial should be aware of a rebound after stopping, especially if the stopping is when the children are still growing. And the intervention with proven efficacy are multifocal contact lenses, ortho-K and atropine eye drops. There are new drugs coming. They are promising that they still need more research. And importantly, these papers still don't give you any guidelines on when to use what. So I'm going to tell you a little bit of how we use our epidemiologic data in the clinic and how we do it. So we really look at the eye growth as a starting point. So when we have a child, we plot him in these growth curves. And these growth curves have been published in the October of 2017. And so we give the child a starting point and we give him a risk profile. So we kind of know what to expect. And we also very much look at the history. Is there a genetic myopia? Is there a lifestyle that predisposes to it? And what I also want to point out here is that when you look at progression of actual length, you have to bring into account the age of the child. When it is younger, so those are the blue graphs, it is the children that are between six and nine. They grow faster, as you can see in the growth curve. When they are older, they grow slower. So when you compare and look at trials, you should realize this, how old are the children and are there even the distributions in cases and controls and what are we actually looking at? So what it comes down to when we compare these different regimens is that the ortho-K and the multifocal contact lenses have an efficacy between 40 and 55%. And atropine has an efficacy depending on the dose, but for high dose, it's usually between 70 and 80%. I'm not going to give you a lot of data yet on ortho-K and the multifocals. We're currently doing some trials on that and I don't have all that data yet. But we know when we're talking about ortho-K among ophthalmologists, there's always this hesitance because there is a risk of microbial keratitis. So how high is that risk and which age group is actually the most risky for that? Ortho-K, the annual incidence is 19 in 10,000 children. When you compare that to soft contact lenses monthly, that is 15 in 10,000. And both of these, of course, are much higher than hard contact lenses, which is 1.2 in 10,000 children. Then when you look at the age group, it's actually the older, the people in their 20s that is the age group with the most risk, then the teenagers and the lowest are the younger children, which is actually the age group where you would like to do this. I'll focus more on the rest of the talk on atropine. We know atropine is a muscarine receptor blocker. We don't still don't know exactly how it works, but we are getting much more hints with recent studies. So we know that atropine can release dopamine and the dopamine is also the vehicle of why outdoor exposure works. So that's probably a real stopper. We know that it also works on other neurotransmissions like GABA and it actually is a mediator of nitric oxide. It doesn't only work on the retina, it also seems to work on the sclera. We know that there are muscarine receptor blockers in fibroblast and in chickens, it has a proven effect on fibroblast. So it probably works at multiple targets. The most important one from historical reasons is the Atom study. It was a Taiwanese study and it looked at different dosages of atropine and the outcome mostly was a referent of error, spherical equivalent progression. And I'll walk you slowly through it. It was a two-year study. Then the children were on different dosages. Here, the one with the triangles were the ones that had CBO and of course they had the most progression. At the red line, that trial was stopped and then the children were, the high progressing children were randomized again and the fast progressors were given 0.01% atropine. And what this shows that during treatment, high dose atropine has the slowest progression but when you stop, it seems to have a much higher progression. It seems to have a rebound and this is not so much the case for the children that had 0.01% progression. So let's look at that dose response and rebound more closely and I want to point out that after the red line in the third year, it wasn't a randomized control trial again. And because of this data came out, a lot of people said, oh, well, if in the end 0.01 works best, that's what we should do. And people say, this is interesting because it will have the same effect at lower dose but it doesn't have the side effects. And I think from a lot of medical school lessons we know that that is usually not the case and then I do dare to question that conclusion. So, and this data just got yesterday and I'm gonna share it with you. So here we looked at the real progression in all the studies that have looked at spherical equivalent and that have looked at actual length at different dosages of atropine. And let's look at spherical equivalent first. So we hear we have the different dosages, the dots in blue are the ones having treatment and the dots here in orange are the ones having a placebo. And what you can see here on the Y axis progression of refractive error. So if they're on the orange line, sorry, you can see that the children are having a steady progression rate. But on the blue line, you can see that the children having the higher dosages of atropine have less progression and this actually corresponds here with actual length progression. The children on the high dose almost have no progression of actual length. The children with the lower dose are quite close to the placebo group. So there really is a dose response effect for atropine. So let's look at rebound a little bit closer. So this is data from the atom one and two study. And here are the different dosages that they looked at. The blue represents the difference in actual length in treatment. The first year, the orange in the second year and the gray is the progression after the treatment was stopped. And you can see here actually in 1%, yes, there is a rebound, but it's actually even smaller than it was at the other percentages of atropine. And here you can see indeed in 0.5%, there seems to be a rebound, but you can see also in the 0.01%, the rebound is even more than it was in the placebo group. And actually when you look at this data very closely, the placebo group is kind of peculiar because it actually shows a very low progression during the entire time course. So when we first saw that atom data, I did get quite excited. I thought, let's just try it out in our clinic and see what it does when you treat children with severe myopia progression. So we did this study. We got referrals of children that were almost highly myopic. The mean spherical equivalent was minus five and a half diopters. They were already on the high percentile of the growth chart. We gave them 0.5% atropine in both eyes every night. To get rid of the side effects, we prescribed them multifocal photochromatic glasses. And we followed them up for three years. We saw that most were able to stick to this regimen. So here are our results. So we included those children that had a progression of minus one diopters per year prior to treatment. And this is what you can see after treatment. The progression was much lower and this corresponded with the actual length growth. We didn't have the actual length prior to treatment because when we got the referrals, optomologists still didn't measure actual length. And we looked to see how does the entire group compare to the growth that you would expect from a high myopic or from a myopic progression to an hematropic progression to a hypoopic progression. And those are the light gray, the medium gray and the black. And you see that actually about 80% of the children grew as an iPrope or as an hematrop after we started the treatment. So really slowed down the progression in the majority. 14 to 22% was still a non-responder to this treatment. Of course, there are safety issues with high dose atropine. We did experience allergic conjunctivitis. The frequency was about 3.5%. Also a dermatitis 1.3%. The first year that we did this, we didn't prescribe them any glasses or any adjusted glasses. And then the children did have lots of problems. So during the second year, we started prescribing them multifocal photochromatic glasses right away. And that really solved a lot and made the children stick to the regimen. We looked at ERGs, we looked at IOPs and we found no changes. So how do we do it in practice? When we get referrals of progressive myopia, we of course measure actual lengths. We plot it on the growth curve. We ask about risks we give in the 2022 rule. When the growth curve shows that they are on the 75th percentile or more, we prescribe them 0.5% atropine and we prescribe multifocal photochromatic glasses right away. When they are at the lower percentile on the growth curve, we talk to the parents and to them and we give them a choice. We will go for a lower dose of atropine, 0.5%, but we can also go to multifocal contact lenses and rarely we're okay. And we've discussed this regimen in an article that we just published last year. So let's look at an example. We have a girl seven years old. She has a familial risk. She is a reader and she's already at the 95th percentile of the growth curve for her actual length. We started her on 0.5% atropine. She did well, but at some point she kind of lost the control. We increased the dose to 1% and then it was really stable. And now she's about 12. We are actually lowering the dose again and looking at the progression. So this is what we will do continuously. We will look at the progression rate, plot it in the growth curve, see what her expecting growth is and then either taper the dose, increase the dose or leave it there. How long do we treat the children? We usually go up to 15 years. And this is what parents and children really like. We actually plot it in the growth curve so that they can see the results of their treatment. Now I will end with a case to wake you up in case you fell asleep with all these slides. So I have a girl 11 years old. She has no history of my OPM. She's otherwise healthy. When I asked, did anything ever happen in your life? Parents said, well, she had a sepsis postnatally and it was a staphylococcus aries. I saw her, she was minus four and a half diopters on the right eye, minus five and 25 on the left eye. She had an actual length of 22.7 and 21.6. And I think anybody looking at these children probably already sees that this does not correspond well. So for that refractive error, I would expect a much higher actual length. I looked at the slit lamp, whether I saw anything peculiar. I found a normal cornea, but I did find some lens, some pigment on the lens at the front of the back, but the lens itself was otherwise healthy. I also found a normal retina. So I was puzzled. I don't really find anything in the eye that explains it, but this really doesn't correspond why is the child myopic. So even though I didn't have a hint, I did consider that she was having a carrot bonus. And I did a pentacomb, and although I'm not a corneal specialist, I did see that this was a normal cornea. So then I went back to my biometry and something peculiar I did see when I looked at the lens thickness. The lens thickness of this girl was 3.9 and 4.5 millimeters, and normal for this age is 3.5. So she had a lentil myopia, and of course I didn't treat her. So in conclusion, myopia and a long actual length are becoming a problem for all of us, especially for us ophthalmologists, because we will see much more of the complications than we were used to. One in three high myopes will become bilaterally, visually impaired, but low and intermediate myopia also have considerable risks of ocular complications, retinal detachment, glaucoma, and counteract. Prolonged near work, low outdoor exposure in children are indeed major drivers. And when you translate this to the clinic, the 2022 rule is good advice to children. Very importantly, myopia control should target actual lengths, not spherical equivalent. Start at school age and continue long, do it up until the age of 15, especially fast progressions and those with high risk of high myopia ask for very tight control for a long time. And I've come to the end of what I wanted to share with you this morning. I thank you very much on behalf of my research group for your attention. And of course, the floor is open for questions. Thank you. Thank you, Caroline, for this wonderful, exciting and impressive presentation. Thank you for sharing this with us. Now, Ellie is helping us a little bit with the questions and they may be in the chat or you can raise your hand and maybe I may start with the first question. It's a question as an ophthalmologist but maybe more as a concerned mother. So right now in the situation with corona, with lockdowns, especially in Europe, what do you expect from this time? And I would be interested, do you already include this research question in your work if this situation, my experience, you mentioned seven hours a week. I'm a little bit afraid because of course my boys exceed this time. And what are your thoughts on this? Caroline, you will need to unmute yourself. No, I said, no, I recognize exactly what you say. My boys are a bit older and they're 14 and 16 but they walk around like this everywhere. And I really struggle of getting them outside. I'm so happy, I chose a school that is far away. They have to bike to school. So at least I get an hour there. Then I put them on soccer and they play soccer three times a week. So at least I got that, but it is difficult. And I think especially with the lockdown and the severe lockdown that we're going to get next week, it's difficult. And so actually when this editorial came out, I did make a press release out of it. And I've already been interviewed by radio a lot and there's a television program also paying attention to it. The newspapers are interested. So I really think we should make noise about this because we will get much more myopic progression than we used to. And what we've also done is we have, are collaborating with people that are youth doctors, pediatricians, orthopedics, and people that are on the educational experts and looking at the healthy schools. And we're actually trying to get in the schools a program that children at school will have much more secure outdoor exposure than right now. So when you just walk into an average school and look what they do during recess, actually a lot of children are inside working on a computer. And we're trying to change that attitude so that they are put outside, door is locked and they really get outdoor exposure. But I agree it is difficult and it requires a lot of effort from a lot of people. Dr. Klaver, my name is Jeff Petty and I can't thank you enough, it's been extraordinary. I have two questions that if you'll allow. I was really struck by the Lenthal Myopia case and I just like your recommendation for following axial length rather than simply following repraction. And then the second question is in regards to an IOVS paper, a review paper of Myopia, and there they noted that African blacks have the lowest progress. Non-African blacks have a higher progression and then they even found that within the community of African blacks that in urban settings as would be expected, Myopia progressed more rapidly. So my question is, I think it's easy for us to assume that certainly there's less near exposure broadly in these rural areas in Africa. But do you also feel that there's something genetic about Africa populations that is indeed protective for them in the progression of Myopia now? Yeah, thank you. Your first question, can you repeat it just a second? Sorry, what should the role of tracking axial length be as opposed to simply tracking the program? I'm actually happy you asked that question and I really wanna make a point this morning that you really have to look at actual lengths because that is where you get your morbidity from. It's really the structural changes at the back of the eye, the thinning of the sclera that is causing the problem and spherical equivalent is such an indirect measure. And when you look at the population at large it does correspond quite nicely, but especially our clinical referrals, they're mostly not the typical patient and you really have to do your clinical workup really very extensively to figure out what is the cause of the Myopia in this particular patient. And yeah, so I think it's kind of difficult 50% of the population is turning Myopic, we cannot see all the children in the clinic, right? We need to work with opticians, orthoptists and people that are working outside the hospital. But right now we're making a big fuss that they also have actual length measures. And they, whatever, if they treat or it okay outside of the hospital, do it with follow up of actual length. And I really think we have to convince that community to get these devices. Second question, so it's interesting because when we first started our genetics of course we thought all the Asians like AMD they have different frequencies or maybe some different genes. We were quite convinced you couldn't get there only by environmental factors. And we really looked hard in a cream when we had the Europeans and the Asians and I really didn't find anything. When we did find changes it was more the G by E interaction. So it was what they did with their genes that gave more Myopia than what the Europeans at that time were doing with their genes. So it's really an enhancer your environment. And actually right now I'm looking at sex, female versus males. And in our older cohorts we see the males are predominant the ones developing Myopia. But in our children cohorts it is the females. And when you do a mediation analysis and you really look closely at lifestyle and education you see actually that explains the whole sex difference. And I think this is also the case with the blacks. And when you really follow up closely with the environmental factors it will predominantly explain differences. There will be some slight changes of course. But I think most of it is environmental. Many thanks. I think Dr. Dardeen had a question. Thank you for that wonderful presentation. That was just very informative and a lot of great work you've done. I am a pediatric ophthalmologist here at the Moran and have been treating with dilute atropine for a couple of years. And I was impressed how often you were using those stronger concentrations. I just was curious how often are patients having to discontinue that even with those photochromatic or the progressive glasses were they tolerating that 1% and 1.5% fairly well? Yeah, so we looked of course very closely at adherence. So our adherence for three years was 73% which is actually the same thing as what multifocal contact lens trials are getting and what ortho-cagal lens are getting. Everybody's getting between 70 and 75%. And so I think with the right regimen you really have to discuss it well to the parents. I make a big deal out of that. And I also tell them the first month is the hardest. But it is really amazing after a while how well they tolerated. I'm even surprised at it. And when I just started, we just thought we actually did it ourselves too. We started doing these atropine high dose drops ourselves just to get a feeling of how terrible that was. And with the right glasses on it is tolerable but the children do much better than we do. That's my experience entirely with children. They're very adaptable. Another question is, so do you think the lamp study when the phase three and four come out about these different lower concentrations of atropine comparing 0.01 to 0.025 and 0.05? Do you see, it sounds like that those results may not change your algorithms because they still probably won't be as potent as the 0.5%. Do you see that adapting, changing your clinical care at all? Yeah, I do. So of course, I'm a retinal specialist. So I came from a different angle doing this. And I just thought I was worried about these retinal problems. So I was a bit more aggressive than most of the pediatric ophthalmologists that are taking more care of the person behind the eyes, I guess. And so right now they are promoting very much atropine 0.05 because it did very well in the lamp study. And right now I'm saying, I'm not convinced that's what we should go to do that for all. So we've been setting up a trial, 0.05 against 0.5 and we hope to start that this year. So I think that should answer a bit who really should have high dose, who is okay with low dose and if you can actually combine it. You know, this is what, in practice, we do taper a lot. So I never stop a high dose treatment all of a sudden. I always taper back to 0.1, 0.05 before I stop. Oh, that's very interesting. The, I'll look forward to those results. I've got just, I'm so sorry, I've got one more question since I do a lot of atropine treatment. The, do you ever use this since kids who have genetic causes for myopia like sticklers or congenital stationery night blindness? Yeah. So yes, because as a retinal specialist, I actually got lots of referrals for children with retinitis pigment, TOS, CSMB and et cetera. I thought, let's just try it. So I did try a lot. And so my experience is the response is usually less. There's more non-response, but it does work in about half. And right now we're getting our data together to, you know, to see what we actually had. But this is my clinical feeling that in about 50%, it really reduces the speed, especially like RPGR, you know, those are really fast progressors of myopia. And we know that our PGRs, they do better if they have a lower refractive error. So I think there is an incentive and there is a group where we should try to lower their refractive error. The sticklers actually you often see them with a very high refractive error, but they're usually pretty stable. So for those really monogenetic cases, I wait. So I want to see progression of actual length at least for half a year before I start a therapy. Wonderful. And what about patients with ROP status post laser? I know that's a different mechanism. That's not necessarily actually a length elongation. Have you tried it in that population? I have tried it, but I don't have really good numbers to come up with any conclusion there, but I do try it. It's quite easy, you know, to start with atropine. And if you have a progression line and you can see that it stabilizes, I think you have a point. Thank you for such a wonderful presentation and answer my questions. Thank you. It looks like there is a question in the comments from Dr. Dick's Petty. It says, have you looked at combining treatments such as atropine plus or okay, and its effectiveness compared to atropine alone or okay alone? I'm sorry, I didn't hear everything, but I think the question is combination therapy versus monotherapy? Yes, sorry about that. Yeah, so we do actually clinically do it, combination therapy, especially, you know, those almost 20% non-responders for high-dose atropine. I did try to combine it particularly with multifocal contact lenses. And because you get rid of the side effects right away and it also works by another mechanism. So that's tolerated pretty well. I don't have enough numbers to really show that it works better than monotherapy. But in my clinical experience, I'm pretty happy with it. Okay, are there any more questions? If not, I think we all would like to thank you again so much for this wonderful presentation and also this really insightful discussion. Caroline, we will give you a small break, but maybe you stay in this room so we can talk about the one-on-one meetings and then at 12 o'clock. Caroline will give another presentation and this will be more basic size and genetics. And we are looking much forward to hear from you at 12 o'clock. Thank you so much. Okay, thanks.