 and I want you to be kind of aware of it to begin with. And we'll have, you know, I think as patients come up and what I'd like to see in the fluorescein conferences, instead of having only fluoresceins, we have imaging because a lot of times we don't do fluorescein angiograms anymore. And especially with OCTA, and we'll show you some of that. We're not doing it necessarily as much. So we should do, I think like for the residents, bringing cases to have like OCTs because we can learn a lot from them. They're in a way, they mimic very much what we see in histopathology, okay. All right, so some of this is going to be, so the purpose of my talk today is kind of to go over things that are important from what your reading was, but the quiz is really to help guide your reading. And we'll go over the quiz, but some of this might be stuff that like what we just went over, I don't think is in your basic science book right now, because it's really new. The classification was just published. It's an international consortium that put it together about a year ago, but Greg Hagamann is starting a clinical trial. And so you'll be hearing more about that because he's going to be trying at patients who like fit more of an early intermediate AMD. Okay, so AMD is a leading cause of vision loss worldwide in patients over the age of 50. And you know, the dry form of AMD is the most common, 80 to 90%, but the wet form historically before anti-vegeta was the one that caused quick legal blindness and still can. Now with anti-vegeta, about 40% of patients can be helped, but if we look at long-term, there's a gradual decline in their visual acuity. And some of it's from geographic atrophy, and some of it is from, well, we don't know, maybe it's just because of compliance with the numerous anti-vegeta injections that are needed. But the epidemiology is still that the most common form is the early or dry form of AMD, okay? It's more common in Caucasians. So, and, but when we look at Asians or African-Americans a little bit with Hispanics, they can get a form of neovascular AMD that's called polypoidal, carotovascularopathy. It's actually getting a new name too. But it's associated with bleeding in the outer retina, hypertension. And it's from these polyps that might be associated with the coroid and this packy coroid. So I can't tell you a lot about it because honestly, it's confusing to me. I don't think that it's been clear exactly what the distinctions are. So I'm still trying to work that out before I try to spread the confusion. You know, it's normal to have age-related changes in the eye. So photoreceptors can reduce their density. The RPE loses melanin. It has increased lipophuscin, which is an age-related pigment. So we don't necessarily see that when we look in the eye, but if we were to histopathology, we would see these where the melanin granules, instead of having only melanin in them, they're connected with lipophuscin, this other pigment. And then as I mentioned, the RPE basement membrane gets thickened and we have involution of the Coriocabularis. And then early AMD, which can be asymptomatic, you have small drusen. So, or small drusen would be under 63 microns. It would be considered normal, but drusen that are larger than 63 microns are considered early AMD. And then as I mentioned, the subrednal drusenoid deposits and focal pigmentary changes. And then advanced AMD, we think of the atrophic form, the outer rednal atrophy, but also geographic atrophy, where the RPE is lost as well, and the Coriocabularis, and then the neovascular AMD, which can have a number of different forms. The risk factors for AMD, there's certainly, I mean, the interesting thing is that it's so highly associated with genetics, right? Compliment factor H is a really widespread genetic variant throughout the population, but it's strongly associated with AMD. That's on chromosome one, but also this HDRA arms two, focus on chromosome 10 is a big risk, okay? And yet here we have a condition where it has a high genetic predisposition, right? But then people don't get vision loss until much later. So we know there are environmental factors as well. And they can be, what we think while smoking is a huge environmental factor, but possibly high BMI, and possibly blue light. This is hard to study. And people have done association studies looking at the epidemiology of AMD at different latitudes, you know, based on how much light there is. And so it's certainly we can make a hypothesis how blue light could increase oxygen free radicals and lead to death of cells and all that. But it's more of association study. And I don't think we'll ever have a clinical trial, you know, to be able to really study that question. So this is a diagram. This is an example here of, actually the RPE is up like that. So this is a small Jerusalem, but it's underneath the RPE basement memory. I don't have, I'm sorry, I get examples of STDs, but I don't have like a great example. There's one right here. But the STD would be up here. If this is the RPE photoreceptors here, this is Brooks memory. You have the apical processes. And then you have basal infoldings. And when it's within the basement memory of the RPE, those are basal laminar deposits. And when it's beneath that, that's where we get soft tourism and RPE detachments. And the wrap, the wrap occurs high up sort of in the outer plexus, so of the, of the regal vasculature and has connections to the inner plexus. So at least the evidence to date really suggests it starts in the outer plexus, but it has connections to the inner plexus and you get a feeding arterial into this plexus and a draining vein. And if over time it can form a coriorethal anastomosis, but it's within the retina initially. So I think it's how, I think it's actually fun to think about a fluorescein and all the imaging and how much we can learn about what's going on in the eye. So when you inject the dye, right? So where does it, what's the first, I mean, in the eye, related to the eye, what's perfused first with the fluorescein? That's right, it's because of the ophthalmic artery though, right? So the ophthalmic artery splits, we get the corioreth, we get the retina. Sometimes you see a silio retinal artery early because it's really fed by the corioreth, right? And then what about, what time do you start to see, retina picking up fluorescence? Yeah, 10 to 12 seconds, something like that. Is that what I heard? Okay. So heart drusen are often associated with either loss of RP melanin, right? Or they can just be potentially squished RPE, so you get a little bit of see-through. And so when the coroidal flush, so you get the coroid filling, you get the large vessels, the different vessels of the corioreth, I mean the ophthalmic artery, large vessels of the coroid, and then the coriocapolaris, so you get the coriocapolaris flush. And usually the RPE is a mask, right? You just get a kind of a flush you can see, but then the RPE prevents you from seeing like a, and a called coroidal new vessel, for example. But if the RPE is missing the melanin, then we're gonna see hyperfluorescence in the coriocapolaris. So we call that a window defect, but you're gonna have different kinds of window defects, right? So if it's only the RPE, the melanin that's gone, then you'll see the hyperfluorescence early, and it'll fade late in the entergram. So that's like a typical window defect. But if the coriocapolaris is also gone, then you won't get early hyperfluorescence. You'll have like decreased fluorescence, you might see the coroidal vessels through, and then you'll get staining late. So it actually gives you an idea of what's actually going on. Just a fluorescing entergram, it's pretty amazing. In soft genes, these are kind of like pigment epithelial detachments, and so you'll see that they're similar to that, where you might have early fluorescence. It pools, so it stays within a well-defined area, doesn't extend outside of that area, and then it just sort of can increase in intensity, but it doesn't leak outside the boundaries. Whereas if you actually had coroidal neovascularization, you would have some leakage outside the area, right, the boundaries, okay. So PEDs similar to soft genes. The ICG, it varies on what kind of imaging you use. If you use a Heidelberg or something with a scanning laser ophthalmoscope, you can sometimes see early fluorescence, but if you use like a Topcon, you may not. And it kind of depends on, or does we think it depends on how much protein is within the fluid in the pigment epithelial detachment, and whether or not it blocks the ICG. Let's see, anything else here? So RAP, you tend to see, it's not always associated with the pigment epithelial detachment, but it can be, it tends, if it does, it tends to be in the center of the pigment epithelial detachment, whereas coroidal neovascularization that breaks through the RPE into the neural sensory retina, if it's associated with PED, it's associated with a notch. So it shows up on the edge of the pigment epithelial detachment. RPE tear, so these are sometimes hard to pick up, but you'll get early fluorescence, it's extremely bright and stay that way, and where the RP is folded over, you will actually see reduced fluorescence, and there's like a geographic line, so it really looks like someone just scrolled the RP, and if you look at the OCT, you see that. And then polypoidal coroidal vasculopathy, the best way to really see the polyps are with ICG, and then we talked about this already, we have the type 1 CNV, we didn't talk about this, we're gonna talk about occult CNV. This is one of my favorite areas, actually, of research. So this is coroidal neovascularization that actually is underneath the retinal pigment epithelial. Type 2 is what we classically treat, right? We treat it with laser, in the macular photocoitalization study, we treat it as well with anti-vegap, and this is when the CNV breaks through the RPE, and gets into the neural sensory retina, and I'll show you pictures of them. And then the type 3 AMD is the RAP, or the retinal vascular anomalous complex. Okay, so these are examples of type 1, and actually this was a patient that really got me interested initially. So this patient came in here where just a little bit of pigment in the macula, I actually had pretty good vision like 20, 20 now. This was an infrared imaging, so this was pre-OCT, and I was studying infrared imaging in AMD to be able to detect early CNV. This is another form of infrared imaging, and we don't really use it that much now, but it's where, so with the scanning laser ophthalmoscope, anyway, I'm gonna show you in a second, but this is, these were all of the same visit with the indirect mode, and I'll show you what that is. We saw this strange lesion. One month later, this was the endocrine, and it's visually dropped, and we were pretty sure that we were detecting early CNV underneath the RPE with this indirect mode. So let me show you what it, we've studied a lot of patients, but basically what we learned was that when you have, so the scanning laser ophthalmoscope, so the Heidelberg, right, so when you put light, and it scans across the image of the macula, and the light is detected back, and what you get, actually, is you get directly reflected light in a certain optical plane, so it's really good at picking up things like classic or type two coronal neobascularization that has broken through brooks membrane and the RPE barrier, and is in the neural sensory retina, but when you have this curidol neobascularization underneath the RPE, then it's not detected by confocal imaging, but if you put a stop, so you prevent that directly reflected light, you use a larger aperture, so you still can get light down to the eye. What gets reflected back is actually from the deeper layers of the retina or laterally scattered light, and so you can actually detect CNV that was beneath the retinal pigment epithelium. So we were among the first to really start to understand that CNV could exist, but in different planes of the retina, and that's kind of fed into why some of one of my research areas, but we won't go into that. I wanna keep clinical right now, so this is what the angiogram I'd show in a cult or this ill-defined curidol neobascularization where you get sort of early hyperfluorescence and kind of late leakage. And sir, here's another example, and this is a recent patient actually where you get, you just had this sort of ill-defined late hyperfluorescence, but you don't see a nice lacy CNV like you do with classic. The ICG doesn't really give you a lot of information potentially, but look at the OCTA. So OCTA, does anyone know what that does? Is, yeah. Okay. It takes multiple OCT images over time and looks at the motion between them to essentially map out a vascular network. Very good, right. So it depends, it's different than an angiogram because an angiogram's looking at flow. So you have to actually flow within vessels and whereas the OCTA, as Becca said, it works on particle motion. So if the particles are really slow or the detection of your OCTA isn't great enough, you can miss CNV, but you can also see without dye this kind of vascular network right here. So here is an example. This is what the OCT looks like. So we have these softers, but we have this kind of fluid, right, between the photoreceptor outer segments and the apical part of the RPE. And sure enough, we see an OCT, we see a CNV, which is, this is deep. So here, this is a superficial plexus. This is a deep plexus. This is the outer retina and we actually see it really deep. So it's beneath the RPE. And that's one that we don't know what to do. I'm posing that we wanna prevent or at least my hypothesis is that we wanna figure out ways to prevent the coronal endothelial cells from being activated to migrate above the RPE, but we don't wanna inhibit them. We don't wanna kill them because we need vasculature to clean out the debris in the outer retina and to bring oxygen and nutrients. So that's kind of where my research is, right? I mean, that's what I'm working on. So here's a type two or a classic coronary vasculin membrane, right? So you see, you see a well, this is not well-defined, but you definitely see leakage late. And that's when the vessels come above the RPE into the neural sensory retina. And then this is an example of a retinal angiometrist proliferation or type. And you might, what you see are, you see AMD signs. This is a pigment epithelial detachment here with exudates and you see them in the deep retina, but you also see hemorrhages or retinal vascular abnormalities, sort of, which is unusual. And it's associated with an angioma, which you see leaking here and here. And it's in the center, you know, it's not at the edge of the PDT. Does that make sense? Any questions? So we went over this, there are, but this is an important thing to think of too. There's a way of predicting what the risk of advanced AMD in the fellow eye is. This is pre-erid, so this is from the erid study, but basically, if you assign point value to pigmentary abnormalities, one or more drus, bilateral interbedia drusen, and you look at the five-year risk and 10-year risk, you can come up with a percentage. Like there's a 1% risk at 10 years of having advanced AMD if you have nothing. So you already have a risk, right? And then as you increase the number of points, you increase the risk. And of course, if you have new vascular AMD, this is for the fellow eye. Okay, so what's a risk to the fellow eye? That was published by Rick Ferris. I'm sorry, I didn't, I can get you that if you want to look at it. But it was in the Jama ophthalmology. It was probably archives ophthalmology. This is a formulation of, this is what it was with erids one, and we found a 25% reduction in advanced AMD and 20% reduction to moderate vision loss. It's like the only clinical trial that has been associated with, any clinical trial using antioxidants has been associated with a positive outcome. I mean, how many clinical trials have been done for antioxidants in cardiovascular disease? Antioxidants and cooling, you know? And none of those work, but it did work here. Erids two, we don't have the beta carotene, for example, Michael had talked about before, but we now have the zeaxanthine and the lutein. And it's safer. All right, just a few things I want to talk about. I'm going to switch gears now and talk about angiogenesis because we're using anti-vegeta. There are a lot of studies, and I'm not going to go over those. They're in your basic science book on the macular photomethylation study, PDT, all that stuff, but angiogenesis, there are lots of growth factors involved in neovascular AMD, but the VEGF signaling pathway is like the one that so far has been the most studied. And we think about VEGF as being triggered by hypoxia or loss of oxygen, right? And VEGF, the vascular and stele growth factor, is angiogenic, but what else is it? What other, what was it first identified for? Is anyone there? I'm sure. Okay, but I mean, what other thing does it cause biologically besides angiogenesis? Yeah, okay, good. And actually it was described in uterine, but what, does anyone know what it was? It was a permeability, it was known as vascular permeability factor. And so the way anti-VEGF works may actually be more to reduce permeability. Although when you look at OCTA and anti-VEGF, I don't know how many of you went to David Wong's talk, but you definitely saw, at least by OCTA, it seemed like at least less flow, right, in the coronal neovascularization. So I think there may be an effect on angiogenesis as well. So hypoxia trigger or stabilizes hypoxia-inducible factors, which then translates to the nucleus and they bind in this hypoxia research, or HRE hypoxia, something element, where they bind and then they help with the transcription of numerous growth molecules, so not just VHF, angiopoietins, erythropoietin, that kind of stuff. But it can also be triggered by reactive oxygen species, inflammation, and other types of stresses that are stresses associated with it. And the RPE appears to be the main cell, but the buular cells are also involved. And the angiogenesis involves activation, a lot of biologic, not only causing the chorital endothelial cells to become activated to migrate, but there are changes over time in the extra center matrix. So just if we think about how does AMD start and break down a barrier, the RPE makes up the outer blood retinal barrier, so we need to break that down to allow blood vessels to grow into the neurosensory retina. So VEGF, yeah, there are a number of family members. There are a number of receptors. Receptor two is the one that we think about in AMD. And it's hard to study because knocking out, usually we use animal models to knock out certain alleles or receptors and see what happens and when we stress the animal model. And a single allele knockout of VEGF or its receptors lethal. So it becomes challenging to study it. There are five splice variants, so there's a parent mRNA and it gets spliced into these factors. So we've looked at macogen is actually, is an aptamer that it binds. So it interferes with binding of VEGF 165 and probably 189, which is the cell associated. But what we don't know is whether it binds to the part that actually triggers signaling down the pathway and leads to angiogenesis. So the macogen study, which was an aptamer to VEGF 165 and found that it did reduce severe AMD. It wasn't as effective as like Lucentus or Evastin. And it may be because the binding site, where the aptamer bound to inhibit VEGF 165 was not actually the part where it inhibited signaling through the receptor. Okay, so I'm gonna move on because as I said, there are a number of trials and there have been combination trials. So this is important. I wanna just show that the cat, which was the comparison between Lucentus and Babacizma, it found that in two years it was basically the two drugs were pretty much equivalent. But even with vision improvement in the first two years, nearly half, it was not maintained by five years, but nearly half of the patients saw 24 year better at five years. And 15 years ago before anti-VEGF, all those patients would have been legally blind. So it's been remarkable what anti-VEGF has done. But basically the Babacizma and Meranibizma story right now seem to be equivalent in the vascular ending. What about the effects on geographic atrophy? So VEGF is an angiogenic factor. If you inhibit it, are you gonna like knock out the coriocapillaris and other vascular beds that might be helpful to the ARMA-E or motor retina? And there have been some studies that find that geographic atrophy is increased with monthly injections compared to other treatments. But you know what, it's, oh my gosh, it is so difficult to figure out how to design a study like this. Because if you have an eye that has curidoneovascularization and forms a fibrovascular scar, you really can't see the geographic atrophy underneath that well. Even you can kind of see with those two. So, and it's hard to say that fibrovascular scar is what led to the geographic atrophy. So it's, you know, the way we're kind of thinking about it is that the evidence most strongly supports that anti-vegetable treatment does not slow down the progression of geographic atrophy. And we don't know if it contributes to it. So that's at least how I'm thinking about it. So now this is sort of a philosophy that I take with every disease I have. We want to think about prevention, acute care, and rehabilitation. So we want to think about that with diabetes, with AMD. So what's our prevention in AMD? Oh, they are its vitamins and the health and lifestyle, right? Don't smoke. You know, people who don't smoke actually can reduce their risk of vision loss from AMD. Acute care, right now we have the anti-angiogenic treatments. And then remember that when your patients start to develop difficulty with vision and it can be at any stage, even with advanced AMD, it could be that sort of outer retinal atrophy and intermediate AMD, that they can be helped with lovis genase or with at least seeing what's available to help them with some of what they wanted. Okay, so just take away in your vascular AMD can be reduced by irids, vitamins, treated with anti-vegetable drugs, despite successful treatment, geographic atrophy continues. Geographic atrophy was not slowed by irids, vitamins, and there's no treatment other than maybe to avoid high light exposure. And we don't know if anti-vegetable drugs actually worsen. Okay, so let me see here. I want to make sure we have time for our quiz. I have a few quick unknowns that we'll just go through. Okay, does anyone know what this is? So this is not AMD, by the way. I heard it, I remember. Excellent, yes, very good. So you've got the hemorrhage that goes through all the layers, kinda. It's like there aren't a lot of things like that. You've got this white thing, and then you see an obvious hyper fluorescent area. And the important thing with this, I think, is physicians, it's associated with hypertension. And there have been some studies that suggest when you see this, you have an increased risk of stroke. So these are patients that are really important. I mean, we should always be thinking about the overall patient's health. So these are patients that we want to make sure they're being seen by their internists. And there may be some benefit in displacing the hemorrhage, but think about where the hemorrhage is. Like if the hemorrhage is here, I mean, it's probably not affecting the vision too much. It's small, you can monitor it. If it's in the macula, removing it or displacing it with an air bubble, that can be very helpful. If it's down below, though, you know, I mean, you can, if you're worried about it going into the macula, you can have the person operate, but what you don't want to do is force it into the macula. Okay, how about this? Anyone have an idea what this is? It looks like ESCR. That would be on the differential. This is auto fluorescence here. What would be a hyper auto fluorescent? And this is, I can tell you this is an older patient. Good, all right, great. So it's supposed to be associated with a starry night, which is the basal laminar deposits, but I don't see it that often with a starry night, frankly. And the yellow material may blot the early fluorescence and then hyper fluorescence late. And you know what's interesting about these? They can get CNV, but they often, I mean, it's not clear that they are benefited by anti-vigil. It seems like it just, the CNV just is not that active. And the interesting thing to me, I always thought it was related to RPE lipophuskin, but it's kind of like, you know, here's the, I mean, this is the photoreceptors and here's the RPE here. So it's kind of like a PED, I think it can be in multiple places. I think that we're gonna learn that there are probably different classifications of adult fatalities. Okay, how about this? So let's say this, this is associated with hemorrhage, hypertension, packing coreroid, maybe. Kind of, this is actually polypoidal, PCV. Okay, and this is an example of the, showing the area of the polyp, right here. And we have a sub RPE hemorrhage and some kind of agitation of it. Cursing males and females. I think when it was first described, it had a sex preference, but over the years we realized it really isn't. Hemorrhage is intra-brooks neobascularization. So that's a little bit unusual. All right, you heard this one earlier. This is a 40 year old man. That's right. Yes, right. And what, you know, what is the most common finding we see on floors in CSCR? Pardon? Expansion does. Yeah, right. It's not the smoke stack, right? I mean, a smoke stack is great. We look at it and say, wow. Yeah, that's right. But it's not the most common thing. So it can occur usually without drusen. You know, I will say that it's hard because people with CSCR can also get up when they're 60 and they can have drusen. So sometimes it's difficult to distinguish CSCR from other conditions. And the thing to remember with CSCR too is that it can be made worse or it can recur with even topical steroids. So like people who use it on their skin. And I've had several patients like that who, you know, sometimes you have to, they say, well, yeah, I do use this thing. They won't know it's steroid because you can get it over the counter. So anyway, okay, that's it. Any questions for that? And we can go to the quiz. In geography, you know a well-defined area of early hypofluorescence with appearance of hypofluorescence early, which you can see the deep chorodal vessels. And then in the late phases, the lesion remains well-defined. It doesn't leak. It doesn't extend beyond the boundaries. The fluorescein stains around the chorodal vessels. So what would you think this represents? RPE and choriocavaline is the attribute. That's correct. So tell me why, Rachel. What you're using early hypofluorescence. It could be, well, it could be window defect like the RPE is lost, but you also aren't seeing the bright choricapillaries. So they're both lost. But then you still see the chorodal vessels. Excellent. Very good. So does that make sense? Okay. Any questions for that? So PDT, leucentus, and macagin share the following. So you can, so we'll go one by one. All were associated with about 40% improved vision after one year of trials. All affectant genesis. True. All interfere with the VEGFC. Now, all of these up-regulate VEGFC. In the, in BCSC it says that PDT actually up-regulates VEGFC. Really? Yeah. I don't know if you've heard it. Okay. That's a hypothesis. I don't think, you know, I'll tell you what. I have read about PDT and it's often kind of speculative, right? It's sort of, you know, you use, you get the dye that gets stuck there and then you have the light that kind of closes off the vessels, right? And maybe it reduces reactive oxygen. That's somehow doing something. But you know, reactive oxygen, when it's outside the cell, it probably is injurious. But for it to trigger signaling, which it can do, it's usually inside the cell, right? So I was never really clear. I'll have to read that. I'll read that. It's like a one-liner. Right. So first of all, A is not true because PDT may be about 11% at best, okay? All affectant genesis. So question, let's see. They don't all affect intravitrio. How do we do PDT? What kind of injunction? Because it does require, well, it's not an injection. It's actually infusional or intravenous. Intravenous, okay, good. Okay, check all that true. VEGF is neural protective, true or false? Okay, it is. It's a neural protective. VEGF receptor one functions as a decoy receptor limiting VEGF signaling in development. Actually, it's true, okay? But in adult, it's probably involved in angiogenesis. And it may be even through lucid sites or that's where placental growth factor is one of the family members that triggers signaling through VEGF receptor one. And what about ILEA? Does anyone know what ILEA is? So the VEGF trap? It's like a sink for VETF. It is, right. But it's actually a fusion protein between a domain from VEGF receptor one and VEGF receptor two. So it not only gets VEGF A, but it also gets placental growth factor. And that's why it's thought to be more potent. And I will also mention that there's some evidence that placental growth factor might be more common in polypoidal type of conditions. So sometimes people like to use ILEA for polypoidal basulom. Okay, macgigin interferes directly with the receptor tyrosine kinase activity of VEGF receptor two. Right, that is not true, right? And that might be why macgigin was not as effective. We don't know. And placental growth factor is a member of the VEGF family. I just gave that away. True. The following are recommended for category two AMD. Which one? Or is it two? Right, and green leaf evangelists in diet are always good. I recommend that for everyone. But category two, we don't, that might even be normal aging. That's not really considered. Now, that mean we don't recommend arids for people who have a family history, who might have, you know, I mean there's a judgment there. This is just based on the evidence from the clinical trial. But we have to remember that a clinical trial was over five years. Why don't we do a 25-year clinical trial? It's too expensive, you know? And after a while, things change. In fact, even with the arid study, so this is really interesting, a little historical stuff. Arids one, this is when we were using beta-carotene. That's when that New England Journal came on about beta-carotene being associated with lung cancer. So, you know, things like that, that was only over five years. So, fortunately, they were able to stop and roll, and that was only five years. Okay. True. So have they ever banned the study like giving amines to people with genetic variants like cup of factor H or something? So that's a really good question. There has not been a study like that done, but I don't know how many of you are, do you know the DRC or not, the diabetic research clinical trial, diabetic retinopathy clinical research network? So it's a network through NEI that sites can join, and initially started out to do small, well, to be able to ask questions about diabetic retinopathy. And it's, you know, we have protocol S, protocol T, you've heard about those, I'm sure, through deep diabetic retinopathy. Well, they're now going to have AMD. So they're continuing the network, but it's not just gonna be limited to diabetic retinopathy. And so that is one of the things, so we had a think tank on AMD last year. And one of the ways, I mean, there's really neat evidence that compliment factor H that might actually interfere with lipid deposits of Brooks membrane. And that may be the way that it reduces the advanced AMD, because one of the theories is that Brooks membrane starts to accumulate oxidized cholesterol and seven keto cholesterol, and that that then sort of initiates a process that leads to curative and vascularization and dry AMD. And so compliment factor H may actually interfere with that. So when you have the variant to it, and it's not working as well, then you end up getting this accumulation. So that's one of the studies that I think they're gonna try to look retrospectively initially, because you could data mine, the error it's studying, right? Go back and look at patients and try to get the genetics, if you can identify the patient. So that's a really good question. I hope they do it. Changes in pigmentation within the macular in a person over age 60 is pathognomonic of AMD. It's false, right? Because think of things that CSCR, you can have pigmentary changes and a lot of things that can be used in the patient. You can't then associate with this risk of AMD. So how about CFH, how low is it? Low body mass. Genetic variant on chromosome 10? Yes. And what is that? Yes. HDRA arms two. Characteristic of a rap lesion is associated with a PDD, is the location of a notch appearance on the FAA. And this would be at the center. It's in the center, right? But what is that, when you get a notch on a fluorescent angiogram with a PDD, what does that make you concerned about? CMP, a good thing. CMP, good. Wet AMD is less common than dry and accounts for about 50% of legal products. Dry is more common, but wet AMD untreated accounts for like 80 to 90% of clearance, so that would be false. And that sub-rentinal fluid was associated with better vision after five years of treatment with anti-veg F, than was intra-rentinal fluid. I think it's in your book. If not, it was in the literature. The answer to that is yes, true. Now, I don't know what's gonna happen in the long term, but it has made several of us in retina not be as like, oh, we gotta treat this because there's a little flimmer of sub-rentinal fluid. And you'll notice, okay. So, this patient, you'll notice this, right? It's a little bit of sub-rentinal fluid. They have a cult, CMP. I'm monitoring her, you know? I mean, partly, it's because in the past, well, first of all, in the past, right, before we even had OCT, this would not be a patient. Her angiogram didn't show anything. It was concerning for EMD, for CNV. So, but because of the CAT study, I'm very carefully monitoring her, but her vision has been stable at 20, 25 for a while. So, I'm not saying that's the right thing. I mean, we had a conversation, the patient understands risk benefits all that, you know? So, but I don't think we really know yet, you know, what the best thing is in these patients. With a cult, CMP. Does anyone have any questions?