That's just the outline. OK, so shall we get started? And then so you had a number of chapters to read, right, for this. So there's not going to be much on the chapters. And more of what I wanted to outline is some of the clinical trials that have been done both for diabetic macular edema and for diabetic retinopathy. I don't even think they're in your books yet. And it's been really an exciting time in diabetes. And so I thought that I would focus on that. And some of the quizzes on that as well. If you have any specific questions about anything that's in the text, though, ask me. And we'll try to get to those at the end, OK? So anyway, this is kind of the outline. We'll talk about some of the rationale for vegetative inhibition, because vascular endothelial growth factor is a hot, or maybe not hot topic, but I would say a prevalent topic in diabetes and other diseases. And then we'll also talk about specifically diabetic macular edema, PDR, clinical trials, but also safety considerations, because I think that's something we always have to think about when we're treating our patients. So first, just a little bit on the epidemiology. This is, I think, mainly in your book, that diabetes is estimated to affect 18 million Americans, 8.3% of the population. And in some states, it's really higher than that and on the rise. And it seems to be associated with the obesity epidemic as well, so especially the type 2 diabetes. Children are also now developing type 2 diabetes, so it's not just type 1. We used to think of children as being just insulin-dependent type 1 diabetics, but because of obesity, we think that that's increasing that risk. And it's the leading cause of vision loss in Americans, 20 to 64, so kind of the working class, the working age group, so an important group. These are the terms that you'll hear type 1 diabetes mellitus, which insulin-dependent or immune-mediated type 2 is non-insulin-dependent. Type 2 is, interestingly, the one that seems to have a genetic, more of a genetic predisposition or, I mean, a genetic association. Pre-diabetes is high blood sugar, and gestational diabetes would be high blood sugar around 24 weeks gestation pregnancy. So the national health and nutrition examination found that the epidemiology of diabetic retinopathy now, we're talking about blacks, 27%, Mexican Americans, 33%, and whites, 18%. These are just numbers that I think are good to remember, because they do tend to be on boards. The Wisconsin studies, 20-year duration of diabetes, 99% of type 1 diabetics have some form of retinopathy, and 60% of type 2 diabetics. And remember that when we think about risk factors, we think of the duration of diabetes. That's very important, and it's easier to figure out when that occurred in type 1, because they often present with ketoacidosis or some major event. But type 2 diabetics, it's really hard to figure out when the duration is. And we don't know what if that pre-diabetes also might be having to that whole equation. So duration becomes problematic in studies of type 2. Glycemic control is very important. And the DCCT, which is the diabetes complications and control trial, I believe, that was done in the US. And the UK PDS was done in the UK, that the recommendations are still to keep A1C less than 7. The Accord study in the US has also looked at even more stringent control of glucose, as well as blood pressure. And I think the more stringent the glucose control, the better. But the more stringent the blood pressure control, there can be a risk of other mortality and morbidity. So what I do is just try to get my diabetic patients in with their internals and have them do what their internals recommends. Because the rules are, I think, a little more complicated based on how old the person is and what their sort of cardiovascular risk factors are as well. Protonuria and cholesterol or dyslipidemia, these are all considered risk factors. And so I talk about the ABCs to my patients, A1C blood pressure cholesterol. But I also strongly encourage them to work with their internals for just the reasons I gave you. And then remember that if a patient is having trouble with their glycemic control, that in diabetes, your wound healing is off. And sometimes their ability to sense pain is off. So they can have a tooth abscess and not really know anything going on. So make sure that, think about infections, occult MIs, dental care, foot care, all these things can be very important in life saving for diabetic patients. And then the other thing, too, that sometimes comes up is that it's important that they have vision that's good enough so that they can take care of themselves, particularly if they're on insulin and they're trying to administer that. So it's a complex interweaving when we manage the care of diabetic patients. When somebody comes into our office to be examined, it's almost like looking at an x-ray in a way. You think of the visual acuity. You think about cornea is healthy. You look for NVI of the iris. You check their pupils, obviously.  And we'll go through that. And then you also classify whether or not there's macular edema. And then based on your classification, you can make a recommendation either for treatment or when the diabetic patient should have continued follow-up. And in patients without any retinopathy, pretty much the recommendation now is yearly eye exams. It is a little different for type 1. I think it's if they've had a five-year duration. But yearly eye exams to come into just be screened. But then if they have retinopathy, that gets shorter in duration that we see them. But despite the fact that yearly eye examinations can reduce the risk of blindness by almost 98%, that the compliance rate is less than 50% nationwide. And when you think about what a patient with diabetes has to do, I mean, they're going to their internals. They're taking all this medication. So there are a lot of things that we can improve on to manage their eye care as well. And some people are exploring telemedicine, but also even the idea, we worked on this in New Orleans, the idea of having the primary care physician have a camera right in their office.  But sometimes things that seem to make sense and work aren't always easy to implement because of insurance and whether or not people want to lose patients. Anyway, but these are things that may be changing in the future. So remember that diabetic patients, especially type 1, can be at high risk of vitreous hemorrhage proliferative. They can have proliferative retinopathy and have absolutely no symptoms at all. And so that's why we want to do these screening exams. The main causes of vision loss and diabetic retinopathy include macular edema, macular ischemia, which is not, we used to say is not that common, but we're actually able to quantify macular ischemia better than we ever were. So I don't think we really know how much of an effect it has. Proliferative diabetic retinopathy. And then metabolic effects and possibly ischemia as well on retinal ganglion cells and neurons. And so it's diabetic retinal neuropathy in a sense. So that can also be a cause of vision loss. So I think one of the things that I find very, so just practically, you have the patient and your slit lamp, they're dilated. And what I'd like to do is, so I know we have OCTs now, so we don't have to, I mean, we still want to look at the macula and look for retinal thickening. Thickening is the key to associated with vision loss. So that's the important thing to look for. But then you want to look at the areas, let me see if I have a picture of that. So you want to look all the way around the optic nerve and the arcades. So they used to think of the seven standard fields that one was centered on the optic nerve, two was centered on the fovea, three was temporal, then four, five, six, seven were in the quadrants around the arcades. I don't think anyone really does that and I don't think it's very often. And I don't think it's, you can get by with less than that now. When we do a montage, we kind of get that picture. But basically those four, five, six, seven, those fields around the arcades are the ones that we use to characterize the severity of retinopathy. And then we look for things like hemorrhages and microannurisms, venous beading. I'm going to show you examples of this. Irma, which is intra-retinal, microvascular abnormalities. And there's some controversy what Irma is, but I think people, so it's sort of add their remodeling of the capillaries and when there's some ischemia. So you'll, instead of seeing sort of nice, I'll show you, but they form shunts. And some people also think of Irma as intra-retinal neovascularization. So it has to, and they can leak as well on angiography. And so the, I think of it, this practically, okay? I see a patient and I look at the four quadrants and I think the four to one rule. Four quadrants of microannurisms or hemorrhage, two of venous beading and one field of Irma. And I'm going to show you pictures of each of those and you can find them, you can actually get them online now. So you just Google and it's like the Wisconsin, I think epidemiologic studies where these come from. So this is a standard field and this is based on studies like in the diabetic retinopathy studies way long ago. But this is the fields that's, this is considered what you need, hemorrhage and microannurisms for one quadrant to make severe, severe diabetic retinopathy. So you need four quadrants of this to be considered severe diabetic retinopathy and this person probably has hypertension as well. It sort of looks there a little bit. It doesn't matter if you say, oh, I don't know if that's a hemorrhage or microannurism. According to the study, it didn't make a difference. It's just that basically red spots of that characteristic, four quadrants of that is severe NPDR. Venous beading, venous beading is different from tortuosity, okay? So tortuosity, the vessel does this. Venous beading, the vessel does this. And you can see an example of that here where it looks, we don't really know what it is but some people feel that it's where the endothelial cells are trying to, are getting stimulated to grow out or up. So they're going in the wrong, in the wrong direction. Two quadrants of venous beading, severe NPDR. Irma, okay. So this is the least amount of Irma you need to call severe NPDR. So Irma here, we have sort of capillaries that are dilated and sort of stopped. Or here, maybe this is starting to do some neobascularization but it kind of goes off into this capillary here. So basically you need three areas of Irma within one field to be considered severe NPDR. And then if you have two of those, so if you have four hemorrhages and two of venous beading or four hemorrhages and one of Irma, that's very severe NPDR. And then based on that we make recommendations, oh, not here, sorry. We make recommendations of how soon to see the patients based on what the risk, and this was from the diabetic retinopathy study. And this is under a little bit of change now because a lot of this was based on when do we put patients through pan-retro-photo-coagulation which is that 1600, 1800, 2000 spots all in the peripheral retina of laser treatment. And that treatment is very effective but it also leads to visual field decline and night blindness. So it does, and it may make macular edema worse. So at least from protocol S, it does seem that those patients may not do as well as anti-vegeta, but we'll go through that. So basically if they have, so I look at severe practically, this is what I do with my day, I say does a person have severe NPDR? Consider PRP in type two and I go two to four months. I probably, and there are a lot of times where I say moderately severe and I thought, oh my gosh, what am I doing? And then it turns out everyone does that. Everyone says moderately severe. So I go two to four to six months. Anything less but with diabetes, I try to do less than a year. I tell the patients to come in earlier and hope they come in in a year. And then macular edema, we actually, we don't use a term clinically significant macular edema and I haven't spent a lot of time going over it. It's based, but it may be on your boards. It's really based on retinal thickening. So retinal thickening is a key ingredient in macular edema. And then it depends on how, whether or not it's within 500 microns of the fovea in association with or without edutates. So they're all in your book and it's good to know them for the boards but when practically when we take care of diabetics now, there is a little bit of a judgment call when we treat patients for macular edema. And we don't consider laser as often now. So neovascularization elsewhere and of the disc. So here this is just showing NDE. This is a part of proliferative. So I showed you what's severe. That's all the category of non-proliferative retinopathy. Now we're going into the category of proliferative retinopathy. And proliferative retinopathy means that blood vessels grow outside of the internal limiting membrane into the vitreous and they often leak with fluorescein dye. And that's called neovascularization and it can be neovascularization of the disc, neovascularization elsewhere. And the other part of proliferative retinopathy is the result of neovascularization which is vitreous hemorrhage. So once the vitreous hemorrhage occurs, there appears to be an interaction and maybe also from the blood vessels in the leaky blood vessels and the neovascularization elsewhere with the vitreous collagen fibers. And it's like a wound healing effect.  And that contraction causes the retina to be detached and attraction will detach from you. So neovascularization of the disc. Oh, this is blown out. But this was the standard figure 10A or something like that from the DRS study. And it was about a quarter to a third disc diameter but this turned out to be a big disc. So that's why people say maybe it's a third disc diameter. So that was considered significant neovascularization of the disc. And then high risk proliferative diabetic retinopathy, that's when we consider treatment. Okay, so if you see a little bit of neovascularization of the disc, that's early proliferative diabetic retinopathy. But again, practically when we have a patient in our office, and now with anti-vegaff and that, I think we're gonna be changing the way that we practically take care of patients and there'll probably be a lot more clinical trials testing whether or not what seems like a good idea are actually clinically good ideas. But this is how you would define, this is how I thought was the easiest. So there are four characteristics that you wanna take into account when you're thinking about high risk PDR. You think of neovascularization just by itself of the disc or elsewhere, that's one. Neovascularization of the disc. So automatically, if you have neovascularization of the disc, you score it two. Then size, and if it's about a quarter to a third disc diameter, here it's less than a quarter, but it's about that size of NVD, that's another risk factor. So if you have NVD, that's a third of a disc diameter, that's three risk factors, that patient has high risk PDR, automatically. If it's NVE, it has to be a half disc area. And then vitreous hemorrhage. So each one of those gets one point and you want three or four points. Now where it becomes sort of a judgment call again is if you have a patient with type two diabetes who comes in with a vitreous hemorrhage, you can't see NVE because there's vitreous hemorrhage. And then the other eye has no retinopathy. So what do you do first? Yes. Okay, check their credits, that's a good idea. That's, I mean, good for the, and you're thinking like. It's very good, very good, good point. And what would you do as far as a test in ophthalmology or even a potential, an ultrasound? Because what are we thinking? It might be just a PVD with a retinal tear. So you always want to make sure it's not that.  But always think about that if it's that asymmetric. But you can look at the other eye. If you see like very severe NPR and then I, you have a vitreous hemorrhage and the ultrasound doesn't show a retinal detachment or a retinal tear, which you sometimes can see with ultrasound. Then you would probably initiate treatment as if that were PDR. And I would probably at this stage give anti-vegeta at this point. That's probably what I would do, but each patient is a little different. Okay, so vitreous PDR causes vitreous hemorrhage, fractional retinal detachment. The reasons why PRP were done, it was thought that there were areas of a vascular retina which were hypoxic that stimulated the production of growth factors like the EGF, which caused blood vessels to grow into the vitreous. And so if you reduce the photoreceptor metabolism by killing them, you reduce the demand for oxygen, so that's one theory. You reduce the cells making the angiogenic factor, that's another theory. And then one theory is thinning the retina and allowing cortal oxygen into the retina. And that probably has the least evidence. But there are other treatments, steroids. There's evidence that like Ozardex and other steroids can reduce at least for diabetic macular edema, right? And we also, the anti-veg up, we're gonna go through and then potentially neuroprotective effects. PRP, I don't wanna make sure we have enough time. So PRP, I like if you have a patient who's got proliferative diabetic retinopathy and has a lot of evidence of inflammatory effects because inflammation also is important in diabetes. And the way like a lot of Irma, leaky on fluorescein or a very ischemic fundus looking, I like to slowly do the PRP rather than do it all at once. And the reason I do that is, especially if you have a lot of NVE and D, is I think you can get a crunch phenomenon with a lot of PRP just like you can with anti-veg up. So it's sort of the same approach that you're pharmacologically modulating your effect by only doing a little bit of PRP at a time. The other reason is I think PRP is inflammatory as well. And so you're adding inflammation. So that's my approach with that, okay. And we know there are complications. So there are also complications from injections.  Then they can come back with a much, I mean, they time elapses and they may have more severe disease just from not getting the regular treatment because the anti-veg up wears off. Okay, so there has been a paradigm shift that based on anti-veg up in macular Dema. Visual acuity is significantly better two times more in patients treated with anti-veg up than laser. And there's clinical trial evidence for that. So why do we even think of anti-veg up and diabetic retinopathy? Well, you know that I just talked about the theories about why people get proliferative retinopathy. Well, in diabetic macular Dema, VEGF is actually a permeability factor. In fact, that's how it was first discovered was it was called Vaso, or Vaso, what was it called, VPF? What did that stand for? Vascular permeability factor, that's what it was. And so it's, and so that's a reason why we would think about stopping its effect. The other reason is that it is essential for viability. A single allele knockout of VEGF or one of its receptors leads to death of the animal and mice, but that requirement wanes over development. And then it's also been increased in patients with diabetic retinopathy, diabetic macular Dema and proliferative retinopathy. And as I said, it causes processes involved in the pathophysiology of diabetes and our diabetic retinopathy and DME, permeability, angiogenesis, and it disorders cleavage planes of dividing endothelial cells and it's also a survival factor for endothelial cells. There's also crosstalk between VEGF and other signaling pathways that are important in diabetes like inflammatory pathways, oxidative pathways, metabolic events. So all these things can feed into each other and you get these feed forward loops that drive the pathology. You know, our body usually wants to restore homeostasis. So if you do one event, there's usually another thing that comes in that makes everything okay. Copaesthetic, so to speak. But then if you have something that's driving the process, then it overwhelms the natural mechanisms to restore homeostasis and that's what's really needed in pathology. There's early pericyte and endothelial damage and there can be late consequences of hypoxia from avascularized retinopathy. So we know the current treatments. We really, Renovizumab and Bevisizumab are antibodies to the ligand. So they bind the VEGF ligand so it can't get to its receptor to trigger signaling. A flibbercept is actually a fusion protein of VEGF receptor R1 and R2. So it's actually like a little trap taking the two receptors so that the ligand binds it and then the VEGF doesn't go to the other receptors. So it works a little bit differently in that regard. And because it has R1 and R2, it also gets placental growth factor. And pegaptinib is a VEGF-165 aptamer and an aptamer is a type of RNA type of drug and it's not as effective as the other drugs. So this just shows the different isoforms of VEGF-165 is the most abundant, expressed. And it has both, the longer ones have this heparin binding domain which makes them cell associated. So they tend to hang out in the extra center matrix. 165 has both. So it can be soluble, released, secreted. So when it's released by itself, it can circulate throughout the retina and have effects in a cell that's not right next to it. Okay. And that just shows sort of the difference is the fusion protein of the R1, R2 and then they have an FC portion of IgG. And then this is actually an antibody that's created against the ligand. Okay. So I'm gonna skip through a lot of these because I want to, and you have access to this, right? Yeah. Okay. So we know about the OCT. The one thing is that the DRCR net did, I think, a great study. I don't know that people use it very much, but where they looked at OCT association with visual acuity, and it's not directly correlated with that, but when you take the log of the OCT, there's a better association. But remember too that a lot of things are happening. So we tend to think of retinal thickening, so bigger OCT with poor vision, right? But you can have a patient that has retinal thinning because they've had a vein occlusion or they've had some neuropathy, right? So their retinas are thin. And you can even have that thin retina then get edematous and be normal. So OCT is not quite necessarily associated with visual acuity, but it's still a good thing to measure, to use quantitative measure. I recommend that you look through all the slices because you can then evaluate these other processes. Oh, basically just time in spectral domain. They can't be interchangeable, but they're both good. So if you have a time domain OCT and you follow it over time, that's a reasonable way to follow your patients, just like a spectral domain OCT. So there are a lot of studies, but I'm just kind of gonna go through the one line caption of them. So initially, Bevacizumab was found to improve vision, reduce OCT thickness in the short term, and then Ranibizumab and deferred laser, this is just for diabetic macular demer, was better than laser alone. And that this was a study where it seemed that if you continued, this is through DRCR net, that if you continued to do monthly Ranibizumab injections, but then only, so you did that initially, but then only did Ranibizumab injections if you had OCT thickening. It turns out that over time, the number of injections needed for diabetic macular demer became less. Man was a critical thing because it was kind of like, well, are we changing the natural course of diabetic retinopathy? Then this is from the protocol T, where they looked at a flipper set, this was like a landmark study because it was head-to-head. A lot of times we look at studies and we have one that treated with Bevacizumab and one with Ranibizumab at 3 milligrams and 0.3 milligrams, and then you can't really compare those. Those are separate studies, different patients. I mean, you get an idea, but you cannot say, well, this was 25% and this was 30%. This was a head-to-head study of a flipper set, Ranibizumab and Bevacizumab. And this note that it uses a 0.3 milligrams and this was for diabetic macular demer. So we could actually compare the three different treatments. And what they basically found was that a flipper set or ILEA did better for patients who had 20, 50 vision or worse than either Bevacizumab or Ranibizumab. And it did better in visual acuity, but also that they needed fewer laser treatments. And OCT Central Subfield Thickness was driven by the initial visual acuity and worse visual acuity was associated with greater reduction in thickness. Okay, I just asked you on this. Have you found that insurance companies are supportive of these findings that are they still making you, like do you have a diabetic macular demer patient that has worse in 20, 50 vision? Or they still want to need a trial A-10? I've, some have, yes. But they, I think, so what I usually do with Erica is I have to write a letter and give the reason and the evidence. But I don't know, I don't think I've had enough of them. It's a really good question. I don't think I've had enough of them to be able to come up, you know, have a sense. Have you heard of others having trouble? I know when I was on, but it was just like right after it came out. I didn't know if I hadn't changed. Yeah, I think, hopefully, yes. And then RANibizumab, the rise and rise studies, those are the key studies with this. These were phase three randomized clinical trials, testing the efficacy and safety of intravitrile RANibizumab compared to sham. And they found more serious events with the 0.5 versus, well, the 0.3. Actually, they're both have serious events. But remember the rise and rise study, the way that they were designed was they had imposed monthly injections. The DRCRNET studies are based on whether or not there's OCT thickening. I mean, it's, they're sort of complicated formulas, but it's not that the investigator would make the decision whether or not to give in an injection. Okay, so the patients didn't necessarily get 12 injections the first year. You saw it was like eight to nine. Rise and rise, the first two years were imposed injections. So the take home for me, I'm gonna skip through a lot of this. I think you've seen those before, is that there is a safety risk in diabetic patients with macular edema if you impose monthly injections. So you should review the OCT and make a decision based on that. Okay, now I wanna get into the PDR study and protocol S too. So why do we even think about diabetic retinopathy severity? So the VEGF pathways that are relevant to severity include those that disorder, angiogenic growth, there are survival pathways, PI3 kinase, NOx4, JackStat, signaling, you probably won't be asked that. But there can be an increase in retinal non-profusion and this is something that is counter, but this is one of the things we did in our lab. We thought that if we gave anti-vegab in models of intravitrile neovascularization, sort of neovascularization into the vitreous, that we would reduce that but we would also increase a vascular retina because it's an angiogenic inhibitor, right? But what we found out one of the ways that it works is that it reorders the dividing cleavage planes of the endothelial cells, the cleavage planes of the dividing endothelial cells. And when the cleavage planes are set up so they're perpendicular to the long axis of the vessel, the blood vessel goes straight out. But when they start to become erratic, the blood vessels grow up into the vitreous. And if you normalize them by reducing the VEGF without totally abolishing it, you actually get more vascularization into the vascular retina. The other reason that it may affect this is by reducing adhesion molecules in the endothelial cells. So you get less blockage of the capillaries so that non-profusion goes away. So, and, okay, you have pictures of that, okay. Actually, I'm just gonna, sorry, I thought I would, it's not like I did plan this talk. I just want to make sure we have time for the talk. Okay, and then there were, I mean, for the quiz, and then there were these studies that actually showed that when you gave the Sysimab, the Boltz study, there was no difference in retinal non-profusion. And people were like, wow, that's interesting. Then RISE and RISE actually showed there was reduced retinal non-profusion in patients who were given retinobizumab compared to sham. And then there was a study that retinobizumab for diabetic macular edema reduced worsening of retinopathy in patients. So in other words, the patients, if you follow them over time in the retinobizumab versus sham group, these guys didn't go on and get more severe whereas these did. Then they found there was actually improvement in diabetic retinopathy, holy cow. So they had to do these studies, the reason they did studies like this is because to say with a bunch of patients, we're going to give anti-vegab for your diabetic retinopathy when you already have standard of care. You know, we're going to do this and we're just going to follow you out and see if you get worse. It would be unethical. So they had to take this kind of strategic approach in the clinical trials. And then the recent protocol S, retinobizumab was non-inferior to PRP and proliferative retinopathy. And they had less visual field law, fewer new DME. And so one of the things to remember about protocol S is that patients who had diabetic macular edema, so this protocol S was you had proliferative retinopathy. Okay, so it was testing PRP versus retinobizumab for proliferative retinopathy, right? And you had the, so you had laser and you had retinobizumab. But the patients who had DME already, because it's already been, you know, this is the standard would be to give anti-vegab, right? Those patients or laser, those patients could be treated at the discretion of the investigator with retinobizumab or laser. So 54% of the patients in the laser only group were getting retinobizumab versus the retinobizumab only group, okay? So you actually had three groups in a sense, even though they were two. And so they were powered to look at just the two groups, but when they did sort of a post hoc analysis, what they found is that the patients who had DME and PDR, they improved their average vision. So again, that's another thing. They looked at the area under the curve to get sort of the average visual changes over time. So they improved their average vision when they were only given retinobizumab versus when they had laser and retinobizumab. So it almost seemed like laser itself. I mean, that has to be tested. The other seems like laser itself may be harmful to the whole process. So, I mean, I think that's really interesting. And so how it's changed my clinical, how I take care of patients now is if I have a compliant diabetic, and that's the key, right? Because PRP, if they don't come back, you can do PRP and you can sort of say, okay, I can sleep better at night. This patient's not gonna have tractional attachments or less like, they still should have follow-up. But if they're compliant and they've got PDR and diabetic macular DME, my first recommendation is retinobizumab. The other thing that's important to remember is that the patients with diabetic macular DME, and there are clinical trials that I think I skipped over here, but just, this is a take home. If you defer treatment with retinobizumab, those patients don't seem to catch up if you give it later. So their visual acuity, on average, is not as good as patients who get retinobizumab right off the bat. So if you have someone who comes in and you feel that they're indicated to have treatment, then I would treat them early. What happens when you have 20, 20 vision? That's tough because there's always an injection issue. I would follow them very closely and work with them and try to get them, remember that all the studies with the DRC are not, they're talking about little changes in visual acuity, 2032, 2040, but those are still important changes to a patient. So maybe we should be treating macular edema with 20, 20 patients. I know a lot of time, if it's in the fovea, I do. If it's not in the fovea, I don't always. So what about risks? The main risks, because VEGF is important in adult homeostasis, there've been a number of studies that have shown that if you take away VEGF that you lose the coriocapolaris, that you hurt the photoreceptors, that you hurt mule cells, okay, all these things, so. And we don't know, we have no way of knowing what VEGF is in a diabetic patient when they come into our office. We assume that it's high when they have the macular edema, right, and we assume that it's high when we see the navascularization. We assume when we give the anti-VEGF that it goes down, but we're not measuring VEGF and seeing it for really neutralizing how much VEGF happens to be in that individual diabetic eye. So there's a little bit of an assumption there. So that for the eye, there's been sustained intracular pressure elevation with rentabizumab. This was done through DRC and NET. In pharmacokinetics, there's been reduced plasma VEGF after bevacizumab, mainly, but also a flibbersep and less free plasma VEGF. Rise and ride had vascular and non-fatal MI or stroke. So initially when they only looked at the APTC indicators of what would be a severe event, they had smaller, lower risk rate, but then when more was known about what anti-VEGF does, I mean it's when you give it for tumors, you get hypertension, you can have stroke. So when you include all those others and the broader definition, the risk factors are much, I mean the adverse events are much higher. DRC and NETCH in the protocol as found no difference between PRP and rentabizumab. And that was, I think, 0.5 milligrams. So, and you might say, well why if it's 0.3 and that's what we get for diabetic macular edema, why did they look at 0.5? And it sort of depends on when the study was started and what the decisions were made for the clinical trial. But those are important things to consider when you're thinking about your patients and trying to make a plan for them. So, I'm sorry, I really did go through this. The bottom line that I think of is, I use 0.3 because the rise in ride, because recent studies, let me just go back here, showed an increase in diabetic macular edema patients with the highest exposure. So, of a flibbersep or rentabizumab, 0.5. And when it was imposed monthly. So, I think we're safer if we don't impose it monthly. I also consider very carefully if a patient has a previous stroke or has risk factors for that and isn't being treated, I might not go with bevacizumab, for example. I might do rentabizumab, 0.3. The question is, if you have a 20, 30 diabetic patient with macular edema, would you use bevacizumab or rentabizumab? I think it's fine to use bevacizumab if you don't have worries about safety and systemic health. I think after 2050 or worse, I would use a flibbersep. I would try to do that. Okay, so let's go over, and these are conclusions. Let's go over the quiz. Oh, and then what I gave you, so I went through, because I gave this, like I gave part of this talk at Arvo, and then I also recently gave a talk in Vienna on the PDR stuff, so I just gave you kind of a sketch of, and these are from like 2012, various clinical trials. I mean, I encourage you to read them, and if you find, if you don't agree with some of this, I wouldn't take my stuff as the absolute, but this is, it can give you just a little bit of a sketch, because sometimes it's hard to remember all these, I think, putting them together, and so I went through and did it systematically. Okay, so let's go over the quiz. We still have a few minutes to do that. Oh, I'm sorry. Okay, anyone have questions that they, anything that? Okay, all right, let's go. Which are believed mechanisms for reduced capillary support for diabetic retina? You can just, it might be more than one. So A is one, right? I can, that's one of the adhesion molecules that can, okay, and then D, pericyte dropout, reduced permeability of vessels, that's not true, and they do have antithrombin three deficiency, but that, I don't think should cause non-profusion, right? Why does diabetic retinopathy have reduced vision? Do we think of? Mm-hmm, right, and then I don't think seed, if anything, they probably have more cytokine release, and what is the other, what is another reason that they can have decreased vision? Retinal detachment, that's right, but also retinal neuropathy. Diabetic retinopathy occurs in about 90% of type one diabetic patients by five years, okay? And it's like 20 years, right, when you start to see any retinopathy in type one. So if OCT is not available, okay, so pretend like you're somewhere where there's no OCT. Diabetic macular dima is best diagnosed by central visual field, fluorescein angiography, or slit lamp biomechroscope, pardon? Actually, slit lamp. Well, I mean, does somebody else tell you something else now? Because things are evolving, but we always think of retinal thickening as the key thing, and you can do that by slit lamp biomechroscope. The macular dima, sometimes it can be a dima or staining. I don't know, so Russell, have other people said something different? No, no, it's my book. I think that for your boards, it's probably still better to think of retinal thickening, but be on the lookout because we may find, that may be changed as we have better ways to quantify things. I mean, we have better imaging. Everything is different now. It's just constantly evolving. But way back, it was retinal thickening, not agitates and not necessarily fluorescein angiophage. High-risk PDR is classified as, okay, not of the intrinsic capillaries. Sorry. I hate questions like that. Who made these? I guess I made these. I'm sorry. That's a terrible question. I'll have to change that. Vitreous hemorrhage in a diabetic patient was severe. So let's look at each one individually, okay? The reason, so it's dilation and leakage, but it's not of the intrinsic capillaries. They have to grow outside the interlimiting membrane into the vitreous.  How about vitreous hemorrhage in a diabetic with severe MPDR? This is after the ultrasound, so it shows no retinal detachment or break. Yes, I think so, because you're making the assumption the NB is a big enough size and it's underneath the vitreous hemorrhage. The vascularization into the vitreous in association with clinically significant macular demo. What do you need to know there before you can make the call? The size, right? Okay. Okay, aspirin use can slow the progression of nonproliferative diabetic retinopathy over three years. Good. You read. Since the advent of anti-vegetable agents, improvement in macular demo is seen in 80% of patients. It's false. It's about 40%. So even though I said it's a paradigm shift, it's not the end all be all. We still need to know more about why diabetes. So practically, I start with anti-vegetable and a diabetic patient with macular demo. If it doesn't work after three or four times, then I may go to, I try a steroid. Why is this not working? The 4-2-1 rule in diabetes diagnosis that four microannurisms associated with two disc areas of retinal thickness and at least one exudate within three disc areas of the fovea indicates an eye in need of photo coagulation. That was false. I thought that was a pretty clever, don't you think, question? So what is the 4-2-1 rule? Yes? Good. Very good. Excellent. And then that would be severe NPDR and we would think photo coagulation and I have to look at protocol S. Does anyone remember if they considered, I think it was only PDR for that. Okay, all features below that are predictive for severe NPDR or are part of NPD, let's say are part of NPDR. So I think you gave them, right? We have venous feeding. Okay, what are, and hemorrhages, right? Those are both two. What about exudates? Are they in the classification for, no, they're not. What about cotton wool spots? No, very good. And intra-retinal and microvascular abnormalities on Irma. So, okay. So a patient with diabetic macular edema presents with OCT thickening and visual acuity of 2060. Based on the DRCR NET study, treatment may be best by, excellent. And why is that? Based on the visual acuity, right? And visual acuity 2050 or less. The single common feature of the definitions of clinically significant macular edema from diabetes was heart actions, false, right? What is it? Good. Treatment of PDR with ranivizumab was found non-inferior to treatment with here. True, good. All right, I'm a little over, but thank you all. You're welcome.


Climate change is real. It is caused by human activity. It is already causing devastating harm to our country and around the world. In my view, we have a moral responsibility to leave this planet in a way that is healthy and habitable to future generations. And that means transforming our energy system away from fossil fuel to energy efficiency and sustainable energy. I understand that when you do that, when you make that transformation of our energy system, there will be workers who will be hurt. That is why in the climate change legislation that I've introduced, we have $41 billion to protect those workers in terms to protect the coal miners and the other workers to make sure that they get the job training and the jobs and the education and the extended unemployment that they need. We have billions in that bill to invest in those communities that have been impacted. We're not going to leave these workers high and dry.