 Next, moving on to another one of our first-year residents, Chris Ricks is going to talk to us about the phenotypes of AMD and Ghana, which is a place near and dear to some of us here. Spent a bit of time there, and we're anxious to hear what you have to say. Thank you. My name is Christopher Ricks, like Dr. Hoffman mentioned in one of the first-year residents. So I recently was able to go to Ghana with Dr. Hageman, and the Still Center for Translational Medicine to study macular degeneration in West Africa. And, you know, this doesn't just apply to the genotypes and phenotypes of AMD in West Africa, it applies to really all forms of AMD. It's been alluded to several times already today, some of the genetics that have come out with AMD and the big changes that we've discovered in the past decade or so. So we all know what macular degeneration is, don't need to go into details there. A lot of people have these very differing phenotypes and raise the question, why are they so different? What are we really seeing? So one of the big things that's changed in the last decade is understanding what genes are associated with AMD. It turns out that chromosome 1 and chromosome 10 contribute a vast majority of the genetic risk factors to macular degeneration. There's several others that you see there at the bottom here that also associate with it, but studies have shown that it's less than 5, about 5% of AMD is attributed to those other cases and 90 to 95 are associated with either chromosome 1 or chromosome 10. So that gives us something we can really look at, really study and really try to make a difference in. So chromosome 1 is the main focus of this study. I will touch briefly on chromosome 10. It's a very complex focus. There's six main haplotypes we look at, two confirm major risk, two confirm major protective factors, and then two are sort of neutral. So these SNPs associated with the protective haplotypes are the ones that are most associated and a significant in chromosome 1 variance of AMD. So why Ghana? To sign a couple reasons, one we have one of the doctors we worked with, we'll talk about later on, he is from Ghana originally, he's now in the UK and he was able to set up a lot of the connections for us, but really it comes down to the genetics and we'll probably see this in a broader West African population as well. But in chromosome 1 frequency, with just pure chromosome 1, we see about 11% of Caucasians and about 9% of Ghanaians we think there's not great population studies. Whereas in chromosome 10, we see about only 1% of the Ghanaian population. And then this is the big factor here. Almost 45% of all the chromosomes studied in the Ghanaian population have this protective alleles that make it so AMD is very, very rare in the West African and probably the broader African population as well. So this gives us the opportunity to use an experiment of nature to really look at the difference between these pure chromosome 1 AMDs and then another aspect of this study that's ongoing is in the Asian population you get almost pure chromosome 10 association. So we can really look at the two and say what's different, what's the same and how are these two diseases really playing out in the rest of the population, particularly Caucasians where we see a huge mixed genotype with 1 and 10. There's also a lot of evidence that they don't interact with each other and that they're two very, very different diseases. So this gives us the current problem with any attempts at treatment. If you don't know what you're treating, you don't know if you're going to get any good results. So if you try to treat AMD and it's really you're treating one, but someone has 1 and 10 risk factors, you're not going to get much benefit, they're not going to get better, the treatment will fail. Even if it did affect the chromosome 1 risk, so that makes it crucial to find out how these are different and how to treat them separately. So that way when you down the road, we can treat them both together. So a couple of the main differences, chromosome 1, directed AMD, you see a lot of these PEDs, you see a lot of Druzen. Whereas chromosome 10, you don't really see the PEDs, you don't see the Druzen. You see this chronic, this progressive atrophy. So that takes us to Ghana. While we were there a month ago, we saw 218 patients over the course of the week, which adds up to, there's more than 800 patients that have been examined over the past years and previous trips of Dr. Vitale, Dr. Bernstein, been involved in this for a long time now. We did clinical examinations, macro CTs, fundus photos and drew blood samples and spun out the DNA in a lab there with some of the staff from the Still Center for Translational Medicine. So I want to show some of the unique phenotypes that we saw there and some of the thoughts that we've had about these. A lot of this is preliminary, but you can see we did see some of the more classic macular Druzen that we're used to seeing here. But if you'll notice, this fundus is very light. We don't see a huge population of African Americans or Africans in general here in Utah, but this is a very light fundus compared to some of the fund that we saw. Wood C. geographic atrophy, which is actually quite rare there as well as CNV, which is also quite rare. This is the same patient, one I had had a lens exchange the other had not. And then we saw what we called this colloidal Druzen, these really big, soft looking, chunky Druzen that when we would see this, it was almost always associated with pure chromosome one risk and, you know. Homozygous. Homozygous, yeah. With zero chromosome 10 risk. So you can see this chart just briefly shows some of the different alleles we looked at and the hugely associated chromosome one deficiencies versus the chromosome 10 is not associated hardly at all with AMD and Gnans. So we also saw a lot of really unique dystrophies that weren't really associated with any of the known AMD genes. So this is just, you know, we did see a few pseudo Druzen, very, very rare though. One thing we saw and probably 50% of the patients we saw whether they were known AMD patients or just our controls, we'd see this peripheral cuticular Druzen we called it, or PCD, this really fine Druzenoid looking appearance of material that on genetic analysis over the past decade of looking at these patients has almost no association with chromosome one or 10. We'd also see what we termed this cauliflower Druzen where it's just these big beefy unique looking almost CNV-like but kind of interesting phenotype. Again, not associated at all with any of the chromosomes we know affecting AMD. And we see what we call this green dystrophy. We saw this in not a small number of patients of the 200 we saw, just this green looking appearance that doesn't associate with any of the AMD factors again. And then this is something that we may have read about. I think it covers about two lines in our BCSC clinical series, this West African crystalline dystrophy. It's very unique green crystals right in the macula. Used to be said that maybe it's associated with coloseed or colon nut in the diet but a lot of the docs we've worked with out there, they said that's, no one eats that stuff maybe out in the bush but not the general population. They think that's bunk. But there's not a lot of research, we don't know. So this leaves us with some burning questions. AMD is so rare in Africans. So it was what we're seeing really AMD. And if it is, is it from the European influence? There's been four or 500 years now where Ghana has been either ruled or visited very frequently by Europeans. And so some of these patients with lighter funda is this some European genetics getting mixed in there possibly a little bit of chromosome 10 because we do see it very rarely. Next question, why is chromosome one associated protection so high in Africans? Even if you have the risk factor, alleles, if you have even one protection allele, you don't get it, you just don't. And why is that so high in Africans? We've mentioned earlier maybe the theory of these genetics adding some sort of immunological factors. You talk about the Europeans getting wiped out every couple hundred years and the people that survived. Maybe this helps keep us alive. And then what causes this green dystrophy, these cauliflower dystrophies in some of the West African crystalline dystrophy? This all is gonna take more study and more research. So next steps are gonna be to continue studying these genotypes and phenotypes associations to really understand the differences in the process that goes into play when macular generation does manifest itself. Really trying to work to understand the differences in chromosome one and chromosome 10. And currently Dr. Hageman and his group at the Still Center for Translational Medicine preparing for clinical trials of a gene modulated therapy that targets chromosome one, which is really exciting. Shows a lot of promise and if that works for one, then that can treat a large section of the population with AMD and the next step would be to work on chromosome 10. And then down the road, we could realistically see a cure for macular degeneration. And then further research into these unique dystrophies with no known cause. So I wanna give a huge thanks to Dr. Hageman and the SCTM staff. They did a lot of work on this trip and were kind enough to let me join them. Some of the other doctors from around the world we worked with, Dr. Julie Sylvester, from Belfast, Dr. Winifred Amaloco, in Nottingham and then the two local doctors we worked with a lot, Dr. Steven Acafo and Dr. Questy Amisi Arthur. And then the entire 2017 Ghana team. Any questions before I move on to my quality improvement project? Yes. So, you know, fascinating to these differences. And the most fascinating group that they looked at was Easter Island. Have you heard about this? Yeah. They essentially looked at the entire population of native Robinouli of Easter Island and it was zero macular degeneration. And they did not have risk to do chromosome 10.1. Again, a lot of them had protective. It's considered a group that moved from Africa very, very early on. And so if you think again about the hypothesis that there is a difference in association with an increased risk of infection for the protective type. Because what this does is that this is a regulator gene that protective really is effective in turning off the complement system. And when you have a defect, your complement system is always red and always going. So I just think it's the northern crowding that when you're protective you just had a slightly decreased risk and over a period of multiple generations. Whereas in Africa, infectious disease was an issue but never that huge acute crowding concern that they had. And therefore there was just not that acute change and that's the differences between those two different populations. There's one other theory that's pretty fascinating. And that is that we picked up in particular a fair amount of the risk gene from the enderfone. And that's really interesting that there may be some aspect of that. And obviously that's something that's more of a noted European than Asian than it is in regards to African. But I think the infectious disease hypothesis, as far as treatments, it's really exciting that gene therapy is put together. I think there's a really good understanding of what it is and is needed in chromosome one to provide the projection. And we're gonna be working with the people in London and it's move as rapidly as possible into treatment and the hope and need is you can produce a protective and a lot of questions. I mean, it's gonna work on advanced disease, why not? But can you prevent it early on? I think that there's a very real possibility. Dr. Rosen, did they ever check for the vitamin D levels for this population? Check for vitamin D. So we do know from the work of Dr. Angelos and several others that there is an increased risk of progression on the nurture side of the vitamin D levels below. But the overall impact of vitamin D in myrtleis in comparison to the genetic is quite small. It's not unimportant, but it's pretty stable. Enough that even several studies sense of not showing vitamin D to be important in regards to this. I think in this particular case, this effect we're seeing is overwhelming in the genetic and not nurtured. Because I've seen some studies in India where the level of vitamin D is very, very low and that's the reason AMD is on a rise in that area. No question that vitamin D does increase the risk, but in regards to the genetic aspect, it would appear to be that it's much smaller. I mean, I think that you can see that large the room we're sitting here is the genetic. Nurture is not unimportant, but it's a relatively small effect. All right, now it's briefly touching my quality improvement project. So I was tasked and undertook the recreation of the residence schedule this year. So we was driven by the addition of a fourth residence. I want to thank Lee for joining us and causing this to happen. So our goal of the project was to create a schedule that maximizes education, training experience while balancing all the needs of the different, the Miranda VA and the university. So we want to measure this by self-perceived preparedness for fellowship and practice, resident wellness, as well as faculty evaluation of resident competency. So you can see some of the changes that are coming into play here. There's obviously a lot to look at, a lot of time spent fiddling with the colors that's probably the most important part. Some of the big highlights are we're going to have dedicated consult months now whereas before we had to try to balance clinical time with consults, early pathology lab exposure, dedicated UVitis time, continuity in oculoplastic training, early neurophemology exposure, dedicated coronary rotations, earlier cataract training, more clinical and surgical flexibility of the VA as well as more residents of the VA, which is going to be a huge help, dedicated glaucoma surgical training, some academic time and then three months of elective time. So part two of this project was validating the increase in elective time. Briefly went over some of the things we, a lot of the alumni maybe received a survey from Dr. Petty asking what did you do with your elective time? How did it help? What would you change? All the things that we do with it here in international work, research, boosting areas of deficiency and then preparing for fellowships and you see all the places we've gone all over the world and how we rank as far as our perceived preparedness versus the average perceived preparedness, about a 10% self-perceived increase of preparedness from our, so if you have more questions that push us out in the lobby, thanks Dr. Petty and all the alumni that helped with that. Thank you.