 It started. Perhaps I should say good evening for those of you from the other side of the world. But we're delighted that you're here and seemingly awake. So that's great. You may notice that the room is a little bit different from the one that you had previously. So this way you can like crick your necks in the other direction and sort of unwind as it were. And you'll also notice that the bathrooms are no longer to the left as you go out there to the right. But hopefully that will be easy to find. Just a couple of things, we will do a group photograph at 10 o'clock, so after our discussion session and before the break. So nobody gets to leave until we all kind of line up. And I'm not sure exactly where they'll do this, but they're very good at arranging that. And I should mention someone left a flash drive. It's red. And it says national security. No, it says disc warrior on it. So we have it up there. OK. And then lunches will be the same way that they were previously. So it'll be delivered, I'm not sure to which room, but one of the rooms here. And then if you want to go down to the cafeteria, there will be shuttle back to the hotel as soon as we leave. So right about, I mean as soon as we adjourn, so right about three o'clock. And that's when it will be downstairs. And if you need a cab to the airport, see Jennifer and she'll arrange that. For those of you traveling back tomorrow, you may have some challenges where they're anticipating four to eight inches of snow in Washington, which in Washington shuts us down effectively. National airplane, well, you probably would be leaving from Dallas, which is a little bit better at handling these things. But even so, you should check with your airline and be sure. And maybe don't check out of the hotel yet until you find out if your flight is going or not. So our apologies for that. We figured in March we would be safe, but we're never safe, I guess. So with that, I think we can go ahead and get started. Moderator for today is Juan Latorra. Thank you very much, Terry. Good morning, everybody. I will moderate this session. We have 10-minute presentations followed by a discussion for five minutes. We need to stay on time, so I apologize in advance if I have to interrupt some of the presenters. But before we go on with international experience part two, we'll have Dr. Neal share, whom you met, of course, yesterday, bringing us a recapitulation from our discussions yesterday. Neal? Any questions? Yeah, you're free to. Thank you very much for the opportunity to recap the day. There are many things I was trying to think of doing, and of course you'd like to perhaps give a very high-level summary that maybe encapsulated the brilliance, the collegiality, and the broad expertise that we had here in just a few slides. But meeting isn't over. There's more to come, and I didn't think that was the role. I think partly the role was to bring people up to date, and just to refresh your minds about what we saw yesterday. So bear with me. I gave a talk on syndromes, and it had a whole bunch of other aspects to it, about the clinical aspects, et cetera. So I'm going to ask the audience a question, and people watching live on tape can answer. And so the question is, the current standard for diagnosing Stevens-Johnson TN is to what? One, measure the granulicin levels, determine the HLA genes, look at the clinical features, look at the clinical features in skin biopsy, or use the Alden system. So how many people have just, anybody want to take a guess? How many people think it's one? Went home? Granulicin levels? No? OK. HLA? Clinical features? That's a fair answer. Clinical features in skin biopsy? Yeah, I think in that split 50, 50, and Alden doesn't have anything to do with this. I think the right answer is clinical features in skin biopsy. You'd like all three, if you remember the triangle, we'd like to have the histology. There are other conditions that can look like this, and with good skin pathology reading, sometimes what clinically looks like Stevens-Johnson TN isn't, and it's nice to have the biopsies, to prove that. Now, then Dr. Chung gave a presentation on the pathogenesis. The frequency and severity of drug hypersensitivity is a function of the chemistry of a drug and a function of which of the following. This was a slide that he used. I will show you that slide, because I didn't make this up. This is a slide he really used, and I'm sure that the mathematicians of the audience are quite familiar with this formula. HLAs? Sips? Age of the patient, biology of the individual, and this is not a real equation. Anybody who thinks it's the HLAs that are the most important function here? Chemistry and HLAs, OK. Function in sips? OK. Age of the patient? Oh, he's getting everything here. Biology of the individual? Yes? And this is not a real equation. The correct answer is biology of the individual, but this is also not a real equation. And that's why I did it. This is a slide when you strip it from the builds, and I congratulate Dr. Chung on getting all 140 slides in his time. The frequency severity of drug hypersensitivity equals the function of the chemistry of the drug plus the biology of an individual. This is a made-up equation. This has no scientific or mathematical validity. I assume that's what it means, but the point is that there are different aspects to it, and it's not a real equation. But the biology of the individual, and I think we heard that there were many aspects, both in my talk and in Wenhug's talk, but all the biology of the individual, how that would affect whether or not you're going to get Stevens-Johnson TN, or whether or not you're going to get another hypersensitivity disease, and whether or not you get anything at all. Continuing with Dr. Chung, the association of HLA B-star 5801 with allopart, allopurinol-induced, severe cutaneous adverse reactions, SCARP. Which of this is true? Universal across many ancestries? Do people think that? Or only associated with Stevens-Johnson TN? Statistically insignificant, or associated with renal insufficiency? Which of those do you think would be the right answer? How many people think what? Across ancestries. Because we heard a lot about things being very specific ancestries. How about only associated with Stevens-Johnson TN? No? Okay. Good. How about statistically insignificant? Nobody? Good. Associate with renal insufficiency. Okay. So, that's true a bit. But I would say universal across many ancestries was the point I wanted to make because we argued about whether there were genes that were, were they all specific to ancestries? And they were not. And while this was strongest in the nation, population, or South Asian population, it wasn't necessarily universally that. And here's the slide that he showed, just showing these very high odds ratios. Across many populations, including European populations. Is that right? Okay. And carbamazepine, or carbamazepine if you prefer, can induce antigen presenting cells to interact with the immune system cells, the immune cells, directly. According to which of these theories, there's the Hafton hypothesis, the PI concept altered self-peptide repertoire, or the theory of everything. So, okay, there you go. So, supporters of the, I didn't see the end in a movie, so don't ruin it for me, I hope he gets better. The Hafton hypothesis, how many people think that carbamazepine is supposed to act through the Hafton hypothesis? Even leader doesn't, but you sort of think it does a bit, right? Yeah, the metabolites do. So, it's not that cut and dry. So that's not, how about the PI concept? Okay, people are walking away from that. I mean, PI is irrational, but it is a concept altered self-peptide repertoire? Oh, that seemed to be the most popular answer. Well, according to the talk, it was the PI concept. Now, PI stands for two different things, it's pharmacology and immunology, but it's also the first two letters of Werner Pechler's name, and that's where it actually came from. So, it should be a capital P and a small I for Pechler, and I think he would own up to that. So, here's a slide about the PI concept and the inert carbamazepine able to interact with the immune system, even without metabolites, but metabolites certainly could play a role and probably do in many patients, if not at all. Okay, Elizabeth Phillips had unmet needs, which of the following was not a challenge as identified by Professor Phillips? Finding the population, biological samples, pharmacogenomics studies, prediction and prevention in finding the bathrooms. And she clearly made it, it was not on her list of priorities in terms of challenges, people were excellent at finding the bathrooms. Though today may be a little more challenging with the switch, it's like driving on the wrong side of the road. Okay, I don't have a slide of that, but she did have some excellent slides. I just want to highlight these because the weaknesses of where we are are relevant, and it's the individual ownership of issues as opposed to perhaps a group ownership. And the idea that these things are perhaps rare and we just live with rare events. Education was highlighted in her talk as well as in much of our discussion. And also looking forward to the future about who's going to be looking at this and all the translational hurdles. I think this was one of the key slides of the morning for me, it really summarized a lot. The opportunities were there for global return on investment and looking at the big, big picture. And we've seen that already with the international, we're going to hear more about that today. Insights into the mechanisms, we've come so far from either clinical or in vitro phenomenology to actually get down to very molecular levels and to the genes. The role of electronic health record reform and how that can help and how it's an opportunity to mine data. And it's not data dredging, you're mining, it's a thoughtful process and multidisciplinary research teams as opportunities. So I thank Dr. Phillips for this. Now the international experience, people didn't have enough time to even describe what they've done and accomplished. I certainly can't do that here. But I think the highlights for me is that EuroScar and all of its guises and names, it's like it gets married and divorced and remarried and it keeps changing its name. I'm waiting for hyphenated names, it'll soon have. But, and now Spain in there can have a hyphenated name. So many successes, many successes and really defined what quality validation is for a disease that was sort of swimming around. And there's a long history to that and it's still relevant. It's had good funding, a lot of it's from industry. And I think that that's a model. And as I showed, we have industry funding, we may have private funding as well, but we do worry about succession and continuity of these great programs and none of us is getting any younger. And so we just, you know, who's next? Who's gonna be doing it next? Taiwan had this wonderful drug relief fund which has helped and had major impact country-wide, large population studies, good science, good clinical impact, great politics as well. Many are presented on the ISAC and the private public partnerships there. Again, international, very collaborative, very inclusive, coming up with new observations. We didn't hear them all today, but there's more coming and we're still looking forward to that. So that's great news. And Thailand had the great success with wonderful national and hospital funding that helped support programs that came up with good concepts like these pharmacogenomic cards and made this kind of thing a reality, which is really nice to see. So in terms of the case finding part of the day, we talked about what's going on and Dr. Legrenad presented on what's going on at the FDA and talked about the pros and the cons of all these various systems and trying to work with them. I think that was a great insight into what's going on and what could be done and raised the idea of having something like dill in for liver but having it for skin. And a network then, again, building on the kinds of collaborations that we need. The electronic phenotyping, we heard from Josh about the possibilities here with this rich context to get at comorbidities and long-term effects, et cetera, it's a unique opportunity. And in Thailand, again, hearing about the National Data Collection of Validation and the genetic testing and how all of that is playing out. So there are a lot of successes. So Terry's goals at the beginning of the day for this were to review the current state, examine the role of genomics and pharmacogenetics and identify gaps in our needs. And I think based on those three objectives, it was a real success and I congratulate everybody for that and I look forward to another successful day today. I'll end there. Thank you very much. Thank you very much, Neil. We're now open for discussion. We have three minutes. Please be focused with your questions and we'll continue the session otherwise. Questions? Well, that was a very clear presentation. I know it insulted, this is true. Very, very, very nice summary of the discussions and presentations yesterday. So we will continue then with international experience part two and the first presentation we deal with the experience in Singapore and we have Dr. Cynthia Sung who is a Young Associate Professor at the Duke NUS Graduate Medical School.