 That actually has been a major challenge in the Immersion Network is trying to integrate the ophthalmologist notes, so we're continuing to work on that. So again, let me add my thanks and recognition to the incredible amount of work that people have done in the past two days, and actually in the several weeks preceding this meeting. This was incredibly helpful and especially to get such a large number of international experts on this particular horrible syndrome in the same room addressing this has been really very useful for us. So I thought I would start out by identifying sort of some of the questions that we had hit on that were sort of neat to consider and things that really hadn't been addressed about this condition. Maybe talk a little bit about some of the innovative approaches that were proposed. I think something that we really would like to come away from this is a consensus amongst us is to the highest priority research needs, and that's why I kept asking that question. We have a series of research needs identified by the working groups. I won't go through those. Those were very useful, and we'll put those together in a summary of the meeting and can kind of go back to you and say, what order might you put these in? But really, we're not ever gonna have you all together again in the same room to be able to address this, so let's really try, if we can, to see if we can come up with those. But just to sort of start with intriguing questions, so I think one of them was, we sort of started off with this question of nomenclature. It really didn't come up very much at all in the rest of the meeting, which surprised me, because it sort of threw out the literature, although Jay and Maya raised it a little bit this morning. But is there some way that we could develop a molecular taxonomy of these conditions that would provide for better characterization and agreement on what it is? Then there were a series of questions early on about why is there so much variation in the presentation, in the course, in the histology, et cetera, such as, the degree of inflammation histopathologically? Why is the skin reaction so patchy when many other skin reactions, particularly to drugs, tend to be much more generalized? What's unique about the stratified squamous epithelium? Why is it, it really sort of stopped at the border of that and what is it about that particular tissue that makes it susceptible? Something that came up also in terms of, less the diversity than the commonalities, why are the same HLA alleles implicated over and over again? What is unique or common in their structure that makes them more likely to cause this reaction? I'm sure that there's research in that area going on. It didn't seem to come up as a topic, or maybe I just missed where it would fit in from the basic research group, but it seems to be something that you might want to consider, and again, we can talk about it in the research directions. And then, what can be learned from ethnic specific associations? I think repeatedly we've heard mentioned Meniere's data on the Italians and why they're driving that particular association. That's probably only one of many such findings and we'd like to understand it better. Other intriguing questions, what's the impact of rare variation in the HLA locus? So even though there are a number of common alleles, there's also obviously lots of rare variation. How do we assess that? Can we use burden tests, et cetera? Again, repeatedly, why does such a small minority of people who actually, for some drugs, for other drugs, it's not always such a small minority. But why are many of the carriers not affected and can take these drugs with impunity, and what are the cofactors that might produce this? Are drugs recognized the same ways as viral antigens or are there differences in the way these are approached? And probably a question that all of us were wondering, should Steve Leader become a US citizen? Steve, are you serious? I mean, give up your, you know. Oh no, that card is out of the barn. It's out of the barn. I already passed the exam. You did? Oh, congratulations. And you've already lost your health insurance, right? Yeah. So, thank you. All right, moving on. In terms of innovative studies that we might do, can we look back in the drug trials that were halted because SJS-10 developed? And, you know, was DNA stored from those, and could that be looked into? Many of those are industry-sponsored trials, but couldn't we work with industry in some way to be able to get access to those? A point that was made, I think, a couple of times that oftentimes we don't appreciate is that negative predictive value can be as helpful as positive predictive value. And there are times where the FDA will not say, this never causes such and such. You do, I think, often say it's not been reported or it's not commonly associated or that kind of thing. So even their negative studies would be useful. One really needs to sort of step backward from the identified risk allele to understand the immunopathogenesis. And I think many of the things that were recommended by the Basic Science Group get at that. Move more toward an in vitro preclinical testing of drugs, and the point was made that if we get to the point where we have to do case control studies, in a sense, we've failed. We've let a drug get out into the population that causes this, and shouldn't there be a way that we can pick that up before? And then, as was mentioned a couple of times here, surveillance or research in burn units and working with the burn association since they see so many of these patients. Also, we heard this morning about HLA expression levels. What an interesting idea, and is there some way we could use that perhaps to distinguish between the people who carry the risk allele, and maybe they're not expressing it, maybe there's something else about them. And study the, as I said, the risk allele carriers who don't get the disease. Some of the real challenges we identified were difficulties in early diagnosis. The fact that these patients often go for several days or longer, sometimes moving from hospital to hospital before they're actually definitively diagnosed and treated, a lack of systematic reporting. Is there some way to mandate that or at least to strongly encourage it and the potential maybe to work with patient advocacy groups to encourage that to happen or the CDC or others. We talked about how practitioner education was critical but it might not suffice. And I think especially this morning we heard from Cynthia in Singapore that yes it was useful to send out a newsletter to doctors at least that let them know that this condition existed. But that didn't change anything until their Ministry of Health mandated it as something that was standard of care. Did I quote you correctly? The importance of balancing individual utility against societal impact in societies where individuals can actually go out and get these tests and find a way of getting that information used. Is that something that should be at least facilitated if not encouraged? And then the need to balance that against societal impact recognizing that really we as a society, particularly as Howard pointed out, these are our atrogenic diseases and if we cause them we need to do something about them and take responsibility for doing that. The point was made that animal models really are lacking but even if we had them it's not clear how useful they would be because of the differences in the way they process antigens but maybe they could be used for testing pathways and really even a basic definition of a landscape certainly in the US where we just don't know the burden of this problem. And then some opportunities and we heard a couple of times how we just or Mark just recently mentioned comparing and harmonizing case report forms across the multiple networks that are doing this kind of work. We already have these forms. There's no reason to develop another. There's certainly no reason for a hospital to develop another and trying to find some way to bring those together and agree upon them would be very useful. Working with patient advocates as I mentioned to encourage adoption of reporting. Mark Avigan suggested, is there some way to capture research reports? Not research reports, but the case reports that are being collected it's in some of these hospital systems like the CERNR system we heard about earlier and send those directly to the FDA electronically. And it sounds like that's something you can now accept which would be fabulous to get those to you. So can we figure out a way to make that link happen? And the point being made that why not get our HLA typing done now before we become organ donors and we can use it for ourselves as well as for the people who eventually use our organs. So these were a number of high priority research needs that were identified yesterday. Again, I won't go through them because many of them were picked up by the working groups but we'll have these slides, we'll put them on our website and so you'll at least have them available. But I really wanted to spend most of our time here. So can we come to consensus as to what we see as being the highest priority research needs recognizing that we can propose something really, really big and overarching in that and maybe that will happen maybe many years from now and maybe there are things that are a little bit smaller and a little more constrained that could be pursued earlier on that might facilitate some of these. So collecting good biosamples early in the course was I think recognized as a key issue for early diagnostic and prognostic biomarkers. That's not something likely that the burn unit, correct me if I'm wrong, you clinicians who treat this but most of the patients by the time they end up in the burn unit, it's not early in their course. Is that a fair statement Neil? That it's not, yeah, so you need to get them before then. So how might we go about doing that? Does everyone agree that this is a high priority need? Is there any disagreement to that one I guess? Great, and these are not in priority order, they're sort of in temporal order. And then we, I think everybody sort of crystallized around this idea of a large scale international network for collecting biosamples, harmonized phenotyping, it actually would address a whole bunch of the research needs. But this is gonna be very challenging to do and I'm not totally optimistic that it's gonna happen tomorrow. I don't know that it would happen even after tomorrow. But would the group agree that this is one that, if we could do it, it would be probably the most important thing we could do, that's what I heard. Does anybody want to say anything else about this? So Jay, very briefly and then we'll. Yeah, that's very, very nice. I would encourage you, in this type of thing you should include what we call a retrospective study too. So everybody calls their patients that have survived in a year or two ago, because you can use that for DNA testing. It shouldn't be the sole reason, but it will enrich your numbers quite a bit and you can do research with the drugs that did it then versus now and so forth and it's fairly simple. One type of problem that we run into is the consent form and if you have a lot of centers, it's terrible burden on everyone and this is where we really need this idea of a centralized consent form. Okay, NIH approved, approved by your institute, several institutes. Other institutes should accept it and so now in your RFAs that you go out with, you can say you have to agree that you will accept a central consent form. Yeah, no, that's the next. It's really a big problem, a very big problem. Okay, thanks. It also, so if you're sitting in Toronto and you heard of a case in Edmonton, you could send the consent form to someone in Edmonton and say, get the blood from this guy. That type of thing. Great idea, okay, thank you. The only thing I wanted to add was the comment about developing a way to deposit this information, ClinVar or something similar to that. I don't know that that's necessarily captured in that bullet, but I think that would be something that could in fact be turned on more quickly than building something. No, excellent point, yeah, and I'll guess. So I just want to add something to Jay's comment about the centralized IRB consent form. So we are working with the centralized consent forms but I just want everyone to be aware that when you cross international borders, if you also want your international collaborators to use a common consent form, you might get questions about if you have my nationals data, how does that protect them? How are they impacted by our Patriot Act? So it's just things that we sitting around the table wouldn't think about, but these are things that will come up and we just need to be prepared to answer. That was from Canada and we actually did work it out, but it took us a while. We can make Canada the 51st day, that's what I'm saying. That's right, exactly. Oh yeah, good, so it sounds like there's still a lot of consensus around that recommendation. We also heard from the Pharmacosurveillance Group, the race-ethnic breakdown in SJS-10 in the US which is completely unknown as far as we could tell. So we understand that the FDA had previously not been allowed to collect that information, did I get that right? And now you may be allowed to collect it if we can provide it to you. So, and this is something that actually NIH mandates to be collected, so in our studies, we do have it. Does anyone disagree with the way that that's stated or the importance, sort of the primary importance of? I wanna raise a question. Several people have said that HLA is not restricted in animals and I thought it was discovered in animals. HLA restriction was discovered in mice, right? So, they have different HLA. So perhaps I could suggest this to be a good topic for after the meeting. But it would be nice to find an animal model, so maybe we could ask our veterinarians, does this occur in horses, cows, sheep, so? Well, SJS-TEN doesn't occur in dogs, give it sulfonobytes, in dogs. To the race-ethnic breakdown, wouldn't that fit in with the epidemiology that you wanted to look at better in the US that would go together? Yes, yeah. No, that's an excellent point because you really have to have that and there's a lot of other information from the epidemiology that we would need. The standardized case definition I think was another that seemed to be pretty universally agreed upon. Any disagreements with that? Okay, and then engaging the burn units in research and the fact that there are only five dozen or so, I didn't know that, but that's nice, as Bob says, that is a very tractable model. So here's the really hard question late in the afternoon, is there anything really critical missing from this list? Recognizing we'll have all the working group slides on that, but I just wanna be sure that you all have the chance to discuss anything that we sort of identify as being a crucial. Is Dave Finstra still here? Am I, I can't, okay. So I mean, I think it's more of a pilot project, but I do think that he brought up some good points and sort of identifying small pilot projects, both for qualitative research and also, including stuff on patient preference and other information that was something that would be an easy priority to start towards. I just had a question on the race ethnic breakdown. I don't know if it's possible for you to also collect. I mean, little bit finer granularity in Asians than just Asian. Absolutely. So what NIH is mandated to do in its office, actually by the Office of Civil Rights, I believe, in the census, is to collect our five or six major ethnic groups. But the US Census actually has a much longer list that goes into the subgroups of various ethnicities. And so I think it's something that we could add into a research program. We wouldn't have it across all of our research programs because it's not mandated to do that. That's a good point, so. So including subgroups, I guess, we could say. Other things that we're missing that really should be on here? Cool, yeah, I think we had a pretty reasonable consensus around the team, which is unusual. Sometimes you have lots of competing agendas. So then I think the question is kind of what are our next steps? And what we will be proceeding with relatively rapidly is to do closed captioning, which is, for the hearing impaired, is something that Alvaro does in record time, and it's really quite an extensive effort. But in the next week or so, we'll have the webcast archived and up on our website. So that will be done quickly. We'll be drafting a meeting summary, and we try to put in an executive summary. The meeting summary tends to be almost minutes of a meeting, except we didn't have really a decision in action items. And an executive summary that you could just point your colleagues to a page, page and a half or so of the major recommendations. We're also planning to draft a white paper for a peer review publication if they'll take it. And generally, we've been fairly successful in trying to get these kinds of things published. If you have ideas for what would be suitable venues for that, that would be great. Generally, we try to have these authored by the meeting presenters and so the speakers and the moderators. So even though we had a larger group in the room, probably sort of focusing in on that group, if there are any huge objections to that, let me know and we can try to work something out. I would say that though that we do need to hear, once we start to distribute drafts, we do need to hear from every person whose name is on the paper in order that you would meet International Committee of Medical Journal Editors requirements for authorship and that you have reviewed and approved anything that goes out. So we'll do that. Then considering possible research initiatives is something that we are constantly doing within the NIH and we will pursue that. But we can't say much more about it than that because if we told you much more, it's like, if I told you we'd have to kill you, no, but it's more the idea that if you're too closely involved in that development, then you kind of have a leg up in competition over other groups and so you're sort of precluded from competing, which would not be a good thing. So we've heard the need to work among various federal partners and I list many of them up there. Unfortunately, only two of which are represented at this meeting and we recognize that was a mistake on our part and for those of you who may be listening, we are sorry, but we do need to engage the CDC, the Agency for Health Research and Quality, the Office of the National Coordinator for Health Information Technology and the Patient-Centered Outcomes Research Institute or PCORI, which is a quasi-federal agency, to try to see how we can come together for some potential joint efforts in this area. Also, facilitating the comparison and harmonization of the phenotyping and case report efforts should be something that could be done short term without tons of money and just with some volunteer effort. Stimulating interest among the home agencies and the collaborative efforts would be something that you all can do. So I sort of color-coded these here. The blue ones are the things that we will do within NHGRI. The yellow would be more for the federal partnerships and then really sort of your name here for these other efforts. We really like to see amongst this group, those who are involved in these collaborations, can you come together? Can we help to facilitate that but we really need to rely on you to actually do it to harmonize your phenotyping and case report efforts. And then those of you who are from abroad and who are going home, can you go home and stimulate some interest in your home countries, among your agencies and people that would have an interest in this and who want to work with us in potentially collaborating in some effort going forward. We don't even know what that might look like but if we can at least hear that there is interest in the welcome in the MRC and the time industry and various ministries and that, I think that would be very helpful to us. So those were kind of the next steps that we're thinking of. Are there any that we're missing other than writing a check? Yes, Lars? I don't know if it's missing but there are meetings on drug eruptions where some of us meet but several of us are at meetings of different interests in our own specificities, ophthalmology, dermatology, immunology, genetics. And I think one way to get all these things moving in a regular is seeing, meeting each other regularly in a small group and this is a really small group and if we were to exchange some data, I think that would stimulate a lot of collaboration and get things going. So that's maybe something that should be considered too. What do people think of that? I realize that it's a big world and trying to, yeah, that's right, I know they're enough. Well, even, we can meet virtually. I mean, we can do web meetings which are not as good obviously as meeting face to face but yes, so there are meeting grants that we can support, it becomes a challenge. There are very strict criteria for those and the various institutes have different approaches to how they support them. But I think something to keep in mind is, yes, you do all go to different meetings and we've spoken about particularly in SJS10 how there's a wide variety of practitioners prescribing these drugs. Wouldn't it be cool to maybe have a couple of slides that you could take the photograph of the beautiful group of us there and say we had a whole group of people that came together and recognized that, the guidelines in this area are desperately needed and here are some of the things we think would be useful in those guidelines. When we heard from Neil, he went and talked to the burn association. It was like, oh gosh, the burn association. We never even thought of that. Is that something that maybe we could facilitate putting together? I wouldn't be more than a couple of slides but I don't know, Neil, does that seem, you get a lot of these kinds of talks. Do you think it's feasible to add on a tagline like that? I guess it doesn't hurt if you see it often enough. It would just be nice to have something, even half a page in some of their major journals, just something with the patient's component to it as well because I think that resonates if you were a neurology patient and this is what happened to you. Let's hear from you. And the patient's stories are just so powerful. So I think it has to be seen in a social context, not just research, not just administrative but really in the full social context and it just might resonate. Not that we haven't been trying for a long time. I presented at epilepsy meetings, I presented at neurology meetings and I think the attitude is often I've never seen that. So that's not enough, that's not good enough. Maybe that's the title of the whole thing is I haven't seen that, it's not good enough. And so there's opportunities I think to do that. The caregivers where it's dermatology, burn patients, hospitals that have to look after patients like this, they really care a lot and of course the patients. And something that we have found to be relatively useful in our genomic education efforts is to actually try to come up with model cases that are relevant to a subspecialty. So you may say you've never seen this but you certainly have seen patients that come in with a little bit of neuropathic pain, you give them carbamazepine and then oh my goodness, they develop the sorrel thing and die. So those might be gripping as well. Mark. To add on to what Neil was saying, I think another place where we've occasionally had a little bit broader audience is a viewpoint article in JAMA and this is, I think again, a really interesting idea that we convened a group to talk about eradicating a terrible disease through the implementation of genomic medicine. And I think having something like that appear in JAMA that big, hairy ass deal sort of thing is not a bad thing and then make it a call to say here are the people that really need to be engaged in this effort. Excellent point. I hope my colleagues are taking notes because I'm not getting all of these but that's true. Yeah, but I still hope my colleagues are taking notes. The last thing I wanna do is, but yeah, a call to action that was sort of broadly disseminated in that and published in a major journal and there could well be some interest. I mean, we have to come up with a synthesized, concise message in that particularly if we can engage Andrea in providing us with cases, case stories that the patients are willing to share of what happened with it. You know, the climate was made in our working group too that whether you're polio or measles or some other successful thing, one of the rewards of success is the impending failure right after where people would say, well, we don't really see this anymore. We don't really care. And people stop screening and you run into stuff. But I mean, that'd be nice. If we're there in 2020, that'll be fine. But still, you still have to be vigilant for it. I think it's a valuable comment because I think that is true. No, excellent point. Well, and actually your comment reminded me of one of the guidelines I think Dave Vinstra showed from Anthem where it was basically, if there are no viable alternative drugs, so we'll pay for this testing if there are no viable alternatives. And yet we heard yesterday that essentially what happened, I believe it was in Hong Kong or maybe it was in Taiwan that basically physicians moved away from carbamazepine into phenytoin and that had as high or maybe even a higher risk in that population. And so you kind of wanted to say, Anthem, maybe that's not the thing to have in your guidelines. Other points or comments? So I think we may be able to let you out a little bit early, which I know is gonna break everybody's heart. But actually, this may give you an opportunity to develop a few other collaborations. My understanding is that you were giving Jennifer all of your cab information and that you are all now set for rides back to the airport or back to the hotel. The shuttle will be here at three o'clock. Yeah, and Jennifer will be organizing the shuttle if you wanna check with her on your way out. So with that. Thanks to Terry and everyone for organizing this meeting. This has been fantastic. And on that note, in addition to a specific thanks to Jennifer and Josh, who I think are watching in the overflow room, I also wanna thank Deborah for all of the work that she did in organizing this. So thank you, Deborah. Safe travels home, everyone. Thank you again.