 So, I'm in the unenviable position of being the last speaker between you and dinner, and talking about periodontal disease, and then I realized that I'm a friend of Mark's dentist, so there you have it. So, this is, I'll try to be very, very brief, periodontal microbiome working group was formed at the last meeting, and this is really in response to some of the missing data that we have in terms of predicting, you know, the genetic risk, or risk to complex diseases. Clearly, there's going to be environmental factors, and among those factors very important is microbiome, and so in working in looking at complex genetic disorders, the, characterizing the microbiome could help us stratify some subgroups of these patients, so, and I've also been asked to look at potential demonstration projects, so I'll talk about one of those which would be in the dental context, response to dental analgesics, and also to anticoagulants, which, you know, some patients are on, and then they have to have oral surgery, so they have to go off of those, and so, you know, what's the, what's the, kind of, half-life from a genetic point of view for things like warfarin, and clearly the microbiome and periodontal disease in particular has effects on complex diseases such as coronary artery disease, potentially, and certainly type 2 diabetes, so the goal of our working group was, we set to establish an oral systemic health research network, and our aim then would be to share and pull patients and data across this network to advance translational medicine and dental care. The process that we focused on was to institute standards and best practices in setting this up, so we've had, in addition to the last meeting, we've had two teleconferences, and we've had representatives from various organizations shown here, and I won't go into, you can see who that is, and among our discussions were, you know, inclusion, exclusion criteria for this, expected sample sizes in these different, from our different centers, how do we classify a periodontitis, the types of oral samples to be collected for microbiome analysis, and timing of collection, et cetera, and again, for, because we're running a little late, I won't go into it in great detail, other than to say that we're close to settling on most of these, so for inclusion, exclusion criteria at the Marshfield Clinic, these are some of our inclusion, exclusion criteria, and importantly, we want to make sure that these individuals have both the electronic health record, electronic dental record, so that they see our dentists and have a primary care provider in our system, and haven't had antibiotic treatments in the past three months, and I must say that we've started recruitment, and that seems to be going pretty well. At the Marshfield Clinic, we are interested in recruiting about 2,000 such patients. Our definition for periodontitis is from the American Academy of Periodontology, a case classification system. Okay, so there is controversy about coronary artery disease, or more specifically, atherosclerotic vascular disease, and periodontal disease. There is certainly an association between these two diseases, but a very recent review article sponsored by the American Heart Association did not support, looking at meta-analysis did find this strong association, but not a causal relationship. However, it didn't take into account microbiome variation, and it did note that short-term periodontal disease treatment decreases systemic inflammation and endothelial dysfunction. There's an error on this slide. This one is about a recent study in diabetes and periodontal disease. Present studies do support an association, and that should read with type 2 diabetes. There was unfortunately a duplication, and it supports a bidirectional causal relationship between periodontal disease and type 2 diabetes. In our system, we have nearly 2,000 diabetics who have had a dental visit within the last year, and about 900 of them have not had a dental visit within the past year. What this population can help us do is shown here. This is one of the short-term demonstration-type projects that we have. It's management of patients with both diabetes and periodontitis, and our dentist would refer patients who have periodontitis to the clinic for type 2 diabetes testing and vice versa. We feel that together with genetic and microbiome data, we could stratify these patients and come up with more effective ways to treat both of these disorders. Among other demonstration projects would be pharmacogenetics related to the management of dental patients, as I mentioned in terms of pain management and coagulation management. We're working on a pharmacogenetics panel for a specific for dental patients, and clinical decision support tools tailored to these medications relevant to dental work in an integrated electronic health record, integrated between our electronic health record and electronic dental record. This is what our electronic dental record looks like, and it's probably difficult to see, but in the bottom left panel, there's an alert box that talks about medications and such. This is where the pharmacogenetics data would be, and we're referrals, say, from our dentists to our clinicians would be in case of periodontal disease findings. Many of these ideas have recently been published in the journal Oral Diseases, one we recently published talking about our personalized medicine model at the Marshfield Clinic, and one that was published a few months ago by Jeff Ginsberg's group, and they're shown here for your reference. Recently, NIDCR awarded about $67 million in a seven-year grant towards a national dental practice-based research network. This is to University of Alabama at Birmingham School of Dentistry. Marshfield Clinic supported this application, and we'll join this Midwest regional note of this network, but we will also continue our efforts to form a national network of like-minded institutions across the country to establish a large and diverse cohort of dental medical patients with electronic health records, electronic dental records, and oral microbiome samples. And if anyone's interested, there's contact information at the bottom shown in red, so, and that's where I try to be very quick. So I'll stop here for any questions that you may have. Questions? Murray is single-handedly driving this, and you know, it's going to happen. So I do really think that, you know, by taking into account the effects of the microbiome, we will be able to stratify a number of patients that previously genetics alone doesn't give us such significant data, so. Okay. If there's, Jeff? Yeah, I was just going to ask you or maybe Joanne and Iome whether the dental environment you feel is an environment that actually will facilitate some of the genomics research in ways that the medical environment cannot, particularly from a payer point of view. Yeah, I would just say that at least from an Aetna research perspective, there's actually a lot of collaboration with Columbia Dental School over this connection of oral health and cardiovascular disease, and I've been involved in the preterm birth connection of it. So my questions were, you know, you could also look at this in the prenatal care arena. Absolutely. In fact, the Marshfield Clinic opened up dental clinics because we noted that our population, which is essentially indigent and rural, lacked dental care. We had patients coming in that hadn't been to the dentist in many, many years, and we're having, you know, we saw lots of type 2 diabetes, coronary artery disease, etc. So the clinic invested in opening up now eight different rural dental clinics throughout northern and central Wisconsin to serve people who otherwise weren't getting dental care because of really poor reimbursement Medicare type rates. Maria, I'm wondering if you could comment maybe on what you're learning from the microbiome, or is this, you haven't done it yet and you're hoping to learn, but maybe give us a feel for how that will contribute? Right. So right now we have not analyzed anything yet. We have probably about a dozen microbiome samples, a dozen individuals with microbiome samples currently collected. So I can't really comment on what we're finding yet, but that it won't be long, I suppose. Deborah? And also I'd just like to mention that among the other interested people in this group, Mount Sinai is already collecting actually significant numbers of patients with microbiome samples. So do you imagine that testing the microbiome, I mean sequencing all the organisms, will move into clinical care or will you do research that identifies certain characteristic organisms that then would be just targeted testing? Well, I think that the, my understanding is what's emerging are sort of microbiome communities and certain subtypes of communities and some of those are more associated with disease than others, periodontal disease being one of those. But in clinical care, do you have to do the whole microbiome or can you just look for characteristic organisms within that community that predicts the disease risk? Right. What you look for is it's not a single a single microorganism, but sort of you can classify it by the presence of several types. So my understanding is there's three or four major microbiome types. So you imagine that in clinical care, we will need to sequence the microbiome and that's the only way to do this testing in clinical care. Maybe Irwin has a, you had a comment? No, no, I just wanted to speak to the chair. I have a comment that speaks to your question. I think that, yeah, my mic's on. I think that the, there's a lot of interest amongst the microbiology community in the possibility that sequencing is going to be going to replace culture for the speciation of both bacteria and viruses in the microbiology lab. The leader in this area is George Weinstock at Washu. He's actually doing whole genome sequencing and in the pathology community, I think there's a lot of interest. You probably know these people in Bree at our places, the person that's most interested in it. So I think that, you know, in my view actually next to cancer, this is one of the areas where there's the potential for a huge impact of sequencing in terms of clinical practice. I think there's a lot of hurdles that are going to have to be overcome in terms of the time it takes to speciate and so on and so forth and how do you store the data and everything else. I think on the research side, you know, my own particular interest, and I think there's a lot of evidence to support this, that in autoimmune disease, particularly in the development of asthma, which is the disease I'm most interested in, how human beings tolerize is a function of what the microbiome is at birth. And for both obesity and for asthma, there's elevated risk that's associated with C-section that those of us that are studying this think is related to the fact that these infants are not exposed to the microbiome as part of the birth process and that this is a process that's set relatively early in life. And so we're actually testing the hypothesis that the fetal microbiome may be a risk factor for the development of autoimmune disease and specifically asthma. So I think there's research implications, but there are also clinical implications. And the way we would be looking at this is really sequencing 16S RNA and that's one of the major techniques for determining the species. Yeah, just to follow up very briefly with a comment on Scott's statement, I think that's exactly right. I think our group here at SINA is very, very involved in the pathogen characterization using sequencing. And that's certainly something going to be very big. Maria, I was interested in your current inclusion criteria. Is it diabetes only, or are you also extending to pre-diabetes, which could be very, very interesting from a research point of view and then adding microbiome as a predictor? Right. So what we're doing in the recruitment process is as these people come in, they, we take a fasting blood sample to look at, you know, at the time of that they're recruited, what their blood sugar is. We also look at hemoglobin A1C status and such. And then because they're part of the Marshfield Clinic system, we can look back and we can look forward for their diabetic status. So it's not, we don't know whether they have diabetes when, when they come in to the clinic. So, so that's not one of the recruitment criteria. Keras? Keras? I also want to emphasize that we're sequencing our DNA and not the whole microbiome. And it's, it's pretty quick. But again, the 454 sequencing versus saying sequencing arguments coming out, because what we have found, and we look at head and neck cancers, is that in head and neck cancers versus healthy people, the oral microbiome is less diverse in disease. And that diversity is hidden with 454 sequencing, because with sanga sequencing, you're going to actually subspeciate better. And the consortium microbiome might actually change somatic methylation of certain genes, which is what we've found is that information is an immune system. And it also changes the metabolome and sometimes it's the metabolome that promotes whatever the disease is. Yes. Thank you. You, Sobri, thank you.