Okay, take it away. All right. Marty, are you going to ask a question? Yeah, I wanted to ask this question to Alex, two questions, but I can't remember the second one. So the first question is, have you or anyone studied people who have fecal transplants that failed and to look at the composition of the failed donor microbiota and to compare that with the successful microbiota? Okay. That overlaps a little bit with the gap that I mentioned. So I've done 120 fecal transplants for refractory recurrency difficile infection. Out of those, so there's a 90% efficacy rate, which is very good, considering how difficult this condition is. So that means out of those 120, we have about a dozen failures. And those would be a wonderful group to study. Had we anticipated that we need to propose a study for that many patients. I believe that every patient walks in, gets something like this done, or walks in an academic health center, should be part of a subject, should be part of a research study, that some material should be saved and to go back. But we just didn't have the resources to collect everybody on that scale. So at this point, yes, I wish we had. Now, I did show on the slide, we did have one failure there, and it seemed like it was poor engraftment. There was still a big proteobacteria fraction there. That particular patient got treated with the same donor material and did fine. There may be multiple factors. We studied the households of these people, for example. They're universally contaminated with C. diff. That isn't the question. The question is, what's the difference in the microbiota between the successful donor and the failure? Certainly that should be looked at in the future. I can add two, Marty, it's over here. I can add one microbiologic failure, but not symptomatic. In other words, a patient who continued to shed C. diff, but didn't, but was still shedding, but was not symptomatic, not having diarrhea. And one where there was a clinical sort of failure. And these are samples that I got from Johan Baca and Johana Sos. And those still had that proteobacteria dominance in there. So, again, that's an N of three out of how many. But again, is that cause or effect? Is that just a marker that there's still C. diff there? It's still dysbiotic? Is that just a marker of dysbiosis? Or is that responsible for the fact? No, my question is about the donor. Oh, about the donors. Those two donors look fine. But maybe they didn't engraft the same thing. Detailed informatics could identify something that's missing. So clinically, we've used majority of our cases, just two donors. And the success rate in the failure of doing the repeat procedure is still 90%. Yeah, so you have two very good donors. So now I remember my other question. And that is that the literature says that about 3% of adults are carrying C. diff. But 100% of babies in the first year of life have C. diff. Or some very high percentage of babies. And my question is, what happens to the C. diff from baby to adulthood? And where are those babies getting their 100% C. diff from? I'm not sure. I know the answer. But it seems to be squeezed out as they mature. The babies are not symptomatic. There's really not much C. diff associated disease in the first year of life. So squeezed out makes sense. Except then the question is, where are they getting it from? Well, there's probably a lot of it around. We've gone around in swap places and we find a lot of it in the environment. And it is moving in the environment. It used to be a hospital associated disease. And as Elaine alluded, they get antibiotics. They get a C-section. That floor may well be contaminated. We've gone to the homes of people with recurrent disease. And they are universally contaminated as well. And 50% of C. diff today is acquired in the community. Question of that? Yes.  But they're obviously a very hot topic. So the discussion today revolved around replacing a totally disrupted microbiota. But there's great enthusiasm for at least the potential of therapeutic fecal transplant with dysbiosis. So do you or anyone else on the podium have thoughts on how one might prepare a patient with Crohn's disease, osteoclitis, other dysbiotic conditions, obesity, whatever. How one might clear the existing organisms to best have a niche, to have a hope of an effective replacement? It's an entirely different situation in my mind than trying to complement something that used to replace something that used to be there rather than totally replace an existing microbiota knowing that it's less diverse than the norm, but still a lot of niches are covered. Right. And then that is exactly the next thing that we would like to do. There are last count, 12 ongoing trials for osteoclitis with fecal transplant. And to my knowledge, they're not taken into account this question. So doing a fecal transplant for C. diff is like doing a bone marrow transplant after a Hiroshima. Right. The patients are naturally conditioned by the radiation in that case. All they need is some stem cells. These C. diff patients are exactly the same. They've been carpet bombed with antibiotics for long periods of time. You look at them, there's not only lesser diversity, but there's just fewer bacteria. So the niche is open as possible. I think it's the closest adult human version of germ-free human that we have. So that just needs to be studied. I don't think just putting in poop and thinking you're going to reverse something. That sounds too naive. There's a little, I think not a lot, this past DDW with one before, there was a European study and a small pilot study in IBD and they didn't see any effect of fecal transplant, but they also looked at engraftment and there was no sustaining engraftment either. So I think we need to explore that. How exactly do you, what antibiotics do you choose? For how long do you target particular suspected species that may be involved in IBD? Probably not just look at the fecal material, but also look at what's in the mucosa because that may be a more resistant place, as we heard from Sarkis. Bacteria could hide in the mucin layer and be undisturbed, et cetera. It needs to be done. Yeah, I totally agree. Yeah, and in my view, the murine studies could actually, you know, preclinical studies and mice could actually answer some of those questions rather than human experimentation. Thank you. Gentleman in the middle? Don't say Raju from NICHD. It's a great session. Getting back to the fecal transplantation issue, YEC factor. Much of it is in the name. Instead of calling fecal transplant, why not just say gut microbiome transplant or GMT, something like that. Just a comment. Right, and when I started writing about it, I said it was a gut microbiota transplant. And then we got together with a group of people who were doing clinicians and to write some guidelines. And there was a uniform opposition. They felt patients know what fecal means. It's an honest thing to do. That's not confused them. And that's why the fecal word was chosen. I'm trying to get away from that now and have some sort of center at the university. I don't want to have a fecal U of M center. The names, thanks for now. Thank you. Okay, any more questions? I'd like to ask Dr. Blazier if he feels that the use of antibiotics in infants is contributing to the increase in food allergies? Yeah, it's a good question. I don't have any data about it. But certainly food allergies is one of those diseases that has been rising in recent years that has to have an environmental factor. We know that the microbiota plays a role in providing context for the developing immune system. So some microbiota effect is good. And one could imagine that antibiotics and other aspects like caesarean sections or cumulative approach could have an impact. And that's the kind of thing that should be looked at in cohort studies. Does anybody else have any information about it? Okay. Dr. Wendelback? Yeah, sorry if I bring it back to the fecal transplant. But maybe I can broaden it up a little bit to the clinical and research side. So with all this research on the microbiota, the idea that we have maybe a method to manipulate the microbiota and make things right again is very exciting. And there's a lot of different initiatives, not just C. diff, where it works really well. But there was a study in Europe on obesity. But there was another study, I think in the literature that talked about ulcerative colitis patient that was symptom free for years and was treated for a C. diff infection and had a U.C. flair after the fecal transplant, I believe. So I was just wondering what your ideas or your perspective, where should this all go from here? Should we keep on trying fecal transplant for all kinds of microbiota associated problems? I mean, we don't really know what's happening yet, right? But it seems to work in many cases or at least have an effect. So what do you think where we should go from here? Well, I think the answer is we need systematic approach and go step by step. Perhaps starting with the question Dr. Balfour asked, how do you actually do it in a non-C. diff case? I also think we need to take control of the donor pool, either with what Elaine is doing with actually designing it bottom up, or if you're starting with full spectrum microbiota, then you have to know everything about those donors. You can have, of course, you can do taxonomic classification of what you're actually putting in, but also metabolomics and also donor characteristics, some end product, microbial community end products, fecal gases, whatever. You collect as much information as possible, so you have a panel of biomarkers, and as these things go into different trials, whoever has a passion for a particular disease, we should know everything about the donor as well as learn everything about the recipients because there's a lot of variability there, and I think that's the only way to make progress forward. Until we haven't made much progress in this field since 1958, it has remained static. It's been practiced all along the way at a small scale. The C. diff epidemic made it much bigger, but to look at this as an opportunity to learn a lot about microbial ecology and host physiology and that interaction, I think the opportunity is there, and it's one of the challenges and gaps that NIH can help us with. I mean, we're focusing a lot on replacing bacteria, so we see this biosis and we think we could replace it with different taxa that could protect or restore homeostasis, but like Jonathan was pointing out this morning, we need to know more about the physiological action of these bacteria. So if we think about IBD or cancer, is there an activity promoted by bacteria that could be blocked or replaced with another activity? Do you really have to start from a complex community and try to put back an environment and a new ecosystem? Or could you just have a function put in back to restore disease? That's where we need to move into more detail activities. What are these bacteria doing and how do they relate it to health and disease and come up with a little bit more focused approach? If you go transplant, we haven't progressed that much in terms of medicine. It's like a little bit of a stormage. But I mean, we've seen with L.N. Petrol that you could narrow it down and then come back with maybe some activities that will refrain C. diff action. This is where we need to move. That's a great point. Sure. I actually have a non-FMT question. One challenge that seems to be emerging for us as a community to deal with is we've seen a lot of very interesting data presented over the last couple days about the impact of antibiotics on microbiome. Dr. Blazer presented some fascinating results today. And I guess I'd like to ask the question, especially since Dr. Goodman is here, how is the FDA and also how should we as a community be having a conversation not just about how we should be thinking about safety and regulation of potential microbial-based therapeutics but of antibiotics themselves? Well, I think that understanding that antibiotics have more than potential acute side effects and benefits is a really important conceptual leap that understanding the microbiome better helps us make. I think we need a lot more data to understand what those effects may or may not be because right now there's also a lot of people who die because they don't have antibiotics. So I think it's a complex issue. It should certainly make society... We have a lot of good reasons to reduce the unnecessary use of antibiotics in our society without any of this information about the microbiome. So I think some of these concerns should really add impetus to that movement. And I get back to I think we need science such as people here are trying to do to understand where bacteria are good, where they're bad. And I was interested that in some of the studies presented, for example, the use of an antibiotic created what seemed to be a healthy phenotype, for example, with respect to carnitine, et cetera. So I think antibiotics perturb a complex ecosystem and the effects are going to be complex and not always predictable and they do clearly have a role in saving many people from life-threatening infections. But I think it's a blunt instrument and people have thought of it as a very finely tuned instrument and it really isn't. It's a blunt instrument because we think of it just treating the pathogen but it's obviously also dramatically affecting the host in other ways. And I also think, again, there were plenty of other reasons for doing it but I think Marty may have mentioned this. To me, it's another reason to point us in the direction of more targeted antibiotics, narrower spectrum antibiotics. But I will say frankly to do that we also need a model, for example, of reimbursement and healthcare behavior and improved diagnostics that will let clinicians responsibly use narrow spectrum antibiotics. So to me it's very exciting because it lends weight to something that I've been passionate about for a long time is that antibiotics are a very important tool and we should really optimize how we use them and not use them when we don't need them and use them properly when we do need them. Okay. Did you want to respond to that? I just wanted to perhaps continue this discussion a little bit and the data like Dr. Blazer presented look very convincing that there's correlative data linking for obesity and antibiotic use and there is great animal data. At what point does the FDA come out at least to warn the pediatric population with a little black box warning that there are potential risks that are still unknown? I mean I think you need some pretty credible data and at this point I would focus more on this as part of educating physicians about prudent and responsible use of antibiotics. We do, by the way, we did introduce labeling that does pertain to the inappropriate use of antibiotics potentially leading to resistance because we did this some time ago but so the FDA has taken a position on the label about appropriate use of antibiotics but there's not something magical that the label on the FDA product does. As you know, they can be difficult to read, they're technical. What we're really talking about is a healthcare technology and tool that is, like many others, has appropriate uses and inappropriate uses and I think it's also our responsibility as a medical community. There's also not a lot of science that helps us know how best to use some antibiotics so I think it's a broad issue but if evidence develops that there is harm to children that needs to be balanced with benefit then that's the appropriate time to look at that kind of thing. Just before we take that question, is the person who asked a question from the first day about probiotics and regulation of health claims around those or lack thereof still here? Did you want to ask that question again because it just seems relevant to... Where is the hype? I mean we see commercials daily on TV for probiotics and how do we separate the hype from the reality and the promise of them? I think that's a major issue because the public is going to be thinking they do things that they may not do and yet there can be significant advantages in the right situations. Well I would say that's why we need sound science and clinical trials in some of these areas where the use is being promoted and I also think the scientific community... I was a couple of times struck by... I think in general people have had a very measured approach to their data but there are a few times where people even in this meeting showed this study or that and there's an inference about something like autism or whatever. I think the scientific community in our excitement about some of the data and some of the associations we see needs to be very, very careful not sort of to send patients down a road that could be potentially harmful to them or maybe at best just might not be the right road to help them when they have a desperate problem and again I'm really enthused and I heard from some components of NIH that there are a number of studies starting to be done in these areas to really address where do probiotics have effects in some of the areas that they've been shown potential promise. And as I think I had said earlier in response to questions what FDA's role is in probiotics is sort of determined by the authority FDA has been given and if a manufacturer makes a disease claim then that becomes a drug claim in essence and they really have to provide evidence to support that but short of that is where sometimes confusion develops. So I think the community has to be... the science community and the clinical community should be very... people are intelligent and I think if they hear from responsible physicians and scientists that we see promise here but what the reality is about the gaps in the data and what's not known about many of these products at least they can make informed decisions and most importantly is when we reach that threshold for a clinical trial something makes sense there's promising data, there's a defined product then for important public health needs hopefully begin to get that kind of information. Patient desperation is a big force in driving them to alternative medicine. I'm not saying probiotics is alternative medicine I'm saying that it's an easy... the way they claim is put to them it's an easy potential treatment for them and it's the wild west that's for sure and the claim just came going up. I will say we recently took action on for example people may have seen a diabetes issue where some supplements were being claimed to benefit in treatment of diabetes and obviously that's something where we do have medicine where it is a potentially fatal or unstable disorder and that's where we would normally prioritize limited resources in terms of going after concerns that might really endanger people. So I think there's a question I think maybe more for NIH or maybe a comment maybe David can comment on this as well when I'm done but one of the challenges that I face working on probiotics or even trying to develop next generation probiotics from the gut microbiota is that there really isn't a study section for me to send my grants to at this point. Most microbial research in NIH is focused on pathogens the only microbial physiology study sections that's left is now called PCMB there used to be two study sections that's collapsed into one and so I find it really difficult to figure out where to send a grant unless there's an RFA or a specific call for beneficial microbes so I would implore NIH to try to figure out how to take at least this big program that we have and maybe have a study section that allows for R01 that are specific and I just want to point out David made some really important points today one is that the strain specificity of activities is really dramatic so just knowing what a 16S sequence is is not going to tell you what that bacterium is going to do and David really nicely highlighted that and that's where I think the need for microbial physiologists microbial geneticists and a mechanism to study these bugs without necessarily having to have a big focus on a disease and a grant is really critical again self-serving this is what I do but I do it because I believe so strongly in it and so I don't know if David wants to comment on that or anybody else does but I think that that's going to be critical moving forward can we get a microphone to David does anyone from NIH want to respond well I want to say it's not self-serving because that's what I do too I appreciate that yeah there's, I mean NCAM is where we've been submitting and there really isn't a spot unless you partner with somebody and you're addressing some other issue so you become a tag along on another grant so it would be nice if there was is this on? it would be nice if there's a focus on these organisms I wanted to actually amplify what you said before and that in addition to strain specificity is this issue of genetics we have a lot of organisms that we're investing a fair amount of money in clinical trials and NIHs in terms of probiotics that we, in many cases we don't have genetic systems for it all and so the ability to try to get down to a mechanistic level so you know which genes are turning on what mechanism it becomes impossible unless you have decent genetic systems and you can't write as Rob pointed out before that kind of grant and so there's a tool development aspect that's desperately needed we have done lots of mechanistic work on bifidobacterium infantis we have yet to knock out a gene you know we do what we can but the tools don't exist and it really hampers the research moving forward so that would be another area that I would also amplify as well thank you any other responses to that? okay have some questions here the topic of self-administered people transplants certainly been brought up and I know it's somewhat controversial certainly I understand the concerns although I run a website that gets lots and lots of questions for various people out there and one of the questions was what can people do if they're doing these outside of a clinical setting to I guess do them in a way that would be basically safe and effective because I know for many people I wasn't even aware until today that you were doing these and had such a standardized process set up so many people aren't aware that there's access to these types of things for people doing it in a non-clinical setting what would be some recommendations to make sure that they're safe and effective and conform to standard medical guidelines did a question for me or for the FDA well that's a question for you well I guess we have standardized and we're material and we're trying to work on it it's not it's not a approved license it's not ready for distribution to anybody and certainly there's a lot of resources that went into that setup so that material hopefully will go through a series of trials and will be reviewed and hopefully make it to a licensed product and then it will become a lot more available to physicians anywhere to administer in an easier fashion than this is done currently I don't have a particular I do get emails like yours can you help me with some technical tips on how to do this and I'm going to do this anyway and I'm placed in this position because a lot of these stories are really heart-wrenching and the people that really are suffering and you want to listen and you want to make sure they don't do something that is completely crazy or if you read something in their email that just doesn't sound right and I kind of point it out but I don't give out advice and solve to do home transplants because that's just too far removed from the patient for me to treat a patient and to see the patient have to do the physical exam I have to form that doctor-patient relationship if it doesn't exist that's whatever it's not exactly a professional advice at that point so I try to draw that line but it's a challenge with every email where exactly do you find that line or if you feel there is something that you think is potential harm you have to probably step in and step back and not encourage something that you have no control over do we have another question of that? so speaking of understudied aspects and standardization I was wondering if you guys have thought about characterizing the phage in the fecal transplant material or in general that's something we haven't really talked about aside from rick bushman's talk about phage I've thought about it during this meeting for sure and another thing to characterize we haven't looked at archaea we just looked at bacteria so far all of those are interesting questions and phage is probably important to the stability and behavior of the microbial community is rick still here? no I think he just left so I just wanted to address a question that came in through the emails that we've been receiving which changes the topic slightly a few of you I've spoken to about the issue of evolution we've talked about a lot about dynamics and descriptive studies and a few people have mentioned the evolutionary context of the microbiome but this question says we throw around the term of co-evolved microbiome but I think a grand challenge for us as a field is to establish what this means and how we might prove or disprove this claim I think we need to look much more at conserved functions rather than hosting the microbes performed for each other and evidence for selection on these traits rather than just focusing on phylogenies and this will require broad comparative studies across many host species rather than just humans and their close relatives does anyone have any response to that? I mean obviously evolution has a way to select for the microorganism that you need I mean if you eliminate a group of microorganism that involves in a new environment but you conserve the activities I'll conserve in some ways but the taxa is gone because another one could take the same function this is a dynamic selection that happened we heard from ancestral community that we have quite a different microbiome but we live in a different environment we said that all these functions that we have right now with these microbes for our lifestyles I mean we have disease associated with some microbial dysfunction is it because we are evolving in a more harsh environment than ancestral community likely but the evolution is I think an action that is happening from your environment I don't see a problem of making the evolution of microorganism selection with how we are now housing and coexisting what I would say is we know a lot about how pathogens have co-evolved with hosts but there's been very few studies I think that have looked at commensals I would point you to one paper from Yens Walters labs at the University of Nebraska where they actually looked at lack of social right distribution across a lot of different vertebrate that kind of track nicely they group together based on their animal host and so I expect we will see more studies like that coming out as we start being able to culture and it does raise the point that we do have to look at other animals other than just humans which hasn't really been part of HMP yet and just adding to that about the co-evolution there's another study out of David Rehlman's group where I think it was a cell paper last year where they took microbes and put it into germ free mice and then human microbes and put it into germ free mice and they actually saw there was less T cells in the intestinal compartment of these mice so they kind of pointed to the fact that maybe there is some sort of co-evolution that you have if you've got microbes over time and this could be kind of due to some sort of host factors and colonization factors that the host has and our lab has seen similar things when we've come in with trying to humanize germ free mice and they become somewhat immunodeficient and they don't actually there's no particular components in the immune system that can actually recognize microbes so that's maybe another kind of paper similar to that as well Okay so I had a question for David that was along similar lines your studies with milk glycans have you looked at the relations between the effects that those have on microbiomes in other mammal species or has anyone else, do we have any other data on that? Human milk glycans are kind of hard to get a lot of and so we haven't really been able to take large quantities and put them elsewhere if you look across the animals you can look at the milk glycoms across different animals and actually none of them are as complex as human human has a large number by comparison even to lower primates but we start to see the same trends across different animals and so it's clear that these are selective across different animals but they're selective in different ways and one of the ways that it sort of follows what Rob was saying about Jen's Walter's work which is really wonderful work in addressing this evolutionary question we've isolated bifidobacteria longum from monkeys and from cows and sequenced their genomes and it doesn't have all the glycolytic capacity that the ones we get from humans have which makes a certain amount of sense matching to the milk glycom of that particular animal but that's just early early data and so one would imagine that it tracks but we have to play it out Okay there's no one standing from Mike so am I taking it that there aren't any further questions I want to ask kind of a crazy question No, not that crazy but sort of taking a lesson from the FMT talks David's talk and Julian's call for important metabolites has anybody tried to experiment with the fecal water we always target the microbes in that stool right but is there anything of benefit that can be learned from looking at the fecal water, the metabolites in the stool, are there any important beneficial compounds or anything that people have tried to explore which is an open-ended question anybody in the audience or we just throw away all that stuff and just keep the microbes John Braun is gone but the studies he showed this morning were on fecal water he has this cool way of in the rectum inserting a sponge and actually soaking up the free fluid and then does metabolomic analysis on that and he's compared to a proposal kind of that's not really fecal water but that's luminal water but I would imagine the same concept to be amenable to fecal water it's just that some of the metabolites are volatile and aren't in source maybe better than in a stored sample and that's one of the challenges is how to metabolomic materials from metabolomic analysis how long how do you store it, how do you collect it how do you process it, how do you store it how long can it go great and what about I don't know any prebiotic properties or anything in that material do you know anything about that oh here's somebody in the back do you know no, quite an answer to yours okay I mean I can't speak for John but I think that certainly the proteomics side of this, it needs to be compared with the proteomics at the same time to see what residual that's actually wouldn't be proteomics because those are carbohydrates in general so I would think that that would be part of the metabolomic analysis although they're usually looking at products rather than residual substrates okay, thank you in answer to your question regarding studies of specific metabolites I'm a director of a group in Canada that's looking at short chain fatty acids the simple metabolites propionate acetate and butyrate which have been talked about a lot in the talks with beneficial properties, cholesterol lowering and in low amounts very useful but from our approach we've taken propionic acid which is interesting because it's a main metabolite of autism associated bacteria, clostridial populations so the models we've been using in an animal model also clinical we found that these compounds as a bit of a worry they're beneficial in some ways but small amounts given in a particular times of development cause autism associated hyperactivity antisocial behavior effects in lipids gene expression and mitochondrial function so that's there's a good point about translational cleaner studies using simple metabolites that we take for granted but again it's a caveat where you have compounds that seem to be beneficial in terms as I mentioned in low amounts, coloprotective lowering cholesterol talked about as an appetite suppressant and actually I would note with propionate also used as a food preservative and at the wrong time or in the wrong place can lead to autism associated features and these are good points too the other really excellent work that's suggesting even though it may be against at one level what we're doing using vaccines against autism associated bacteria clostridial associated ones it's a very intriguing possibility and it's partly what we're looking at in Canada but and again a caveat some of these clostridial populations early on in development are actually very good they're the bacteria that seem to promote catecholamine development it's almost like the microbiome is jump-starting brain and cardiovascular function because a lot of preemie babies don't have any bugs and they look hypotensive so meetings like this are great in terms of finding potential risks and benefits carnitine was discussed as well but again it's the caveat of trying to do good translational science to show some things are good in some patients and maybe bad in others thank you one more comment over there I was just going to add to let us when we do our human fresh fecal collections we usually have to get those within 15 minutes because someone already mentioned the volatile short chain fatty acids if you can't get those acidified they're you know floating away so moving into the metabolon and those kind of data sources so just making sure you're moving and processing those samples very quickly otherwise you know the translation of that data they're just floating away essentially what you can smell is part of the reason when you're doing the fecal collections and then phenols and endols you can measure those someone was speaking about tryptovan metabolism you know in humans higher protein diets associated with you know higher phenols and endols because remember in humans we're very heterogeneous and we all eat very different diets and so we've got you know different material populations in our colon because of what we're feeding them and so you know makes it difficult to measure that as well but we have some PCA analysis with one of the posters that was here and was in Journal of Nutrition with George Fahey and Kelly Swanson is some of the groups that will do those things in humans thank you okay just with one quick question and then another one you mentioned there are 12 I believe 12 current studies fecal transplant used for ulcerative colitis can you briefly expand a little bit on a little bit about some of those studies oh this is just a catalog of things that are listed on clinicaltrials.gov they're around the world so there's I mean most of them are just toxicity studies see if it does any flares and certainly in ulcerative colitis there is a real concern that doing that because you don't have a protected barrier to see a little barrier that actually could trigger a flare of ulcerative colitis and I think those kinds of things should really be done under very very very close supervision because of that are there any studies then basically using anti-inflammatory drugs or other drugs to restore the barrier as much as possible in preparation for fecal transplant maybe say making sure that immunosuppressives or other drugs are used before and maybe during the fecal transplants do you know of any studies that are currently doing that I don't know those details okay question over that so just going back to Alita's question just putting in a plug for the robo guts for you because we've been doing a little bit of stuff on fecal water essentially looking for metabolites in fecal water is tricky because it's just so complex and everyone is so different and so one of the things that we've been trying to do is standardize a little bit by taking samples from the robo gut now that has a benefit so this would be for any chemist that kind of study so it would be equally applicable to the sort of things that Rob's doing too but the real benefit of that is that a lot of metabolites are rapidly absorbed by the host and if you have an in vitro system those made of glass you're not going to get that absorption so you're perhaps going to see some of those metabolites a bit better plus you can much more strongly control for what you're putting in and the effects that you might have so we've been collecting all of our Elaine called it waste we call it liquid gold we keep it and we have a whole repository of this stuff it's different between different people we're starting to do some proton NMR stuff on it now and that was really tricky at first because when you try and do that with fecal water you get a mess but when you do it with chemist that liquid waste you can really start to pick out some patterns and so I think that's probably where it needs to be expended let me just ask the kind of connecting question there's no way that the fecal water in the absence of the microbes could be beneficial to treating any of these patients that's something that we want to look at yes I think that would be a really useful way of looking at things because then you're taking a live organism out of the picture and making a lot more controllable and there's definitely some work going on in my lab and other labs where that's exactly what we're trying to do but it is really like pulling needles out of haystacks it's really tricky to do well if our hypothesis is correct as I said there could be multiple others it could be secondary bile acids in fecal water maybe what actually fecal transplant does that's why I'm asking the question comment over that I just wanted to speak back to the fact that a couple of questions and issues have been brought up about review over the course of the meeting and we're met with kind of a resounding silence from program officers from the various institutes and there is a reason for that there's also I'm still sitting down because I'm trying to stay under the radar but we don't have anybody from Center for Scientific Review here I want to remind all of you that they review the bulk of the investigator applications that come in the institutes don't really have much to do with that but they do have ongoing reorganizations they look at science as it changes and I think the way to reach the attention of the Center for Scientific Review is for large groups of people like this to get together the scientists, the investigators universities, academic societies contact them on a large scale level I'm not talking thousands but certainly more than an individual investigator to let them know of your concerns I think if you get their attention that will make a difference Thank you Hi this is a question for Eric I've been sitting struggling with a little bit of an intellectual conundrum from one of the stories you told and yesterday Maria Domingo's Bello told a very beautiful story looking at comparisons of the diversity and composition of microbiomes from more western microbiomes to the sort of more ancestral state in the in Venezuela and in those populations they are having in many cases a higher diversity of microorganisms and a different composition from our western microbiomes however adhering towards sort of our western diet and western lifestyles we tend to have higher incidences of immune problems and GI problems that aren't necessarily witnessed in more of these third world situations but you are telling sort of vignettes about how vaccines have decreased efficacy in those types of environments can you think of a way to reconcile that? Yeah I don't think diversity can actually explain all of it so yeah there is increased diversity in these areas of the world and I think what you maybe were confused about too is the paper I presented from Claire Fraser and Marcelo Stein where they showed increased diversity and microbiota actually helped the cell media responses but I think you can't just view it through a diversity issue I mean obviously you need a diverse microbiota to stimulate the immune system but I think in regards to the Venezuelan study and that there is all kinds of other effects such as parasites which can shift your microbiota and really can dampen some immune responses and of course exposure to more environmental antigens so yeah I think there is much more of a complex issue that you can't just start tying just diversity but maybe other aspects of their gut physiology there is some sort of asymptomatic gastrointestinal issues a lot of these children have in the rays in these areas such as environmental entropathy which is sort of this subclinical disorder of the gut where they get this flattening of the villi and less nutrient uptake and we're kind of thinking of maybe that's one of the reasons that this reduced vaccine efficacy is actually sort of more of a physiological gut response to the microbes all right we have pretty much one last quick question we've got two minutes I was going to follow up on Lita's question I think that's an important point to especially in the context of the fecal transplant we're focusing a lot on living bacteria either I'm not aware or there's not much much research on whether you really need the living bacteria or whether there might be some interactions happening between bacterial components and the host that might be responsible for a lot of the effects we see so I think it's an interesting question I would like to know if the people know more about that whether there could be other factors involved whether for example a fecal transplant with killed cells would still have potentially healing effect or maybe even in other contexts which would get around a lot of the problems that we see that maybe we're establishing a wrong microbiota in the patient which we would not have to if it's just about triggering some response through parts of the cell that don't require living bacteria okay any quick responses to that for what it's worth the way we prepare the donor material it is washed extensively and most of the fecal material other than the microbial fraction is washed away and that's still the therapeutic part we thought of as a control in a trial to irradiate this so it would look identically and that would be our placebo actually in our pre-IND conversation with the FDA we didn't like that control because we needed to do a lot more science on the irradiation but that's a one idea if I could just add one more question it sort of follows with LIDA when you look at germ-free animals their intestinal epithelial renewal rate is so much slower than conventional rates and when you look at different lactobacillus the studies that have been done suggest that there is a real differential in lacto-embifid intestinal epithelial renewal rates so in a way it argues that the commensals play a role in intestinal epithelial growth and renewal and therefore that there's something about being alive bioactive that may have potential overall value in the fitness over time but I would really really appreciate a comment from any of you on that okay very quickly time for one response well I mean if you use a germ-free mouse remember you never saw in a microorganism at least bacteria we're not controlling strangely for virus so when you introduce a new brain there's a profound response that you could see but we're not germ-free if we introduce lactobacillus in our system right now I doubt you're going to see this massive epithelial response because you never saw the immune system never saw it you epithelium never saw it you don't have a biofilm formation musin is not there very little so the interaction is totally different maybe if you have a C. diff patient prepared for transplant where you have massive round of antibiotics maybe they're going to get some proliferative response I'm not sure if someone looked at that but in term of germ-free mouse this is a transient response profound response and after that you look at the germ-free mouse that is colonized with one box of cocktail of bacteria it's really similar to a complete biome and then they just have a separation status and everything is comparable so it's a transient response alright let's call that a wrap thank you very much for everyone who participated in this discussion thank you very much to our organizers our speakers and the trillions of microbes that have kept them well fed and healthy for the course of three days please go home


Since our Special City Council meeting last week, we've seen an outbreak of coronavirus at the Sonny Ridge Nursing Home in Sheboygan. The Sheboygan County Public Health Department immediately evaluated the situation. Residents were isolated and the staff that had contact with the COVID-19 positive staff member were relieved from their duties until tested. They requested an emergency shipment of personal protection equipment from the state. I was contacted by Kalinda Napa, the director of Sonny Ridge on Friday morning asking for assistance to find additional staff to fill in for those missing because of the isolations that were due to the outbreak. I contacted County Administrator Adam Payne to get the background information on the situation and we both got on the phone and called representatives of our local hospitals who agreed to assist having their staff work open shifts at Sonny Ridge. It was great to see the cooperation between these local partners to focus on the problem and make sure that the 94 residents of the nursing home receive proper care. Public Health worked with the State Department of Health and Family Services and the Bureau of Quality for Appearance and arranged for the Wisconsin National Guard to be mobilized on Sunday. They tested 164 patients and staff and this needed to be done so we truly understand which patients and staff needed to be isolated to deal with this COVID-19 outbreak. Currently in their 21 active cases of the coronavirus in Sheboygan County, 19 of those 21 cases are associated with the outbreak at Sonny Ridge Nursing Home. My thanks to the great work done by Sheboygan County Public Health, the emergency directors Steve Steinart and Chuck Butler, the Wisconsin Department of Health and Family Assurances, the Bureau of Quality Assurance and the Wisconsin National Guard and our local hospitals for the cooperation to control this coronavirus outbreak. During the COVID-19 restrictions residents have been allowed to go for walks in the community and in our parks and currently the city is also allowed to skate park located at Kiwanis Park and the Frisbee disc golf course at JC Park to be used. I've received reports that some of the residents using these facilities have not been practicing social distancing. Yesterday we put out a reminder that if these individuals do not either mask up or observe social distancing that we will have to close these facilities so we hope that everybody will observe those parameters. Last year the council approved allowing remote meetings as long as there was a quorum of members at the meeting or attending remotely. With the current pandemic we have begun to use this new policy to continue to hold all of our normal meetings and the meetings will take place here in the council chambers so that they can easily be broadcast to the community and normal business of city government can continue unimpeded. No one knows when the situation will end so I'm asking for your patience and understanding during this difficult time. I appreciate the commitment of all the staff here at the city of Sheboygan and our local essential businesses who are doing their best to continue to deliver the services that residents expect. If you're a snowbird or you know a snowbird who has just returned to Sheboygan we're asking you to see that when you come back please isolate yourself for at least two weeks in your home. Consider getting your groceries or pharmacy delivered or ask another family member in the community to drop them off. By isolating yourself this will help us to eliminate the community spread of the coronavirus. Yesterday we held the spring election. This is not something that really should take place during a pandemic but it did. Early on the city clerk faced the news that two of the polling locations were not going to be available. Other locations were obtained and notice was mailed to the voters in those districts. Then as the election approached about 80 of the hundred poll workers that normally help out asked to be relieved of their duties and because of the coronavirus the clerk's office put out the call for other residents to consider filling in the ranks in the polls and with this new manpower and some help from city personnel they were able to staff all the locations. By having all of our polling locations all implemented and implementing new measures to reduce the chance for virus transmission we were able to conduct the election and keep all parties as safe as possible. The total votes cast looks to be just under 10,000 votes which is about 41% of the registered voters. For comparison if you go back to 2016 spring election there were 14,000 votes cast which was about 60% of the registered voters. I want to extend a special thank you to our poll workers, the staff in the clerk's office and most of all our city clerk Meredith de Bruin for the great job in organizing the spring election in this difficult environment. Let's give her a well-deserved hand. Now remember to wash your hands often. Keep a six foot distance from others, cover your cough, stay at home when you're sick, do not assemble in groups, restrict your weekly shopping to groceries and pharmacy and take out dining and stay safer at home.


Thanks a lot great to be here Especially proud since it's my hometown and I was raised in Malmo and I said when I came in the last time I was here in this place. I was not a very I was not very smart. I was probably a lot more intoxicated than I am now So hopefully I learned a thing or two on the way so Great to be here and I'm here to talk a little bit about the e-book industry and especially how we consume books in this kind of new digital age and I come from a company out of Berlin called read mail. So, yeah, as I said raised in Malmo So I'm this is especially nerve-wracking for me to stand on this stage. I think I've done a lot of different things, but all of them has kind of gravitated towards this amazing city, which is Berlin and I went there specifically to build this team Which it's a team of 13 people now from six different nationalities And we came together to build Something that would change the way we read books On digital devices and on screens and we call that thing read mail So if we jump forward to two and a half years We're now available on a range of different devices with hundreds of thousands of users spending Millions of minutes reading on these devices in our apps every month but There was a big question when we started like what's what's gonna happen with reading What's gonna be the device? Where people are gonna read books going forward? The when we started in 2011 The e-reader has been had been out for a couple of years, especially people were focused on the Kindle The iPad had just been released and the iPhone obviously was the phone that everybody was talking about But there was this Feeling that when you're talking to e-book people everybody was like yeah the the the e ink reader the e-reader That's that's where everybody's gonna spend time reading books going forward But we always thought they were wrong. We thought it was something different that turns out that we were wrong as well So let's see what actually happened. So The rate of change in the book industry has been really tremendous over the last couple of years I mean the book is Over 2,500 years old, right, but it's only in the last 25 years We've seen a lot of the big milestones as being passed that has changed the industry forever The paperback for example 150 years old Then we saw Adobe's portable document format come along which was a big milestone is still one of the leading formats for publishing today and Then obviously 10 years ago e-reader came along for the first time and then just four years ago we saw apps and When we launched our product there was over 28,000 e-book apps in the Apple App Store only for iPhones and and iPads which I think is quite astonishing So what's happening with the market then what's what's happening to e-books are they taking over? The short answer is yes, they are taking over Print and and audiobook sales has been in steady decline since 2008 Whilst e-books has been an impressive growth curve I think that in the US now e-books account for 20 percent Of the global trade book market, which is like 3 billion out of a 15 billion dollar market So it's quite impressive what happened over the last couple of years and What about the e-readers they're going through the roof as well, right? Well, it looked like there were in 2011.  I can sit on it and I'm not this disturbed by anything else I can just spend time reading but Something happened in 2012 there was actually a huge a jaw-dropping drop in sales Actually so much as 36 percent People are usually saying like oh, yeah, it's because of the update frequency You know, there's not so many more features that are brought out and things like that So I don't have to upgrade every year or every second year as we do with phones and tablets and things like that But I actually think there is more to that story than just that thing so If we take a look at the growth of e-readers over the last three years And compare that with tablets we can easily see that wow, okay wait They started in 2010 Approximately in the same ballpark, but what happened 2011 and 2012 is crazy, right? Now there are tons of more tablets available and people are buying them a lot faster than they are doing e-readers And this is quite crazy because I mean the price point for a tablet is actually still quite high when the iPad was introduced It was I think four ninety nine dollars Whilst the Kindle the cheapest model was one thirty nine dollars So there's kind of a big of a difference, right and they're also seemingly less choice in tablet market I mean there are kind of Samsung galaxies. There were blackberry tablets, but none of them were specifically popular The iPad was kind of The one that people were buying so from this graph we can definitely see that iPad is eating Kindle for lunch basically But there is obviously a third category of devices that would put both of these growth numbers to big shame and That's phones Smartphones, I mean the growth has been just tremendous. I think nobody could see the amount of growth that we've seen in that market Just for reference in 2012 there were five times as many tablets shipped as there were E-readers and there were 40 times as many phones shipped in 2012. So Very very very big difference But why am I talking about phones? Nobody reads books on phones Or do they? When if somebody would have asked me three years ago like oh, what do you think about like? e-book apps for iPhones and Android phones, so I would have said like yeah, I don't think so But things have happened since then especially on this When you're talking about screens and and especially when we're talking about pixel density So the amount of pixel that are pixels that actually fit on the screen with the current iPhone the latest model There's five times as many pixels on roughly the same screen that was in the previous model so the amount of pixels that fit on the screens has really gone through the roof and It might not seem like a game changer when you're talking about like features for phones How many pixels there are on the screen but for reading it definitely is when you're spending tons of time with your eyes Flicking up and down on the screen. It matters a lot But let me take a local example For those of you that don't know what this building is. This is croon prinsen It was the skyscraper in Malmo when I was growing up like before they built that twisted thing and down in the harbor and It just so happens that it's built out of small squares or pixels as you can see in the top left corner and You can also see that the building has kind of a nice gradient very few tourists. It's very impressive skyscraper I have to say It just so happens to fill croon prinsen with pixels or with these squares. You need 1.9 million of them Which means that if you take off the sides and you only take the the frontal side on it It's about the same amount of pixels that's being used in an iPhone 5 So around 750,000 pixels So if you were if you could imagine these amount of squares to actually fit on One iPhone 5. I think that's quite impressive So if you want to read a book in the city, you should read it on croon prinsen. I think it will be the resolution will be amazing Okay, let's take a look at some more data Just to kind of set the set the stage a little bit that read me. Let's not like some crazy company where we are Very big in some country that don't have phones or don't have tablets or something like that. We considered slightly more popular on tablets We have a 60 40% male female split 35% of users are 25 to 34 and we're biggest in the US 25% of our users are from the US and then Germany is Following up after that. So it's kind of a normal demographic I would say but if we compare The engagement across tablets and phones on read mail today a Pretty weird picture emerges. I think If we start by look we have tons of signals for engagement on our platform, right, so I'll go through them one by one Let's start with use frequency So people use their phones much often for reading then they do the tablets and It's kind of a no-brainer, right? I mean you carry the phone with you all the time and like it's it's there. It's convenient, right? So not a total no-brainer People also spend more time in the phone than they do in the tablet And I mean since you carry with you all the time. It's yeah, of course, you will also spend more time Phone users also spend more time reading per book so it actually takes them a little bit longer to finish the book than it does on the tablet which is also kind of Fair enough. It's smaller screen. It takes maybe a little bit longer to read on it But then when then it starts getting really really interesting and this is something that caught us by total surprise Phone users have more books in their library. They share more quotes They write more comments They start reading more books. They finish reading more books. They have more they follow more people They have more followers The only thing that they're actually doing less than tablet users is spend time on the web and For us The only thing that kind of stands out here is the amount of time that people are spending More time they're spending in the book so compared to phone and tablet But it's actually not that big of a difference only kind of a 10% difference So if you're spending five hours in the book, it's not that much more time to finish it on a phone Since you can use it more often will probably lead to you finishing books In a faster pace calendar time, which we'll come back to so How unlikely it might seem There seems to be a clear winner here for us Which is the phone something that we could have never guessed two to three years ago on second place definitely the tablet it's growing like wildfire and Third runner-up. Well e-reader. Sorry. You're out better luck next year One really good thing about the two winners is that they have amazing platforms platforms where you can build apps upon apps That can let you track user behavior over time So how do we actually read books or when do we have dinner in Germany because we can see that quite clearly So the first graph is people actively reading Across a day and the bottom graph is the amount of time they're spending So there are a few things here that really fast stands out. First of all There is no explicit dinner time in the US or we know exactly when Germans have dinner It struck us by total surprise that it seems to that Americans have a you know a sandwich in the mouth And reading all through dinner time. It just increases until they go to bed the second Funny thing is like the two bumps in the big beginning of the German graph on the top graph if anybody can guess what that is No wild guesses We think it's a commute There is two bumps one at 7 a.m. And one at 10 a.m. And we'll see more proof that this probably is the commute later on and Last but not least it seems like Americans go to bed or start going to bed earlier or at least to do something else before they go to bed Then reading so obviously everything else more boring If we drill down a little further we can see more proof that this is the commute, right? We can see mobile taken off or phones taken off really fast in the beginning of the day and then kind of they grow At the same pace and then tablets taking over in the evening Which kind of fits the mental model of tablets, right? You have them at home and you sit on your couch and reading some So it fits the mental model But mobile is much bigger Much bigger if you compare it to the US where there are a lot more tablets And here we actually see a commute bump as well, but only on phones So this also strengthens the case that like tablets. It's nothing you bring along Maybe on the subway or something like that Hopefully Americans don't read and drive. I think that would be a bad idea And then we can see them grow kind of similarly Until like tablets eclipse for a short while at 8 p.m. Where maybe you sit in the couch and like Have a glass of wine and read a book and this romanticized picture So Lastly, I just want to show you one more thing which is a question that we get asked a lot how long does it take for the average person to actually finish a book and Are we faster than the Americans or not? Okay, average Americans takes about a month to finish a book calendar time, right? They're slightly faster on the phone actually Then on the tablet and this is calendar time not effective time So since they're reading a lot more often on the phone well, then They can finish books faster. So million-dollar question. No, we're slower than the Americans. It's terrible, especially on tablets So actually if you look at this graph Americans have the time to finish one more book a year Which is definitely not good. We need to shape up We definitely to shape up and read more or as you can see phones are exactly similar So we just scrap tablets in in Germany in general and just go with phones so this was just a little scratch on the surface of Data that we can generate and we can analyze in how people are consuming books and how their reading behavior looks like and It's super exciting to play a very very small part in making the publishing industry a little bit more data-driven So if you want to check out read me and see what we do and try out our apps check us out on read me calm Thank you so much


Hi, this screencast is about getting up and running with an OpenShift service mesh. In this screencast, I'm going to show you how to install a demonstration application and then bind it to its service mesh and then control the application's behavior through the service mesh. The demonstration application is a fairly simple one. It's composed of three microservices. One is orders, and the orders microservice talks to a Kubernetes deployment named orders. And in turn, orders will make payments, and then when a payment is made, part of the response will be to get a recommendation along with the order return. The payment service uses a payments deployment, and the recommendation service uses two deployments. One is recommendations music, and the other is recommendations food. Now when the service mesh is first applied, what will happen is that the orders service, which uses the orders deployment, will get recommendations from both the food and the music deployments in a round robin fashion. However, after the service mesh is running, we're going to apply a destination rule. And the destination rule, what that will do is it will tell the recommendations service to use only a specific deployment. First we'll start out using only the recommendations food deployment, and then we're going to alter the destination rule usage to show the recommendations music data, data coming from recommendations music. So that's how it's going to happen, and you might have to refer back to these slides as you go through the video because there's going to be a lot of stuff going on, but pretty much this is what we're going to be doing. The steps, there's going to be 10 steps. It's a little bit of an involved video. We're going to install the OpenShift service mesh. Actually that's going to be happening already. We're going to have an OpenShift service mesh start installed at the start. Then we're going to create an application namespace, and then we're going to bind the application namespace to the service mesh. Now I'm going to go through the mechanics of that, but underneath it all the namespace has already been created and it's already been applied to the service mesh, but I'm going to show you the details of how that works. Then we're going to install the Kubernetes resources, and that's going to be the service for the orders and the order deployment, and then the service for the payment and the payment deployment, and then the service for the recommendations along with the recommendations food and recommendations music deployments. Then we're going to add a gateway to the OpenShift service mesh, and what a gateway does is it allows external requests to get into the service mesh. In number six, we're going to add a virtual service orders to the service mesh, and this is going to make it so that the orders is subject to the service mesh. That means that the service mesh will be in charge of the order service, and then we're going to apply a destination role to the service mesh. Then in number eight, we're going to create a new virtual service called virtual service food, which will be bound to the recommendation service, and that will return only back the recommendations from the deployment recommendations food. We're going to delete the virtual service food, and then we're going to add the virtual service music, so that only recommendation data coming back from the deployment recommendations music will be applied to the payment response. And I'm going to use Postman to show you all this stuff in action. OK, so that being said, the thing you need to understand, as I mentioned earlier, is that I did indeed install all the operators for the service mesh to the OpenShift cluster, and the way you do that is you go into the OpenShift web console and select the administrator tab, as you can see on the upper left.  And then from operator hub, you're going to select the operators that are shown in this diagram under installed operators. And that's OpenShift, the OpenShift elastic search operator, the Red Hat OpenShift distributed tracing platform, the Kali operator, the Red Hat OpenShift service mesh, which is indeed a service mesh. And also, if you want to use the web terminal, which we're going to use, you're going to want to install the web terminal operator, which will allow you to use a web terminal in the OpenShift web console. So that's pretty much what we're doing. The source code for this application is online, along with all the configuration files. And let me show you where that is. OK, so that's here. So if you go to Red Hat Developers Demo, you'll see a repository called Simple Service Mesh Demo. And in there, you're going to see the Kubernetes configuration files. You're going to see the service mesh configuration files. And also, you'll see the source code for the application itself. The application is installed as containers out on KIO.  You need to know that. And if not, you might want to go back and review. And then I'm not assuming a lot of knowledge about a service mesh other than understanding a service mesh is really a one-ring to rule them all approach to controlling applications in a Kubernetes, excuse me, in an OpenShift cluster. So given that, let's start. So this is indeed my OpenShift cluster. And in this case, I'm running one under Azure. You need to have a fully functional OpenShift cluster. That means that you have the ability to create namespaces and install operators. And in this case, you can see I have both operator and developer. The other thing I'm going to do is you can see here, I'm going to add a terminal window to run directly within the cluster. And this is going to automatically bind the OC command line utility to the cluster. So that being said, let's move on. So the first thing I need to do is I need to create the namespace and I'm going to use the OC command line tool to do that. And so I'll go to here and you can see I'm going to use OC create namespace demo. And I'm going to do that and it's going to get the saying I can't create it because the namespace already exists. That that's to be expected. That's not a server. When you run it from scratch on your installation, you'll say, oh, no problem. But in this case, I do have the namespace not only installed, but I also have it bound to the Kubernetes cluster. And the way I'm going to do that is I'm going to go into administrator view and I'm going to show it to you. I'm going to go to operators and I'm going to go to installed operators. And let me go down to OpenShift here and you can see here under OpenShift, there's there's a lot of a lot of stuff. OK, and you can see that I have provided APIs, in this case, ServiceMeshControlPlane, ServiceMeshMember and also Istio ServiceMesh member role. And what I'm going to do is I'm going to go and I'm going to go into the member role here. OK, and excuse me, do I have to create a member role? OK, I'm going to create the member role. I guess I forgot to do that. So to do that, I'm going to create the member role. And what I'm going to do here is I'm going to copy this and this is going to go out and create, use the member role out on the repository. And what the member role is, is once you define, you you bind the namespace to the member role, that means that the ServiceMesh can see the application. And we're going to install our application under a namespace called ServiceMeshDemo. So let's run this and see what happens. And it's thinking. OK, so let's go back here and let's see if we can go find the ServiceMesh role. Let's go to YAML. And if we go in, oh, but OK, sorry, I didn't do it happen. So I'm going to just do it right here. I'm going to say, OK, my membership here, namespace. Oh, I'm sorry, duh. No, here's the problem. I'm sorry, I do this all the time. So let me respond. You have to go into the Istio system. This is I do this all the time. Sorry. And because the namespace, the ServiceMesh is going to be running under Istio system. Sorry about that confusion. And if we go into here, you'll see that indeed, there's the ServiceMesh role, member role. So if we go to here and again, this is very important. And again, I apologize for creating the confusion, but all of the ServiceMesh is going to take place under Istio system. And when you run, install the operators, it's going to be installed under Istio system, that namespace. So if I go to ServiceMesh, member role, I go to default and I look at the YAML. What you'll see here is if I go down here, you can see that the members ServiceMesh demo has already been installed. I did that previously.  But this means now that the ServiceMesh is going to know everything about what's going on in that namespace and that namespace is ServiceMesh demo. So now I have the potential for configure, for binding the application to the ServiceMesh, but I have to create the application and bind it. So in order to do that, what I'm going to do is I'm going to get the, I'm going to get the source code from, I'm going to install, I'm going to clone the demonstration application from Red Hat. And it's under demo, simple ServiceMesh demo. Okay. And now I have the source code. And now what I'm going to do is I'm going to go into the working directory for the source code. And then what I'm going to do is I'm going to run in a shell script I wrote called app setup. And let's go back here and let me go into the source code and show you what I mean by that. I'm going to go KAS. And app setup, what it does is it's going to create all of the Kubernetes resources that we need in order to get the application up and running. And you'll see here that it's going to try to replace the service role. It's going to try to create the namespace. This will error out because the namespace has already exist. And then it's going to create the recommendations service and deployment, the payment service and deployment, the orders service and deployment. And then it's also going to return the route to the to the service mesh demo. But we're not going to use this route. This route will be ineffective because the service mesh will already have taken hold. I'll explain what that means. But let's go back to here and let me run the setup here. I'm going to go paste. Oh, sorry. Let's go to here. Let's see what happened here. Let me go to simple service mesh. There you go. Okay. Okay. Let me clear the screen so that we have a little more real estate to work with. And then we go to LS. Let's see if it's there. Do a little typing. Yeah. Excuse me. Then I got to see you. Show you what I know. I've got to go to K8S. Okay. Let's go to LS. Okay. And there is app setup. So we'll go SH. Okay. And you can see now it's going to run the setup script. Okay. Okay. So now let's see. Everybody should be in place here. Okay. So we're saying everybody here is created. Everybody here is created. And so let's go into developer mode here. Developer view. And you can see here. Here is this is in the Istio space. But let's take a look at service mesh demo. And you can see here's everybody. There's here's orders. Here's payments. And then here are here is the recommendations food and recommendations music deployments. And then also what we'll do is we'll go back to administrator just to make sure everybody's happy we'll go to administrator and we'll go to operators installed operators and we'll go to Istio service and we'll go down here. We'll go to service role and we'll take a look at we'll go into the default and we'll take a look at the YAML and you can see that there's the service mesh members. So everybody is set up just hunky dory. Now one last thing we're going to do what we're going to do is we're going to do OC get pods and I'm going to get the pods by the namespace service mesh. Oops. You need to learn type over the weekend demo. And what you can see here is the pods the deployments were initially configured to run only a single pod in each deployment. However, if you see that there's two containers in each pod. OK. And what that second container is that second container is a sidecar container that the service mesh injected into the pod. And it's actually an envoy container. And what that can sidecar container does is that's the means by which the service mesh talks to the deployment. So instead of Kubernetes talking directly to the orders or payments or recommendations, what happens is Kubernetes talks to the service mesh, the service mesh talks to the sidecar container and the sidecar container talks to the deployment. That's how control is exerted. So right now we have the containers deployment up and running and the the sidecars have been injected. The next thing we need to do is install the gateway and the gateway is the mechanism by which requests make their way into the service mesh. And if we go into here, you'll see here, there's a gateway and this is the gateway we're going to execute, but pretty much it's a gateway. We're going to put it take take a look at anything in service mesh demo, use a default gateway that gets shipped with the service mesh and anything coming in over port 80, send that into the service mesh. That's what that's about. So let's go to here. Let me give yourself a little more window. And then let's go grab the YAML. We'll do that and let's put that here. There's the YAML and we'll see here. And now we've created the gateway. However, the gateway that lets you into the service mesh, but there's really nothing there once the requests arrive. And in order to put it there, there, we need to create a virtual service. And in this case, we're going to create a virtual service called order. So let me go back into the sort of the configuration code here and we'll go to and this gets this is the orders. This is the YAML file and what this is saying is saying, OK, here's a deal. Anything that comes in on the root of the request, any request, what to do is port, direct them, route them, send them to the orders host. Now, in service mesh parlance, a host translates into a Kubernetes service. So in this case, what's going to happen when a request comes in at the root, what the gateway, what the excuse me, the virtual service is going to do is it's going to send it to the Kubernetes order service going up against port 8080. That's what's going to happen. So let's go back to here. Let me grab the command, the OC command. Let me clear the screen so we have a little more real estate. OK, this is the OC command that's going to execute. And now you can see the virtual service has been created. What this means is that now the request can come in, the virtual service is looking, oh, there's a root request, I'm going to accept that and push it on to the orders host, which in KAS is the order service. And if remember the order service, what it's going to do is any request coming in, it's going to submit to the payment service and also to the recommendation service. And upon return, the recommendation is going to give a recommendation text. So let's see if that works. Hopefully. So what I'm going to do is I'm going to go to postman here. And this is my postman instance. And I have a little post going on here. OK. And what I have here is let me go to body and you can see here I have a simple post and it's going to go to Barney Kelly. It's simple. Post this this is how the post supposed to go in and it's just going to send an order in with order information credit card product ABCDFJ. So let me go send it. And now you see I got a 200 a 200 return. This is successful. And what it's saying is it's giving the product and the credit card number. And then if you look, you can see a recommendation came back and that recommendation says buy more nuts. And I just happened to know that comes in the recommendation food service. So that's that's the response. And then if we go to get the get value and I send it, you'll see here, by the way, this is all of the orders that have been placed in the service. And you can see there's by some more recommendation excellent nuts. So effectively what we've done is we've put this layer of inspection on the service mesh through the virtual service called the orders and request comes in the virtual service order says oh request coming into the route. I can see this. I'm going to pass it on to do Kubernetes order service and let Kubernetes have its way with it. So that's one thing. All right, that's done. Now what I didn't show you had to do and I'm going to do that now is I'm going to show you how to get the actual URL to call of the service meshes URL so you can call make a request to make a call. Sorry, I got a little fumbled on words. And the way you do that is you use the OC command Istio system get route. And this is very particular to my installation of OpenShift on my platform, which in this case is Azure, I put that in. And then you can see this is this is indeed not this thing here, but here is this is the route I've been using. And so if I go back to postman you can see there's the route there. That's just a nice you need to have that you need to know that the service mesh will publish its own route and the way you're going to get it is to use this command here. OK. All right, that's done. Now the next thing we're going to do is apply a destination rule. And what a destination rule does is it sets up some routing rules for lack of a better term. So let's go back into the source code and look at the destination rules. Go to service mesh and we'll go to destination rule. And we'll see destination rule here says OK, I have a virtual type kind destination rule and I'm going to apply this to service mesh demo. And then what it's going to say is here's the spec. Any this rule applies to any host recommendations. Any host recommendations translates into the kuminetti's recommendation service.  And in this case, the destination rule has two subsets. One is named recommendation food and recommendation music. And these names they're arbitrary. They're just fundamentally arbitrary. I just named them the same as the deployment sort of so that they made sense. And what this is saying here saying OK, whenever you see a request that gets eventually ported to the underlying recommendation service, apply the label version food, in this case, recommendation food, or if we're using the rule recommendation music, apply the the label version music. That's what the rule does. However, in order to enforce the rule, we're going to have to make a virtual service that uses the rule. And I'm going to show you how to do that in a minute. But right now what I'm going to show you is how to apply the rule. So let's go back. Sorry, what happened here? That's strange. OK, let's open up. Let's see what happened to the terminal. Oh, it's down here. Oh, there's the terminal. Sorry, I got a little lost. All right. So let's apply the destination rule. So go to here. Oh, sorry, typo. OK, forgot to put the L ready. Here we go. There's the L. OK, the L then. Sorry about that. OK, let's put that in. OK, so now we've created the destination rule and the destination rule is out there, but it doesn't do anything yet. In order to make the destination rule work, what we need to do is to create a virtual service that uses it. So let's go back into the source code to go back to service mesh. So let's take a look at virtual service food. We're going to create that. And what virtual service food says, OK, go into the namespace service mesh demo and then find the host recommendations, which translates into the Kubernetes service named recommendations. And we're going to apply a route based on a destination rule. And the destination rule says, OK, go find the service recommendations, the host recommendations, and go use the destination rule recommendations food. Now, there's a lot of conventional logic in play here. Sorry, I apologize on behalf of the service mesh. But remember, the service mesh food recommendations food was defined in the destination rule here under the subset. And this is really a subset name recommendation food. So if we go back here, we go back into it and I look at the virtual service, it's going to create a virtual service mount recommendations. And it's going to go out onto the service mesh and look for a destination rule that has a subset name recommendation food. That's what this is going to do. So let's do this. Let me go. Now let me apply. Let's create the search. Let's create the virtual service. So I'm going to create the virtual service. I'm going to leave the L on at the end so we don't get errors. OK, the virtual service has been created, OK? So what this means now is that any request to orders and then delegates down to recommendations is only going to use food. So let's test that. Now, as you might recall, I said that until a destination rule is applied, what will happen is that the order service will feed up recommendations on a round robin basis, alternating between food and music. And the first time we did it, it was food, all right? So typically we should expect if indeed the destination rule wasn't applied, we should expect filtering between food and music. So what I'm going to do is I'm going to change this. I'm going to call it Bobby. Oh, excuse me. I've got to go to the post. Let's look at the post, Bobby, here. And I'm going to change data a little so we have something easier to keep track of. I'll change it to Bobby Kelly. OK, and I'll just do a little cut and paste magic here. OK, and the food I'm going to eat, we'll let Bobby use Jerry's credit card. Why not? Life short. All right, so I'm going to send this 10 times just because I can. I'm going to go one, two, three, four, five, six, seven, eight, nine, 10. And then I'm going to go back to the get. I'm going to get all of them. And now as you can see, I have a whole boatload of orders that have been processed. And you can see all of them are returning recommendations from the foods, in this case, by some more excellent nuts. OK, this is the food recommendation, food only. OK, that's good. So effectively, what I've done is I've applied a destination. I created a destination rule that has both recommendations, food and recommendations, music filters for those. And then also I implemented it by creating a virtual service for the recommendations service. I know it's a little bit confusing, but I created the virtual service recommendation, which sort of takes over the recommendation service under Kubernetes. Now, the other thing I do need to point out and this is somewhat this is important because you need to remember about how selectors work under a deployment. So if I go back to my developer mode and I go into service mesh demo and I take a look at the recommendations food, excuse me, I want to go look at the deployment, my fault. Let's take a look here. I go to topology. Let's go to here. Let's take a look at the deployment. And if you look at the deployment, in this case, there are two labels, application recommendation and version food. And this is for the deployment for recommendations food. And then if we go back and take a look at the deployment for recommendations music, you'll see that the selector ships with two labels, applications, recommendation and version music. So food has music, excuse me, music has app recommendations, version music has their labels. Food has app recommendations, version food has their labels. So what is the relevance here? So if we were to go back here and we'll go back to the command line because it's a little easier. Let's go to the command line here. It's a little easier. And if I go to get, excuse me, OC get services, and it's in the namespace, sorry. And if we were to take a look at the recommendation service, so what I'm going to do here is I'm going to go OC describe. Okay, if we were to look at the selector for the recommendation service, you can see it only has one selector label defined and that's app recommendations. So the Kubernetes recommendation service is going out into the cluster and say, give me pods that have the label app equals recommendations. However, the destination rule is applying another label. And in the case of recommendations food, it's applying the label version food. And in the case of recommendation music, it's applying the label version music. So what's happening is the service mesh is injecting labels into the service definition of the virtual service. I know that's a lot to go on and if you're not really familiar with Kubernetes selectors, it's a little hard to grasp. But the important thing to understand is that you create the rule and the destination rule and you apply a destination rule in a virtual service. And in this case, we have a virtual service that's filtering on recommendations food. What we're going to do now is we're going to take away the recommendations food virtual service and we're going to apply the one for music. So the first thing I need to do is I need to delete the virtual service for food. Let me clear this. Okay, that's gone. There's no more virtual service or food. All that filtering's been taken off. And now what I'm going to do is I'm going to apply the virtual service for music. And before I do that, let's just go back here. Let me review and go virtual service music. And it's saying, hey, go look for pods that have not only app recommendations and that's there implicitly, but also for the injected labels that are defined in the subset. And if you might remember, the injected label is version music. I know, not going on. You might want to go back and review this video a couple of times just to keep track of things. So let's go back here and I'm going to now apply the virtual service. Notice the spelling is correct now. Hit enter. Okay, good. So now that music virtual service has been applied. So let's go back to post, man. Okay, and let's go to my post. In this case, I'm post and we'll make another one. And we'll call it Betty Kelly just because we can. Okay, and we'll go here, Betty. Do a little cut and paste magic here. Go Betty. Okay, we'll make Betty, Betty. And in this case, we're going to say, oh, this product is a music. Okay, again, this is arbitrary. There's nothing, this is nothing that you have to do. And we're going to make, we'll call this guitar strings. Whoops, just because we can. Okay, so maybe I should learn how to type over the weekend. All right, so Betty's buying some guitar strings and remember now the filter for recommendations music is in play. So I'm going to send one. Good, 200. And let me, let's see what happened here. Okay, oh, that's a music recommendation. Buy another album by the Temptations. And let me send 10. Remember the contract was no more robbing. Everything is going to be filtered according to music. So we'll go to here. We'll go to get, I'm going to send, get all of that. There's the old recommendations for food. But if we go down now, we'll see, oh, by the way, all of these orders are now filtered to use recommendations music. There you go. I just bought 10 guitar strings, guitar strings over and over again. So there you have it. That's really pretty much as it goes. So let me just bring up the, this diagram again. So we're very clear about what happened. So what happened was I created a gateway. Okay, and the gateways are reflected as this gateway URL. And I told the gateway to take any incoming requests to port 80 and forward it on to the virtual service orders. And underneath the covers, virtual service orders uses the Kubernetes orders service which in turn uses the Kubernetes orders deployment. Then what I did after I exercised general orders around Robin fashion, getting back music and food and music and food and music and food, I have created a destination rule. And in the destination rule, I created two subsets. One is called version food. The other one's called version music. Not called, the name is actually recommendations food and recommendations music, but I define the labels version food and version music. Then what I did is I applied the virtual service named virtual service food. Virtual service food is going to go out and look for the recommendation service. And then it's going to inject the labels defined in the subset recommendations food. And in this case, the label is version food. And as you might recall, only the deployment recommendations food supports that label in addition to the originating label of app colon recommendations. Then what I did is I deleted the virtual service or virtual service food, reapplied a virtual service for virtual service music. And then I executed postman to get, to send orders for some sort of a musical item. And I got back recommendations for music as defined in the virtual service music, virtual service. I've never repeated myself. All right, so there you have it. This is a lot, lot going on. It is confusing. I know it took me a while to say, oh, now I sort of get it. So what I recommend doing if you have a chance, just go back and review this video informally, take some time and spend some time in the manifest files and in the source code so you can get a sense of what's going on. Thanks for taking the time to view this video. I hope it helped you understand OpenShift service mesh a bit better than when it started. Thanks for watching.