I'm not sure what I can add to what we just heard. This is the title that I think I said myself. I'm going to take a look back and look forward and tell stories that will be familiar to many of you. But I thought my job here is to sort of set the tone. I'm going to show data that I think most of you have seen before and are familiar with, but in a context that sort of sets forth what we've learned and what we don't know, and the roadmap is down here. I think it is important to emphasize that we will never get anywhere unless we understand the underlying biology. We have to make discovery in order to implement discovery. And I think that's self-evident. I know we're here to implement. I'm not going to dwell on the discovery part, but I'm going to talk a little bit about it.  Everybody expects there to be variability in response to drugs. These are old data from the Pharmacogenomics Research Network. Julie will recognize this graph. Maybe it's a long, long time ago. And the notion is that no matter what metric of drug response you look at, there is always variability around a mean effect. What we're much more interested in and what catches people's attention is the rare adverse drug events. And some of those are pictured here. And for those of you who can't figure out what they are, they're shown here. So just to make the point, and I think Simone will probably make it later, that there is a lot of activity across NIH looking at basic mechanisms. These are web pages from the current Pharmacogenomics Research Network. And this is us, and this is the Stevens-Johnson project going on at Vanderbilt, supported through a P50 award. And the important project is the QT project that is highlighted here, because that's what I do. Adverse drug events are rare. And in the practice of an individual physician, come up so rarely that they may not be recognized as Mr. Anderson highlighted for us. That said, they are an enormous problem across the country. These are old data, venerable data. People love to quote these as adverse drug events being the fourth to sixth leading cause of death in hospital. Those are 1998 data. In 2010, the data were really not very different. 100,000 people a year would be the equivalent of one jumbo jet crashing and killing all the passengers aboard every single day. So this is not a small problem. This is an enormous problem. In the United Kingdom, Manir Parmohamed and his colleagues looked at hospitalizations in three years across 18,000 patients, and 6 and 1 half percent of them were due to an adverse, 6 and 1 half percent of admissions were due to an adverse drug reaction. These are the drugs I don't expect you to look at the list and memorize them. But the estimate is that somewhere around a third of these have a prominent genetic component to risk. For those of you who can't remember why drugs work and how drugs work, this is my simplified version of truth. That is, you give a dose of a drug and it's delivered to its molecular target. Lots of things happen in between. And those are the pharmacokinetic variants that people worry about. And then once it reaches a molecular target, good and bad things happen at the whole organ and the whole organism level, and that's the pharmacodynamic piece. And of course, all the genes that are responsible for transducing pharmacokinetics or pharmacodynamics are candidates for variable drug effects through pharmacogenomic mechanisms. This is a venerable slide from Mary and Bill in a science article in the last century listing major drug metabolizing pathways. I used to highlight which ones had polymorphisms in them, but I don't do that anymore because they all do. But I think this is the framework. That said, I think this is not a terribly, this is a catalog. And I think another good way of thinking about it is this concept of high-risk pharmacokinetics that Mike Steen and I actually wrote about 10 years after Mary. And I think it's a concept that's sort of self-evident to everybody in this room. And that is there are certain situations in which a polymorphism in one of those drug metabolizing pathways assumes particularly clinical importance. One setting is a pro-drug that is bioactivated by a pathway that either is absent for genetic reasons or because of phenocopying by administration of an inhibiting drug. The best example is enkinide, but that's no longer in the market. And I spent 10 years of my life with enkinide, so that's why I put it here. But I do put it in smaller type. And clopidogrel, tamoxifen are like this. Coding, of course, is a pro-drug that's bioactivated through this pathway, not bioinactivated through this pathway to morphine. And you all know the stories around that. The other high-risk pharmacokinetic setting is where a parent drug is bioinactivated through a single pathway, the same idea. That only becomes important if there's a narrow margin between efficacy and safety for these drugs. If a drug has a very wide margin, then inhibiting the pathway doesn't have as great of an effect. Examples of that are warfarin, urinary t-can, is a thioparin. And the other way in which this can happen is if you have failure of the excreter organ. That's not genetic. But I'll come back to that and give you a specific example of sodalol and renal failure. Somebody on sodalol develops renal failure. They will develop toxicity because of very elevated plasma concentrations unless the dose is reduced or the drug is stopped. I want to talk about warfarin. And I do this with very mixed emotions, because I think warfarin as a drug is going away. But warfarin has taught this community a lot. And I think the thing to take away is the lessons that we have learned good and bad over the years. So Alan Reddy described a paper, described warfarin metabolism, and described the fact that there was a specific high affinity pathway for warfarin metabolism in liver microsomes, again in the last century. That turns out to be CYP2C19. He actually described the Star II polymorphism as suggested that might be a mechanism for variable drug actions. And again, in the last century, people noticed that there were patients who received very low doses of warfarin and had a high burden of reduction or loss of functional leels in CYP2C9. And interestingly, they had an increased incidence of bleeding, an observation that's really interesting, and I'll come back to later. My throat is better, in fact, than it's been for the last two weeks. So if you ask somebody at the beginning of the 21st century, what's the pharmacogenetic story around warfarin? This is the story, S. warfarin bioinactivated by CYP2C9, and there are variants in CYP2C9. And the FDA was all ready to start a trial looking at the effect of preemptive genotyping for CYP2C9. Some of you will remember that. And around that time, there's this paper in Nature that describes variants in B-core C1 as a cause of warfarin resistance, and it becomes clear that there's another piece to this story that involves the pharmacogenomic piece, B-core C1, which is the target for warfarin action. Terry Klein and others organized the International Warfarin Pharmacogenomics Consortium that put together 5,000 people and their genetic data from across the world. And there are a couple of observations that we made that were important. Number one, though a steady-state warfarin dose varies by ancestry. Number two, a lot of that variability is attributable to changes to a common polymorphism in the promoter of B-core C1, as well as to rarer variants in CYP2C9. We catalog the variants in CYP2C9 in European populations, it turns out there are others in African populations that we just didn't look at in those early days. And then you could compare an algorithm based on pharmacogenetics, an algorithm based on clinical features alone, or an algorithm that said start with 5 milligrams a day and go from there across all the patients that we had in the consortium. And you could show that adding genetics makes a difference in people who end up on higher low doses. The fact is, most people end up in the middle. So this is one of the lessons that if we're going to implement pharmacogenomics, it only benefits a subset of the population. These people don't need genetics. Another piece of the puzzle that I think we haven't paid as much attention to as we should is this idea that there are rare coding variants, rare non-synonyms variants in the coding region of V-core C1. This is a really nice study looking at people who take very high doses of warfarin. And the reason they take very high doses of warfarin is basically because they're non-compliant. But when you start to do genetic testing in those patients, you find occasional patients who are compliant but who have variant genetics. And this is a nice example. This is D36Y. It's a rare variant, except if you happen to be running an adicoagulant clinic in Israel where it's quite a common variant, and it accounts for high doses. So that's the story in 2008. Fast forward to 2017. You can look up in Nomad as I did last night. There are 231 non-synonymous variants in V-core C1. So each one of those is a candidate for transducing high warfarin dose requirements in a rare patient. Carol, this sounds like GM9, doesn't it? I mean, the challenge to us is now to figure out the functional genomics of each one of these. And as, of course, the warfarin lesson has been that there have been randomized trials, I'm not going to get into the details. They are very important. The details that are important are what the ancestry is, what the genotyping is, what the endpoint is, and you know that the US trial showed no difference when genomics were added to a clinical algorithm. The European trial showed a difference when genomics were added to a standard warfarin dosing regimen. One of the things that all those trials were underfunded. They were underfunded and underpowered to do is look at important endpoints like bleeding. So this is the US, the COAG trial and the bleeding events. There were very few, but the trend, interestingly, is in the right direction. At Vanderbilt, we used our EMR to look at a very, to continuously ascertain a large number of patients, around 500 patients with bleeding events that led to admission to hospital and 500 controls. And what we found was that CYP2C9 star 3 is a predictor of that event, not a, not a, with an odds ratio of 1.7, so not a huge effect, but an effect nevertheless. And Dave Veenstra has very similar data, but he landed on CYP4F2 and Josh Peterson and Dave are going to put the data together, along with Mike Steen, to figure out, and many others in this room actually, to figure out what the right, what the right predictor is. And then GIFT was announced about two months ago. I asked, I asked Brian Gage for the slides and he said he would ask the steering committee and the steering committee is still deliberating. So this is what I know from the, from the American College of Cardiology website, 1650 patients who are randomized, who are going to get Warfarin randomized to a pharmacogenetic algorithm or a clinical algorithm with sub-randomization to various INR targets. There's a composite primary endpoint, which is listed here, which I think is very important, because genetics beat, beat the conventional therapy. This is the first time that genetics in Warfarin have actually shown this big effect in the United States. This is a largely Caucasian trial. The African-American alleles are not included. And there are sub, I think it was major bleeding in the INR greater than four, but Julie may know better. I can't remember, Julie, which, which are the components of the component composite endpoint, but you're not allowed to look at components anyway. So, but this is, this is calming. This is in review and, and I'm not sure how this will affect Warfarin use because Warfarin, I think, is going away, but I think that there's an important lesson here. This is a really interesting, there's a lesson in this study, and I think it's important to say it. So, azathioprine and TPMT, this is a study done in, largely in Europe, randomizing patients with IBD who are going to get inflammatory bowel disease, who are going to get azathioprine to a conventional therapy or an intervention arm. The intervention arm requires genotyping if you have, if you're intermediate or if you're homozygous, now the doses are reduced or reduced drastically and, and then followed. So, one question is, when you reduce the dose of azathioprine, do you actually change the outcome in inflammatory bowel disease? And they have lots and lots and lots of metrics in this study that show that there's no difference in the disease course when they adjust the dose. What's interesting is, when they look at the percentage of patients with hematologic adverse drug events, there's no difference. Whether you, whether you use genetic guided therapy or not, so you'd say, okay, I don't understand why that is, but there is no difference. But when you then look, not across all the patients, but only the ones with the TPMT variants, then there's an enormous difference. Then the number of people who get adverse hematologic effects is very, very small, almost zero in the, in the intervention arm and about 22% in the conventional arm. So, this again highlights the idea that if we're gonna do pharmacogenetics in this way, the benefits are there, but the benefits are there in the people who have the variants, and that may be a small subset. I don't wanna dwell on this. It's a prevent, it's a terrible adverse drug reaction. It's terrible and predictable. Simon Malal and Elizabeth Phillips showed over 10 years ago that there's this huge odds ratio for a back of your related SJS, and you know that there's a trial called Predict that looked at a genetically guided therapy versus conventional therapy. You're kidding. Conventional therapy in the initiation of a back of ear, and basically you could get rid of all a back of ear related skin rash, which is this line down here by doing genetic testing, and this has become part of therapy. The same story holds true for carbamazepine and HLA B-1502. This is the study in nature that described that in 2004, and 1502 is interesting because it's highly prevalent in Southeast Asia, and not so prevalent across the world. There are other alleles that are prevalent in other parts of the world that transduce carbamazepine induced Stevens-Johnson syndrome, but again, it depends on where you are and who you are. There is this interesting Hong Kong carbamazepine experience. They saw the data. They put in a policy that you had to do genetic testing. So what happens when you do that? New prescriptions for carbamazepine just fall. People just don't do the genetic testing. Instead what they do, and the incidents of carbamazepine induced SJS falls, instead what they do is they increase the use of phenitine, a drug that also has SJS associated with it, although we don't know exactly what the right mechanism is for that drug. So the total number of SJS cases stays stable. And the moral is not that you don't do genetic testing. The moral is you have to do genetic testing and an educational program and tell people what to do with the results, not just sort of say don't use carbamazepine because it's a pain in the rear so people stop. So I can't talk about implementing without showing this slide. I've been showing this slide for probably 17 years now. And I think it says a lot about the expectations of the public when we see cartoons like this in the New Yorker. And this is what Francis Collins said when he became director of NIH about pharmacogenetics. And many of you have seen this slide before. Basically, what Francis says is if everyone's DNA sequence is already in their medical record is simply a click in the mouse to find out all the information. So we all, I think many of us in this room have drunk this Kool-Aid and agree with this, but it's not simple as we're, and that's the reason we're here. And it's probably not as inexpensive as Francis thought it was going to be. So I told you I'd say something about Sotolol. This is an 82 year old male in Sotolol for atrial fibrillation, develops renal failure and no dose adjustment is made. And he develops this really interesting long QT related polymorphic tachycardia due to Sotolol toxicity. And if you look at the label for Sotolol, it says adjust the dose when renal failure occurs.  But this is the way we practice medicine. So is this a case of genetic exceptionalism or a case of Sotolol exceptionalism? I don't know, but I think that we have to sort of think about what kind of evidence do we want, do we need to have before we implement? And that's one of the reasons we're here. Clopidogrel was approved in 1998, was known to be a pro drug. The bioactivation pathway was not defined, but it was approved anyway. In 2006, the pathway was defined. And what was interesting about this study is a small CRC related study. And they studied heterozygates for the loss of function allele CYP2C9-2, and what they show is that this is platelet function on the y-axis. At baseline, there's no genotype effect on platelet function. After a week of clopidogrel, you have reduced platelet function in people with a wild type allele, but with tremendous variability across the population, across this small CRC population. And in the star twos, there is a small effect, there's no effect on average, but there's an effect in some people. That translates into retrospective looks at a difference in the incidence of clopidogrel related events. If you carry a variant, you have less good clopidogrel outcomes with higher incidences of adverse events compared to. If you don't carry the common alleles, we don't know anything about the rare alleles. At Vanderbilt, we have the Predict program, and the Predict program has been genotyping. It's genotyped about 15,000 people. And what we find is that 2% of our population are homozygates, so those are high risk for not responding to clopidogrel. About 20% are heterozygates. High risk for not responding to ordinary doses may need higher doses. So, if you're a cardiologist, you're looking at a difference between 12% and 8%. You're gonna genotype a lot of people to chase down a little bit of an event, and you sort of say to yourself, why do I bother to do this? If you're a geneticist, you say, well, you're doing it to chase this group here and perhaps some of this group here. Sarah van Driesen, our group, looked at five drug gene pairs. Clopidogrel is one. There's a group at high risk, a group at moderate risk, and for each of the drug gene pairs, we define a group at high risk and moderate risk. The important point is that 5% of the population is at high risk for something, and these are data that have been repeated worldwide. And 91% in our hands, just for five drug gene pairs, are at moderate risk for something. You just don't know what the drug is, and you don't know whether they're going to get that drug. So that's the argument for the idea of large preemptive pharmacogenetics, not across a single drug, but across large numbers of drugs, and we're doing that in Predict. Mary's doing that at St. Jude. There's a program at Mayo. There are others in this room, I'm sure, and I apologize that I haven't included them. We did that as part of the Emerge PGX project that Laura will talk about, and there's a large project in Europe, the UPGX project that is also doing that, and there's interesting design challenges in those studies. So this is my last slide. So what do we need? We need to not lose sight of the fact that we don't know everything there is to know about what we might want to implement, and we have to stay grounded in the basic biology and the basic science of variable drug actions. We do need methods to identify, accumulate, and study those outliers, so I'm fond of saying, if you want to study a group of people where an event occurs 0.001% of the time, you have to start with a very, very large denominator. So that's the argument for doing these kinds of things within Emerge or within the All of Us cohort or within other very, very large cohorts to capture the small number of outliers that become interesting, whether that's through passive methods or through active methods, like the kinds of networks that Elizabeth Phillips is trying to put together remains to be seen. I don't think there's one answer. I think there are many answers. We need good genetic tests. CYP2D6 is not easy. There are people in this room who know a lot about that and it's not a simple test, and we will need functional genomics because there are tons and tons of variants that remain to be defined. I had this thing that we need guidelines on how to use drugs, but I put that in sort of gray letters just to acknowledge the fact that Mary and others in C-PIC have done an enormous amount of work to try to actually answer the question, what would you do with the result once you got it? And that is the go-to place right now. And I think that's still a need. I'm not trying to take Mary's funding away, God knows. But I think it is a big step in the right direction. We will need IT infrastructure to do this right. We will need data on what works and what doesn't work, whether it's panel testing or preemptive testing. I'm an advocate of preemptive testing if it can be done. We obviously need education. We need data on outcomes. There are people in this room who are desperate for outcomes data because if they don't have outcomes data, it's hard to go to their stockholders and stakeholders and say that we want to support this. And there are lots and lots of partners. There are patients that are partners. There are payers that are partners. There are users that are partners. And this is a worldwide effort. This is not something that is gonna happen only in the United States for all the reasons that I've talked about. So I hope that sort of sets the tone for what we will talk about. I hope that's what you wanted to hear about. And I'm happy to take questions if there's time. Great, thank you very much, Dan. Yeah, I think we do have a few minutes for questions. You ended early, which is. No, I ended on time. I ended on time. You ended on time. I thought these numbers being flashed in front of me. Well, thank you for doing so. Questions for Dan? Okay, Howard. Dan, I wonder if you'd come in on the technology, thinking back to Angela Anderson and obviously that's a very complex case, but the turnaround time for results, even if that hospital or that clinic, that Dock in the Box, I can't remember the name of the one you went to, but had the technology, it might have been two weeks before the results came back to say what her HLA status was in order to make a decision. Where are things going in terms of trying to change that because that's holding things up as much or more than some of the other aspects? I have my biases and I wish I had included this slide. Josh has seen this slide and a couple of you have, but not many. I used to show, so one idea is the woman has her genetic information. So first of all, the answer to the question is you have to have your genetic data done beforehand and you have to have it accessible. So is that on a piece of paper that a woman has to a pharmacist? No. Is it on a smart Christ to go around talking about this stuff and I'd have something called the international gene card and I have a picture of myself with a little dot of DNA and I think that was very cool, but I think the way it will work is that you'll have a QR code on your phone and you'll have a reader in the pharmacy or in any podunk hospital in the country or in the world. You put the QR code under that, it accesses a website that's secure and it says, oh, by the way, this person has X. And it's only if it's been done beforehand, done, validated, high quality data, stored against the day that it needs to be used. So I think that some way of sticking stuff for lack of a better term in the cloud and having it accessible on the fly to healthcare systems, big or small, rural or urban, is the way that it may play out. And I'd be interested, I mean, I'm not married to that concept but I think that that's something like that is the way it's going to work. To do proper HLA typing, to do proper CYP2D6 typing, I know there are people, some of them in this room who have experience with whole genome sequencing in neonates but whether they do whole genome sequencing in neonates that includes CYP2D6, which is a tough nut to crack or HLA, it's awkward that the two genes we're most interested in are the ones that are among the hardest to sort of annotate properly in the genome. So I think that has to be done preemptively. And I look forward to the day that people will have DNA sequence and have it accessible with the proper point of care decision support. Rex, oh, sorry, where was I? Somebody said, yeah. Question over here, good morning, Dr. Melissa Clark. I was curious in your predict trial and the preemptive pharmacogenomics, how are you accounting for in your design the ability to translate any positive results that you have to community-based physicians given that there's that large learning curve and the need for education that you mentioned before. So I'm not the right person to answer that question. I will let either Josh, Danny or Michael over there answer that question because our IGNITE project is trying to do exactly that, trying to sort of crack that nut and I don't think it's a simple nut to crack, no offense, Michael. So one of you should answer that question. Well, I think it's probably early for us to really answer that question, although I think we can point to other efforts that you can look at national efforts, for instance, in southeastern Asia countries that have looked at screening for SJS-TEN and efforts there have shown differences with what's happened by sort of national awareness campaigns. I think in our efforts, we saw differences, Vanderbilt's not a community hospital, but it is interesting that without a lot of ground education to providers, people do sort of seamlessly follow what the decision support recommends and alter their prescribing based on our advice and predict. And then community experiments are ongoing. Okay, so that would be clinical decision support integrated into their EMR. So we do want to leave some time after some bonus presentation for questions, so maybe we'll do one more from Rex and then we'll go on. So this may be not something you can answer in a short answer, but obviously the medical outcomes of even saving one life is really significant, but to think about the economic outcomes, if we actually calculated the elimination of SJS cases, we calculated the known cases that we have, do we have any estimates of what the economic benefit to the healthcare system might be? I'm not aware of that, there may be others in this room who are the, but I think it's an important calculus because putting in place a large program like Predict or like UPGX or like Mary's program at St. Jude is not cheap, but when you start to think about, the calculus of human life is, that's difficult, but when you start to think about the costs of taking care of critically ill patients for days and days or weeks and weeks, that's also incredibly not cheap. And so the calculus is in there somewhere, maybe John Wilson at Optum can figure that out for us, John, but I will hear from you later, I'm sure, but that's the, and Mark has an answer. Right, I always have an answer. So the- No comment. So the answer is that there hasn't been a comprehensive economic look at this at present, but there have been a number of cost effectiveness analyses that have been done on individual drug gene pair. So for the back of ear, for carbamazepine, for warfarin, clopidogrel, et cetera, we have those. Now my understanding is that Josh Peterson at Vanderbilt is actually working on a comprehensive pharmacogenetic economic model to try and get an answer to the question that you're doing, but to my knowledge, that is not, the results from that are not quite yet available, but it is being worked on because I think that is an important question. So Mark, I had a conversation with Josh about five years, Josh Peterson about five years ago, and I said, you know, it ought to be possible to build a Markov model and you attach, to every transition you attach a probability and then a cost, and then you stick it in an Excel spreadsheet and you just push a button and say, well, if the cost are this, then the outcome is that. And I said, it feels like an afternoon's worth of work, Josh, and five years later, and one very large NHLBI grant later coming soon. But I think that's an important point. Great, thank you very much, Dan, and we may have a few minutes after, afterward before the break for the discussion. So it's my pleasure to introduce my colleague, Simone Evolpi, who will be reviewing NIH-supported PGX research to sort of help us identify what gaps there are and where we need to go.


So the ranger assessment is to bring folks out of New Hampshire soldiers and airmen and give them the opportunity to see if they have what it takes to go down to rangers won't be successful. The first event is the ranger physical fitness test. So that's push-ups, sit-ups, a five mile run and pull-ups. The second thing we do is a combat water survival test to assess how capable of a swimmer they are and if there's a fear of water. The third thing that we do is a ruck march or land nap. A 12 mile ruck is just to make sure that they can move the 12 miles in under the three hours with the 50 to 65 pounds on their back. And then land nap, you have to pass land nap at ranger school. You have to be able to navigate using a compass and a protractor on a map. The last thing that we do is a written test and that's just an assessment of their knowledge of small unit tactics. Some of the things that we evaluate here and the way we stack them deliberately in increasing that stress or false stress where you get an opportunity to see who possesses the attributes that we can't teach. So I think a lot of the word that's going around is that it's a selection and it's not, it's an assessment. So what we want is for soldiers to come out, give it a shot, see where they're at. We assess how they perform and then we kind of put them on a plan on how to get there. Because the intent of the ranger assessment is to get people qualified to go to ranger school and for them to come back and be successful. I think the biggest thing is are they mentally tough, meaning they're not going to quit? And are they a team player? Because those are really two of the biggest variables to success at ranger school. So anybody could benefit from it, so I don't encourage anybody even considering it to show up and give it a shot.


It is this time of year when joint chair should make their way into every household irrespective of what the individual circumstances are. One will recall that following the July 26th general elections, the relevant ministerial portfolios were signed on August 5th just over four months ago, given the fact that the poorer people of this country have been marginalized for the last five years. The expectations from our government are huge. One understands because with the stoppage of the NICE program, the STEP program, the HOPE program and every other that targeted the poor and marginalized, coupled with the effects of the pandemic, it has not been easy for our people. Whilst we navigate these extremely subduant waters of governance, one that we found in a state of financial demolition, we continue to make do with the little that we have. And in keeping with the rubric on which this government was elected, we had definitely put in the people first. In that regard, the average solution citizen who either lives in or operates from the CDC units have been given some sort of relief. Those who operate in the craft and provision markets, the arcade and the small vending booths around town have not been left out. In its quest to put the people first, the government has waived the total of approximately $7.2 million for the benefit of its people across the political divide. Our people cannot be secondary to any other. And whilst we encourage foreign investment, our people must participate in a very meaningful way. These must benefit from the resources that inherently belong to St. Lucia. I am certain that throughout the length and breadth of St. Lucia, one can witness the changes. The changes in castries central and modern conspicuous. Serenity park has been brought back to life. Garbage collection and clearing measures have been strengthened. Even the clearing of bush and demolition of old structures have been witnessed. We are government with a difference. Trust me, folks, as time unfolds, things in this country can only get better. I want to thank the Honorable Prime Minister for having me as part of his team. I want to thank my cabinet colleagues and all my other team players, like my permanent secretary, the mayor, my attache, counselors at the CCC, as well as all the workers at the National Housing Cooperation. Thanks to all of you. In appreciation of your efforts, we decided for the first time in history to give and pay for each and every castries constituency council worker medical insurance. In further appreciation, we have also decided to give every CCC worker and every worker at the National Housing Cooperation a small financial Christmas bonus. Thank you all for your efforts. Let me take this opportunity to wish all of you, my colleagues, my team members, all residents of this beautiful country of ours, castries central people, St. Lucia residents in the diaspora, or wherever else, they may find themselves a very merry Christmas and God's richest blessings for 2022.


Your coca-cola bottler presents Claudia based on the famous play and novels by Rose Franken Brought to you transcribed Monday through Friday by your friendly neighbor who bottles coca-cola Relax and while you're listening refresh yourself. Have a coke and now Claudia Hello, David. Don't you feel sorry for the people who have to buy their Christmas trees in a store? Heart bleeds for them. I didn't ask if your heart bled. I asked you if you felt sorry for them. No No, no, what do you mean? No, and you can quote me. I do.  Just imagine buying a tree in a store when you can chop it down your own backyard If you don't hurry up get dressed we're not going to have any Christmas tree out of anybody's backyard Me hurry. You hurry. Besides acres of farmland are not called a backyard They are to me and I'm getting dressed as fast as I can That's as slow as it can be You feet too big There Did you decide where to chop the tree down David? I think a good spot would be the road towards Matthew Warren's place Oh This saw is getting dull waiting for you. I got your ski pants and sweaters I don't worry about the trees every time you bludgeon me to take five minutes off of my work It turns into two hours You just finish changing your clothes yourself, you know, I'm ready. I've been ready for 15 minutes Oh, I think you just think it's husband later rush me. I think you just think it's wifely to keep me waiting How'd you guess not hard there last sweater?  I'm ready. Oh, I wish Bobby were old enough to realize it's Christmas Christmas is a nice time of the year for children. Well, you ought to know This is a nice time of year for everybody Including adults and old men like you. Where do I put my teeth in? Just think David last year We had to buy our Christmas tree from a grocer's. Oh, how unromantic.  I loved you for it So please don't spoil it. Well, I didn't suggest it for sentimental reasons the way you seem to think Much you didn't I suggest it because I have to clear out the grove down by the road Yes, I know I'm crazy growing much too thick to thrive and this is a good time any to start Oh, I know I suppose it just happened that Christmas decided to come the day after you Decided to cut down the tree your coincidence. Very sweet of Christmas. Well, I don't right think what you will I just told you Where I stand can tell me all you like I draw my own conclusion. Oh, don't forget you saw Oh You want to go back in and put on another cold. Oh No, what do you take me for an orchid? I'm a rugged new England. Hmm. Not much of a new England What do you mean? Yankees are solid people not given to being sentimental. Well, I'm not given to be sentimental No, not much. You've been cooling about growing her own Christmas tree all day It isn't sentimentalism. What is a careful the ice you break your neck. I'm not sentimental Maybe not Maybe you wanted to chop down one of our own trees because it's cheaper than buying one of the grocery. I'm not mercenary either And what are you? I have sentiment, but just something no one should be ashamed of who said anything about being ashamed Oh There's so nippy and cold Funny, I used to hate winter, but I love it. No, what caused the big change you just you No winter used to be so lonely kind of sad Now it makes me feel all brisk and strong And you are very very handsome in that old wool shirt. I'm gonna have to stop wearing it's turning my head No monkey business. We're out to chop down a tree now. Not for monkey.  All right one monkey to keep you quiet Like monkeys your nose is cold yours Guess you're right. This one all said and done. I'm not much of a Yankee at heart. Why not? Sandament is in the heart, isn't it? Oh, well can't be David. Do you think that? Oh My ears feel like icicles. They're freezing or crows don't have ears so you can stop worrying. Oh And then how do they hear? David that's really something to worry about. You have to look it up or something David, we're not just being selfish about the tree. Are we I told you that that grove has to be thinned out Saying that are you so I want to do a sentimental to me count to ten one two three No, we're here. So see for yourself. Now take a look. I see I think it does look pretty big Yeah, you win you win Which one David the tallest or the shortest how about this middle-sized? Oh, I love middle-sized everything You're gonna let me hack and chip chop This tree is supposed to look decorative and not scarred up and chipped and chopped Chopper Just know from chopping spinach. No tipping David would you be embarrassed to say you know Matthew Warren or Jeremiah could be drove by and saw you chopping a Christmas tree I pine tree. I would not sure of that and stop trying to make me self-conscious A man has to supply a Christmas tree when he when he has a mother-in-law and a wife and a son to plead with him for once Oh, I just love it when you tease me when you're being husbandly Oh, this is nice. This is wonderful. This is Christmas What's the matter You know, you've started an echo even before you started chopping that makes great sense. No, no, no listen David Yeah, somebody's chopping all right firewood probably We don't hear Matthew Warner or Jared Tucker chopping. They're the only people who live close enough Well, they're certainly not the type to chop anything else but firewood. Oh No Christmas trees for they they're too hard bit How can you recognize a person by the sound of his chopping? Oh, I didn't recognize a person I just recognize who the person wasn't that's very different. You know, they'll stand back. Oh, let me help I'm doing the chopping. You can do the decorating tonight with mom. Why can't I have any fun? All right, you chop and I'll decorate Just to make things even I'll come down with fits and bring the tree home in the pick up You will decorate young woman the rest is man's work. Oh poofal man's work poofal. I repeat I wonder who that is So if he called for mr. Tucker to be out chopping wood, but certainly sounds if it's coming from over at his place I suppose you won't be contented until you know exactly who it is. How did you guess? I know my Claudia Mr. Tucker He's not like a yodeloo. Hey Let's go over and say hello.  Tucker knowing you have a Anybody know what they want to know. I don't care only the song anyway. He might not understand You know Jared Tucker's a chip out of an old pilgrim stone if there ever was one could you be thinking of the Plymouth Rock? I don't know. I think you're good. Yeah, I guess I could David, I'll bet you that even when he was three years old. He didn't play play under a Christmas tree Good heavens and Jared Tucker was three years old. I spent off a long time ago What do you think you'd look like 83 years ago? Just as toothless as he is today. Oh He's such a funny old man. I love him. I think Oh just uh Taking a walk that's mighty shrew we stayed to be out taking a walk. Well, you're out aren't you that's different with me I was born just about the same time as the weather was born. We're equal What are you doing, mr. Tucker? Oh, just a choppin some firewood. I thought you did that in your own backyard You doubt my words. Oh, but this is pretty far for you to carry your own firewood home Isn't oh, there ain't nothing too far when you got a mind in the back to do it guess so Well, how are you planning to celebrate Christmas? Oh ain't planning much Oh, what are you gonna give Delilah for Christmas that sister of mine? Yeah, I didn't give her anything since you passed a cold on to her Three winners past that was very generous. I've seen too many Christmases to make a fuss about seeing one more Maybe that's why you should because you've seen so many Christmas. I ain't softened with the years You know, I'll say you have it.  I just feel the wind mr. Tucker.  What do you take me for a decrepit? No, no, I just offered now.  No surprise seeing only one when one's all chopped Well, that's certainly isn't gonna keep you warm very long ain't meant to keep me warm I don't need much to keep me warm this partial of bones can keep their cells warm That's a pretty hefty log. Mr. Tucker. You've got any criticism?   Well, you got another guest coming my brains is just getting into high gear. Yep In the high gear Let me help you load this log on your wheelbar. Here.  That's a well water day. Well, that's better take it home Yeah, I'll give you a hand. Yeah, I'm well still I can't imagine where yet I'm all the way over here to chop one log Are you sheds packed with firewood in the house? Oh, that's there's wood and there's wood. Mr. Nought never hears of that No, I can't says I have I've only heard of wood some woods for burning other wood ain't new one on me What's uh, what's this wood for burning sort of way? This here's a log wood is set on fire Christmas night and it burns the whole day and whole night through Mr. Tucker, do you mean to say that this log of wood is a you'll log of wood? What case? Oh nothing nothing folks been burning you'll logs ever since a long time past it says it's a tradition That's what's what's called it tradition. I see yes That's when folks lived in big stone palaces a brung in a you'll log to brought it in with a load of bandangles and hullabaloo season Set in the fireplace set a spark onto it and when it started burning why then it was then it was Christmas But mr. Tucker, it's so sentimental paint paint sentimental at all. It's tradition. It's Christmas ain't it? Well, I never said it wasn't no right to keep warm before the fire ain't I I never said you didn't So if I'm going to burn a log of wood it might as well be a you'll log of wood, but mightn't it? Yeah, it might as well say What's the funny look there son you saying to yourself that old Tucker's a sentimental fool That's what you're saying to yourself, David No, you you young ins think you know better than to stick by the old traditional ways Well, that's what you think you're from crazy. I'm gonna get in the wheelbass Oh So mr. Tucker and mrs.  Well, nobody said you should you had that look Yep, I'm good and sentimental and I'm a Yankee too and I'll be All darned if it isn't a fine thing to be And if you ask me I'd say with old mr. Tucker You're in pretty good company hand-in-hand with a chip-off of the old Plymouth Rock itself If ever there was a season when unexpected guests could be said to be expected. That's the Christmas season Now telling who may ring your doorbell But you'll be ready for anyone young or old if you have lots of coca-cola cooling in the refrigerator There's still time to bring a case home from the grocers or a service station when you're getting the tree and last-minute supplies Say one of them two young and whispering about mr. King. Oh A little private joke mr. Tucker My ears was burned. I got a feeling I was in on the joke.  Tucker mean compliments So stop worrying worrying who's worrying say young fellow. What's the news about the Norton's cow? She's getting set to freshen up. I think she is yes You better stay around close tomorrow mr. Tucker better stay around close You know in a case of extreme delicacy like this. You may be needed. Yes, well, I'll be around it's Christmas Eve tomorrow, too It wouldn't be a bad present for the Norton's if majesty delivered us a heifer well I better help me you'll log along. I'll see you son. Goodbye mr. Tucker Every day Monday through Friday Claudia comes to you transcribed with the best wishes of your friendly neighbor who bottles coca-cola So listen again tomorrow at the same time And now this is Joe King saying or a guar and remember Whoever you are whatever you do wherever you may be When you think of refreshment think of coca-cola or coca-cola makes any pause the pause that refreshes And ice-cold coca-cola is everywhere This broadcast of Claudia was supervised and directed by William Brown Maloney And now here's a word from your friendly neighbor who bottles coca-cola


Hey, everyone. I'm Amin and I'll be presenting the metrics dashboard that I built for the Saturn team. For those of you who do not know, the Saturn team is part of Thoughtcoin retrieval markets and we're building a decentralized CDN to improve the IPFS gateway performance as it's currently morbidly slow. Part of achieving this is generating like a monitoring tool and that's key for the following reasons is to monitor the vitals of the CDNs, such as latency, request served, etc. And also our goal is to beat the IPFS gateway. So a dashboard is a great way to quantitatively and visually track that effort. And additionally, the dashboard is useful in debugging errors and also testing response to the network to new optimizations that get launched. This is a dashboard, it's on Grafana right now and currently like it's in production. One of the first graphs we see is something called time-to-first byte. And time-to-first byte is a metric that measures the time between a request for resource and when the first byte of that response begins to arrive. And here we're basically trying to erase the IPFS and Saturn time-to-first byte values. And well, it's not really like a race anymore because thanks to the engineers on the Saturn team, the Saturn CDN is now making the IPFS gateway look like Internet Explorer. And it's clearly like outpacing it at this point. The cache rate graph is basically like a measurement of how many content requests Saturn's cache is able to fill compared to how many requests it receives. And one good takeaway from this graph is that Saturn does not miss pretty often. Hi, everyone. My project is Outercore Plus. And so what it is, 247 Hub, where a place for all of our events can live, focus on Outercore events, but also some of our community events. So it's supposed to be a virtual experience. Even though you can't attend live, you can still go in here, you can feel connected to the community. And you're not just kind of like sitting behind Zoom. So this is just like the menu bar that will show whenever you're in the environment. And it just kind of outlines like what all you can do while you're in there. You can watch live streams, you can watch on-demands, you can talk to other people that are in there, you can network with the community, with other PL and people that could be in there at the same time. There's also some fun elements, a photo booth, you can get PL swag. You can also go to the exhibit hall and get resources on IPFS, Filecoin, Filecoin Green, and our community as well. This is the exhibit hall. It just kind of gives a picture of kind of what it could look like. It's supposed to have a look and feel like as if you're inside a trade show, these will kind of be like booths and that's where all the content would live. I also just put a Hackathons banner up because we have a lot of Hackathons that coincide with Arvents. That would be really good to have that connection there as well. So if you were to click on one of the booths, this is kind of what you would see on the inside, a scissor roll playing when you walked in and then you could see how on the right hand side, you can click on our previous events and at any time go in and watch all the videos related to that. You can also contact us, schedule a meeting, all those sort of things as well. Cool. So what's the problem I'm addressing? Even if somebody has an ability to learn, but they don't have an idea that they want to build on, where do they go? They could go to the ecosystem websites. They could look at GitHub repos, but there's no single place right now for the PL network where all of these ideas can be found together. So I'll first walk you through all of the data that I've put together and then I'll show you the website which sort of presents all of this data to the end user. So I have collected data from the IPFS ecosystem dashboard, Filecoin ecosystem dashboard, all the Hackathon winners that we have. These are from 2022. Awesome IPFS which has all of its information on GitHub. And then there's also the PL network air table, which is an overlap with some of these, but has some unique companies as well. And all of this is like real data. This is not demo data.  So say I want to look at all the past Hackathon winners, then I have all of this information, their project names, what were the building, if there's a GitHub repo that's like available open source, and then they can actually just like start contributing. The different categories that I have so far is one where does this originally sit? And I'll find a way to link it in each card as well. What stage is the idea in? So our solution is to rely on the DRUN network to achieve time lock encryption. So we use DRUN mostly as a reference clock because the DRUN beacons are issued every 30 seconds currently with a new test network that's issuing every three seconds and your round. So you can really use the different beacons to map to a given time. So we can say round number, we know exactly when it will be issued. The main idea behind these is that we use the BLS signature scheme, which is already used by DRUN. And then we use some identity based encryption schemes that are compatible with the pairings we are using in BLS so that we can use the signature from BLS for the DRUN beacons as a secret key. And we can use the round number, which is in the future as a public key mostly. I got a very short demo for which I will share my screen. We click our encrypt the crypt button. It goes and works out what round it should be encrypted for and does the magic. We get this lovely ASCII armored output here, which if I clear the plain text, we should be able to now decrypt to the hello launchpad that we put in before. Of course, anyone can try this to make sure I'm not cheating or even suggest some plain text to try it. If we wanted to encrypt something way toward the future, let's put it to tomorrow, we would get a very different cycle text and attempting to decrypt that will hopefully not work. Yeah, it's too early to decrypt it. Stuff still to do is obviously make it look a lot prettier. This UI is showing my art skills to the max, unfortunately. Once we release a DEF CON next week, all the code will be live in the mix and you can all have a look and enjoy it. Thank you everyone for tuning in. So when I first started chatting with the IPFS team working group, they mentioned this idea of including a diagnostics and or a metrics view within the web UI and desktop app. I set out to conduct some user research with the goal of delivering a research-backed dashboard UI for IPFS web and desktop that would extract necessary metrics and diagnostics for IPFS users so that they could find and understand information about their node in order to optimize performance. So this is just an idea of what a dashboard could look like. Ignore the data, but some really important features would just be to provide more information. You really want to focus on storytelling here so that people know what they're looking at. Some customization, too, is great. But again, this was kind of dependent on the data that we have. A lot of what you'll see here, though it is dummy data, is based on existing information that we have. So like a DHT check if we couldn't integrate into the web UI or desktop app, that would be something that users are looking for. Nice seeing everybody. Let's talk about moon landing. Big goal here is to bring as much SP to our ecosystem as possible and to have them store actual data and grow the network as quickly as possible. We're doing that through the project moon landing by raising awareness around Slingshot and Evergreen. These are two programs to onboard as much data as possible, mostly the public datasets through Slingshot and the Evergreen program will renew all those deals in the future. Also during the program, we're going to introduce DSPs to each other so they can match make in the future when they need to store data replicas themselves. So it's an ongoing process on educating them on everything that's possible on onboarding data. In the back here, you can see the moon landing website that we put up. We have a landing page now for moon landing where we talk about the program details, the incentives for SPs like why you should participate in moon landing, what you're getting out of it. And the rest are some slides that we gave the presentation on last week in Vegas. There's good traction. We got a lot of questions asked after the presentation from SPs that are kind of new to the ecosystem about our milestones, including our requirements for onboarding as much data as you can into our ecosystem. Hello, everyone. I'm in all basically my project for this launchpad cohort is basically to migrate the current content of the launchpad curriculum to a new platform. So for this platform, we have chosen Hugo. Hugo basically is an static site generator, you know, is widely used across the PL network. For instance, the Lotus docks are built on Hugo or the Filecoin docks are built on Hugo. I've been working on several design changes. As you can see here, firstly, this landing page which basically contains all the different sections dynamically fetches all the different, the number of lectures and tutorials that we have. Then we also have this other feature and based on whether you're a shallow or deep resident, you know, the main shows like a different content for different personas that we have in launchpad. And so basically the idea in the upcoming weeks is to gather feedback over this site and improve it and include more features. We probably will be like quizzes or some other features that might be useful for upcoming launchpad residents. So the project that I worked on for launchpad is SHAP explainability tool for machine learning models. So essentially, if you have a bunch of data that you're kind of like, you know, need to figure out what's going on there rather than like looking through dashboards and hunting and packing and like scrolling through spreadsheets, just let a machine learning model ingest that data and tell you what's important. So step one is you need to train a machine learning model. You need to come up with a hypothesis of what might organize this data. And so you have input variables and output variables. Step two then is applying the SHAP explainability package. So running the this explainability process essentially goes through the machine learning model and it zooms in on all of the data points. Essentially the orange surface is this windy parametric surface created by your machine learning model to kind of weave through and fit the various data points. And what you're doing essentially is you're zooming in on each data point to create a more well-defined, maybe like a linear model is one way to do it. SHAP does it slightly differently, but you want to get a simpler model that in this picture is modeled by this blue plane so that you can explain it better. What you get from that is feature importance. So how important are those various input variables to the impact to the prediction of the output variables? So on this graph, you can look at it and say, oh, the biggest drivers in this hypothetical example are input variable one and two, but input variable eight is not a very big driver. And that can give you a lot of good insights into the data. So the first project was actually taking a look at what it would take to build a sort of more sort of enterprise ready for one of a better term storage system around IPFS. I also wanted to align with Web3 ideals and so just make sure that we weren't just re-implementing some old sort of Web2 style stuff and making sure that we're still on the right path, even though we're learning from sort of 50 years of storage industry. And then go into some specific details around how to implement some of this. The missing components, what we might need to develop to build out a system like this. As I said, IPFS gives us content addressability. It gives us a way to refer to the content and if the content changes, then the way we address the way we retrieve it changes, as we all know. Now, even on your laptop, the Mac or Linux PC in front of you, or Windows for those that are using that, if you open up a file, write some data, and then save that file, you don't have any guarantees that that data is actually still there. It hasn't been written correctly now. Will it still be there tomorrow? If I go back in a year's time, is that data still in one piece?  And so the answer to that could be, we'll just make more copies. So instead of three copies, we'll make 10. But now you're talking about having 10x storage cost for storing one amount of data, which for small amounts of data may not be a problem, but for large scale out stuff, that can be a real problem.


Hi there! My name is Sandy and I am bringing you a watercolor powders series. This is number three in the series so you may wish to go see number one or number two first. This video is going to present my way of labeling my brush-o bottles and I'm also going to talk about how to swatch out your colors and make a chart for yourself so you know what colors you have at hand. This video is primarily focused on brush-o since it needs the most work to get the bottles ready to use. So I have the 24 and the 8 here. This is I believe the US packaging. There are also other types of packaging you can get and I ordered a set of 12 and that came in a different box but it's the same product so if you get a different one don't worry about it. If you get the 12 those colors are duplicated within the 24 pack but the 24 and the 8 make up the entire 32 with no crossover and the 12 and the 8 can be used with no crossover but you don't want to cross over the 24 and the 12. Does that make sense? I hope so. I'm going to write it out on my blog just in case you forget or if it helps to read it in writing. So any of these boxes that you unbox come with a beautiful little flyer and the flyer lists out the colors. Those are somewhat accurate to what the colors are but not superbly and here are the 8 bottles from the 8 pack. I'm going to swatch out two things. I want to use this hex shape to make myself a hex chart with spritzed powders and I want to do spritzed powders for a specific reason and I'm using the fourth from the fourth shape from the smallest one because that's going to fit this PDF that I posted on my website. It's a free PDF so you can follow along and make your own hex chart if you have this die set from Lifestyle Crafts. I'm also going to punch circles to put on the tops of my bottles and those are going to have solid color. It's going to be painted with a brush so I know what the solid color looks like as well as what the spritzed color looks like and I'm going to prepare for all of this by cutting a bunch of strips of one and three quarter inch paper and I've die cut a whole mess of these hexes. So they're going to be ready for my charts. I have another set of strips that have sticky on the back so you can use different products. I used here some B Creative Tape on the back so that I could make circles that are stickers to pop onto the top of each one of these in a certain order. Be sure to follow the way I say to do it because I did it wrong on a few of them and made a mess for myself. So you want to do as I say not as I started out doing I want to save you some trouble. So I'm going to get all those punched out and I also have some thumbtacks. I ended up getting clear ones after I got my 24 and my 8. I used white on the other ones you've seen in the other videos but I wanted to write on the back first the color on the back of the hex chart piece so I can match them up later with putting them in the right order.  Now I'm using thumbtacks you can use a piercer. These bottles don't tend to leak a whole lot but I left the little thumbtack in the tops of each of mine just because I want to make sure they don't spill out ever. The hole is so tiny it's not likely to actually spill but for me it also made them so I can grab them real quick by that little little thumbtack. Now I'm going to do a quick spritz on the hex chart piece and then I'm going to let that go. I'm going to leave it all all mushy and then after I'm I have a little bit tapped out as well onto my work surface and you want a work surface that you can get wet and that will clean up really well. I have a little bit of the powder so I can take a clean brush you want a super clean brush. Don't let yourself contaminate one color with another because when you're swatching out you want them to be perfect and so I'm just going to put my color on the top of the bottle. After it's dry I'll repunch the hole through it and then add my tack back in. If you put water in and you have a hole there you're going to get water into your bottle potentially that was one of the mistakes I made. So do as I say I'm trying to help you and I'm using a magnetic craft assistant from Ellen Hudson as my base here. You can also use a craft mat or something. You want something you can clean up really well in between every color and don't have your extra pieces all those extra white watercolor pieces anywhere near where you're working because any stray powder that flies through the air is going to contaminate your future colors and you don't want to have to redo any of this process because you've accidentally contaminated things. So I just went through every single color. I did a hex piece, I did the circle for the top, painted the color on and then added my thumb tax after it all dried and cleaned my water. I actually changed my water between like every two colors because I didn't want to get any contamination going on. Here's the set of 24 and you can see they all nest beautifully in their little box and once I got it all finished this is what I ended up with. I'm looking for good storage for now. I've got them in an envelope box and all 32 fit nicely in this and you can see the little thumb tax weren't great as handles to just grab one and pull it out and use it and I'm finding this works for the moment at least. I've uploaded all my swatch charts to my blog including blank charts that you can print out on regular card stock and then cut out your own hex shapes to add your own spritzed swatches too and that's probably overkill for a lot of folks. You can print out my pdfs as well but just know that the colors will be more accurate when you swatch it out yourself. This is the Color Burst set and if you've watched the other videos in this series these are the ones that are much brighter, much more intense than the the brush show colors so if you like really really bright these are fabulous for you they do come in a smaller bottle. These are the 12 sets of brush shows and if you're going to just get into one set and you only want the one set this is a good one it's got a really good rounded rainbow of colors but remember that this will be duplicated in the 24 so if you eventually think you may get the 24 I wouldn't go for the 12 so you don't get multiples. You can also buy them all individually though and totally save yourself the headache of trying to worry about duplicates. This is the set of eight and I think what happened here is they had the set of 24 and these are filling colors additional colors but this would be a great set if you wanted to try them out and use it for Christmas cards because look at the reds and greens in there. So here we have the set of 24 and I'm just showing it to you with the empty spaces for the eight that will fill in and then you have the full set of 32 brush show colors. There is a white here I don't know how to use it yet I don't find that it works in the ways that I would think it does but I will let you know as I discover more about them. Thank you so much for joining me for this series if you liked it please click the like button and feel free to watch one of the others in the series if you have not yet and if you want to subscribe to get more videos on watercolor powders I would love to have you come back again sometime. I will see you guys later have a wonderful day