All right, the social dilemma. This is the popular documentary that you may have seen being promoted on social media that we should all stop using social media because it's evil, addictive, manipulative. It takes our data and sells it to advertisers. So I thought that I should make a video about this because, well, I use social media in my business and I teach other people how to use social media in their business. So let me share with you my thoughts on the social dilemma. All right, the first thing I'll say is that there's one thing I agree with about the social dilemma, which is children. Children should definitely be guided, maybe even restricted from using things like Facebook and Instagram, Twitter, to some extent YouTube, although YouTube has YouTube for kids. But yes, but here's the thing. Just like we restrict or moderate children's behavior in other areas of life, such as their social life, who are they hanging out with? What are they doing when they're hanging out? Is it taking too much time away from their other activities?  We don't say, well, children should stop hanging out with people. No, we just say, well, you gotta hang out but hang out responsibly. Social media is essentially a global virtual social life. They are interacting with other human beings or content created by other human beings, and of course by artificial intelligence as well. But it is affecting their mental development and emotional development. So of course, if we care about our kids or the children in our lives, we're gonna be cognizant and guiding them towards using it responsibly. Same thing with junk food. We don't allow kids just eat as much as junk food as they want. We moderate that. We say, well, it's pleasurable and maybe we allow them to indulge every now and then but then it's not something that they should just have their own free reign. So of course, children or anybody that you feel they need that guidance because their mental health or whatever should be guided in that way. Similarly, we should be guiding ourselves. If aren't you a responsible adult with free will? I hope so. So those of you watching this, I hope are adults that are responsible with free will. And if so, shouldn't you be guiding yourself and your behavior on social media or are you gonna give away all your power and say, oh, it's Facebook's fault. Facebook manipulates me. It makes it so interesting. It's like a lottery. It's like being in a casino. I can't help myself. Is that really your argument that you can't help yourself? Well, that's the phrase is, if you can't help yourself then I'm sorry. But the truth with a capital T is of course you can help yourself. Who else is gonna help you if not yourself? First of all, people can try to help you but if you don't help yourself, you're not gonna benefit from anybody else's help. And if you are gonna give your power over a way, it's not just social media that's manipulating you. Television has been manipulating us for decades. And before that, it was the radio that manipulated us. And before that, it was books that manipulated us. Ever since books were created, I mean, you could look back, I think it was like ancient Greek. There were, yeah, in ancient Greek times, there were complaints about how books are gonna ruin our minds because it's going to influence us in this way or that way. Come on, ever since content has been available to humankind, people have complained that, oh, it's manipulating us. Yes, social media is more powerful because now it has our sort of behavior and it's able to give us content that it thinks we want. So here, so let me be really clear about what Facebook and YouTube and Instagram and Twitter, what are they trying to do? Are they trying to manipulate us? No, that's not the intent, that's not the profit models manipulate. No, the profit model is to give people what is so pleasurable to them that they're going to keep coming back and they're gonna stay there. And so the advertisers can put ads in front of them because that's how we make money. We make money by selling people's attention to the advertisers. So how do we get their attention? We study what their behavior is. What articles do you click on? As you scroll, what topics do you hover longer than others? Yes, they time, of course. I already knew this before watching the documentary. I already knew all this. The documentary taught me nothing new about what social media is doing to us. I knew this all along. And I just, and I'll get to how I use social media but it times everything. How long do you stay on the topic? Okay, so now they know they're interested in that topic whether they captivate you in some way. If you keep scrolling past something, they're gonna say, well, that didn't captivate you. So based on that behavior, they're gonna say, well, let's serve that person more of the stuff that captivates them because we want their attention because the advertisers make us money. Of course. Do you want the social media sites to not understand you? And so therefore serve you boring stuff? Let's be clear about this. There are certain websites you used to go to that you don't go to anymore because it's boring to you now or you outgrew it. Well, that website failed in keeping your attention. Facebook is really smart because Facebook is obviously dynamic Instagram, YouTube, all the platforms. They're dynamic. They keep serving you the content that you get captivated by. So whose responsibility is it? Well, obviously you have at least 50% responsibility because you can turn it off anytime or you can scroll past something anytime and train the algorithms to say, well, no, I don't want that kind of stuff. Let me keep going. And yes, I want this. I'm gonna click on it because then it'll give me more of this stuff in the future. So whose responsibility is it? At least 50% is yours. I would say it's more like 80% is your responsibility. And maybe 20% is social media's responsibility for giving you things that are so addictive that you actually want. You won't be addicted by something that's not pleasurable to you, obviously. So guide ourselves well. So the other thing I wanna say is this. If people are gonna blame social media and say, we're gonna stop using it, we're gonna make sure they're regulated so they're not so entertaining and addictive, this is going to be the same argument for the next technology that's virtual reality. I have never used virtual reality. Well, I have maybe in like really advanced video games at some arcade, it's kind of like virtual reality, but I don't have a virtual reality device at home. I don't know if you do or not, but can you imagine one day when many of our homes have virtual reality devices, you think Facebook is addicting? You haven't seen anything yet. The virtual reality is fully immersive. You feel like you're in a different world.  Of course the VR companies are gonna make it even more addictive. They're like, oh, you'd like to do these kinds of activities on virtual reality. We're gonna make sure to serve you more of that content. So it's not social media. It's really any kind of entertainment is what we're really talking about. And any kind of entertainment needs our own moderation of ourselves, self-responsibility. It shouldn't be called the social dilemma, it should be called the self-dilemma, right? So here's the thing, every technology is an opportunity to practice self-control. Every technology and every substance is an opportunity to practice mindfulness and self-moderation. And if you practice self-moderation and mindfulness, that is going to benefit you in all areas of life, not just with that technology. All right, so the next thing I wanna talk about, the next point is that social media is a blessing to advertisers like me.  They know what topics you hover over before you scroll past it.  They know what kinds of groups you tend to participate in. They know everything about you, right? I mean, all of your interests in terms of content, how you interact on that platform. So because they know you so well, they allow me to reach you. If they didn't know you well, I wouldn't be able to reach you because then they would just say, well, we don't know anything about our users. So we're just gonna put your videos in front of random people. That's not gonna help us advertisers. That's not gonna help us small businesses to reach people like you. And by the way, most of the advertisers on social media are small businesses like myself. We're not trying to manipulate the election or anything. Of course, there are that kind of elements too, but most of us advertisers are just trying to get our content and our offerings in front of the right people, which is you. So if there's two sides to it.  But if social media knows you well, they're gonna give you ads that feel like it was meant for you. They're gonna be, you're gonna see, if it's the way it's supposed to work, everybody, is that they're supposed to know you so well that when you see ads, it feels like, wow, this product was built just for me.  I'm so glad I know about this pillow, this shoe, this online course, this service. I'm so glad I know it exists, or I'm so glad I was reminded of it. That's how it's supposed to work. It's that they know you well enough to do that kind of thing where you don't feel like it's annoying. You're supposed to feel like it's perfect for you. That's how, that's what I'm trying to do. So, and for us advertisers, that's how it's supposed to work too. We're hoping that the social media platforms know everything about us so that we can put our things in front of just the right people. You have problems in your life that I can solve, but I should be, you see what I mean? Like if social media doesn't know your problems, I can't, as a business owner, I can't put my solutions in front of the problems that people have. So like for example, social media doesn't know me well. It's gonna put like trucks, advertising for trucks in front of me. I don't care about trucks. I care about climate change. I don't wanna see trucks. I get offended by it, right? Like don't show me another GMC ad. It's like, you see what I mean? Or let's say you're offended by veganism. I don't know, you're like, you're big into eating meat. And if they show you a vegan ad, you're gonna be like, no, this is terrible. I don't want this. You want the ads to be tailored to you for your own experience. Why wouldn't you? Why wouldn't you? You'd rather see bad ads or good ads, right? And of course, if you don't see ads, I don't wanna see any ads. Well, if you don't wanna see any ads, social media is going to go away and you won't have this tool anymore. You see what I mean? Like however it plays out, however reality plays out, there's gonna be some technology that tries to know you well so that it can then sell your attention to advertisers so that it can be a good fit. Think of it as matchmaking. You don't wanna be matched with bad people. You wanna be matched with people who have just the right solutions for you. You see what I mean? So okay, so that's the advertisers. And it's never been easier for us business owners to reach people like you. It's never, there's no other thing that's easier than Facebook and Instagram ads to reach just the right people. Do you know of anything else? I'm a business coach. I don't know of anything else. If you know of an easier way to reach just the right people at scale, please, please let me know because then I would love to use it and teach it. But right now there is nothing else. There's nothing else besides Facebook and Instagram ads that is easier for any business owner to reach just the right people and to reach as many of the right people as they want. So that's amazing. It's a blessing to advertisers which are most advertisers are small business owners. Okay. All right, so the last thing I'll say is this. For the people who are trying to boycott social media, so I'm not gonna use social media anymore.  Here's the thing, you, all of us good people can leave social media, but the technology is so convenient and so entertaining that most of the people, most of humanity is still going to use it. So us few small, you know, good people are going to leave. Most of the people are still gonna keep using it. So let me ask you the question. Do you want to leave most of the people to the wolves? Or wouldn't you rather most of the people have the opportunity to occasionally see good content from you? You have a choice. You can either participate with your good content and so therefore add to the conversation or you can leave the conversation and let the pool of social media be shallow junk content. It's up to you. I would rather stay in the conversation rather than leave. So let's stay in the conversation. This is where people's attention is gonna be.  Good luck, not gonna happen. It's too entertaining, it's too convenient. All their other friends are there. Good luck, it's not gonna happen. My friends have tried, they're back. So it's, if you can't beat them, join them and it's not something you need to be. You just need to be there as a good presence, using the ads, all of us can use ads, right? And one more thing I'll have to say is this. I really decry the social media platforms being restricted and being regulated. I detest this. You know why? Because as an advertiser, every time I go on, there's yet another restriction that I can't talk about this or I can't talk about that.  Oh, now they say we can't talk about anything related to anything suggesting negative mental health. We can't talk about that because we might trigger people. It's like, oh no, I'm trying to help people with anxiety, no, no, no. You can't use the word anxiety or your anxiety. You're gonna trigger people. Really? I'm trying to help them. I'm trying to give them some good content to help them with anxiety or depression. No, you can't say that. See, Facebook ads restricts us from this stuff. And YouTube ads probably does too. It's to some extent and other platforms too.  Even if my article is just mentioning Trump or Biden or whatever for mental health purposes. No, you can't say that. You can't say anything political is highly restricted. It is on Facebook ads now. It's like if it's very restricted now because it's being regulated or they want to prevent regulation so they're trying to restrict themselves. Mark Zuckerberg is doing his best, people. That's my experience. Having been on Facebook since mid-2000s and watched the evolution and watched and been an active advertisers for all these years, I see it becoming more and more restricted because they're trying to do their best even though there's no congressional restriction yet, regulation, the platforms are trying to restrict themselves. So anyway, that's my opinion about the social dilemma. I'd love to know what your thoughts are and your questions. And I hope this is helpful. I'm George Kau, authentic business coach. I love talking about how do we build a business that is based on meaningful engagement and meaningful impact on society and also on our own inner life. All right, I wish you well and I look forward to your questions and your comments below. Take care.


I think in terms of the scientific and research experience here ranks at the top, and now that's partially a consequence of my being here as a scientist and researcher, there's nothing more exciting than being a scientist and researcher, I mean it's like playing roulette, and you get paid for it.  I mean I remember when we had the typhoon Didang and there was so much flooding that the Ministry of Agriculture tried to develop, asked us to develop a technique for growing a 70-day rice crop because so much of the season had been lost, and by double transplanting and so on we managed to do this. It was basically placing a bed that this would work, we'd done some research on it before, we'd never really put it all together, we couldn't test it anymore because there was no time for it, we had to just go with it, and it worked, and it gave them at least about 80% of the yields that they used to have. The excitement of conducting research is not enough talked about, scientists have pretty dour, but it is a very very exciting existence, so that's a highlight, and as I mentioned the other highlight, the best job in the system in my opinion is that of research, the director of research, it's tough on people, and it's tough on the people's side, you've got to interact and deal with an incredible amount of interpersonal problems among scientists and between the direction and scientists and so on, so that's a very tough part, but I think it is an extremely rewarding position.


What's going on everyone? Sam here with the latest 4-car drip and 22 top scrum update baseball sapphire edition 5 box break number 11 random team style Here's a look again at our random results as always you can find these on the websites Oops under the results tab as well as the link that's currently in chat So there you guys go, let's get started on some more sapphire number 11 Let me drop you guys the link to our contenders 4 box multi-year mixer 16 to go 2019 and 21 contenders, so there's gonna be 20 autos in there Gotta shot at some big names from 19 Danny Dimes Kyler DK Debo Samuel. Who else we got? 2019 Terry McMorrin I can't think of anybody else Help me out Hunter Renfrow. I guess 2019 was Kyler Nick Bosa that's pretty solid There's a lot it's a really really stacked receiver class really stacked receiver class Steve I know there's like one or two other ones at AJ Browns another one. Yes, Hollywood Browns another one Yeah, there you go. So yeah, very stacked receiver class. We got an orange to start off here It's gonna be Sam Hillier nice one there that is 8 out of 25 For the Rockies nice one there Colorado Edward P Chad cool and Nick Lidole. Yeah, my home says an auto in 2019 as well He has an auto that ticket Voight Guardians Tommy Fam and Cesar Hernandez Wander rookie Alec Thomas debut and a Jeremy Pena debut Aces up Kelvin Gutierrez and Hunter Dozier Eddie there are a crazy amount of receivers. No Jefferson was 20. I meant to ask and answer that that was like him lamb Judy Hurts is 20 as well Joe Ryan, we've got green Jordan loop low going to the Diamondbacks one out of 75 first one stamped Joe Kelly and Isaac critics He's 2020 as well the glodolo rookie debut Chris Bryant I'm gonna move this a little closer if you don't mind. Oh, I'm a left. Yeah. Oh, I got you I put one behind you. I got you Right, yeah, I'm a left left-hander for some reason I don't know why J rod true rookie Tony Gonzalez Camilo dole ball and Bobby Whit debut Stephen Kwanrick So Seth Brown and AJ public Got one more of these after guys number into football for the biggest portion of the night and we got iMac as well 23 series one Jefferson was a steal for sure. I thought it wasn't my homes What's up, Greg? What'd you get in 23? Kenzie Gordon Andrew Stevenson and sonny greck column around He's no longer our friend Kirby rookie. Oh, no, what happened? Oh, no. Oh Good god, Aaron Zavala Caleb deal bar. Is that green key and Gabriel Arias debut rookie for the Guardians? Jayrod green is Cole Solster. That is for the Marlins 38 out of 75 I Do is trashy it sounds like him MVP caliber Angels and Nico Goodrum. I have not pulled one tussle forest pulled the wanderpad parasha earlier today Which is kind of nuts Nice Steelers gone in one of the impeccables. Thank you there. I believe that was Ethan. I want to say Yes, Ethan s. Thank you, buddy Yes, we got some impeccable PYT's later on in the night as well gonna be fun Yon-Gones Joe Ross Donovan Walton and say a Suzuki bias Send in Adam Engel Here, right. We have one red earlier Ryan That's para for the angels, but that's been the only way I got a gold coming up here non rookie is Brad Miller for the Rangers 30 or 25 of 50 nice one there Grats on that. They're Texas going to Edward P Fox burger and Shane Balls CJ Abrams Steven Duggar Drew Smiley and Mackenzie Gore Yeah, right, honestly Jim Kimbrell Joe Ross Matt Olson and Bryson Stott Rowdy Tiles. There's a green Eric Fetty for the Nationals 27 out of 75 nice one there. He's just better about Xander Yeah, I know Mira Garrett and Tyler Molly.  I'd be trash in the fan of the better team too if I were a If I were a Red Sox fan for sure Absolutely, I would be doing that. I'll be fitting him. All right. Perfect mouth It's Nick Flummer and Randall Gritchuck. I'll tell him that I'm telling him that Greg. There's Steven Duggar We've got Matt Strom and Paul Sands Purple Royce Lewis Garrett Stubbs That is Hunter Strickland for the Reds 5 of 10 nice purple Congrats Cincinnati is Jesse Kent and Logan Webb Taylor Walls Jake Walsh Dickerson and Luke Williams. Yeah, that's true.  That fact or what yeah, that's true Bryson knows it's true Yeah, no salary Theoretically you could spend unlimited money Austin Meadows Hansa Alberto Cole Irvin Brendan Donovan rookie nice one there for the Cardinals as seen by Steve Cohen Adam Frazier There's Garrett Stubbs Derek Hill and Jerexon Perotfar. Yeah, I mean I think I think the free agents you guys signed this year are gonna be decent Shane Joandron M'kauchen. Who's the the Japanese guy again? I forget his name off the top of my head Hunter Strickland and Jason Creson Uh, what is his name? Why can't I think now? It's not Akiyama right now. That's a different one It's a different guy. Uh nice green freddy freeman 26 out of 75 for the Dodgers and be free Danny Mendic and Sergio Arromo I kind of think of the guy's name. He was good because it's here in the Mets guy. We're both the two, uh, Japanese guys that came over Uh, Jose Trevino. There's a Giants, uh, rookie combos. Geraldo Perdomo and Felix Bautista Tani just texted me goes how's Bryson hanging in there? Jose Miranda Uh, opening day Bronx Bash Nelson Cruz and Corey Seager Where they from Korea? Where did the where'd they come from? I forget now Carlos Rodan, Alex Thomas, Kurt Kasali and Sergio Alcantara Orange coming up here Archie Bradley, we've got orange rookie Spencer Torkelson boom Dylan Jay congrats man 23 of 25 Big time hit for the Tigers, let's go dude congrats. We'll get this magged up for you. This is awesome Awesome card right there. That is a true torque rookie Very nice Connor Pilkington Yeah, uh, Masatake Yoshida.  He's gonna be a stud. I'm not happy that he is that Yoshida's in the al east I'll be fun to get his rookie stuff He'll probably be like a decent decently high chase maybe in like an update or a series too Last box. Good luck guys. That was an awesome card by the way Big time torque Gold Stephen Kwan gold Felix Batista. Nice one there. That is 27 out of 50 for the Orioles Sandor Kaye and field crew in Rich Hill Julie Shushin Matt Beattie, Tyler Wade and Gabriel Rice. Is that uh, Turkey Corota from there as well? It's not I think Tanaka's Japanese as well, right? This is Renee Pinto O'Neill Cruz rookie Dakota Hudson and Kyle Schwaber Should I maybe get some there? How's that Iglesias? There's Desert Coolo Uh, you'll hear it's Montero and um Uh, Tyro Strata wasn't um, uh, it's Hyunjin Ryu from there as well Forget now Spencer Torkelson debut got a green coming up Michael Franco That is gonna be a Colin Moran. Nice one there for the reds 40 out of 75 Yeah, you Darvish is the man. He's good dude. He was so good still is good Kevin Smith talk about a great career you Darvish put together Josh Harrison That is Denilson Lemet Steven Matz and Marcus Strowman. Yeah, pulled one earlier There's only a couple of Jay Rods earlier pulled like two in one break. I'm pretty sure No number and stuff though. Lucius Fox, Hunter Renfrow, Tyrone Taylor and Josh Rojas Oh, yeah, of course Matt Sui. Sui was the man World Series MVP in 0-9 for the Inks. Love him Uh, Ron Marich, uh What is it? Marinaccio. Think of it Dodgers all-time strikeouts leader Kershaw, Kyle Isabel and Rob Ruff-Schneider Let's do a quick recap here everybody. Thanks again for filling this on up. This was fun Sapphire's when you hit good color in sapphire, man. It is a good time. Uh, greens to 75 Jordan Looplow Uh, that is Cole Solcer Uh, Eric Speddy, Freddie Freeman, Colin Moran, Golds to 50, Felix Matisse the rookie Brad Miller, Orange to 25, Sam Hilliard Purple to 10 is Hunter Strickland And we had a Spencer Tockelson on the orange true rookie 23 of 25 for the Tigers That'll do it for the break guys. Thanks again for the fill. Next up. We've got one more sapphire


The Russian telegram channel Astra reports that two more aerial bombs were accidentally discharged from Russian aircraft onto Russia's Belgorod Oblast, bringing the total to 14 such incidents in the region over the past two weeks. The bombs, identified as 2,500 kg FAB-500s, were found two kilometers from the village of Krukov on March 30. As per Astra.as Russian aerial strikes intensify, there is a growing number of reports detailing accidental discharge incidents involving bombs and missiles due to malfunctions Astra says that over the past two weeks, there have been reports of 14 bomb accidental drops in the region of Belgorod on March 20. It became known about the discharged FABs in the villages of Bedenskaya, Gatnyat and Zamestay. On March 21, two FAB-500s were discovered in the area of the village of Antonovka, Gravoron Urban District, and in the Borosovsky District, in the area of the village of Krukov. On March 22, two FAB-250s were found in the area of the village of Shalevo, Beluiki Urban District, and five kilometers from the village of Kazinka in the same district. On March 25, an FAB-50 was found in the area of the village of Smorodino, Yakovlevka Urban District. On the same day, an FAB-250 was found in the area of the village of Zayabino, Borosovka District. An FAB-500 was discovered in the area of the village of Besanovka on March 27. An FAB-250 was found in the area of the village of Besamino on the morning of March 28, according to ASTRA sources. Over 140 residents of the village were evacuated. By evening, the bomb was removed and destroyed. On the same day, an FAB-500 was found in the village of Nichevka. On March 28, a guided aerial bomb weighing 1.5 tons in TNT equivalent was discovered between the villages of Besanovka and Veselaya Lopan in the Belgorod region, which was accidentally dropped by a Russian bomber. Due to the discovery of the KAB-1500, the road between the villages was closed. Two FAB-500s were found two kilometers from the village of Krukov on March 30. Russia used the powerful ODAB-1500 aerial bombing Ukraine for the first time. The field published the information. According to information, the bomb was thrown in Bolsheya-Pisarevka village of Sumo region. A Soviet-era aviation bomb is a thermobaric projectile. 10 meters before reaching the target, it releases a fuel liquid in the form of an aerosol and burns it. This is called a large-scale explosion, and the smoke rises to a height of 1 kilometer. Russian military expert Julian Repke called the use of the 1,500 kilogram bomb in Sumo province a new low in Russia's war against Ukrainian cities. The total weight of the bomb with a length of 2,765 centimeters and a diameter of 630 millimeters is 1,550 kilograms, and the warhead is 675.6 kilograms. According to information, previously Russia used a 500 kilogram ODAB bomb of the image of the explosion of the ODAB-1500 aerial bomb dropped on Sumo province was shot on telegram channels.


Good morning. I'd like to thank the organizing committee for inviting me to speak to you today. I will be speaking to you about the use of coronary artery calcium score to determine the benefit of aspirin therapy. As we've seen over the past couple of decades, technology has incorporated itself in every aspect of our management of patients. We've gone from only using clinical history and physical exam to an example, comical example, is this gentleman who his physician is telling him that he has a sensor in place that detects his cholesterol and when it's too high it'll lock the kitchen door and turn on his treadmill. A little background on the incorporation of calcium score for determining aspirin therapy is that since 2018 there's been three landmark randomized control trials that have addressed the use of aspirin for primary prevention and aspirin has not fared so well. There's been two large meta-analysis and the findings have been that there's limited benefit of low dose aspirin for the primary prevention of ASCVD events which on average is offset by an increased risk of bleeding particularly in higher bleeding groups. Increased use of statins, better blood pressure control, treatment of diabetes, may have blunted the benefits of aspirin therapy. The 2019 American College of Cardiology and American Heart Association guidelines for primary prevention has decreased the classification for as a recommendation for the use of aspirin from a class 1 to a class 2b recommendation because of the availability of this data. And to summarize these trials briefly, I mentioned here the trials of aspirin because it's led to a decrease use of aspirin. At the Esprit trial took 19,000 elderly patients who did not have atherosclerotic cardiovascular disease at baseline. A median age was 74 years of age and this study showed that low dose aspirin versus placebo did not prolong disability-free survival or reduce the incidence of the composite secondary cardiovascular endpoints over a four-and-a-half-year period. It also led to a significantly higher rate of major hemorrhagic events in the aspirin arm. The arrived trial took 12,500 primary prevention participants who did not have diabetes. It included men over the age of 55 and women over the age of 60 who were at moderate cardiovascular risk. Low dose aspirin again did not significantly reduce the incidence of the primary study endpoint was a composite of cardiovascular death, MI, unstable angina stroke, or TIA. It led to a two-fold increase in gastrointestinal bleeding events, most of which were described as mild. The ascends study took 15,480 diabetics without known atherosclerotic cardiovascular disease. The mean age was 63. Low dose aspirin in this group of patients did reduce the risk of the composite endpoint, which included myocardial infarction stroke, TIA, or death from a vascular cause by 12 percent. However, this benefit was offset by an increase of 29 percent in the risk of first major bleeding events. These three studies were incorporated into a meta-analysis in 2019, which added 10 prior trials comparing low dose aspirin with placebo individuals who did not have a history of MI or stroke. The findings of this trial showed a 11 percent relative risk reduction, therefore a modest reduction in the composite cardiovascular outcome of cardiac mortality, MI, and stroke. However, it was offset by a 43 percent relative risk increase in major bleeding events. I mentioned this study because it is important when we look at the studies using calcium score, which applied these benefits and risks to their populations. So if we look at the primary prevention guidelines, low dose aspirin might be considered for primary prevention in patients who are between the ages of 40 to 70 years of age, who are at higher ASCVD risk, which is not absolutely defined in the guideline, but who are not at increased risk of bleeding. Patients who are above the age of 70, it receives a class III indication for harm, more than benefit, and in any patient who has an increased bleeding risk, aspirin has a class III indication to avoid its use. So calcium score has been advocated as a tool to capture subclinical atherosclerosis and potentially affect how we utilize primary prevention therapies. CT coronary calcium score is a relatively cheap modality. You can get a test anywhere from 90 to 150 dollars, which is roughly what you'd pay for a generic statin for 18 months. The dose of radiation is somewhere around 0.89 millisieverts, with modern tech jolly probably a little bit lower than that, and this is using as a frame of reference that the average person receives about three millisieverts of radiation from ambient radiation. As you can see to the left, the calcium score can very easily detect calcium deposits in the coronary, in the frame to the left, you see the structure in the middle is the heart, and there's no coronary calcium, and as you go from right and then left to right on the bottom, you see a progressive increase in calcium deposits. We know from the multi-ethnic study of atherosclerosis that these calcium studies, these calcium tests, which were evaluated at baseline in patients and looked at prospectively, were very clearly linked to an increase in atherosclerotic cardiovascular events. Patients who had a calcium score of zero had a much lower risk. Patients with calcium scores of over 300 had a seven-fold increase in risk of atherosclerotic cardiovascular events at five years. Furthermore, this modality has been used to assess the potential benefit of statin therapy. This study, which was performed in 13,000 healthy volunteers without pre-existing cardiovascular disease at Walter Reed, who had undergone baseline coronary calcium scores, they were matched to patients who were on statin therapy at the initiation of the study, were matched to controls not on statin therapy. What you can see from left to right is that patients with a calcium score of zero, there's no difference in the curves and the Kaplan-Meier curves over time between statin and non-statin treated patients. As the calcium score increases above zero, the curves start to separate, and then clearly above a calcium score of 100, there is a significant advantage to being on statin therapy as far as risk reduction with the number needed to treat of 12 patients to reduce one event for patients who receive statin therapy versus those who don't. Because of this, the primary prevention guidelines have incorporated coronary calcium as a tool to help clinicians in decision making. Patients with a calcium score of zero are thought to be at very low risk and it is reasonable to withhold statin therapy and reassess it five to ten years, particularly if there's the absence of other enhancing factors such as diabetes, premature atherosclerotic disease, and the family and tobacco use. With these studies as a background, there have been several studies that have looked at the use of calcium scoring to further define what patients may be at more risk with aspirin therapy and which patients may benefit. This study from the Dallas Heart Study, which is a large prospective population-based multi-ethnic study in the Dallas-Fort Worth area, sought to examine this association. The patients in the study were free from atherosclerotic cardiovascular disease and were not taking aspirin at baseline. They found 2,100 patients in their cohort. The average age was 44 years of age. There was a high prevalence of women in this study, 57 percent, and 47 percent of patients were black. They followed patients for a median of 12 years. In the study, there were about 116 major bleeding events, 123 atherosclerotic cardiovascular events, and they did an excellent job of capturing events through the Dallas-Fort Worth Hospital Council data initiative database. Of the bleeding events, 70 percent were gastrointestinal, 16 percent were intracerebral. Of those total events, 21 percent were fatal. They utilized the meta-analysis that we discussed previously to apply the relative risk reduction of 11 percent and relative risk increase of 42 percent to the population at different risk profiles from the pool cohort equations and from calcium score. One finding that is of interest is that on the figure to the right, we see that as calcium scores increase, with a calcium score of zero as the line in black and a calcium score of 100 or more is in blue, there is a progressive and expected increase in events, as we see in the Mesa cohort. But interestingly to the left, you see major bleeding events which also seem to track with increased calcium scores. This increase was not as apparent after multivariate analysis, but it was the trend still existed showing that increased calcium score, increased vascular disease frequently tracks with increased bleeding risk. If we look at the risk of atherosclerotic events, in other words, the estimated increasing bleeding event rate versus the reduction in atherosclerotic cardiovascular events on the left upper quadrant, you see that it doesn't seem that for the population as a whole, there's any point at which the risk of ischemic events is lower than the risk of major bleeding events. If we start looking at to the right and then from left to right on the bottom, we see that as the estimated 10-year ASTVD risk is calculated by the pull-court equations, patients with an ASTVD risk of more than 20% do have a benefit of reduction in atherosclerotic events that's higher than the increase in bleeding events. If we look at this data in a little bit more granular fashion, if we look at the patients with lower bleeding risk of the population, we see in the left upper corner that patients with a calcium score for the total population have an improvement in outcomes that's better than the increase in risk when calcium scores are above 100. And this is particularly true in patients who have, as seen in the lower corner, in patients with an ASTVD risk of over 5% who have a calcium score of over 100. Those patients and those with ASTVD scores of over 20% derive a benefit that's higher than the risk of bleeding. Mind you, the numbers of bleeding events were very low in the over 20% arm, so it makes it difficult to clearly assess this trend in this population. So it's estimated that in these lower risk bleeding patients, you have a 1.6% reduction in the 10-year of expected ASTVD events versus a 0.9% increase in bleeding in patients who have a greater than a 5% ASTVD risk at 10 years. How about in those patients that have a higher bleeding risk? Well here what we see is that in the total group and regardless of ASTVD score and regardless of calcium score, patients who receive aspirin and have a higher bleeding risk in primary prevention seem to have more bleeding risk always than reduction in event rates, suggesting that in patients with higher bleeding risk, aspirin generally should be avoided. In this group of patients, a 0.5% reduction in the 10-year expected absolute ASTVD risk with aspirin was mitigated by a 1.2% increase, absolute increase in bleeding risk. Who is not at low risk of bleeding? Well for this study, they looked at, they classified patients as being at not low risk if they were on non-steroidals, on corticosteroids, anticoagulants, SSRIs, PPIs, antiplatelet agents, or if they had a history of peptic ulcer disease cirrhosis, cancer, CKD, thrombocytopenia, or uncontrolled hypertension. There were several limitations for the study including the low risk population, the patient's 10-year AASCVD event rate in some of the low group bleeding risk patients was as low as 0.5%. So it may have been a suboptimal setting to assess the potential benefits of aspirin, which we generally consider in higher AASCVD risk patients. The second study I will comment on is the MESA sub-study. The MESA sub-study looked at calcium and the name of the study is not the MESA sub-study but just to denote the population looked at. The study aimed to assess the value of calcium for guiding aspirin allocation in primary prevention. They used the 2019 aspirin meta-analysis data to apply risk to the different populations of AASCVD risk divided in less than 5, 5 to 20 and more than 20% like in the previous study. They also defined calcium score groups as 0, 1 to 99 and over 100 in an exploratory analysis. They looked at calcium scores of over 400. The outcome of interest in this study were CVD events which were composed of fatal and non-fatal MI, non-fatal and non-fatal stroke, other CVD death and major bleeding events which were bleeding events that they could capture as hospitalization. They excluded patients in this study who had at baseline high bleeding risk so patients with CKD, patients with severe liver disease who are on anticoagulant drugs or who had uncontrolled hypertension were excluded in the analysis. Of the total MESA population which is 6,814 patients, 1,200 were excluded due to baseline aspirin therapy, 1,200 were excluded who were over the age of 70 and patients who had high bleeding risk were 410. So for the total population there were 3,540 patients with a mean age of 56 years of age, 55% were women. Median estimated 10-year ASCVD risk was 4.1%. There were 10% patients on statin therapy and what you see is with higher baseline calcium you also saw higher ASCVD risk and that's what we see in the left side panel in orange. As you go from a higher calcium score from 0 to 1 to 99 to over 100 you see a graded increase in the number of patients or percentage of patients that have a moderate or high risk. To the right we see the assessment of calcium score according to baseline ASCVD risk and I will highlight that almost 20% of patients had a calcium score that was over 100 in the low and moderate risk patients. I will also highlight that in the patients with the highest ASCVD risk the over 20% almost 40% had a calcium score of 40 but a significant number of patients 32% had calcium scores of 0 which by outcomes assessment would be a population we would consider maybe withholding aspirin therapy for because of a lower risk. When we look at the number needed to treat with low dose aspirin for five years to prevent one CVD event and plot that with the number needed to harm to cause a major bleeding event by baseline coronary already calcium score we see that it's only and I'll highlight that the red line denotes the number needed to harm in that group. The number needed to harm becomes favorable on when the when the calcium score is over 100 in light green where you see that the number needed to harm is 518 compared to 140 number needed to treat to prevent one event and in darker green the exploratory analysis of look appears even more favorable although they didn't have bleeding events to account and and make an assessment of harm the number needed to treat is more acceptable in that group of patients and to the right it's the same data but separating by sex and you can see that in patients who have calcium score of more than 100 again in light green the number needed to treat is lower than the number needed to harm. Interestingly ASCVD group separation did not seem to clearly separate for benefit with regards to number needed to treat versus number needed to harm if you look at it in blue which is the total group of patients with ASCVD risk of less than 5 5 to 20 and more than 20 the number needed to harm is barely beneficial in the group as a whole in patients above the the above an ASCVD risk of 20 percent 10 year risk of 20 percent it's not until you look at the calcium scores that are higher namely in the light green and dark green where the number needed to treat is lower than the number needed to harm which is the line in red so this suggests again that calcium score is a valuable tool to separate the patients who may derive benefit from aspirin and whose benefit is is higher than the potential harm of aspirin major bleeding again these studies this study equates bleeding risk and ASCVD risk and for a patient for an individual patient and the physician they may not see those as equal in the patient and so that's important in discussion you have with with the patient regarding the risk benefit of treatment so you need to consider the totality of available evidence for CD risk inclusive or appropriate of risk enhancing features such as strong family history of premature MI if you can't control the lipids the blood pressure of the glucose to targets those patients may be at higher risk and aspirin therapy may be particularly beneficial in them and obviously as we mentioned significant elevations in coronary calcium you also need to incorporate bleeding risk so older patients patients on concomitant any thrombotic therapy patients with history of GI bleed CKD thrombocytopenia or drugs that may affect anticoagulation should be incorporated in your decision making I want to mention this specific case because I I like to show it it illustrates the importance of follow-up and in patients with calcium scores of zero this 53 year old male with hypertension whose mother had four vessel cabbage at age 56 and did not want to take statin therapy with a modestly increased LDL at 94 and a low mildly decreased HDL we decided to do a calcium score as my thoughts were that it would be elevated and we would be able to start therapy his ASCVD risk would put him in a low risk score at 4.9 at five years we repeated the scan and just to follow up and assess and his calcium score had gone up to 20 224 his ASCVD score would have qualified him for statin therapy and were super statin was started 12 about 15% of patients will become positive after a zero calcium score at four years and at five years about a quarter of patients will have a positive calcium score as seen in the Mesa population so in conclusion in the primary prevention of atherosclerotic cardiovascular events individuals considered potentially good candidates for low dose aspirin therapy namely patients less than 70 years of age with no high bleeding risk features who are believed to be at higher atherosclerotic risk clinicians may want to quantify the calcium scores to guide personalized aspirin allocation individuals with calcium scores of over 100 and in particular patients with calcium scores over 400 may be good candidates for aspirin therapy for primary prevention although the net expected benefit will likely be modest in the presence of coronary coronary artery calcium scores of zero the bleeding risk is greater than the potential benefit and aspirin for primary prevention should be avoided so with this I conclude I'd like to thank the organizing committee for giving me the opportunity to speak with you thank you very much


We work on a disease, it's a fungus that affects frogs and this disease has been found out to be a major contributor to the global declines and amphibians that we're unfortunately currently seeing. This fungus, I'm going to say the name, it's called betrachocytrium dendrobatidis but for obvious reasons we call it BD, it's a bit of a mouthful, has been spreading around the world and these frogs that you see around you are affected by this fungus. The frogs we use here are, they're called midwife toads and this species is found widely across Europe. The zoospores that are produced by BD swim through the water and when they strike the amphibian skin they deploy some very potent enzymes called proteases. These zoospores literally burn their way into the amphibian skin and they then become intracellular and go through subsequent reproductive cycles to colonize the skin of the amphibian and it's that point that skin function is disrupted and that the animal will fall sick. These midwife toads are the most susceptible species to the fungus so we work in the high Pyrenees above 2,000 meters we see very aggressive die-offs of these elities in a number of populations and in the number of populations they now no longer exist because the fungus has killed them all. So until 2014 we thought this was a single disease, BD. In fact we thought it was a single lineage of the single disease which we call BD GPL which is the global panzerotic lineage. This is the bad guy which has been extirpating amphibians around the world but then scientists working in the Netherlands discovered that the fire salamanders there were going extinct and that they discovered that there was another chytrid which has subsequently been called Batrachokytrium salamandravorans, the salamander killer. There's now at least two chytrids which kill amphibian species. What we're finding that in these amphibians which are taken out of tropical rainforests and traded around the world quite a high proportion of these are infected with BD and we've actually shown that some of these infected trade animals when released into the environment have spread their infection to the environment so we believe that the amphibian trade is a very important vector of this infection around the world. What the United States has done is they've thrown up a trade barrier to all to 201 species of salamander from southeast Asia and from Europe in an effort to prevent that infection coming in on traded animals. It's perfectly possible to breed amphibians in facilities like this and to have them certified as pathogen free and then to be bought as pets. The treatment that we have developed here in these laboratories is an antifungal drug called archiconazole. This is commonly used in humans and in pets but we've found that if we use very dilute concentrations of this antifungal with tadpoles all these metamorphs then they will clear infection. The chytrid is thankfully very very susceptible to archiconazole. So by finding the exact dose that we can use on an animal without harming it we can then go into natural environments and try those doses on infected animals and then to clear them. So I have a fantastic collaborator in Spain called Jaime Bosch and he works on the island of Mallorca. Jaime Bosch went there year after year. Sometimes he had helicopters to lift these tadpoles out. Sometimes it was just backpacks with water bottles with tadpoles in and air bubbles. Once these tadpoles were in a captive environment they then got the archiconazole treatment. They were kept until we were sure that they were clear of infection and then were reintroduced back into the environment. In association with this we also use some chemical disinfection in the environment where we wash rocks with this compound called vercon which cleared any residual stages that was of the fungus that were clinging to the rocks and by doing this we eventually cleared the infection from the island of Mallorca. So this is a massive coup because this is the first time that a wildlife disease has actually been combated and eradicated in nature. We're now moving to mainland Spain where there are larger populations and they're more connected than this isolated island community and we're going to now try this treatment on a much wider set of population to see if it has any utility in a more real world context. So already scientists are using our iticonazole treatment protocol in other species in Panama, in Costa Rica, in South Africa. They're having some success in at least being able to create captive amphibian arks where they have clean animals without the fungal infection that are breeding so that when we do come up with a mitigation approach that we can use in the environment then we actually have these captive species that you can then reintroduce to the wild.