And here we start with the lineups, let's look at the Naprima College lineup first. Of course, Thierrys Romain in goal for Nafses, Hills, Pascal, Cooper, Bailey, Francis, Vespri, Kalees, Panto, Alexander, Raymond, and the skipper is in fact the goalkeeper, Romain and Travis Mulrain, the coach. Let's have a look at the formation. Yeah, there's a 4-3-3, they have youth national team experience in there with Cooper and of course Pascal. The little brother of Andre Raymond is playing for them as well. He played last night in Trinidad and Tobago's Caribbean Cup game. Let's have a look at the press lineups, Lazarus in goal is Pemberton, Young, Clement, Jones, George, Raffwitt, Elliott, Barclay, Felix, and Cody Cooper who is the son of the coach Sean Cooper. The formation, right? Yeah, when they line up in a 4-2-3-1, of course Lazarus, a key goalkeeper for presentation college.  And it meant that the game has ended in a stalemate here at Lois Street in San Fernando. Here is the crowd making their way out, but let's have a look at the highlights here. As the corner came in and cleared away, the long throw from Khalees eventually cleared upfield. Here comes Naparim again, this was Panto, hurried the shot here, he had his time, could have taken his time to bury that one. He hustled the shot and it went wide, but this time the corner from Naparim and Lazarus takes that one nicely, that's a good take, really a good take. And the shot from Barclay, that's a good shot, it's kitted across the outfield, the turf, and the keeper had to get down quickly. Then the corner from Naparim and the header from Cooper, you had to think he should have at least hit the target and jumped early, headed it wide and then the shot from Francis never really got old of it, was always leaning back and went over the bar. And this time Lazarus coming out quickly, as France was coming in, ball chipped, Cooper with the header and Lazarus started to come forward and it nearly sneaked in and then the final minute here, the ball slipped out of the hand of the keeper and the header came from Cooper right at the end, couldn't score. So here are the final stats, 10 shots from Naps, 5 from presentation, 4 shots to 2 in favour of Naparim, shots on target, that is 5 falls each, yellow cards, 2-4 presentation, none for Naparim and no red cards, off sides, 1 each for both teams, 10 corners for Naps, 9 to presentation, 2 saves from the Naparim keeper, 4 saves from the press keeper and possession, 55%, Naparim 45%, but the more important stat is right at the top there in green, Naparim and Nill, presentation, Nill, let's go downstairs to hands, he's got the man of the match with him.   Well, from this draw, what does it mean for the team, for the rest of the SSL Premiership division? What kind of fight are you all going to put on and what can we expect? I mean, we hope the results go off key for the other teams, I mean, we'll keep pushing until, you know, anything happens so that we could top the league. Alright, thank you very much Josiah Cooper, I'm out of the match, congratulations to you from one Cooper to the next, Brent Sancho has the coach of presentation, college with him right now. Coach, 90 minutes plus of football, 0-0 at the end of the day, your assessment of the game? Well, I think, you know, after we, we, we spilled the penalty, I think was even Steven, even Steven. Well, of course the game meant a lot for both teams and school historically, but a points perspective with five games left in the season, do you think it's still possible for presentation college? No, I don't think so. It's, it's a, it's an easy street going forward with Fatima and Sanwa. I don't think they have any games in hand to trouble them. So it's their league to lose. This game was a derby, so we expected a very close one. Thank you very much coach and all the best to you for the rest of the season. Thank you very much. Thank you. Coach, Marine, of course, 0-0 at the end of the day, you had one or two chances. A missed penalty from presentation college, your assessment of the game so far? Well, besides the missed penalty, I think it was a very even game, a lot of ebbs and flows. I think it was an epic battle, befitting a prez, naps, derby. We have to look forward, we can't do anything about this game and just hope to win the rest of our games and hope results go our way elsewhere. It's two back-to-back games without scoring any goals, is that a concern for you moving forward? Well, it is a concern because we were scoring goals and conceding. We worked a bit defensively, now we're getting the clean sheets, but we're not converting up front, so we just have to keep working on the training field. Thank you very much coach and all the best to you. Still a celebratory mode here.


Before I get into this video, I just wanted to say happy Father's Day to all of the fathers out there. I'm a father myself of three beautiful children and you guys, I hope we're having an awesome day. Being a parent is one of the most difficult but most rewarding aspects that any human being can go through in their adult life. That being said, I would also appreciate if you would subscribe to the channel. We are on a road to 133,000 subscribers. We're close, but not quite there. So I would appreciate if you would go ahead and subscribe to the channel because if you do, we might just make it. All right, guys, we have to talk again about a Nintendo Direct. And look, this has been a very interesting time for me, not just because I've been dealing with a few personal things that have led me to not keep up on things as much as I want but also because we talked last week about a Nintendo Direct, right? We talked about how there were rumors out there of a potential Nintendo Direct next week. Or just a Direct in general in June. Nate, the hate, pretty much repeating as he has many times and did over the weekend that we shouldn't forget about June. That June could be a Direct. That June may be a Direct. That June sounds like a good time for there to be a Direct. These are his words or paraphrasing his words. And some people over speculated a bit on his 6.21% thing which wasn't related to Nintendo. But then, now he's kind of making a joke out of it, saying, oh, something will happen between 6.20% and 6.23%. Look, I don't really know if any of that means anything. He could just be trolling at this point because he's not very happy with how some of the reports we're doing with his 6.21% thing. But here's today where we have a actual report, not just some Reddit stuff or some speculation from Nate the Hate. But we have an actual report, I believe from a Brazilian website. If it's not Brazilian, please let me know. But I believe that's where this is from called Nintendo Universe or Universal Nintendo. Look, I don't really know. I don't speak the language, so I'm just using a Google translate here. What it says, report, Nintendo prepares a new Direct presentation for next week. And he posted this on Saturday, so what he meant next week, he means this week. And he said the company should just close news for the second half of Nintendo Switch releases. And this was posted up by Necro Philippi Lima who was already sort of teasing there would be a Direct this month last week. And he said, with traditional video game, news events happening since the end of May and beginning of June, one of the companies that owed news to their fans was Nintendo so far, but that should change in the coming days. According to information obtained by Nintendo Universe from anonymous and reliable sources, the company should hold its traditional news presentation through a Nintendo Direct next week until the 23rd of June. So he means before the 23rd of June. So sometime before the 23rd of June. The format of this presentation, whether a mini or general, is still unknown to us. But we understand that it contains first party games among the announcements and updates. And the company should not use partner showcase as an option. So far, the company has not made any announcement or given any indication of this presentation, which may be announced next Tuesday on June 20th, but stay tuned for more news. It could also obviously be announced on the 21st to happen on the 22nd, of course, as well. So it could be Wednesday or Thursday. Seems to be what he's suggesting. But yeah, the fact that he says there will be more first party games and it does tell you it's either a mini or a general, not a partner showcase. They don't put first party games in partner showcases. So that's cool. Again, mini or general, doesn't really seem to matter to me. We haven't had a full mini from Nintendo in quite some time. And the last one they did was actually quite beefy. So whether it's a mini or a general, either way, I'll be pretty excited. Now again, this Necrophilipe Lima, he's been really accurate in the past with some of these reports. I've actually known of him for a while because I follow him around Nintendo Direct Times because he seems to have pretty accurate insider sources. I don't really know who his contacts are. Maybe it's somebody directly at Nintendo through one of their local branches. But what I do know is I am pretty excited at the prospect of a direct this week. And we need one. I mean, look, some people are overreacting a little bit talking about how, without a Nintendo Direct, let's say there wasn't one this month. Let's say they didn't do one all summer, that Nintendo was in trouble, which reminded me of the whole Nintendo is doomed thing. There's actually a whole website called Nintendo is doomed because Nintendo is always eternally doomed by anybody who doesn't pay attention. But I do think it's interesting thinking about the prospect of there not being a direct versus obviously Nintendo was gonna have a direct. Let's be clear here. Nintendo is going to Gamescom when they hardly ever go to Gamescom. Nintendo is having a Nintendo Live 2023. They don't do one of those every single year. Nintendo has a tour going on right now, which is gonna feature games like Pikmin 4. Okay, well that means they have to have a way to present news on Pikmin 4 if they're gonna have a demo tour featuring Pikmin 4. Oh, also Nintendo is collaborating with PAX West, which means they're probably gonna have demos at PAX West. And while Nintendo was at PAX East, it was just games that were already out, right? And they could do that again at PAX West. It just seems timing it around Gamescom and Nintendo Live really does suggest that there's going to be more. But the point is that Nintendo already has plans to show games at these events. So they clearly have plans to reveal games. And I think what happens is because there's no E3. And Nintendo has, as of yet, to do a general direct in June during a year without E3. There's just this assumption that Nintendo won't do one this month. Plus you have things like, you know, Jeff Grubb saying he's only really heard of something happening next month. And he doesn't even know what that something is. Just Nintendo's got some sort of plan to do something next month. Okay, well that could be anything. Could be an indie world. Could be a partner showcase. Could be a Pikmin 4 direct. And I know someone on Twitter told me, yeah, I don't think Pikmin's big enough to get his own direct. Look, Pikmin 3 Deluxe sold over 2 million copies. At the time of me writing this, officially, Xenobrid Chronicles 3 hasn't even sold 2 million. And that had a dedicated direct last June. So I'm just saying, you know what? We can't dismiss the possibility they might do a dedicated direct for Pikmin 4 next month. But what we can point out in all of this is, look, Nintendo always has a plan. We may not know what the plan is. We may not know what their reasoning is for that plan. And I think some of us lack some patience. And I will say this. If you're someone who doesn't like tears of the kingdom, you're not a Zelda person, then yeah, it's probably been a bit of a waiting period for you. Let's say the last game you really enjoyed was, I don't know, Fire Emblem? Let's say you were a big Fire Emblem person, Fire Emblem Engaged back in January. Then for you, if there's been nothing Nintendo has really released since then that interests you, you've been waiting a while. And let's say that wasn't it. Let's say it was Splatoon 3. Let's say it was Xenoblade. Let's say it goes all the way back to Kirby and the Forgotten Land. Like, you start to see where it could, for some Nintendo fans could be a while. I think there's this misnomer that because Tears of the Kingdom is popular, that, you know, Nintendo could get away with not releasing anything besides Pikmin 4 for the next four or five months.  Let me explain. There's 125 million switches out there. Let's say that Tears of the Kingdom moves 20 to 25 million units this year. Let's just say that happens. You're telling me that Nintendo wants to ignore the other 100 million switch owners that aren't interested in Zelda? No, of course not. So this is one reason why people say, oh, well, I'm glad that Pikmin comes when it does or I wish Pikmin 4 came later or, you know what, if Metroid Prime 4 is coming this year, man, you know what, I might not be done with Zelda yet. I hope they delay that. I know a lot of us only think selfishly about game releases, but we need to be honest. Not everyone likes and plays Zelda. That's just reality. Not everyone likes and plays Mario. Even Mario Kart, think about this, the most popular IP Nintendo has is Mario Kart. And even that, even that hasn't sold to half of the switch owners. It's close, but it hasn't sold to half. That means half the people that own a Nintendo Switch do not care about Mario Kart. So I'm just throwing out there that we need to be considerate of others. Nintendo is never gonna not do something this summer. They were never gonna not reveal more news on games and reveal more upcoming games because Nintendo knows you can't just leave 100 million plus Nintendo Switch owners out to dry with nothing to play for months on them because they weren't into Zelda. I'm sorry, I know it seems crazy. How could you not be into Zelda and be a Nintendo fan? Believe it or not, it happens. Happens quite frequently, 100 million plus we sold only eight million of Twilight Princess. Actually, if you look at the sales of Zelda in general, Zelda over the years has never really been a massive seller until Breath of the Wild. And even when you count Breath of the Wild and you count tears of the kingdom, compared to the system it's on, there's still so many other people that own it that didn't play Zelda because they're not into it. So again, Nintendo is never gonna leave people out to dry whether they do it this month or next month, I don't know. But according to Nintendo Universe over here, they're saying we're getting one this week. They're obviously a lot more credible than some random person on Reddit. And they says he's got multiple sources on this. So that's pretty cool. And we've obviously had a lot of hints from Nate the Hater saying, you know, hey, June sounds like a good time for a direct, don't give up on June, blah, blah, blah. It kind of sounds like he's heard something about June and he does have a podcast dropping this week talking more about that. But we'll see when that drops. Cause I mean, if it drops too late in the week, maybe it's already happened. I don't know, maybe he's waiting cause he doesn't want to put it out there that it's happening this week. Maybe he doesn't know, be it to me. Anyways guys, thank you so much for tuning in and I'll catch you in the next video.


The floor may not be in your robot. Have you ever wondered why Disney is evil? Okay, let me rephrase that. Have you ever wondered why everything the Disney Corporation does is related with cynicism? Why it is that even the most benign things made by Disney are treated as if there is still something fishy about them? Well, I can assure you that it has nothing to do with an overzealous dose of skepticism towards a family-friendly company. But in order to understand what I'm getting at, we need to take a little trip down history lane. In its early days, Disney's competitor was known as Fleischer Studios. Based in New York rather than California, Fleischer could be considered more adult, raunchier than the more family-friendly tamer Disney. Of course, we all know how this rivalry of sorts ended. With Disney becoming even more popular, and Max and Dave Fleischer fading into obscurity. Yet still, every time an animator at Disney makes a mistake, writers don't really think things through, or some girl from one of those dumb teen sitcoms finds her g-spot, someone somewhere will cook up some cookie conspiracy theory to explain it. And now I know there's a reason for that. It all began in my quiet town in New York State, when our local theater decided to auction off some of its old film reels they had kept in their attic. The new manager was apparently more interested in making a quick buck than preserving pieces of film history. Either way, I got some really old reels from the 30s, and even two from the 20s. All in all I got five reels for a hundred dollars, a pretty cheap price considering collectors would probably pay ten times the amount. When I then started watching them on the old projector, my grandfather passed on to me after he died. I was surprised to find that they were all Fleischer cartoons. And in good condition too. The ones I got were titled, Cogwrap Hotel, There's Something About a Soldier, The Old Man on the Mountain, and Gimbo's Initiation. The last one's reel was also bigger, which caused me to believe that it was Gimbo's Initiation, and a few other shorts added as bonus features of sorts. This immediately got my hopes up in seeing a never-released short or even a making of. Now sure, all of these shorts can be seen on sites like YouTube, and I've seen them myself before too, but putting in the actual film reels gives watching these shorts another feeling entirely. All of them played out like they should, nothing out of the ordinary. All of them except for Gimbo's Initiation. For those who don't know, this short tells the story of how Gimbo, a dog-like figure, gets pressured into a cult, and has a rather comedic twist at the end. The short began normally at first. We see Gimbo walking down the street and whistling, walking over three gullies as he goes on. He then falls through the fourth gully, where he gets trapped by Mickey, who seals the lid with a giant lock. Not kidding, that actually happened. Go watch it for yourself. We then get various scenes of Gimbo being badgered into the obscure cult, and we hear the catchy, wanna be a member, wanna be a member from the cult leader, after which Gimbo emphatically declares no, before he's tortured in various ways by the cult in order to be forced into it. After some more scenes of torture, Gimbo falls through a door, and is asked one last time to join the cult, again refuses, and it's revealed that the leader is actually Betty Boop, here in her early dog-like persona, and that the cult is made up of nothing but Betty Boop clones. Gimbo then accepts his initiation and the short ends. But this is where my copy differs from the original release. Instead of falling through the door and into another room, Gimbo then falls into a cave. Eerie music begins to play as Gimbo makes his way through, staring at the stalactites above him as he walks. Then a loud screech of a trumpet sounds, as a strange bird-like creature appears before him. The previous music begins to play, and instead of wanna be a member, the bird sings, welcome to Zabelba, welcome to Zabelba. And instead of saying no, Gimbo just stares at the bird at first, then breaks the fourth wall, before his eyes widen while displaying a wide creepy grin, before the short fades to black for some good three minutes. I was bewildered, and stopped the projector immediately. But then I realized that this reel was bigger than the others, and since I was curious about what else was on it, I started the projector again, and waited for what was to come next. The black screen cuts to a white title card that reads, The Butcher's Purse. The Butcher's Purse? What does that mean? The title card cuts out, and Gimbo again walks through the cave, this time accompanied by native-themed music. And when I say native-themed, I don't mean some old-timey borderline racist imagining of native music. So, I mean actual native music, that one would hear an authentic native band playing. It consists mostly of flutes, accompanied by a beating drum, designed to convey an eerie mood. Gimbo walks into a large cavern filled with all kinds of strange beings and monsters, two of them sitting on thrones. One was skeletal in appearance, the other more birdlike. The strangest thing about all the characters other than Gimbo is the way they are drawn. While Gimbo's outline and features are very bold and simplistic, the outline of the other characters are thin, and they have very realistic features. So much so that one can even see the gimbals in the faces when they speak. The birdlike figure on the throne then stands up, holds a scepter in the air and speaks. The reason I put it in quotations is because it doesn't actually speak. Instead, rhythmic clacking sounds, like small pieces of wood being smashed together, and a set of strange symbols emanate from the figure's mouth. The short cuts to Gimbo looking horrified, and emphatically declaring no once again. Loud shrieking of trumpets sound, and out of the mouth of everyone else comes but one symbol. Gimbo shrieks in horror and wants to run, but gets seized by a skeletal figure wearing eyes, and a second figure carrying an axe. They violently rip Gimbo's shirt from his body, and take him out of the cavern. What happens then is difficult to describe. The skeleton and axe monster take Gimbo into a small room with a single blood-stained altar in the middle. They bind Gimbo onto it and look at each other. We then get a close-up of each of the figures smiling. This is spliced together with close-ups of Max and Dave's faces. First the skeleton, then Max, followed by the axe monster, and then Dave. But not a kind smile, as if posing for a photo, or something similar. It's more of a deranged smile that starts out as a grin, then gets ever more maddening as the close-ups progress. This goes on for about a minute. The film then cuts to Gimbo's throat, as we see the axe swing in and out of the frame, and as soon as it chops Gimbo's head off, the short cuts to a close-up of a lifeless decapitated cub of some great cat, bleeding from its throat. The close-up dissolves into a cartoon form of the shot, and the two figures laugh and cackle, while Gimbo is nowhere to be seen. Drums begin to play again, as the decapitated head is carried to the center of the previous cavernous room, where we see an effigy of Walt Disney. Max and Dave fly sure in their cartoon form enter, and are spoken to by the other skeletal figure on a throne. This is again indicated by the symbols emanating from its mouth. The two are subsequently each given a strange black knife of sorts, and we again cut to live action footage of them cutting into one of their hands, thus bleeding excessively, before we see them smearing their blood on a real-life effigy of Walt. The short again cuts to the cartoon, where the axe monster from the decapitation scene does the same with the effigy of Walt, and the characters in the cavern find it a good sport to play with it, like a basketball, tossing it around and around. Eventually, the head makes its way to one of the figures on the thrones, which places the head in a box, and then points his scepter to Max and Dave Cooneal down before him. The scene darkens, and a large piece of text is displayed all across the screen, and seemingly written in the same strange symbols as seen before. This is the end of the short. That is, sort of. After the text, the short cuts to a black screen, with text saying, After the real ended, I stalked the projector, and just stared at the now blank screen for what seemed like an eternity.  Sure, Flicious Studios was no stranger to the hellish or occult. One of their shorts, Red Hot Mama, even shows Betty Boop literally going to hell in a dream, and freezing it and the devil in it. But Max and Dave never actually depicted graphic violence in their work. So what was this? An obscure personal project? A desperate attempt to save their studio? I decided to find out. A few days later, I had a digital copy made of the real, so that I could take screenshots, and post them on forums in search for an answer. It took several weeks but eventually, someone did answer me. The user known as Vintage23, told me that the writing displayed was Mayan, as was the entire theme of the butcher's purse. The user told me that the scene with the skeleton and X guy, was a well-known scene in Mayan mythology depicting the god of death, skeleton, and the rain god, X, sacrificed something called, the Jaguar baby. Vintage23 also told me that the figures in the cavern were the lords of Zabelba, the Mayan underworld, and that they were drawn in what was known as Codex style. Vintage23 was even nice enough to translate the emanating pieces of writing for me. This is what was said during the butcher's purse. First scene in the cavern. You, Gimbo, are to be sacrificed as an act of revenge by your creators. All figures in the cavern, roughly translated. Sacrifice him, sacrifice him. Max and Dave are spoken to.  And this is the entire text at the end of the short, again, translated very loosely. On this day, the 31st of October 1940, we, Max and Dave Fleischer, take revenge against our enemy, Walt Disney. May he never find peace. May all of his works be frowned upon, and may his name forever be associated with the stench of foulness. May Disney forever work with their dark shadow looming over him. Vintage23 also told me that I would have to concur with him that this must have been an elaborate scope someone had pulled on me. I asked the person why that was, and he sent but one reply. Because we haven't been able to decipher and read mine until the 90s, 80s at best. Reading this, I just sat there staring at the screen for who knows how long, just as I had done after watching the short film. But I knew this wasn't a clever forgery. It couldn't be. As you recall, I bought this reel at an auction at my local theatre, where it had been lying in its attic for who knows how long. If this actually was a forgery, it would have meant that someone would have learned to draw and animate like the Fleischer's, learned to draw and animate the Mayan figures, learned how to read and write Mayan, recorded the additional music, find the live action footage, learned ancient video editing techniques, and then slap that onto a film reel. And what for? To leave it to rot in an attic of some small town theatre. This was very clearly real. But what was the point of all this? How did Max and Dave learn to read and write Mayan decades before it was found out by linguists and historians? And what was Walt's part in all of this? This got my curiosity up, and I started doing research on all of this. On Fleischer Studios, their relationship with Disney, the demise of the former, and the rise of the latter, and the various myths, legends and rumors surrounding the Disney Corporation. And then it all made sense to me. In 1940, Fleischer Studios was on the verge of closing its doors. They closed for good in 1942, but the Fleischer's weren't willing to leave without a fight. So they burst their competitor, and Disney's family-friendly image became its burden. Everything it would produce from now on would be stained by or laced with an aura of cynicism. This is why you get these conspiracy theories, and that's why you read creepy stories upon creepy stories dedicated to the mouse and the family-friendly image. The bishop's boner in Little Mermaid, the unintentionally implied incest in The Lion King, the naughty test picture in The Rescuers, Miley Cyrus' radical transformation from goody-goody to sitting naked on a wrecking ball, all of these things are the result of being cursed almost a hundred years ago. This is why everything the Disney Corporation does is regarded with cynicism.


Well, Jean, thank you very much for that kind introduction and thank you all for the opportunity to be here this morning. It's really fantastic being able to get left with you all and talk with you about a topic that's near and dear to my heart, that being horror auto-inflammaticus, the adventures and the genomics of inflammation. And of course, the term horror auto-inflammaticus is sort of a take-off on the term horror auto-toxicus, which was a term that was proposed by Paul Ehrlich back at the beginning of the 20th century. He was one of the great early immunologists who recognized the severe consequences when the immune system turns against its host. And so Ehrlich coined the term horror auto-toxicus. And what we're going to be talking about this morning, horror auto-inflammaticus, is just basically the turning against of the innate immune system, of a part of the immune system against the host. And so we'll focus on that particular aspect of the immune system. But anyway, I hope that over the course of the next three or four hours that I have with you, that we can really get down to some details in terms of these fascinating auto-inflammatory diseases. So in any event, I have nothing to disclose in terms of commercial relationships, but probably the first thing, at least for some of you, is to get down to the question of the systemic auto-inflammatory diseases, what are they and why should you care? So in any case, first of all, just in terms of the definition, they are a group of disorders in which there are episodes of seemingly unprovoked inflammation in the absence of high-titer auto-antibodies, antigen-specific T cells, or other features, cardinal features of the adaptive immune system, and no evidence of infection. Despite the fact that there isn't any strong evidence for the adaptive immune system being involved in these diseases, they do really manifest dramatic systemic inflammation. And I'll just illustrate this on this slide. First of all, in the left-hand side, you can see a laparoscopic view of the peritoneal cavity of a seven-year-old girl that we saw at the NIH a few years ago who has traps, the TNF receptor-associated periodic syndrome. And this is one of the diseases that we will be discussing this morning. This child had episodes of intermittent sterile peritonitis, and what you can see here are basically adhesions that have formed because of the repeated episodes of sterile peritonitis. The next image is the forearm of a young man from Kansas City who has papa syndrome. Papa syndrome is pyogenic arthritis with pyoderma gangrenosum and acne. And what you see here on his forearm is, in fact, pyoderma gangrenosum, basically the breakdown of the skin and the infiltration of the area with polymorphonuclear leukocytes. And this particular lesion, in the case of this patient, actually it took us a year to resolve this lesion in this patient. And then finally, the image on the right is from a patient with one of the newer auto-inflammatory diseases, the more newly recognized auto-inflammatory diseases. And this is a patient with Dura, the deficiency of the IL-1 receptor antagonist, something that we published in the New England Journal about three years ago, and I'll be telling you about that in a little bit as well. So anyway, as I mentioned, one of the important aspects of these diseases is the fact that they are disorders of the innate immune system. And just to remind those of you who aren't thinking about immunology every day if there is any such person in this auditorium, but in any case, the adaptive immune system, of course, is that part of the immune system where the players are lymphocytes?  And the receptors for various pathogens are receptors that rearrange in the genome and somatically mutate, whereas the adaptive immune system is that part of the immune system that's a little bit more ancient in terms of its history in organisms. And it's the part of the immune system in which the myeloid lineage of cells plays a more important role and in which the receptors are actually hardwired in the genome and do not somatically rearrange or mutate. Now this slide here is just a table of at least a number of the auto-inflammatory diseases, the print is probably too small for you to read, but I will just highlight the fact that there are a bunch of different classes of diseases now that have been put under this rubric of auto-inflammatory. The first ones that were recognized were disorders that are hereditary periodic fever syndromes, as Jean was alluding to in the introduction, diseases like familial mediterranean fever. There are a host of other diseases that are also categorized as auto-inflammatory, such as the idiopathic febrile syndrome, Stills disease in children, adult Stills disease in adults, various pyogenic disorders like Papa syndrome that I mentioned earlier, granulomatous diseases like Blau syndrome and some would regard Crohn's disease as being auto-inflammatory. Disorders of the skin and bones such as Dirac, we'll be talking about a few of them, and then a host of other things such as metabolic diseases like Gout that we will talk about in a little bit. In any case, my exposure to auto-inflammatory diseases and sort of the dawning of my interest in these diseases actually happened when I was a beginning fellow in rheumatology at the NIH back in 1985. I was five at the time, of course, and I happened to see in our new patient clinic this man, Sarkis, who was a man who was referred to us with a mystery illness. And basically, at the time that we saw him, he was in his early 20s of Armenian ancestry, and he presented with a history of episodic attacks of monoarticular knee or ankle arthritis since infancy. These would usually occur on the order of once a month or so and would last for several days at a time. They would be accompanied by fever and an erythematous rash over the involved joint, and he would have massive effusions of his joints at the times that he would have these attacks. Between the attacks, he was totally normal, and the attacks would resolve spontaneously. So this was someone who in his early 20s had probably had a couple hundred of these attacks over the course of his life, but had had actually no lasting damage of his joints, and when he walked in to see us, he was between attacks and looked totally normal. And the question was, what does he have? Well, actually, at the time that I saw him, I didn't know what he had, either just as a number of other physicians who had seen him over the course of his life, but fortunately there was a fellow in the lab that I was working in who was from Israel. And he said, Dan, it's obvious what this patient has. He has familial mediterranean fever. And sure enough, we witnessed an attack. We aspirated some fluid from his joint, from his knee. He had like 100,000 polys per cubic millimeter in the synovial fluid, which is typical for the arthritic attacks of FMF. These patients will have an arthritis that looks like a septic arthritis, essentially. So this is something that's a cardinal feature of FMF, and at the time that we saw him, it was already recognized that colchicine is a fairly effective treatment in preventing the attacks of FMF. We put him on colchicine, and essentially he has done well ever since, for the 27 or so years that it's been since we first saw him. In any case, just to illustrate some of the features of FMF, it's a recessively inherited disease. It's a disorder that is seen as the name implies and individuals of mediterranean ancestry. That means Jewish, Arab, Armenian, Turkish, and Italian people. Recessive disease, attacks of fever that last on the order of usually one to three days, sometimes a little bit longer with the arthritis. They can have severe abdominal pain from sterile peritonitis. They can have sharp pleuritic chest pain from pleurisy. They can have arthritis, as I described to you. They can have a skin rash as well. So these things are illustrated on this slide. This is an upright film of the abdomen of a patient having a peritoneal attack of FMF showing the air fluid levels. My pointer isn't very strong, but you can imagine that there are air fluid levels there. A left pleural effusion in this chest radiograph on the lower left. Here in the center you have a posterior pericardial effusion. And actually, asymptomatic pericardial effusions are relatively common in patients with FMF. Up in the upper right, you can see a radiograph of the hip in a patient with chronic arthritis of the hip. Usually the arthritis of FMF is a non-deforming, non-erosive arthritis. But in about 5% of untreated patients, you can get this picture of a destructive arthritis. And then down in the lower right, you have erycipalloid erythema, which is basically a reddish raised rash, usually on the dorsum of the foot, the ankle, or the lower leg that occurs in these patients, a lot of times mistaken as being an insect bite. Now histologically, as I mentioned, these patients have lots of polys in their synovial fluid or in the skin, if you were to biopsy the skin. So really the thing that was the most devastating manifestation of FMF before colchicine therapy was systemic amyloidosis. Now amyloidosis is a term that refers to the ectopic deposition of protein in a number of different tissues in the body. And there are different forms of amyloidosis, as many of you know, so that there is AA amyloidosis, AL amyloidosis, transthyretin amyloidosis, and a host of other amyloidosis in which one can have mutations in various proteins, a lot of them that are serum proteins. In the amyloidosis of FMF, what is being deposited is serum amyloid A, which is an acute phase reactant which is produced by the liver during the inflammatory attacks of FMF. And a cleavage product of SAA is what deposits in the kidneys and several other vital organs. And before the advent of colchicine therapy in FMF, amyloidosis was actually a major cause of death in FMF patients. Now back in the mid-1980s, this was a fascinating disease. It was a disease we didn't know what caused it. It was a disease with dramatic inflammation. And this was really at the advent, at the dawning of the human genome project. And so at that time it was just becoming possible to map genes that cause human diseases by basically comparing the inheritance of those diseases in families with the inheritance of DNA markers, which were just being discovered at that time of known chromosomal location. And so I thought that if others could be mapping and cloning the gene for diseases like cystic fibrosis, why couldn't Dan Kastner find the gene that causes FMF? And of course the naivete of youth is a good thing when you're five years old. These kinds of things are great. And so fast forward a little bit. This is a HIPAA-approved photograph of a family that I visited in Israel. So basically in the summer of 1989, I spent the summer with this guy here, Dr. Mordecai Pras, who ran a very large FMF clinic in Tel Aviv. And he made available to me patients with FMF as well as unaffected family members. In some cases they couldn't make it to the clinic, so we went to them. And you can see after getting informed consent, there's a notebook with the informed consent documents. Everyone would roll up their sleeves and give blood. We would have lunch. It was a great thing. And here this happens to be a family from Akko, which is a northern coastal town in Israel. They are of Moroccan Jewish ancestry and actually a consanguinous family. The parents in the family were first cousins to one another. And you may note the strong, intrafamilial resemblance between mom and dad in this family. And then also pictured here are several members of the family affected with FMF as well as one of the members of the family up here in the upper left, our upper left, who's totally unaffected and turned out later once we had the gene, not even to be a carrier for FMF. So in any case, we did do what we set out to do, which was to map the gene for FMF and it turned out to be on the short arm of chromosome 16. And then we became sort of the genome project for that area of the human genome. This was back at the time when things were just really getting underway in terms of the genome project. And so we developed fairly high resolution maps of this region of chromosome, oh, that's where it is, in the middle. High resolution maps of this area of chromosome 16 narrowed things down to about a 200KB interval. There were 10 genes that we had to figure out were encoded in that region and of course as our luck would have it, it was the 10th of the 10 genes that we looked at that had mutations in it that were in fact associated with inheritance of FMF. So in any event, we did find then a gene depicted here, MEFV, mutations in which cause FMF and it encodes what was then a predicted protein shown here, which we called Pyren after Pyrexia. Now at the time that we were actually at the point of finding the gene, we were in a fight to the death with a French group, a race to the finish line. And so this was actually in July of 1997, so 15 years ago. And so we and they found the same gene, fortunately it was the same gene at the same time and we named it the encoded protein Pyren after Pyrexia for fever, the French group being much more erudite than we called it Marenostrin after Marenostrin for the Mediterranean Sea, that was the Latin for the Mediterranean Sea. We chose a name that would be relatively short, easy to pronounce and perhaps easy to remember, hoping that then we didn't know for sure that the French had something but we figured if they did, it would be good, at least in terms of what name would finally stick that our name would be one that would be easier to remember. So anyway, we called it Pyren after Pyrexia. And at the time it was a novel protein, it was a protein that hadn't been recognized before and it turns out that the N-terminal 90 or so amino acids, at that time again it was not known but that domain turns out to be a domain that's found in some 20 different proteins in humans that are involved in the regulation of inflammation and apoptosis. And so this actually became something that was more or less a key to understanding a whole branch of regulation of the innate immune system. And that domain, I will tell you, everyone refers to as the Pyren domain, not the Marenostrin domain, but the Pyren domain. So the Pyren domain, it turns out, forms this six alpha helical structure shown here in the upper left and that structure is sometimes referred to as a death fold because it's seen in death domains, death effector domains, caspase recruitment domains and Pyren domains. Now Pyren domains are actually the most numerous of these four families of domains. The interesting thing about this structure is that it allows the formation of a dipole with positive charges being shown in blue here and negative charges being shown in red. And the idea is that by forming this dipole what happens is that you can get then cognate interactions, self-interactions between Pyren domains. And so Pyren domains of one protein can interact with Pyren domains of another protein, basically to allow for intermolecular interactions and for various regulatory processes to happen in the cell. So the Pyren domain of Pyren interacts with a protein that it's sometimes known as ASC, apoptosis associated spec-like protein with a card domain, which is why most people call it ASC. And ASC is a fairly small protein that has a Pyren domain at its end terminus and a card domain, which is also a domain in the same deathfold configuration at its C terminus. The card domain of ASC interacts with the card domain of caspase 1. And caspase 1, some of you may know, is actually the enzyme that catalyzes the conversion of pro-interleukin-1-beta to interleukin-1-beta. And interleukin-1-beta, IL-1, is one of the major mediators of fever and inflammation in humans. And so this basically ties Pyren to the regulation of this process of IL-1 activation. We have generated mice over the course of the years that have actually that harbor mutations in them, in the mouse Pyren, that are the same mutations as what we see in humans with FMF. And you can see on the left here's a wild-type mouse and then a glitter mate that has the V726A mutation. That's one of the FMF-associated mutations, substitution of aline and prevailing at position 726. And you may see here that, in fact, this mouse has arthritis of its hind paw. And if you section the joint, there's lots of polymorphanucleolucocytes in the synovial fluid. Moreover, if you compare the peripheral blood of the leukocytes in the V726A bred onto a wild-type background, there's lots of, there's a granulocytosis in these mice. But if you breed it onto an IL-1 receptor knockout so that you're blocking IL-1 signaling in the mouse, that goes away. Now, you may say, well, we don't treat mice, so what? Well, so I'll tell you so what. So in any case, back in, I think it was 2005 or something like that, we had this patient who was sent to us from the Mayo Clinic, who was a man from Baghdad, Iraq. He was 18 years old at the time. He's homozygous for the M694V mutation at the FMF locus. Now, that's the most severe. That's the mother of all mutations at the FMF locus. And patients that have that mutation, if they're not treated aggressively, can develop amyloidosis. And so at the age of 18, he actually did have systemic amyloidosis. He had amyloid in his kidneys and had a creatinine at the time that he came to us of 3.5. He had amyloid in his heart, which is actually relatively unusual for AA amyloid. But he had it, and he had an ejection fraction of 37%. He had amyloid in his gastrointestinal tract, which led him to have malabsorption in chronic diarrhea. And this is just all illustrated on the images here. So this is the glomerulus of the kidney. And you can see it's stained with Congo red, looked at under regular light. It looks like this. Under polarizing light, you can see the apple green by refringence. It's typical for amyloidosis. Stained with anti-AA monoclonal antibody, which shows up this way. Here's amyloid in his duodenum, causing chronic diarrhea, malabsorption. Here's amyloid in his heart. This is an anti-AA stain. So anyway, given the fact that he had amyloid in his GI tract, that he had chronic diarrhea, and that actually what happened was that I went to give a talk up in Connecticut at a Gordon conference. And I got this message at the end of the talk that I should call the ICU at the NIH as soon as possible. So I called the ICU. This guy had, while I was away, gone into renal failure and heart failure and was in the ICU. And there was the question, even as to whether we should support him because of the fact that he had already such advanced amyloidosis. And what were we going to do for him? And could we do anything like a kidney transplant for such a patient as this? Because this is a process that seemed irreversible. But at that time, there was just beginning to be the thought that amyloid is actually a dynamic process in which you have deposition of whatever is the protein that's being deposited as the form of amyloid. But there's also a resorptive process. And that if you could block the deposition of amyloid, that the resorptive process would eventually lead to improvement in the patient. Well, we couldn't treat him aggressively with colchicin because he had diarrhea. And as many of you know, colchicin causes diarrhea. So what to do? Well, we were just beginning to see the light with regard to the connection of pyrin with IL-1. So we thought, well, maybe we should treat him with an IL-1 inhibitor, which we did. And here, this is just on the y-axis acute phase reactants, either the serum amyloid A or the CRP, while he was on, at least in this image, while he was on anakinra, which is the IL-1 receptor antagonist, you can see that, in fact, his acute phase reactants were well controlled. We had to stop it for a period of time because he was septic. But in any case, we continued the treatment with him. And actually, his amyloid has not totally gone away, but certainly much improved, so that at this point, his ejection fraction is 55%. He's able to eat pizza for lunch. He's had a kidney transplant, and here's a picture of him, a recent picture of him. So in fact, this has been, for some patients, a life-saving kind of thing. And there's actually an article that's going to be coming out in the Annals of Internal Medicine, a study that we were involved in at the Clinical Center using a different IL-1 inhibitor, Rolonisept, in a randomized placebo-controlled trial, showing that Rolonisept is effective in the treatment of FMF. That's another IL-1 inhibitor. So in any case, let's move on to another disease. I think you've heard enough FMF for the morning. So let's talk about another patient, Cristina. Now, Cristina is a patient that was referred to us at the NIH while we were looking for the gene for FMF. And she was not of Mediterranean ancestry. Instead, she was Irish. She was actually referred. Her husband worked at the Irish Embassy. There was an Irish anesthesiologist at the NIH who called me up one day and said, I hear you're working on familial Mediterranean fever. I said, yes, that's true. Well, I've got something for you. I've got a patient with familial hibernian fever, Irish fever. So I said, all right. So anyway, she came to the NIH. We saw her 27 years old at the time. She had a 14-year history going back to age 13, I guess, of three to five weeks, febrile episodes. Now remember, I told you that the episodes of FMF last on the order of one to three days. So this is way too long for attacks of FMF. She had abdominal pain with her attacks, which of course you can have with FMF. But she had a couple of other things that usually you don't see with FMF, periorbital edema and a migratory rash. We saw her about one week after she had delivered a healthy baby boy. And she was just going into an attack. During her pregnancy, she was totally attack-free.  She had high white count, elevated acute phase reactants, and had a history of responding to corticosteroids, but not colchicin. So she was not of Mediterranean ancestry. She had these prolonged attacks. The attacks had manifestations that aren't manifestations that you usually see in FMF. And she responds to steroids, but not colchicin. And here she is in the pedigree. And you can see that this looks more like a dominant pattern of inheritance. She's got three sisters who are affected, and others affected. Well, the maternal aunt isn't. But then there's a maternal cousin who is. So what is this? And this actually had been called in the literature. There were a couple of cases reported, a family reported. It had been called familial hibernian fever, because it had been described amongst the Irish. And there even had been the hypothesis that perhaps the Irish are actually descended from Jewish sailors who were part of the Spanish Armada, which was shipwrecked and that they swam ashore in Ireland and actually intermarried with the Irish population and introduced a dominant form of FMF into the Irish population. This was the thinking that was going on at that time. Well, in any case, so we had this patient, and for a while we just took care of her and didn't know what it was, and we didn't have the gene for FMF at the time. Once we found the gene for FMF, then we screened that gene for mutations to see if there was some different kind of mutation that would cause a dominantly inherited form of periodic fever, nothing there. In the meantime, my former fellow, Mike McDermott, a good Irishman, actually finished his fellowship at the NIH, took a job over in London and tracked down the original hibernian fever family and mapped the gene in that family to the short arm of chromosome 12. In the meantime, we had accrued several other families with dominantly inherited fever, and so it did appear that there was this region on chromosome 12, short arm of chromosome 12, and of course the FMF gene is on chromosome 16, so it can't be that gene. Some gene on chromosome 12 that might be causing this. Now the region that Mike had mapped the gene to was much too large for us to just look at a few candidates and actually Mike came back to my lab to do a sabbatical to try to figure out what the gene was. So at first, while we were trying to find more families to narrow down the region, we subjected this interval of the genome to a very important test, the embarrassment test. So the embarrassment test is, you look at all the genes that are known in a given candidate region, you think about the phenotype and you think, well, what gene would it be that would be the most embarrassing that if we spent five years looking for it and then we found it by some positional approach or whatever, and then people would say, well, we could have told you that at the beginning. So the gene in that interval that seemed to be, would be the most embarrassing if it turned out to be it, was this one here, TNFRSF1A. And it's the gene that encodes the 55 kilodalton receptor for tumor necrosis factor. Now, tumor necrosis factor is another mediator of fever and inflammation in humans. There are three major mediators of fever in humans, IL-1, TNF, and IL-6. So this is TNF, the TNF receptor. There's actually two TNF receptors in humans, a 55 kilodalton TNF receptor that's encoded here and a 75 kilodalton receptor that's encoded on chromosome one. The protein that's encoded by this receptor is shown here. It has four cysteine-rich domains, a transmembrane domain, and intracellularly, a death domain. So it's actually a cousin of pyrin. Because remember, death domains and pyrin domains are similar in structure. So in any case, Mike McDermott and Yvonok Sentievic, one of the people in my lab, set out then to screen this gene for mutations. They started actually in October of 1998. And on Thanksgiving Day, I have a very hard-working group in my lab. They came in to check their electrophorograms of their sequences, and they found on Thanksgiving Day. Thanksgiving Day, mutations in seven different families with dominantly inherited fever in this gene. That was the discovery of this disease on Thanksgiving Day. 1998, we had Thanksgiving dinner as a lab. Afterwards, at Ivona's house, actually. So anyway, the mutations that they found are mutations that disrupt this loop-de-loop structure. See, there's a fancy folding structure of these cysteine-rich domains that basically involves the formation of disulfide bonds. And the disulfide bonds essentially form between cysteines. And if you have a mutation that substitutes something else for a cysteine, the disulfide bond can't form. And if the disulfide bond can't form, it doesn't fold right. So this thing doesn't fold right because you have mutations that substitute something else for the cysteines, such as, for example, C52F here, where you have a phenylalanine instead of a cysteine at position 52. So, in any case, that then leads to this disease. Now, in the original, now this is just sweet irony, in the original hibernian fever family, it was actually a family of mixed ancestry. One side of the family was Irish. The other side of the family was Scottish. They were being seen at a center in Nottingham, England. And I guess that the group in Nottingham figured that the fever must come from the hot-blooded Irish side of the family. But in point of fact, when we knew what the gene was and what the mutation was, turns out it came from the Scottish side of the family. So it should have been Caledonian fever, not hibernian fever, but actually at that time with the seven families that we had, we had a Finnish family. So should it be Finnish fever or something like that? Well, we decided, probably best, just as a matter of international diplomacy, to take the ethnic attribution out of the name. And so we came up, again, thinking of short names that would be easy to remember and that people would quote, we came up with the name Traps, TNF receptor-associated periodic syndrome. And so that's what this disease is called nowadays. And here are just some clinical images of patients with Traps. I already showed you this one. This is the adhesions in the seven-year-old girl with repeated episodes of peritoneal inflammation. This is plural thickening in a middle-aged man with recurrent episodes of pleurisy. This is the migratory rash of Traps, which is quite interesting. It's a rash that starts proximal and moves distally, oftentimes on an extremity. In this case, this man has the rash on his inner thigh on this particular day that the picture was taken. And then it might be on the knee the next day, the calf the next day, the foot the next day. So it moves down. It's not spreading, it's moving. And if you look by magnetic resonance imaging, you can see that the inflammation actually goes down into the muscle compartment. It's not a myositis, though. It's a fasciitis that these patients have. You can see there's conjunctivitis these patients can have. They can have periorbillodema. And they can develop amyloidosis. This is a kidney biopsy stained with an anti-AA monoclonal antibody. So in any case, what causes this? We had thought at first that the mutations led, and they do, lead to a problem of shedding of TNF receptors off the self-surface. Retention of the TNF receptors would then lead to repeated signaling through the receptors. That does happen, but it appears to have a rather minor effect in terms of the inflammation. What actually is the problem in traps is constipated monocytes. So in any case, what happens is that when these receptors misfold, there's a problem with the trafficking of the receptors from the endoplasmic reticulum to the Golgi apparatus and then to the cell surface. So that if you compare what happens with wild type receptors in this transfection system, you can see that you get, the green is the receptor, the red is just a marker for the Golgi, and you can see that there is co-localization of the wild type with the Golgi apparatus. But in the case of mutant receptor, you can see that it just gets stuck in the endoplasmic reticulum. And you can see actually in cells from patients, these are human patients with traps, and you can see that there's a retention of TNF receptor intracellularly compared with wild type. What that does is shown here on this slide. So when you signal through the TNF receptor, when TNF signals through the TNF receptor, what happens is TNF is actually a timer in the bloodstream. The timer of TNF binds to three of the TNF receptors. It induces trimarization of the receptors. And when that happens, it brings together in close opposition three of these death domains on the intracellular side of the cell membrane. And that then engages a signaling complex that leads to cytokine activation in the cell. When you have these mutant receptors, they actually aggregate in the endoplasmic reticulum. And so there is actually then constitutive aggregation of these death domains intracellularly, which leads to constitutive activation of the pathways that lead to inflammation through the TNF receptor. So that's at least the major mechanism of inflammation. Let's now turn from FMF, from traps, to three other diseases, this is a threefer, that are caused by mutations in the same gene. And this is one that's really near and dear to my heart because, in fact, it turns out that this gene encodes a protein that's a cousin of pyrin. So, anyway, so these three diseases are sometimes known as CAPS, cryopyrin-associated periodic syndromes. So the common feature in these diseases is that these patients have fever, recurrent fever, with a hives-like skin rash. It's not true hives. They don't have mass cells in these lesions. They don't have elevated levels of histamine in their bloodstream. It's neutrophils, actually, that are in these skin lesions. And there are three diseases. One of them is called F-Cas, familial cold, auto-inflammatory syndrome, or urticaria. It's cold-induced hives and fever that these patients will get. It's dominantly inherited. The person, if they go out in the cold for an hour or so, they'll break out in hives and have a fever. If they walk into an air-conditioned room, if they live in the south, and a lot of these people have moved to the south because of avoidance of cold weather, basically, if they go into an air-conditioned room, they'll break out in hives after an hour or so. And they feel lousy, and they have to actually go to bed in order to recover. The second disease that's also caused by mutations in the same gene is a disease called Muckel-Well syndrome. It's not cold-induced, but the patients get fever. They get the same hives-like rash. Actually, this patient here has muckel-wells. They have arthritis. They can develop sensory neural hearing loss, and they can develop amyloidosis. And then the most severe is a disease called NOMID, neonatal onset, moldy system inflammatory disease. In Europe, it's called SINCA syndrome, Chronic Infantile Neurologic Cutaneous and Articular Syndrome. And it is a disease in which there's fever, hives-like rash, brony overgrowth of the epiphasies of the long bones, and most devastating CNS disease. These patients develop basically a chronic, aseptic meningitis that leads to blindness and deafness and mental disability. So it's a very severe illness and actually wasn't thought to be genetic at first because most of the patients who develop it have it as a spontaneous, de novo mutation and never have children of their own. So it was thought to be a sporadic disease a few years ago. So in any case, Hal Hoffman at the University of California, San Diego, looking at some families with Colder, Decaria, and Muccal Wells, mapped the causative gene to the long arm of chromosome one. And in the candidate interval, this was around 2000, 2001, he found a predicted gene that had a pyrone domain. So he applied the time-honored embarrassment test to this region and decided that he would screen the gene for mutations associated with these two diseases. And lo and behold, he found that there were mutations in this gene and the so-called nacht domain, which is just an acronym. It has nothing to do with falling asleep at night or anything like that. But in any case, this protein has a pyrone domain at its end terminus. It has a nacht domain, which is a protein interaction domain in the middle, and a leucine-rich repeat domain at its C terminus. It can interact with ASC, that same protein that pyrone can interact with, and it also can have a role in activating IL-1. Now, at the time that Hal was doing these studies, we were seeing a patient with Muccal Wells. And my colleague, Raffiella Goldbach-Mansky, was seeing this young man from North Carolina named Jonathan. And Jonathan had been sent to the NIH with possible stills disease, systemic onset JIA. And here's his picture back 10 years ago or something like that. And here he is. I don't know that you can make the diagnosis of systemic onset JIA from this picture, but there were some other features that didn't seem typical for systemic onset JIA. He had a hives-like rash. He had papillodema. He had some element of ventriculomegaly. And he had these knobby-looking knees, which are pathonomonic for nomad. This appearance of the knees is what nomad knees look like, or SINCA if you're in Europe. So Raffiella correctly diagnosed this patient as having nomad neonatal onset and multi-system inflammatory disease. And it was the two fellows who were on service that actually catalyzed this discovery. So these fellows had been seeing my patient with Muccal Wells and had been seeing Raffiella's patient with nomad. And they said, well, the skin rash of these two diseases looks very similar. Are you sure that they're not the same disease? We said, no, they're not the same disease. What are you, haven't you been reading? But they insisted. And so we thought, well, maybe they're right. Maybe there is some connection there. And of course the gene for Muccal Wells had just been identified by Hal Hoffman. So we knew what that was. So we decided, well, we'd check it and see whether or not Jonathan, this patient with nomad, in fact had mutations in this gene. The gene that encodes this protein cryopyrin. And so here's Raffiella, the person that saw Jonathan and Ivona who did the sequencing. And lo and behold, what they found was that in fact, there was a mutation in cryopyrin in nomad. And then this is one of these great NIH stories. So we were telling people about this, wasn't it interesting? And it happened that there was this guy, Sergio, from Argentina, who was a fellow up on the 11th floor, two floors up from us, who had brought a couple of DNA samples with him from Argentina of nomad patients in the hopes that there would be someone at the NIH doing studies of the genetics of nomad that he could then collaborate with. So he gave us these samples after appropriate paperwork was done. And sure enough, they had mutations in this gene too. And it turns out that about half of the patients with nomad have mutations in this gene. The mutations are clustered in the nach domain just as they are for the other two diseases.  And you can see they're all clustered in the same region. We have no idea why one mutation causes one of these diseases and another mutation, the other disease. The pyrin domain is almost invariant. The leucine repeat domain seldom has mutations either. And so the gene encodes this protein cryopyrin. Pyrin, because it has a pyrin domain, cryo, because at least some of the patients have cold induced symptoms. And cryopyrin forms a macromolecular complex. And this is actually something that if you're taking boards or whatever, you probably ought to know. The macromolecular complex is called the inflammasome. And the inflammasome, you don't need to know all the components of the inflammasome, but it is basically a complex that's involved in the activation of IL-1 beta. It's one of several complexes that can activate IL-1 beta. So you have this inflammasome, and basically the mutations that are associated with these diseases are in the nach domain, and they're activating mutations that turn on this process all the time, constitutively. So we reasoned that if IL-1 is turned on all the time in these patients, just like I told you about the patient from Baghdad, Iraq that we decided to treat with Anakinra, we decided that we would do a trial of Anakinra in nomad, because this is a devastating disease. And we thought that if there was something that really deserved some attention, it was this disease. On the left-hand side of the image here, you can see how IL-1 ordinarily signals. You can think of IL-1 as blue bubbles just for purposes of this discussion. And IL-1 has to bind to two chains of its receptor in order to signal. The green type one IL-1 receptor and the purple IL-1 receptor accessory protein. It has to engage both of those receptors in order to deliver a signal. In all of us, we have something called IL-1 receptor antagonist, which is basically a protein that can bind to the type one receptor, but doesn't bind to the accessory protein. So it competes with IL-1 to bind to its receptor. And basically it can bind, but it doesn't signal. So it's basically a way of turning off signaling by IL-1. And it's something that normally happens during inflammation in people, is that you get IL-1 receptor antagonist levels going up in the bloodstream, at least in part as a homeostatic mechanism to tone down the inflammation. There's a recombinant form of this that's known as anakinra, or kinrat, the trade name. And so anyway, we did a trial of anakinra in NOMID. And essentially the results are shown here. It was published in the New England Journal in 2006. Within two or three days, the hives like skin rash goes away completely. The conjunctivitis goes away completely. Within three months, this white here, this is the chronic aseptic meningitis. This is an MRI with a flare image. And basically all of the white is inflammation, and you can see it's gone basically within three months. The arrow points to the cochlea. This is a fiesta image of the head. And this is cochleitis. This is what leads to deafness in these patients. And the cochlear inflammation goes away as well. So anyway, this has been a very effective treatment for NOMID. So now we have a little quiz here. And we'll go a little bit more quickly through the other diseases, because we have several other diseases to talk about in only 14 minutes to do it in. So anyway, here's your quiz. So could this be NOMID? So here is a patient, a nine month old child from Canada, who is referred to us with this total body, pustular ranch. And here's the hair. So this is the fold of the neck. Pustules all over the body. The patient had a multifocal osteomyelitis, aseptic osteomyelitis. And you can see here some of the punched out lesions the arrows are pointing to throughout the body. And then the patient also had evidence of vasculitis. So from what I told you about NOMID, is this NOMID? No, of course not. Because the skin lesions of NOMID are hives-like, not pustules, because the bone lesions of NOMID are overgrowth of the epiphasies of the long bones, the knobby-looking knees, not multifocal recurrent osteomyelitis. And I didn't say anything about vasculitis in NOMID. So this was not NOMID. We were asked, is this NOMID? Just given the pictures, we said, no, it's not. We actually did sequence for mutations in cryopyrin. Didn't find any. But the referring physician from Canada was an obstinate character. And so he treated the patient with anakinra anyway. And this is what happened. So here's the child before treatment, and you can see pustules on the face. Within three days, this child is starting to shed his skin. You can see he's kind of smiling here. And within a week, he'd shed nearly all the skin. Pustules went away completely, and the multifocal osteomyelitis resolved within two or three months. So what is this? What could this be that basically responds to an IL-1 receptor antagonist, but it's not NOMID? Well, again, this important test, the embarrassment test, once again, comes to the rescue. So we were thinking, well, okay. So here's a patient who responds to the IL-1 receptor antagonist. So what gene would be the most embarrassing that if it turned out to be it, and we hadn't looked at it at first, which one should we look at first? Well, of course, it's the gene that encodes the endogenous IL-1 receptor antagonist. So we looked at that, and lo and behold, what we found was that this patient was homozygous for a two-base pair deletion in the coding region of the IL-1 receptor antagonist gene. That's almost too good to be true. Homozygous for the same two-base pair deletion, how could that be? So we sequenced the parents, sure enough, the parents were carriers for it. Kid really is homozygous for the two-base pair deletion. And then, of course, we took a better history and it all became clear when we learned that the patient was from Newfoundland. And so basically the explanation there, of course, is that Newfoundland is an island off the eastern coast of Canada. And many of the current residents of Newfoundland are descendants of settlers who came to Newfoundland actually 200 years ago. And they are at least distantly related to one another in the sense that there's a founder population there. And so probably one of the early settlers to Newfoundland had this mutation, just as a heterozygous would have no symptoms associated with it. But it just happened that the two parents both were carriers for this and then the child was as well. We now know that there are other mutations in this gene. For example, a STAP codon amongst people living in the Bible Belt of the Netherlands. There's another mutation that we see in the Middle East. Yet another mutation in northeastern Puerto Rico that are associated with this phenotype. And so we again thought that because there are mutations in the same gene associated with a particular phenotype, we would give this disease a name. And the name that we have given it is DERA, the deficiency of the IL-1 receptor antagonist. Again, adhering to the naming conformity of short, easy to pronounce, and easy to remember. So in any case, this table just summarizes the comparison of NOMID with DERA. Different genes are involved. The functional consequences for NOMID, it's activation of the inflammasome. For DERA, it's decreased inhibition of IL-1. Different skin rashes, different bone manifestations, different CNS involvement as well. And then finally, the last of these monogenic diseases. And maybe we'll curtail things a little bit so as not to get into the lunch hour. But in any case, this disorder that we'll talk about just briefly is PAPA syndrome. So here is a very severe cystic acne on the back of one of our patients with PAPA syndrome. And it's caused by mutations in this gene, PSTPIP1, which actually encodes a protein that's a pyrin binding protein. And so it just goes to show how mutations in all different aspects of this pathway of regulation of IL-1 can actually lead to different inflammatory diseases. So in this case, actually, PSTPIP1 binds to pyrin. And in fact, the disease-associated mutations are associated with increased binding of PSTPIP1 to pyrin, which leads to increased IL-1 production and other cytokine production. So this schematic is just a depiction of IL-1 activation, some of the steps in IL-1 activation. And what I've shown you is that depending on where in the pathway you're looking, if you're mutating pyrin, you can have this erycipalloid erythema skin rash. If you're mutating PSTPIP1, you can get pyoderma gangrenosum. If you're mutating an LRP3, you get these urticaria-like skin rashes. If you're mutating the IL-1 receptor antagonist, you get this total body hives-like rash. So in any case, there's a number of different diseases that are all caused by mutations in this pathway. And in fact, DRA is the prototype for a group of diseases in which receptor antagonists are mutated. And just one that was published in the New England Journal a year or so ago is a disease now called DITRA, deficiency of the IL-36 receptor antagonist. And basically IL-36 signals in a similar way to IL-1 with a binding of two chains of a receptor and a receptor antagonist that only binds to one chain. And those patients get a form of postular psoriasis. Now maybe I'll just finish up by indicating to you that in fact, these pathways that I've told you about, that we've learned about through these monogenic diseases, are pathways that are important in some much more common genetically complex diseases. So that we now know that monosodium urate, for example, activates the inflammasome. And that at least some of the inflammation in gout is due to excessive IL-1 production. And in fact, there have been successful studies of IL-1 inhibitors in gout. Type 2 diabetes actually is another disorder, genetically complex, that has an IL-1 component to it. It turns out that islet cells of the pancreas synthesize IL-1 beta induced by hyperglycemia. IL-1 beta is actually toxic to islet cells. So hyperglycemia causes islet cells to make IL-1, which causes them basically to commit suicide, which then leads to further hyperglycemia. So that actually if you treat patients with type 2 diabetes with an IL-1 inhibitor, as shown in this paper in the New England Journal from a while ago, glycemic control is actually improved. And then probably the most common of these diseases, atherosclerosis. So atherosclerosis has, as I think many of you recognize, an inflammatory component. And if one looks at mouse models of atherosclerosis, here's cholesterol deposition in a wild type mouse. But if one knocks out various components of the inflammasome, NLRP3, which is cryopyrin, ASC, or IL-1 knockouts, these mice do not develop atherosclerosis. Now you may say, well, that's great for the mice. But in fact, there is a trial, the Cantos trial, that is going on right now. It's a trial that Novartis, the maker of a monoclonal antibody against IL-1 kinemab, or Ilaris. And this is a trial of 17,200 patients who have had myocardial infarction, treating them either with placebo, or with three different doses of this anti-IL-1 antibody. And the outcome, what they're looking for is the primary outcome, is the number of second cardiac events, effectively in these patients, with the idea that blocking IL-1 will prevent recurrent cardiac events. Just the drug for each patient that's getting active drug is about $100,000 a year, so that for 17,200 patients, you're talking about a trial that's a billion-dollar trial. So definitely these pathways are important, or thought to be important, we believe they're important, in common diseases. Well, we don't have time to talk about candle, which is another interesting new disease that we're working on, or about plaid. This is another disease, we published in the New England Journal earlier this year, we'll just flip through these slides, or about a disease that's coming out next month in the American Journal, or about Betchette's disease either. But you see, these are all things that maybe would get you to invite me back some other time for another talk, for part two of this. So I'll just go through these slides, some very interesting associations along Marco Polo's Silk Route, but you'll have to hear the next installment to know about that. And here's just maybe to finish up, a pie diagram of some almost 1,900 patients that we have studied genetically at the NIH in our auto-inflammatory diseases clinic. And the interesting thing is that only in about a third of them do we have a genetic explanation. In two thirds of them we don't. Now not all of them probably have a Mendelian disease, but this just highlights the point that there's plenty more to be found amongst these patients and that there's, I think, still a rich source of patients for study and that we can learn a lot from these patients. So just to summarize, the auto-inflammatory diseases manifest constitutive or easily triggered innate immune activation. Mendelian auto-inflammatory diseases have provided important insights into the regulation of inflammation. IL-1 beta activation protein misfolding, and well, we didn't talk about proteasome dysfunction, but take my word for it, are three mechanisms of Mendelian auto-inflammatory disease based on the demonstration of an important role for the inflammasome and their pathophysiology. A number of common disorders such as gout, type 2 diabetes and atherosclerosis have been shown to have an auto-inflammatory component. And again, for the next talk, genome-wide association and next gen sequencing studies allow the identification of susceptibility loci for more common but genetically complex auto-inflammatory disorders. Here's just the cast of characters that really made all this happen. And of course, the clinical center of the NIH where we carried out most of these studies. So anyway, it is now one minute to nine. I apologize for talking a little bit over, but hopefully you've learned at least a little bit. Thanks a lot. We tell it just, I treat a lot of inflammatory disease and I rarely see amyloidosis. So number one, am I preventing amyloidosis by treating inflammation? And number two, how do you tell these that risk for amyloidosis and inflammatory population? Yeah, those are both great questions. So we do believe that the more effective treatments for inflammatory disease have led to a reduced frequency of amyloidosis. Certainly chronic infectious diseases, things like tuberculosis, were common causes of amyloidosis back in the age before there were effective treatments for tuberculosis. And we see less amyloidosis associated with things like rheumatoid arthritis as the biologics have become more widely used. So I do think that aggressive treatment, and that's certainly what we do with the periodic fever syndrome patients, is that we really aggressively treat their underlying inflammation to the point that we want to normalize their acute phase reactants. Now in terms of who's at risk for amyloidosis, that's also an excellent question. Now it's probably been looked at most systematically in patients with FMF. And so in FMF, certainly the mutations that are associated with more severe disease, as you might expect, are associated with a higher probability of amyloidosis. Males, for some reason, are associated with a higher risk of amyloidosis. Non-compliance with treatment, associated with a higher risk of amyloidosis. There is a polymorphism in the amyloid locus, actually, that is associated with a higher risk of amyloidosis, probably because it prevents the normal degradation of the amyloid protein. And then the most captivating of all association is that it depends on where you grow up as to what your chances of getting amyloid are, at least with FMF. Armenians who grow up in Armenia, for example, have about a 25% risk of developing amyloidosis by the time they're 30. Armenians in the United States, with the same spectrum of mutations, even if not treated with colchicine, have less than a 1% risk of developing amyloidosis. And there was a big study done by Isabel Two or Two, published in Arthritis and Rheumatism a few years ago, that looked at country of origin as being really one of the major predictive factors in whether or not you get amyloid. And people who come from countries where infant mortality is higher, and therefore we think the healthcare availability may be lower, have a higher risk of developing amyloid for reasons unknown, but that seems to be the case. Could you comment on whether the populations that are pregnant, cousin marriages, some of them are almost the same? I'd say again. So, populations that use cousin marriages, if they were to move away from it, how long would mother nature take to extinguish those fears? Well, so we do think, and I didn't have time to talk about this, that at least at one time, there may have been a selective advantage for mutations at the FMF locus. And in fact, if you look at the carrier frequency for mutations in this gene in Mediterranean, Middle Eastern populations, it's incredibly high. It's like one in three to one in five. Now, if you contrast that with the carrier frequency for cystic fibrosis, which is the most common lethal recessive disease in Caucasians and North America, one in 20. So this is incredibly high, one in three to one in five. And there's been a lot of speculation as to whether there might have been some infectious agent that was selecting for these mutations over the centuries. So far, at least in various epidemiologic studies and studies of experimental animals, we haven't figured out what that agent would be. Apparently not, no. Does it have a gene? Yes, so both excellent questions. With regards to the amyloid of Alzheimer's disease, it's a different protein that is being deposited, a beta, as opposed to AA. So it is a different chemical process, although it does appear there are some studies that would suggest that IL-1 does play some role in the pathogenesis of even the amyloidosis in Alzheimer's disease. So that's an area still under study as to whether or not maybe that would help in some way. But the thing is, all amyloid looks the same under the microscope when you stain it with Congo red. It all gets this, if you look at it under polarizing light, this apple green by refringent appearance to it. But it's different proteins that are being deposited, but probably there's some final common pathway that makes them misfold and deposit in that way. So that's an interesting question. Now the question as to whether or not Colchicine would have a role in treating some of the other amyloidosis, that's something that one could consider. There was the thinking back in the old days that Colchicine might be effective in FMF even if you can't prevent the attacks that it might still prevent the amyloidosis. Colchicine does prevent the amyloidosis of FMF, but it appears that that's related to its ability to prevent the inflammatory attacks of FMF. So it's not that it has an anti-amyloidogenic effect, it has an anti-inflammatory effect in that disease, which then leads to less burden of SAA in the blood and less to deposit. So we don't think that it's because it has a direct effect on amyloid deposition. As far as the cost of Colchicine, just a word about that, as some of you may know, Colchicine used to be available as several generic forms in the United States. And then because of some well-intentioned legislation, it turned out that if a maker of a drug like that, which had never undergone appropriate clinical trials, if a maker of the drug went through certain tasks with the FDA, they could then get exclusive license and put all of the other companies out of business. So there's a company, Union Pharmaceuticals, that did just that using GAUD as the prototype. And so essentially, at this point, there's only one form of Colchicine that is available in the United States. The trade name of it is Colchris, and it's made by this company, Union Pharmaceuticals. And the cost of Colchicine has now gone up from roughly 10 cents a tablet to $5 a tablet, which will persist for the length of time that they have an exclusive license on this. And again, this was something that was well-intentioned in the idea that this would encourage further rigor in terms of the testing of agents that had never been subjective to the scrutiny of modern trials. But it's ended up sort of causing this issue with regard to the cost of the drug. And actually, Colchris itself, we've seen in some of our patients, is perhaps milligram per milligram, or 0.1 milligram per 0.1 milligram, a little bit less effective than some of the other generic forms. And so in fact, one has to make dose adjustments in the patients when they switch from their generic to Colchris. So an interesting thing, sort of a quasi-political, medical-political kind of issue, I guess. Is there a dark side to turning down the enzyme in terms of risk of infection? It's a great question, Gene. So we don't see a lot of problems. Certainly the TNF inhibitors are a lot more associated with opportunistic infections, with mycobacterial infections, with fungal infections, than IL-1 inhibitors. We do see some increase in risk of upper respiratory illnesses, but at least at the doses that we give for these diseases, no, we do not see. Part of the problem, or the thing with these patients, is that they have a very hyperactive innate immune system, and so what we're doing, treating them with the IL-1 inhibitors, is sort of bringing it back to normal. In a lot of cases, parents of kids with these diseases will say that everybody else in the family will get a cold or the flu, and this child who's not been treated yet doesn't. They may get their recurrent fever syndrome, but they don't get colds and flus. When we treat them with IL-1 inhibitors, or whatever other biologic, then they no longer have their periodic fever episodes, but they, like the rest of us mortals, begin to get colds and flus, like anyone else. It's going to be very hard on them. Thank you very much for coming. Thanks, sir. Thank you.


It's if it's gonna be a girl then you're thinking about how many boyfriends. I'm gonna have to beat up I can have to buy a shotgun. Yeah, I'm gonna have to buy a shotgun, hang it up on the wall What do you think?  That's a great question So yeah, I think it's interesting so it's a little bit of a background of where we are So we're like eight eight months in basically Do date coming up in about six weeks. Yeah, and we are choosing not to find out the sex okay, so That puts an interesting spin on this idea of thinking about who I'm gonna be as a father because I think If I knew the sex that I would be thinking about specific events that I think are gonna be happening in the future Yeah, how those events would play out So thinking about so if it's gonna be a boy then thinking about like playing catch in the backyard or You know hot wheels. Yeah hot wheels. Yeah, whatever. Whatever. There's more You know what season of Power Rangers is gonna come out next basically what version of Power Rangers is gonna come back out next They're gonna do cops and robbers pretty soon eventually While West team Power Rangers something or so It would be nice if they did that they never touched that Opportunities. Yeah. Anyway, so then you know you think the other spectrum It's it's gonna be a girl then you're thinking about how many boyfriends I'm gonna have to beat up But then you think about like, you know, the tea parties or the dances, you know, whatever these, you know girly themes are right since we aren't finding out the sex it makes it a little bit more interesting of Trying to figure out what that means and so you've talked with my wife, so you know that you know gender roles aren't You know, hugely foundational and kind of hard of thinking like I I don't Necessarily think that if it's a boy he has to play sports or he has to play with hot wheels I think he can play with Barbies if he wants. Right, right, right. Or he could choose to Play Flute or you know, whatever you think are the the more feminine things that you know typically or if it's a girl She could play, you know, she could play sports.  I don't know whatever So It just was an interesting aspect. So coming back to your question of you know, do I do I think about? Who I want to be as a father and kind of what what Context that comes in Yeah, I mean I think about it a lot, you know, I think about You know yesterday, we were we were sitting on the couch Watching some stuff watching the Preds game on TV and I was thinking, you know, it'll be fun here in a couple months When the playoffs are happening just having the the baby lay on my chest while I'm laying on the couch watching the Preds game Okay, you know other things that that may be coming up in the near future and then thinking, you know Longer term being able to take our kid to a game or share those experiences And I don't think that I just trying to catch up. Yeah. Yeah, so it sounded before that you were saying like I don't want to bias myself with a kind of father on and be based on the sex of the kid Yeah, it's easy to fall into the practice of like, oh, it's boy now These are on the list and these things are off the list. Yeah, you and in the process of trying not to be Biased you've discovered this whole other tier of things that are like Jess is important to you, but are in any way related to like the the sex of the the new member of your family in a sense Yeah, and you're also keeping both of these things open in the event that if we want to play cash We can play cash if I do sports we want to do sports if we want to play flu How is flute playing female? Don't you know some of the greatest food players are like I Was a band kid, okay, you know, it's just stereotypical that the flute and clarinet players are female Oh, this is not the case. This is not the case No, if you're a smart kid you play clarinet because that's where all the girls are but Right, okay. Yeah For okay, maybe maybe it was just my high school But for whatever reason it was like basically woodwinds are female brass or male.  Yeah, like touch the floor But for some reason the bassoon players at my school were Asian, but I don't know Takes all kinds I do worry. I hear it's not so much a worry, but I wonder like Dear in the headlights moment. Mm-hmm. You get born and you're like, oh crap in in my heart of hearts, I I'm just totally not prepared for like any of this because I think when it's born right when a baby's born I have two little sisters, right? I Was thinking here. I'm gonna be a big brother. Let's go through the steps Yeah, but it just turns out to just be out screaming blob of flesh for like the first three weeks And then when the second one or when the second little sister came out I'm just like, I know I'm gonna go through it doesn't matter whether it's a boy or a girl either way exact same thing So there's a point before it even becomes and this is only from the brotherly perspective But before it even becomes like a person it is a project It's not mine It is related to me, but yeah, I'm developing a relationship with it with my sisters and I found that Because of that all these things that I had planned down the road are like shelved to deal with like this Relationship building exercise that I'm doing with this person that I've never met before So like I'm started doing things that I never ever thought about doing with like Like what what I had planned for a little sister like we do tickle face Things where I just like kiss around her face until she's like laughing stop Same thing like you had said and then just like rub the face and then she's like, oh, she thinks it's funny Like I would never have planned that out But that you now that's a thing that I do even when I see them regularly. That's cool. It's a weird thing. So like I guess it's a roundabout question, but like Are you prepared or how do you even prepare yourself for the random things that you'll do as you start to build a relationship with this new person that you think like I Mean given that was that a good move? Was that a bad move? Like are you even like is it? That goes on like so many different levels to me like on one sense I'm sitting here thinking like so you said how do you prefer for these random things? Well, there's a random things Because you don't do them until the moment, right? It's almost like an improv thing like you don't You don't think about doing them until you're in that moment So to me, yes, you know, that's like I can't really prepare myself for that but then you touched on that that second point of almost Thinking about it after the fact and saying like was that appropriate in a way or what you know, right that I Don't know like did I do the right thing in that moment?  I'm like I Don't as I mean as long as it's not like super inappropriate, which I don't think I would do anything super appropriate I wouldn't but you know As long as it's super inappropriate Is there anything that you could do with your kid that would be the wrong thing to do in that moment like as a Parent at least in a newborn, you know, I mean clearly, you know, you get into later ages and we're kind of beyond objectivity here But I figure like the the the issue The vex is a lot of parents as as far as I could tell from the siblings of what my parents have told me is that you're always Thinking about what you could have done better Hmm and that seems to be something that's really hard to let go particularly for I imagine like brand new parents Just like today. I did this or like today We have an argument with the kid and I told her, you know, I Can't deal with you. You got to go to your room and you're thinking about that on a completely different level than the kids Thinking about it like the kids angry, but in five minutes. So she or he will be like I'm totally fine with it Where's my candy or like yeah worse food, but you're like I did that like four and a half years ago Is this coming back to me again? I mean I think what could I done better? I mean like you could always do something better, right? There's always a way to improve on a situation, but I mean kind of like we talked about something simply trying my best Yeah, I'm doing You're trying to do your best in every moment and doing your best isn't always going to be You know the best that that there could be in the world, but at that given moment It is your your best. It's still your yes And the other thing that I you know I thought about as you were asking that question is you know, I think it's it's about building those Relationships and having those experiences even if those experiences aren't always the best that they could have been later on in life Hopefully you and your kid are gonna be able to gather like look back on those experiences fondly and know that you know You were building this relationship You were building this great thing and I don't know laugh at stupid things that happened or you know Maybe make amends on things that went wrong or you know, whatever the case may be But I think just building those experiences, whatever they happen to be is is gonna be a great experience. That's so cool It sounds like this kid isn't just that the test I would say the capstone of growing up, but it's not just a new chapter and growing up. Oh, yeah, that's nice It's a very life-changing event to to have I mean I assume I think it's gonna be like I'm just pointing would be like, oh dang it. That was easy Wasn't that easy? Let's do this again. I Just It's like going back to college all over again, I know right. Thank you so much for the time