Victor mature Hey, hey two gun. Why are you shooting those pistols off at your car? I'm tired of just shouting at my car's wasting gas and hard to start. That's why we'll come Well to gun why not go straight to your nearest auto light spark plug dealer and have him check your spark plugs You mean spark plugs could be the trouble will cock this you're good to gun because spark plugs are the heart of a car's ignition system And they've got to be right. That's where your auto light spark plug dealer comes in He's the only one who has the exclusive auto light plug check indicator To quickly tell whether your spark plugs are right for your style of driving He'll do that for me. He sure will and more too because if replacements are needed He'll recommend ignition engineered standard or resistor type auto light spark plugs to give you smoother performance Quick starts and gas savings So friends take a tip from me and see your nearest auto light spark plug dealer soon and remember from bumper to tail light You're always right with auto light And now with blackjack to kill and the performance of mr. Victor mature Auto light hopes once again to keep you in Here he is mr.  What is this anyhow?  You didn't hear me say that did you? No Once around the table face up high card High card makes one of you employed with a job to do You got anything to say radical for a deal. Just be alive. Thank you, Mr. Rattick So polite that Cleo kills me Ace is high card winner to kill a man. Let's go cut him Cleo Thanks. Now send the door and don't let anyone in. Yes It's a matter doesn't Cleo get a card you five just you five ready Then it clubs for you ready Six of diamonds for you talker nine of hearts for Barney Jack of clubs for Johnny goodbye Johnny seven of hearts for Mackle You Johnny I'm a lucky fellow. I tell people that one may ask me about you How lucky you are not a scratch and you've knocked over three hoodlum bore I Operated before I met you Moyer for my mind good looking boy like you It's the talk how hired killers don't come as pretty as you Yeah, you know Cleo You like it here in Miami Johnny sure I like it. Why shouldn't I like it? Oh, I shouldn't you like it here Miami pretty palm trees pretty ladies pretty ponies and No penny culling you're doing it again more you have a chance you get you say penny culling to me Why because you're lucky a big man like penny and you say the right word to the wrong guy and pennies gone Kicked out the board had run out of the country and nothing happens to you You're sure the one Johnny. All right, I'm the one now What did I get the high card for for this? 10 grand to do a job 15 more when you come back and it's all over when I come back Where am I going Havana Havana in Cuba? All right? I go to Havana. I kill somebody Who you get a plane ticket and a name and an address Address for a man. You'll see he'll tell you who he wants the job done.  I never saw before flashing against the white columns of the house Taste it for a minute Then walk into it And a butler in knee britches tells you to wait You are who senior Damon Johnny Damon. Oh, I have been waiting for you senior Johnny Damon I am the on tape. We have business to discuss.  Well, well pennies here, huh since three months The criminal your country deported Europe has fled from there came here to Cuba This killer this gangsta this filth you have read yourselves up in your country. I want this also to me But to rid me of him dead.  I have flourishing enterprises in Cuba senior Your penny Cullen wants to share in them. This he has whispered to me. He asked for an answer quickly You are my answer. You came up with the right answer Chico Where do I find penny? He has a house in the Plaza Vista Number 23 Four days Chico, that's how long I need Then the weepers for penny Cullen can start crying over his dead body for days three days to watch him the fourth the kill My assassin, you know, that's something penny taught me if the man has a schedule that lasts for three days He'll do the same on the fourth. I see this is very interesting to me Sure, you see you can't be sloppy in this kind of work No, a man's habits. No worries going to be at such in such a time know when to kill That way you can walk away from it. I have not known assassination was such a delicate art senior Delicate art huh? See a suggestion if I may go right ahead a thing I know about senior Cullen each day at six at twilight He sits on a bench the same bench always and looks over the embarked arrow the embarked arrow the waterfront He sits there and looks out upon the ocean Where's the bench? There is a statue, senior of a dying hero Miguel Perez To the left of the statue. Thanks. Yeah, that's all I need Senor yeah When you kill, Senor Say him my name Say who said the ante? I just penny Cullen in a Vanna Penny Cullen set up to be knocked over by me a boy who could appreciate a nice thing like that There was nothing complicated about it Penny Cullen was a man. I hated a man. I put the finger on a man I had a ported and now I was going to get close enough to killing and he'd never even know I was in the van Now to work first an investment 1095 for a pair of binoculars nothing fancy but good enough magnification three and a half times Very fine for seeing Penny Cullen sitting on a bench watching the ocean That evening get to the waterfront sometime before six Find a spot that overlooks the bench to the left of a statue of a dying man and wait A quarter of six of vendor pedals by the bench on a bike. He's selling ice cream and Wait and Far away a bell tolls six o'clock and in the middle of it a man a man who walks over to the bench sits on it a man named Penny Cullen and Penny looks pretty good a little heavier, but just a little bit Yeah, Penny looks pretty good. He's carrying something with him a paper bag At five minutes after six he opens the bag and throws breadcrumbs to the pigeons Penny Cullen throwing breadcrumbs to the pigeons At 12 minutes after six a cop walks past the bench touches his cap to Cullen Cullen nods back The cop goes away Penny sits 20 after another vendor an old woman. She's selling flowers Penny buys one the old woman puts it in his lapel goes away a quarter to seven Penny goes away Next day practically the same 545 ice cream vendor six Penny Cullen five after pigeon feeding time That's 612 the cop 620 flower in the buttonhole 645 Penny gets up and walks away The next day the same Next day the fourth day day for killing Mr. Cooper live a senior. Thanks. Put it on the table. Yes, you know Will there be anything else take a buck from the bundle? Oh Kid senior I'm liable to nap have the desk call me Five she's in your four hours away from killing time Time enough to have your drink then lie down in that soft bed and relax Think about it, and he didn't even know I was here Penny Cullen pigeon feeder Tomorrow the pigeons would have to find a new boy Between 620 and 645 I was going to walk up in back of him and let him have it Wouldn't even know where it came from Yeah Johnny hmm to whatever you were doing Johnny. I'm not going to be at the bench today Penny yeah Penny Cullen boy Welcome to Havana auto light is bringing you mr. Victor mature in blackjack to kill tonight's production in radios outstanding theater of thrills So spend Wilcox you said auto light spark plugs are ignition engineered I sure did to gun because they're designed by the same auto light engineers who designed the coil distributor and all the other Important parts of the complete ignition systems used as original factory equipment on many leading makes of our finest cars trucks and tractors I mean auto light spark plugs are tops and quality in performance. Hey Wilcox exactly to gun And that's why so many millions of wise motorists replace worn-out spark plugs with auto light Standard or resistor type spark plugs for smoother performance quick starts and gas savings You just can't buy better spark plugs than world famous ignition engineered auto light spark plugs I'm going to see my auto light spark plug dealer right now Friends to quickly learn the location of your nearest auto light spark plug dealer Just call Western Union by number and ask for operator 25 She'll gladly tell you the location of your nearest auto light spark plug dealer who is equipped to give you the best spark plug service in town And remember from bumper to tail light. You're always right with auto light And now auto light brings back to our Hollywood soundstage mr. Victor mature in Elliot Lewis's production of Blackjack to kill a tale well calculated to keep you in So now it was different Any color knew I was in Havana and he knew why But only a little different only a little tougher a matter now of killing a man who knew he was going to be killed Look at it this way. It was a job and it was going to get done Only now it was more even up More interesting Penny color to me Two good boys each holding a good hand and the winner that was going to be me Yes, I was the good boy who was going to stay alive new plans Penny knew where I was So get out of this hotel and find another one pack carry your own suitcase Walk down five flights of stairs Leave through the service entrance Down an alley down a side street keep walking keep alive Okay, get a senior what I asked you what you want rum rum Hey, boy tender Another room. Uh-uh. No, okay. Get a senior that sign outside says you have rooms upstairs See you wish a room. Yeah for four days. It can be a wrench.  I see it, sir. I want a boat for a boat trip. When when in four days Look at it again Chico money mucho mucho mucho money for a boat. You said it Chico Conmigo with me Mario This man has taken a room. He also wants to arrange for a boat. Huh? I want a boat in four days I need something to take me over to Key West But to me senior there are fine steamships airplanes. I can't wait for schedules I want something that will get me out of here when I'm ready to move. Huh? What about it? In four days Well, what about it? In four days senior on the fourth day from today will be ready for you whenever you want it So it started all over again the killing of penny Cullen This time it had to be played another way before I set him up I had to think of myself About a getaway No commercial transportation After I killed penny who knows how many of his people would be asking around for me at airports and at steamship docks A private boat all my own The way to do it The way to assassinate Number 23 Plaza Batista That was the address the auntie had given me That's where penny was I already had the jump on him. I knew exactly where he'd be So started all over again Find a spot nearby Park your car Get out hide watch And it went like this Had a few minutes past midnight the sedan drove up at number 23 Two men got out of the front Looked up and down the street Then one of them opened the door for another man Penny Penny and a blonde The two of them walk up the steps Go into the house The lights go on And so does some music from inside And the two men out front They stay there Talk a little while tell a joke But they stay there That way for two hours Then one of them looks at the other shrugs They walk over to the sedan And get in And in a little while They're dozing And there are silhouettes of penny and the blonde behind the windows That's all you need to know That night The next And the night after that The same thing Penny culling the blonde in the music And the two men who got tired after a couple of hours and went to sleep Then it was the fourth night The time for killing had come around again Penny and the blonde So wait And the two men So wait An hour Wait Two Wait And then The two men dozing Let them sleep The time for killing Fascination A delicate art And it was done Señor Let's go bartender Let's tell your boss I'm ready for that boat Your business here in Havana is completed Four days and it's all done let's go Mario, he is here He says that his business is completed in Havana And he wants a bouquet today Look bartender, what did you tell him? He has a big bouquet for the bouquet Mario Is everything ready? I ask you something, what did you tell him?  You got the boat for me He said you have a lot of money Show me Sure Do you hear it? Whispers to you Bullies, señor So much money to wave it is such a stranger as me You know what else I got? A gun Right under the gavardine You have money, you have a gun It takes now only the boat to Key West to make you happy, see? Yeah $2,000 $2,000, huh? For you, just for you All right When you put me on the boat Who are you talking to? Look when you talk to it in American so I can understand what you're saying In American Mario My friend speaks only Spanish You do not believe me? You talk to him, señor You tell him what you need Talk to him Sit down, señor Make yourself at home What did your friend say? One hour, he will call when he's ready I told you it had to be ready when I wanted it Try someplace else, señor You sure your friends got the boat? One hour, I already said it Sit down You play cards, señor Call him back and tell him I haven't got an hour Everybody has an hour, señor Except they're dying Deal of cards Poker? Deal, except they're dying And that didn't include me Penny Cullen dead Johnny Damon healthy and wealthy But how long does an hour take? How many poker hands? And how many times did the door open like that? And a man standing in the doorway looking at you Just standing and looking Then goes away A man, no woman, but another man And Mario across the table Not looking at his cards Looking at you and laughing like that Where be I? Come with me guys It was not about you, señor It was of another matter Things like that The people who stood in open doorways staring A phone call that was not about you Things that lead up half an hour Things and Mario What's funny? What are you laughing at? That's you, señor You're such a bad poker player Sure, maybe you're not getting a boat Maybe your friend's not getting me a boat either How come it takes an hour to get a boat? You had four days How come it takes another hour, Mario?  Yeah Moyer wrote me and said you're being replaced He's got a kid named Cleo he liked Moyer wrote you? You're kidding, Penny Moyer was contracted for what I was supposed to do to you Oh, Johnny You really lost touch Not Johnny Johnny, he didn't hire you to kill me I hired him To send you to me Tricky What'd you expect, boy, getting me He'd out of the States and all Yeah, I thought that was very patriotic It was, it was I'm going to tell you something, Penny Moyer's jaw is going to drop when he sees me Then he's going to pay me the 15 grand He owes me for killing you Then he's going to run Hey, hey, Johnny, you're not getting back to Miami Oh, you think you can Oh, kill me Presented by AutoLite Tonight's star, Mr. Victor Mature And here once again is our star, Victor Mature Victor, it was great having you on suspense again Thanks, Huylo And thanks to AutoLite for giving me such an exciting story You know, Huylo, the plays the thing Aw, great, Victor But all elements, both the play and the actor, must be right to ensure the best show possible Now, take your car, for example To ensure its best performance It needs AutoLite Ignition Engineered spark plugs, either standard or resistor type I say AutoLite spark plugs because they're designed by the same engineers who design complete electrical systems AutoLite actually makes over 400 products for cars, trucks, tractors, planes and boats These include the world-famous AutoLite Stay Full Battery Automotive wire and cable, bumpers and hubcaps and many more No wonder from bumper to tail light You're always right, with AutoLite Next week on suspense, our star will be Mr. John Hodiak in another story taken from life A dramatic report we call The Case History of a Gambler In weeks to come, we shall also present Mr. Herbert Marshall Mr. Jeff Chandler and Mr. Charles Boyer All on suspense Suspense is produced and directed by Elliott Lewis, with music composed by Lucian Morrowick and conducted by Lud Bluskin Black Jack To Kill was written for suspense by Morton Fein and David Friedkin Feature in tonight's story were Herb Butterfield, Clayton Post Harry Bartell, Jack Krushen Eddie Firestone, Joseph Kearns and Steve Roberts Tonight's appearance of Mr. Victor Mature was made possible through the permission of 20th Century Fox Studios whose current release is Next Bayonets starring Richard Basshart And remember, next week on suspense, Mr. John Hodiak In The Case History of a Gambler For the location of your nearest AutoLite spark plug or battery dealer or your nearest authorized AutoLite service station phone Western Union by number and ask for operator 25 Switch to AutoLite Good night The Christmas season is also the Christmas SEAL season. By using and buying Christmas SEALs you directly aid in the fight to conquer tuberculosis, which kills more people than all infectious diseases combined. Your Christmas will be more worthwhile if you buy Christmas SEALs This is the CBS Radio Network


So this is Phil and I want to thank everyone for coming and joining us today for the Magma Day event. We had a fabulous day throughout with presentations covering a range from Magma's construction, how it's being used in various applications, how it's impacting the wireless business and being a foundation for a much broader impact or collection of projects that LF is putting together to support wireless applications and the democratization of wireless worldwide. So I wanted to give our speakers, our key speakers, a bit of a last word. There's also a Q&A chat available if anyone wants to come and join us for a closing Q&A. So with that I'll let Arpit open things up. Arpit, anything that you want to close the day with or thoughts that you may have about the Magma project and what we've shared today? No, I think hopefully people who stayed on really got some very deep insights not just from the developers but also from the users and you know while we have not explained all of the bits and bytes and how projects come together you know we have the experts. If there's questions you can ask on the live session for sure. Obviously you know information is on the website, there is lots of projects putting everything together, the community is vibrant let's put it this way and 5G is here and you know we're building on 4G but it's for a whole different ecosystem. I know the cloud native community typically view you know this ecosystem as you know it's just a connection what's the problem right but there's a lot more than just a simple workload whether it's a search or you know it's a social media search connection right it's a very complex but our goal is to open it, simplify it, automate it and and I think that's why you're seeing the traction specifically with industries like 5G coming on so you know very excited to have all of you join and be part of this community. Amar and Shah. Yeah, yeah our all out I think the magnet community is super excited about joining LF and working together with you and the other LF networking and LF Edge projects that we can together take into a very comprehensive view of how to deploy networks in an open source manner. Amar anything you'd like to add on our day-to-day? Yeah no thanks a lot for the opportunity to talk here and also present some of our ideas but things that we want to highlight is that you know while cups has been fairly well understood we'd like to think of magma as an evolution on cups so as part of that you know we're also going to be publishing a series of blogs as well as you know I think with the help of the LF edX platform we're also putting together a high-level introduction to magma that gives an overview of a lot of these concepts so all of that is going to be coming soon so please stay plugged in with the community and you know we'll hopefully clarify a lot of these concepts. I just got reminded that the session is starting at 5.55 so we might be a couple of minutes early we may want to restart sorry about that. No no no problem. Yeah it just gives people time to just like come between sessions and get back so because I was wondering you know where's the Q&A and all and now you know you can see that people are joined so.  No no no we are fine I think we're good it's just the timing we started a little bit early so let's restart the whole thing sorry. Phil. So for everyone who watched us rehearse our closing session here apologies. I'm Phil and I'm the magma community manager community evangelist and I wanted to thank everyone who took the time to join us today as we shared about what's happening with the magma project and we were able to share a very broad range of views about magma starting with a developer's insight from Ammar and some directions we're going with Brian a number of I think very interesting user views and lightning talks and an insightful thought on how magma fits into a larger ecosystem of projects being put together by LF to develop a much more comprehensive view of how you can bring open source software and systems to support wireless networks going forward and provide the foundation for an open source by the ecosystem. I wanted to take a minute and remind everyone here that we do have a Q&A chat up and if anyone wants to put questions for our closing speakers there we'd love to address them for you and while we wait for that I'll let each of our speakers take a turn to summarize their thoughts and give any closing comments for the day and we can start with Arpit. Thank you so I think first of all we're very excited that you took the time to look at the magma project in general I think the the interesting thing is if you look at net telecom in general from an end to end perspective you have the core you have the edge and you have the access and a lot of the core in terms of the infrastructure has already opened up through projects under LF Networking specifically as 5G requires network automation edge is opening up in terms of open source open RAN is there now to enable the RAN and desegregation so one of the big missing pieces with the mobile core or the back-end core as we call it and while the cloud community is quite you know eager to help on this it does bring in a lot of complexities historically because of brownfield deployments and things like that so our goal with magma and with magma as part of the overall integrated solutions as part of LF projects is to make it simple make it open make it automated and you know please help us get there and if you want to participate it's magma's website I think we've mentioned it in several of the chats as well as pulling magma into an end-to-end ecosystem through what is called 5G super blueprints which is which is an initiative under LF Networking so you can join there as well and participate but that's kind of where bulk of the ecosystem players are pulling it all together and we're really excited then you know of this vibrant community. Thanks Harput. Amar any closing thoughts and again one more reminder the Q&A chat is open if anyone wants to bring a question to to our conference hosts. Amar. Awesome thanks everybody and thank you for the opportunity to you know present at magma day so a couple of things I just wanted to wrap up on is so the first one is that you know CUPS is a fairly well understood architecture and so what we're trying to do with magma is a bit of an evolution on CUPS it's almost like taking a lot of the principles that have proven out in the data center with like hierarchical control planes and you know marrying it into a sort of a CUPS framework and that is a fairly fundamental evolution in terms of how the architecture is going to look like going forward so while this is a new concept we hope to you know put out a few blogs as well as you know also there's a introduction to magma course that is going to be available sometime in june through the venus foundation edX platform that clarifies a lot of these concepts and so please stay tuned and continue to follow us on magma core.org we'll have a lot more you know articles around this new architectural evolution that we're trying to propose and lastly the plug for the 5g side so 5g is an active development in fact we've just sort of aligned on scope for a lot of the slicing functionality that we're going to introduce into the magma 5g code base so this is a great place for folks to contribute as well as you know a great way to stay engaged with the community as sha mentioned in the new enterprise sort of use cases that are also coming up so thanks again and hope to see you on Slack and magma core. Thanks Amar. Brian any closing thoughts you want to share with us? Just a couple I'll note that we think in addition to what Amar mentioned one of magmas neat differentiations is its ability to run at the access edge for telcos or all the way at the user edge in the case of decentralized wireless networks we think both of those are pretty integrative and differentiating versus alternatives I'd like to invite everyone to please join the community and help build your projects on magma if you're looking to resell magma as part of a broader solution the project's designed for that and we'd love to welcome you to do so if you're an academic researcher there's a lot of emerging standards and supports for for new use cases coming in 5g and we see those showing up first in open source so it's a it's another great way to get involved and so like Amar mentioned we look forward to seeing you on Slack and in the community. Thanks thanks Brian we really would love to have people come join us on this journey with magma and sha the last word thank you Phil yeah yeah it's been exciting and thank you for the opportunity just like all of your saying I really don't have much to add on top of that feels great job and moderating throughout the day great presenters my heartfelt thanks to all the magma participants today Arpit always I watch your talks what connects the end to end challenge every time I think about you I think about like how it's not just about the core or not just about the edge we talk about end to end which is very very you know refreshing and Amar definitely the the the cups evolution I sometimes call that cups 2.0 which is we hope that it what the future of the cellular networks are going to look like and not just a cellular well as the cellular technologies get more and more into the enterprise side supporting consumer networks and so on I think it's just gonna evolve in that direction and Brian obviously the edge edge is a clear part of that so thank you for all the great callouts and last but not the least those who attended the sessions today I hope that you found the sessions worked your time and you have some takeaways from the sessions right and it's a developer community so there is no point in making a marketing or a product pitch here I think what's would be the best just echoing everybody is that come and join us and you know get have a slack join us watch it from the sideline and when you see there's something interesting and exciting for you participate and start contributing there's a lot of excitement that I mean exciting things that are happening as Amar pointed out there's some slicing stuff the 5G perspective there are all these different network models that are coming up yeah that's my biggest say that you know don't yeah hopefully you're just not gonna just watch it from the industry from outside you're gonna come in and join us and contribute there's a lot of interesting things that you can you can hopefully take away and hopefully their impacts you can make at the industry level that's all I appreciate once again the time taken to to to watch the sessions that's okay so Shah just as you started talking I a question came in from her cash which is do you see the possibility of trying the 5G edge deployments with blueprints to get some sizing numbers for the hardware and software and I know I promised you the last word but I think I'll toss that question back to Amar or Brian to see how we might respond to that please do thank you Amar sure yeah so I the the as Arquit already commented yeah so a lot of the end to end blueprint is about dimensioning and integration interfaces and so what we're actually working with you know the LFH team as well as the actual blueprint is precisely around that in parallel there are other community members like canonical who are also trying to offer magma on their infrastructure and so that is a parallel dimensioning exercise that we're also undertaking between with both canonical and and AWS so the key takeaway here is that everyone has a slightly different like forwarding plane and so you know a lot of this dimensioning has to happen within the context of the solution that magma is running on so well the nuts and bolts look similar the actual like sizing would be a little bit yeah thanks Amar and with that I want to offer a heartfelt thank you to everyone who came and shared their morning or afternoon with us depending on where you're at in the world and thank you to our speakers and the hosts that you have here and hope everyone has a fabulous remainder of your day and enjoy the rest of the kubecon CNCF event the remainder of this week thanks everybody bye bye thank you felt great job thank you


Welcome to the journey today. We're talking about how to use Twitter for your business. Let's jump in. I Hear a lot from different businesses that Twitter is dead. It's irrelevant. Why should we be on Twitter? Give me what are some pros to using Twitter? So I hear that all the time too, and it's absolutely not the case It's on the rise popularity is growing and Twitter is really unique in that The real time that embraces is what makes it so special So should all businesses use Twitter should some or there are certain use cases where you probably should avoid it? I'm a big fan I'm a huge advocate of using all three platforms Facebook Twitter and it and Instagram because they work better together Okay, but the thing about Twitter is in some view this as a con is the Algorithm so you're not going to just see things in a chronological order. Okay So to keep your content actually coming up and being found you want to make sure that you have quality content Not quantity don't need to be Tweeting on mass producing content, right? You want to make sure that you're giving something of value to your audience What's kind of the first steps once I sign up? What should I really look at? So first steps you definitely want to start following like-minded users, okay? And that can also help you to get in front of their followers, which will give you a really organic Presence and then also go and engage with other users on Twitter You'll go and click retweet on something that makes sense to your business. That would also be a value to your followers So what about my profile? I know it there's some things that I should probably do just to make sure it's consistent What does that look like with your profile? You want to make sure that you have usually do you have a logo? Yeah, yeah, so you want to put your logo out on your Twitter and definitely make sure your handle is consistent So that's that out symbol and then the name of your business preferably make sure that's consistent across Twitter Instagram and Facebook right after all You're branding yourself, right? And then from there you have like a little bio description to write fully beneath the photo and your handle cool So one of my like just absolute favorite topics ever are hashtags hashtag. I did it all for the cookies, right? Tell us about kind of the best practices using hashtags Like should we just go on a hashtag tangent? Are there best practices? What should we avoid? Give us a lowdown Yes, so definitely reel it in don't need to go hashtag crazy. Okay, but I also love hashtags It's a great way to get more exposure. They're free to use And it can help you to be found by someone who doesn't even know you exist also Including an actual Caption that you're writing so one of my favorite things to do when I'm traveling the country Let's say I did this seminar right on social media and I got a cool picture Me at the microphone feeling I could see it now feeling pretty cool had a train show And so I want to like get that out to my audience and I caption it like Having a blast sharing hashtag social media tips So then it's in my caption and then now if anyone's searching in the area or social media tips in general, right? I have a chance to be discovered seems more natural right then just having at the very end make it part of the conversation Exactly part of the caption, but do both by all means. Okay. You can get real localized with it So yeah, so when I travel like for example as an Austin recently And I just wanted to know where's a good place to eat or get a craft beer You know, that's a big thing in Austin. So I would just search hashtag Austin eats and from there I found out what? Tourists locals where they were going to get food and then that helped me make my buying decision So think about it as a small business owner, you know, how does this relate to you? Well, consumers are out there searching hashtags when they're looking for a product a service a cup of Joe And then so if you have these hashtags on your posts Like you're more likely to be found when someone's searching coffee perfect And what I would say to like when searching that joining on that conversation with those hashtags that are relevant to what you're searching And that's what that's what's most important about Twitter, right is talking to people and being social social media for a reason Exactly. It's a two-way street. That's the beauty of it, right? You're not just talking at your customers anymore You're engaging with them. It's a conversation and at the end of the day That's is gonna make your presence more powerful if you have this Two-way conversation right on I dig it. So next up we have really paid Advertising because I know I've seen some paid promotions on Twitter every now and then is there any relevance to that should we test it out? What are your thoughts? I always say start small and be sure you're paying attention to the metrics otherwise, you're just Just blindly Right at the end of the month. You're like, wait, where did my money go? Yeah, so just start small. So Emma, so we're we're we're tweeting a lot. We're searching hashtags. We're using hashtags How do we know if what we're doing is working and relevant? Is there any place to go in and check what we're doing? There absolutely is a way to track Twitter has this account dashboard that you can actually see Even what time of day people are looking at your tweets, which could really be informative You know, I used to work at a coffee shop and what we found is There were certain times a day that made sense to tweet to get people to come in right coffee early risers You can tweet something at 5 a.m. About what you have on what your drip coffee is or your specials on your lattes And that made sense, you know And then so thinking about the time of day looking at your Twitter analytics to see what works best Yeah, but also the top tweet is really informative Like the tweet that got the most impressions the most engagement that's gonna help inform the next tweet and your strategy, okay Oh, also the retweet if I'm getting a lot of retweets from users. I know. Oh, they like that You know, they want to tell their friends. Yeah, I should include more photos of me skateboarding That got way more retweets and then that informed my next Tweet so there's there's two different types of retweets if you will there's retweet and there's a quote tweet Yeah, so while it's fast and efficient to simply click retweet You know back to the million other things you're doing We've found it to be more beneficial to quote add your own caption because then you're adding your personal flair to it And you're really explaining the relevance of that tweet to you. Why are you retweeting it? Sometimes I feel like I'm spending all day on Twitter. Is there a way for me to not have to do that? Like can I just go and do it just once a day because like schedule things like help me out here? I don't want to spend all day on social media. I've got a business to run Absolutely, so there are ways to outsource. Okay, if you don't want to do this Go to any social There are teams that can take this off your plate But if it's something you want to do on your own you want to be beneficial with your time So I strongly strongly encourage a content calendar Okay, so that way you so you get a calendar a blank calendar And you just plan out a couple days a week that you want to tweet and do it months in advance So then you don't miss piggybacking off of a holiday even unofficial holidays like national Hot dog day or there's really a random holiday for every day. Yeah, and not all of them are going to make sense to your business But if they do you can really piggyback off of that with Twitter But the content calendar is gonna be key to help you plan out in advance You're not rushing and scrambling like I haven't been on Twitter for a few days I just need to go out there and tweet. Yeah, no one tool that I found that was pretty cool is tweet deck Have you checked that out? No, I haven't so tweet deck actually lets you it's inside of Twitter itself But it lets you schedule out your own tweets so that you don't have to have to go in every day and post You can literally take some time or chunk out of your Monday, right and schedule out your your content calendar And it'll just spin it for you. Yeah, and I would just be cautious with that though because While that's maybe a good way for you to Prior or manage your time rather you want to make sure that those times of day are working for your consumers because that's the key You want your tweet To connect with your consumer At the most optimal time. All right. Thank you so much Emma. This has just been a blast I'm I'm going to invest in Twitter now like it's changed my life. So thank you Awesome, well, thank you all so much for watching. This has been the journey make sure you like subscribe comment below Let us know your thoughts. Let us know you want to see next and thank you for watching


Create a 12-meter yacht that can win back the America's Cup for the United States was an achievement realized by skipper Dennis Conner, his winning team, and the boat stars and stripes on February 4th, 1987. Many enthusiasts felt that the loss of the America's Cup four years earlier to the Australians was due to a failure to keep up with the latest technology. In an effort to ensure that the Americans had the faster boat in the final rounds of this year's competition, many changes were made. The design team, led by John Marshall, elected to make use of a new drag reduction technology called riblets, developed by NASA's Langley Research Center and manufactured by the 3M Company. These sheets of thin vinyl plastic placed on the underside of stars and stripes are actually glued with microscopic scratches or riblets that form the perfect triangular peaks and valleys running the entire length of the boat. John Marshall explains. The boat itself looks a little bit like the space shuttle in the sense that the surface is paved with these separate plaques of riblet material rather than having a meticulously smooth surface. This is an intentionally rough surface and it is the microscopic roughness that makes it work and that leads to testable drag reductions in a variety of different research. By placing a small section of the 3M riblet film under a high-powered microscope, it's easy to see the riblets and their near-perfect triangular grooves. The idea for riblets came out of research to modify airplanes so they moved through the air with less resistance. The same researchers also found that some sharks have riblet-like skin that allows them to glide effortlessly through the water, according to Langley's Ben Andrews. We noted from some Russian literature that certain sharks have a structure, a skin structure, very similar to a riblet structure. You look at these things under a microscope, they're tiny V-shaped grooves aligned with the flow of the right scale according to our wind tunnel experiments to reduce drag. Only the fast sharks have these, the slow sharks do not. It was engineer Mike Walsh who originated research on riblets at Langley. The microscopic V-grooves were first studied on machined aluminum plates in this low-speed wind tunnel. 3M then developed a way to put riblets on vinyl. Test samples of the riblet film have been flown by Boeing aircraft company and aboard a NASA-leared jet to confirm its efficiency. According to Ben Andrews, the reduction of skin friction by riblets is on the order of 6 to 8 percent and that translates directly into savings for the airline industry. We estimate the savings for the U.S. commercial airline fleet at roughly $300 million dollars per year. Since it's lighter than paint, 3M is also looking at the riblet material as a protective coating for our plants. Because the technology is new, there are still many unanswered questions, but scientists feel that riblets can be used in a host of applications, from natural gas pipelines to submarines and race cars. NASA's riblet technology, a high-tech solution that helps keep America on the competitive edge.


So now it's a great pleasure to introduce the next panel and our moderator. The panel is Rare Diseases and as a leading company in rare diseases, an area for which I also as a medical geneticist seeing patients with these rare diseases over my clinical career have a great passion for and with 7,000 rare diseases and 400 million people across the world affected by one of these rare diseases. In fact, rare is not so rare with 5% of our population having one of these diseases. 80% of them are genetic and unfortunately, we only have therapies for 5%. So that means 95% of patients who walk around with the rare disease are untreated. 50% of these are kids and 30% of these individuals fail to live beyond their childhood years. It's a really sad area, but it's an exciting area. If you actually combine specialty and rare diseases, about 50% of the investment, 50, 50% of the R&D investment in our industry is targeting these diseases, diseases that for which only 2% of patients take medicine. So there's great hope for the future. And with that said, it gives me a great privilege to introduce the moderator of this panel, an old friend and the chief scientist at Biogen. If there's anybody of all the great people and all the famous people and brilliant scientists that we have today, there's anybody that doesn't need an introduction given the events of the last four to eight weeks. It's Al Sandrock. And I'll say that it's been great to see the dialogue that's ensued with this approval of Adju Kananab and however you feel about this approval, whether you agree with it, whether you disagree with it, however you feel, no one could argue to the great passion and advocacy that Al has brought to the table. And he's championed really what he believes in. So Al, going from a common disease now to rare diseases, I'll hand the panel over to you. Thank you very much, Andy. Thank you for your kind introduction. I have a fantastic panel. And I'm so excited to get going on this discussion. You have their bios, but I think you'll agree that they are fantastic. And I also have two additional people who are going to help me with questions as well, Lina and Tim. And so let me get started. I want to start with the patient and ask Liji to start with, you know, he's the founder of the Lulu Foundation. And what got you, what prompted you to start the foundation? And what would you have to say to the people in the audience here and the folks on the panel in terms of the patient perspective? Thanks, Al, and great to be here and a big thanks to Karun and Andy for making it happen. So I'll just give you a quick summary of our seven-year odyssey just because it's quite representative of many rare disease patient odyssey. So just over seven years ago, our eldest daughter, Alia, was born, was born totally healthy. And then 10 days later, she had 10 seizures. And we went through a diagnostic odyssey that took many months and were finally diagnosed with CDKL5 deficiency disorder, which is a rare neurogenetic disorder causing epilepsy and developmental delays. And I remember at the time, you know, we were distraught. We were in the hospital, my wife and myself and I said, look, 10 years ago, we wouldn't have even known what was wrong. And 10 years from now, hopefully this will be a treatable disorder along with many others. And she said, I want to be 10 years from now. And I said, well, we are the generation of humanity that needs to get from the knowledge of the genomic age that is already there to the ability to implement that therapeutically. So we launched the Lulu Foundation and with clear goals. And I think that's an important first lesson. You have to set your goals and we set treatments in five years, symptomatic treatments and cures plural quote unquote within 10 years. And that was back in 2015. And I think our objective was really kind of laser focused on how to de-risk our indication for industry. We quickly realized that actually it's industry that makes that makes the drugs, but what do they need? And the three elements that we focused on, which I'll just summarize, the first is building a patient community, a one of partnership, one that's cohesive. So when when Ali was born, we were told there were a few hundred patients in the world. We now know many thousand. The incidence rates now well defined at one in 42,000. So it's actually tens of thousands of patients potentially. But then we have a global alliance of patient groups over 20 now. And we really built on some of the excellent work they did. But we learned from from other indications the importance of remaining united and cohesive. The second step was funding the science. And we have a grant program. And we partner with the orphan disease center at the University of Pennsylvania who helps us implement that. And our CSO is based there. But also building the toolkit in parallel. So that might be the models, whether it's cellular models, better animal models, also the clinical infrastructure, better patient registry, an endpoint study in ICD-10 code, educating the regulators on what this disease is, both the FDA and the EMAs. And the third one is engagement in parallel. So the old idea, which has never really been true anyway, that you need to first work on the science and then engage with industry down the line once you get more answers. I don't think that's true of any disorder really, but it's certainly not true in rare disease. So we took the decision to engage early and often with industry, with the regulators. We have a symposium. We host an online app to keep scientists connected. So today there's a better biological understanding. We have the toolkit. We've had multiple trials. Still no approved drug, but hopefully soon. But we also have exciting proofs of concept pre-clinically of mice that have had the condition reversed with gene therapy. Also some theoretical transgenic approaches. But we've always seen that ultimately our customer is industry, but what do we need to bring together to make it happen? Thank you, Majid. That's very compelling. Beautifully articulated the ecosystem that you figured out how to navigate essentially. And I think what you just said for the Lulu Foundation applies to many, many other rare diseases. It's very similar to what I heard from the SMA Foundation in the early days as well. And so thank you very much for that. I'd like to ask each panelist, Majid mentioned the revolution and genomic medicine and Andy did too. But what has enabled us to actually tackle rare diseases from the technology point of view? Maybe I'll start and then maybe you can list some of the successes as well. So I'll start with Kathy. Well, thanks. And I think I would name as a critical foundation scientifically the human genome project and the ability to identify the genes that cause so many of these rare diseases. And I think part of the hope of the human genome project had been that that by identifying these diseases, we would greatly expand therapeutic options for people born with serious inherited diseases and at least part of that hope had also centered on gene therapy. And of course, as you know, in the in the event, it took a good deal longer to work out successful gene therapy than it did to sequence the human genome. But I do think that now with a handful of approved products for serious genetic diseases, approved gene therapy products for serious genetic diseases, what seems especially exciting to me is that over the last couple of years, we've begun to hear about very promising data in late phase clinical trials for what I would call the more common rare diseases. For example, sickle cell disease, thalassemia, hemophilia, Duchenne muscular dystrophy. And so some of these diseases that really affect very large numbers of people are in phase three testing with promising results. And so I think we are poised to move from gene therapy as a treatment for a handful of ultra rare disorders, pediatric neurodegenerative diseases, inherited retinal dystrophies and so forth, to more common inherited diseases. And so I see that as a sign of progress for the field. Thank you, Kathy Frank. Do you have any thoughts on this? Yeah, I would add to what Kathy said. I think the Human Genome Project was really a landmark for giving us the encyclopedia of the human genome and the genes. And I think another really important technology events that's enabled us to be where we are today is the sequencing technologies. I think it's amazing today that we can sequence a person's genome for a few thousand dollars. And that gives us a tremendous amount of information and has probably, you know, been watershed in our ability to diagnose these rare diseases. And, you know, the implementation of that is, I think we're really at the tip of the iceberg as far as seeing what we can do with that. And my hope is that that would lead to newborn screen sequencing basically at birth so that we can treat patients prophylactically rather than treating them, you know, after they have symptoms on sets.  And, you know, my field has been in antisense oligonucleotides. And, you know, the sequence information has been critical for us to really leverage the technology that we've been working on for 30 years and applying it now to these rare diseases. And as you know, we're beginning to see some success come out of that effort there. Thanks, Frank. John and David, do you have anything to add in terms of what has enabled us to tackle rare diseases? Yeah, I would just add, Al, in addition to the new technologies and sequencing of the human genome, which has clearly accelerated our understanding of the biology and therefore new targets in rare disease, I'd like to highlight the Orphan Drug Act itself because that was really revolutionary in terms of the investment creating incentives for developing new therapies. Prior to its authorization in 1983, there were only less than 10 therapies actually that had come to market. Since its approval in 1983 to the end of 2020, we've had 599 Orphan products developed and approved to treat rare diseases. So that's absolutely tremendous. And it's interesting that over the past 15 years, Big Pharma has really jumped into the fray of their dominant force in this sector right now, clearly for various reasons, including addressing their pipeline and engineering competition. Thanks, John. David? Yeah, Al, the only thing I would add is non-scientific, but the internet. And again, it's many things. But with all this amazing science and ability to diagnose, understand the biology, the challenge for many of these communities is that they're just not organized and they're too small. So whether you're the patient being diagnosed and you're suddenly alone and who do you talk to, how to get information, whatever, that's all been enabled. And importantly from a clinical development standpoint, as many conversations with patient organizations, if you can do anything to increase your chance of having a cure, it's organize yourself and the internet's been foundational to that. Thanks, David. Well, one thing that was sort of was touched on but not really talked about was prices, drug prices. And each one of you in the industry are aware of this, but how important is that to enable this or to continue to sustain it? And are there any clouds on the horizon that you'd like to highlight that may impede our progress? You know, we talked about successes, but is this assured? Is this sustainable? Who wants to start? David? Maybe I'll dive in. I think I fanged up early. I mean, we all, I think we're all concerned about this. You know, it's under the sustainability of the model. And if you go back to the early nineties, I'm being one of the pioneers here. At that point, when we were discussing, you know, the treatment of precochet that one of the first rare disease treatments that came forward, it was a price at a very high level, you know, for the world, it was, you know, sort of unbelievable, how could that work? But society really embraced that. They understood that the pricing was a function of rarity that, you know, if there wasn't a price that allowed a company to recover on the work that went into it, and acknowledging there's a very small number of individuals who might benefit, in a sense, society had to step up. So the foundation was laid there, but we've come a long way. And I think it's, you know, this model, it's not guaranteed, it's not magic. And increasingly, the rules around rare diseases are the same as the rules elsewhere, meaning that we have to demonstrate value. There has to be clear value. Just because you have a treatment for a rare disease doesn't mean that you should be, you know, reimbursed. It's what is the value you have created for that individual patient or that individual community. The second thing I think we need to be thoughtful about is industry pricing in general. I think from an industry perspective, there's this societal contract, which says, yes, you're going to pay more for the drug when it's first approved and over its patent life, but then it will go off that. And you, society, we will all have that drug for a fraction of the cost forever more. And I think in the rare disease world, that evolution hasn't fully played out, in part because many of these are biologics and they have their own challenges in terms of going generic. But I think as a community, we have to think about how do we fulfill our side of that societal contract that says you're going to pay more in the beginning, but it's not a lifetime contract at that same price. That's a really good. Yeah, go ahead. If I could just jump in here and just add something to what David said. You know, I do think as a society, we have a challenge here. If we applied the current model to the remaining 7,000 or so rare diseases that still have no treatment, we'd have a big problem because healthcare budgets are finite and we're already experiencing some challenges with pricing and market access. So we need to come up with innovative market access solutions and maybe that involves some kind of public-private partnerships that takes the onus off the private sector entirely or partially. That also keeps the incentives for developing new therapies for rare disease. And the model for gene therapies is of course evolving rapidly, but we shouldn't apply traditional or outdated approaches to assess the value there. The most important distinction here being that gene or cell therapies or other regenerative therapies are intended to be given as a one-time treatment with long-term benefits versus the traditional product therapy that requires recurring payments. So the value of these new one-time therapies needs to be demonstrated using non-traditional approaches. So standard cost-effectiveness frameworks don't fairly represent the overall value of these treatments. Thanks, John. Before we move on to the next question, I wondered if Brigitte had a patient perspective on what we just talked about. Yeah, so I totally agree with John's point. There does need to be innovation. I'll take it away from the paying side to the approval process and the regulatory side. I just think that the way the trial design and the hurdles, certainly efficacy still has to be proven up, but the way it's done for smaller populations like rare diseases just has to be different. It's too much of a burden now relative to the population size, and that's what drives the cost up, which ultimately affects the price and of course the time to development. The other thing I would add is I think with some of these new technologies, gene therapy, gene editing, there are some common infrastructure needs which government can step into. It's starting to. There's an NIH initiative that was announced a couple of years ago, but beyond just sort of vector manufacture, actually trying to crack the knot of delivery into key organ systems. Once you've done it overall, then hopefully it's not going to be quite as straightforward as plug and play, but you will see an acceleration of progress for multiple indications. So there are some areas where government spending can really move the needle quickly as we've seen it can with COVID-19. Thank you very much. I want to now move on to ultra rare diseases, and I'm even though Tim is here to be a questioner, I'm going to also treat him sort of like a panelist, but we talked about rare diseases, but then we have the ultra rare and sort of the end of one, if you will, or the end of a few. What are the issues associated with that? I'm going to ask Tim to start how he thinks about that as he practices medicine, but also how he approaches thinking about therapeutic therapeutics, and then maybe also ask Frank to talk about and more. Excellent. It's a pleasure to be on this panel and to follow up all these distinguished guests here. I think that as a geneticist and neurologist at Boston Children's, we get approached a lot by families, especially those with disorders that no one has ever heard of that haven't made it to perhaps the stage of having a foundation like Majeed's that haven't made it to the target profile portfolios of companies like yours, Al. And they're in that early stage of looking for help, looking for scientists and looking for industry partners. And I wanted to come back to the point that John made about public-private partnerships, that as we think about this long tail of ultra rare diseases, and there are many, the great majority of the 7,000 different genetic diseases have incredibly tiny populations. How do we see, it's clear that the populations are so small, the patients that are coming to us often will tell us that there may be only three or four other patients like them that their doctors are aware of in the world. And so how do we incentivize the activities of these public-private partnerships? How do we band these groups together? What we try to connect a lot of these families to one another, and there's been ideas floated, for instance, by Andrew Lowe at MIT of forming a national CRO to coalesce under an umbrella many ultra rare diseases. Do you see, how do you see that working? Given that we have experts here who have seen single disease efforts really well incentivized under their current system, how do you imagine this working under a larger umbrella organizations like that? John, I think he was asking you. Well, you know, I do think we need something like that, a framework that creates this umbrella so that we can sort of defray and share the cost of developing therapies for these ultra ultra rare diseases. At Alexia, we kind of, you know, some of this is related to pricing strategy, and when you are able to capture more patients in a particular platform, obviously, you have a lot more flexibility on the pricing side. So that's the direction we've taken because there hasn't been something like this in place to incentivize us to go into those ultra ultra rare conditions. So absolutely endorse the need for that. I don't exactly know what the solution is, but honestly, but it's something that we need to apply some effort to. Go ahead, Frank. Yeah, so one thing to consider is how expensive it is to identify and develop a drug. And, you know, one area that we really haven't talked about is ways that we can increase the efficiency of the process. And, you know, it's, you know, just the discovery of the molecule that you're going to be using for a drug consumes teams of people to partake in that. And, you know, one of the areas that we're really interested in is really, you know, thinking about machine learning technologies that we can really capitalize on past experiences to be able to make it a much more efficient process for the discovery. That's just really the starting point. And I think everybody on the panel recognizes that the discovery of the drug is actually the cheap part of the process. And the expensive part is the development and showing that it has clinical utility. And, you know, I think that the point is that, you know, for these rare, ultra rare diseases, we need to think differently about how we're going to demonstrate efficacy. And, you know, maybe even go back to the point where we may not need to demonstrate efficacy. What we have to demonstrate is no harm to the patient and, you know, or reframe how we're trying to approach going forward with the technology.  And we spent quite a bit of time thinking through this issue about the benefit risk and how do we, you know, continue patients where there may be just one patient on treatment and Tim had to deal with this. How do you justify continuing to treat that patient with a medicine that could have some adverse effects and getting that balance right. And I think those are the kinds of discussions we need to have to really advance the field and advance where we can treat many more of these patients out there. Al, one additional thought there just to pile on here. I think the disease foundations and the patient advocacy organizations can do a lot to support drug development and rare disease more broadly maybe not the ultra ultra rare, but somewhere in between by creating disease registries that will bring a better understanding of the natural history and disease progression because with a lot of these diseases we don't really understand and we have to define and refine clinical endpoints, PROs that can serve as a basis for regulatory and approval and market access. And so there's a clear gap there that is quite a challenge for companies to pursue if that hasn't been, that groundwork hasn't been laid. That's a good point. Sorry, David, did you want to say something? Yeah, just one quick point. I just want to go back to Frank. So the risk benefit issue, I think this is, you know, back to regulatory frameworks. We do think there's a bit of a cookie cutter and, you know, you have to have and Tim's already, you know, this standard, you know, expensive approach and Tim's already proven, well, that's not true. You know, it can be done and risk benefit, of course, and small populations, you can think absolutely differently, right, about the overall risk benefits. So that's a key component. And the other thing I think about is for these ultra rare organisms, entities, it works if we can leverage something. And the question is, how do we incentivize the party that has something to leverage to allow it to be used? And so you can think of R&D tax credits and the like, right, which is to say, you know, if I've got a technology delivery, Majid, you mentioned delivery is an issue, right? I mean, I might be a company that has, you know, I don't have anything to do with rare, but I see that I could contribute to that.  Somebody else has got manufacturing expertise and, you know, they can devote a reactor and get a tax credit. I might do that. Yeah, I know it's like, those are good points, David. It seems also that all these innovations and genomics and in terms of therapeutic modalities, gene therapy is Kathy pointed out and all you can do three times as Frank did. And even potentially do efficacy type studies with registry comparisons to natural history. It's exposed some of the bottlenecks, though. One of the, I think, frankly, you were telling me that one of the most costly and time-consuming aspects is the pre-clinical safety. And that has a major innovation in toxicology that I know of anyway, and maybe I just don't know, in a long time. And I know that the FDA has put new guidelines in that has reduced some of the hurdles, but it still takes a long time and it's pretty costly. Yeah, me for, in Lawn Foundation, we're trying to develop individual therapies for patients free of cost to the patient. The most expensive part of the whole process is the IND or the talk studies that would support treating the individual patients. And as I'll point it out, there really hasn't been any change from doing, luckily the FDA has reduced it to a single species, instead of having to do two species and they'll allow rodents for the single species. But you still have to do extensive talks work that adds cost to individual patients. And we're getting to the point where patients are having bake cells to raise money for talk studies. And I know Tim said to deal with that a bit as well. Thanks, Frank. Look, we only have five minutes left. It's amazing how quickly time flies. I wanted to ask Lena if there were some questions that she would want to ask the panelists at this point. Yeah, so, you know, our focus in TMA Precision Health, which is a company representing here, which we created based on our experience, because I'm a patient with a rare disease, and a scientist and an entrepreneur and all that. So, but something that I have realized is that, yes, 80% of rare diseases are monogenic and probably targeted therapies are going to be good for those. But there is something that we rarely think about and is that rare diseases and many of them are syndromes. And they are present with different types and different, yeah, that the patients are confronted to different development of the disease. So, what we are doing integrating now information, you know, and then basically what we can understand is analyze the patient journey and then identify the segment, you know, segment the patients and really understand how they move forward and how what are the patterns of disease presentation that we can anticipate how to control and better treat those patients. And I think that we came to realize that information that we gather is crucial for drug development and for clinical utility as one of the panelists was mentioning. So, what I want to raise here is the how can we use that information that companies like ours are gathering from the primary care before we actually go to the before the disease is totally identified because we actually help as well to identify the disease and if there is a gene involved etc. But what is most important is these patterns of presentation and these patterns of presentation allow us to understand better diseases that academics can do more work in terms of understand targets and then pharma can do a better approach of patient to take a therapy rather than molecule to therapy. So, I would like to sort of put that information on the table and get the discussion trigger for that. How can we use better than information in pharma? Precision phenotyping perhaps. Frank touched on something that he talked about newborn screening and he wondered whether that could really improve things, accelerate this area.  And that's sort of the catch point too that you can't get newborn screening until you have therapy. But I wonder whether Frank you were suggesting that you could accelerate this whole process if we had newborn screening that was more comprehensive and I wondered whether each of the panelists would have a view on that. You know just one thought is you know as I mentioned the sequencing cost or getting to the point where we can consider sequencing at birth for every every baby born. And you know the issue that I think we struggle with is that there's a lot of sequence information that's not actionable today. But yet the sequence isn't changing. And so maybe one way to approach this is that you have a book with your sequence information and every few years when there's scientific advances you kind of go back into the book or your physician goes back into the book and identifies maybe you know at this point you need to get more exercise or you need to change something in your lifestyle that could impact your health you know 20 or 30, 40, 50 years from now as you know science advances. And it seems silly not to do you know new total genome sequencing rather than do a piecemeal for only the diseases that are actionable today. Or maybe not if not newborns at least some systematic process whereby for example any unknown rare disease any patient that presents with something that's unknown perhaps should at least be considered for genetic testing or for... Yeah, may I just add I think it's more related to natural history of the disease what I'm mentioning rather than pre-screening and genotyping everybody especially for underserved communities that you know that's probably an impossibility to get genotype everybody but natural history is so important. So can we follow those patients learn from it and then try to better type rare diseases and then identify the target. But you can combine the two where you're you're collecting a rich natural history that's sort of tied to your your genome history. Right. And you know I think that will be actionable at some point in the future. And just to follow up on Al's point about genome sequencing you know I do think that in pediatric genetics people are moving to this more and more quickly to avoid the kind of diagnostic odyssey that Majid talked about for his daughter and so I you know I think that's that's not so far away. Application to the entire population you know I'm not sure we're going to see that right away. So just just just to add to that I mean it totally would be just our example our disorder you know it used to be 10 years plus the age of diagnosis in our case it was about six months now it's a matter of weeks more and more and there are more hospitals applying that you know any child into the NICU they do the sequencing first before the whole odyssey but actually the UK government this week is having a public debate on whether every newborn child should be sequenced. So it's not that that's beyond the realm of the possible but certainly every child with something clearly wrong at birth that's becoming far more straightforward and unusual. Thank you. Well it's 1022 I don't know whether Andy and Caloon are going to let us keep talking because I think we could talk all day about this very exciting area. Why don't you end at 1025 and then we'll move on. Okay all right wonderful. Are there any do you in terms of gene therapy Cathy do you see any advances that could sort of replace the current therapies for example I'm thinking about gene editing. Well I think that actually some of the results that are coming out from clinical studies using gene editing and I would cite for example the sickle cell results from CRISPR and others to me are proving the the worth of gene editing approaches and I think that base editing is not far behind and I think that what will be important for people interested in gene-based therapeutics is to understand the best ways to combine and utilize or choose among the options that we have and everything from mRNA, anti-sensical nucleotides and gene replacement and gene knockdown to gene editing and base editing and so I think the proliferation of gene-based strategies is only a good thing for people with rare disease. Thanks Cathy I was thinking that you know there must be criteria at each company on which diseases to tackle and put into their pipeline and you know for us at Biogen for example we have taken on SOD1 mediated ALS along with IONUS even though only one or two percent of patients with ALS have it we estimated the prevalence to be about 500 or so when we started the program in the US. Tim talked about the ultra rare you know the ends of one to five to ten that and Lauren I think is tackling is there a gap in between the ultra rare and the 500 to a thousand plus that we haven't addressed? I think one of the age old beliefs about rare diseases was it was an entry point to larger diseases I think A that may be true I mean you know we may be able to apply a gene therapy to a rare disease and run a maybe a quicker trial I think that's better than misnomer but but I do think that the expansion so for example rhythm right now the company I'm at we're looking at rare genetic diseases of obesity the first genes that we are studying literally there's you know tens of people that we are pursuing for you know in the US at the current time but the number of genes that may be benefited is much larger and so the whole research plan is to work through those different genes and try to understand that incremental opportunity so I think a company has to decide are they are they in that disease and trying to pursue it to its natural end following the science or they in it to simply get to something else and there are two different things I just wanted to I'll just you know sort of a message of hope as Andy said that you know just five years ago and we started none of these things were approved and now we already have multiple approved gene therapies as well as for rare disorders such as your own for for SMA and even I remember that conversation with my wife being told that you know Alia was missing one letter from one copy of this gene and she said can't we put it back and I said honey that's not how DNA works and today we're actually working with a lab with prime editing to do precisely that and the field has moved so far in just these few years I think it is very exciting and hopeful well on that positive note it's past 10 25 it begins and ends with the patient thank you very much Majid and I want to thank all my panelists for very stimulating and wonderful conversation I'll turn it back over to Andy thank you very much Alan thanks to all the panelists and I'm going to hand this to Karun to kick off our polling thank you Andy thank you Al wonderful panel can you put the polling slide please for the rare diseases writes what measures are most needed to accelerate drug development in rare diseases Paul starts we have 50 seconds to Paul please go ahead the question is what measures are most needed to accelerate drug development in rare diseases next year Karun will need some elevator music during this one minute period yep or the jeopardy song exactly yeah for them well everybody and welcome back thank you for participating in our polling if we could please please bring up the polling results so that we can share them with the audience and I'm just going to bring this up on my screen so I can read it there we go great so the question that each of you addressed was what measures are most needed to accelerate drug development in rare diseases and actually I was suspecting that this one would be more even than the results have turned out and it looks like the majority in almost 50 percent of you Paul believe that the most needed activity is to more use of real-world data for rare disease patients to understand natural history of disease and disease heterogeneity so thank you very much for participating in that poll


Myself, Mr. Yusuke Kulkarni, assistant professor at Balchand Institute of Technology, Sholapur, I am here to discuss with you on topic Concrete Mixed Design by IS Method. Learning outcomes of today's session. At the end of this session, students will be able to explain Concrete Mixed Design by IS Method. They will be able to perform Concrete Mixed Design in laboratory. Mixed Design can be defined as the process of selecting suitable ingredients of concrete, remember, and determining their relative proportions and what will be the object. Object will be of producing concrete of certain minimum strength and durability as economically as possible. Economy is also important, remember. So, determining the proportions of ingredients of concrete is mixed design. Now, one more thing is that for workable mixes, the strength of concrete varies as an inverse function of water cement ratio. This thing is important, one should know it. Now, since the quantity of water required depends upon the amount of paste, remember, it is important that this paste should be as little as possible and hence importance of grading is there. Here we can see concrete freely flowing. Now, there are certain variables in proportioning which are those water cement ratio is there, cement content is there, cement aggregate ratio is there, gradation of aggregates is equally important, consistency of the paste is equally important. Now, let us see step by step procedure of mixed design. There are different methods of mixed design, but today we will go by IS method. IS 10262 2009 gives detailed procedure of this particular method. So, which are the steps? First step is calculation of target strength of concrete, remember. This is the first step. Then, selection of water cement ratio. Next, selection of water content from it, selection of cement content for concrete, then estimation of aggregate proportion, estimation of the mixed ingredients and trial mixes. These are the important steps. We will see one after another these steps. So, this is the first step. So, calculation of target strength. Target strength FT is given by FCK plus 1.65S, where this S stands for standard deviation. For different grades of concrete, these are the standard deviation values which are to be used. Then, selection of water cement ratio is the next step. So, there are standard curves given by IS codes and IS 456 gives these curves. These curves are to be used for determining water cement ratio and these curves are, this is one curve for water cement ratio of concrete mixed design. Here, you can see water cement ratios and here you can see 28 days compression strength of concrete. So, you can choose water cement ratio from here. Here, this curve also is important depending upon grade of cement and water cement ratio and concrete strength. So, these two curves are to be used. Now, step three, selection of water content for concrete. So, concrete is to be designed with selection of water content by referring to this particular table. Say nominal maximum size of aggregate, if it is 10 mm, maximum water content should be 208 liters, remember. For 20 mm, it is 186 and for 40 mm, it is 165. So, these are the limitations given by code and these have to be followed in order to get good mix. Now, selection of cement content. Cement content depends upon exposure of concrete to environment. For mild exposure, minimum cement content is given as 300 kg per cubic meter, remember. And pre-water cement ratio is 0.55 for m20 grade of concrete. Likewise, these are the values given by ice code. These are to be referred. Then calculation of aggregate ratio. Aggregate ratio for zone 1, zone 2, zone 3 and zone 4 ratio are to be found using these tables. Then here, mass of fine aggregate is first calculated using the relations given in the codes. Then, coarse aggregate, then estimation of mixed gradient and then trial mixes. Remember, once you got the proportions, they cannot be used directly unless and until they are tested in the form of trial mixes. And once the results are satisfactory, they can be used on site. So, here we will see one sample mixed design for m25 grade of concrete, remember. So, here all the steps are given, step by step the procedure is followed and the results are obtained. You can go through this. Determination of target strength. Target strength comes to be 31.6 Newton per mm square. Then step to selection of water cement ratio. So, using IS-456 table 5, get for maximum mild exposure condition, the maximum water content is 0.55. So, adopt 0.5 likewise. So, selection of water content from that, maximum water content comes to 186 kg from table 2 of IS-10262. For nominal maximum size of aggregate, 20 mm. So, here for slump say from 50 to 75 mm slump, the correction in water content should be like this. These things are estimated water content by after applying the correction comes to be this much. Then selection of cement content is there. Minimum cement content given by IS is 300 kg per cubic meter. By calculations done here, we get 383.2, it is greater than 300, hence it is okay. Maximum cement content is 450, remember. Limitation on maximum cement content is 450 kg per cubic meter. Then estimation of aggregate proportions. For zone 2, this is a zone 2 sand, zone 2 aggregate. And the content water cement ratio is 0.5. Volume of coarse aggregate per unit volume comes to be 0.62. Then the workability considerations are there. Corrections are to be made in the aggregate proportions. And see here for every plus or minus 0.05 change in water cement ratio, the coarse aggregate proportion is to be changed by 0.01. So, these adjustments are given in the code are to be done. And then estimation of mix and get ingredients we get for 1 cubic meter of concrete. Cement so much so many cubic meters. Volume of water is also there. Volume of aggregates, mass of aggregates can be found from them. Because we know the density, we can find mass. Mass of fine aggregate is this much. And then trial mix proportion is obtained 1 is to 2.089 is to 2.837. Now, this proportion is to be checked by mixing a trial one or taking a trial mix. And then only they will be finalized. So, we will stop a while here. Here is one review question friends for you. Number one, in IS code method of concrete mix design, proportions of ingredients obtained are to be measured by weight, by volume or by both methods. So, get the correct answer right here. And IS number dash dash is used for concrete mix design, pick up the correct answer, write your answers. So, here are the answers. Question number one, A is the option, correct option A by weight. And question number two, B is the correct option, IS 10262 dash 2009. So, these are the answers. See, these are the references for today's session. Go through these references. Thank you.