My name is Jamie Plower, myself and Evan are here from Fidelity Investments to talk about our software delivery platform. And we'll go into some of the details. So Evan, do you want to kick us off? Absolutely. So thank you so much for joining us. Quick disclaimer, I'll click it. This is just our experience at Fidelity. We are not endorsing anything. This is just here to tell you about the fun stuff and opportunities we've had enhancing our software delivery platform. Quick summary on Fidelity, I want to make this super fast. My job is to get the base foundation and then pass it to Jamie for the fun stuff. Fidelity started in 1946 with each generation and enhancement in computers. Fidelity has had a key point and we really took off in 2016 with our first application in the cloud. And even now, today, we have over 6,500 applications in the cloud. So when we went through this transformation originally, our software delivery platform was fragmented. We had individual departments with their own type of standards, automation, and nothing was consistent. So when we went through this and enhanced our software delivery platform, we wanted to redo it from the ground up, focusing on the user experience. Our goal with this was to have the key objectives, the first one being developer focused and focusing on the developer experience. So we switched to an inner-source model where all of our DevOps automation is focused on input from the developer. Anyone in the entire enterprise can contribute to it. We have great automation that has given us the ability to allow the developers to drive all of these types of capabilities from self-service onboarding and release orchestration. From this, though, we knew we needed to have platform stability. When we give developers control, we're going to have more and more deployments. And so that was the other big key objective. From this, though, we also realized a lot of pains developers had with security and compliance. And so we also built in the working with the security audit and compliance teams. We built into the platform the ability to call their CLIs and APIs to give developers more input at a faster rate. So instead of having to go open tickets and wait for weeks for a security officer to come back to them, we now can deliver it faster to them. And from this, we wanted to also deliver to our business partners and to the developers themselves key data analytics. Having a central capability, we were able to drive more data insight, giving DevOps metrics and giving developers insights. The whole goal, though, we wanted to help remove some of the pain points. So the ones that you'll see, the first two are all about the developer's experience and how each BU would be fragmented. So not having copy and paste capabilities and not having a standard governance really was a pain point for a lot of them. The other one was security. Developers would write code and then have to wait weeks to get input and then try to remember what that code was. From that, we also saw that maintaining the software consistency and maintaining these capabilities were limiting for the developers, such as the log4j. And so when we went through this transformation, we realized we could have a lot better enhancements and standardizing going from this legacy application. You can see it was highly fragmented where we had multiple enterprise level audits, friction for developers not having a consistency. And these BU DevOps teams that would have to maintain and support these deployments as they scaled and as we got to the cloud. And it just was costly. They were unable to maintain all of these independent and fragmented capabilities. So I'm going to pass it to Jamie to talk about our newer platform. Great. Thanks, Evan. How we went about solving this problem is, as Evan mentioned there, we worked with our overall DevOps Council leadership and agreed some sort of key standards that we wanted to bake in from the start. So we focused on the key domains there. You can see it's broken down into five across source code, build, security, validation, and obviously production, logical access checks, et cetera. As you can see on the top, we have our key platforms. Like the goal was to shift left, not bake too much into the pipelines themselves. Let's use the platforms for the power they are so we can actually, I suppose, let the developer in the middle make sure that we're, as they're going through their journey of releasing code, that various checks and balances could come out. And then by simplifying then our processes around the pipelines, we can achieve and bake in standards that we want to achieve. And just an example of some of the checks that we want to build is making sure the approval process is being done correctly, everything, the way the artifacts are being built, consumed. We want to build a lineage right the way through from concept to post deployment that we can enable and trace for every single artifact that we're building within Fidelity and make sure they're consistently built around the standards and be able to update that as we go forward. So the whole idea, move faster, move safer, and enable a sort of key developer experience. So what this diagram is explaining on the left, you can see some of the key assets that we're working with across our DevOps tool chain. And what we're doing is, as I say, we're using key lineage points and data points across our STLC process that we're capturing and linking together that sort of steel threading. This is super important because it's not only for all the compliance for security, it also provides many benefits around specific metrics and KPIs that we can hand out to our overall engineering managers and development community back. So there's a carrot for adopting this process as well that they get huge insights that would up till now be difficult to transcribe. So how are we enabling this? And we've been partnering with CDEvents team. We work with Andrea and the team there as part to understand, first of all, it's a fantastic project. Like, why is it important to us? It's really enabled. Apologies. What's important for us is being able to link together a standard language that we're building. Like, we have many different platforms, many different systems, and without being able to talk to each other in a consistent way, CDEvents was something that allowed us to sort of model consistency across our organizational groups. That's been really, really powerful. We started off with cloud events, a lot of customization, but having a sort of standard as we ever or future adapt our tool chain platforms, we have a standard contract that we're going to work within. So this was, again, borrowed this from the guys, but it helps explain how the various, if we're dealing with multiple SEM systems, like specific events, like a change merge event, how we can tie that to the specific artifact that's being published, and then using the SHAs and the various data points that are being provided, we can then link that, for example, to deployments. So this allows us not only to, again, tie that lineage back to who committed it, when was that deployed, and where, and what different systems it will be going. It doesn't matter how many targets we have, to us it's a service deployed to service updated events. And again, as they're maturing the specification, there's going to be S-bomb linkages, instant, as was mentioned today, test queue with their test events. So it allows us to sort of work in that overall ecosystem really, really well. So this is just a sort of quick example. Evan, you want to talk to this a little bit? Absolutely. This is a template catalog on Jenkins. So it's immutable, and it's easy for developers to onboard. All they have to do is provide a properties YAML file. And what you'll see is at each stage, as we're kind of going through the data, we're able to collect the properties that are passed into the function. And you can see right here, these are the properties, all the properties from their Docker to everything that they want to do. And we're able to gather insight into each individual build. The changes that are going, we're able to track the commit ID, and through and through we can see in the pipeline what they executed and what changes were tested in the pipeline. Yeah, and this is really powerful because a lot of stuff is dynamic, and obviously this provides us the context on top of actually leveraging the platforms themselves. We have standard pipeline libraries. Now we're getting real down to the detail of the specific commands. We can actually append dynamic data, for example, the shas that have just been pushed up for the artifacts and passed them through our backend.  Like, as I mentioned earlier on, we want to meet developer where they are. So it ensures consistency as part of our legacy, some of the challenges we had is that it was sort of a trust-based policy. We were hoping teams would basically buy in, use these tools. Whereas now we can actually enforce it in a standard way across the actual pipeline, leveraging the webhooks, leveraging the various data that's actually coming out to actually make real-time contextual feedback. What also is important is we can actually bake in and adapt and evolve our policy as it goes. Because it's centrally managed in the platform, these controls can be abstracted and injected in. So we have a way to evolve as we go forward. So one of the key net effects of this that's really beneficial is is that it allows us to simplify now our pipeline constructs. So as we mentioned before, we have standard libraries. That's a challenge in any firm, especially a size of fidelity. So what we've provided is like standard templates, composable item called segments, then these fine-grained capabilities that bring it all together to allow a sort of common marketplace of capabilities. So as new tools come and go, as technologies evolve, we can update these fine-grained capabilities to move forward from there. And this just talks to that a little bit more. If we step back and look at the overall platform, right on the left-hand side there, you can see the core platform assets that we work within. We can swap in new tools as they go. Using our catalogs just allows off-the-shelf immutable templates that teams can just pick up and go that have the prescribed golden paths. Segments is something that we've built out that sort of takes the idea of a phase in your tool chain that will allow more of our power users, I suppose, to scribe their workflow, but you still use a standard set of capabilities. And then Fidelity Pipeline Library is basically the LEGO blocks that provides all this. As you can see, we use all this data, gets pumped into our evidence store, which allows us to do a lot of really interesting things. Not only collate specific data points that we can use from an operational context back into the pipeline itself, our audit and compliance teams can directly query this attestable data. So at the moment, audits are much more streamlined and the data is available for them and uncover a lot of potential data points that we've never seen before. And as I mentioned, the net effect of this is that we get a lot of real-time correlated data that we can actually use for engineering managers, for insights and so on, that we can publish out to dashboards, reporting, and general fitness checks for the applications themselves. So as we're trying to say, the key thing for the platform is essential adoption is that the right way is the simple way, and therefore teams don't even know this is going around, but they're constantly being kept up to date. So how are we achieving this technically? This gives you a little high-level view on how we're approaching this problem. So on the very left-hand side, as I mentioned, anything that can publish an event in fidelity can effectively integrate with this system. And then as we go along, we've created these collectors, some are plugins. We've actually, as mentioned, we've contributed back the CD plugins to the Jenkins that's available now for everyone to use. Or we've got various collectors, which basically allows us to, again, if it's coming from multiple SEM systems, we can provide a standard sort of template around that, and we use the CD events to allow us sort of tie together this sort of meta model in a consistent way. In the middle there, you can see the context data stores. These are our immutable ledgers. These capture the raw events and provide the raw evidence that we can use, and we can put APIs on top of this, or we can publish data out to other teams, for example, that may want insights data around the various stores that we're collecting. And then on the back end, what we do is we leverage some servers, hooks to be able to sort of clone a copy of the image and have a fan-out pattern effectively where we do some interesting processing where we can actually target specific controls we're interested and combine data from multiple different data sets to answer those questions. And that's what we publish into our evidence store, which is a roll-up, and I have an example query in a few minutes just to describe for that. But again, the idea is that in the pipeline, this is a real-time event, so we can actually query the evidence store, so we can actually allow teams have smart gates across their tool chain, or a production hard gate which will enforce the whole list of controls that we want to do. And because this is a nice fan-out pattern, we can obviously funnel that data into a more analytics-type data store where we can roll that up for other uses. And as can be seen here, this is a slight example of a snippet of a sample GraphQL API that we provide back to our development community where just by passing in a SHA of the... there's a few different access patterns that we provide, but this one's demonstrating by providing a SHA from a merge request, for example, how we can provide that lineage right the way back from the SCM data to the pipeline data. In this case, the sonar scan and the artifacts produced. But as we mentioned in the earlier slides, this would be decorated with the security data, all the test data, any of the additional audit controls that we want to do, container rehydrations, anything like that can just be continually added into this bucket. So the real benefit for the end user is that we are ensuring they have control over the data that they're getting, but it's clearly very powerful from an audit standpoint that they can just access the data in a simple manner as they want to. So this is this that isn't shown in the data. It's behind our ledger table. The key driving point for this that drives the end-to-end capability is actually the CDEvents plugin. Without knowing the start and stop of the pipeline in the individual stages, we wouldn't be able to collect this data in a seamless way. Our pipeline is critical, and so without the CDEvents plugin, we wouldn't be able to kind of create this ledger. Good point, yeah. So we evolve forward. The use cases aren't just necessarily what we describe there in the pipeline. There's the overall usage. We can obviously get a complete metamodel of what's going on in the pipelines, whether it be the container rehydration that they're using, if there's anomalies going on. So we have a prescriptive area of mining that we can go along, which we touch upon in the next slide a little bit. But the stakeholders who use this system, obviously there's the end engineers and they can benefit. So we create central teams, have full control over the templates that they provide and offer out to various teams. So it's very flexible from that point of view. The composable manner, we obviously have currently over 6,500 applications gone out. They're in different flavors, different tools. So the segments model provides huge flexibility for our teams to focus on handling the needs that they have. If there's a gap, they can contribute into our process.  So just to tie this all together and allows us to make some really smart decisions, as you can see on the very left-hand side, we're just summarizing that the core platforms and the pipelines themselves are providing our data foundation. As we mentioned as well, anything that can produce an event can emit the data points into this and they're modeled in our ledgers, as we mentioned beforehand. The Data Trust Foundation is where we're focused specifically on the ledgers and the evidence store. That's our source of truth. There's no way that anyone can come in and it's basically the core foundation for any of the other data points that we provide out to the wider organization. Other than evidence and compliance reporting, one area that we're focused on is data for smart analytics and insights that we can provide. And this is an evolving space for us. We're not fully there, but it's been very exciting for us to actually answer some critical problems that we've had that I talked about at the bottom. But by funneling off the data on the back end there, separate to the evidence store, we have the ability to pre-process that, roll up the various data points maybe around the domain itself, or cross collate data from, for example, SEM test or pre-production data to answer some complex questions that we can then gauge from our pipeline point of view. But just to give you some examples of how we can use this data, like we have different standards of application, some are tier 0 mission critical applications, some are less so they could be up to a tier 5, for example. So we want to have a similar approach to how we look at policy but allow the actual contextual data allow us to make decisions around the posture that we can actually apply to those controls. Like everyone, root cause analysis is one key area that can be a pain point for everything else. So on the back end pulling these different data threads together and getting input from our engineering managers and stakeholders alike we can provide key data points to what the change was that potentially broke something and actually provide them the lineage back to the actual commit that it helped with. Again, the beauty of this is that we're providing the key data points so that these engineering teams can build solutions on top of and work with our SRE teams for example that allows them for much fine grained evidence across the wider enterprise which in a large regulated firm like Fidelity has not been traditionally easy to achieve. And again, like I mentioned beforehand Evan said there with CD events and getting that meta model of the pipelines itself it's like water when it comes to data engineers have fun trying to obviously get data points so we can actually understand key things like the containers being pulled in if there's anomalies if they're injecting for example bad code or doing some bad practice within the pipelines themselves this will provide insights to how they're using it and what we can do to remediate. And then in general I think this comes down to just looking at historical analysis of the data that comes through understanding build scanning successes just general meta data that's really important to understand trends of usage for a various tool chain that's available. So it's a high level overview of what we're doing but you can see how the data is king for us but allows us to as I say answer questions from a security audit standpoint but also provides these roll ups in a way that will allow us answer quite technical challenge that we can allow the tooling read in and make decisions based on and that's the future of where we're going with this. So in summary that's pretty much where we are today and I want to make sure that there's plenty of time as long as there's anything else you want to add, Evan? No. Okay. So thank you. Hope that was insightful. Maybe we have a question. Let me grab the mic. Absolutely. I want to make sure there's enough time at the end for... You're going to take the questions. You can go around. Oh, now I have to answer questions. You took my job. Absolutely. So how did you... Fidelity is very much about proprietary value, right? You've got competitors and you compete with people. How did you ever persuade them to open source the CD events plugin? Why not do it proprietary? Why not hide it from the rest of the world? It's impressive. You've open sourced it. What was it like to do that and what was the experience like changing the company that way? Well, in fairness my boss, Jerry, and his boss, Joe are big proponents of open source. And there's a big... I think it was mentioned in the previous talk there about providing a culture for the developers to get involved. And again, we're set up in a way in Fidelity that every Tuesday is a learning day. So there's basically a physical day per week where we can focus on projects like this. I personally had a need, and we used these as part of our toolchain. There was a gap out there, so we've been involved with the sort of event sig for some time, got in touch with Andrea. And as we understood this project, as I said, we went down a custom route for cloud events and it just did not make sense that we were reinventing the wheel. And obviously this specs maturing but allows us to infer our domain problems. It's really interesting to see how other enterprises are. It's not like we're special, this is a common problem that's happening across many different enterprises, so we're encouraged, we've baked it into our actual work and delivered that pretty quickly. They're a fantastic organization to work with regarding very clear contribution guidelines. And again, we find it really important because we learn how other firms or open sources do that. So we can bring that shape back into Fidelity and improve our own processes because nothing's perfect, but we can evolve and evolve. So I think we see open source as a clear way to sort of decouple ourselves from potentially some corporate proprietary systems. That's one of the really important issues and it's being pushed. And that's just one example where we're involved across our whole ecosystem. There's a lot of involvement. So I think we've already made around too many contributions in the last quarter alone to open source within our group. Hi. No go for it. We've got loads of time. You talked about the difference between some of the capabilities between a platform level and a pipeline level. Can you explain a little bit what you mean? Be closer. How you think about the pipeline as part of the platform, uses the platform, where do you draw the line and how do you think about those two separate things? I think in the area that we work with in the central platforms itself, we're focused predominantly on the developer journey. So up till now, a lot of these checks were, as I said, put into the pipeline itself. So it just made sense that we simplify that and focus on actually using the platforms for their core purpose, apart from the functionality they provide. They provide this ecosystem that we can not only extract data signals from, but we can enforce and guard. The pipeline challenge was pretty much, as you can see it as the sugar on top, because the platforms are consistent and central. They're non-negotiable. If someone wants to release code, they have to interface and go through these platforms. And we can invoke scans from that, for example, as artifact pushes. High complex workflows that beforehand were prescribed in pipelines itself. So it allows us then to have the discussion with the development community about the core building blocks that they require. Because really, they want a clone, they want to scan, they want to learn, they want to push. They want to pull down, config, deploy, test, and push out to code. And it also allows them to simplify. It was amazing understanding how common it was a matter of dealing with database deployments or microservice deployments. They all had the same challenge, but they were just pushing that complexity into the pipeline. So it allows us to have much richer discussions around the core capabilities that we want to have in the pipelines. So we built a dictionary around that, a domain where if it's APIs or whether it's data, we can actually now describe tool agnostic, what are we trying to achieve and codify those in. And that allows us to have the composable model with our segments that we're building. So that's been a bit of a game-changer from how, because they're now involved in solving the solution. And that's where we're trying to marry simplified but has to do their core job but pushes much to the platform. So the real hidden value is handled there. But the core thing is the data I think the pipelines provide a much richness of context that may not get necessarily from the platforms itself. But it's very clear, that's again when the engineers see what they can get from that. It's no brainer to adopt. So that's where we're getting a lot more traction around that. So I hope that answers your question. But it's a bit of the spine, for example, is coming from the platforms itself. But there's just jobs that are no better done than the pipelines itself. But the point is, there's a common marketplace that we use and share across all the business units now that were originally built with duplicative capabilities. No governance, no insight. And that's where we're losing. Sorry, you had a question? Oh, thank you. Can you hear me? Okay, cool. So I had a question more about the adoption element. Fidelity clearly has a huge history behind and you mentioned the fragmentation of the ecosystem, which is very common in companies of this scale and history, right? So I was going to ask, what sort of scale of changes would teams need in order to opt into your pipeline? Because sometimes I hear people saying, well, we have to change our architecture to be able to use the nice stuff out of the box. And also because there's also a tug of war between delivering for products and delivering to customers and delivering value versus improving the delivery the SDLC generally, the software development. No, it's a great question. I guess the question is, how did you persuade the engineering teams to get that work done? Also the management, right? Absolutely. So I came from before I joined the central capability. I came from one of those fragmented DevOps teams who supported a specific department. And what we wanted to do was we gave first off, we said, this is inner source. You have the ability to contribute. And we also wanted to meet them where they were at now. We understood certain departments are more mature than others. And so we work with them to say, okay, what is it going to take to adopt? We're not going to force you to say, okay, by tomorrow, you're done.   What can we solve now? And how can we help you adopt this in the future? Because, like sometimes they might say, hey, for Q3, I have five VPs who are trying to push me in. And we'll say, okay, we'll work with you. You have, like, a two-year time frame. We try to give them, I'm just making up, you know, several-year time frame. Let's work with you. Let's build also a lot of learnings. So we try to really drive and go to these specific departments saying, let us teach you so that you can be engaged, so that you can get involved, and then plan out what it's going to take and do it small steps at a time. And so it's really a balance act on, this is where we want to go, but we have 10 different departments or 50 or however many. One area that's really helped us, and I think it's going to be the crux, your question is, is that you'll notice it was the next generation platform. So as we modernize our tools and consolidate, we traditionally had multiple orchestrators. So with our next generation orchestrators, this paid path was built. So they had to migrate off these anyway. So the fact that the capabilities were pre-baked and they're the, as I said, simplified, they were rationalizing as this part of the work was going on, the convergence to the new platform, the pathway was there. And then the fact that they were actually involved in a discussion, inner-source has been really, really powerful because by breaking down the problem into core capabilities and discussing it, teams don't want to naturally build their keen to ship value. So for them, the fact that there was something off the set, was a lot more reliable because a lot more eyes plays much more quality. And then as we propose some of the actual value that you get off that, that sort of was one of the key draws into it. So a lot of, as long as we sort of met them halfway, we sort of, you can't solve this, you can't come out of a cave and go to da, like you have to bring them in and just a bit of communication. And that's the sort of role that we play, but it's really the convergence to the new platform strategy was one of the key points. And they weren't going to rebuild Rome. Again, they had it there. So that's the sort of, so there's a combination of a few different factors, but that's been the key point of it, but engaging having that path there. And then as I said, once they shift, they obviously want to adopt the new platform capabilities because of the, maybe some legacy issues they may have up beforehand. So for them, it was a win-win. But being involved in it is how we've grown and we have some key partners that we've built strong relationships from the gecko so that they feel part of the model that we're doing. And then the platforms itself just adds that sustainability and security that they're getting. Yep. So you used a phrase inner source. Could you illuminate that a little further? What inner source, I know what open source means. Tell us more about what inner source means and how you use that. So for example, like the whole pipeline strategy that we mentioned there, so we call it Fidelity Pipeline Library, but really, we engaged our business unit community, the 20,000 developers out there. And as opposed to creating multiple ways to do scans or builds and this and that, we created a framework that was very, very lightweight, very, very simple on purpose that we weren't negating this really complex tooling solution. So the capabilities, multiple lines of code, we have some rules. If it's something richer, we put a tool behind it. But the idea was, is that anyone in the firm can submit a pull request and within an hour, their change would be available to the whole firm. So this is how we were breaking down barriers for and again, you have to understand, like, they're very smart individuals. We want to make sure that they're brought into the process as well, so everyone's getting the benefit. And then we built in some sort of key design decisions just around, like we use maps a lot so we can extend, for example, optional parameters and the whole point of it is, is that we don't have breaking changes and we bring the teams into it. But by doing that it's not something that's open to the wider, like potentially these projects could go out to open source but they're currently within the fidelity construct, hence why we call it inner source. On the note of inner sourcing, my experience was we tried inner sourcing but there's a PaaS team that sort of maintains and owns that platform for the company. And that became a friction point because they felt uncomfortable getting all these full requests from for snowflake codes and then having to maintain all of these. How did you solve that? And again, I think this domain applied really, really well to that. Not all projects are successful inner source projects but this was a problem that affected everyone. So I think having key partners where you have that trusted committers within your group that you can actually have, when a pull request is put up, people swarm in it straight away. So a lot of discussions happening across time zone and very quickly if it's a sort of an interesting new point you might have a long thread around it but the point is that discussion is really valuable because you're solving it there and then but it actually provides more confidence in the overall community because they see the input, good discussions happening for smaller changers, they're self-organized but our group actually took on the mantle, like it has to be managed by some respect. So again then Evan can attest to this. It's more the certification process, the validation process, making sure that that is still really optimized but as we found teams, beforehand central teams that were doing fragment were just throwing code out and it was breaking so the community was effectively testing it this way. It's a lot more robust and it's a very clear model as to what they're getting and we've automated the whole process, the documentation, everything so teams can just see what's there and commit to it. So it's worked very well for us, I'll be honest with you and I think we do have some robust discussion at time but overall the fact that everyone has a voice and it's democratized process, the cream rises to the top and I think like anything we want to get the input and I think just alone that gives a lot more confidence to the end users. We'll add to that. So one thing that we do have fidelity that was just started a few years ago is called the DevOps Council. We're all across the different departments, the CIOs came together and agreed to certain standards so we had this opportunity to approach it from both sides where upper management agreed saying yes this is a great opportunity and then working with the individual developer to say absolutely we agree with this and so tackling it from both sides really helped lead for adoption across the enterprise and so I think that was the other big key initiative. Yeah, no, it's definitely the values undeniable. I think just the fact that I think in over 18 months we've I think we've got like over 250 capabilities now that have been built and scaled and it's just even the chatter that you see that the community gets involved and works with it but we're just using this framework to hive off the data for our own needs and then they're getting the functional beneficial because at the end of the day teams don't want to build something that's already there that's robust and solves the need and if there's a gap they can contribute it. Look, thank you so much. I know we're over time a little bit but really appreciate your time and effort and hope you enjoyed that. Thanks so much. Thank you all.


A new study shows that there is a growing number of people who are having Dating app burnout David people are tired of it Yeah, the title of this viral new york times article is a decade of fruitless searching the toll of dating app burnout 10 years after the launch of tinder some long-term online daters say endless swiping has been bad for their mental health And of course there's a huge long article. There's thousands and thousands of comments They're mostly focusing on two women, but one of them is named Abby Andrew She's been on dating apps for eight years between okcupid bumble tinder e harmony match Wu plus coffee meets bagel hinge And basically she said I have not had a single long-term relationship that has blossomed from my efforts Whoa, so is it her fault or the dating apps fault? Let's talk about it guys There's some interesting Statistics here and a lot of comments obviously will also tire in our own personal experience So please hit that like button and check out other episodes of the hot pop boys and also check out small loss sauce bring it on your next Dating app date Well, the good thing is the bullet style bottle allows you to bring it to the restaurant where you guys are probably meeting Obviously, it depends. You like coffee dates. You like dinner dates. You like drinks dates great for dates Hey, you want to try this new sauce? It's hot. It's spicy. Just like me Um quick thoughts, man. It's interesting because you never hear anybody talk about how much they love using dating apps Maybe unless you are a girl that's a model or a guy that's a celebrity I could see that being a little bit of a different situation Nobody ever talks about how much they like you but it seems like is there any other way to meet nowadays It seems like seven out of ten people meet on apps. Yeah, my overall personal opinion And we're gonna get into the stats of the article though. I think apps dating apps are a necessary evil They are sometimes unpleasant But they really do open up the market and they really do allow you to meet a lot of people that you're not Meeting in your daily life period. Okay. Let's be honest now With that said, I do know people who got married off the dating apps But I will say this with the caveat that they got married because they had a strong idea of what they were looking for And what was it because some of that Do people get married off tinder or are people getting married in or let's be honest off like e harmony or coffee meets bagel Right. It was coffee meets bagel and hinge. So I think uh, not so much tinder yet But maybe somebody got married off tinder, you know, somebody has been married off tinder. Let's be honest But yeah, anyways, more people have been cheated on through tinder. All right tinder has ruined more marriages than it has created Yeah, um, I guess what I'm saying is uh, the best marriages that I do know Or the best relationships that I've personally been in were developed not on the apps though for myself Like the longest relationships I have had Over the past 10 years met even at a club even meeting at a club is different than meeting on the apps Sure. Because that's a physical place. That's a old school analog way of meeting some people met at the club in the 1950s The Copa Cabana back in a day what they call it is a shared space. It is a shared space But I guess what is your personal experience? Like so I'm saying that I'm not saying that it hasn't worked because obviously statistically It has to work, but I'm just saying that it seems like meeting At some sort of like shared interest group might might be better I think that a lot of people go into using the dating apps with no idea of what they're looking for and hoping They're like what I match with all these people. Well, one of them's got to fall in love with me and I got to fall in love with them I'm like, no, I think it's still a very very intentional thing, you know The longest relationship I've been in was off the app And I don't think that's like weird or crazy to say, you know what I mean But I think I've also met people outside of the app as well So I guess what I'm saying is my suggestion is if you're going to keep using the apps, I know it's tiring I know there's burnout. I've been burnout in my life But you got to have a clear idea of what you're looking for so that you can find it and vet people that way Right and that's why you see people try to be very detailed in their Profile sometimes right it really depends. Um, I would say, you know, what's really interesting Do you think the problem with the apps is that it's matching people that don't have shared interests and they just like How each other looks so inevitably it's going to break apart versus meeting each other At the pre-selected place where you already have shared interests exactly because you're bringing people from like disparate Interest groups that would never mix or tribes that don't necessarily vibe. Yeah Well, I mean dude, there's so many different ways to get married I think and have a long relationship But I think ultimately the most important thing to me is communication of what you actually want Because that's the thing it's when you match with each other and you think it's gonna work But you don't verbally tell them what you're looking for and then you find out that you too are not on the same page Right, right, right And you could even be two puzzle pieces that do fit But one of the puzzle pieces is like has got a time lock on their puzzle piece matching that's like no Need three more years of playing around before the puzzle pieces open So now it's like you're like and the other person's freaking out because their timeline's ready to match with the other puzzle piece And they're like, uh, I finally found a match. I've been searching for 10 years on these apps and the other person's like Well, I got a time lock on there. It's not breaking. Right. Right. Right. Anyway, let's get into the comment section Somebody said so you're saying they're trying to find your forever person on an app that requires you to swipe left or right Based on physical attractiveness is a bad life strategy. Good to know. I didn't see that coming. I'm shocked Is that is that a interesting way to put it or I mean I again man. I think the dating apps I always stand by the fact that I think it is useful But with caveats and you got to be using it, right? This person said habitually single men are the ones who refuse to settle down And habitually single women are the ones who refuse to settle period Dating apps exist specifically to introduce these two categories of people to one another So that's not going to work that well because the dudes don't want to settle down and the women don't want to settle Obviously, they're referring to Hypergamy or etc. Or I guess dating up, right? Right. Um, somebody said, um, you know what the real problem is nowadays It's not about that. It's not about gender roles or like guys, you know being man-child It's just about everybody gamifying the whole experience Everybody thinks it's so fun to meet new people. They love the magic the dopamine release of that first date And guess what? It's just simple marginal value the more you go out with somebody the more you get to know them The more that extra first date spark goes away and you're just addicted to first sparks. Yeah. Yeah, that is true I do think that it is so exciting to meet someone for the first second third time And you have the sparks flying that is very exciting. Let's be honest, but That is not like at the end of the day to have like a long-term relationship You have to like have that long-term mindset if you don't have the mindset And they don't have the mindset It's probably not gonna work. You're saying if both people love eating delicious foods from different cultures for the first time But they want to just do that every day because you know how it's so exciting to like try a new dish You're like, oh, I hadn't had this dish before. Yeah, but if you're just so addicted to that feeling Yeah, if you're addicted to that dopamine feeling of the first date in the chase That is eventually going to fall back on you. It's your fault. It's not the dating apps fault The dating app is there to just put two people in front of each other and you guys decide what happens That is literally what it's there for so if you are losing out at that game It's because you don't have the emotional training or the emotional fortitude or The direction in your life to figure out what you want somebody said maybe it's not the apps Maybe it's just us as humans and it was always this crappy burnout before the apps existed And nothing's changed But just like the format of how this crappiness is taking place is more frequent dating Burnout happened whether it was people at your church fixing you guys up together whether it was parents trying to introduce you What was it before dating apps david? It was your parents saying hey, you should meet uh Sandra or no, I used to I know that friends used to be way more proactive about setting up their friends because you kind of had to Or you had to go to nightclubs non-stop Oh, you want to talk about burnout Oh go to the nightclub and try to approach a bunch of women then you'll really burn out that night Bro, I just approached eight different girls man. I'm so tired man. I'm done for the night I want to get drunk and then go eat a burrito and I'm knocking out and then I'm You know gonna squeeze one out I'm just saying there's burnout from that and then there's burnout From being introduced to a bunch of people through your friends and family because they didn't work So I'm saying dating burnout always existed. Okay. Okay. I agree with you But I do agree. I I don't fully agree with you because I actually agree with this Follow-up comment because they got into an argument somebody said no It's society has become increasingly superficial. It's all about being conventionally attractive And that has changed over society because everybody has a perfectionist mindset because there are seemingly endless opportunities in 2023 It's not just with dating. It's with buying any product People used to just go down to the local dealership and pick up a car Nowadays people are like flying across the country to get a good deal on a whip and drive it all the way back That I agree. I agree. That is true. Listen. I think society's changed both Things can be true that dating burnout Has always existed before the apps and that society did change. I think those two factors are true They can both be true now percentage wise is a 50 50 60 40 70 30 I don't know but i'm just saying both things are true Yeah, I think society changed which changed like the Probability outcomes, but then online dating also increased the frequency that everybody's dating Do you see what i'm saying? So that it's like one is the the apps increased the frequency But the search for perfection or endless opportunities But but this is more the outcome to me. This is the same argument as anything in this world like sports Oh sports is better people are more athletic now because they have all the great nutrition and training from a young age Oh, and then people are mad. Oh, it's so competitive in sports now But i'm like everybody has access to the same training to a certain extent So so it's interesting and one was just uh blaming the human experience another was dating how society blaming how society's changed But this third commenter was blaming the apps saying the apps have a vested interest in creating this like hamster wheel of everybody to Create more profitability. So this is a little bit. I don't know if this is like getting into conspiracy theory territory, but I Hey, that would make the hell of a plot of a movie though, right? If the apps all were like trying to like change dating dynamics to the point to just create profitability But it like ruined society to do the family dynamics Dude the dating apps did not change society. They are a symptom of the changing society before dating apps It was the dating website before dating websites It was you getting introduced by your friends or you meeting people at the club that you thought were good But but maybe people at the same club or the people that are meeting through friends. There's a higher likelihood of matching That's what people are saying because it's not looks based. Yeah, but that's also because society was different Yeah, I mean Did society changed first or did the dating apps come up you guys tell me Well, people are eating a lot of new types of foods nowadays and watching all different types of programs on the internet too So anyway, i'm rolling on self-responsibility on this one guys This person says my daughter went to harvard. She makes big money and she still can't find anyone good She's attractive too.  So nobody's thinking about, you know Raising that pta life. Yes. So nobody like wants to Live a traditional life, which is also leading to it It's just the desire to not get married and the people people are using the apps to have a series of hookups To delay that feeling of like not wanting to be a boring married person So basically I just cycled into this gigantic thing But obviously some people were blaming the men and saying that in 2023 All men are being manned children for as long as they can because they are enjoying it Right, Leonardo DiCaprio. He is a man child. Yeah, listen, maybe maybe hey, maybe it's the man's fault 60% You know, because women their role, you know, they've always They're always going to be the ones giving birth so they that you can say they have a certain clock or time or whatever But then guys Is that that the guys we're messing up because we want to play around longer It's leo. So you're saying it was leo DiCaprio. Is it the leo? The it did leo ruin things or did the app ruin leo and nick cannon Somebody said it's because of hypergamy because women are always trying to date up when they're already high up That's why your daughter went to harvard can't find anybody She probably wants a six foot harvard grad who got better grades than her earns more than her Is of the same ethnicity or a globally higher ranked ethnicity and that's just way too hard for her to find You know what guys man Yeah, what was the last comment somebody said people used to actually go outside and join groups And nobody does that anymore. Huh? What happened to join you? You need to go join groups You need to go have meetups and meet people in person. It's true 100% And I guess the last comments were all surrounding basically hook up saying that this allows you to get the physical side of a relationship without the emotional time investment of a relationship and uh Somebody said you know due to the apps nowadays There are so many people with such a large number of sexual partners that they are no longer able to pair bond This is a biological thing and this will lead to a much larger demographic collapse So this to and then probably, you know, they didn't say this but i'm again I'm assuming that's when ai steps in is like caremans are no longer recreating It's time for me to dominate. Let me let me tell you something man Whatever you guys want to blame it on the new generation technology contraceptives You want to blame it on the party culture? You want to blame it on the chase of dopamine? You want to blame it on the dating apps? The fact is people are still getting married nowadays whether on or off the app so If you know friends who are not necessarily two beautiful people or two ugly people getting together There's all different types of matches going on people are still getting married and having kids and having families So i'm saying if you talk to your married friends who are young and have dated around You know what they're going to say they're going to say man love Pairings marriage it's a choice you both have to make that decision and commit to each other It is not going to just happen because you magically just I sure hope that taylor swift in uh travis kales workout. Yeah, well don't focus on the celebrities man It is true. Everybody wants to taste everything. Everybody wants to experience everything It is what it is But at the end of the day if you know what you want then you go seek out what you want You know what i mean because people are still getting married people act like nobody's getting married nowadays Yeah, I do think that there's more room for more apps to be developed in the future that are better at matching people for marriage And I think that hinge as a middle of the road app that like is like as a catch-all I don't know. I think it'll have its moment and it's probably in its moment right now But it's hard to believe that it won't niche back out into you know, it's specific silos Yeah, for sure e harmony things like I heard of some people they're in how many dating apps right now that are in ghost mode are developing right now That are based off like a trillion for sure. There's a lot of different niches the league raya Oh meet other exclusive celebrities and like influencers.  I think it's on you To understand what the app is and understand what you want if you're trying to play around you get on the apps If you're trying to look for a long-term partner, then you that's what you look for you have to you have to know what you're looking for Number one key. That's my opinion. Hey, listen guys thousands and thousands and thousands of opinions comments ones that You know disagree agree with each other if you don't know what you're looking for you're always going to be lost Let us know what you think in the comment section below guys Very hot topic a lot of people married unmarried got a lot of opinions on it go to smallassos.com until next time Topic but also a nicely hot chili oil. Check it out smallassos.com


he was on the field working out today yesterday he threw from a distance of more than a hundred feet we see him obviously doing some running in the outfield we don't know if he's absolutely going to be ready to have his first turn but so far things look good where would you go Michael if Tanaka was not ready to take his first start in 2020 well the Yankees have a lot of places to go with this Jack they could go with an opener which I would not do because I think the bullpen is going to be overly taxed because you're not going to get that many innings out of starters for the first two or three weeks so I said this the other day and I repeated because he turned in a good performance after we said it I would look very seriously at a Clark Schmidt I think that he could give you three or four innings and really impressed people I think he's got that sort of stuff and that that kind of demeanor but they can go other places as well but they certainly have depth and that's the important thing in this day and age where you know one one positive test could send everything spiraling they have the depth to send people out there Jonathan low Isaac a Michael King those guys can pitch if they have to but it'll be very interesting to see if they elect at least first time through if Tanaka is a little bit behind to go with the opener because I just don't like getting 27 outs out of the bullpen because you're going to need to get 12 to 15 outs pretty much every time except for maybe when Garrett Cole pitches


multiple myeloma. I worked in the research lab of Ken Anderson and really focused on multiple myeloma also in Pittsburgh and coming to Columbia with a very strong background in cardiology, nephrology, pathology. I have to say they have a very strong pathology. I saw more and more amyloid patients and I have a huge amyloid population right now and I think that's the reason why David invited me to talk about amyloid. We also have a very interesting approach how to treat amyloid. We have a monoclonal antibody and I will spend half of my talk to give you a little bit of insight on the newest developments of that monoclonal antibody present some data we have in a clinical research trial. Okay, so to kind of you know talk about amyloid dose I think how do we make the diagnosis? How do we select the right therapy? That's important amyloid doses. We use usually steal all the drugs from multiple myeloma but there are some I would say special things in amyloid doses we have to take into account and we cannot just kind of you know use our approach from myeloma and amyloid doses one to one. I think what is really interesting is the development of the monoclonal antibodies as in amyloid doses to help the body to break down the amyloid. So amyloid doses is a protein misfolding disease and what you can see here nicely you can have over 28 different proteins that are able to form amyloid so that reaches from abnormal enzymes like lysosomes or proteins apolipoprotein transiratine that's especially in older patients the TTR amyloid doses transiratine amyloid doses but we usually deal with the light chain amyloid doses where free light chains form an abnormal protein and typical for amyloid is the congorate staining in another microscope and in polarized light microscopy you've seen the typical apple green staining for amyloid. So what types of amyloid we can have in the beginning as I started to work with amyloid dose I was always confused but all the terms are ALATTR so very simple when you see patients with amyloid doses and they come to your clinic and you see there's a capital letter A that stands for amyloid doses and then second you see this is light chain TTR mutational that's hereditary amyloid doses white type amyloid doses that's H related so the transiratine just becomes clumpy or sticky with H so that's why patients especially older men develop very often TTR amyloid doses other types of amyloid doses fibrino gene apple lipo protein I mentioned that already there are certain organs that are predominantly involved in amyloid doses and patients for instance with AL amyloid doses almost all organs can be involved this is a nerve system soft tissue whereas the white type TTR amyloid doses mainly affects the hearts or kind of you know sometimes the GI tract so based when patients come how they present sometimes we already have a little bit of idea in which direction it goes so this is a nice work from the Mayo Clinic the Mayo clinic has probably the largest population for amyloid doses so they evaluated over 5000 patients which they treat between 1960 and 2009 for the percentage of certain types of amyloid dose and you can see most of the patients have primary light chain amyloid doses followed by localized amyloid dose and then central our TTR amyloid doses and only a fraction or kind of in a very small number of patients have other types of amyloid doses so how does amyloid develop usually monoclonal plasma cells secret free light chains they found the amyloid and indirectly we can only measure the tissue damage there's currently no and that makes it a little bit hard there's currently no test that really tells us this organ is affected or how many organs are affected or what the extent everything is basically an indirect measurement so that results also in the clinical manifestation almost all organs can be affected nephrotic syndrome with real this or without real insufficiency so if you have a patient for instance with an amyloid and an nephrotic range protein urea think about amyloid doses that means if the patient loses four gram of protein in the 24 hour urine that's kind of you know raises a high suspicion for amyloid doses peripheral peripheral neuropathy carpal tunnel syndrome very often we see that very often and when i ask my patients you know have you ever had a carpal tunnel surgery and they said yeah doctor you know i had that couple years ago very often they don't bring it in connection with their amyloid doses hipadomegaly for because of amyloid involvement macroglossia and purpura the typical racoon eyes that can occur spontaneously or after minor trauma or pressure they're very typical but not seen very often so you should also think about amyloid doses when you see your patients suddenly unexplained dyspnea and especially diastolic dysfunction so when you read for instance when i read the echo of an amyloid patients i don't care about the e f the ejection fraction is usually preserved because the ejection fraction is a volume of what you pump out from the volume you have in and it's a hypertrophy and you have a small volume the the left chamber is still able to pump an amount a potentially good amount of volume out of the heart but you have to look really for the diastolic dysfunction that is really important so left ventricle hypertrophy and a systolic blood pressure below kind of 100 110 i asked my patients where you before on blood pressure medication when they come the first time and we kind of you know try to find out do they have amyloid doses what's going on i asked my patients where you're on blood pressure medication and very often they say yeah i was but my doctor stopped it because my blood pressure is low right now so that should always raises you know the suspicion to look a little bit what is the reason for this i mentioned already protea urea epatomegaly for amyloid involvement but also for volume overload very often we see in our patients an increased ALP that is due to the right heart failure autonomic nerve dysfunction low blood pressure that's the main issue we have to deal with i have patients who have such a low blood pressure that they're not even able to leave the bed you know that really brings us it's a huge medical challenge to deal with those patients amgas smoldering myeloma milder than myeloma wall storms just think about amyloid doses when those patients come to you and they suddenly have a low blood pressure or heart failure or more shortness of breath i would think about that almost all of your patients have an echo and if you look for diastolic dysfunction it might give you a good hint so how do we make the diagnosis first the patient presents with some the symptoms with the syndrome then we have to prove um kind that the patient has amyloid doses usually by a biopsy of an organ and then we have to make sure that we type the right amyloid i mentioned already that we have several types of amyloid doses so it's really important that we do the typing either by immunohistochemistry it depends on pathology how familiar pathology is with the typing of amyloid at columbia they have a pretty good method to digest the amyloid open up the binding sites for the antibody that's usually the issue the amyloid does not bind the antibody so when their pathology is not able to do this or they have not convincing results or doesn't fit they some suddenly say okay that's an kappa light chain amyloid doses but you have lamna light chains in the serum then you have to discuss with pathology that this cannot be the right typing then usually mespectometry is the right way to do and mespectometry um we don't do that at columbia i'm sure you know that yeah we send that usually to meo clinic meo clinic is excellent they have an enormous kind of an amount of samples and experience so what we do we send the samples the biopsy samples to the meo clinic and they um do a micro dissection of the amyloid this is a congruent staining so they cut out the amyloid tissue and then they do mespectometry so the sequence and according to the sequence they can say okay this is probably i g g lamna light chain multiple myeloma very elegant method and that really confirms you know i would say 99 or 100 percent you know that you have amyloid doses what about prognosis what determines the prognosis and amyloid doses it's um and it's the heart it's the heart and then hematologic response so we're a little bit lost you know so in multiple myeloma we can achieve responses and we can say you are doing well and amyloid dose unfortunately it really depends on the heart and then we come in with our treatment and then next it depends on the organ response and at last the numbers which are involved kind of how high the free light chains are and in contrast to multiple myeloma cytogenetic doesn't really play a big role in amyloid doses so we know that a lot of patients have translocation 1114 that open up new treatment opportunities we need to collect for instance a bcl2 inhibitor so interesting new drug also maybe for amyloid doses but you can see it differs from multiple myeloma um how did we came up with a response criteria which also differ from amyloid doses so shashi cumo did a very nice job and evaluated a couple hundred of patients for their risk factors and he found out that one of the risk factor is really the difference in the involved and uninvolved light chains so if the difference between kappa and glumna light chain is more than 18 you have a higher risk factor for my amyloid doses and a pro prognosis also and you see that goes back to the heart if the nt pro bnt that's a marker for the stress of the heart is over 1800 1800 or your troponin t is over 0.03 you have additional bed prognostic markers that give you a worse prognosis so based on this he established a prognostic scoring system you can see the difference in the free light chains more than 18 gives you one point troponin t more than 0.025 another point nt pro bmp more than 1800 another point you can get three points three points bring you in stage four and stage four has really a grim prognosis you know this is our kind of you know patient population this is stage four there's a median oval survival of 5.8 months that really beats multiple myeloma so if the patients come late stage horrible prognosis and that slide tells you the responsibility you as a physician or vs physicians really have you know it's really important especially when you see patients with amgas think about amyloidosis because when you have a patient and you diagnose a patient earlier you can see stage one the median oval survival 94.1 months there they're sometimes cured if they come right away they have a low amp spike sorry a low difference in the free light chains they have limited organ involvement we give an autologous stem cell transplant they don't even see a lot of chemotherapy they go in complete remission and they are cured i have patients who are cured that's what i think but 10 years in a complete remission without any amyloid symptoms that's really i would say kind of you know a huge progress we have criteria for the response assessment in light chain amyloidosis which differ a little bit from multiple myeloma you can see complete remission is always easy negative serum and urinary immunofixation with a normal free light chain ratio a vgpr in contrast to multiple myeloma is when the difference between involved and uninvolved light chains is less than four or 40 milligram per liter so that's i would say is a main difference otherwise in amyloidosis we also measure when i say amyloidosis sorry i talk about al amyloidosis just to make sure so in al amyloidosis we also measure the organ response and i think what is most important is to measure the cardiac response and progression usually we use the anti-pro BNP and the troponyl tea here's some kind of you know decreased by 30 33 percent a kind of you know determines organ response yes there's a disconnect between the immunological response and in the organ response and improvement so what is not just advanced stage i mean what do we think of this disconnect yeah there can be a total disconnect because you have to um what i want to emphasize is the hematologic response we can achieve pretty fast many patients go into complete response after transplant but the organ response needs more time the body needs to be able or the body has to break down the amyloid and that takes up to one or two years and usually it's a race when we start the amyloid treatment we want to bring down the light chain as soon as possible but patients can in the meantime undergo organ failure so there's a point of no return for your heart or for your kidneys usually for the heart so we have patients who die from amyloidosis in complete remission yeah so this is more the amount of damage that is already there that is difficult to return that yeah see when you when the structure of the heart is so damaged you know if between the myocytes are so much amyloid you know you cannot reverse this so and that's a big problem and the other problem is the longer you wait and the more organ damage you have the kind of you know the less treatment options you have you cannot do a stem cell transplant you cannot really be aggressive with your steroids 40 milligrams of dex is almost impossible in patients with advanced heart failure so that's why I think early treatment is really key I had an argument with a young kind of you know amyloid patient she was 74 she had her stem cells harvested she was after cyborgy in a complete remission and what should we do should we give her a stem cell or not so we called everybody you know we called the Mayo Clinic Comenzo everybody said give her a transplant she is in good shape give her a transplant that's the best option make sure that you eradicate the disease if the disease comes back I mean she was very sick you know before couldn't tolerate the transplant got chemotherapy got better what do we do you really want to eradicate the disease in order to avoid that the disease is coming back and I would say amyloid is an ugly M-gas and in contrast to multiple myeloma we treat in kind of you know the M-gas because we know if we wait it can really result in a very devastating disease damaging the organ damage maybe we use our kind of you know this from myeloma later and say you know you have to treat the disease early yeah if you go kind of you know really to the kind of you know genetics you will see that the certain certain genetic markers or certain kind of you know variants and the light chains kind of you know have a predisposition to to the organs but that's not ready for prime time it's not that we say okay you have this light chain abnormality you will have you know heart amyloid doses you know that's there some some work how much time do I have but but the tragedy that happens and is that you know somebody gets identified as having a myeloma whether it's molding myeloma or an amyloid or whatever and that the decision is made I'm going to watch this there's no clinical justification so it's that patient who who is is most important to to evaluate for evidence I mean we get those patients all the time they've been watched for 10 years and now they're finally getting symptomatic from from their amyloid and and if we had looked five years earlier or 10 years earlier we could have saved their lives I have patients who had only protein urea, kidney biopsy, amyloid doses so we we we check the free light the free light chains were normal so we did the bone marrow the bone marrow had 3% monoclonal plasma cells we gave the patient a transplant the patient is kind of you know you can see after two years that protein urea goes down and the patients are doing but I mean it's very nice to treat those patients you know when they recover as an organ function they're cured yeah but that brings me kind of you know when do we start treatment thank you for the nice kind of you know transition to my next topic so usually patients present when they have symptoms you know that's that's the problem of amyloid doses what we have doesn't matter which organ is involved if you have a patient and you do a fat pet biopsy and you determine amyloid doses you know usually then we start treatment and we don't wait before they have really organ failure you also treat localized forms of amyloid doses if they kind of you know really have only we'd only treat them and they really have symptoms like I had a patient who couldn't sit anymore because he had big bugs of amyloid and was not able to sit in those cases we treat localized amyloid doses otherwise if it is in the tracheobronchial tract or cutaneous lesions we just wait and watch so we do nothing with this clinical trials I think that's important try to put the patients on clinical trials and we discussed goals of therapy again deep hematologic response and durable hematologic response rates that can result in organ response keep in mind the all the reverse or the breakdown of the amyloid takes one to two years so even if you're in a complete hematologic response it takes one to two years before you have organ response and you only get organ response when you stop the further build up of the amyloid that means no light chains no abnormal light chains that's a challenge for all doctors who treat amyloid doses you need to kind of induce a complete remission but you are very limited by the physical ability of the patients to tolerate transplant treatment options good old melphalan is still an option for amyloid doses believe it or not patients who are really not in good shape very often tolerate melphalan very well I don't use it very often but officially it's a treatment option cyber D usually we start most of our patients on cyber D otologous stem cell transplant if you have any doubt that transplant is not really kind of you know the key player and multiple myeloma I think an amyloid dose is a key player so what we do is very often if patients do not have a lot of or not a high amount of tumor burden only few free light chains we take them to transplant right away I don't know how you do this we don't give any induction we say right now you are able to tolerate the transplant I don't mess around with any cyber D maybe you have side effects maybe you're not able to tolerate the transplant in four months I don't know what will happen with your heart we start the transplant right away heart transplant we do heart transplants not at columbia we send them to mgh usually but in selected cases patients who are younger first the heart transplant and then the otologous stem cell transplant monoclonal antibodies I will talk about that here's some data from proteasone inhibitors you can see cyber D it was a very small trial but I think it's pretty well tolerated it has a nice response rate in amyloid doses so in patients who cannot undergo transplant right away I usually start with cyber D transplantation that's a nice work from mori girls who evaluated 400 patients for the outcome in this cardiac amyloid doses and you can see patients with a limited cardiac stage have an excellent outcome he estimated the transplant related mortality was around 10 percent I think that's a little bit high we don't see 10 percent but maybe we are more selective it really depends on the center when you actually ask him that he says that the that 10 percent transplant related mortality is the same whether they transplant them or not so it's just that the mortality rate is higher but I think 10 percent is high oh what do you think transplant related mortality studies are like in the five percent range but we're more risk-adapted decision making so they're culling out the bad hearts based on what you're showing exactly that's that's really key you know that you but that's the point that I want to make is that they're they're saying we don't want to do transplants on those higher risk patients because the transplant related mortality is so high but it is it is no higher than if you choose not to do the transplant you exactly you can argue you know the patient kind of disease either way right right right that's true so but based on his work he came up on the evaluation of those 400 patients he came up with some criteria that he would not recommend transplantation with an nt probian p above 5000 troponin t if it is above 0.06 also there are certain age limitations I don't agree with a serum creatinine you know I would kind of you know also transplant patients with a higher serum creatinine be careful if more than three organs are involved I think that's important then patients are very often very disappointed when you tell them you know transplant eligible that I tell the patients you know only the minority of amyloid patients are really transplant eligible but but but again the you know you have to understand where he's doing his work and why is it so they're at the male clinic none of their patients are their patients they're coming in from outside and so when they transplant them and they they have mortality you know it's it's a better reputation if you yeah you said the patient at the patient coming back here the reality of it is is that the transplant itself probably isn't contributing as significantly to the mortality rate as you might think it was where you're where you're doing all the care so that for six months of care is all in your hands whereas in the male clinic it's it's either transplant over a home so they don't see the mortality rate so I think that a lot of that kind of data I think I think what we have to keep in mind when he shows the data this is for all hematologist oncologist for all transplant centers and it makes a huge difference whether you transplant one amyloid patient a year or whether you transplant 20 so I think you know centers like kind of you know your center our center are much more generous and really kind accepting patients but when you give a recommendation who to transplant to somebody who doesn't see a lot of amyloid patients I think you have to be a little bit more careful and that's why he kind of you know gives those data so that gives us a little bit newly diagnosed amyloid doses like multiple myeloma we decide first transplant eligible or transplant ineligible if the patient is transplant eligible very often goes right away to transplant if there is the goal is you know at least to achieve a vgpr then we go on observation if there is no hematologic vgpr then the patient needs more chemotherapy in order to bring him to a better remission yeah that's so officially under the amyloid experts there is no role for maintenance in amyloid doses I have patients I put on maintenance I shouldn't say that officially but I have patients who had really kind of you know advanced cardiac amyloid doses were able to I brought them kind of you know through transplant and they still have an M spike should I give them a second transplant should I kind of you know I give induct I give a consolidation with two cycles still there is some disease left I give them maintenance I have to say you know I don't do that on all patients I know you don't believe in maintenance there's again I do that in order to kind of in a void further progression and more organ damage but officially there's no role for maintenance in myeloma I know but it would make sense given the mechanisms are warm the deeper the response from the clinical response but if you a lot of these patients go into a complete hemorrhagic response yeah they probably don't need yes because they don't make their their tumor burden is not high it's because of tissue deposition so they don't need a lot more therapy besides the mouth line because we've eradicated the clone which is small and they probably can get by you know she may have some patients that if they still have something left you could argue for potentially doing consolidation but the majority of these patients did very good hemorrhagic responses yeah we all know that any disease in a completely medical response has a lot of a gynecology right and it's hard to measure the MRD but but it would free free like genes are relatively sensitive okay and so we do pick these up yeah yeah yeah all righty so but there's we talked a lot about chemotherapy but we still have the urgent need to improve organ response and that brings me to my next topic you can see we are able and we discussed it to eradicate the plasma cell clone but we still have the tissue damage you know and that is the question what we discussed you know what can we do to really improve the organ damage or head to break down the amyloid and the idea occurred I would say already 30 years ago as Alan Solomon University of Tennessee in Knoxville had the idea to really create monoclonal antibodies that target not free light chains which are circulating and you produce all the time but only to target light chains that are misfolded and kind of you know to target the amyloid directly so and what he developed he developed a monoclonal antibody 11-1-4 based on a urine of a patient he collected the urine for three days was able to extract the protein out of the urine it was a bench light chain amyloidosis and immunized mice and was able to develop that antibody and the specificity of that antibody is when you have light chains you know this is a native confirmation and when they undergo fibrologenesis they form a new epitope as you can see here in B you know this is not a kind of you know present in the native state but when they form fibroids you see the new epitope and the antibody binds to that new epitope shown here in B so it's very specific for amyloidosis so what he did is he implanted amyloid pieces subcutaneously into mice labeled the antibody with iodine and did a mouse pet CT and I think that's very elegant as you can see here the 11-1-4 antibody binds to the amyloid pieces and glids up in the pet CT he also showed in mice that he was able to shrink with the antibody the amyloid pieces so very he was very excited about that and said okay that's the first time that the antibody might bind to the amyloid directly and helps to break it down he wanted to do a clinical trial at this time point I mean I'm talking about drug development that's probably 20 years ago but at that time point the FDA came and said now you're not allowed to use your antibody in human you first have to show that it's binding to amyloid you have to do a clinical trial and show that 11-1-4 really goes to the organ of the patients so again he labeled the antibody similar to the mice studies with iodine injected the patients with that antibody and did a pet CT and the result you can see here very nicely he could show that the amyloid antibody the 11-1-4 binds to organ which have amyloid deposition here a patient with alumna amyloid doses you know it goes to the liver but also to the bone marrow he also did a biopsy of the liver to make sure that the antibody is really present in the tissue and this is you have to believe me the yellow dots are congo red positive and the 11-1-4 was found in the liver so that was approved that the antibody is really binding to the amyloid infiltrated organs that's another patient you can see here this is the congo red staining of the biopsy out of the liver this is the pet CT so that was very exciting and he was also able to use his antibody not only as a diagnostic tool but also as a marker for response so he did for instance 11-1-4 imaging of a patient with amyloid doses you see here the liver 2009 three years later there was a substantially decrease of the amount of the intensity of the uptake so based on that he wanted to start a clinical trial to use it antibody for the treatment of amyloid doses to break down the amyloid in the organs the FDA gave him finally the okay but at that time he was 80 years old and said you know i'm too old to do this i give it to susanne and to columbia so we started the clinical trial with support from the FDA and nci nci produced the antibody i mean it's a huge huge ordeal to do such a trial you need the drug under gmp conditions produced you need quality assessment stable stability assessments so it's a lot of work sometimes i spend kind of you know 80 percent of my time to do this study objective first was just to do kind of you know to establish a maximum tolerated dosage but also we wanted to see whether there's any organ or any evidence of organ response key eligibility criteria we were pretty generous with our criteria good performance status but you can see patients should have you know a decent ejection fraction and creatinine clearance this was our study treatment plan for the phase one we only gave the drug one time it was a first in human study so we were very careful we started with an extremely low dosage 0.5 milligram per meter square we went up to 500 that's in the rituximab kind of range um but again due to the fact that was first in human study we really wanted to know you know what's what's the side effects of the study so the safety summary it was very very tolerated i have to say we we barely saw side effects um the biggest concern we had was if you have heart amyloid doses and you give the antibody and the antibody breaks down the amyloid will you completely destroy the structure of the heart and will you undergo heart failure um we didn't see this so that was i would say kind of in a big relief for us but nevertheless that was the biggest concern i want to mention one patient really had a grade three for a rash um and i will show you later that patient um but in general we saw patients responding very nicely uh there's a dramatic response especially this patient you know there's an anti pro bnp um this patient um was a patient who had the rash this is his anti pro bnp he started around 9 000 um and was doing excellent this was the response after the phase one treatment only one treatment you also put him on the phase two part of the treatment and yet another response so he developed unfortunately around i would say a week after we gave him the medication a full body rash and we didn't know what what what is that rash we were not aware that the patient had skin amyloid dose and what happened in this patient is that the antibody infiltrated the skin bind bound to the amyloid as you can see here that's kind of you know uh apple green positivity and we were also able to see um the special staining's the antibody around the amyloid so that was really a good example that the antibody binds to the amyloid and induced um a local inflammation a rash that took a couple of weeks before the rash subsided probably the antibody also takes a couple of weeks before you really excrete the antibody but the patient had a dramatic response i have to say uh his anti pro bnp went down from around 10 000 to 3000 uh he was almost bed ridden with anasaka but had another adverse event playing lacrosse versus grand daughter after he finished the trial so that was a very nice adverse event i never kind of you know was happy about you know a fracture of the pelvis um organ response uh around 60 of that phase one trial had an organ response and we are almost close to finish the phase two the phase one b trial um which is listed here the phase one b trial kind of you know includes treatment four times weekly uh we will present the data at ash this year and we have even higher response rates in the phase one b was around 80 percent so in conclusion anybody is well tolerated we were able to establish the maximum tolerated doses without dlt we saw organ response and kappa and plumber patients in both types of amyloidosis again phase b is ongoing um i hope you know i really hope that we can use that antibody not only as a treatment tool but also as a diagnostic tool that would be really great to just label it and do a pet ct and see which organs are involved uh we are missing funding from industry from from the fta but hopefully kind of if we have that soon uh we are planning a phase two trial a smoke phase two trial visit antibody but we are not alone other researchers had the same idea i want to mention the new d zero zero one it's the same principle the antibody binds conformational change in the structure of the amyloid they also presented their data they have a nice response around 60 of the patients have organ improvement under this trial they're planning or the ongoing is a phase three vital trial for newly diagnosed amyloid patients and we are very excited about this um and that brings me to my last slide already i think i'm over the time um when you treat amyloidosis or you think about amyloidosis i think we should try to treat all the patients in clinical trials it's a rare disease and i think it's important to collect the data be certain of the diagnosis um going back in columbia i have a couple of patients before my time who were transplanted with ttr amyloidosis with a senile amyloidosis that's nonsense nothing to do with plasma cell dyscrasia so i think that's really important uh make the diagnosis as soon as possible because it has important implications uh i mentioned the response criteria many good therapeutic options but again clinical trials are the best uh future outlook i think in the future we will use monoclonal antibodies in parallel monoclonal antibodies against the amyloid in parallel there's a treatment probably like right like we use right toxin for lymphoma i'm pretty sure that this will come there is some fine tuning um i want to acknowledge nci you know for their funding especially solomon who is the father of everything and i kind of you know have this from angela dispensary i think that reflects all what we have in amyloidosis


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One week after Kentucky Governor Andy Beshear enlisted the National Guard to aid in the fight against COVID-19, Pikeville Medical Center held a press conference to welcome those soldiers on Monday. You know, knowing that the Kentucky National Guard was able to respond and to help us in a time of crisis. And that's what we're in is a time of crisis, having professionals soldiers on the ground here helping us battle this pandemic. And that's what it is. It's a battle. Today fighting for their lives in our ICU. Since July, PMC, as well as the state, has seen an increase in positive cases. CEO Donovan Blackburn says that increase is being felt. I mentioned earlier yesterday we were at 82 COVID patients in the hospital. That is one off from our peak all of last year. Our high was 83, so it took us two months to get to 82 patients to where it took us about four and a half months to get to 83 patients. So this surge is overwhelming and we're doing it with less people, less employees. Here at Pikeville Medical Center's Heart and Vascular Institute, we have assembled a comprehensive team of cardiac specialists bringing expertise from all regions of the nation and the world. We have coupled that with cutting edge technology, providing them the best equipment and operating rooms available. The result is comprehensive cardiac care for the people of our region that is second to none. The Heart and Vascular Institute at Pikeville Medical Center. With 30 soldiers assisting the hospital, we spoke with COVID response officer, Captain Kirby Schwear, about their roles and duties. We're going to be doing three primary jobs out of six departments. The primary jobs, they're all non-clinical. They're going to be helping transportation of patients. We're going to be helping with janitorial duties and then we're going to be helping with traffic control, although all of those are non-medical jobs. The key is that by us doing that, it enables the actual clinical staff to do the life-saving work that right now, their hands are tied, they're busy doing all that other stuff. The National Guard is expected to help out the hospital for three weeks. For Mountain Top News, I'm Joel Chorjol.