
Every year, approximately 795,000 people in the United States have a stroke, killing 140,000 Americans and causing reduced mobility for over half of stroke patients over 65 [1] . Strokes can be caused by either a blockage (ischemic stroke, ~87 percent of strokes) or a burst or leaky blood vessel (hemorrhagic stroke). From the time of stroke to the point at which patients are admitted to the hospital, the brain is starved of oxygen and neurons, without a supply of blood, die. In 1996, a therapeutic, tissue Plasminogen Activator (tPA †), was approved by the Food & Drug Administration (FDA) after it was demonstrated that intravenous tPA (IV tPA) effectively dissolves clots, which cause blockage and ischemic stroke, and reduces brain damage in patients, improving their recovery. Currently, our healthcare system is designed to get the hospital to the patient as quickly as possible so that they can receive IV tPA within 3 hours, and if they do, their wellbeing may be preserved. But one Yale faculty member is trying to change that paradigm and bring the patient to the hospital with a patient-centered and -independent, rather than a hospital centered, technology.

Medicine, in Socrates' view, is a cooperative art, i.e., an art that helps a natural result come about and Kevin Sheth, M.D., has in contemporary medicine, found a way to practice the art beneficially and uncommonly, by connecting developments in Silicon Valley to the clinic in order to help a proven solution come about [2] . Dr. Sheth is the founder of Alva Health, a company which uses smartphone and wearable technology to detect stroke symptoms and quickly connect acute neurological injury patients with the healthcare system, especially those patients who might be incapacitated, disabled, or unable to get help. Kevin Sheth is also an Associate Professor of Neurology and of Neurosurgery at the Yale School of
Medicine (YSM). He is the Associate Chair for Clinical
Research in the Department of Neurology, the Division Chief of Neurocritical Care and Emergency Neurology, and the Director of the Neuroscience Intensive Care Unit (ICU) at YSM. Dr. Sheth's research investigates the causes and mechanisms of inflammation and swelling after acute central nervous system injury and his work seeks to identify and develop new therapies for patients with acute neurological injury (stroke, brain hemorrhage, and trauma). Dr. Sheth is the author of over 140 publications and is the recipient of numerous awards, including the Derek Denny-Brown Young Neurological Scholar Award, the Stroke Care in Emergency Medicine Award, the Family Centered Care Innovation Award, and the Robert G. Siekert Stroke Investigator Award. Kevin Sheth, perhaps, can best be described as a contemporary artist in the Augustinian view, namely, as an individual who transforms matter into works of reason, though in the modern vernacular, he is a physician-scientist-entrepreneur.
Medicine (YSM). He is the Associate Chair for Clinical
I became particularly interested with Dr. Sheth's work because, as a distinguished academic physician, I thought he had an extraordinary ability and the potential to solve, substantively, the glaring lack of usefulness, with respect to our wellbeing, of Silicon Valley tech. And indeed, he is doing so. People interact with the environment, the culture, the economy, and with technology and Dr. Sheth seems to have an unusually firm grasp of all of these interactions. Observantly, he has exploited the way in which we interact with technology every day and capitalized on its potential to improve our quality of life. It takes a unique and, dare I say it, innovative individual to make such a connection and to do so thoroughly and meaningfully. In order to get a sense of his career trajectory and the promising impact of his technology on neurological care, I interviewed Dr. Sheth. Our discussion, edited for clarity, is reproduced here. In addition to excellent insight about clinical practice and research in acute neurological care, he also provides nuanced career advice for young researchers. As personally inspiring as he has been, I hope you will find that his framing of an important problem in neurology stimulates your own ideas and furthermore, I hope you find, as I do, that his comments motivate you to continue working on bringing your own ideas into the clinic.
Why is time such an important consideration in treating patients with acute brain injury?
A common thread in neurocritical care is time-sensitive diseases. Consider stroke, for example, as the prototype, although some of this is true for head trauma, spinal cord injury, and a lot of other different neurological diseases. When a patient has a stroke, with every passing minute, more neurons die. With time, there is more brain injury: time and brain injury correlates with clinical outcomes. So, truly, "time is brain." Starting in 1996, you started to have therapies which were proven, undisputedly, to be effective for clinical outcomes. tPA 1 and revascularization of a blood clot was one of them and, in recent years, endovascular clot retrieval, that is, going in and mechanically removing the blood clot from the patient and restoring the bloodflow…these therapies improve clinical outcomes but they do so in time sensitive ways. So, people talk about therapeutic time windows. What that means is that it is not a binary calculus: it's not "getting the therapy" or "not getting the therapy." Instead, it's about getting it earlier and that is better. So, time is very important.
Why is time such an important consideration in treating patients with acute brain injury?
What does tPA's therapeutic time window have to do with patient outcomes after stroke?
Why is time such an important consideration in treating patients with acute brain injury?
Stroke is kind of tricky because in most illnesses, you have pain as part of the presenting symptom. For example, even a cough is painful. Stroke is not like that-it's one of the few things where you can have language disturbance or a motor deficit and not have any pain. And it turns out that pain is a pretty powerful motivator of seeking help. The second thing that's tricky about stroke is that, by virtue of disability, oftentimes, you can't get help even if you've recognized that you need it. The reason that this is important is that people might think that their arm is falling asleep and think, "it's not painful, my arm is just falling asleep," and then they realize, five hours later, that their arm is actually not working, and they need to go and get some help. But now, they're out of the therapeutic time window or later in the time window. Yet another problem is that patients can be disabled-they might have a stroke and fall down. Then, they can't get up or call 911 so they can't get help. This is a problem, especially with time-sensitive therapies.
Why is time such an important consideration in treating patients with acute brain injury?
Why do so many ischemic stroke patients have poor outcomes after having a stroke?
Why is time such an important consideration in treating patients with acute brain injury?
Even in recent years, more than 20 years after FDA approval, only 5 to 10 percent of patients that are eligible for intravenous tPA (IV tPA) actually get it. That's unbelievable. Despite massive public health campaigns for educational awareness of stroke, which has been largely ineffective, few ischemic stroke patients receive the available therapy.
What is the current strategy to improve treatment for ischemic stroke patients?
What the medical system has done is to reorganize itself to get the hospital closer to the patient. This is why you have tele-medicine, which connects neurologists to emergency room providers around the state, around the region ... and this happens in every major health system: to try to cut into that time between the stroke and imaging to make the diagnosis of ischemic, and not hemorrhagic, stroke. You even have this sort of very exciting thing that's happening in the entrepreneurial landscape about putting CT scanners in ambulances. This is now happening in Europe and several health systems around the U.S. And the simple idea is that, if you're going to give a blood thinner to someone who has a stroke, the one diagnostic test you need is a picture of the brain to rule out a brain hemorrhage. You rule that out, you can give a blood thinner, (e.g., IV tPA), and you go forward. But that's a rate-limiting step. So the strategy is to try to cut down the time. In all of these things, it's the medical system going towards the patient.
How did you come up with the idea to bring the technology, that surrounds us every day, into the clinic to improve acute neurology injury outcomes?
Well, one of the ideas that I had during residency and fellowship, and actually anybody could have had these ideas, really, but I thought that, if you were to design the system from scratch, what you would do is flip the whole thing on its head and start with the patient-start when the stroke happens, in that moment, and not after the stroke. The challenge is that you need a system that is patient-centered-that starts at the patient but doesn't depend on the patient because they may (1) not recognize that they need help or (2) they might be disabled. That was the fundamental tenet. Then I started to think about how you could do that? I started thinking about what happens, clinically-speaking, in those initial seconds and minutes. I started thinking about the disability that you have-motor disability, language disability-and I began to realize that, actually, we already have technology around us that can pick these symptoms up. And part of this genesis was timing-when I was training, everybody wasn't walking around with a Fitbit. That has changed now: we all have accelerometers and gyroscopes all over us, all day. Every week now, you see something new happening with wearable technology. So, you could imagine, very quickly, how you might attack this problem. And, indeed, it became an engineering problem about false positives and false negatives and what you would try to detect-facial weakness, language disturbances, motor disability-what sensors would you employ-how would you do this. The therapeutic time window problem became an engineering and practical problem very quickly.
How did you come up with the idea to bring the technology, that surrounds us every day, into the clinic to improve acute neurology injury outcomes?
After framing patient-treatment within the therapeutic time window as an engineering problem, when did you start to crack it and find a solution?
How did you come up with the idea to bring the technology, that surrounds us every day, into the clinic to improve acute neurology injury outcomes?
So, we've been kicking around this idea for years and then, when I started at Yale, I teamed up with neuroengineers and people at the Yale School of Management and others and we started asking, "what's the best way to further develop this?" We started, basically, just doing ewilson@example.com. Developing our own prototypes, thinking about how to clinically solve the problem and how to collect data. Early on, it still involved proof-of-concept development. And some of the early questions we had centered around "well, if this works, how will you push and develop this forward? Are you going to write about it? Are you going to get grants? Are you going to present it to the stroke community? What are your goals?" And I would say, actually, we started doing, and still are doing, all of those things. We're still in an academic environment and the dissemination of knowledge is important, peer-review is important, acceptance of the community is important and doing all of those things helps. But what we recognized was that the world is moving fast, and there is a pressing need for our technology. We recognized that we may be able to push this forward, in the most compelling way, not through the traditional academic route but through commercializing it. We had a lot of discussions about that and we got a lot of input about commercialization because have a stroke? That seems unfathomable! So, you really start to see all these settings in which Alva's technology could be valuable.
How did you come up with the idea to bring the technology, that surrounds us every day, into the clinic to improve acute neurology injury outcomes?
The technology that Alva is built around is, in a way, simple and accessible but, when I think about medical technology, the first thing I think about is something like the CT scanner or some sort of complicated device and I wonder if you think that neurology is at the developmental stage where the simplest technologies have the greatest potential, compared to more sophisticated technologies, to improve patient outcomes?
How did you come up with the idea to bring the technology, that surrounds us every day, into the clinic to improve acute neurology injury outcomes?
We think so … well, I think it's true and it's not true. It is true that if you have simple logic flows and logic arrows, that that's always better-don't make things over-complicated. So, in that sense, I think you're right. You don't have to have very fancy technology. We started working with off-the-shelf, available technology and you're absolutely right, that's the bottom line. On the other hand, what ends up happening, along with everything in science, is that once you peel back a layer of the onion, it turns out to get more complicated very quickly. So even with the things that we're working with, we've had to think about having, for example, the best miniaturized batteries that have a long shelf-life. Or, we've had to think about communicating with the cloud in a seamless way. We've had to think about making a product with a form factor for devices that patients would actually wear, connecting it to the medical health system and so on. So, it does get complicated quickly but technologies that can improve clinical outcomes can start off very simply and, in fact, the goal is to keep it as simple as possible at every step.
How did you develop an interest in neurology and neuroscience?
In college, I studied neuroscience and political science, and, at the time, it was the "Decade of the Brain" 2 so there was a lot of attention and effort, at a national level, to stimulate people to go into the neurosciences. That didn't really hit me initially; I took introductory psychology courses my first year because I thought that they would be fun. That was the segue-I discovered that the cellular and molecular aspects of psychology grabbed me more. At Johns Hopkins, they created a neuroscience major where you could take psychology courses but also courses in cellular and molecular biology. I ended up getting connected with, by chance, Solomon Snyder's lab at the 'commercializing' can mean a lot of different things. It can mean partnering with a company, it could mean developing our own technology, it could mean writing about it-all of those options were open to us as different ways to attack this problem. But basically, that was how Alva Health was born-it was about building the right team, asking the right questions, and keeping all of our options open for attacking this problem in the best way.
What is Alva Health all about? What is its goal?
The mission for Alva is to help Americans, especially older Americans, that are at high risk for stroke, to prevent disability from stroke, to help our patients live independently and to bring peace of mind to their families. Everybody has moms and dads that are at home or at work who have high blood pressure or diabetes or high cholesterol-who are all vulnerable and at high-risk for stroke and, yet, we have no way to get to them, to nail those first minutes and hours of stroke, make a diagnosis, and give these patients proven therapies that can maintain their quality of life. Around 800,000 Americans, every year, suffer from a stroke. That's a huge problem! So, we said, "we're going to try to attack this," and that's how Alva Health was born. Ultimately, the point of Alva is to diagnose stroke and acute brain injury in as close to real time as possible and, in doing so, improve outcomes. We're not trying to prove a new intervention. There's an intervention that already exists and is proven. The relationship between intervention and clinical outcomes is already established. We want to continue to build on that and to build on that in a way that the outcomes that are already established mean something to patients. As a result of the landscape that's already there-specifically, the cost-benefit to the broader US public, to individual health systems, and to insurers-it's very easily worked out. Our goal is to get patients to definitive, proven therapies, in as short a time as possible.
Who will Alva's technology help?
Well, you start to think that there are all kinds of situations for Alva's utility. There are people who are at highrisk for stroke, who are walking around-people who have atrial fibrillation, who have vascular risk factors, who have had a prior stroke but leave the hospital-and in some ways, you can think of them as a ticking time bomb every day. There are even people that go into cardiac surgery, who have a stroke-risk going into surgery and come out of surgery and, while they're on sedation, even though they're in some part of the hospital, have a stroke. They're in our grasp and we don't know the moment they If you're a lay person and you've never interacted with the medical system, that is weird. This is an opportunity because you constantly have to teach-your patients, your colleagues-and communicating that well, because it seems like those computers, that's fun! Also, there are clearly major problems at a public health level: aging populations suffer from Alzheimer's and neurodegenerative diseases and these are big problems, by any measure, and, along with stroke, there isn't a solution. Because there are not as many therapeutic options to offer, people were staying away from neurology and that is always an opportunity-to run in the opposite direction, or what felt like the opposite direction, which was to go into the neurosciences. It's fun, it's interesting, and if you communicate it well, you don't have to know that much to dig down. And particularly in acute neurology, you're often dealing with patients and families where things had been going well and then, there's a sudden catastrophic event.
Who will Alva's technology help?
That creates a premise to have a very intimate relationship with patients and families right away. That's pretty unique. There are few other areas in medicine where you have that.
Do you identify as a physician, a scientist, or an entrepreneur?
To be honest, in some ways, you're all of those things at any moment. The best docs, by the way, even the pure clinical physicians, they're constantly hypothesis testing at the bedside. So, I'd say that in some ways, whether they recognize it or not, they're scientists. Part of self-identifying is, and this is the entrepreneurial part: you're always pitching ideas. As a physician, you're always pitching ideas. As a scientist, you're constantly pitching ideas. So, I think a little bit, it depends how you present yourself.
What do you think it takes to be a successful researcher?
Something I say all the time to students, residents, fellows, and junior faculty is, what ends up happening is that you go through so many years of training and at the end of that training, you become an excellent physician. By the end of your residency or fellowship, you become comfortable taking care of anything in your area. You start to have more time to delve into research and at the same time you're starting to change where you are in your life. What often happens with research is that there are new uncertainties and new skills and you feel like you're back on the tricycle, while on the other hand there's this thing that you're an expert at. All of these things represent anxiety and then there's this other box of stuff, the clinical medicine, which you're a pro at and, well, what's human nature? To run toward things that are comfortable medical school. Solomon Snyder is one of the most influential neuroscientists of our time. Solomon's lab studies a lot of different things, but they are known for describing and identifying neurotransmitters and neurotransmitter receptors. One of the biggest discoveries made in the Snyder lab was identifying the opiate receptor. This was at the time when servicemen were coming back from the Vietnam War and having problems with heroin and addiction. Snyder's lab was a very exciting environment to work in. I went on to medical school at the University of Pennsylvania but throughout medical school, I did not think that I would go into neuroscience. It's one of these things that becomes a self-fulfilling prophecy-I did something by chance and then, when I was exposed to neuroscience modules in clinical rotations, perhaps because I already knew a little bit about it and found it interesting, I gravitated toward neurology more and more. Whenever neuroscience came up in my clinical rotations, I would be more interested. That told me something.
Do you think neurology is still a propitious field for young researchers?
Something funny happens with neuroscience-it's kind of like computers for older people. If you try to explain to your grandmother how to send an email, it can be complicated but younger generations know it's so easy-you don't even have to know how the computer works. Neuroscience and neurology are the same waybecause of the details and the anatomy and the confusing ways in which neuroscience is taught, what happens for a lot of people is that they see all these wires and diagrams and it's just too much-it is like those computers-and instantly you turn off and start getting a migraine. I found that was true in medical school and it is true in clinical practice. I know colleagues, in other areas of medicine, who are smarter than I am but when they hear neurology, they turn off because it sounds just like those confusing computers. What's nice about that is it's an opportunity, if you happen to understand neuroscience, because you don't need to know all of the details to make a big impact in neuroscience research. When I was a resident, people were going away from neurology even though it is clearly fascinating, I mean, what's more fascinating than the brain? For me, thinking about having patients, that you take care of every day, and the important problems they face, that are often times devastating, and the fact that there is very little to nothing to offer them tells me that if you could make a small dent, it'd be a big relative change.
What do you find interesting about clinical practice in neurology?
To patients, neurological illnesses are weird, they're mysterious-why is one side of your body not working? I've found that having, without any formal training, a lot of exposure, through my family and having a business perspective has helped me a lot in academia.
Do you have an over-arching goal in your work as a physician-scientist-entrepreneur?
What I would say is that, ultimately, all of these things that are very prestigious in academics, for example NIH grants, publications in high impact journals … all of those things are good but imperfect markers of great science and true contributions. There are things that are published in Science and Nature and the New England Journal of Medicine which never hit clinical practice. What I recognized or what I thought about was, personally, I wanted to focus on trying to make a difference over and over and over again. You always work from your goal backwards so if your goal is a NIH grant, you'll work to get the grant and work backwards from that but if your goal is to make a difference, the difficult question is, "how do I work backwards from that goal?" The way I looked at it is that you can look anywhere for opportunities and not just academia. You can work with industry partners, you can work with foundations, you can work with individuals, you can work with high school kids and college kids, or you can work with a successful collaborator and all of the above may work, in part, but you can't predict that. You can be open to any opportunity. I think that intersects with how we've approached our work-trying to go wherever the opportunity is.
What insight can you share with budding physician-scientist-entrepreneurs?
What I would say is that I think your question about technology having to be complicated is one of those anxiety things-it doesn't have to be exactly. What I do think is happening is that technology is becoming more and more available to the broader marketplace and to more and more people-we've seen that in a lot of different areas-but for a number of reasons, healthcare has always been tough to embed and incorporate. I would say that one of the rate-limiting steps is just people doing it and having good ideas, just like the rate-limiting step for people going into science and asking important questions. Some of the questions in our research programs, standing in front of us, require a measure of breaking the question down and attacking the problem. A lot of people get excited about a question but very few people actually attack an important problem and break it down step-bystep. One of the things that I think happens in academic medicine or in environments with young entrepreneurs is that we have structures in which we think that being young somehow is a rate-limiting step: that you can't do something because you haven't had the experience. And and away from the things that give you anxiety. What you have to actively do is spend energy to actively fight against that and reset where the pendulum is. That takes some deliberate thought, I find. People say, 'you should do what makes you happy' and you should but I'll tell you, doing those things in that moment will not make you happy. That will make you unhappy. Going to the lab and learning how to do PCRs … that does not make anyone happy. Learning how to do genome sequencing analysis, at the very beginning, that is not making anyone happy. You have to go through that anxiety, spend that energy, go through that brief period of unhappiness and then, like anything else, once you become a pro at it, you love it. You have to do the same thing with research to really give it a shot. What I find is that people escape right before they go through that wall.
Do you feel like you went through that wall?
I think that happened in a number of areas: thinking about how to really design clinical studies, how to answer a question in the best way possible, how to intersect that with being practical. I don't know if this is true for other people, but I had a lot of clinical projects along the way that went nowhere and that's frustrating, but I do think that going through several of those told me how to look for an attack for the next question. One of the lessons I learned, that's true for research and for business, is that doing things that are not important turn out to be really hard work, just like doing things that are important; so, if you can, don't do things that are not important! It becomes more about learning how to identify what's important. People want to do things that are impactful, that make a difference but it's hard to know what that means and how that's identified-your version of "impactful" can be different than your chair's or institution's version but you have to align these.
Do you feel like you went through that wall?
Have you always had an entrepreneurial mindset, or did you stumble upon the opportunity for commercialization as a researcher?
Do you feel like you went through that wall?
I went into Harvard's Brigham Women's Hospital and Massachusetts General Hospital Partners Neurology residency program where I did my neurology residency and later intensive-care neurology and vascular neurology and stroke. I found in that environment, as much as I was getting pulled into clinical research in neurology, I think by way of background, I probably wasn't a researcher-I came from a family where there were no physicians: everybody went into business in some way or another and so doing such training and research was not practical to me. I think my mindset had been about getting commerce to, somehow, be a part of my work.
Do you feel like you went through that wall?
I would actually say that the whole thing is a fabrication. There's actually no reason why, in clinical practice, a fellow can't be a better practitioner than I am. The game you should play is, there's no difference between me and somebody else. Our institutional structures impose a lot of vertical hierarchy, but people should throw it out of the window. I think students, medical students, residents, fellows and young junior faculty-anybody you can come up with-nobody has a monopoly on good ideas. You simply have to start pushing these ideas forward. I do think a big part of the game is learning how to do that respectfully and how to effectively build good teams. I've seen so many great ideas blow up at the beginning because people don't think about how to do build teams and collaborate in the best and broadest way possible. So, people should just start, actually. I've had medical students come to me with ideas and for advice and that's great but, I always think, "what's stopping people from attacking these things today?" Nothing.

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