Dr. Eric Topol (2:46)

That's right, Alan. If you're trying to just show that you can get humans to live longer, it takes a really long time to prove that because you've got to wait decades. Whereas if you're just trying to show that you can prevent diseases like cancer, neurodegenerative diseases, cardiovascular, the big three of our age related diseases, we have really good ways to show that those diseases are being suppressed. We have markers like biomarkers and scans and things to show that we're doing the job. So this is a, a more attainable goal as compared to saying, oh well, we got people to live past 100 or 110. It's possible, Alan, that there will be some way to do that to promote truly longevity in the future, but we're years away from that many years, if ever. And the other thing is there's not any truth to this concept that you live perfectly healthy till you're 110 and then you just fall off the cliff, you know? No, it turns out the longer you live, the more chances of these age related diseases showing up. That's why we've got to work as that as our principal target.

Alan Alda (4:03)

You have an interesting phrase that mirrors that. You want to shift from becoming elderly to staying on the welderly path.

Dr. Eric Topol (4:11)

Yeah. The welderly was a project that we embarked on, you know, more than 15 years ago. And at that time doing whole genome sequencing on a large cohort just wasn't possible. But we got together these 1400 people who we called the welderly because they were over age 85 and they'd never been sick with any chronic condition. So we wanted to see what was in their genes that made them welderly, like Teflon coated to get the diseases that everybody else does get.

Alan Alda (4:42)

A lot of people live by the joke. If you want to live a long time, choose old parents.

Dr. Eric Topol (4:47)

Yeah.

Alan Alda (4:48)

How much of healthy long living is attributed to the genome and how much do things like nutrition and exercise?

Dr. Eric Topol (4:57)

Yeah. This is, I think, one of the most important things that we've learned and that all the evidence backs it up, is that the genes are far less important than we had suspected. I mean, you always were taught, you know, as you said, Ellen, about good genes. And the main protagonist of the book, Mrs. LR, she's 98 and her relatives all died. Her brothers and sisters, parents, you know, when they were in their 50s and 60s. Why is she the only one left standing? It isn't genes, but it Is as you said, lifestyle factors. And they're not just diet, which is not just of course so simple. I mean it's also, you know, how much protein and what type of fats and avoidance of ultra processed foods and sugars and whatnot. Nutrition is a big part. Also sleep is much bigger than we had estimated in the past. It turns out it's the main way our brain during deep sleep gets rid of all these waste products. And you got to have this seven hours of sleep or else you're not going to have much deep sleep. So that's really important. And then you get to these other, besides physical activity. Vital, absolutely vital. You get to these other layers of data like environmental exposures, like air pollution, like microplastics. You get to things like social interactions and loneliness, isolation, nature. How much time do you spend in nature? Which is really a very important determinant as well. So there's all these other factors into this, what's, I call it Lifestyle plus because it's not just diet, exercise and sleep. There's lots of other layers of that data that make us more likely to avoid these age related diseases. So we have to give much more attention to the lifestyle factors than we've ever given before.

Alan Alda (7:00)

I never gave much thought to being outside rather than inside the house as a factor leading to my healthy old age. I have a not very commendable habit of going on a vacation to another country and spending most of the day in the hotel room.

Dr. Eric Topol (7:19)

Yeah, well, I think what we've learned is that time in nature is really important to maintain a healthy life and we don't do it enough. And so that's why we're talking about prescriptions for nature. So it's not even just being outdoors, it's just kind of listening and experiencing nature. It's revitalizing and something that we can't do enough of really.

Alan Alda (7:52)

Besides Lifestyle plus, what are some of the other factors that lead to this healthy outcome?

Dr. Eric Topol (7:59)

Yeah, well, we do a lot of dumb things right now. So one of those is how we screen for cancer. So we do it because you're 50 or older, which is really dumb because not only does that miss for cancer, some of the younger people now that are showing up more than ever, but even more importantly, we're putting these people who have no risk for cancer or that it's infinitesimal. Take for example breast cancer in women. Only 11 or 12% of women will ever have breast cancer in their lifetime. But we put at least recommend that women have frequent mammograms which are very high false positives, especially because so many women will never have breast cancer. It's a recipe for, for false positive. And it puts so much more burden on these women having more scans and more and biopsies, sometimes unnecessary surgeries. And that's just one example. The same holds true for all the screening that we do, whether it's for colon cancer or PSA for prostate cancer. We don't look at the high risk people.

Alan Alda (9:10)

How do you identify the high risk people?

Dr. Eric Topol (9:12)

Yeah, so that's what's really exciting, this idea of this full stack of data, layers of data. So, for example, if I wanted to know your risk for cancer, Alan, I would not only have your gene risk, so called polygenic risk, which is now very well validated, but I'd have all these other layers of data and one of the most exciting ones is called organ clocks. So basically it's kind of like if you took your car in for a checkup and it checked all the different parts. Well, now we can do that with plasma proteins, 11,000 plasma proteins in a sample of blood, and say it's your kidney, it's your heart, or to your brain or your immune system, or in fact, none of these are aging at an accelerated rate. But the point is we can pinpoint a person's risk, how high it is, when it is, what organ is involved. We didn't have this capability before, but the biggest jump is the organ clocks because it really zooms in on what is going to be the issue for any individual person someday in the future we'll be getting organ clock assessment probably every year, every couple of years, that's going to find out the high risk in addition to all these other layers of data, like for example, you don't do any physical activity, you don't have good nutrition. Obviously the genes are important. And also another layer of data we don't incorporate today is our gut microbiome, which is a hidden treasure chest of information about us. And it interacts with every disease that we could get, but particularly the big three that I, that I mentioned. And so what we're going to see in the future, which is exciting and it's just getting started now, are these pro and prebiotics and other ways to manipulate the gut microbiome. Not just because we want to get one bacteria present more than another or a metabolite in our gut, but rather to keep our immune system intact. This is a, we might even see genome editing of our gut immune system. So this is one of the new frontiers that Adds to the other layers of our capabilities. It's really quite exciting for the future.

Alan Alda (11:42)

You mentioned blood, checking the blood. You reminded me of the idea that young blood is supposed to affect the aging of organs. That's a scary idea to me. Am I wrong to be scared? Because if you take somebody else's blood, it might be nice that it's young, but it might have stuff in it I don't want in my body.

Dr. Eric Topol (12:01)

Yeah, well, that hasn't stopped some clinics out here in California that are transfusing young plasma into older people at a ridiculous cost. And as you say, some risk. The interesting thing about that, Alan, is that in all these experiments, particularly these are animal experiments, when you do this, you see the youthful effects of the younger plasma, or in fact even the younger gut microbiome into the older organism. The problem is we don't know what's in, what's the magic factor. There's like several have been nominated. Well, it must be platelet factor 4 or it must be Clotho or it must be, we don't know. And before we start ever doing this, transfusing young into old in people, we have to really first point out, as you did, it's safe, which we don't know for sure. And secondly, to figure out what it is so we don't have to give a person's whole plasma. We can just say, okay, we're going to give you an infusion of this or that. So we have to get smarter on that. That has some promise, but it's too fuzzy right now as to what accounts for this potential benefit.

Alan Alda (13:27)

What do you think are the most beneficial approaches that we're taking? For instance, work on senescent cells. I'm a little confused about the whole, whole idea of senescent cells because I had to look it up. And when I looked it up, it said that senescent cells are useful in healing.

Dr. Eric Topol (13:45)

Yeah, that's another hot area. Like this idea of the young to the old. So the problem with the senescent cells is that this is a normal age related process, that our cells become senescent. And there's a protective aspect of that. When a cell becomes so called senescent, it doesn't mean that it just became old, it means that it now no longer can divide. So it protects us against cancer. Now the idea of these senolytic drugs that you would take to just take out your senescent cells so you would get rid of them, eliminate them. We're not smart enough to know which of the senescent Cells we should take out. So we can't take out all of them because some of them are doing good things. The point is that there are some that are secreting bad things, proteins that are unhealthy, that are pro inflammation. And inflammation is one of the common themes across these age related diseases. You don't want too much of that because that accelerates these diseases.

Alan Alda (14:50)

I've been hearing this for years about inflammation. I don't think I understand what inflammation is. What's going on with inflammation?

Dr. Eric Topol (14:59)

Well, you know, what really is the basis for it is our immune system. And these cells, the various cells of neutrophils, white cells, and the subtypes like lymphocytes, they can secrete so called cytokines, chemokines. And what that does is it revs up our entire body's inflammatory process. So like think of it, if you bumped your knee and it got all inflamed, red and swollen. It started with these immune cells that were reacting to the injury and then you had this really swollen, painful red knee. Well, that's going on inside of us. And the problem with the senescent, the bad senescent cells is they're basically secreting the same kind of proteins like chemokines, cytokines that are revving up the inflammatory process. So if you already have a condition like you have a potential cancer lurking that could help promote the cancer's growth, or if you have atherosclerosis in your arteries, plaque, it could help increase the risk of that plaque having a crack or a rupture for a heart attack or a stroke. So we don't want too much inflammation. And of course it's a fine lie like Goldilocks. You know, you do need your ability to react with your immune system, but you also don't want it to overreact because that's when you get into trouble.

Alan Alda (16:29)

You mentioned in the book that there's been research on dogs with regard to senescence. Is that going to lead to benefits to humans?

Dr. Eric Topol (16:40)

Well, it might. And the reason of course, is we don't have to wait 80 years to see if their lifespan and health span has been extended. So in dogs, you know, that's compressed to let's say 12 or 13, 14 years. So on the one hand there are a lot now, some large studies to see about modulating the aging process in dogs. One of them just got the fda. Go ahead. Loyal Dogs is a company, but they have a pill which they haven't disclosed what's in the pill that they think is going to improve the health span and lifespan of dogs. But these dogs were only given the pill when they were getting older, and so we await the data from this company. But that's just one of several studies. And this is an intriguing idea because if you can prolong healthy aging in dogs, that may well be able to translate in people. So there are several shots on goal for our dogs. And it wouldn't just be something that will help our pets and how close we are with pets to have them around longer, which would be great, but it also may someday help people as well.

Alan Alda (18:11)

When we come back from our break, Eric Topol takes on the issue that's now alarming the whole biomedical community at the same time that the medical breakthroughs we've been discussing are poised to deliver research funding and research priorities are under attack. Just a reminder that Clear and Vivid is nonprofit, with everything after expenses going to the center for Communicating Science at Stony Brook University. Both the show and the center are dedicated to improving the way we connect with each other in all the ways it influenced our lives. You can help by becoming a patron of Clear and vivid@patreon.com at the highest tier, you can join a monthly chat with me and other patrons and and I'll even record a voicemail message for you. Either a polite, dignified message from me explaining your inability to come to the phone, or a slightly snarky one where I explain you have no interest in talking with anyone at the moment. I'm happy to report that the snarky one is by far more popular. If you'd like to help keep the conversation going about connecting and communicating, join us at patreon.com clearandvivid P-A-T-R-E-O-N.com clearandvivid and.

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Alan Alda (20:36)

This is clear and vivid. And now back to my conversation with Eric Topol. I asked him if the optimism for real advances in healthy aging that he expresses in his book Superagers has been tempered at all since he finished writing it.

Dr. Eric Topol (20:51)

Well, that's a really important point, is that, you know, we're at a kind of monumental time now because we've never really achieved this fantasy of primary prevention. And we have the new tools to do this as we've been discussing. But at the same time, we're confronted with an unprecedented attack on biomedical research as we're seeing through the nih, the National Science foundation, and public health agencies in general. Grants are frozen. There's a threat of being a very profound reduction in support. This is, of course, the jewel, the crown jewel of the world for biomedical research.

Alan Alda (21:37)

Does it have an immediate effect? I mean, for instance, would a trial be halted midstream?

Dr. Eric Topol (21:45)

Yes, I think we're gonna see that, which is really sad because the NIH supports many of these trials. For example, we are doing this, all of US that has 850,000 participants and that's now threatened to stop or to no longer enroll. So, yeah, I think the clinical trials that we need those to get proof. We're always looking for proof and validation, but we're not gonna have many of those if the funding is so constrained as what we're seeing is starting to come in right now.

Alan Alda (22:19)

I get the impression that the people who are stopping this flow of funds don't realize how hard it is, how much time it takes, or even if it's possible to get rolling again if they feel they've made a mistake and reinstate the funding.

Dr. Eric Topol (22:34)

That's right. It took from 2016 to now, actually 850,000 diverse participants, the largest in the U.S. the most ambitious research program we've ever launched in this country. But that is in jeopardy. But so many other projects are as well. You know, I think we all would agree. We want to be very efficient. We don't want the funds that support this research to have any waste in it. But there's also a way to do this intelligently, you know, and, you know, if there's going to be some cuts for biomedical research, let's do this in a way that makes sense, that is not just a across the board massive reduction that isn't being done with any real intelligence. That's sad.

Alan Alda (23:28)

And then there's not just research, there's the problem of vaccine hesitancy, which is now more than vaccine hesitancy, it's vaccine opposition.

Dr. Eric Topol (23:38)

Yes, absolutely. Hesitancy would be a nice term to ascribe. It's much worse. It's not just, of course, that we saw with COVID it's now rippling over with measles and all these other conditions. We talked about primary prevention of these age related diseases, but the best primary prevention we have in medicine today is vaccines. And they're going to get into, if we let this happen, we're going to see vaccines help prevent cancer, help treat cancer, help prevent neurodegenerative diseases and even cardiovascular. So their opportunities there are extraordinary to build on the successes. And so sad that we're going backwards with this opposition, as you said, to using vaccines for the things where we have the most data that's ever been assembled in the medical field.

Alan Alda (24:35)

We talk a lot about communication on this podcast. Is there any kind of communication improvement we can make to educate our culture about the value of vaccines, for instance? Just that alone.

Dr. Eric Topol (24:51)

Yeah. Well, you know, you're the master in my view of communication, communication across the board, no less, in science and medicine, and I probably should ask you that. But my sense is that first of all, you have to keep it simple. You can't use any fancy. You taught me this years ago. Keep it simple and communicate in words that everyone can understand. But also the idea is you talk about the uncertainties, you talk about what we are certain about, you talk about how everything in science is a hunt for the truth. And it's a never ending one. We learn all the time, it's continuous. These are some of the principles I think that are important. But for example, if we just take the measles vaccine and the recent idea that somehow rekindled that it causes autism, which is one of the most studied things ever, it doesn't cause autism. And the main study that introduced this, of course, as you know Andrew Wakefield in the Lancet, many, many years ago, it was fabricated and it was withdrawn. It took too long to have it withdrawn, but it nevertheless was. And so that has been studied ad nauseam and is nothing to it, but still Today we have many parents, mothers, who believe that vaccines are causing their kids autism. And so we have to work on this because it's completely wrong. And we have now an HHS secretary who has been a main proponent of this issue. So our work is cut out for us. I guess I would go back to you on this too, because you know this feel better than anyone I know. And maybe you have some new ideas of how we can get this straight.

Alan Alda (26:47)

Well, I do give a lot of thought to it, and it's such a complicated, daunting process because one of the crucial elements of good communication, I think, is telling the truth. You devote a lot of your life, a lot of your time to communication, your blog, your podcasts. All I can say is keep it up.

Dr. Eric Topol (27:07)

Well, thank you. I mean, we have a tough road because the anti science community is very well organized. It's funded, highly orchestrated, and even with less people in it, they're very effective, powered on social media and their own blogs. So we don't have enough of the science community standing up. Like, for example, we have over 300,000 scientists in the United States who are funded by the nih, which is threatened now in a major way. What if all 300,000 or even 150,000 were to stand up and write blogs and be part of social media and crowd out some of the anti science that we're seeing now? But unfortunately, it's hard to mobilize this crew. I've tried. They tend to just want to get into their work, keep their head down. I understand that, but now is not the time for that. We really have to achieve unity and have a voice, a big voice.

Alan Alda (28:19)

Yeah. When we began offering training to scientists to communicate better, more effectively, we were often met with the objection that that went like this. My job is to do science, not to sell it. But if you do science and it goes off into the ether and never reaches anybody who could benefit from it, have you really done science? You've done one part of it, yeah.

Dr. Eric Topol (28:48)

And if you can't be able to explain what you're doing to get people excited, who's going to want to fund that research? If the only person who reads your paper is your mother, that's not really going to help much. Right. So you really, you have to start to think about impact and significance and being able to have that in a succinct way to communicate, to get people excited about what you're trying to do.

Alan Alda (29:19)

Well, on that positive note, we're kind of coming to the end of our time, but we always end every session with seven quick questions. Not necessarily what we've been talking about, but in a rough way to do with communication. First of all, of all the things that there are to understand, what do you wish you really understood?

Dr. Eric Topol (29:39)

Wow, that's a really tough one. You know, I think there are so many things that are in this kind of black box, unexplained. So a lot of work we do now is in this generative AI, large language model AI, and it's beyond human comprehension how it's doing certain things and it's argued, oh, it's because it got trained in this and that, or no. Well, this is happening more and more every day. But I sure would like to understand how some of these just unfathomable jumps are being made more frequently than ever. It's pretty extraordinary and no one can really give us the answer so far.

Alan Alda (30:30)

Interestingly, as you point out in the book, as I remember, some of the confabulations, the hallucinations that AI comes up with are actually helpful because they give you a different way of looking at it.

Dr. Eric Topol (30:46)

Yeah, it's not just a bug, it's a feature. We're getting new drugs, new protein design from the hallucinatory aspects of AI. Who would have guessed? So we want to take. Everyone's trying to get rid of hallucinations, but some of us would like to see them be accentuated in certain ways because it can be helpful. The imagination of AI, if you can call it that, it's from a machine, but imagination and creativity, that's part of its hallucinatory property. So this is wild, Alan. I never would have guessed this would be an attribute, but there's something to it.

Alan Alda (31:24)

Okay, question number two. How do you tell someone they have their facts wrong?

Dr. Eric Topol (31:32)

Yeah, this is really a good one because you need to do that in a way that's soft. If you're going to ever convince the person that they have it wrong. If you just try to blow them away like you don't know what you're talking about, that's not going to change anything. So you basically want to try to get in their head in a way as to why that might not be quite right and then present the evidence for that. And if they're not going to accept the evidence, maybe you want to probe. I recently had a discussion of a fellow who is attacking me and I got in touch with him. It was on social media, on a blog, and I said, I don't understand why you did that. And it had nothing to do with what I wrote it was these priors of something totally outside of what I had written about. So you never know what it is causing a person to come up with an idea that's off track, not based on anything real. And oftentimes if you have a, as I've learned, a calm discussion without being confrontational and probing, you can get to the answer.

Alan Alda (32:51)

Okay, next. What's the strangest question anyone has ever asked you?

Dr. Eric Topol (32:57)

I think that's it right there. I think you nailed it. Now, I don't know that I've had anything quite that I can remember that was as strange as that one. Yeah, I don't know if I could come up with something offhand.

Alan Alda (33:16)

It's funny. Okay, how do you, how do you deal with a compulsive talker?

Dr. Eric Topol (33:23)

Yeah, that's a good one. Wow, I haven't been asked that one before. Well, you know, you try to get in the conversation. That's hard because it's not really a conversation, it's a monologue. Right. You try to get in and steer it, but sometimes you just, there's no way out and you just have to, you know, you have to kind of move on. But being a good listener, you can only go so far. Right. If the person just never stops and you can't press the off button.

Alan Alda (33:57)

Let's say you're at a dinner table and you're sitting next to someone you've never met. How do you begin a genuine conversation?

Dr. Eric Topol (34:06)

Yeah, you know, I really do like to do that because I, you know, just talking about the weather or, you know, something like it's trivial doesn't really get to me at all. So. Yeah. How do you do it? Well, I mean, I think it's, you know, it kind of depends on that person that gathering as to where could you find some common ground that would be not shallow, that would be, you know, really make it an interesting conversation and find out if this is a really interesting person that is really worth a longer term relationship than the few like the hour or two that you might be sitting next to each other, that you didn't choose to sit next to each other. And actually, Alan, I'm sure like you, I've met some phenomenal people that way who I'd want to hang out with forever. But if I hadn't struck up the conversation and hadn't gone away from just shallowness, I wouldn't have known that. These are just fascinating people to want to be with.

Alan Alda (35:12)

What gives you confidence?

Dr. Eric Topol (35:16)

I think the confidence is, well, first getting old. Maybe you get More confidence. You know, you kind of been around the block. You know, both of us, we kind of had our experiences, so you have a little more of that wisdom. The other thing, of course, is when you. When you are well read, when you know, the data, the evidence, whatever you're going to talk about, it's in hand, you know, you're not making stuff up. It's real. You know, you have a backstop. And you're not, you know, you're not just pontificating. And when you have original ideas, they're not just come out of the blue. They have. That you're building on. And you're always saying, you know what? This is an idea. It still needs to get proven right. So I think, you know, having those types of ways to go about how you communicate with evidence and without jumping the gun in terms of advocating something, these are things that help make me have more confidence in transmitting something.

Alan Alda (36:28)

Okay, last question. What book changed your life?

Dr. Eric Topol (36:33)

Ooh. Ooh, that's a tough one. You know, many. One of the most notable books that I think made me more aware of how to communicate was by my friend Sid Mukherjee, emperor of all maladies. And why I found that book so impactful is that in such a clever, extraordinary way, he could convey the history of cancer through his patients. So with real stories and, you know, the ability to tell stories, which is kind of the core of good communication, is. I found that book, you know, very much, you know, from many years ago now, to help me to be a better storyteller, to help the. The interactions I've had with patients over the years, to help be a way to be grounded and help, you know, to tell others about their stories so we could all learn from them.

Alan Alda (37:43)

That's great, Eric. Every time I talk to you, I learn from you. And I thank you for being on the show today and thank you for all your.

Dr. Eric Topol (37:51)

Oh, gosh, it's mutual. It's mutual. You know, by the way, just happened by this morning. Alan, this is interesting. You may not know him, but the dean of the medical school where I graduated from, University of Rochester, who's also the CEO of the medical center, we got in the mail, the magazine for my alma mater, and there's a big story in that by the dean and CEO, and it says, why did you go into medicine? And his answer was, because I watched Hawkeye on MASH and I saw what he did. I'm not kidding. This is real. And I wasn't going to go into medicine, but he inspired me. And look what happened to him.

Alan Alda (38:38)

That's amazing.

Dr. Eric Topol (38:40)

Just by wild circumstance this morning I'm reading this thing. I said this is amazing. I'll send you the link to it.

Alan Alda (38:47)

Thank you. I have to tell you though, it's not the first time I've heard that. I've heard from many, many doctors that watching this show made them become doctors, but nobody has told me that it made them become an actor.

Dr. Eric Topol (39:05)

Yeah, well, this is certainly one of the leaders of American medicine and I wouldn't be surprised if there's many others that have pursued this career, but also at the top level. Really very impressive.

Alan Alda (39:17)

That's great. Thank you so much for telling me that. Thank you, Eric. Thanks for being here. It's fun to be with you.

Dr. Eric Topol (39:22)

Oh, same here.

Alan Alda (39:31)

This has been clear and vivid. At least I hope so. My thanks to the sponsor of this podcast and to all of you who support our show on Patreon. You keep clear and vivid up and running. And after we pay expenses, whatever is left over goes to the Alda center for Communicating Science at Stony Brook University. So your support is contributing to the better communication of science. We're very grateful. Eric Topol is chair of the Department of Translational Medicine at Scripps Research. He's the author of three best selling books on the future of medicine, and his new book, an Evidence Based Approach to Longevity, will no doubt soon be joining them on the bestseller lists. He also writes a regular and influential substack newsletter called Ground Truths. This episode was edited and produced by our executive producer, Graham Chedd, with help from our associate producer, Jean Chaumet. Our publicist is Sarah Hill. Our researcher is Elizabeth Oheny, and the sound engineer is Erica Huang. The music is courtesy of the Stefan Koenig Trio. Next in our series of conversations, I talk with the actor Colman Domingo. He's now starring in the Netflix series inspired by the movie that I wrote and directed a while back called the Four Seasons. And earlier this year, he received his second Oscar nomination for his role in the movie Sing Sing, which he also produced. It's based on a true story and it follows a group of convicts taking part in a program called Rehabilitation through the Arts at Sing Sing Maximum Security Prison. Most of our cast, what 95% of them were, they went through that program. A lot of them went through that program at Sing Sing Prison. And they, they joined this theater because they feel like, oh, it's a way to express themselves, do something different, create some art. And then also they started to notice there was change, changing, having a profound change on their lives. You know, giving them more access and agency to feel, to transform, to name feelings. Colman Domingo next time on Clear and Vivid. For more details about Clear and Vivid and to sign up for my newsletter, please visit alinalda.com and you can also find us on Facebook and Instagram at clearandvivid. Thanks for listening. Bye Bye.

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Of your favorite brands. Earn more cash when you do more with Stash. Venmo Stash terms and exclusions apply. Max $100 cash back per month. See terms at Venmo Me Stashterms.