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And so I'm guessing that I already know the answer to this question, which is like, how much do we know about the strength or variability of those different types of contact with lightning? That's a great question. I don't fully know. It definitely, like, the less direct the contact is, the less total amount of electricity or energy that you're being exposed to. But in all cases, the duration of contact is unbelievably short in all of these cases. And then there is also ground current. And that is if the lightning hits the ground near you and then spreads out like radially and then comes up and hits you from the ground up. Those are the main types. There's also, and I think this is just, oh my goodness, there has been reports of something that's called an upward streamer. So you know how I said that all those positive charges are running along the ground and up to try and get to the cloud as that energy from the cloud is coming down? So there has been reports of people being struck from the energy just from those upward streamers of energy, even without them making contact with the actual lightning strike, which is like, what? Well, it's also interesting, like, because how do you determine what it was? I will post the paper where they did this. It was a really interesting forensic analysis paper where they showed they determined it wasn't all of these other types and it couldn't have been from the electric lines they were working on because of the patterns of injury, etc. And so, yeah, that was what they were left with. And I think it had been a theoretical concept prior to that, but this was one of the first documented, look, this is what caused this injury. Oh, man. Yeah. Yeah. There's a lot. Oh, Erin, there's just so much. And so much of what it comes down to that I think is so interesting is that, A, we do not understand lightning. We do not understand the effects that it has on the body. And two, the rules that apply to electricity and electric shocks and the body don't seem to apply to lightning. Why? Let me get into it. So a lot of the papers that describe both lightning and electricity injuries talk a lot about the characteristics of electricity that determine how much of the electric current actually flows through someone's body, right? So these papers tend to focus on six main things, six components of electricity. They talk about the type of current, which is whether it's an alternating current or a direct current. They talk about the voltage, the voltage being the pressure that causes that current to flow. They talk about the amperage, which is like the volume of electrons that are flowing. It's a measure of like the rate of flow. And then they talk about the resistance, which is an intrinsic property of an object and different body tissues have different resistances. It's like the ease or the difficulty with which the electric current can actually travel. And then they talk about the pathway that the current takes, which I kind of talked with lightning, the different ways that you can come into contact. And if you're thinking of household electronics, you can grab it with your hand by accident. Little kids might put electric cords in their mouth, right? So that will determine literally like where in your body is this current going to flow. And then the duration of contact. Now, when it comes to lightning, the voltage and the amperage that we're talking about, unbelievably high, like 10 or more million volts and 40 or more thousand amps. I don't really, I don't have like a frame of reference for that, but that sounds like a lot. So your household electric outlet is like 110 volts and like 15 or 20 amps. Oh, okay. Yeah, okay. That's a lot. It's a lot. But lightning does a few things that regular electricity doesn't do. First of all, it's a very different type of current. So your household electric outlet is alternating current. A battery is direct current. But lightning, some papers that I read said that lightning is like a direct current.
Right. It's a strike. It's not a current in that there's not a continuous flow for long periods of time. Exactly. And that's the thing that makes it so massively different from any other source of electricity is that the duration of contact is instantaneous. It's fractions of milliseconds. Whereas, especially if you come into contact with a household electric source or something that's like putting out alternating current, your body reacts to that alternating current by having repetitive contractions. So it can force you to actually grab and continue to hold on to that source, prolonging the duration of contact and therefore prolonging the damage. But this is the literal opposite because it's such an instantaneous thing that it actually causes an effect that I still don't fully understand that's called flashover. Let's talk about flashover. So if you think of your body as an empty can, bear with me, when you come into contact with like our home electricity, an AC current, it flows in and out of that can, in and out, in and out. And every time that it flows in and out and that current reverses, it's doing damage the whole time over seconds and seconds, or even just a fraction of a second, but a long fraction, like almost a whole second. That creates a lot of thermal energy, right? Because that electrical energy gets transferred into thermal energy. That results in a lot of burning, superficial as well as deep burns, as it penetrates through our tissues or burns through the can or whatever. With lightning, the amount of current and the rate at which it travels is so massive that that can gets filled up instantaneously and the rest of that current flows out and over the can. It spills all around it rather than staying contained within and causing damage. That is flashover. And so as it flows over, it can cause other damage that like normal electricity wouldn't cause because it's flowing out over your body rather than through it, even though it's going through it also. Yeah. But again, it happens so quickly that we're exposed to all of that current for a matter of fractions of milliseconds. So it can definitely cause superficial damage. It can melt our clothes to our skin. It can rip apart clothes from steam vapor explosion of the steam within our clothes. It can singe your hair. It can heat up metal buckles and melt them. But it's a very different pattern, especially of burns, than we see in typical electric burns. It's like very, very different. Isn't that interesting? It's really interesting. And I think it's like very, and we can't see what that ends up doing. Whereas electricity, if you're exposed to it from a household source, because that duration of exposure is longer, that electrical energy gets transferred into heat energy. So you have a lot more typical burns. You have a lot more visual and physical damage that we're able to see. And these type of injuries that your brain probably associates with electricity. Yeah, that makes sense. Let's hear it. Because it's not to say that lightning doesn't cause physical damage. It certainly does. It's just quite different than the damage that we see with other types of electricity. So the most instantaneously deadly injury that happens with lightning strikes is damage to our heart. Our heart has its own little electrical system. So especially if current of any type, not just lightning, is passing vertically through our bodies, it has a pretty good chance of passing over our heart, which sits kind of right in the center. And that current can then disrupt our heart's internal electric system and lead to arrhythmias. It can lead to asystole, essentially stopping the heart entirely, or it can lead to what's called ventricular fibrillation, which is when the bottom of your heart, the part that's supposed to pump the blood out of your heart to the rest of your body, stops contracting and really instead goes like, and fibrillates. It's not a good, sorry. You can't see my hands, but. It was a good, I think it was an adequate sound effect. Thank you. So what lightning can do is it can cause one single instantaneous depolarization of the entire heart.
And that's what it does. Often, because your heart has its own little electrical system, it will start again on its own. But if the respiratory centers of your brain, which control our respiratory drive, also get affected by this current, then you can have respiratory arrest as well. So you stop breathing. If you stop breathing, your heart stops beating. That then can prolong the cardiac arrest. So lightning strike can cause death, I read, anywhere from 5% to 30% of the time. Most sources said 10% to 30%, and a few papers said 5% to 10% of the time. And usually it's immediate death because of that cardiac arrest, either without the heart ever returning to normal function, or if you have both a cardiac and a respiratory arrest without resuscitation, then you have death because of that. And one thing that's really interesting about lightning strikes specifically is that it's actually far more likely to have successful resuscitation in the case of a cardiopulmonary arrest from lightning than from a lot of other reasons for cardiac arrest. And there's a lot of different hypotheses as to like why. Part of it might be that because it happens so, I just keep saying this, like it feels repetitive, but it is so instantaneous, this complete stop, that there's a thought that maybe you have more time Right. seconds or minutes. So you've already lost time. But many times people who are struck by lightning are otherwise young and quite healthy. So it might just be that they have more reserves, so to speak. We don't really know. But it's really interesting because it changes the paradox of, for example, in an emergency situation, who should be the first person that you go to to try and save? Right. The triage is like opposite. Exactly. With lightning, it's the person who looks dead. That's the person you go to first because their heart probably stopped. They might have stopped breathing, but you'll probably get them back. Whereas if someone is breathing, is moaning, is making any kind of movement or noise, they're going to be okay, most likely, in the immediate emergent period. But so that's kind of the most extreme thing that happens. But lightning can also cause a lot of skin damage. It can cause linear burns from water on the skin being vaporized. It can cause these fascinating feathery snowflake lightning strike patterns that actually aren't burns at all. And we don't even really understand what causes them. But they tend to disappear in a matter of hours. It can cause these small, round burns that can be deep, but they're really small in diameter or in area. So in general, the skin and burn injuries that we see from lightning tend to be much less severe, first of all, than you would expect from such a huge amount of electricity, but also less severe than what we see from a lot of other electric sources. Lightning, though, can cause a lot more trauma damage than some other electric sources, except for perhaps high-tension wires. But because of the shockwave that's generated by lightning, that shockwave itself can actually cause barotrauma, which can cause injury to our internal organs. It can cause a concussion. It can rupture the eardrums. That is very scary. It's terrifying. It's also thought that during flashover, the current can actually re-enter our body through our eyes and our nose, which can then cause ocular damage like cataracts. And then, of course, you can have trauma from falls, from being blasted away or from shrapnel from a tree, etc. So there's a lot of different ways that lightning can harm you. Yeah. But then, of course, there's the neurologic damage. And the neurologic effects can also be pretty wide-ranging. They can be transient, where they go away really quickly. And it's actually pretty common to have something called coronal paralysis, which is pretty specific to lightning strikes. It's a total paralysis, especially of the lower extremities, but it's transient and it goes away within a matter of hours. Not fully understood.
Right. So this can manifest as temperature instability, as a fast heart rate for seemingly no reason, as blood pressure problems. But again, these type of findings tend to improve relatively quickly. There can also be immediate effects from a lightning strike neurologically that don't recover as quickly, that are more prolonged. And that can happen either from direct damage from electric current or from things like ischemic injury from like a hemorrhage or a stroke if you have damage to blood vessels, etc. Gotcha. And then there are a lot of delayed onset of symptoms that can be anything from movement disorders, like if there's motor neuron damage. But then, of course, there are neurocognitive and neuropsychiatric findings that in many cases can be profound and can be completely life changing. And we do not understand the mechanism or the extent. It's so I feel like lightning is portrayed as like, oh, it's this deadly thing, which it absolutely is. And if you survive it, then you have special powers afterwards, where you can suddenly play the guitar or speak nine different languages that you didn't know before. And like, first of all, those stories, I looked into a couple of them, and they're not, they're not true, obviously not true. But I think also what's glossed over is that, yes, you can survive lightning, but it can be hugely disruptive for the rest of your life, or at least for like way longer afterwards. I didn't know that. No, I absolutely did not either. So the neuropsychiatric effects, they can be very wide ranging. They can be anything from like photophobia, so difficulty with light, hyperacusis, so like really sensitive to sounds. It can cause emotional lability, mood swings that go in a second from like really, really overjoyed to like everything is terrible, but something that you have absolutely no control over. Sleep disturbances. It can cause anxiety or hypervigilance. It can result in a lot of memory deficits, especially in working memory or difficulty with word finding or auditory memory. There's been studies that have shown that it can affect your processing speed. Post-traumatic stress disorder happens in about 30% of people after a lightning injury. It's so wide-ranging, and I think what's so important about this type of neuropsychiatric findings is the downstream effect that these can have on somebody's life. Because they not only can affect the way that somebody interacts with the world, but they then can go on to affect a person's relationships, marriages, friendships, things that like make a person who they are, which is terrifying. Yeah. And it also seems, I think, probably very frustrating that we know so little about this, which means that we know so little about how to treat or help provide any sort of symptom management in terms of those sorts of things. Yeah. And I think it comes down to we know so little about how the brain works. Yeah. That how do we know how this, you know, instantaneous, massive force of electricity, how has that affected the wiring of your brain? It affects it. Right. We know. But we don't understand how. But yeah, Erin, that's a very long-winded and probably not detailed enough lightning. It's so interesting because there's so much there, but it's also like so many questions. Oh my gosh, I know. Making me flashbacks to the multiple sclerosis episode. So Erin, tell me, how did we get here? I'm definitely not going to answer those questions. I don't even know how to ask a question about lightning, honestly. Well, I will take you on a tour through the history of electricity. Let's begin. Just kidding. There's absolutely no way I'm going to do that. Not even going to try. Never planned on it. Yeah, that's outside my reach. But instead, what I decided to do was to pick four topics or stories or whatever in the history of electricity and tell you about them. Okay. So it's not going to be as deep of a dive as I normally do on like a topic, but I think it's going to be a fun or at least interesting time.
I can't wait. Right off the bat, I want to shout out the primary source I used, which is the newest book from Dr. Timothy Jorgensen called Spark. It's all about electricity from a biological perspective. It is a fascinating and excellent read, and I really loved it. And you might remember Dr. Jorgensen from our episode on radiation that we did a couple of seasons ago, when we had him on to explain like how in the heck radiation worked. And since Dr. Jorgensen does such an amazing job of explaining these super complicated topics in a way that I feel like I can actually understand, I wanted to have him on again to explain how precisely electricity works. So tune in next week for the bonus episode where I get to ask him a bunch of questions about how electricity works and why it's so important in understanding biology. Yeah. Okay. But are you ready to hear my little vignettes? Yes, I can't wait. Do you want to know the four topics or do you want to be surprised? I think I want to be surprised. Okay, here we go. Number one. I've got to start, of course, with lightning. Oh, yes. And specifically, one of the most famous stories in the history of lightning. Is it BF and the kite and the key? It is. Finally, a history story I at least have heard of. But starting way before that, people have long observed and revered lightning. Like it holds a really significant place in many historical religions or mythology. You have Zeus in Greek mythology, Thor in Norse mythology, Indra is the Hindu god of storms, Ukko is the Finnish god of thunder and sky and weather, and the Finnish word Ukkonen means lightning. And in the traditional religion of Bantu tribes in Africa, lightning is a sign of the gods being angry. And there's also representations of lightning in art and etchings going back thousands and thousands of years. And the fascination that people had with lightning and the power, like the mystical power they ascribed to it, it's completely understandable, right? I mean, it's still fascinating and terrifying. But I'm not here to talk about lightning in mythology, even though I would love to do that. But what I really want to talk about is when people realized what lightning was, and how they gained that understanding. Electricity itself has long, long been recognized by people, and not necessarily in the context of lightning. People didn't look at lightning and immediately go, that's electricity. Hmm. piece of wool gets statically charged. And so you get little shocks of static electricity, which is actually the way you can tell whether it's real amber or not. But people saw this characteristic of amber, and it was believed to have mystical or healing properties for that reason, for this like electrical reason. There are amber pendants dating back to 12,000 BCE, for instance. And over time, people began observing static electricity in other materials and began to characterize as much as they could about how this electricity worked and how these materials behaved under certain circumstances. And this process of observation and recording and reporting and so on, it allowed people to harness the power of electricity at least to a certain degree, a small degree, pretty small. For centuries, and I'm glossing over a lot here, the only way that people could intentionally produce static electricity is by rubbing materials together, petting your cat really hard, just kidding. Like rubbing amber with wool. Right. Huh. And people would only become more and more fascinated by this over the rest of the century. So where does Benjamin Franklin fit into all this? I teased his name and now I haven't talked about him yet. Okay. So the classic story of Ben Franklin is what? Oh, he like flew a kite into a cloud and got electrocuted by lightning. Yeah. Right? Is that it? Something like that. I feel like I learned it as Benjamin Franklin discovered electricity. Oh, yeah. Okay. By flying his kite in a lightning storm. But that obviously, that didn't happen, right? People already knew that electricity existed.
But it seems probable that it did actually happen. So if this story has been like misrepresented over time, and it's not really quite truthful, why do we all still know about it? Yeah, tell me why, Erin. Okay, so several people, including Ben Franklin, had floated the idea that lightning storms were electrical. A lightning strike looks like a giant spark in the sky, basically like a giant-sized version of that static electricity discharge spark on your cat's nose. And so people thought that maybe electricity was stored in storm clouds and then discharged under certain conditions. That's a reasonable hypothesis, but that's all it was. It was just a hypothesis and no one knew for sure. And so Ben wanted to find out. Ben, we're on first name basis. Of course we are. So he devised an experiment that fortunately went through several revisions because the first versions were like incredibly dangerous, even more so than the final one ended up being. And they involved like a person standing on top of a wooden platform holding a metal rod in the middle of a storm and stuff like that. Not. Cool. Okay. into the key that was tied to the twine. And then Ben was like, is this key charged? Is this key have electricity in it? He felt a little spark. And so he was like, perfect. So he was able to collect some of the storm's electricity and store it in that lighten jar. So he did it just with the storm, not with lightning. Yeah, it's a big difference. Well, it's a big difference. And I think that there probably were strikes that happened. Like it was clearly like a, you know, thunderstorm, lightning storm or whatever. Right. But he was able to collect that electricity without a lightning strike. Fascinating. Yeah. Yeah. It was a huge deal. And I also just want to take a moment to say don't do this at home. Yeah. Probably. Because it's still a very dangerous experiment. And actually the year after he did this kite flying experiment, another scientist tried it elsewhere, but was killed by ball lightning. So anyway, so newspapers all over published the accounts of Ben Franklin's experiment. And it made him like quite the celebrity. And even though he didn't discover electricity in this kite situation, his experiment did teach us several things. The first is that it showed that lightning is indeed electrical, right? The phenomenon that you had when you rubbed amber was the same, but on a much, much larger scale that you saw in nature when there was a thunderstorm. Right. Another is that it hinted at the enormous electrical power in storms and how we could possibly someday either harness it or that we could maybe generate great amounts of electricity ourselves. Right. Oh, wow. And the last big thing that I'll mention is that this experiment kind of immediately showed that lightning rods, like the rod attached to the kite, could be used to protect structures, which is an idea that Ben Franklin and others had been working on for a few years. I think that many of us, or at least I'll speak for myself, I definitely take it for granted that when I am inside my home, I'm protected from lightning. Oh my gosh, yes. Or in like in a public building, right? But A, that hasn't always been the case. And B, it still is not the case for many people. Yeah. And in Ben Franklin's time, lightning posed a serious risk to people's houses and their crops and their lives. And there were always like newspaper reports of like these deadly lightning strikes. And it seemed to like be a very scary and real constant threat. Yeah. I absolutely reading this made me so much more terrified of lightning because I never realized how easy it would be to not have the protection that I have inside my home. Yeah, absolutely. And so when this experiment showed that lightning rods could be used to protect your house or your building, people jumped on the idea and they began installing them in houses and public buildings.
That's pretty cool. I know. But I also just think this is interesting. And this is sort of where I go right into like trivia mode here. These lightning rods weren't universally popular. Churches actually didn't readily adopt lightning rods because many of these churches had bell towers, ringing bells, and ringing bells were widely believed to protect the church from lightning. And apparently there are bells that have this inscription of a Latin phrase that translated into English means, I break the lightning. I think that's so interesting. Turns out, bells do not protect you from lightning, and in fact can be quite dangerous, especially because in a storm, bell ringers were called to go ring the bells. Oh, no. And so they'd be ringing this wet rope and then get struck by lightning. And so a lot of deaths happen that way. So I want to wrap up this first story with a few pieces of trivia about lightning. In 2016, this is just like literally like bullet points here. In 2016, 323 reindeer in Norway were killed, like all at the same time while huddling together during a storm. What? Uh-huh. The longest lasting recorded lightning strike was 17.1 seconds in a storm over Uruguay and northern Argentina in June of 2020. Oh, no. And apparently the longest single flash was 477.2 miles or 768 kilometers, which is like across parts of the southern U.S. in April 2020. Wow. his experiment, electricity researchers dug deeper into the characteristics of electricity, and especially whether different special types of electricity existed. Was all electricity the same? And this ultimately led to a huge debate over something called animal electricity. And that debate, in turn, led to one of the most impactful advancements in the history of electricity. Okay. So animal electricity was this idea put forth in the 1700s and championed heavily in the late 1700s by an Italian researcher named Luigi Galvani. Okay. And it was the idea that all animals created and stored electricity in their bodies, particularly in their brains, and that this animal electricity was responsible for movement. Okay. So he believed that this type of electricity was unique to living things only, and it was not the same electricity that you could store in a Leiden jar, for instance. And part of why he was so adamant that this was the way things were, and that animal electricity was unique, is because he was deeply religious. And he believed that it was heresy to try to understand the inner workings of God's creations, or to try to imitate them. And so he was like, no, if you can generate static electricity and store that in a Leiden jar, there's no way that that could be the same thing that is in animals. Okay. Okay. So to prove that animal electricity existed, Galvani did this series of experiments involving dead frogs and different metal wires. So when he attached these frogs' legs to the wires, he noticed that they jumped or twitched, which he concluded was proof that the wires were simply allowing the stored-up animal electricity to be released. It's like opening the valve. I know. I know. I don't understand how you reached that conclusion, but okay, Galvani in like every way. And so he looked at this experiment and was like, just like you said, I don't know how you could conclude that it was the frog and not the wires. So on the two sides of this, Galvani saying, no, the movement is coming from internal electricity from the animal itself. And Volta was like, no, it is the application of external electricity causing the movement. And the two went back and forth in their feud until Volta decided that he needed to settle the matter once and for all. So he was always experimenting with things. And he had noticed that when he placed coins made of different metals on his tongue and like, yeah, put them down, he felt a bit of a tingle, kind of like an electric shock. And the strength of that tingle depended on which types of metals the coins were made of. And so he wanted to understand what was going on.
And so he went to the literature. And he came across the description of an animal that gave him a little spark of inspiration. I love that you keep dropping these. Uh-huh. The torpedo fish, also called the electric ray. Oh, yeah. Torpedo fish are so cool. So torpedo fish are kinds of rays found in the eastern Atlantic Ocean and in the Mediterranean. And what makes them so unbelievably fascinating is that they have the ability to generate an electric shock so strong that it can knock a person unconscious. Wow. Yes. They use this to stun prey, of course. Oh, I was so tempted to go into the evolutionary history of electricity, electrosensory organs in fish and stuff like that, but I resisted. But people had been aware of these torpedo fish for hundreds, even thousands of years, and they were thought to have mystical properties because of this shock. Of course. They were used by some physicians in ancient Rome to treat various medical issues. Like they would just like put the torpedo fish on the person. Shock them. One of the ailments that they were used for is hemorrhoids. It's like an, ow! I know. Like, terrible. But the nature of this shock that they delivered was debated. Was it electricity? There was no visible spark. So was it actually just the sting? Or was it something totally different? In the 1770s, so a couple of decades before the debate between Galvani and Volta kind of came to a head, an English scientist named Henry Cavendish showed that the torpedo fish produced electricity. But still, there was this question of like, well, what kind of electricity is it? Is this the same kind that we could artificially produce, or is it this animal electricity? And so when Volta came across descriptions of this fish, and particularly their electric organs, these columns of jelly-filled disks, he thought, I wonder if these work in the same way that my metal coins on my tongue do. Like just a couple of coins stacked together give me a light tingle, Huh. shock. So he tried it out. He stacked disks of copper and zinc and other metals along with cloth dipped in either dilute acidic solution or salt water until he had this big pile of disks. He attached wires to each end, and then he tested it on his tongue. Again, bad idea. And sure enough, a stronger tingle. But not only was it a greater shock, he was also surprised to find out that it was continuous. Electricity was flowing out of his pile like water. Hence why we call things like electrical current or the flow of electricity. It was like liquid. People thought it was liquid in nature. It wasn't this one and done shock. And that is how, inspired by the torpedo fish, in 1799, Volta created the first true battery. Battery! How cool is that? What? I love it. It's so cool. And also, not only did he just like create this incredible source of electricity that would forever change things, he also proved Galvani wrong. Because he was like, I can generate electricity in the same way that the torpedo fish did, but without any animal parts present. So he won. Wow. Yeah. So that's where Volt comes from. Yeah. And also like galvanized too. Galvanized. Yeah. Wow. I know. So are you ready for number three? Yeah. My brain is still just like reeling. This is great. I want number three. Okay, so let's now see one of the things that people did with this new knowledge of how to generate larger amounts of continuous electricity. Okay. Jumping ahead to the 1880s. So by this time, the world had come a long way from Ben Franklin and his kite. Several cities had streetlights powered by electricity.
But many people who were living in these cities that were lit by electrical lamps, they were still pretty wary of this power, especially as newspapers reported on an increasing number of accidental deaths from electricity. One of these deaths would inspire the invention of one of the U.S.'s most gruesome devices. On August 7, 1881, in Buffalo, New York, a man named George Lemuel Smith had had a bit too much to drink, and he stumbled into a power plant, What? death by electrocution was presented by a coroner to an audience of medical professionals in Buffalo, and in that audience was a dentist by the name of Alfred P. Southwick. You know, people find inspiration in all kinds of ways. Like maybe an idea comes to you when you're in the shower, or when you're reading a book, or when you're on a long walk. Or maybe it comes to you in the form of an autopsy report of an electrocuted man. As Southwick listened to this case, an idea began to form. What if we could harness this power and put it to good use, which in his eyes was to kill people who had been sentenced to death. Southwick teamed up with a physician and the head of the Buffalo ASPCA to test out this new method of execution on the stray animals of Buffalo. I know, it just gets worse. Oh dear. It always does. at the time, capital punishment was done primarily through hanging, which is not always reliable and was associated with a lot of pain and injury and just bad. Yeah, gruesome. Yeah. And so there was a series of botched hangings that had led to quite a bit of pushback against both hanging as well as capital punishment in general. And so Southwick viewed death by electrocution as a much more humane option. It seemed quick and painless and with practice more reliable. So he took the calculations that he had gathered from his animal experiments, scaled them up for humans, and designed a delivery method. A chair, not unlike a dental chair. And that is how the electric chair was born. So he brought this design to New York politicians and lobbied them to replace hanging with his electric chair. The governor at the time was like, huh, you know what, you might be onto something here. So he put together a commission to investigate the electric chair alongside the other common methods and not so common methods of execution that were used, which by the end of their investigations totaled 34 different methods. Whoa. Yeah, I know. It's disturbing a number. Some of these methods were tossed out pretty quickly, but others proved to be stiff competition, like decapitation via guillotine. But the commission concluded that electrocution was the winner. They still had concerns, but it seemed like the best choice. What also helped make this be number one choice was that the electric chair got a vote of confidence from one very prominent figure in electricity, Thomas Edison. You know, Erin, I would love to spend so much time talking about the electricity wars between Edison and Nikola Tesla and Westinghouse. But I just, I can't. If there was ever an episode for it to happen, it would be this one, but I decided against it. I'm actually shocked by that because I know your feelings about Thomas Edison. You're shocked by that? So what you need to know, essentially, is that Thomas Edison was a huge proponent of direct current. That's what he worked in. That's what he invested so much time and money into having that be the type of energy used in homes, commercially, everywhere. Nikola Tesla, on the other hand, had worked with alternating current. Edison was extremely threatened by Tesla and Westinghouse's alternating current, and so he launched essentially a smear campaign against it. One strategy of this campaign was to get the alternating current-powered electric chair approved for executions. Because if AC was used to kill people, would you really want it in your homes? And on August 6th, 1890, nine years minus one day after the death of George Smith that kicked off this whole situation, the first execution via electric chair on a person was carried out.
His electrocution did not go well. I think the eyewitness account says it best. Oh dear. And if you would rather not hear a pretty gruesome description of an electric chair execution, I would suggest skipping ahead about a minute and a half to two minutes. Okay. Quote. electricity, as it slowly, too slowly, disintegrated the fiber and tissues of the body through which it passed. The heaving of the chest, which it had been promised, would be stilled in an instant of peace as soon as the circuit was completed, the foaming of the mouth, the bloody sweat, the writhing of shoulders, and all other signs of life. Horrible as these all were, they were made infinitely more horrible by the premature removal of the electrodes That's horrific. It's absolutely, it's horrific. There were debates about whether he was brain dead and actually like had any pain sensation. And I think that that has long been a controversy in terms of electric chair. Oh, I'm sure. Execution. But I think one of the things that surprised me the most, or maybe it shouldn't have, but this happened. And people were like, you know what? It's fine. We're gonna keep going. Yeah. Let's try it again. I mean, in popular news reports, the doctors were completely slammed. They were like, you botched this. This is terrible. You need to do better. And so, yeah, maybe they were just convincing enough that like, no, we can do better next time. Right. Yeah. And so in the months and years that followed this first electric chair execution, the entire process was tweaked a bit here and there to avoid a repeat of what happened with Kembler. And death by electric chair became a very common method of execution in the U.S. and basically nowhere else. Hmm. how our bodies worked, but in electricity. One of these, Robert G. Eliot, was the state executioner for New York and ended up executing 387 people during his lengthy career. At the end of his life, he wrote an autobiography reflecting on his whole life and career and experiences. And I wanted to mention it because I think his takeaway is super interesting. He believed at the end of all of this, that the death penalty should be abolished. And it's not that he felt morally responsible for these deaths or worried about the people that he had executed having suffered. He thought that it was a painless process and he was like, I'm just doing my job. But he felt that capital punishment in general wasn't any use. It wasn't a deterrent to crime and it was really more society taking its revenge. There was no good outcome of this. He felt that witnessing an execution should be a civic duty, like jury service for all citizens, and felt that if that were to happen, if there had to be like, oh, this is the committee that's going to watch this execution, that he was like, the death penalty will be gone very quickly. That's an interesting thought. Isn't that an interesting thought? Yeah. or in like pop culture, there are famous electric chairs like Gruesome Gertie, Old Smokey, Old Sparky, and it's been featured in countless songs. Shout out to Ride the Lightning by Metallica, which I was about to say forced to listen to for the first time the other day. And also it's featured in books and movies and shows. Like off the top of my head, I can think of history. Mm hmm. Mm hmm. OK. OK. So I wanted to end the history section on a bit of a happier note by talking about how electricity has been used not to kill people, but rather to try to help them. Okay. I'm going to just do a very, very quick tour through this history and hope that one day I get to do a deeper dive on something like electroconvulsive therapy, for instance. Okay, so I already mentioned how both amber and electric fish were used thousands of years ago to try to treat or cure people. But the age of electrotherapy really began when the study of electricity kicked off in the 1700s.
Turns out they still don't, I guess. But they still tried to use it to treat basically any condition they could think of. Throughout the 1800s and into the early 1900s, electrotherapy became incredibly popular. And physicians who practice electrotherapy actually call themselves electricians. Isn't that great? Yeah. And it was an incredibly lucrative field to be in. And apparently, I learned that many of the early advances in electricity technology were driven by physicians wanting to have better control over the electrical charge that they applied to their patients. Huh, interesting. Yeah, because unlike many of the electrical scientists at the time, the physicians actually had a strong revenue stream from their patients to be able to focus those research efforts. Yeah. And so many of these early electrical innovations were-focused. Some of these devices may have helped people a little, but as you can imagine, this was a field full of snake oil. For example, I just want to talk briefly about one of the most popular electrotherapy devices in the early 20th century, which was the Pulvermacher belt. You could get it by mail order only. Okay. of the belt and rest your genitals inside. It was just like, I think you have to see like the drawing of this belt. It kills me. It's so funny. So it was advertised as improving sexual vitality. Of course. And it was an absolute bestseller. Like so much so that, you know, those clickbait headlines that are like, doctors hate this one trick. That's, that is essentially the Pulvermacker advice. They wanted it to be banned. They were like, we need patients to come in to see us. And they're just sitting at home with these belts on. Also, maybe they wanted it to be banned because it didn't work to do anything really. And that's what people were generally realizing about electrotherapy, especially as things like germ theory revealed the underlying pathologies of various diseases, which didn't necessarily have any overt link to electricity. Whereas in the 1800s, electrotherapy was considered essentially a cure-all, by the early decades of the 1900s, it had fallen out of favor, more or less, and was kind of seen as a specialist treatment. But it didn't go away entirely. In the 1920s and the 1930s, there was a lot of research looking into a possible relationship between epilepsy and schizophrenia. And several physicians mistakenly believed that they represented opposite ends of a disease spectrum. And the implication of that was that if you induced seizures in someone with schizophrenia, you could treat the disease. And that is how electroconvulsive therapy first began to be used for schizophrenia. And it seemed at least somewhat effective, but the how and the why was not, and I think is still not, fully known. And despite the bad popular reputation it has, mostly owing to issues with informed consent and negative media portrayals, which I would love to talk more about in like a bigger episode, it's still used today to treat many different disorders in addition to schizophrenia, one of the most common being certain kinds of depression. And it's like successfully used. And it seems like we've come a long way from the 1920s and the 1930s in the way that we treat people with this. And so I think that ECT is kind of this example that we have where like something that started out a long time ago, electrotherapy in general as snake oil or mostly placebo effect has now evolved so much over time that it is used very effectively in many different types of conditions, right? You have ECT used to treat types of depression, vagus nerve stimulation to treat some epilepsy, deep brain stimulation to treat Parkinson's disease. And there are many, many more examples. And even if we still have more to understand about how electricity works, it's amazing to me to think of how much it has taught us about ourselves with like different nerves and different muscles, or maybe in the future, what lightning strikes can teach us about brain functionality. Yeah. So speaking of lightning strikes, Erin, what's happening with electrical shocks and lightning strikes and whatever else today? Well, I don't know.
So bringing it all the way back to lightning, where we began. First off, like I said earlier, we truly have no clue how many people are struck by lightning or the death toll from lightning strikes straight up. Two recent studies estimated between 6,000 and 24,000 fatalities per year, which is a very huge range. Yeah. Really big differences in different studies. And a lot of papers kind of assume that globally there are at least 10 times as many injuries as there are deaths. So for estimates of 24,000 fatalities, that's over 240,000 injuries globally. How has that changed over time? It's a great question. It definitely has changed. The biggest problem, there's two biggest problems. Number one, most countries simply don't report this type of information because they're not collecting it, right? Even in the US, our lightning data, from what I read, and I think that this is still true, it's mostly gathered by like NOAA. Mm-hmm. And the same is true in most, if not all, other countries. And also, of course, lightning isn't exactly evenly distributed across the globe. So there are some areas that at certain times of year have a lot of lightning and other places that don't really have much lightning year-round, etc. In general, from what I could gather, the overall death rate does seem to be declining, especially in developed and high income countries where we have good infrastructure that can help protect people from lightning strikes. So for example, in the US, older papers that I read estimated like 100 fatalities a year, even older ones said it used to be as high as 400 a year. More recent numbers cited about 30 deaths annually in the U.S. So in the U.S., we've certainly seen a decline. In many other countries, likely a decline. But there are still so many risk factors in a lot of places in the world associated with increased lightning deaths that really come down to infrastructure issues, right? Yeah, I didn't realize, and this made me so much more terrified, even though I'm in San Diego, we don't have a lot of lightning. Although I heard thunder this morning. There are more than 20 million cloud-to-ground lightning strikes annually in the lower 48 states alone. Hmm. 20 million cloud-to- cloud strikes. That is so many. In one year. In one year. Yeah. Wild. So the other question then is like, what is going to continue to happen in the future? Certainly, we know what types of infrastructure and what types of dwellings can help to protect people from lightning strikes. What happens globally, especially as our climate changes? Yeah. Our favorite thing to talk about on this podcast. I was wondering about that. Yeah, I'm still wondering about it. One paper that I read, which was a modeling paper, estimated that global lightning flash rate could actually decrease with climate change. They estimated about a 15% decrease in lightning strikes with climate change based on their models. But other papers have estimated the exact opposite, an increase of anywhere from 4% to 16% in lightning with climate change. And from what I can gather, there's definitely a strong theoretical possibility that warmer global temperatures, especially in the tropics, can result in greater lightning frequency because of those warm air fronts. And we know that like those are the kinds of conditions under which lightning can occur. But it really comes down to it's not as simple as temperature equals lightning. And I mean, climate change isn't as simple as temperature equals anything. Right. Yeah. Other papers have looked at more of the secondary effects of lightning. Right. And which we didn't even get into because that's a whole nother situation. But other papers have looked at things like an increasingly dry climate increases the risk of things like forest fires that are associated with lightning. Lightning is a major cause of forest fires. And so even if the actual amount of lightning might decrease or not change, if the dry season is longer, then that could actually contribute to an increasing risk associated with those lightning strikes. That makes sense, yeah. Right? Yeah.
We're supported by Panacea Financial, digital banking built for doctors by doctors. At Panacea Financial, you can have your own free personal banker and a support team that works around the clock just like you do. Open your free checking account today at panaceafinancial.com. Panacea Financial is a division of Sona Bank, member FDIC. Pretty much, we are responsible if you screw up. You should. Jorge Castillo. And as a reminder to the audience, this episode will be available for free CME credit through our partnership with VCU Health. You can get that at curbsiders.vcuhealth.org. Stuart, since Paul's not here, can you please tell the audience what is it that we do on this show? Sure, Matt. So we frequently have existential crises where we try to bring you information from the land of internal medicine. We use expert interviews to bring you clinical pearls and practice change of knowledge. Hopefully you glean something of use from these episodes. I think it's almost impossible for them not to glean something useful from tonight's episode unless they don't work in healthcare, in which case, maybe, maybe not, but still, it'll be very interesting for them. Nora, can you please tell them about our wonderful guest? Actually, I don't know that we introduced you yet. The great Dr. Nora Plout-Toronto. Nora, a fantastic middle name. You're a fantastic medical resident. Please tell the audience about our guest. Why, thanks. That was such a flattering introduction. Got to shout out to my German roots with that Plaut. But we have a really wonderful conversation with our guest, Dr. Jorge Castillo, tonight. Jorge Castillo was born in Peru, received his medical degree in Mexico City, and then completed his internal medicine and hematology and oncology training at the University of Massachusetts and Brown University, respectively. He is now an associate professor at Harvard Medical School and serves as the clinical director of the Bing Center for Waldensherm Macroglobulinemia at the Dana-Farber Cancer Institute. Today, he actually teaches us about Waldenstroms and more. He specifically teaches us how to follow up on that SPAP that's always still pending at discharge and ends up in your inbox somehow, when to think about how to order one in the first place, and how to think through the difference among the paraproteinemias from MGUS to myeloma to Waldenstrom's. Without further ado, let's get to it. Jorge, thank you for joining us. We're very excited to have you on the show. And the audience is dying to hear your one-liner and something about yourself, something you do outside of medicine. All right. So what can I say? I'm 46. I'm happily married to one woman, and I will be married to that woman for the rest of my life. I do believe so. I'm a father of three. And if I were not a doctor, I think I would be probably a chef. I'm Peruvian. I was born in Peru. Peruvian men, if there's anything we can do, is cook. That is my second passion after medicine, I would say. Do you have a favorite book that you think that every physician should read? I have two books that I think are important. One of them is Microbe Hunters. A very good friend of mine who, you know, was my mentor, one of my earliest mentors actually gave that book as a, you know, gift to me. I enjoyed that book greatly. And that really piques your interest to become a researcher. More recently, I think the history of cancer, the emperor of all maladies, I think that is a must for any oncologist in this country, I would say. It's an amazingly well-written book, very entertaining, lots of very important history in that book. So I think those two would be very high up on my list. Yeah, I actually really like The Emperor of All Melodies. It's very easy to read and just interesting. So can you tell us about a favorite failure you've had and what you've learned from it?
I'm all success. What are you talking about? You know, I think, you know, it's really hard to pinpoint a specific failure. All I can tell you is probably that my entire career has been chiseled by failure. And I think that is the only way in which you can succeed, right? I mean, you keep trying and then you keep getting grants proposals rejected. You keep getting manuscripts rejected. And that's the only way to move around. You run a clinical trial, and it doesn't work the way you would like it. And then you have to still create a report of a negative study and put your name in it and put there the evidence that you created in some some way. So yeah, my successful career has been chiseled by failure. Let's put it that way. Before we get to the show, I wanted to ask you, what is your favorite advice that you've received along the way as a learner or when you were in training? I think a couple of them. I think one of them would be it takes a village. Really, you cannot do things just by yourself. You need to have, you know, before we used to think that we need a mentor. I think we need a series of mentors. You know, we need a network of mentors who will basically tell you what are you doing well and the most important ones who will tell you what are you doing wrong or what are you doing suboptimally. And I think that context, specifically for academic medicine, I think it's very important to understand that perspective. The other concept is to be at the right place at the right time. And again, the same way failure shapes the career sometimes, also lucky strikes shape the career to some degree. And I can tell you exactly when your luck changes, specifically from the perspective of being a foreign medical graduate and trying to get into a higher degree of training, into a bigger place, into a better place. It's always a struggle. And I think, you know, if I wouldn't have been at the right place at the right time, that might not have happened. But it also depends on how you want to look at it. Because at the end of your career, you can say, well, you know, this is where I was lucky. You know, at that moment, you were not, you didn't know that, right? I mean, you just took that decision and make that decision and then something happened to you. And then also makes you kind of think of all the things that you did not do and where would have, you have ended up if you have taken just a different path on that specific sense. It's a fascinating sequence of events that takes you to where you want to be. Nora, before we get on, since you're not on the show all the time and you give some great picks of the week, did you want to, before we move on to the case and start to talk with Jorge about his expertise, did you want to give a pick of the week? Yeah. So my pick of the week this week is a new podcast called Her Story. It actually, it ties really well into what Jorge was speaking about, about having a series of mentors. It's a podcast that was created by women for women that explores the intersection of women, medicine, leadership, and healthcare. And it features guests kind of across the board from policymakers to CEOs of big healthcare corporations and insurance companies to the former CDC director. And it's kind of only getting started. So I highly encourage listeners to jump in and get some pearls there about how to find the right mentors for them. Panacea Financial provides physicians and medical students with free checking, a personal banker, around-the-clock customer support, and loans designed with you in mind. No one should borrow money more than they need, but with Panacea Financial, physicians and physicians-in-training can get money as needed in as little as 24 hours with their PRN personal loan. It has an interest rate that is less than half the average credit card, no cosigner requirement, and a fully digital application.
In addition, physicians in training can have a period of no or reduced payments on their PRN personal loan. Go to panaceafinancial.com today to learn more. Panacea Financial is a division of Sona Bank and member FDIC. All right, Nora, do you want to read the first case? Sure. So our first case is a case about Mr. Michael Loma. He's 67 and he comes to see you in primary care for follow-up after a one-day hospital admission for community-acquired pneumonia. He's feeling much better now without cough or shortness of breath, finished his antibiotics, and was noted to be a little anemic during his admission, has a history of diabetes as well, and has had CKD that's worsening the last year or two. States that over the last six to 12 months, he's been a little bit more fatigued, and he's been having more of his arthritis act up. But otherwise, he's actually feeling basically at his baseline. However, during this admission, he did have an S-PEP sent, which has just resulted to your inbox. So he asks you what this test is and what it was sent for. So I'll throw that question over to you, Jorge. How would you explain what an SPAP is to a patient and what information do you look for in using it? Good. So that's a very important question because that really gives us an idea of what exactly might be happening with these patients. So the way I'm looking at this is, you know, and I explained to the patient is your body has many different ways of, you know, fighting infections. And one of them is creating antibodies. So you have different types of antibodies. And the way I would look at it is, you know, these are weapons that your body uses to fight infections. So if you were infected, right, then you bring all your weapons and you bring all your friends with all their weapons. So all the antibodies would be elevated. But in the situation in which we have an aspect that is abnormal, you know, then we have a specific antibody that is higher than the rest, you know. And so that is not a natural state because either you are not infected and all your antibodies should be within normal limits, or you have an infectious process and all your antibodies should be elevated, you know, across the board. So the fact that only one of them is elevated and the other ones are not, then that really gives us an idea that just something is not right there. And what I say is there are different populations of cells in the patient's bodies that are producing these antibodies. And the fact that one of them is elevated, that means that there is a population of cells that have essentially gotten out of control and is producing these antibodies. Now, the whole other discussion to have is if that increase in those antibodies is a benign increase or a malignant increase. And that takes to a completely different discussion. But at least the initial idea is how to express this abnormal S-PEP and what it means in very lay terms. That's a great way to explain it because this is such a common thing. Stuart, I'm sure this happens to you all the time. Too frequently. Because every internal medicine patient has a slightly abnormal hemoglobin. In fact, when I'm looking at hemoglobins, certainly on hospitalized patients, but even in my primary care, chronically ill population, most people have some degree of anemia, it seems. It's weird to see a normal hemoglobin. That's like a red flag. I know. Like, wait a minute, what's happening? What am I missing here? Does this person have sleep apnea? It's like pseudo normal. Anyway, so I think there's a lot of terms to define here. When we check a hepatic function panel, we get a total protein. Jorge, can you talk a little bit about the two main fractions of protein? Because this is going to relate to when we talk about the specifics of the SPEP. Yeah, absolutely. So I would say there are multiple different types of proteins, but the two main types of proteins are albumin and globulin.
Well, the globulin is more like the antibody protein. So in a patient who's normal, then you should have a specific level of albumin, a specific level of globulin. In that ratio, their coefficients should be within normal limits. Usually, the globulins are lower than the albumin, and that's the typical situation. Now, in patients with any type of monoclonal paraprotein problem, either myeloma, amyloidosis, or Waldenstrom's, for example, then the globulin level goes up. Now, in some patients, the albumin hasn't changed yet, but in some other patients, when the disease advances a bit more, then the albumin also decreases. So as you can understand, the ratio gets inverted, right? And the gluvalin gets to be higher and the albumin gets to be a little bit lower. So that would be one potential, very early, easy way to understand that something is just not right with the production of antibodies. Interestingly enough, for example, a patient of mine that I saw just today, she said, well, my doctor saw my protein levels and she told me that I need to start taking protein shakes to increase my albumin. I'm like, so this is the disease that is driving that. I don't think protein shakes are going to fix this problem. I think we need to treat you for your disease. And that probably wasn't going to fix the problem. But just to give an idea how some other people look at this with good heart, right? But from a different perspective. To call the audience back to an episode of the Things We Do For No Reason, Dr. Lenny Feldman was talking to us about albumin and how it's like a negative acute phase reactant. So if someone's like inflamed or acute, you know, ill with something, often the albumin will start to drop. And no matter how much you feed that person, often, unless you reverse what's causing the low albumin, you can't get the albumin to go up. So that's, yeah, albumin, I'm sure we could talk for hours about that. So what are the, let's say for Mr. Mike Aloma, what sort of things might we get on this S-PEP that was sent for him? And what might that report read like? Yeah, so the electrophoresis curve is actually a curve, you know five smaller curves. And the big one, as we were talking about, is albumin. That's the big one. That's the one that is going to be the highest peak at the beginning. And then you have other peaks. You have the alpha 1 peak, the alpha 2 peak, the beta peak, and then the gamma peak. And we know what the distribution of that electrophoretic distribution is in normal scenarios. So when we think about a monoclonal process, a monoclonal gammopathy issue, typically we see a spike on the gamma region. That's the typical presentation. But the reason we call it typical is because most of the times in myeloma and other conditions, the most common protein that is affected is IgG. And IgG likes to kind of travel into the gamma peak, and that's why we see it there. Having said that, when we see other conditions that carry more like an IgM-paraprotein, like Waldensham, for example, or IgA, that some myeloma can also have IgA, then those can also, you know, travel into the gamma peak, but sometimes they travel into the beta peak. So if you don't have a pathologist that, you know, is very interested on how the curves actually present, they could potentially tell you that there's no M-spike when the M-spike is actually hitting into the beta area. Very rarely, you know, we see these proteins kind of giving you false peaks into the alpha region, but has also been described much more rarely. Is there any good way of trying to reduce the risk of that happening besides just trusting your pathologist? Like, is there a specific threshold of the beta peak above which you would say, hmm, maybe that's actually beta plus an M spike?
You're going to have to trust on your pathologist up to some degree. And at the end of the day, it's the shape. It's the shape of it. At the end of the day, what is going to give you all that? Now, the issue with S-PEPs, they're very useful. I'm not trying to minimize how useful they are, but they are up to some degree semi-quantitative. There's a lot of operator-driven evaluations, mainly when you have these microscopic, very tiny M-spikes, you know. And I mean, I wish there was a little bit of a better test. I think we could come up with a better test, but it's a little bit more difficult. I think the better test could be an immunofixation test. You know, the immunofixation is then what that gives you which type of monoclonal protein this is, you know. And you can have a gamma peak, but you still do not know if it's an IgG, kappa, kappa, or IgG kappa mixed, or kappa alone, or lambda alone, or IgA. So running this immunofixation in addition to the protein autophoresis, that actually helps you understand which subtype of paraprotein that we're talking about. And that can refine a little bit better the quantification of the paraprotein in that specific regard. But all these techniques are still semi-quantitative. So I want to bring this, I want to try to summarize a little bit of what you're saying here and then bring it back to our case and we can use Mr. Aloma as the example. So we're sort of quantifying if whether we're saying whether or not there's an M spike with the S-PEP and it's semi-quantitative and then the immunofixation, that's more of a qualitative test that tells us like which type, if there is an M spike, which type of protein is present there. And that could tell us if it's like IgG or IgM IgA, or one of the like the kappa or lambdas at two, I think, right? Okay. So with Mr. Aloma, his test was abnormal. He has an M spike in the gamma region. They tell us there's protein of 2.1 grams per deciliter. It's kappa free light chain restricted. And I don't understand exactly what that means. Neither do I. Yeah. Well, that's what I'm here for. So this is where, you know, I'm always like fingers crossed when I open an SPEP that it says no M-spike detected. And then I can just like high five everyone around me. So tell us, what do we do with this? Yeah, so these monoclonal processes, you know, these plasma cells, actually, let's talk about plasma cells, because these are the ones that produce immunoglobulins. And obviously, there's a clone of plasma cells that are overproducing this protein. So these monoclonal plasma cells will produce only one type of protein, right? And in most scenarios, I would say they secrete a heavy chain, could be an IgG, IgA, or IgM, and that is almost always paired with a free light chain. But because it's a clone, it cannot produce two or three different heavy chains or two or the different or the two different free light chains so typically you have an IgG kappa clone and the myeloma will be an IgG kappa myeloma with Waldron you have an IgM and it will be either kappa or lambda so you have an IgM lambda Waldron's right so that's the typical way it goes you have a heavy chain the light chain on the side and that's what the these malignant cells produce. Having said that, very rarely these malignant cells can produce only the free light chain protein. In that scenario, the myeloma will be kappa only malignant myeloma. In some scenarios, they have only the heavy chain without the free light chain. So that's a little bit more rare. Typically, it's a heavy light chain, heavy chain, and your light chain on the side. Right.
That's the quantitative part of it? Exactly. So that result on itself is semi-quantitative because you need to assume that there's an area under the curve that is normal for everybody, which is a polyclonal globulin. And then you have the monoclonal spike on top. So you basically have to assume what the baseline is for you to be able to estimate the spike. So even though they're giving you a 2.1 from the spike, you're, you're still missing a little bit down there that, you know, you're assuming is polyclonal just because of the shape of it. And that's why in those scenarios, sometimes we tend to, you know, ask for actual serum immunoglobulin levels just to get a sense of what the actual level is. That's a fully quantitative process. What you lose by doing serum immunoglobulins is that you're measuring the entire scenario. So you don't know how much is polyclonal or monoclonal. You just know that it's beyond normal or higher than normal. So I would say both values kind of complement each other, right? They are trying to measure the same thing. They do it up to some degree, but none of them is perfect. Yeah. So with polyclonal, if someone had like a rip-roaring pneumonia and we were to, for some reason, get an S-PEP right in the midst of that, we might just see all the immunoglobulin levels, like the alpha, the beta, the gamma region, it would all be up. But if someone has some sort of a monoclonal thing going on, they're going to have more of like an actual sharp peak. Like I saw Church Spire as referenced. And so in this case, they looked at it and he had a distinct peak. I know there's some cutoffs for these values as well. Oh, Stuart, what were you going to say? I was just going to say, I think said the that you would have immunoglobulin elevations in alpha beta and gamma region but that's what i think for polyclonal for polyclonal if it was like a poly right right but just bear in mind that most of the alpha and beta elevations are not uh immunoglobulin that's like your acute phase reactants your transferrin ferritin stuff like that okay one way of looking at this is you can just put your hands like this and this is essentially how the the s-pep looks like this is your albumin this is your alpha one alpha two beta and this is your gamma so the gamma is typically like this kind of a kind of a mount this way kind of a little wide and that's when you have you have, for example, hepatitis, HIV, or lupus, or any acute infection, then you will have a wide distribution of the gamma globulins, which is different than when you actually have a monoclonal process in which, you know, the curve will be the same, but then you have like a peak on top of it. As you said, the church spire, you know, so the shape of it is very distinctive. And, you know, that would be one way of understanding what the shape of this is. This is kind of... So for the audience at home, if you take your right... If you're driving, please don't do this, but if you take your right hand in front of you and hold it up in front of your face and put out your pinky finger and your thumb and bend down the three fingers in the middle, then your pinky is the albumin, and then you have alpha 1, alpha 2, beta. They're just smaller humps, and the gamma is your thumb, which is kind of pointed out to the side in like a nice round mound there. There you go. That's a good description. All right. And hopefully we didn't cause any car crashes with that. But I think that's pretty cool. I think that was worth mentioning so the audience can try to look at that because I think I will remember that. All right. So what do we have? What do we tell Mr. Aloma? He has an M spike. He's freaking out.
It's kappa-free, light-chain restricted. How would you explain that to him? Yeah, I think the next step would be to say, well, there is a monoclonal process in there, and we acknowledge that it's not normal, right? So something is going on there. So the way I would say is we need to know if this is a benign monoclonal process or a malignant monoclonal process. Because there's a benign condition called monoclonal gammopathy of undetermined significance, or MGUS, M-G-U-S. And if we go around, you know, just taking blood randomly from people, you will see that the rate of MGUS in the country is anywhere between 3% and 5%, which is very prevalent if you think about it. Having said that, that changes with age. So if you take all the 50-year-olds, the rate will be probably about 1%. If you take the, they'll go up to 3% with 60s, 5% with the 70s, and over kind of close to 10% in the 80s. So there's something about aging that is related to the monoclonal homopathic no significance. So there is a chance that this patient might have an actual MGUS. The things against this being MGUS is the situation of the patient is somewhat anemic. And you can make a case that maybe the anemia is driven by this process. If the patient will be hypoalbuminemic, that will even further my concern that this patient might have a malignant process. So therefore, how do we differentiate a malignant process from a benign process? And that's where additional testing, including a bone marrow biopsy, could be of help to understand a little bit better what's going on with these patients. So I've got the dumb primary care physician question. At what point do I not look stupid consulting hematology for this patient? At what point am I okay to hit that button? Yeah. So, I mean, I think if you have an IgG, the issue is the most common subtype of MGUS is IgG. So you have an IgG MGUS in which the patient is completely symptomatic, in which the patient has, you know, the blood counts are completely normal, calcium is normal, kidney function is normal, everything is fine, and your IgG is barely elevated with an M-spike, maybe, you know, less than 0.5, I mean, those patients are most likely to be benign. Now, if your M-spike is over 1.5 and there's a little bit of anemia, a little bit of hyperbolemia, a little bit of hypercalcemia, then those are the patients that classically you will need to refer for evaluation. Nowadays, at least in bigger institutions, there are a number of different programs in which they are following these patients with MGUS for other research and things of that nature. So I think if you find an MGUS or a monoclonal gammopathy on a patient, I think it's safe to refer to a hematologist. Just the sole presence of the monoclonal gammopathy, I think you're better off making sure that the patient doesn't have a malignancy or doesn't have a benign process. Why? Because can you be completely sure that with an M spike of 0.5, the patient does not have a smoldering myeloma? You cannot be sure of that, you know? Can you be sure that because the IgM is not that high that the patient doesn't have wild mushrooms? You cannot completely say that even the patient is not anemic. So you're almost always safe to, once you find an M-spike, to send the patient to a hematologist. I think we should define asymptomatic. Yeah. So, I mean, when we think about myeloma, for example, you know, I think we all know about the CRAB criteria, you know, the hypercalcemia, renal disease, anemia, bone disease. So if a patient has any of those, the patient will be considered symptomatic. If the patient doesn't have any of that, then the patient could be considered asymptomatic.
So we do have neuropathy, hyperviscosity, so complete different sets of symptoms. The anemia is the only thing that myeloma and Waldenstrom share, but everything else, kidney disease is very rare in Waldenstrom's, bone disease is very rare in Waldenstrom's. So it's a little bit of, they're different diseases. They do have the gammopathy in common, but really they are clinically very different conditions. So if a patient with Waldensrom's doesn't have neuropathy, is not anemic, there's no evidence of hyperviscosity, we'll talk about the symptoms in a minute, then those patients could be considered asymptomatic. Having said all that, I think the best person to assess the presence or absence of symptoms in somebody with myeloma or suspected Waldron-Schramm's is the hematologist. And trust me, some hematologists sometimes have that concept a little bit confused as well. So don't feel bad about it. So I think in that sense, sending the patient to be seen by a specialist is reasonable, even if you felt the patient is actually asymptomatic. And if you don't know if the patient is symptomatic or not, then more reason to actually send the patient to be seen. Are there any supplementary lab tests or procedures that you would want done before you got that referral? I think what we typically tend to, you know, just to get a good idea of what's going on, I think, you know, getting the S-pepid immunofixation key, right? I think getting a complete blood count and metabolic panel just to get at the kidney and the calcium level, right, specifically in myeloma patients. The actual immunoglobulin levels, those are really important because if you have an IgM of 1,000 in Waldensham, for example, you have an IgM of 5,000, that has different implications in terms of what you might expect the patient to be experiencing or not. If you want to be fancy, you can send some free light chain, you know, free light chain levels, KAMBDA, and that can also give you an additional idea of what might be going on. But I think those are the tests that we typically tend to order when we want to see what's going on with the patient. And obviously, depending on what we see, then we can order additional testing. We can order urine tests if we think the kidneys are suffering on the patient. Additional testing for the hypercalcemia. I think in a patient present with hypercalcemia, doing a complete workup for hypercalcemia is very reasonable. You know, running your PTH, your intact PTH, and your ironized calcium, running your TSH or vitamin A or whatever you think might be going on, evaluating the patient is getting vitamin D, you know, externally or maybe overdoing that. You know, I think so. I think you're doing your anemia workup in the first place, making sure the patient is not deficient or vitamin B12 deficient, folic acid deficiency, things like that. You know, in that way, you cover all your bases. And in that way, when the patient comes to see the hematologist, we don't have to be running all that, all the same workup all over again, you know, just to make things a little bit easier. So Mr. Aloma, he has evidence of kidney disease and it's been progressing. He has some mild anemia. So he seems to have, and he has an M-spike. So we're concerned for myeloma regardless of, you know, how high the protein is here. And would you also add to the list for him the skeletal survey? And do you get all the bones or do you just get certain spots that are more high yield? Yeah, so I think when we think about what can be done from the internal medicine perspective, I think a skeletal survey is a reasonable way to move forward. And that implies x-rays of the skull and the spine and the ribs and the hips and the long bones. Having said all that, once the patient comes to see the hematologist, then we tend to do more specialized imaging testing.
So it's very specific, right? If you find a lesion, then you know something is wrong. But if you don't find a lesion, sometimes the patients might have lesions that are not detectable by skeletal survey. And in that scenario, we tend to do other testing. We tend to do MRIs, we tend to do PET scans and all this type of stuff. But I mean, that would be more in the realm of the hematologist, oncologist type of work. I think getting a baseline skeletal survey makes a lot of sense. So we're getting a skeletal survey for him. And then I want to add on two other things that let's say that we sent. So I think we're going to send a urine protein electrophoresis also with immunofixation. And that needs to be a 24-hour from my understanding, or can we do that as just like a spot urine? So the recommendation would be in somebody with kidney abnormalities like this patient would be to actually do a 24-hour. And you have to send a couple of things. So you accumulate your 24-hour urine, and then you send it for protein quantification, just to see if there's any excess albuminuria there that can sometimes give you an idea that maybe some amyloidosis could be going on in the kidney and things like that. And also your electrophoresis to understand if there's any Ben's Jones protein in it, right? In myeloma, that's very important because kidney disease in myeloma usually associates with these Ben's Jones proteins, you know, or amyloidosis. So by doing this 24-hour urine with albumin and the electrophoresis, you can actually figure that out a little bit. You know, if your albumin looks normal and there's no Ben's Jones protein, then you can say, well, maybe it's not the myeloma that is driving the kidney dysfunction and maybe the diabetes, right? In that way, it can help you out. With diabetes, you can also see some albuminuria, right? But it will be not as marked as the one that we see typically with amyloidosis. And if you could remind us what a Benz-Jones protein actually is. Yeah, so the Benz-Jones protein is essentially this excess gamma globulin that we tend to see in the urine, and specifically tends to be monoclonal because of these abnormalities. Now, you need to be careful with that because if you do urine electrophoresis on all the patients with gammopathies, they're all going to have a little bit of monoclonal protein coming out of the urine, right? So you have to take it in the right clinical context. If you have somebody with myeloma and kidney dysfunction, then I think that's a good indication that the light chain or the electrophoresis there, the excess of protein is the one that is driving the disease in the kidney. One more question about the UPEP, the urine electrophoresis. Would you always get it in a patient in whom you're getting an S-PEP? Or do you reserve it for a kind of second line set of diagnostic tests in patients with kidney disease, for example? Yeah, so I typically do not get it for diagnostic purposes, you know, because I think the S-PEP and the free light chains are, or the immunoglobulin immunofixation is sensitive enough to actually make a good diagnosis in understanding what's going on. But, you know, but if somebody has kidney disease, then for sure, I tend to obtain the erythrophoresis in the urine in those patients. Or if I suspect amyloidosis, that's another reason to do that. Okay, Jorge, I think this is interesting to talk about. And we've talked about this with our great friend, kidney boy Joel Toff before, where the urine dipstick tests for albumin, but it doesn't necessarily pick up if there's protein like in the urine, like light chains.
Whereas you might miss that if you just did the dipstick because, because of the albumin fraction. And you mentioned the Bench Jones protein. So that would be on the, you would know that from the, there would be an M spike in the urine, just like there was in the serum. And then when you do the qualitative part of it with the immunofixation, it would tell you that those were, would they be the light chain portion or could it just be the heavy chain or light chain or both? So typically is, most commonly is the free light chain components because those are smaller molecules and they can be filtered out easier by the glomeruli. But in some scenarios when the damage is much more pronounced, then you can actually have the entire heavy chain and the light chain in the urine as well. All right. And I think that sets up Stuart. Stuart, you had another question? I just wanted to ask just overall whether or not we need to order the free light chain ratio at this point and how we would interpret that. Yeah, because I think how to interpret it too, because a lot of the times I'm seeing people order like SPEP, UPEP, IFE, free light chains, and then that gets dumped to me. And I'm like- And you're like, what do I do with this? I mean, it's 1.75. I mean, do I do something with that? I don't know. It's red. That's all I know. This is literally why we wanted to do this show. I know. It's just the slab. Just the slab. Yeah. So, I mean, I think in the right context, having a free light chain is important. If you have, again, we talked about myeloma and how there are different subtypes. So you have the IGGs, the most common IGA, less common IGM, very rare, and you have the free light chain only. Now, if you do the free light chain only, you have a free light chain only myeloma, your S-PEP might actually be normal. You might not pick that peak in the electrophoresis, and that could be a little tricky if you think about it. You need to have the heavy chain to be able to see that if you have only free light chains, it might be missed. And that's why, just to be on the safer side, a free light chain is added to the whole process to understand that a little bit better. Now, in myeloma, we looked at all these proteins as a group. And then when we treat the patient, we actually follow these levels of proteins to assess the response. And that's where I think it's much more important. The free light chains are more important because the IgG is going to drop. It's going to go within normal limits and that M spike is going to disappear. And we want to think, oh, the patient might be in a complete response. That's where the free light chain SA really comes into place. And then it it was abnormal before and still abnormal even though the the heavy chain has normalized then the disease has not really gone there's not a complete no there's no stringent complete response so for response assessment the free light chains are very very important in that specific sense but for us to be able to quantify that we need to have a baseline free night light chain. So that's the value of having an initial free light chain. So not much more for what you can do with that, because you can suspect somebody has myeloma without actually having the free light chains. But in the case in which you don't have a strong heavy chain mark, then the free light chains can give the answer. And you, you know, you wouldn't be surprised to actually see that sometimes IGG, IGM, everything looks normal. Your answer looks fine. And you look at the free license and the Kappa is like 5,000, right? And then you're like, oh, I'm glad I ordered the free license. And just one more question about that. Is it the absolute value that you look at, or is it the ratio of right?
That is not problematic because your kappa is normal and your lambda is below normal. That is not an issue. So you need to look at the absolute number first to make sure that it's abnormally high, right? Either the kappa or the lambda. And then your ratio actually does make sense. Now, this becomes a little trickier when you have kidney dysfunction, for example. In kidney dysfunction, both your kappa and your lambda will be actually elevated just because of the kidney dysfunction itself, and that can actually mess up your free light chain evaluation. So again, everything in the right context. And whenever in doubt, just curbside hematology. Yeah, we're clearly we're capable of doing that. That's what the whole show is based on. Jorge, this, this has been a great overview of testing. And I know we're like hammering you with questions. I think it's just because this cause causes all of us a lot of anxiety, but it sounds like the good news is CBC, BMP, the S-PEP and the immunofixation, a lot of the times that will get us there. And we might, as a second round of testing, do like quantitative, like IgG levels, like the total levels, maybe free light chains. And then depending on what we find, if there's hypercalcemia, that might send us to that workup. We might do the skeletal survey before we send them to you. But hematology is going to really help us try to figure out what this is. And you also gave us a bunch of the symptoms to look for, which were like cytopenias, the calcium, the kidneys, and those were the main ones. So I think this is a great overview and framework for the audience. So I guess that leads into the next big question that we have, which is how you think about the different disease processes that are actually causing these abnormalities on the SPAP? And do you have a general diagnostic framework kind of using clinical clues or SPAP to break it down into a nice, organized, logical step-by-step approach? Yeah, I mean, I think, you know, when we think about monoclonal gammopathies in general terms, there are three big diseases that we tend to treat. I think the big one, the one that is most common is myeloma. Then we have two more rare conditions. One of them is Waldenshrom's macroglobulinemia, which is really a lymphoma. And then we have the other is amyloidosis, which is truly a plasma cell dyscrasia as well. There are other much more rare conditions that I don't think we have all the time to talk about all those more rare situations. So I think we'd like to start by saying that all these conditions have a pre-malignant scenario called MGUS. And depending on the heavy chain of the MGUS can actually give us the potential scenario in which what this MGUS might actually progress into. If you have an IgG or an IgA MGUS, those patients are more likely if they progress or to progress into myeloma, for example, while the IgM MGUS, they tend to progress more likely into Waldron, so much less likely into myeloma. The free-light chain MGUSes, Kappa or Lambda, they can basically turn into myeloma, but they can also turn into amyloidosis as well. So all these plasma cell discreations have these pre-malignant MGUS conditions. Now, if somebody has an MGUS, diagnosed with MGUS, the risk of turning into myeloma is about 1% per year. And if you have an IgM MGUS, that is actually a 1.5% per year of progressing into Waldenschutz. So the way I tell my patients is, well, you have this MGUS condition, IgG, for example, is a 1% per year risk. So that means you need to be alive for 100 years from today to actually have 100% risk of progressing into myeloma. And for wildness, I use 70 years, which is the appropriate calculation.
And then these patients need to be monitored just in case they actually progress to a malignancy. Now, the patients who are symptomatic, typically diagnosed with myeloma, I think I mentioned the CRAB criteria, right? These patients have this hypercalcemia, the renal dysfunction, which is typically associated with light chain cast nephropathy, but it could be many other reasons. The anemia tends to be normochromic, normocytic. And then you have the bone lesions that are typically allytic lesions, and they can be seen in skeletal service and other imaging like MRIs and things of that nature. So that is the classic clinical picture of a patient with myeloma. That's the classic picture that comes in the questions of in the boards, right? And so in those patients, you get the different levels. You understand that maybe an IgG kappa and things of that nature. And then what do you do with a patient like that? I mean, obviously, you need to treat those patients because the mortality in a patient with myeloma tends to be myeloma. You know, about 80% of the patients with myeloma die of myeloma. And also the survival of these patients has improved, actually, over the last decade. And I think it's because of the newer treatments that have come along. I mean, there's a lot of research showing that the plasma cells in myeloma are highly resistant to chemotherapy, highly resistant to chemotherapy. They have a lot of different mechanisms that protect them against chemotherapy. So the non-chemotherapy approach is what we're using nowadays. We're using immunomodulators, we're using proteasome inhibitors, we're using antibodies, all these with steroids. And with that, we have, I would say, myeloma is one of the conditions in which there have been more FDA approvals in the last decade than any other hematologic malignancy for that matter. And that's a lot to say because in lymphoma, we had a lot of developments as well. So I think the overall survival of patients have changed in my lifetime, actually in my lifetime as a hematologist. When I was a fellow, the median overall survival of myeloma was three years, and that was the median overall survival. The median overall survival now is about eight years on those patients. Doesn't sound like a lot if you are a myeloma patient, obviously, but in the whole realm of things, it's a massive improvement on the patient's survival. Now we have about 30% to 40% of patients might be alive for longer than 10 years, which is something that when I was training, that was an impossible thing to think about. So I think the research is important to understand how we can treat those patients. Now, Waldron-Strom's is a little bit different. Waldron-Strom's is actually a lymphoma. It's a lymphoma. It's a lymphoplasmocytic lymphoma, in which a component of the disease is a plasma cell discreation. But the main stem cell of the malignancy is not the plasma cell. So these patients, lymphoplasmocytic lymphomas, tend to have IgM over secretion. You can also see a little bit of IgG and IgA, but that's a topic for a different lecture probably. But the classic is this IgM secretion. And these patients tend to present different than myeloma presents. I think they share the anemia, as we were saying earlier, but the IgM has its own physical chemical properties on its own. It's a pentamer. It's a larger molecule compared to IgG or compared to IgA. And these patients can present with hyperviscosity. That's a classic manifestation of a patient with Waldenschulm's nose bleeds, blurred vision because of retinal hemorrhages, headaches. IgM is typically in the 4,000 or 5,000, 6,000 levels, milligrams per deciliter. And that will be one presentation of patients with Waldenschulm's. The other one is neuropathy.
These patients can have an anti-MAG antibody in about 50% of the times. They have demyelination in nerve conduction studies. And then we have the anemia, which is a classic presentation for these patients. How frequent we see kidney dysfunction because of Waldron's? 2% to 3% of the cases. So it's much lower than in myeloma, which is about 40% to 50% of the cases we have kidney problems. How many patients with Waldron's have actually lytic lesions in the bones? Less than 1%. Very unlikely compared to myeloma, which 30 to 40% of patients will have some lytic lesions at some point. So the management of these conditions are very different. Finally, I think the survival of patients with Waldner's thrombosis is actually better than the patients with myeloma. Number one, the mortality because of Wilder's shrooms is probably anywhere between 10 and 20%. So four out of five patients with Wilder's shrooms don't die because of Wilder's shrooms. They die for other reasons. And the median survival on these patients is anywhere between around 15 years. So it's easily double in average than myeloma is. And the treatments are a little bit similar because we have borrowed a lot of treatments from myeloma. We have borrowed a lot of treatments from lymphoma. So we use a little bit more chemotherapy in these conditions. These cells are actually more sensitive to chemotherapy than the plasma cells are. But we use some of the treatments for myeloma like proteasome inhibitors we use as well. We use antibodies. And we have a new family of medications called BTK inhibitors that are oral agents. So the overall survival of patients with water syndrome have also increased over the last decade with the newer treatments. But the ground gain is much more substantial for myeloma, as you can understand, even though their outcomes are still not as good as, but their ground cover is much better than for wild mushrooms. We're working on that as well. Now, amyloidosis tends to be, I think, the toughest one out of the three. I think the mortality of amyloidosis not only is more pronounced, but also is shorter, mainly when you have cardiac amyloidosis. Amyloidosis is a type of disease that if you find it in the fat pad biopsy or in a heart biopsy or in a kidney biopsy, then you know the patient has it. But if you suspect clinically the patient has this disease and you cannot find it, you're still not sure the patient doesn't have it. That's reassuring. I know. Trust me. Welcome to my life. So this is the toughest part. So amyloidosis can be suspected in many different situations. I think the classic situation is a patient with nephrotic syndrome. That's the classic situation. Now, the kidney damage for amyloidosis is different than the kidney damage for myeloma. The kidney damage in amyloidosis is glomeruli disruption, and that basically creates a patient being able to shed a lot of these albumin out in the urine. The light chain cast nephropathy that we see in myeloma is a little bit different. That affects the creatinine function, while in the nephrotic syndrome, the creatinine function is not always affected, right? So there are two different ways in which diseases can present. And sometimes the urine findings can tell you, or at least tell you, well, maybe this is an amyloidosis versus a myeloma in that specific scenario. The other scenario will be neuropathy can also happen in amyloidosis, but it's different than in Waldstrom's. This is an axonal neuropathy, muscle wasting, more rapidly produced, progressing, not only the sensation issue, but also pain, sometimes weakness, and sometimes hands and feet are affected at the same time, which is not precisely length dependent like Waldenstrom says. And the other one is patients with cardiomyopathy.
So any of those clinical aspects or features of the patient can make you suspect that somebody has amyloidosis. And for amyloidosis, you need to get the tissue, right? If you suspect the patient has it, an abdominal fat biopsy or a transrectal biopsy can sometimes help you. The problem here is that there are multiple types. There are multiple types of amyloidosis, you know? The one that we're talking about right now is the light chain amyloidosis. The one that is related to a plasma cell discreation, but we have so many other types. We have the AA amyloidosis. We have the TTR amyloidosis. Some of them are acquired. Some of them are hereditary. So the fact that you take a piece of tissue and you look under the microscope and you find the Congo rat, right, that doesn't really tell you it's a light-chain amyloidosis. You still need to send that piece of tissue to the mass spectrometry, you know, at different institutions in the United States that can run that. And then you can actually make a diagnosis of LA amyloidosis. Just to give you an example, a patient was sent to my clinic with Waldenstrom's and cardiac amyloidosis to be treated for cardiac amyloidosis. We decided to do all the additional testing. We took a piece of that myocardium and the patient had actually TTR amyloidosis and not AL amyloidosis. The worst thing I could have done for that gentleman is to actually give him chemotherapy for his amyloidosis because I was not going to fix it, right? So always biopsy and always try to find the tissue that you're looking for before you actually expose the patients to treatment they might not need. I think that's a good can definitely remember myeloma will think about the crab symptoms that you you mentioned, Waldenstrom's, they'll have anemia plus neuropathy, and maybe the hyper viscosity. And then for amyloidosis, it's more of like the cardiomyop, neuropathy symptoms that we think of. Okay. And I know we wanted to maybe talk a little bit about the hyperviscosity just because it's, I don't think I've, I don't know if I've ever seen it. And I just, if we don't ask you about it, you know, we're going to be kicking ourselves. How does that present with Waldenstrom's? And how often is that? Because I really don't think I've seen it, or maybe I just didn't recognize it. So at this time, I think probably about 10% of patients with Waldenstroms can present with hyperviscosity. I think that range has actually decreased over time. And I think it's because we tend to detect these patients now a little earlier. Now, the classic presentation of hyperviscosity are recurrent spontaneous nosebleeds. And they're really, really hard to control. And they are just gushing out nosebleeds out of nowhere. The other finding is these headaches wakes up the patient very early in the morning. They never go away. And it gets worse over time. And the last one classic is blurred vision. That doesn't correct with glasses, just the patient just is blurred vision. These patients tend to have these fundoscopic examinations and they have all these different changes in the retinal vessels, anywhere from just engorgement and tortuosity of the vessels all the way to sausage gene and all the way to actual retinal bleeds and once you have seen you know either a patient's you know losing his sight you know or stroking out because of hyper viscosity you never forget it and you take it very very seriously it very, very seriously. So the answer there is to plasmapheresis patients. If you suspect the patient's having these problems, either a peripheral line or putting a central line to plasmapheresis patient, that's the right answer always. Now, a teaching point here is that because the blood is very viscous and very thick, you tend to bring more fluid into the intravascular volume, and these patients actually could be artifactually more anemic than the usual.
You need to ferrous them first. And don't be surprised if the hemoglobin actually goes up about a point or a point and a half just by plasmapherusing this patient. And then the patient might not even need to be transfused. The point is, if you transfuse a patient with hyperviscosity, you actually make them more viscous. And you can actually make the symptoms worse in that specific scenario. Is there a specific level of IgM at which you should be particularly suspicious for hyperviscosity? Yeah, so we actually did a study, 800 people with Waldron's and we followed them with their IgMs. With an IgM below 3,000, almost nobody had hyperviscosity. So I would say the hyperviscosity problem starts about 3,000 milligrams per deciliter. Now the risk of hyperviscosity between 3,000 and 4,000 was about 2-3%. Between 4,000 and 5,000 was about 5-6%. And between 5,000 and 6,000, about 10-12%. Over 6,000 is when really went up to about 50% to 60% of the patients actually had hyperviscosity symptoms. So as you can see, it's not a linear distribution. It's more like a logarithmic distribution of the risk of hyperviscosity based on the IgM. So anybody over 3,000 can have hyperviscosity, but anybody over 6,000 more likely will have hyperviscosity. I think we're going to have to get take-home points. I think we could keep going for another hour or two with all the questions that we probably still have, but can you give us maybe, if people were just going to remember two or three things from this talk, what would you like them to remember about MGUS and then the three my then the three myeloma amyloid Waldenstroms that we talked about? I think having a high degree of suspicion and just keep your eyes open for these type of things is actually probably the best message that I can provide. Just think about it. You know, just by thinking about it, then you can potentially do a workup that is important. And again, an S-PEP could potentially be lifesaving for people who might be having hyperdiscosity, for people who may be having hypercalcemia or acute kidney injury, which are the worst case scenarios in here. Always have that in mind. And I think running an SPIP is a low cost, potentially high yield scenario. And then they refer to hematology. And now we know how to interpret this now too. So anything that you wanted to plug before we let you go? I think an important aspect of all this is we as academics and scientists and researchers really cannot advance the science without the help of our patients. And the patients can help in many different ways. They can help by providing samples. They can help by participating in clinical trials. So I really, you know, I would encourage, you know, not only the physicians taking care of the patients and the patients themselves to think about participating in research so we can advance the science. All right. This was awesome. Thank you so much. We will fade that into the outro and we'll let you get back to your family. This was, I feel good about all this. And then once I go back and listen to it like two times and read the show notes that Nora makes and everything, I learned this stuff so well. So thank you so much. I know the audience will as well. No, my pleasure. Thank you for the invite, Nora. This was great. Thank you so much. This is awesome. I'm glad to be able to reach out to people from different aspects of what we do. And so I think this is an awesome way to get our weekly show notes in your inbox. That's right, because we're committed to providing you with high value practice change knowledge. And to do that, we need your feedback.
This is the New England Journal of Medicine COVID-19 update for April 14th, 2021. I'm Stephen Morrissey, Managing Editor of the Journal, and I'm talking with Eric Rubin, Editor-in-Chief, and Lindsay Baden, Deputy Editor. Eric and Lindsay, we're now well into the rollout of vaccines in this country. Many states are opening up vaccine availability to anyone who wants it, and supplies are increasing to the point where it's far easier to get an appointment to be vaccinated than it was even a few weeks ago. Are we seeing any effect of this yet? I think we are, Steve. In areas with very high vaccination rates, the best example, of course, is Israel. We are really seeing dramatic effects and lowering the number of cases, but we are seeing effects in the U.S. as well. Now, the coverage here is much less than in Israel, where 60% of the population has already received one dose. And pretty much every indicator is improving. The U.S. is a bit more complicated because our vaccination rate is lower. About a third of people have received a single dose, about a little less than a quarter have received two doses. And in the face of that, the number of cases is continuing to rise slightly overall. But the case numbers is probably not the right metric to gauge the effect of vaccination. Remember that case numbers reflect exposure and a lot more people are being exposed right now and are out inactive. And the fact that new variants are circulating, which appear to transmit more effectively. So those two factors are helping to drive an increased rate of disease. But there are other metrics that probably suggest that vaccines are working. Remember that the groups who have the highest rates of vaccination are largely those at high risk of disease, the elderly and people with immune system defects. And these are the people who are likely not out in public that much and probably not contributing much to the spread of disease. However, they do contribute very heavily to the severe disease, which we can measure through hospitalizations and deaths, because these high-risk individuals are overrepresented in those categories. Of these two numbers, deaths lag behind because people who are critically ill are often hospitalized for extended periods before they succumb. So hospitalizations are probably our most sensitive early indicator of the effect of vaccines. And there, the rate has been falling in the U.S. overall, although there are pockets where it's still rising. Here in Massachusetts, where the vaccination rates have been higher than in some states, the number of hospitalizations has fallen precipitously. And in fact, the death rate and the number of new cases are dropping as well here, albeit more slowly than hospitalizations. So it's a little early to declare vaccination a huge success, but there are good indicators that it's working. I mean, Eric, as you allude to, this is such a complicated situation where the rollout of vaccines, I think, clearly has substantial benefits, particularly on severe illness. But as we know, transmission is impacted both by viral factors and human factors. And we're all continuing to monitor the emergence of viral variants and the potential meaning. But we also need to think about our behavior. And many across the nation, probably us included, are sharing in the frustration and fatigue that the last 15 months of house arrest has imparted. And we need to remember that as we open schools and open other activities where we interact. That also impacts transmissibility of the virus and subsequent associated illness. And we need to continue with our routine public health control measures while we are ramping up immunity through vaccination. And as we watch numbers go up in some areas and some communities, we need to redouble our efforts to try and decrease that transmission as we are ramping up vaccinations. We've talked a lot, Lindsay, about the importance of public health interventions beyond vaccination. And another way to think about them, and I think that it's very relevant for what you're saying, is the speed at which an intervention can take effect. Vaccination is a great way of producing long-term effects on transmission and disease, but it takes a long time. Of course, we don't have enough vaccine for everybody.
And there's a gradient risk during that time. So it's a slow intervention. You can take public health measures tomorrow and have an immediate effect on transmission. So it's important to remember that in places that are having large outbreaks, vaccination is not a rapid way out of the problem. So we've published two case series describing an unusual adverse event seen with one of these current vaccines. What did we learn there? Steve, the two case series we published are from two different European countries describing patients with similar syndromes. We've heard a good deal in news reports about thrombosis following vaccination with CHADOX1, the SARS-CoV-2 vaccine from Oxford and AstraZeneca. According to regulators, it wasn't clear if this was happening at an increased rate in vaccine recipients. But now that we can see details of some of these cases, it's clear that they are very unusual. One report describes five patients, the other describes 11 patients, all of whom had a thrombotic thrombocytopenia with platelet counts that were low, generally below 50,000 and some being very much lower and many different sites of thrombosis. But the striking thing is that there was an unusual involvement of cerebral sinuses. The majority of patients had cerebral sinus thrombosis. The cases ranged, but many of them were very severe. 11 of the 16 patients died of complications from the illness, and some remained critically ill. And along with the unusual illness, these patients had striking epidemiology. Almost all of them presented between one and two weeks after their first dose of the vaccine. And they were very young, ranging from 22 to 54, with most of them in their 30s. And most had no other risk factors for thrombotic syndromes. So I think, Eric, these observations point out that vaccine surveillance for side effects is working. And it shows the importance of having observant, astute clinicians who are able to identify patterns of illness that are out of bounds, that are unusual and unique, and then be able to determine how that might be related to a preceding event such as vaccination. I think this really speaks to having the global community monitoring, interacting, communicating to be able to identify these kinds of unusual events and then determine if they're real and if they're associated with the potential intervention of concern. So I find it very concerning, but also very encouraging that our system can work this way. I think the other thing that this points up, Lindsay, is how difficult that surveillance is. In this case, blood clotting syndromes are unusual, but they're not extraordinarily rare. And if you immunize millions and millions of people, some are coincidentally going to have DVTs or PEs because those things happen. And they might well have happened before. I think what permitted this to be seen was the sinus thrombosis, which was unusual. And I think that when regulators first looked at cases, I strongly suspect they lumped all thrombotic conditions together. And in that, you couldn't see these small numbers because of the noise, the signal to noise ratio wasn't good. And there's no reason to expect this particular complication. But now that you see it, it really does produce a signal that really looks like a strong association. I mean, I agree, Eric. I think that things which are common are very hard to discern because of the noise issue. The uniqueness and severity of cavernous sinus thrombosis, splanchnic vein thrombosis, those are very rare events, particularly in young people. And that may have made it a little bit easier to aggregate cases to look for a pattern. But it's very hard to do quality surveillance for common things. What do we know about the pathogenesis of this illness? The pathogenesis is very unusual. All of these individuals had a syndrome that resembled heparin-induced thrombocytopenia, or HIT, though there was an important difference. HIT results from an antibody that binds to platelet factor 4, or PF4.
So all of these patients had the anti-PF4 antibodies that are seen in HIT, but none of them received heparin at the time of presentation. So it seems likely that something else was acting as a scaffold for PF4 binding, but we don't know what that is. This is very unusual. There are only a tiny handful of cases of a hit-like syndrome in the absence of heparin that have been previously reported. I mean, I think it's important to understand the mechanism. By understanding the mechanism, it increases our confidence that the observation may be correct. It also allows us to better understand who may be at risk and therefore decrease the potential of this type of side effect, as well as determine if this is somehow intrinsic to the virus or the vaccine or some excipient in the vaccine delivery process. So the better we can understand what is going on, the better chance we have to mitigate, diminish, and potentially remove this risk. It's a very good point, Lindsay. There are two implications to this. One, of course, is for the individual patients and their therapy. And the other is because the mechanism is so peculiar, it makes it easier to make the association. So it really helps us understand that there is very likely causality here. So now that we know something about cause, are there implications for therapy with this syndrome? There are. Many of these people were treated with heparin before the underlying pathogenesis was identified. Some improved and some worsened on heparin, but that's not unexpected. Heparin, particularly at low doses, would likely worsen the disease as it would offer a way to cluster the antibodies and cause even more platelet activation. Knowing what we know now, it seems likely that it's safer to treat with other antithrombotic agents, such as direct acting anticoagulants. I mean, it also raises the issue, given the mechanism of ways to block the FC part of the IgG. So there might be other avenues that may emerge that people will recommend as potential treatments. By understanding the mechanism, I look forward to seeing thoughtful approaches to decreasing this complication. And I should point out that many of these patients did receive intravenous immunoglobulin. And that, as you said, might be another effective therapy as it blocks the FC receptors on platelets. And it did appear in this very small number of cases that perhaps it made a difference. So that's an additional therapeutic avenue. I mean, we need to be careful that we don't know how to treat this. However, through understanding the mechanism, these logical approaches have been applied and will be applied if needed, but hopefully will diminish the occurrence of these side effects through other public health interventions. So what does this mean for the CHADOX1 vaccine? That's a really good question. I mean, all vaccines and all drugs, for that matter, have associated rare side effects. This one is particularly severe as it's resulted in several deaths already. But it's important to keep a couple of things in mind. First, we can't tell from this case series how common this is. There have been a very large number of doses administered, and there still are a relatively small number of cases described, although there certainly are more that have appeared in the popular press. But we don't know the numbers yet and we don't know the denominator. On one hand, it's certainly possible that these are occurring at a rate that's as low as one in a million, but that's complicated by a second factor, the fact that all the patients thus far have been young. While there's been a lot of vaccine given out, much of that's been in the elderly to protect that high-risk group from COVID-19. So the rate of this complication could be very much higher in young people as a number of total recipients is likely to be relatively small. So as a consequence of that, several countries have decided to limit vaccination to older individuals to decrease the risk. I think it is going to be important to calculate the risk, however, because this vaccine, Chadox 1, has been the most likely vaccine to be broadly used worldwide. It's crucial that we get vaccine of some sort to the world.
But it's not just a question of equity. It's also self-interest. The more viruses circulating in the world, the more likely we are to see new variants arise, some of which could pose a larger threat even to those who've already received vaccine. So this vaccine is an important part of the world story. And I think we need to have a good assessment of it before we decide that it's not the one that we're going to use. I mean, I think, Eric, there are several very important issues that you've raised. I think global equity in vaccine distribution is really important because it's the right thing to do. It also benefits all of us. And as we look at the rollout in the U.S., we need to be thinking about the rollout globally and how are we as a global community ensuring that those at highest risk for complications are getting access to vaccine and vaccination. Where the ChAdOx vaccine fits in will require proper discussion when all the information is available, including the nature and rate of the side effect, as well as the efficacy against variants. A variety of factors will have to be weighed globally, but we need as many tools as possible to turn the tide on transmission, and we need to turn the tide on this globally. Part of what will hopefully be in our discussion, because this reminds me of a discussion 25 years ago with rotavirus and its vaccine development, and how we as a community weighed the issues of interception versus activity against severe rotaviral diarrhea and morbidity and mortality in little ones. And I think we have to look very carefully about risk-benefit ratios as we understand the burden of infection, the severity of infection, and the risks associated with the vaccines. Because there is no medicine that we use that doesn't have a risk of anaphylaxis or some other risk. And we're always weighing that against the benefit. And I think this will need to be part of the conversation as we all as a global community common in infants and lethal in infants in the developing world, although more of an annoyance in countries that have good access to healthcare. It did fine in its original trials, very comparable to the vaccines we're looking at here. But as it was introduced, it became clear that a complication, intussusception, was occurring in a small number of infants. Then came the difficult question. Intussusception, especially in areas with poor healthcare, is also a lethal complication. But it was relatively rare, and this vaccine could save lives. So the same sort of balancing act had to be performed for the rotavirus vaccine as for the current vaccines. Will this vaccine save more lives by preventing COVID-19, or will it put people at risk? And to a great extent, that's a numbers game. And right now, we don't have the numbers to inform that decision. And as part of those numbers, as we learned with the rotavirus vaccine, that there may be aspects of how it's delivered and the timing of the vaccine delivery that might impact the development of the side effect. So that as we learn more about these side effects, we may determine ways to minimize their occurrence. And that gets to understanding the numbers, the facts, and then determining what's in the best interests of the public health and the health of the public. Today, we also published a letter describing a case of thrombotic thrombocytopenia that occurred after the administration of a different vaccine, the AD26-CoV-2S vaccine from Johnson & Johnson. What happened in that case? This was a case of a 48-year-old woman who presented with malaise and abdominal pain, and it was found to have marked thrombocytopenia that had begun about 14 days after receiving the vaccine. On looking more carefully, she was found to have both splanchnic vein and right transverse and straight sinus thrombosis. She was treated with heparin, but her thrombosis worsened, and she developed a hemorrhagic stroke, and as of now, she still remains critically ill. After hearing about the cases with the AstraZeneca vaccines, her physicians investigated further and found that, like the cases that were seen with the AstraZeneca vaccine, she had strongly positive anti-platelet factor IV antibodies.
If you're enjoying this Crush Step 1 podcast, you can now get the content along with the content of the MedPrepToGo Step 1 Questions podcast ad- for those who qualify. Plus, they accept most insurance plans. To get started, visit plushcare.com slash weight loss. That Prime. Visit Amazon.com slash Prime to get more out of whatever you're into. I'm Ted O'Connell, one of the authors of Crush Step 1, the ultimate USMLE Step 1 review, along with my co-authors, Ryan Pettigo and Thomas Blair. I am also the chief content officer for Inside the Boards. This is the Crush Step 1 podcast based on the second edition of our best-selling book. The goal is to provide you high-yield and high-quality audio content of the book to help you study on the go and reclaim some of the time in your day. This is Nick Nissen narrating part 7 of the hematology oncology chapter. Myeloproliferative disorders. Myeloproliferative disorders, or MPDs, are a group of neoplastic disorders that involve the proliferation of myeloid stem cells. This category of neoplasms includes polycythemia vera, thrombocythemia, CML, and myeloid metaplasia with myelofibrosis. With the exception of CML, these disorders are associated with a mutation in the JAK2 gene and can be treated with hydroxyurea. Polycythemia vera. Polycythemia vera, or PV, is a myeloproliferative disorder that leads to the unregulated production by myeloid stem cells of increased levels of RBCs and may also produce WBCs and platelets. The term polycythemia refers to a state of increased hemoglobin and hematocrit values above the normal range. Polycythemia vera is a true polycythemia, and the first step in its diagnosis is to distinguish it from a relative polycythemia, e.g. one caused by plasma volume contraction, or a secondary true polycythemia. True polycythemias are categorized into primary and secondary polycythemias. In primary polycythemia, the production of red blood cells results from an EPO-independent pathway, as in PV. In secondary polycythemia, the increased production of RBCs results from the excess secretion of EPO that is physiologically appropriate or pathologic. In relative polycythemia, the most common polycythemia, a loss in plasma volume or dehydration results in hemoconcentration of the blood. In other words, the amount of solute, the RBCs, and other blood products suspended in the plasma stays the same while the amount of solution, which is a plasma volume in which blood products are suspended, is decreased, leading to a higher concentration of solute, not an absolute increase in RBC amount. RBC mass is used to distinguish relative from true polycythemias. RBC mass is always elevated in true polycythemias. Relative polycythemia laboratory findings. Normal oxygen saturation, or SAO2, so no physiologic stimulus for EPL release. There's a normal EPO. There's an increased RBC count with concentration of RBCs that has been increased. Remember that the RBC count is a measure of the concentration of RBCs in the blood, which is the number of RBCs per microliter of blood. Normal RBC mass, or the amount of RBCs, has not changed because there is no EPO stimulus to create more RBCs. Remember, RBC mass is a measure of the number of RBCs in the blood. There's also decreased plasma volume. Tissue hypoxia of any cause, e.g. high altitude, pulmonary disorders, decreased hemoglobin oxygen carrying capacity, results in increased EPO secretion that leads to physiologically appropriate secondary polycythemia. The body is attempting to overcome the hypoxic state by upregulating the production of hemoglobin and RBCs, thereby increasing the oxygen carrying capacity of the blood. Physiologically appropriate secondary polycythemia laboratory findings.
RBC count, RBC mass, and EPO will be increased, with EPO causing bone marrow to increase the production of RBCs, resulting in an increase in the RBC count and RBC mass. Plasma volume will be normal. The amount of solute has increased by bone marrow production of RBCs, not the amount of solution. Certain cancers, e.g. renal cell carcinoma, hepatocellular carcinoma, secrete EPO in an autonomous fashion, and lead to physiologically inappropriate or pathologic secondary polycythemia. Pathologic secondary polycythemia laboratory findings. Oxygen saturation, or SAO2, is normal, so there is no physiologic stimulus for EPO release. However, ectopic release of EPO from tumor cells results in increased EPO levels. RBC count and mass are increased. Plasma volume will be normal. Polycythemia vera, similarly to other MPDs, is associated with a mutation in the JAK2 kinase gene. PV is an insidious disorder that is usually diagnosed in older adults greater than 60 years old, but can occur in any age group. PV patients may enter a spent phase after many years after diagnosis, develop anemia, and have fibrotic bone marrow. Most symptoms of PV are caused by the hyperviscosity of the blood from increased RBCs and its effects on organs such as headaches, vertigo, mental status and visual changes, congestion of the retinal vein, and splenomegaly from congestion or extramedullar hematopoiesis. As a result, individuals will be at increased risk of thrombotic events, causing significant morbidity and mortality, such as cerebrovascular accidents, strokes, MIs, deep venous thrombosis, splenic infarction, and Bud Kiari syndrome, or hepatic vein thrombosis. A subset of patients may be largely asymptomatic, not displaying symptoms of hyperviscosity or thrombotic events. In these patients, only presenting symptom may be pruritus after a warm bath caused by abnormal histamine release by mast cells. Clinical and laboratory findings include the following. Hepatosplenomegaly may be present. Left upper quadrant pain can be present from splenomegaly or splenic infarct. A ruddy complexion and conjunctival plethora can be noted from congestion of blood vessels. Peptic ulcer disease may be present with an unclear cause, possibly increased histamine release seen in this disorder. Gouty arthritis is a result of increased cell turnover caused by cancer. RBC count and mass are increased. EPO is decreased. Remember, PV is an EPO-independent polycythemia. The EPO is low because the body's physiologic response to abnormally high RBC levels is to decrease the production of RBCs by decreasing its secretion of EPO. Leukocytosis or thrombocytosis may be seen in some patients. Bone marrow aspirate may show hyperplasia of all three myeloid cell lines. Patients in the spent phase will have a fibrotic bone marrow. Differentiate from CML by the absence of Philadelphia chromosome and increased LAP score. LAP is decreased in CML. Treatment. This is fatal if left untreated, with a 1-3 year survival. With treatment, expected survival can be more than 10 years. Non-myelosuppressive agents include the following. Periodic phlebotomy to keep hematocrit less than 45%. This treatment is effective, but chronic phlebotomy may result in IDA and reactive thrombocytosis. Patients will have increased risk of thrombotic events in the first few years after this therapy. Myelosuppressive agents such as hydroxyurea with reduced rate of periodic phlebotomy and interferon alpha or IFN alpha may also be used. Myeloid metaplasia with myelofibrosis. Myeloid metaplasia with myelofibrosis, or MMM, is a myeloproliferative disorder caused by neoplastic changes in the myeloid stem cells that lead to the pathologic proliferation of fibroblasts, causing myelofibrosis.
The findings in MMM are similar to those in the spent phase of PV, in which there is a replacement of marrow with collagen fibrosis. MMM is also associated with a mutation of the JAK2 gene on chromosome 9. Myeloid metaplasia is another term for extramedullary hematopoiesis. Hematopoiesis can occur in almost every tissue in the body. In MMM, the main site of extramedullary metapoisis is the spleen, which is enlarged in more than 90% of patients. The myelofibrosis develops early in this disease because of the increased release of platelet-derived growth factor and transforming growth factor beta, or TGF beta, by the neoplastic megakaryocytes. These growth factors promote the growth of non-neoplastic fibroblasts, leading to increased production of collagen and fibrosis in the marrow. MMM occurs primarily in individuals older than 60 years. The typical presentation is one of marrow failure, anemia, thrombocytopenia, and neutropenia, with left upper quadrant pain, splenomegaly, and resultant splenic infarction. Constitutional symptoms are also common, such as weight loss, low-grade fever, night sweats, and fatigue. Clinical and laboratory findings. Widespread extramedullary hematopoiesis may be present. Splenomegaly, or left upper quadrant pain, may lead to splenic infarction. Hippolytospenomegaly results from increased splenic hematopoiesis, which increases portal blood flow and leads to portal hypertension and splenomegaly. Hematopoiesis of serosal surfaces can lead to a large pleural or pericardial effusion. Initially, the bone marrow is hypercellular, but early in the disease progression, it becomes hypocellular and fibrotic with increased collagen and reticulant fibers. Figure 11.37 demonstrates hypocellular fibrotic bone marrow biopsy from a patient with myeloid metaplasia with myelofibrosis. Leukoerythroblastosis or myeloptosis is on peripheral blood smear. This is defined as the presence of immature granulocytic precursors and nucleated RBCs found on the smear. The RBCs will have a characteristic teardrop shape called dacrocytes from RBCs being squeezed out of fibrotic marrow. Normocytic anemia from This episode is brought to you by Amazon Prime. from massive splenomegaly, hydroxy're into, it's on Prime. Visit Amazon.com slash Prime to get more out of whatever you're into. Disorders of heme production. The production of heme is a highly regulated biochemical process, a defect in any step results, and the accumulation of pathway intermediates. The accumulation of certain heme intermediates can be toxic, leading to the development of a disorder called porphyria. Porphyria cutanea tarda. Porphyria cutanea tarda, or PCT, is a genetic or acquired disorder of heme production and the most common porphyria. PCT develops from decreased activity of the enzyme in the fifth step of heme synthesis, uroporphyrinogen decarboxylase, or UROD. This deficiency leads to the accumulation of heme pathway intermediates such as uroporphyrin and iron. The pathology of this disease is directly associated with the buildup of uroporphyrin and iron. PCT is characterized by sun-induced blistering and erosion of the skin caused by accumulation of uroporphyrin deposits in the skin. Patients also may develop hyperpigmentation, hypertrichosis, or increased hair growth, mainly on the face, and skin fragility. The accumulation of iron results in siderosis, iron overload, primarily affecting the liver, resulting in hepatic inflammation and cirrhosis. Inherited causes of PCT are mostly sporadic mutations in 80% of the cases in the UROD gene, and the remaining 20% of cases of PCT are inherited in an autosomal dominant manner. It is unclear how PCT is acquired, but several risk factors have been observed.
Diagnosis is made by measuring urine uroporphyrin, which will be increased. Treatment is aimed at eliminating exposure to precipitants, decreasing iron levels, and increasing the excretion rate of porphyrins by the liver. Patients are instructed to avoid alcohol consumption, iron supplementation, sunlight exposure, intake of estrogens, and exposure to chlorinated cyclic hydrocarbons. Excess iron is managed by routine phlebotomy. Low-dose antimalarials, such as chloroquine or hydroxychloroquine, help increase the removal of porphyrins from the liver by increasing their rate of excretion. Patients with HCV should have their infection controlled with antiviral medications for proper control of PCT. Acute intermittent porphyria. Acute intermittent porphyria, or AIP, is a rare autosomal dominant disorder of heme production. Individuals with AIP are deficient in porphyrinogen deaminase, or uroporphyrinogen synthase, an enzyme in the heme synthesis pathway, resulting in the accumulation of upstream intermediates inside the cytosol, namely PBG and delta-ALA. Buildup of these two intermediates is toxic to cells and can also cause degradation of myelin. The symptoms of AIP are variable, with severe, poorly localized abdominal pain being the most common. The symptoms can be categorized by the five Ps of AIP. The first P is painful abdomen, often confused for acute abdomen leading to a belly full of scars. Second P is port wine for port wine colored urine. The urine is colorless initially, but exposed to light, it causes the PBG in urine to oxidize and gives urine its color. Third P is peripheral neuropathy or patchy numbness and paresthesias. The fourth P is psychological disturbances, such as anxiety, confusion, psychosis, and dementia. And the fifth P is precipitated by drugs. Drugs that enhance cytochrome P450 activity, sulfa drugs, barbiturates, some antipsychotics, and alcohol. A feature that distinguishes AIP from other porphyrias is that it has no sun-induced blistering of the skin or rashes. The diagnosis is obtained by observing the presence of increased urinary excretion of PPG and genetic testing, which can also measure porphyribilinogen deaminase activity, but this is less helpful in the diagnosis. The treatment is aimed at decreasing factors that participate attacks and to discontinue any offending drugs and at halting the endogenous heme production pathway. Endogenous heme production can be decreased by inhibiting ALA synthase, the rate-limiting step in heme synthesis. ALL synthase is inhibited by heme, the end product of heme synthesis, via feedback inhibition, and also by glucose. Patients should receive a high carbohydrate HEPRIN Pharmacologic treatment. Anticoagulants. Heparin. Heparin is a glycosaminoglycan administered parentarily, intravenously, or subcutaneously that binds AT3 with high affinity. This fast-acting anticoagulant with an onset of action in seconds works by inducing a conformational change in AT3 that results in a 1,000-fold increase in its protease activity. Clinically, it has been used as prophylaxis as well as treatment of venous thrombosis and pulmonary embolism. Heparin also is used as adjuvant therapy for unstable angina, MI, and stroke. Heparin can be safely administered for anticoagulation during pregnancy because it does not cross placenta. Side effects include bleeding and HIT. Clinical effects are reversed by protamine sulfate, followed by measuring the PTT. Contraindications include active bleeding, bleeding disorders, history of HIT, and aortic dissection. Direct thrombin inhibitors. Lepirudin, bivalirudin, and dabigatrin. A direct thrombin inhibitor, or DTI as the name implies, acts by directly inhibiting circulating and clot-bound thrombin, also known as factor 2A, and provides antithrombin 3 independent anticoagulation.
Dabigatran is given orally. Clinically, it is used as an alternative anticoagulant administered intravenously, or IV, for patients with a history of HIT or heparin allergy. Side effects include bleeding. No therapeutic drug monitoring is widely available for DTIs. Theoretically, it may use the thrombin clotting time to monitor, but it is not generally used in clinical practice. Contraindications are similar to those of heparin. Direct factor Xa inhibitors, like apixaban and rivroxaban. Direct factor Xa inhibitors are another class of antithrombin 3 independent anticoagulants that act to directly inhibit circulating and clot-bound factor Xa. Currently, these medications are only available clinically in oral formulations and are used as alternatives to warfarin and or heparin. Clinically, they are used for stroke prevention and atrial fibrillation, as well as pulmonary embolism, or PE, or deep vein thrombosis treatment and prophylaxis. They have a rapid onset and offset of action, which reduces the need for bridging. Additionally, they do not require frequent monitoring or redosing because they have few drug interactions and no food impairments or food interactions relative to warfarin. Side effects include bleeding. They are contraindicated in severe renal impairment. Warfarin or Coumadin. Orphan is an oral anticoagulant that inhibits the normal production of vitamin K-dependent clotting factors in the liver. It functions by inhibiting epoxide reductase, the enzyme that helps regenerate vitamin K from its epoxide form to its reduced or active form. Orpharin basically induces a functional vitamin K deficiency state in the body. Clotting factors 2, 7, 9, and 10 in protein C and S depend on vitamin K as a cofactor for their complete synthesis. Clinically, it is used for the treatment and prophylaxis of venous thrombosis and pulmonary embolism. Additional uses include anticoagulation therapy for atrial fibrillation and patients with mechanical heart valves. Side effects include bleeding. Clinical effects are monitored by following the PT and INR. Effects are reversed immediately with administration of fresh frozen plasma and, within a few hours, with vitamin K infusion. Contraindications include history of bleeding disorders and active pregnancy. Orphan crosses the placenta and is teratogenic. Antiplatelet agents. Aspirin. Aspirin is a prototypical non-steroidal anti-inflammatory drug, or NSAID. The mechanism of action of NSAIDs involves the inhibition of cyclooxygenase COX-1 or COX-2 enzymes, thereby preventing the conversion of arachidonic acid to prostaglandins, or TXA2. Aspirin differs from other NSAIDs in that it irreversibly inhibits COX enzymes. The inhibition of prostaglandin synthesis results in its anti-inflammatory and analgesic decrease in prostaglandin E2 actions. The inhibition of TXA2 production leads to decreased platelet aggregation, producing an anticoagulant effect. Clinically, it is used as an antipyretic, analgesic, anti-inflammatory, and anticoagulant or antiplatelet drug. Side effects include gastric ulcers and bleeding, central effects like hyperventilation or tinnitus, and Reye syndrome. Clinical effects are monitored by measuring the BT, which will be increased, contraindicated in children and adolescents because it can lead to Reye syndrome. Theonopyridine derivatives like clopidogrel and teclopidine. Clopidogrel and teclopidine are theonopyridine-derived antiplatelet medications that act via a mechanism other than that of aspirin. Clopidogrel works by irreversibly inhibiting the binding of ADP to its receptor on platelets, thereby reducing platelet aggregation. Clinically, it is often used in conjunction with aspirin to decrease ischemic events in patients with a previous history of stroke, coronary artery disease, and peripheral arterial disease. It is also used to reduce thrombosis after cardiac stent placement or in patients who cannot tolerate aspirin therapy.
Ticlopidine is associated with a worse side effect profile than clopidogrel. It's contraindicated in patients with active bleeding. Epsiximab. Epsiximab is a monoclonal antibody that works as a platelet aggregation inhibitor by binding to the GP2B3A receptor on activated platelets. This blockade prevents platelets from sticking together and inhibits thrombus formation. Clinically, it is used as an anticoagulant in acute coronary syndrome and also to prevent rostinosis after coronary angioplasty. Side effects include bleeding or GI bleed and thrombocytopenia. It's contraindicated in patients with active bleeding, recent GI bleed within six weeks, or thrombocytopenia. Phosphodiesterase-3 inhibitors like silastazole and dipyramidol. Phosphodiesterase-3 inhibitors, like silastazole and dipyramidol. Phosphodiesterase-3, or PDE-3, inhibitors stop clot formation by blocking the enzymes that normally inactivate cyclic AMP or CAMP, leading to increased levels of CAMP in platelets. As you may remember, CAMP is an important medi mediator of platelet activity and increased levels lead to inhibition of platelet aggregation. These medications also act as direct arterial vasodilators by inhibiting the cellular reuptake of adenosine, leading to an increased level of extracellular adenosine. Increased adenosine levels then act as local vasodilators. Clinical uses include angina prophylaxis, intermittent claudication, prevention of stroke or transient ischemic attack when combined with aspirin. Side effects are related to its function as a vasodilator, including headache, nausea, hypotension, palpations, arrhythmias, GI upset, and thrombocytopenia. Contraindications include heart failure, especially New York Heart Association class 3 or 4 failure, tachycardia, and hypovolemia. Thrombolytics, alteplase or TPA, retiplase or RPA, tenecteplase, TNKase, and streptokinase. Thrombolytics are medications that can help dissolve blood clots by a process referred to as thrombolysis. These agents catalyze the formation of endogenous plasmin, the protease that removes clots or thrombi from plasminogen. Plasmin cleaves fibrin as well as thrombin clots. You will see elevated PT and PTT without any change in platelet count. Clinically, this class of medication are used for treatment of MI, ischemic stroke, or massive PE. Side effects include bleeding, specifically hemorrhagic stroke. It's contraindicated in patients with a history of hemorrhagic stroke, known intracranial malignancy, known cerebrovascular lesion or arteriovenous malformation, recent ischemic stroke within the last three months, known bleeding disorder or active bleeding, suspected aortic dissection or significant closed head or facial trauma within three months. Relative contraindications include severe hypertension, recent major surgery, or pregnancy. Antineoplastics. Antimetabolites. Methotrexate or MTX. Methotrexate is an antimetabolite medication as an analog for folic acid. Folic acid is required to carry out one-carbon transfer reactions in various synthetic pathways, specifically the synthesis of purine nucleotides like thymidylate and some amino acids, serine and methionine. Methotrexate inhibits dihydrofolate reductase, or DHFR, and prevents the regeneration of folate for continued use in DNA synthesis. This antifolate agent is not selective for tumor DHFR versus normal DHFR. Therefore, it can affect the DNA synthesis and cell growth of normal and tumor cells. However, it does not have a greater toxic effect in the DNA synthesis or S-phase of cells that are rapidly dividing. Clinically, it is used as an antineoplastic agent used with other chemotherapeutic agents to treat leukemias, NHL, and other malignancies. It is also used as an immunosuppressant in the treatment of rheumatoid arthritis.
Side effects commonly include bone marrow suppression, liver damage, and neurotoxicity. Toxic effects can be damaged with the administration of leucovorin, or folinic acid, which is taken up in disproportionate amounts by normal cells versus tumor cells. 5-fluorouracil, or 5-FU. 5-FU is a pyrimidine analog that acts during the S-phase of the cell cycle. Similarly to MTX, they work synergistically by inhibiting different enzymes in the DNA synthesis pathway. 5-FU halts DNA and protein synthesis. 5-FU is an antimetabolite that irreversibly inhibits thymidylate synthesis, thereby blocking the synthesis of thymidine. It is enzymatically converted to its active form 5-fluorodeoxyuridine or 5-FDUMP, which in turn inhibits the mytilite synthase and halts DNA synthesis. This leads to an imbalance in cell development and a thymine-less death of the cell. Thymine-less death occurs when bacterial yeast or human cells are deprived of thymidine triphosphate, or DTP, an essential precursor for DNA synthesis, thereby initiating irreversible cell death. Clinically, it is used in the treatment of colon cancer and superficial tumors, like basal cell carcinoma. Side effects include myelosuppression, GI mucositis, and photosensitivity. Side effects cannot be reversed by lucavorin. Azathioprine and 6-mercaptopurine, or 6-MP. Azathioprine is a prodrug that is non-enzymatically cleaved to create 6-MP. 6-MP, the analog of adenine, is an antimetabolite that works by inhibiting many enzymes involved in de novo purine synthesis in the S-phase. This immunosuppressive medication must first be converted by hypoxanthine guanine phosphoribosyltransferase, or HGPRT, to exert its clinical effects. Clinically, these medications are used for the treatment of leukemias and lymphomas. They are also immunosuppressants used to treat certain autoimmune disorders including rheumatoid arthritis, SLE, and inflammatory bowel disease. Side effects include bone marrow suppression, GI mucositis, and liver damage. 6-MP is metabolized by xanthioxidase and may result in increased toxicity in patients taking L-purinol. 6-theoguanine or 6-TG. 6-TG is a guanine analog antimetabolite that works similarly to 6-MP. It blocks the synthesis of guanine nucleotides and results in the arrest of DNA and RNA synthesis in the S-phase. Unlike 6-MP, it is metabolized by theopurine methyltransferase and is safe to give with allopurinol. Clinically, it is used in the treatment of acute leukemias and chronic myeloid leukemia. Side effects are similar to 6-MP except that it can be given with allopurinol. Cytarabine. Cytarabine is an S-phase specific antimetabolite, an analog of deoxycitidine. A deoxyribonucleoside resembles citidine with one oxygen atom removed that blocks cna synthesis by incorporating itself into the internucleotide linkages in dna clinically it is used in the treatment of acute leukemias like aml or all and in lymphomas for induction therapy side effects include bone marrow suppression and GI mucositis. Cladribine or 2CDA. Cladribine is a synthetic purine analog that is used in the treatment of hairy cell leukemia. It is an immunosuppressant that inhibits DNA processing by cells. It is an adenosine deaminase inhibitor, clinically used for treatment of hairy cell leukemia. Its side effects include bone marrow suppression, neurotoxicity, and renal toxicity. Antitumor Antibiotics Dectinomycin Dectinomycin, or actinomycin D, is an antibiotic used as a chemotherapy medication which disrupts the cell cycle by inhibiting transcription. It works by binding double-stranded DNA and blocking elongation of the chain by RNA Dexarubicin.
It works by intercalating with DNA to disrupt replication and transcription. Dexarubicin inserts itself into DNA, leading to breaks in the chain. Clinically, it is used in the treatment of multiple myeloma, leukemias, HL, sarcomas, and solid tumors, breast, ovary, bladder, and lung. Side effects include significant cardiotoxicity, leading to dilated cardiomyopathy, bone marrow suppression, and alopecia. Bleomycin. Bleomycin is a G2 phase specific drug and is the B part of the ABVD chemotherapeutic regimen. This agent is a mixture of glycoproteins that produce free radicals on binding DNA. The free radicals create breaks in DNA which accumulate and lead to cell death. Clinically, it is used in the treatment of HL, testicular carcinoma, and squamous cell carcinomas. Side effects include skin changes or hyperpigmentation, ulcers, alopecia, and life-threatening pulmonary fibrosis. Pulmonary function must be monitored. It produces minimal bone marrow suppression. Alkylating agents. Cyclophosphamide and ifosfamide. Cyclophosphamide is an alkylating mustard agent. Like other alkylating agents, it exerts its effect by alkylating DNA, which is lethal to cells and is most toxic to rapidly dividing cells. It is the most commonly used alkylating agent. Cyclophosphamide is unique in that it can be administered orally. Both cyclophosphamide and ifafamide require activation by the liver's P450 system to function properly. Clinically, it is used to treat NHL, breast carcinoma, and ovarian carcinomas. It also acts as an immunosuppressant. Side effects include hemorrhagic cystitis, leading to bladder fibrosis. This side effect is decreased by aggressive hydration and administration of mesna and myelosuppression. Nitrosurias Nitrosurias, e.g. carmustine, lomustine, semustine, and streptozosin are DNA alkylating agents used in chemotherapy. Nitrosiureas are a subgroup of medications that work by alkylating the cross-linked strands of DNA to create breaks and inhibit its replication, also leading to inhibition of RNA and protein synthesis. These medications must be metabolized into their active products. Carmosine or BCNU and Lomasine or CCNU are two closely related nitrosurias that are highly lipophilic and readily cross the blood-brain barrier, so they are used in the treatment of many brain tumors. Side effects include myelosuppression, renal toxicity, and pulmonary fibrosis after prolonged use. Busulfan. Busulfan is an alkylsulfonate that acts as a nonspecific alkylating agent. It acts similarly to other alkylating agents and forms reactive intermediates that alkylate DNA bases, mostly purines, leading to cross-linking of bases, abnormalities in base pairing, and DNA strand breakage. Clinically, it was used as the main treatment for CML until imatinib, the gold standard treatment of CML, was discovered. Though it continues to play a role in the treatment of CML, busulfan is also used in bone marrow transplantation and kills bone marrow cells in preparation for the procedure. Side effects include pulmonary fibrosis, which is the main side effect, and hyperpigmentation. Microtubule inhibitors. Vincristein and finblastine. Vincristein, or oncovorin, is a finca alkaloid used in the O part of the MOPP chemotherapeutic regimen. Phencysteine is an M-phase inhibitor of the cell cycle and works by binding to tubulin, thereby preventing polymerization of microtubules and spindle formation. Inhibition of microtubule formation leads to arrest of the cell cycle at metaphase and stops mitosis. Femblastin is a similar medication that is the V-part in the ABVD chemotherapeutic regimen. Clinically, it is used in the treatment of HL, leukemias, Wilms tumor, and choriocarcinomas. Side effects include peripheral neuropathy and constipation.
Finblastine, on the other hand, produces significant myelosuppression. Paclitaxel. Paclitaxel, or Taxol, is the first of the taxane family of chemotherapeutic agents. It is an M-phase agent that prevents the breakdown of the metodic spindle and inhibits completion of anaphase. Paclitaxel, a derivative from the U-tree, acts by binding tubulin and promoting polymerization and stabilization of microtubules, unlike the vinclet alkaloids, which inhibit polymerization. The microtubules created are highly stable but dysfunctional, leading to mitotic arrest and cell death. Clinically, it is used against ovarian carcinomas, breast cancer, squamous cancers of the head and neck, and other cancers. Side effects include serious hypersensitivity reactions like dyspnea, urticaria, and hypotension, peripheral neuropathy, and bone marrow suppression. Topoisomerase inhibitors. Potophylatoxins like etoposide and teniposide. Etoposide and teniposide are potophylatoxin-derived chemotherapeutic medications. Members of the potophylatoxin drug class are G2 phase specific and act by inhibiting topoisomerase II. They form a three-part complex with DNA and topoisomerase II, leading to the inhibition of topoisomerase II and an accumulation of breaks in the DNA, since topoisomerase II normally reseals double-stranded DNA breaks. The accumulation of breaks leads to degradation of DNA and cell death. Clinically, etoposide and teneposide are used to treat lung and prostate carcinomas, small cell carcinomas, testicular cancers, lymphoma, ALL, and AML. Side effects include bone marrow suppression and possible high rate of secondary leukemias in children treated with etoposide with characteristic 11q23 translocation due to DNA breaks induced by medication. Teniposide also inhibits topoisomerase 2 and is mainly used in the treatment of ALL. Side effects include severe myelosuppression, gastrointestinal toxicity, hypersensitivity reactions, and alopecia. Kemptothecan analogs like irinotecan and topotecan. Irinotecan and topotecan are kemptothecan derivatives that act as topoisomerase 1 inhibitors. Topoisomerase 1 is an enzyme that changes DNA structure by facilitating the relaxation of DNA supercoiling during the process of replication and transcription. Clinical uses include colon cancer for irinotecan, ovarian cancer, and small cell lung cancer. Side effects include diarrhea and severe bone marrow suppression. Steroid hormones and their antagonists. Prednisone. Prednisone is a strong synthetic glucocorticoid that is the last P in the MOPP regimen. It has many actions on the body. Prednisone must be metabolized to prednisolone, its active form, after which it binds to a cytosolic receptor and is transported into the nucleus, activating specific corticosteroid response genes. Prednisone acts as an anti-inflammatory and immunosuppressant agent by blocking proliferation of activated T-cells and inhibits production of inflammatory mediators and also inhibits the antibody production. It may trigger apoptosis of immune cells, especially lymphocytes. Prednisone also produces neutrophilia without bandemia via demargination of neutrophils in circulation. It helps maintain blood glucose levels by increasing gluconeogenesis. It increases muscle catabolism and increases lipolysis. It also acts as a weak mineralocorticoid. Clinically, it is used in the treatment of autoimmune diseases such as rheumatoid arthritis and asthma, but is also used in leukemias like CLL and HLs. Side effects include hypocortisolism like Cushing syndrome, hyperglycemia, and increased risk of infections, osteoporosis, muscle wasting, skin thinning, fat deposition, and psychosis. Tamoxifen and raloxifene. Tamoxifen is a selective estrogen receptor modulator, or SERM, that acts primarily as an anti-estrogen but has weak estrogenic activity that competes with the estrogen for the estrogen receptor.
This results in suppression of growth in estrogen-responsive tissues. As a result of the partial estrogen agonist activity, tamoxifen reduces the severity of osteoporosis in postmenopausal women, but it can stimulate endometrial growth and increases the risk of endometrial cancer. It also increases high-density lipoprotein or HDL levels, protecting against atherosclerosis and cardiovascular disease. Reloxifene, an endometrial estrogen antagonist, is a drug similar to tamoxifen, but does not stimulate endometrial growth and therefore does not increase the risk of endometrial cancer. It also protects against osteoporosis. Clinically, it is used in the treatment of estrogen receptor-positive breast cancer and to prevent osteoporosis in postmenopausal women. Side effects include nausea, vomiting, hot flashes, and increased risk of endometrial cancer and tamoxifen only. Other agents. Cisplatin and carboplatin. Cisplatin is a platinum-containing compound that is a member of the platinum coordination complex class of anti-cancer medications. Cisplatin acts similarly to the alkylating agents. It enters a cell and creates interstrand and intrastrand DNA crosslinks. These crosslinks result in DNA instability and cell death. Clinically, it is used in the treatment of testicular and lung carcinomas. Side effects include significant nephrotoxicity, ototoxicity, cranial nerve or CN8 damage, and mild myelosuppression. Carboplatin is a similar agent with less toxicity but greater bone marrow suppression. Hydroxyurea. Hydroxyurea is an S-phase specific medication that inhibits DNA synthesis by blocking ribonucleot used in the management of sickle cell anemia and various myeloid cancers, like CML. Side effects include bone marrow suppression, nausea, vomiting, and diarrhea at high doses. Trastuzumab. Trastuzumab, or Herceptin, is a monoclonal antibody that binds and inhibits the ERB2, or HER2, receptor, a family of tyrosine kinases expressed in some breast cancers. The HER2 pathway promotes cell survival, growth, and division. Clinically, it is used in the treatment of metastatic breast cancer. Side effects include cardiomyopathy. Imatinib. Imatinib, or Gleevec, is a monoclonal antibody that acts by binding and inhibiting the tyrosine kinase produced by the ABL and CKIT genes. There are a large number of tyrosine kinase enzymes in the body. The Philadelphia chromosome in CML is produced by fusion of the BCR-ABL genes, creating a constitutively active tyrosine kinase. The CKIT gene also produces a tyrosine kinase whose active site can be inhibited by imatinib. Gastrointestinal stromal tumors often arise from mutations in the C-kit gene. Clinically, it is used as a first-line treatment for CML. It is also used to treat gastrointestinal stromal tumors. Side effects include weight gain, which is most common, edema, bone marrow suppression, and possibly congestive heart failure. Rituximab. Rituximab is an anti-CD20 monoclonal antibody that is used clinically to treat malignancies like NHL and CLL, and autoimmune diseases like rheumatoid arthritis or ITP. Many B-cell neoplasms are CD20 positive. However, CD20 is also found in normal B in normal B cells and rituximab will destroy both. Side effects include fatal infusion reaction within 24 hours of infusion, reactivation of hepatitis B and other viral infections like JC virus infection leading to PML, and mucocutaneous reactions and diarrhea. Erlotinib. Erlotinib, or TARCEVA, is a reversible epidermal growth factor receptor, an EGFR, Tarazine Kinase Inhibitor, used clinically to treat non-small cell lung cancer. Its main side effect is a rash that resembles acne and primarily involves the face as well as the neck. Bevacizumab, or Avastin. Bevacizumab is a medication that inhibits angiogenesis, the growth of new blood vessels.
In December 2018, after a surge in sales of products containing cannabidiol, one of the active compounds in recreational cannabis, the U.S. Food and Drug Administration stated that CBD may not legally be sold in food or dietary supplements. Some states have responded by pulling products containing CBD from the market, whereas in other areas such products continue to be available. I'm Stephen Morrissey, Managing Editor of the New England Journal of Medicine, and I'm talking with Peter Cohen, an Associate Professor of Medicine at Harvard Medical School. Dr. Cohen has co-authored a perspective article on regulating CBD and other new dietary ingredients. Dr. Cohen, you write in your perspective article that CBD's only FDA-approved indication is to treat intractable seizures in patients with the Lennox-Gastaut syndrome or the Dravet syndrome. What other benefits of CBD have been suggested, and how much evidence is there to support any additional use? So, Stephen, there's hardly been an indication that has not been suggested. CBD today is marketed for everything to help with pain, to relax you after a busy day, and to even calm your pets down. So the evidence, however, to support those indications are minimal. Sometimes they're small human studies, but we're usually talking about preliminary evidence that would absolutely require replication in large randomized controlled trials before we had any suggestion that this was something that we would want to actually recommend in clinic. So what about adverse effects? Is there any evidence of that? What we know is from the clinical trials in which there were some concerns about GI symptoms, specifically liver enzyme elevations, somnolence, and we don't know what CBD's effect is going to be in pregnancy yet. This has not been studied. And there's also preliminary evidence that there might be some genotoxic effects of CBD, and that's being currently studied. You say in your article that in December, the FDA stated that CBD can't be sold in food or supplements on the grounds that it's already been approved as a drug. So what was the impetus for that announcement, and how has the medical community responded? This has led to a lot of confusion. CBD is already out there on the marketplace, widely advertised in every state. And the FDA comes out and states that because it was previously approved to treat these rare seizure disorders, there's no opportunity for it to be a supplement ingredient or in foods. So this has created a tremendous amount of confusion. Now, what's interesting is the FDA has yet to enforce that law. So while they've stated that, they've only sent warning letters to companies that are selling CBD to specifically treat an illness, like to cure, I don't know, diabetes or something, that might get a warning letter. The FDA has not sent any other warning letters about these thousands and thousands of CBD products. So it's very confusing. The FDA is saying one thing on the other hand, but their actions are completely different. So as we've said, some states are taking these products off the market after the FDA announcement. Others are disregarding the announcement. Why is that happening? And is that a basic problem of a state-by-state approach to this kind of thing? Absolutely. It's definitely a major problem because we haven't come to a consensus nationally. I think that CBD is getting this sort of treatment because it has this reputation, this narrative that it is entirely safe, that it provides the relaxing qualities of recreational cannabis without the psychoactive components. That narrative, although not proven, is very powerful. And it's enticed everyone from farmers to start creating more crops with cannabis to the industry, which is very keen on this narrative, and cannabis enthusiasts who are really excited about having this, and even people who never thought they would be interested in cannabis, but say, hey, this must be a safe way of having some of the benefits from cannabis. So that very powerful narrative has captivated Americans and really gotten ahead of the FDA. And each state's trying to figure out how to handle that because consumer demand is high. In industry, interest in selling it and the profit is high. So there's a real tension between the law and this enthusiasm.
Since HIV was first identified as the cause of AIDS, researchers have set their sights on developing a vaccine against the virus. But so far, that goal has proved elusive. I'm Stephen Morrissey, Managing Editor of the New England Journal of Medicine, and I'm talking with Dan Baruch, Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and Harvard Medical School, and a program leader at the Reagan Institute of Massachusetts General Hospital, MIT, and Harvard. Dr. Baruch has written a perspective article on the quest for an HIV-1 vaccine. Dr. Baruch, in your article, you outline several challenges to the development of an HIV vaccine, the first being the virus's tremendous genetic diversity and mutational capacity. So how have researchers addressed this challenge, and what do you see as promising strategies to overcome it? Well, thanks, Stephen. It's a pleasure to be here today. I'll first emphasize the scope of the problem that you raised, which is truly unprecedented in terms of the genetic diversity and mutational capacity of HIV. If we were to draw a parallel with influenza, then we would see immediately that the degree of global diversity for HIV is vastly greater than the degree of global diversity for influenza. And if we need to have a flu vaccine every year, then how are we going to develop immunogens for an HIV vaccine that would be relevant for the global epidemic? It's clearly a problem of unprecedented nature that has never been addressed by vaccinology before. So to date, the vaccines that have gone into advanced clinical efficacy trials have really focused on natural sequences of the virus, and those clinical trials have been geographically localized. So, for example, in the RV144 study, which was conducted in Thailand, the inserts that are included in the vaccine were specific for Thailand. They were clade B and clade E inserts. While that was appropriate for that region of the world, it required the generation of a new vaccine completely for testing in South Africa. And that is exactly what's happening now. A new vaccine that's related to the RV144 vaccine is being made, but it's entirely a new vaccine and therefore requires years of manufacturing and early phase clinical testing before it's ready for testing in South Africa. So unfortunately, using simple antigens in vaccine constructs is technically very difficult and requires many years of effort because it requires the generation of new vaccines for each region of the world. And one could even argue that there is too much diversity in one region of the world for any given vaccine sequence. Also, the logistic complexity of manufacturing, producing, and ultimately delivering different vaccines to different parts of the world may not be logistically possible. So given those constraints, there are research efforts aimed at addressing this problem using bioinformatics. For example, there are efforts to develop so-called mosaic vaccines, which involve the generation of synthetic antigens based on bioinformatic analysis of global HIV diversity. And these synthetic antigens aim to best cover the global HIV epidemic using the fewest number of antigens possible. The degree to which such an approach will indeed address the problem clinically remains to be determined, but will be tested over the next several years. There's also other approaches to try to focus immune responses on conserved antigens, both for T-cell responses and for antibody responses. And of course, the holy grail would be to develop an envelope protein immunogen that can indeed raise broadly neutralizing antibodies against conserved regions. However, that currently is not possible. So in summary, researchers are trying to develop ways to broaden the immune response, to have better coverage of diverse viruses worldwide, as well as focus the immune response onto particular conserved T-cell or antibody epitopes. To dig into that a bit, another key challenge is the lack of any natural immunity to HIV-1 that could serve as a model for inducing immunity. So in that circumstance, how does one go about studying potential immune responses? That is another key challenge for HIV vaccine development, that unlike for pathogens for which we do have clinically effective vaccines, such as smallpox, such as polio, the generation of those vaccines involved clear evidence of natural immunity. For HIV, there is no evidence to date that anyone has cleared the virus through immune responses. And therefore, we do not know what precisely are the immune correlates of viral clearance or viral protection.
So the best way we have going forward is to do detailed immune correlates analysis in the context of successful human efficacy trials of vaccines and, to a lesser extent, successful preclinical studies in non-human primates. Probably the best example to date is the immune correlates analysis in the RV144 study, in which researchers found that there was a correlation between higher levels of antibodies against particular regions of the envelope glycoprotein and reduced risk of infection in vaccinees. That finding, of course, was done post hoc and therefore needs to be validated, replicated, and the degree to which it may apply to other vaccine platforms, of course, is not known. But it is a start. In the context of preclinical studies in non-human primates, there are substantial advances in immune correlates analyses, and those are very informative. However, non-human primate studies have limits, and so feedback from human clinical efficacy trials is the most critical. And because of that, I think it is a strong argument to proceed with more clinical efficacy trials in order to have better feedback about the types of immune responses that are needed. If we did know exactly the type of immune response needed for protection, HIV vaccine development could proceed much more quickly because then we would essentially optimize vaccines to generate that precise response. In the absence of that type of certainty, then we have to proceed in a much more diffuse manner, which intrinsically is much more time-consuming. What have those clinical trials taught us about the HIV virus itself? Well, there have been four concepts that have completed clinical efficacy testing in humans. I think fundamentally, the clinical efficacy trials to date have taught us that developing a vaccine against HIV is a challenge. It's clear that neither simple antibody nor simple T cell responses will alone be sufficient. And so novel strategies need to be pursued. A second lesson that we have learned from the clinical efficacy trials is that the results often are surprising. I think many researchers would not have predicted the outcome of the step study involving the ADD5 Gagpol-Nef vector-based vaccine, and many people were quite surprised with the outcome of the RV144 study. However, despite HIV vaccine development being difficult and often surprising, we do have an initial proof of concept that an HIV vaccine is indeed possible through the modest but low-level protection seen in the RV144 study. And so we do think that an HIV vaccine is indeed possible to develop, which also is another call for the need for more trials to explore those possibilities. And have the trials that have already been undertaken illuminated some possible approaches for those future trials? Well, I think that's a much more difficult question. I think that anything that has shown some efficacy in humans should go forward into further testing. But of course, we hope that future vaccines will be substantially more effective than those that have gone before us. And so we know that there need to be certain immune responses that need to be either greater than or different from immune responses that have been generated by existing vaccines. In terms of the exact type of vaccines that should go forward, there's not a single clear answer, except that I think it makes a lot of sense not to put all our eggs in one basket, and it would make a lot of sense to have several different diverse but promising approaches all go forward. Speaking of eggs and baskets, given our lack of success in producing an effective HIV vaccine, would it make more sense to invest in research on potential cures for HIV disease? Well, historically, vaccines have been the most effective tool for prevention or control of global viral epidemics. So I think history is on the side of vaccines, that if it's possible to develop an HIV vaccine, that will be the most likely path toward controlling and ultimately eliminating the HIV epidemic. But clearly, we need to do both. The HIV research field should not only focus on vaccines, but also on therapeutics and cures. And for a problem of the global scope and magnitude of HIV, having these two major foci of research, I think, is. Clearly both are needed and likely both will be responsible for the ultimate control of the worldwide HIV epidemic. They also don't occur in isolation. The vaccine research field and the viral eradication or cure research field have increasing overlap and synergies, particularly in the area of immunology.
From the JAMA Network, this is Conversations with Dr. Bauchner, interviews featuring researchers and thinkers in healthcare about their publications in the latest issue of JAMA. Hello and welcome to Conversations with Dr. Bauchner. Once again, it is Howard Bauchner, Editor-in-Chief of JAMA. And I'm delighted to be joined by John Moore. John's a professor, a virologist at the Weill Cornell Medical School in New York. And he's written a very provocative viewpoint for us entitled Approaches for Optimal Use of Different COVID-19 Vaccines, Issues of Viral Variants and Vaccine Efficacy. Broad topic, many issues to discuss. But let's start with the larger frame, John. How have you begun to think about the emerging variants? Well, there are two types of variants. I think we need to understand those different categories. The first type are more transmissible. They are more likely to infect people on average by 30 to 50 percent compared to the strain we're more familiar with that's been dominating the US pandemic. Then there's the second type, which actually are more of a concern to us, at least to me, that are antibody resistant that could affect the efficacy of some vaccines to a certain extent that we can't yet quantify. And of course, the combination is possible that you could get a more transmissible and vaccine resistant variant. But so the two different mechanisms, they arise for different reasons within virus evolution and they have different implications. The ones that are most spreading are the more transmissible variants. The B.1.1.7 that arose in Kent in the UK is predicted to dominate the U.S. pandemic sometime this month, perhaps. I mean, there's projections, and we're not sure, but it is becoming more and more widespread. Fortunately, the resistant, the antibody-resistant variants at present, much less frequent, but they do think they're more of a concern. John, have you been surprised by the rapidity with which these variants of concern have emerged? Well, yes and no. We first saw this last April, May, when a variant called D614G that was more transmissible, eventually within the space of a few months, became to be the dominant strain worldwide. The original Wuhan strain was overtaken by D614G within a few months. So we were aware of it, but kind of tuned it out until around December and January when more and more variants started to be reported. And it's partly because they're being more looked for. If you don't look for them, you don't find them. And the Brits have a very good infrastructure here. And they found the Kent variant. And there are others, you know, other nations, including the USA, is now mimicking what the Brits have done to have a better surveillance network. So firstly, it's you only find them if you look for them. And the harder you look, the more you find. But also, you know, you give an RNA virus 100 million people and you give it a year. That's a recipe for variants emerging. We're lucky that SARS-CoV-2 is not that variable a virus compared to influenza and certainly compared to HIV, but it does vary and you will see more over time as more and more people are infected. There are many questions already, but I want to wait on those questions to go through one or two of the major issues that you focus on in the viewpoint. Vaccine interval has become hotly discussed. I thought the issue had gone away in the U.S. I still think it is going to go away now that the Janssen J&J product is upon us. So we have Moderna, Pfizer, Janssen, J&J. I don't think there'll be any others in the next month or two educated guesswork. They're trying to wrap it up in a way that is not a good idea? Yeah, I think what is being done in the UK, it's educated guesswork. They'll try to wrap it up in science, but a lot of it is, a lot of the evidence is quite weak.
I mean, the principal arguments against extending the dosing interval is that you're really not very protected in the interval between the first and second doses. Yes, there is protection, but there's data out of Israel now that shows the second dose doubles the protection. I mean, it's gone from different parameters, but it's a very substantial increase. And the second dose strongly increases your neutralizing antibody levels, you know, 20, 50 fold, that kind of ballpark. So it's very significant. Now, if you're dealing with variants, you want the strongest possible antibody response. So a variant may, well, there are certainly variants that we know just cannot deal with one, one dose mRNA vaccine sera just cannot deal with the variant that arose in South Africa. It's just blows right past them. I mean, it's just like, it's not there. Two dose sera can cope because it's that much stronger to start with. So a reduction can be tolerated. So if we're dealing with variants that are spreading and are more resistant, let's have a strongest possible antibody response. And that means two doses in the FDA recommended timeline. And there's a more subtle point, but it has long reaching implications. How do variants arise? How does an antibodyistant variant arise? Well, it arises in a circumstance where you have a meaningful but not terribly strong antibody response. So if you have a very strong antibody response, the virus can't replicate. If you have a really weak or non-existent antibody response, the virus doesn't care. But if you have something in between, the virus sees a selection pressure and mutates to escape it. And that's how virus-resistant, vaccine-resistant, antibody-resistant variants arise. So the circumstance where you have an intermediate antibody response is exactly the circumstance where you have after the first dose of an mRNA vaccine. You have a measurable antibody dose, but it's not that strong. And, you know, there are lots of grounds to think that this could happen, that that will drive antibody resistant viruses. It can't be proven, but it's a legitimate concern that's widely shared among, you know, antibody people or immunologists in general. We've already seen in Britain the Kent variant acquire mutations that make it highly resistant. It's becoming like the Brazil variant, B.1.3.5.1. So is that a harbinger of things to come? I guess we're going to find out. But it's a troubling scenario. And, you know, the Biden administration is very science driven. And the science says stick with the FDA approved protocols. All the leading figures agree on this. And I just think it's the right thing to do. And it won't become an issue as more and more vaccines become available. Right. I mean, this is a now issue. It won't be an issue in a month or two's time when the projected increase in vaccine rollout reaches fruition. Yeah, we're also at a very fortunate time because the number of cases, hospitalized cases and the number of deaths continue to come down. So it seems to me to be a very odd time to begin to experiment when in general the data are going in the right direction. And we know that the Janssen J&J product is a few weeks away from really increasing the number of doses that would be available. Plus, even with Moderna and Pfizer, I think for the first time, we top 50 million individuals gotten first dose and about 25 million who've gotten a first and second dose. So 75 million. 100 million is the high risk group, essential workers, people older than 65. So we're getting close to vaccinating the really critical group. That's absolutely correct. And then we will get into a situation where the problem is people who refuse to take the vaccine will have more vaccines than arms to put them in, because there's still a significant, substantial fraction of Americans in surveys who say they simply won't take the vaccine for any of many reasons. And if we're ever going to achieve vaccine-induced herd immunity, that will become a major, major issue, because there's a significant fraction of unvaccinated people.
Let's say that's where we are in two or three weeks. that's actually a very plausible scenario. You also touch on a possible way in which that could be distributed. Could you talk about that and then comment on why you think that that could be seen as a reasonable approach if you can put logistics aside? Well, at the moment, and I don't have an issue with this, the three vaccines are considered to be equivalent and there's no discrimination between who should take one versus the other. You know, there's an argument to be made that you should use the J&J vaccine for younger people who, if they are infected, have lower viral loads and therefore may be better suppressed by a vaccine that is somewhat less potent than Pfizer and Moderna. I think there's no doubt that Pfizer and Moderna are the stronger vaccines, which is not to say that the J&J vaccine doesn't make a contribution. But in terms of prevention of weak infection, which is not really important, but, you know, non-critical infections, Pfizer and Moderna are stronger than J&J. So, you know, then we get to the question of do people care about that? Well, they shouldn't care about that, but people do. And they, you know, I had a message from a young science journalist the other day saying that in her circle of friends, not necessarily her, but her circle of age group friends, they're concerned about prevention of infection or prevention of infection that would enable them to transmit virus to other people. And, you know, that's around, that's a concern and it needs to be thought about and managed. You know, if you're in your 20s and 30s and you're probably not going to get terribly sick from COVID, you're interested in not getting infected at all, and not having a risk of passing any infection on to your friends and older people. So these are complicated issues, and there's no simple solution to it. But the key message is, the vaccines work, all three of them work, and they certainly reduce or roughly equivalently reduce severe infections and death. And for older people, that's the key message. Can you imagine, and you talk about this in the viewpoint, and it gets increasingly complicated, and it is one of the questions, a mixing and matching of vaccines. And I fully appreciate that is all dependent upon what happens with the variants. But how have you begun to think about that, John? Because I think the key to think about it now is so that if in July or August, there's a truly resistant variant, we should be prepared for it. So how have you thought about that? Well, there are two ways of addressing this. I mean, firstly, for a truly resistant variant, all the companies are working on redesigning their vaccines, particularly to deal with the B.1.3.5.1 strain that arose in South Africa that's the most characterized of the resistant variants. And so they're just tweaking their designs. But of course, it then takes multiple months to produce new stocks. Another strategy is simply to give a third dose of the mRNA vaccines and the second dose of J&J, which is being tested in phase three trials. I personally think the two-dose J&J will overcome any limitations to the one dose based on animal studies. So a second or third dose will help in and of itself. A new variant design will also be helpful in all probability, needs to be evaluated. But vaccine combinations, my background is HIV vaccines, and it's common in clinical trials for different vaccine designs to be used sequentially, sometimes simultaneously, but mostly sequentially. So Johnson & Johnson, for example, has a large-scale phase 2b, phase 3 trial in southern Africa of an adenovirus vector that's very similar to the COVID vaccine, followed by a protein boost. Well, there are protein vaccines coming down the pipe. The Novavax one is in US phase 3 trials. I'm actually a participant in that trial. Sanofi GSK has a protein-based vaccine that ran into some problems, but is now back on track. So if these protein vaccines are approved, they might make excellent boosts for adenovirus vectors and conceivably for the mRNAs.
Although actually the Russians and the AstraZeneca people are doing a starting or planning a combination adenovirus vector trial in the UK. At the moment, you would not recommend mixing and matching vaccines. There needs to be a science or an evidence base to doing it. Is that an accurate statement, John? Absolutely. We need trial data. The FDA has said that in extreme circumstances, you can get a Moderna first and a Pfizer second or vice versa. And that's sensible. Those two vaccines are so very similar. That's distinction without a difference. I'd have no problems with that. But again, the FDA says in extraordinary circumstances. There's been no discussion of adenovirus prime mRNA boost, but I bet it would work quite well. And I'd like to see trials in this general area, including the protein vaccines, for the reasons I said earlier. Has enough time passed, John, to get a sense? I mean, some people in the initial Moderna-Pfizer trial were six months out. So I know, obviously, they're accumulating neutralizing antibody information about them. Are we far enough out to begin to understand what booster may be necessary, regardless of the variants, but just that simply that neutralizing antibody titers are dropping? Are those people going to be okay for a year, 18 months, two years? Well, firstly, the FDA recommendation to convalescent patients is after a period of time, weeks, you're eligible to be vaccinated. And many people are being. But there's been a flurry of preprints and one published paper in Lancet, I think, from the UK, showing that a single dose of the mRNA vaccines to a convalescent patient very rapidly triggers an extremely strong antibody response. It's a recall response. And the raters that are reached within a few days to a week of that single dose exceed what people had during infection or exceed what the two doses give in a naive people. So this is an argument that a single dose in a convalescent patient may be sufficient. And the French have already, a week or two ago, said, we're only going to give one dose to convalescent. Well, everyone would be happier with clinical trial data on this rather than anecdotes. But the anecdotes are quite compelling. And if you think that there are, what, 30 million convalescent patients in the USA now, it'd be a lot of dose saving. So I think, and the FDA is starting to seriously look at this now. So it's something to explore. Is there a sense yet for people who come, as you call them, people who've been infected and then get Moderna or Pfizer, or people who weren't infected and got the two-dose Moderna and Pfizer. We're six months out from that initial group. Do we know much about what their titers look like six months out? Titers, after you're infected, you get a very rapid peak response that then decays gradually over the next six months. I mean, we're only at six to eight months time points from the... Right, right. But it doesn't disappear. And reinfection cases, except when they're triggered by a resistant variant, which are becoming more common, but with the reinfection by the same virus, it's still pretty rare. It happens. But you also have to remember that the magnitude of the infection-induced antibody response is not the same for different severities of infection. It's strongest for the sickest patients. So people with asymptomatic or very mild infection don't have a very strong antibody response. In terms of circulating antibodies, they may have memory and they may have T T cell responses as well. So again, different convalescent patients might fall into different subgroups. And that's why you'd look at a clinical trial of people who had originally a mild infection and people who had originally a sicker infection and see what a single dose does. Because at the moment, these preprints I'm referring to are all done in hospital employee study. You go and bleed your colleagues after they've had their vaccine. It's not a properly coordinated study, but they're valuable information. I'm not dismissing it.
One of the questions is a role of so-called Sputnik V vaccine. Can you Can you imagine what role that would be in the U.S.? Or is that largely going to be outside the U.S.? I have no idea if the company's even planning an FDA application. I would be very surprised if it was Sputnik V was going to be used in the States or the Chinese vaccines. I mean, we don't need them and they would need to go through a trial program. Having said that, you know, I was very skeptical about the initial reports out of Russia. I thought, what the hell is Putin doing? You know, he said, we have a vaccine. All he's done is tested it in his daughter and a few other people. But it turns out that that's a pretty good vaccine. And again, who saw this coming? It is a better vaccine than the one, the AstraZeneca-Oxford vaccine that was also based on adenoviruses. So all of these, both Sputnik V and J&J and the Oxford-AstraZeneca are all based on adenoviruses, but they're not identical. The Russians came up with the best design, it would seem. I mean, again, assuming that all their published data is completely kosher, you have to take it at face value. But their efficacy was up at 90%, and it's hard to argue they came up with a good design. They're having some trouble making it, apparently, but they're trying to get it into Eastern Europe and other client states. There's a complicated question, and so if you could walk through it, John, slowly. So if you could go through each vaccine against each variant and what you know about it. Sorry, so Moderna and Pfizer against B.1.1.7. So if you could walk through that and what the most recent data are about efficacy. Well, there's not a lot of information out there because we don't have a coordinated way of tracking how vaccines are. There is not yet a central system for looking at all the vaccine serum against all the variants. So it's all being done on an ad hoc basis, small-scale studies in individual universities and medical schools. I have not seen any study on J&J vaccine serum. I mean, it's not available within hospital medical schools. And apparently it's being, you know, the company is doing its own studies in clinical trials and other people can't get access. So we await that result. Moderna and Pfizer serum are much more available because, like I said, in hospitals, you can get access through IRB-approved protocols. And they're pretty similar, Moderna and Pfizer. The B.1.1.7 variant that is the rose in the UK, that is more widely circulating, that is very little different from the wild-type virus in terms of neutralization sensitivity. It's twofold, insignificant, not a concern. No one's losing sleep over this. So that is not an escape mutant. It's not an antibody-resistant virus. I can't imagine it would be a significant reduction in vaccine efficacy for Pfizer and Moderna. It's also been tested against the Novavax sera, and the Novavax sera is not a problem. There's only been one study on that that I've seen. The B.1.3.5.1 variant that arose in South Africa is more of a problem, and Pfizer and Moderna sera in most studies are down fivefold, sixfold, sevenfold in titer. But that's not a catastrophe. That's a sort of eyebrow-raising ground for concern, but not a freak-out situation. Because the strong antibody responses to the two doses of Pfizer and Moderna should be able to cope with this. So if you reduce from a strong position, you still have a reasonably strong position. So there's grounds for concern and we need data, but it's manageable. There is one study out there that says the reduction could be as high as 90-fold, but I think that's an outlier. So, but again, it's better to have a centralized system where all of these vaccines are available against all the variants.
And again, the sera from that Oxford AstraZeneca vaccine doesn't touch the South African variant. So that's a weaker vaccine. It's being relied on heavily in the UK and some of the countries, but it's a weaker vaccine and did not cope as well. And there's nothing on the others at this stage. The other variants you may have heard about, there's essentially no information on. But looking at the California variant mutations, it's not likely to be a vaccine resistance problem. Brazil? Brazil, the variant in Brazil, P1, is quite similar to South Africa. It is, okay. Judged by its sequences, you know, judged by the sequence changes. There have been fewer studies in the literature on P1. I've seen one that says there is a reduction in sensitivity in lab tests, in neutralization tests, but not to the same extent as in South Africa. So it's sort of based on this one study or maybe two studies, it's in between the UK B.1.1.7 and the South African B.1.3.5.1. So it may be in between, but it's resistant enough to be a resistant variant. I mean, and it's also a more transmissible variant. So it's one we have to respect. John, one of the questions that comes up every time and has come up once again and involves literally millions of people in the United States. And the CDC hasn't been precise about this. You are an investigator who's focused much of your career on HIV, immunocompromised individuals and vaccination. Now, we talked about it yesterday in a small group. What do we mean by immunocompromised? It's not a good measure of being immunocompromised. Not many people know what their T and B cells are or their white blood cell counts are. So it's often based upon what your disease, how you're labeled with the disease or what drugs you're on. Do you have a sense of how individuals who think of themselves as being immunocompromised should think about the vaccines? Well, we definitely need studies because different people, as you just said, different immunocompromising means different things in different medical circumstances. I know colleagues here are trying to get off the ground a vaccine study in cancer patients with B-cell suppression in some cases, and others would be less severe immunosuppression. So it would greatly vary. I mean, someone who cannot develop a B-cell response isn't going to do much of a response to a vaccine. And there are studies in the literature, natural history studies, looking at people with immunosuppressive conditions and the magnitude of what their antibody response was to infection. Of course, a significant number of people with immunosuppressive conditions were infected during the pandemic. So there is information on their response to infection, if not vaccination, and you can get some feels from this, but it really tracks with their condition. I mean, people with severe B-cell defects are not going to respond well to infection and vaccination. And, you know, there's a concern that people who are highly viremic because they can't clear the virus because of immunosuppression, There's at least three case reports of troubling variants arising within those people because they have a long sustained viremia course that can't be cleared because there's no good immune response. So these are potentially, unfortunately, sources of resistant variants. And in the hospital setting, they need to be carefully looked after, particularly carefully looked after from the transmission perspective. But we absolutely need more studies on this. I have not seen a single vaccine study yet, and that's not surprising, on immunosuppressed patients. And I know they're being planned, and it is necessary that we do these studies. You end up in a, if you're a patient, it's a very complicated discussion because oftentimes your care provider may not know that much about it. Should these individuals avoid being vaccinated, John, or is it really a case-by-case decision? Is there a risk to being vaccinated or is it simply that they're not likely to respond?
Two days later, she was discharged. So these are circumstances in which passive antibody therapy, now either convalescent plasmas or the licensed approved Regeneron and Lilly drugs, passiveoclonals. Passive immunity to people who cannot generate active immunity. So these are settings where if you can't make your own antibodies, you get somebody else's. And passive therapy is particularly valuable in that setting, both to treat them and for prevention purposes. I mean, we know in a nursing home study that the Lilly and Regeneron Mabs will prevent infection or transmission when it was done in a prevention study as opposed to treatment. And I absolutely believe that would be the case. You would see that in many infectious diseases. So these antibodies can be preventative in circumstances where people are particularly vulnerable, such as immunocompromised patients. Okay, you might have to come in for an infusion every three or four weeks, but that's definitely okay, given the alternative. Two final questions, kind of the two ends of the age spectrum. I am a pediatrician by training. How have you understood the general lack of serious disease in children? We've published on MIS-C a number of times, but it's rare. The epidemiology in terms of age and deaths hasn't changed since last February. 80% of the deaths are in people older than 65. It's virtually unchanged. How do you understand the general lack of serious disease in particularly pre-pubertal children, but in children and young adults even? Well, this is nowhere near my area of expertise. I read. I don't work in this area. I can only say what I've read. I mean, there are a number of different hypotheses on this. One is that the younger people generate particularly strong responses with immune responses and rapidly clear the infection. And that seems to be, you know, a favoured explanation. And I have no reason to dispute that. The question is, do they have high viral loads at all? And I've seen or heard of a recent report that infected younger people can actually have quite a lot of virus, which means they can spread it. But for whatever reason, it's not causing them any disease. Now that, if it's true, is important for transmission risks. But I don't know if it explains why they don't sicken. I think we should just be grateful that they don't. But we all know, because there's so much information, that older and sicker patients are the most vulnerable to severe disease and death. But we need vaccine trials in the kids, and this will happen. I mean, you can't do vaccine trials in kids until you have safety profiles in adults. That's the way it's always been done. But now high-risk season? Where do you think we'll be in August, John? one's going to be on holiday on the beach and whooping it up, spending all their frequent fly miles and just generally not being at work. And I think the economic consequences could be quite severe. That's the optimistic perspective. The more pessimistic one, which I personally don't believe, but let's go there, is resistant variants become a problem. Vaccine resistant variants, so that we have to rejig vaccine designs. And people then get, you know, more and more vaccinated people get infected by resistant variants, natural immunity wanes. We could see a problem. And, you know, the other biggest obstacle to it is something I mentioned earlier, having a very large percentage of underinated people who simply won't take the vaccines for whatever reason. I mean, there are surveys showing that 50% of Republican voters will not take the vaccine. Well, that's just crazy. It's not a political issue. It's a public health issue. But until we reach out into that population and persuade them to take the vaccines, we're going to have a large reservoir of people who would continue to be infected and spread the virus.
Hello out there. This is Dr. Kathy DeAngelis, the Editor-in-Chief of JAMA, the Journal of the American Medical Association. And this week I'm going to tell you about the March 4, 2009 issue of JAMA. And as always, I'll start with the art on the cover, which this issue features a painting by Mary Cassatt, who lived from 1844 to 1926. This one's called The Tea, and it was painted around 1880. Mary Cassatt was American, and I think she's a favorite among women and men who love children, which is pretty much everybody out there, I hope. The first article deals with proton pump inhibitors and clopridogrel efficacy. Clopridogrel and aspirin are often prescribed for patients following a chronic disease like tuberculosis or tuberculosis. Clopridogrel is used in patients following acute coronary syndrome to reduce the risk of recurrent cardiovascular events. To reduce the risk of gastrointestinal bleeding associated with the antiplatelet effects of clopridogrel and aspirin therapy, patients may be prescribed proton pump inhibitors, that's PPI medications. However, some mechanistic evidence suggests that PPI medications may decrease the platelet inhibitory effects, and that the use of proton pump inhibitors may be a risk factor for patients following acute coronary syndrome. To investigate the clinical significance of this potential interaction, Dr. Michael Ho from Denver Veterans Administration Medical Center and his colleagues assessed outcomes in a cohort of 8,205 patients who had been hospitalized for acute coronary syndrome and were prescribed clopridogrel with or without a PPI. The authors found that concomitant use of proton pump inhibitors and the use of clopridogrel and PPI after acute coronary syndromes was associated with a higher risk of all-cause mortality or rehospitalization for acute coronary syndrome compared with clopridogrel therapy without PPI. The second article deals with efficacy of live attenuated influenza vaccine. A trivalent inactivated influenza vaccine, for IM administration, was first developed and tested in U.S. military personnel in the 1940s and since the 1950s has been used annually to prevent influenza. In 2003, a live attenuated influenza vaccine was developed for intranasal application and has been used increasingly for immunization of military personnel. Although some data suggests that the live virus vaccine is not a good idea, it is a good idea to use it in the first place. The live virus vaccine has superior efficacy compared with the inactivated virus vaccine among young children. Efficacy data from adult populations are limited. To inform military vaccination policy and to assess the effectiveness of the live virus vaccine in a healthy young adult population, Professor Zhang Wang from the Armed Forces Health Surveillance Center and his colleagues investigated the efficacy of the live virus vaccine and found that the incidence of healthcare encounters related to pneumonia and influenza-like illnesses among active duty service members eligible for influenza vaccination and stationed in the United States during the 2004-2005, 2005-2006, and 2006-2007 influenza seasons. The authors found that immunization with the trivalent inactivated influenza vaccine was associated with lower rates of healthcare encounters for pneumonia and influenza compared with the live virus vaccine or no immunization, particularly among military personnel who had a past history of influenza vaccination. The third article is the clinician's corner and deals with a patient with recurrent clostridium difficile-associated diarrhea, and this is a clinical question. We'll be right back. Mr. S. is a 76-year-old man with a history of cadaveric renal transplantation in 1988 and 1998 and urinary retention due to spinal stenosis and benign prostatic hypertrophy, which is managed with an indwelling Foley catheter. Following antibiotic treatment for a urinary tract infection, he has had recurrent epidermal infection and a relapse of the lymphatic system. He has been diagnosed with a rare disease that has been associated with a rare disease that is associated with a rare disease. He has been diagnosed with a rare disease that is associated with a rare disease and is currently taking a dose of metronidazole, oral vancomycin, cephodoxamine, and ciprofloxacin.
Many U.S. children and adolescents today are exposed to gun violence, either in the form of a single incidence of traumatic violence or as a regular feature of daily life. The American culture of violence and ready access to lethal weapons can also affect young people's development and promote further violent acts. I'm Stephen Morrissey, Managing Editor of the New England Journal of Medicine, and I'm talking with James Garbarino, a Professor Emeritus of psychology at Cornell University and Loyola University, Chicago. Dr. Garbarino has written a perspective article about the effects of gun violence on young people's mental health. Dr. Garbarino, in your perspective article, you highlight two issues related to gun violence and children's mental health, one of which is traumatic responses in those directly exposed to violence. So what are the scenarios in which children in the United States are typically exposed to gun violence? In the country as a whole, there's a small percentage who witness shooting directly as children. Many of these shootings now are part of this phenomenon of school shootings or other mass shootings where children are either the targets or immediate witnesses. And of course, that's a terrible problem and it has all kinds of cultural and social reverberations. But there is a smaller group of kids for whom gun violence is a regular feature of life. And this is a subgroup of American children, and in many ways, the group that certainly I'm most concerned about because the effects of this chronic traumatic gun violence are severe and in many cases profound, and they're tied up in some of our most troublesome social conditions. So starting with that single exposure to a shooting, how does such a thing, say exposure to a school shooting, typically affect children's development and mental health? immediate crisis, of course, and they may well get some sort of short-term diagnosis of post-traumatic stress disorder or some other reactive sorts of issue. But the good news is that for the most part, that resolves typically over a year because they get the therapy of reassurance. They're told it's over, things are back to normal, and normal is pretty good. And they also are likely to get more professional intervention. And those who are struggling are more likely to get some sort of trauma-informed psychotherapy. But after a year has gone by, typically 80%, 90% are back to where they were. And that was certainly true of kids who witnessed the September 11th events in New York City. The study showed that a year later, something on the order of 90% were back to where they were. The 10% typically who don't have some pre-existing issue. One classic study found the kids who were struggling most were kids who their dog had died before the event, their grandma had died, their father was in the hospital for some reason. So it's really a matter of whether this single incident of gun violence trauma links up with other vulnerabilities, again, when it's a single incident. And then by contrast, how does growing up in an environment where gun violence is the norm alter children's development? Well, when it's chronic, it strips away some of the resources that are used for single incidents. You can't do this sort of therapy reassurance. You can't tell kids it's okay, things are back to normal, because normal is the problem. It's not like you have an event and it's over. It's part of an ongoing threat. And so you learn adaptive strategies. And I've spoken with kids who were taught, who lived in very violent communities, taught from an early age, get in the bathtub when the shooting starts. Not if the shooting starts, but when the shooting starts. So this chronic trauma can lead to a whole set of longer term consequences, which include issues about self-esteem, dependency, other kinds of issues which themselves then have to be dealt with. This is why I think it's important to always think about not just post-traumatic stress disorder, but post-traumatic stress development. Because certainly in the chronic cases, that is the issue. How do you develop in the wake of ongoing chronic trauma?
And it actually is a pathway to future gun violence because you're likely to develop this war zone mentality, which has a high level of hypervigilance. And also that's coupled with a belief in the legitimization of preemptive assault, shoot before you're shot. And I'm working as a psychological expert witness in murder cases for the last 30 the consciousness of young people, particularly those with serious mental health problems. Why are these young people especially vulnerable to media and other portrayals of gun violence? I think the reason stems from something called the audience effect, that teenagers are particularly likely to have this sort of melodramatic sense of the world in which the world is a play and other people are either the audience, or in some cases, the fellow actors in that play. So that's something that's been there for a long time. People have talked about teenagers who get a pimple in the morning and they think, oh, I can't go to school because everyone in school will be watching my face. And so this is a longstanding issue. But with social media and the culture of violence in America, it's become particularly lethal because kids who are troubled, particularly boys who are struggled, young men who are struggling, you know, they're looking for a sort of cultural answer to the question, what do you do if you're feeling angry, sad, hurt, rejected? And social media has offered up to them these images of what you do. I've interviewed school shooters, not a large number, but it's very clear. For example, they studied the 1999 Columbine school shooting as if it were a primer, as if it were a textbook on how you respond. And they get cues and clues. And then, of course, the more as social media has become so much more pervasive and sophisticated since 1999, the power of this imagery increases. And psychologically vulnerable kids are particularly prone to this. So are there strategies for intervening before adolescents who may be prone to gun violence can obtain lethal weapons to carry out a violent plan? Well, of course, like the answer to many questions, that depends. It depends on what society's willingness to keep kids safe by denying them access to lethal weapons. And our track record on that is abysmal compared with most countries. So there's a social, political, structural context here that just guarantees that young, angry males will kill lots of people. So failing to prevent access to weapons, our best strategy seems to be more careful, insightful assessment of where these kids are. There are growing a body of work about the possibility of identifying kids who are at risk through multiple psychological screening instruments, algorithms that use those screening instruments to predict those kids who are at highest risk. And so it's not totally opaque, but having the cultural and political wherewithal to first to do those assessments and then to translate them into therapeutic intervention, and then to have a kind of fail-safe option where if we don't succeed, at least we know they're not going to be able to be armed with powerful weapons. So there is a strategy out there. Some communities are making more progress than others, but clearly by looking at the news, we aren't making a lot of collective progress on this. Finally, looking at the political angle, do you think that there are federal or state policies that could address both aspects of gun violence that you outlined, both alleviating harm to children and supporting their mental health? Clearly, disarmament, in a sense, would be the overarching strategy that there was some number of years ago, the Boston Gun Project focused on taking guns out of the hands of gang members, and they achieved a significant reduction in youth homicide. When you look at countries where guns are not so available, troubled kids still act out. They may, in some extreme situations, find a way to get access, but at nothing like the rate that we have here. There's research in what's called the culture of honor, in which people develop this cultural sense that if your honor is violated, you have to respond with violence. There are countries that have that culture of violence, but kids don't access guns, and so it doesn't translate into a lot of dead bodies. It's hard to have a drive-by stabbing. It's hard to have a mass beating death.
Hello out there. This is Dr. Kathy DeAngelis, the Editor-in-Chief of JAMA, the Journal of the American Medical Association. And this week I'm going to tell you about the November 24, 2010 issue. And as usual, I will begin with the art on the cover. This one is a painting by Mr. Anabal Carocci, who lived from 1560 to 1609. The title is Boy Drinking, and it was painted around 1582 to 1583, and it is Italian. This is a very interesting perspective because I'd like you to look at the right eye especially, as seen through a drinking glass. If you don't know what I'm talking about, go and take a look. And the first article has to do with mediastinal nodal staging of lung cancer. The optimal approach to assess whether non-small cell lung cancer, that's NSCLC, has metastasized to the mediastinal lymph nodes is not clear. Dr. Joep Anema from the Leiden University Medical Center in the Netherlands and his colleagues randomly assigned patients with suspected lung cancer to the mediastinal nodal staging of lung cancer. The authors report that the combined strategy of endosonography and surgical staging, had greater sensitivity than surgical staging alone in identifying patients with mediastinal nodal metastasis. In an editorial, Dr. Mark Iannartoni from the University of Iowa School of Medicine discusses the challenge of providing highly skill-dependent lung cancer staging modalities to all patients who will benefit. And the second article deals with exercise, hemoglobin A1c, and type 2 diabetes. Patients with type 2 diabetes should be encouraged to exercise, but whether they emphasize aerobic resistance or both type of exercise is unclear. To address this question, Dr. Timothy Church from Louisiana State University and colleagues randomly assigned individuals with type 2 diabetes to a nine-month supervised exercise intervention consisting of aerobic training only, resistance training only, or both aerobic and resistance training, or to a non-exercise control group. The authors found that only the combination of resistance and aerobic training was associated with improved hemoglobin A1c levels. In an editorial, Dr. Ronald Siegel from the University of Calgary, School of Medicine, and Professor Glenn Kenney from the University of Iowa discuss what is known about the contribution of exercise to improved glycemic control. Familial and new onset atrial fibrillation is the title of the third article. In an analysis of data from the Framingham Heart Study, Dr. Stephen Lubitz from Harvard Medical School and his colleagues examined the contribution of familial atrial fibrillation, that's AF, to the risk of new onset AF. The authors report that familial AF was associated with an increased risk of new onset AF that was not attenuated by adjustment for established AF risk factors, including the presence of AF-related genetic variants. When familial AF occurred prematurely, that is the onset of new onset AF, the authors reported that familial AF was associated with an increased risk of new onset AF. When familial AF occurred prematurely, that is the onset of new onset AF, the authors reported that familial AF was associated with an increased risk of new onset AF. When familial AF occurred prematurely, that is the onset of new onset AF, the authors reported that familial AF was associated with an increased risk of new onset AF. At or less than 65 years of age, a slight increase in predictive accuracy was observed compared with prediction based on traditional risk factors. The fourth article deals with fructose-rich beverages and gout in women. Intake of fructose increases serum uric acid levels, and an increasing incidence of gout in the United States has coincided with an increase in soft drink consumption. A prior study found that consumption of sugar-sweetened sodas, fruit juices, and fructose were associated with an increased risk of gout among men. To examine this relationship in women, Dr. Haiyan Choi from Boston University School of Medicine and his colleagues analyzed data from the Nurses' Health Study and found that consumption of fructose-rich beverages, particularly sugar-sweetened soda and orange juice, was associated with an increased risk of incident gout among women. And the JAMA patient page has information for your patient.
I mean, it's not like the models magically learned bias by themselves. These models learn from human data. And so the biases in human data get picked up and regurgitated with large language models. People will say like, well, humans are biased and therefore the models are going to be biased or that's okay. And I actually don't think that's okay. I think if we're going to build these systems and put them into the healthcare system, we need to be building systems that are fair and are not going to worsen health disparities or continue to perpetuate them as they exist now. And as I mentioned before, even if you built the most perfect model, like having these systemic issues on the human side, you have to fix that too. Technology is not going to save everything. Welcome to another episode of NEJM AI Grand Rounds. I'm Rajman Rai, and I'm here with my co-host, Andy Beam. And today we bring you our conversation with Roxana Dineshju. Roxana is an assistant professor of biomedical data science at Stanford University, and she's also a practicing dermatologist. She's been working in AI for dermatology and for medicine more broadly for several years. Andy, I think this marks the beginning of season two, and Roxana is a wonderful guest to kick off our new season. So to me, I think Roxana is a clinician scientist who truly and impressively draws and mixes together both her clinical and her technical skills to do unique work at the intersection of AI and dermatology. She also cares a lot about algorithmic bias and healthcare disparities. We really got into that in the conversation. I thought she had a lot of insights to share there about both the potential for AI to exacerbate disparities, but also how it might be used as a tool for good. You really feel, I think, the urgency of these problems when speaking with Roxanna, and I learned a lot from our conversation with her. Yeah, Raj, I agree. It was a great pleasure to talk to Roxana. I first became aware of Roxana, you know, like I do of a lot of scientists through Twitter, where she's prolific. The first time I met her was at NeurIPS, and I was very pleasantly surprised to find that she's as nice in person as she is on Twitter. I agree that her work on algorithmic bias is timely and urgent. And when I think of Roxanna, I really think of her as an exemplar for future leaders who are clinicians who are really pushing the boundaries for AI and medicine. I often get approached by junior clinicians saying, how can I mold myself to have a career and really make an impact at this interface of AI and medicine? And almost always, I point to Roxanna as the template to do that. She's clearly a rising star in the area. And I think she is uniquely good at combining her deep clinical expertise to inform her research directions in AI. And so for a lot of reasons, it was really great to have her on the podcast. The NAJM AI Grand Rounds podcast is brought to you by Microsoft, Viz.ai, Lyric, and Elevance Health. We thank them for their support. And now we bring you our conversation with Roxana Dineshju. Welcome to AI Grand Rounds, Roxana. We're really excited to have you here today. Thanks for having me. Roxana, this is a question that we always like to get started with. Could you tell us about the training procedure for your own neural network? How did you get interested in artificial intelligence and what data and experiences led you to where you are today? Well, I guess how far back do we want to go? I mean... As far back as you want. We like to go back to when the neural net was initialized. Exactly. So take us back. The pre-training that happened. Basically, I grew up to two Iranian immigrant parents who really liked to incorporate science very early on. I have memories of doing these long road trips with my dad and mom. My dad would always play these astrophysics recordings. And so I had to, you know, from a young age, just develop this curiosity for how things work and how to build things.
I went to a high school that was the Texas Academy of Mathematics and Science, and it's just as nerdy as it sounds. High school students get to live on a college campus and take college classes together, and it's a boarding school. And that was actually when I first got into research because I joined a neuroscience research lab with Dr. Jan and Fuchs and was doing a lot of mouse work at that time. And then I went to Rice and I studied bioengineering because I was very interested in understanding how the human body works, but also how to build things that could improve the human health condition. And I think that that was a really formative experience for me because as a bioengineer, we talked a lot about design thinking. We talked a lot about identifying problems and then developing solutions and testing. And I think that formed a real foundation. And to be honest, in college, I waffled a lot about whether I wanted to get an MD or a PhD. I waffled back and forth many times. I ended up actually applying to go to medical school and get an MD. And I landed at Stanford, which has a heavy research focus. And I took, I was taking a bioengineering seminar with Dr. Russ Altman. And he talked about using computational methods to study human genomics. And that really sparked my interest. I was a first year medical student. I emailed him, I met with him. I started doing research with him. And then at some point, I realized two years into that, and then after having done a one year research fellowship that I wanted to do a PhD. So I actually didn't go into medical school as an MD PhD. I was an MD only, who suddenly had struggled with that decision before coming and had just picked one and then decided to add a PhD in the middle of medical school. So I did that with Russ and then I completed my medical school. And right about that time, there was all the interesting work coming out around computer vision. And I had become clinically interested in dermatology. And so to me, it seemed like a real opportunity. AI seemed like a real opportunity to solve problems in dermatology, which is a very visual field and all of healthcare in general. So I ended up doing a residency in dermatology and then a postdoc with Dr. James Zhu in healthcare AI. So I was in training for a long time, as you can tell from that story. Can I just follow up? What was it about dermatology that sort of drew you to that? Well, I think there was a couple. So on clinical rotations, I really enjoyed basically every rotation I went through. The one thing that's really nice about dermatology is that it's a very visual field. You can walk into the room and see what's going on a person's skin and put the pattern together with some history. Sometimes you don't even need the history. Sometimes you walk into the room and you can just tell exactly what's going on. And actually, one of my favorite diagnosis is this like phytophotodermatitis, which is they get geometric brown or red patches on their hands and they've suddenly appeared. And it turns out that this diagnosis is usually after handling certain plant-based products and then being exposed to the sun. And so you start to ask them questions. So lime juice is one of the things that can do this. So you ask them questions like, oh, so this past weekend, did you hang out with your friends? It's actually called margarita dermatitis. Did you handle limes because you were making margaritas or, you know, having a barbecue or doing something else? And their eyes will just widen because that's exactly what had happened. And so there are other diagnoses in dermatology like that as well. Like when you see the pattern, it corresponds to some exposure. So it's pretty fun to like be able to make diagnoses like this. I think that's part of it. I think also I build, I have really great longitudinal relationships with my patients on an outpatient basis. So I see them regularly. I know their stories. I know all about their families and what their travels are.
That's a great overview of your training. What are you up to now? Yeah. So I am an assistant professor of biomedical data science at Stanford and also joint with dermatology. So I practice half a day a week seeing patients. And then I run my AI for healthcare lab the rest of the time, which is essentially like the physician scientist dream is to be able to still have your hand in clinical work. Because I think one, it's very gratifying to work with patients. And two, it gives you a window into exactly what's happening into the healthcare system. And the rest of the time I get to work with my amazing, the postdocs, the graduate students and medical students who are in the lab. Awesome. I think that is a good transition to talking about some of your research. So the first paper that I want to talk about is called Disparities in Dermatology AI Performance on a Diverse Curated Clinical Image Dataset. So one, could you give us the setup for this paper? And then I think we'd like to dive into some of the details. The setup for this paper is that I'm interested in AI fairness and bias. And Dr. Adey Adamson, who is a friend and colleague, had written a perspective piece in JAMA dermatology essentially saying early on that he was very concerned about whether or not data sets that were being used to train dermatology AI models were representative of the full skin tone spectrum. And I think that his concerns were really appropriate because as many other dermatologists had pointed out before, like Dr. Jenna Lester, the education in dermatology, like the textbooks, the training in and of itself is not very representative of diverse skin tones. So you're looking at the training being like that for humans, and then you start to worry about the training for models having the same problem. And before we actually wrote this paper, we wrote a different paper where we actually went through and looked at the literature that had been published in the dermatology AI space and found that almost none of those papers actually even reported what skin tones were used in training or testing. And that for the ones that did report that they basically either significantly underrepresented or excluded brown and black skin tones. And so the impetus for this paper was we wanted to create a data set, sort of like a benchmark, so that we could test how algorithms perform across diverse skin tones. That's great. So could you actually, for the non-dermatologists who are listening, how do you measure skin tone? There's a scale. Could you walk us through actually how you assess the variety in skin tone versus just like dark versus light? Right. So there is a scale. It's actually not a great scale. And there has been a lot of discussion and efforts on developing new scales because the current scale is not very inclusive. However, much of the machine learning world has been using that imperfect scale. And that's actually what we do in our paper as well. But I just wanted to put that out there. I think that scale is problematic. It's called the Fitzpatrick skin tone scale. It was originally developed to help dermatologists look at how easily someone might burn sunburned to in order to help people dose photo chemotherapy. So it was originally about how easily you tanned, how easily you burned, and then it got co-opted into being used to assign color from an image. So that's not how it's meant to be used. And also when the scale was first developed, it actually excluded brown and black skin tones. That was added later. And there's six categories in it, which is obviously not inclusive of the full diversity of human skin tone. But that imperfect scale is what we used when we were trying to collect our images. And we tried to actually assign the skin tone based on what was recorded by the clinician seen in person, because in photography, like the lighting can impact what the skin looks like. So that's a scale. And so we particularly the light skin tones are Fitzpatrick 1 and 2, 3 and 4 sort of in the middle, and then 5 and 6 usually represents brown and black skin.
Got it. Go ahead, Rosh. Roxanna, how are dermatologists trained to rate Fitzpatrick skin types? Are they trained to rate these skin types? So it's definitely discussed clinically, like when you write your medical note. And the reason that people care, again, is to try to make a decision on how easily someone might hyperpigment, meaning that how easily their skin might turn brown from inflammation or how easily they might burn with certain treatments that involve light. So it is something that we actually go through in training and actually in work with Matt Groh, we looked at the variability of labeling skin images, which is different, obviously, than the in-person labeling or asking people about how easily they burn. But for a machine learning purpose, we wanted to understand how much variability there was between people. And it turns out there is some variability, but most of the time, if you have dermatologist labeling images, they're within one point, either below or above each other. Got it. And just before we move on real quick, just because I find this interesting, how does that impact treatment recommendation or a patient's clinical course, what Fitzpatrick bucket they're put into? The real way to get, clinically speaking, it shouldn't just be what you think they're Fitzpatrick, but you should be asking them questions about how photosensitive they are, how easily they burn, if they have a history of having their skin sort of change color after inflammation, because you can't always know that without actually asking. Someone could have brown skin and actually be very photosensitive because of a medication that they're on. So it's important not to make assumptions without actually asking your patients about their experiences clinically. Right. You could be a three or four, but if you're on a lot of antibiotics or something, then you could be photosensitive or something like that. Yeah. Okay. So I think that was very helpful background. So if I understand correctly, you saw that there was this unmet need in the literature that most of the data sets were not diverse. We've seen this in other areas too, like GWAS, where a lot of the studies were done in white Europeans. You kind of had a sense of that this was happening for AI for dermatology. So you actually collected a big data set that had a huge representation of different types of skin tones, right? Could you tell us how you curated that data? Yeah, so we curated and de-identified data from Stanford. It was an effort of many researchers to make sure that we were comparing the, we were using the pathology reports to make the diagnosis. We were not just looking at the image and saying, oh, we think it's this. We actually had the pathology reports. We wanted the labels to be as clean as possible. We had a dermatopathologist sitting with a dermatologist reviewing what's in the report, what it looks like clinically to assign each of those labels. We were looking at the assigned Fitzpatrick skin tone label in the chart, and then having two dermatologists confirm that they thought that that label was correct. So for us, this was meant to be a benchmark. It is not a large enough data set to train an entire, you know, deep learning model on, but it is one that you can use to benchmark against. How many images did you end up with? I believe it is 656. Okay, nice. I mean, it sounds like a lot of manually intensive labor given all of the eyes that sort of looked at each image. Yes, it was. And I know that that is not tenable when you're talking about wanting something like 10,000, you know, 100,000 images for training. Yeah, everything doesn't have to be ImageNet. I think that having very good, high quality benchmark datasets that have a good amount of TLC, which it sounds like this data set definitely does, are super important things to have to understand how these models work. That's how we felt too.
And then we even looked at, for example, we had look at photo quality between the two groups. We had dermatologists label photo quality to make sure that the photo quality was similar between the two groups so that when people are running algorithms against looking at performance in Fitzpatrick 1 and 2 and 5 and 6, we could minimize as many confounders as possible in that comparison. It's almost like you have a counterfactual lesion for each person in the data set. Like the only thing that has been changed has been the skin tone. So it's not quite perfect. I wish it were because, you know, in some cases we had to match categories as like non-melanoma skin cancers had to be a bucket in and of itself because it becomes difficult to match lesions perfectly. But in general, like every benign lesion has a benign lesion that's in a similar diagnostic space. Yeah, makes sense. So what did you find? How do the current dermatology classifiers do? Yeah, so I mean, we, one thing is, I'm all about open science. I think that's why we need open science, because there's a lot of commercial algorithms or algorithms that have been published about that we couldn't get access to. We asked, we went and asked around, hey, you've published on this algorithm. You're making claims that this might be used commercially someday or touch patients. Can we test it on the benchmark? And usually the answer, no. access to the interface at the time or an API or something. And we ended up testing models that were open source. So these are not necessarily models that are going to be used clinically, but there were ones that we could access to and had been previously published on and had really good performance. And we looked at three different models. And the interesting thing, I mean, this is not a surprise to anyone who's kind of been following this space, is that all three models had performance drop-offs in general when they tested on a new data set. And we know this because sometimes these models overfit to features in the data set that they were trained on. And when you introduce some kind of new external data set to them, they'll have some performance drop off. It could be because of differences in the camera technology used to acquire the images, differences in lighting. Dermatology is kind of hard because we don't have standards for how we take our images. So that was the first thing we noticed. But the part that was like most concerning to us was that there were significant differences in how the algorithms performed on Fitzpatrick 1 and 2, the white skin tones versus Fitzpatrick 5 and 6, the brown and black skin tones. That sadly is not surprising. Yeah. Can I ask a philosophical question? Do humans, are they worse at diagnosing dark skin tones also? Has anyone looked at that? That's an excellent question. So I mentioned that a lot of the education materials for humans has underrepresented brown and black skin tones. And this has been something many other dermatologists in there's a skin of color society that focuses on making sure that we have equitable care across skin tones. There are many dermatologists who have brought this up over and over again about representation and education and training of dermatologists. And in terms, you know, there have been survey studies that have shown that dermatology residents, some portion of them don't feel as comfortable making diagnosis across diverse skin tones. There is an amazing TED Talk by Dr. Jenna Lester exactly on this topic. In terms of has anyone sort of systematically looked at this, stay tuned. We have a paper coming out where we did this with just images, which is obviously different than clinical care, but we wanted to look at it in the sort of like the teledermatology where you just have some image and not that much history. So there are differences that we saw in that upcoming paper. Because I ask because I'm wondering like how we fix this. And if you train the model on a more representative data set, but the labels are coming from this very error prone process on dark skin, would that fix it? Or is there something more structural that needs to happen?
And I guess like, what does the path forward look like? So I feel confident about our labels because we looked at things that were biopsies and we had path reports on them. Now, of course, there's variability in pathology that exists. But one thing we actually did was have dermatologists label the images and we saw differences in labeling between the two skin tone groups. Of course, that doesn't, is not representative of what happens in clinical care. That's just giving people an image and asking them to label a disease, which is they don't have the opportunity to ask history or do their clinical exam on the lesion. But from a labeling standpoint, we think that actually if you are just relying on dermatologists for labeling and you don't have ground truth, that's a loaded word. If you don't have a histopathology label, you have more noise if you have the dermatologists labeling the data. To go back to what you're saying, like how do we fix this, right? Because I'm diving into the machine learning side of it. But I think that there's the AI realm, but we need systemic change in medicine too. Like this is not an AI only problem. AI is reflecting the biases that exist in the human realm. And my feeling has always been that you cannot rely on AI to fix problems that you have to actually tackle in the human realm, which is we need to make a concerted effort to improve the training of dermatologists so that dermatologists do a better job. We need to improve access to care. A lot of the health disparities that exist in dermatology are not AI related issues, but they spill into AI. And I don't think that even if you created the most perfect, fair AI algorithm, that it's going to necessarily be a bandaid for the problems that exist systemically within the medical system. At the risk of ruining what would be a perfect transition to the next set of questions that we want to ask you, I just want to ask one quick follow-up. Just since you're an AI researcher and a practicing dermatologist, what's your sense of the penetration of this technology in dermatology? So I've seen in radiology, it just all of a sudden has happened where there are AI systems in reading rooms and triaging chest x-ray reads. What's your sense of how much penetration there's been for AI in dermatology? So it's been interesting. In the US, image-based, there's other forms. Image-based AI, there's been no FDA-approved algorithms as of us talking. There are people running trials to try to get FDA approval. So, and there've also been now, finally, there've been several, for a while, there were no even prospective clinical trials of say, like a dermatologist using AI to see if it improved like their sensitivity or specificity for finding skin cancers. So now there's been some prospective trials. So we in dermatology are definitely, I like to joke that we're a decade behind radiology. I don't know if it's truly a decade. In other countries, there have been things that have received, for example, CE mark and have been used in clinics. They're also direct to consumer apps, which are a little concerning because as I mentioned, some of them make diagnostic claims without actually having FDA approval or published trials. So we actually, one of the things that we've done is we've looked at some of the consumer apps that are available in app stores in the US. And I mean, a majority of this, like, we don't know anything about how they actually perform. There's like no published material. But in terms of penetrations, like, is there AI in my clinic? There's not AI in my clinic yet. How long do you think it is going to be until there's AI in my clinic? In your clinic. already trying to test that out now so maybe before like you know if we're talking about dermatology ai and like image based image based dermatology ai my guess is that the first thing that'll come out and this is just me guessing is something with like a dermatoscope which is yeah the so dermatoscope is like basically a fancy magnifying glass that costs nine hundred dollars no reason.
It's nothing more than that, but it's a little bit more standardized because you put the magnifying glass and everything in that field of view can be captured in an image. And one of the largest public data sets of dermatology AI images for training models, the International Skin Imaging Collaboration, is largely dermoscopy images. And so that space has moved a lot faster than the clinical image-based models. So my guess is the first thing is that there'll be some AI companion to the dermatoscope that comes out. And there've been some clinical trials in that space. So we'll see. Got it. To be determined. Does the dermatoscope plug directly into the EMR or how does it interface? Or does it have its own output and then you have to enter something? No, right now it's low tech. It's a magnifying glass. It can, it has a, it has an attachment. You can attach an iPhone to it so you can take a picture. So my, my guess is that basically based on some of the trials, there'll be some readout. You'll actually have to use like your iPhone to take the picture with the hardware, right? The hardware is just going to magnify the image. You'll use your iPhone to take the picture and you'll have something that runs and gives you some readout. That's my guess. Got it. Very interesting to see. And thank you for entertaining the question because it's a little unfair question too. I could be. Just predict the future. I could be completely wrong. Yeah. We appreciate the speculation and I think you're the top person to do it. So I think this is a good transition point, actually. So you mentioned large language models. We want to stay on the topic of algorithmic bias connecting to your work in dermatology, but now switching over to LLMs, large language models. You published a paper pretty recently, I think it's titled Large Language Models Propagate Race-Based Medicine. And as I understand it, it also hits another theme that you referenced a few moments ago, which is AI picking up bias that is in society, that is in the way we practice medicine, and potentially amplifying it and propagating existing ways of practicing medicine, but not necessarily updating as these models have changed, as race has been removed from some of these equations, not staying up to date with current best clinical practice and recommendations from clinical societies. So could you maybe just set the stage for us by telling us about what motivated this paper and what you did for the study and maybe briefly what you found? Yeah, so I am a dermatologist, but as I like to say, I like to do research throughout all of healthcare AI, having done like a year of internal medicine training, having done rotations as a medical student. I'm not just focused only on things that impact dermatology. And of course, when I remember I was at NeurIPS, as many of us were, and Andrew, I think actually one of your students was the first person to say, hey, did you guys know that there was an update to ChatGPT had just been announced? Yeah, I remember that. We were at like a cocktail party or something. And my student was like, there's this thing called ChatGPT. I think we should probably pay attention to it. We're like, meh. Yeah. Yeah. No, because- This is a year ago now, right? November 2022. It feels like 10 years ago at this point. It does feel like- It does feel like 10 years ago. Yeah. That's how I feel about having started my faculty job. It's been like a month and I'm like, that month feels like a decade. But yes, actually, it's hilarious that we're talking now because I remember the stage. We were walking back from one of the hosted company parties that they have at NeurIPS in New Orleans. And we were walking back and your student said, you need to look at this. And we were both like, well, we've played with GPT-3 and like, eh.
And instead of getting ready to go to bed, I logged on, made an account and started talking to it. And then I said, whoa, this is very different than GPT-3. And I started asking it a lot of medical questions, which I had done with GPT-3 as well. And now GPT-3.5 was just like answering it in ways that shocked me. And of course, I think for anyone who's ever interacted with these systems, like for the first time, there's that moment of being very impressed. And then you start to dig in and try to think about, okay, where the problems are. And I think that over the last year, a lot of people, and of course, GPT-4 has come out now and people have seen where some of the issues are. And so one thought I had, the reason we did this paper is because medicine is very slow to adopt things. And I had been working on image-based AI. We had even done a clinical trial of one of our models. And that model was not even a diagnostic model. And it was just very slow adoption. And then all of a sudden, it felt like overnight, there were hospital systems saying, hey, we're piloting these large language models into our medical systems. And that was a little surprise. I don't know if you guys have been surprised and shocked, but I've been kind of, well, thankfully the hospitals we're affiliated with moving slower than the ones that you're affiliated with. So we haven't had to address that yet. So I said, whoa, like people are actually talking about integrating this into the medical system. So, and we haven't had- I have so many questions, but keep going, keep going. Because I want your perspective also on that at Stanford too. But because it probably is faster than, as Andy is saying, it's probably faster than the way things are moving here. But I think, yes, there is a extreme amount of energy to get these into practice. And I will say that a lot of this stuff is still in the pilot study phase, but it's not just Stanford. It's many academic institutions. I just had never seen something go from it just came out to now we're doing clinical pilot studies in such a short period of time. And so my research group, we've thought about AI fairness and bias for a while, mostly in computer vision. And so then we started thinking about like, how could this show up with large language models? And so one thought we had is that we knew that physicians and patients were likely asking these models questions, clinical questions. And so we pulled, so there's this 2016 PNAS paper that looks at some of the incorrect race-based misconceptions that medical trainees have. So we pulled some questions from that paper. And then we also had a group of experts who are all authors on the paper sit together and think like what other questions we might ask. And so there's been a lot of discussion around the use of race in medical algorithms because race is not biological. It's a social construct. And so studies have shown that there can be disparate outcomes from using race in algorithms. And so that's why, for example, we don't use race in kidney function calculation. And in fact, that change was made before, for example, the chat GPT models came out. So if you ask chat GPT about it, it knows about that change. And yet, if you ask it, how do you calculate EGFR? So it references the new National Kidney Foundation American Society of Nephrology recommended race-free equation, but then recommends using the race-based previous equation. So yeah, I'm just saying, if you ask it, do you know about this information? Okay. So it's aware of it. It's aware of it. It's in its artificial brain somewhere. Yes. But when you ask it, this is my creatinine, this is my patient, or this is my age. What is my EGFR? It will use the race stratified. So we just, we actually made it very simple. We just said, how do you calculate EGFR?
So if you ask it, if it knows about the newer way of doing things, it knows. So that's just to show that it's not that it doesn't know. It does know. But if you ask it, how do you calculate EGFR? It will give you and actually, you know, all the models we tested had problems. So it's I'm'm not just picking on chat GPT. What other models? Did you test the other proprietary models? Yeah. Bard, Claude, 3.5 and 4 for GPT. Were the models meaningfully different from one another? You know, the way that the answers were written were certainly different. We have sort of a heat map in our paper that shows like which models were better than the other. In general, many of them failed similarly on certain questions and many of them passed, for example, most of them, except for one, passed the question on the genetic basis of race, which again, race doesn't have a genetic basis. It's a social construct. So it's just interesting to see what they failed at and what they, I'm sure there's that reinforcement learning with human feedback for some of the questions that we asked is my guess. But actually one thing that was really interesting to me that I wanted to point out is some of the models, not only did they give the incorrect race-based equation, they actually gave an argument for why you should use that equation using like a false racist trope, which is that there's difference in muscle mass between races, which is a completely debunked racist trope. And so that was even more interesting in a bad way. Not surprising, because that stuff is out in the world, but deeply concerning because if somebody comes in with those biases, it just gets confirmed, right? I'm curious, did that sort of rationalization come unprompted? It's like, hey, trust me, I'm not'm not racist like here's the reasoning behind why i'm doing this it was unprompted i'm saying that this appeared simply in response to just asking like how do you calculate egfr there's a or yeah there's a like me thinks the lady doth protest too much component to that it seems like right i mean we also we also, how do you calculate EGFR and give the race of the patient as well? But even if you don't give a race of the patient, so it's interesting because when you talk about lung capacity, if you just ask about calculating lung capacity, it doesn't give a race-based answer. But if you ask it about calculating lung capacity and give a patient race, then it starts talking about debunked differences. It starts claiming that there are differences in lung capacity between races that are not supposed to be used, that don't exist. So, you know, Roxanna, similar to Andy's question about dermatology and how dermatologists fare in rating, basically treating patients with different skin tones. Do you think that the models here, so the large language models, do you think they're also reflecting the societal bias, the way that race has been and currently still remains in many instances embedded into physiological equations and is used as sort of an inductive bias, right, into your model for physiology for many, but I think reducing, applications in medicine. Do you think these models are essentially reflecting that, I guess is the first question? And then my second question is, how do you think large language models, the ones that you tested, compare to practicing physicians in terms of bringing bias into the clinical encounter? So I think for the first question, the answer is yes, because obviously the large language models are first trained on large amounts of text data that reflects human thinking. I mean, it's not like the models magically learned bias by themselves. These models learn from human data. And so the biases in human data get picked up and regurgitated with large language models. I think your second question is a really difficult one. I'm not sure how to answer. People will say humans are biased and therefore the models are going to be biased or that's okay. And I actually don't think that's okay.
And as I mentioned before, even if you built the most perfect model, having these systemic issues on the human side, you have to fix that too. Technology is not going to save everything. Yeah, no, so I agree. And I think the time to do that is now before they are, you know, before they are widespread. But I think understanding human bias is maybe a path to thinking about designing a robust human AI collaboration. And so we have all these nice examples of GPT passing this or that, right? And we're almost desensitized to these papers now, right? Because it's been done so much, but we have very few studies of how humans and AI operate together. And I think we're going to have more of those, but just as in the context of accuracy, I think thinking about bias, if we understand human bias and we understand the way the algorithm is biased, I wonder if there is a path forward that you see where we could design large language models to actually inject some nuance into the way that humans are reasoning. Because humans have a ton of bias too, right? And it's not to say that that excuses algorithmic bias, but it is to say that we should be aware of the status quo and design systems and improve systemic education, all that. But I think design systems that hopefully allow that collaboration of the human and the most up to date and explain to the human doctor why like this is why. Yes. Like the kidney function example that what that would have looked like would be in 2021, the National Kidney Foundation, American Society of Nephrology recommended a race free creatinine based equation. Here it is. And then if they wanted context, they could have context on the previous race-based equations and further information. But that's not what you found. And then an explanation why, right? Because when those decisions were made, there were explanations of why, like how the prior equation could cause disparate outcomes, why some of the assumptions that were made were harmful. You could build that in. I see what you're saying. It could be actually a tool for when you do the human-AI collaboration, the AI helps the human understand the state of the art now. Yeah. Great. All right. I think that was, Andy, is this a good time? I think it's a good time for the lightning round. Are you ready? Oh boy. Roxanna, we have a lightning round. I am aware. I've listened to your podcast. Okay. So you don't even need the setup, so we can just hop right into it. So I think that this is a good first lightning round question just because of how nicely it dovetails. Will LLMs be net positive for medicine over the next five years? I don't have a great answer. I don't. Five years. I'm not allowed to say I don't know. These have to be short answers. Is it going to be net positive five years? I'm a little concerned because we really need to do more research and have frameworks for assessing when they're working, when they're not working and how biased they are. I think in the long term, they could be net positive, but I don't know if five years is long enough. So maybe I'll just say perhaps net neutral because they won't do much of anything over the next five years. Is that? I wouldn't say they aren't going to do anything. I just, yeah, I'm terrible at predicting the future. Now, if there are several companies working on it, helping it write medical notes, and if they get that to work well, that would really make my life better. Right. So. Got it just seems like it seems like a cool job. You get to meet people from all over the world and hike all day. Follow-on question. Top one or two national parks. I live in California, so I've been to Yosemite. You have an embarrassment of riches there. I've kind of lost count number of times. Pacific Symposium on Biocomputing is in Big Island.
And, you know, I know you guys have your competing conference, but we have volcanoes. And that conference was started completely out of jealousy for PSB, just to be clear. So I like that because I learned two things. One is that you like the outdoors and be a park ranger. And two, I think we need to switch up our lightning round questions because that one seemed prepared. It seemed like you had thought about that before. Oh, no. Actually, it's because it feel like every icebreaker that I do always has that question. So literally, we just had a retreat where that was the icebreaker question. Got it. Okay, so the next one. What is the best thing that you have read or watched in the last year? The best thing? The AI Grand Rounds podcast. Actually, the podcast is really good. It's been very... No, no, no. Just get something other than the podcast. Thank you, though. Your check's in the mail. No, no, no. The podcast is quite excellent. You know, I'm just trying to think because it's been hard with small kids to like really watch much TV. What's your favorite episode of Bluey? My daughter loves number blocks. So it's been a lot of, I've been listening to, I've been listening to a lot of audio books. That's how I get through. I'm just trying to see. Sorry, give me a second. I know that it's supposed to be fast. That one. Well, it doesn't have to be fast because we can make it seem fast in the post. Oh yeah, that's true. I'm like trying to even, I like literally can't even remember. I've listened to some audio books, but I'm just trying to remember what I've even like listened to recently. This is very embarrassing. All the like net Netflix or like HBO, nothing. I mean, I nothing. Oh, you know what? I did enjoy, I just recently listened to the audio book Range, which I liked because similar to in that book, I have spent a lot of time in training and exploring different things. And that's kind of helped me put stuff together. And so that book talks about essentially how people have come at problems in new ways by bringing in like past experiences from different fields. Nice. All right. So I think I know the answer to this question, but I'm very, very curious if I'm right here. Will AI and medicine be driven more by computer scientists or by clinicians? I think it has to be driven by clinicians in the sense, I actually think it really has to be driven by teams, not one or the other, and interdisciplinary people who understand both sides. Because domains, I think domain specific expertise is so important. I talk to computer scientists all the time who are going after a problem that's not even a real problem in medicine. And, you know, I'm like, don't spend all your time and effort on this. Or they make some sort of assumption about the data in medicine that's not true. And so then they built this whole model that's built on some assumption about what the data is like that ends up being untrue. So I do think they need domain expertise help. And obviously clinicians who don't have AI experience think that AI can do things that it cannot do or think don't realize how the models are trained and don't realize what pitfalls or biases exist in the model. So really, I think it has to be interdisciplinary people or teams. I think that that's been a recurrent theme on the podcast. So I think there's not much to object with there. Right. So if you could have dinner with one person alive or dead, who would it be? See, you can see I really did not prepare for these questions. That's the point. We like your candy. I know. Who would I have dinner with? Oh, Marie Curie. I mean, as a female scientist, like, Oh, yeah. Yeah, yeah, yeah.
Yeah, that's a good choice. Awesome answer. All right, our last lightning round question. Do you think that things created by AI can be considered art? That is an excellent question. experience and it makes you feel something. And from what I've seen from AI generated art, there's usually a human still behind it, right? A human trying to express using AI to express. The prompt, the prompter. Can I, can I, can I change the setup then slightly? Let's say that we hook chat GPT up to Dolly, which you can already and say, make art. Okay. So that, that doesn't feel like art to me because again, I feel like art is about a human conveying their experience in some way. So I think humans and AI working together can make art because there's some emotion or experience that's being conveyed that can then be taken in by the observer, but maybe not like just randomly generated images from. If I could put on my like elbow patches for just a second, if a human looking at the thing created by the AI has some type of feelings or, you know, beauty being in the eye of the beholder. Right. I guess in that case, I think this is a very nuanced, complicated question that you're trying to make me put my foot down. And I don't want to get canceled on Twitter. We'll leave it at that. All right, Roxanna, you survived the lightning round. That was excellent. We just have a few concluding big picture questions for you. The first is, what areas of medicine do you think will be the most resistant to change. I think we, the human element is just so important in medical care. As someone who's received medical care, as someone who's had family who's received bad news, like there's something so important about, you know, the empathy of another human being in the room, conveying that information, helping answer your question. So for example, we should not be using AI to deliver bad news. And I think that actually people keep trying to use Thank you. is quite nuanced, more than people realize. And this is an example that I actually recently gave, just a very easy, like not even a complicated case. So we're looking at a lesion. We're trying to label some dermatology data, right? We have images of the lesions. We have the biopsy results. Turns out the biopsy results are not very definitive. And then we're looking at follow-up notes, like literally this dermatopathologist and I are trying to like label this image data. And we're reading the follow-up notes to see what treatments were tried, like what the dermatologist thought in order to come up with a diagnostic label. Because I think people think that diagnosis is always black and white. So I actually think that diagnosis is a lot harder than people realize. And I think diagnostic tasks, there might be some resistance there compared to using AI to help with administrative triage, decision support. But like straight up diagnosis is actually a lot harder than here's the diagnosis in some cases. Some things are straightforward, but many things are not. So for the first example that you gave, which is appropriately resistant, and I like the way you phrased that, appropriately resistant to change things like delivering bad news, right? Or counseling a patient that you don't want to come from a computer, you want this to come from another human. A lot of AI leaders now, medical AI leaders are arguing that AI might actually enable doctors to have more time with their patients because they absorb some of that administrative burden or because they're allowing the doctor to make eye contact with the patient and not just be entering things into the computer. I'm just curious, personal stance. Are you optimistic about, let's say, digital scribes or AI agents that are listening to the encounter that allow you to then make eye contact, focus on your patient, have time to be there? I would love a digital scribe. I would say two things about it. One, need to ensure patient privacy on any company that's listening into the encounter and building such a model. Patient privacy is key.
You need to know Providence. Yeah, Providence, exactly. And there are companies who are doing it in exactly that way so i think if you have those two sort of pillars um and also like the third making sure there's not any kind of hallucination that happens i think an ai scribe if you can meet those criteria would absolutely allow more empathetic care more eye contact i actually work with a human scribe. And when I started working with a human scribe, it was totally changed my life because I'm not at the computer at all now with my patients, which is what I prefer. I don't want to be looking at the computer, but when you have so many encounters back to back, if you don't write notes down, you're not going to remember exactly what happened, which is important. And so it makes such a huge difference to have somebody, whether that's human or AI, kind of document that encounter so that you can just focus in. Because the thing is, is that when you're with patients, it's really important to look at their face to make eye contact, but also to sort of read what's happening. How is the person reacting to the information they're sharing? That's an important part of the art of medicine. Do they seem anxious? Do they seem concerned? Do they look like they might cry? Like you need to know that information. You can't do that if you're staring at a computer. Great. So I like to ask a completely different kind of question. So in addition to being AI nerds, the three of us also have something else in common. We're all junior faculty who have small kids. So I have a four-year-old. We have another one on the way. I started my faculty job in the same month as our daughter was born. So that was a crazy time exhaustively descriptive. Yes. I see the little trampoline you have behind you. Yeah. So I have, she just turned five and I actually also have another one on the way. So I'm 33 weeks pregnant. Congratulations. And yeah, starting a faculty job while pregnant has been a interesting experience. But as I tell, I try to tell the trainings, I'm like, there's really no good time. Like also you cannot time it. Sometimes things don't work out the way you expect it to. You just have to do what's best for your family and not try to time things because unfortunately, it doesn't work out like that. I think that for me, my family is very important to me. And so I prioritize. I mean, one thing that's nice about our job is flexibility because I'm a clinician half day a week and I cannot cancel clinic last minute. But if I needed to work on some writing and something happens, like I can write later that day or later in the evening when my daughter's gone to sleep. So I do appreciate some of the flexibility afforded by an academic research career. I think I try to talk about this because the training is so long, especially for MD, PhDs, which is again, why I say like, you just have to do what's best for your family. We actually don't live near any family, which makes it extra difficult, but we do have family that has come in and supported as needed. And I think that's really huge. I think it's really hard. I think institutions need to do a much better job of supporting young trainees and faculty that have kids because whether that's like affordable childcare, because childcare is so expensive, or just having like easy backup options. I don't know. How do you guys feel? No, that all resonates with me. I love that you also share that with your trainees because I try and do the same thing. Like, for instance, Friday is Veterans Day. And so that means daycare is closed. And so that means we usually have our lab meetings on Friday. And so it means that there's no lab meetings. You know, we're recording this podcast interview later than we intended to because my daughter got a fever and couldn't go to daycare. So we had to reschedule. And thank you for understanding that.
I'm Lisa Rosenbaum, and this is Not Otherwise Specified from the New England Journal of Medicine. This season I'm exploring the quiet revolution in medical training. I can't pinpoint the precise moment I decided to write a series of articles about medical training, but definitely one motivating force was that I started noticing arguments on Twitter, often among trainees, about whether medicine is a job or a calling. This is an age-old debate that I'm not sure I find that interesting in and of itself, just because how you treat your work is a personal choice, so there's really no right answer. But what I found super fascinating is how angry many trainees seem to be when people argue that medicine is a calling. That seemed like a change to me and something that we should be paying attention to, and I wanted to understand why. So I reached out to Dr. Dua Abdel-Hameed, who's a fourth-year dermatology resident at UT Southwestern in Dallas, planning a career in medical dermatology. We met when she was doing the medical part of her training at Brigham and Women's Hospital, and have had lots of conversations since about a bunch of stuff, including about some of the challenges in our training environments. So because Duo became part of the cohort that trained, at least partly, during the height of the COVID pandemic, which obviously contributed to changing attitudes about work across our entire society, I asked Duo what it was specifically about COVID that seemed to kind of turn up the temperature on the job versus calling debate for trainees. Our cohort was really unique in that we started residency before the pandemic and were working through it. So we saw the before and then we saw the after. And the before was glorious, at least, you know, where I trained, it was amazing. And, you know, the social aspect of residency, the learning opportunities, you know, the volumes were manageable. It was a busy hospital, but it was nothing like what we experienced during the pandemic. And then all of a sudden, everything kind of flips upside down. And there becomes a lot of, obviously, fear, fear of the unknown. And then the added component of feeling like your institution might not care about you as much as they should. It felt like now trainees were kind of pitted against systems, pitted against, you know, even people on the same floor as you. It felt like there was increasing animosity with some of the other staff, including nurses. And it was just a very strange, uncomfortable, awful time. And I think that led people to really question when you're faced with potentially death. And at the time, really, we really had no idea. Like everyone was dying from COVID. And we, I was very concerned about, you know, my parents, myself, et cetera. Like it wasn't just like, oh, it's just COVID. So at the time there was so much fear and you really have to ask yourself, like, is this something that I'm willing to possibly die for and die from? And I think when people are pushed to that point, you really start asking, huh, if it's a calling, then the answer is yes. If this is just a job, then absolutely no, this is just a job. And I come first. And I think that pushed a lot of people to kind of have to make that decision. Okay, but now the pandemic, at least in terms of healthcare workers feeling like they're risking their lives, has in a lot of ways receded. But it seems like a lot of this disillusionment or this decision that medicine should be a job remains. So what do you think that's all about? We continued for months and months and months being deprived of our, you know, support systems and just still having these feelings that were kind of never addressed. And so you have a lot of time to kind of let that sink in. And that decision kind of becomes part of you. Like those feelings become part of you. It's like, it wasn't just one fight. Like this was the fight, you know, like when you're a partner and you have like a tiff, no, this was like the fight. I don't think we can come back from this fight.
I don't know what it is. I've been blaming it on Gen Z forever, but that's obviously not accurate because it's a lot of millennials just like myself who, you know, in my age group who might have this kind of this idea and this opinion that, hey, this is just a job. We're done. We're finished. I think COVID just showed you a lot of ugly truths about the system. A lot of patients died. It showed you just how unfair and how racist our system is. And it makes it really hard to want to operate within that system and give it your all. And then it sticks with you. And you kind of just want to get out of the whole thing. And the way to do that is to say, this is a job. I have no emotional connection to this anymore. I'm just going to do what I need to do to keep my job. And then I'm going to clock out at 6 p.m. and go home and try and recover from whatever trauma I experienced that day. I'm wondering now, as you are a senior resident, if you observe a cultural shift in terms of how we set expectations or even if part of what what's happening is that people who weathered the storm are transmitting new cultural norms to younger people. And maybe that transmission is also colliding with what you also pointed out, where Gen Z values, which are essentially not to make work the center of our lives. There really is a very noticeable shift. And I don't know if it comes from, hey, I had so much trauma with, you know, my experiences that I just don't wish that for you. So I want to impose something else going forward. Or if it comes from, I want to treat this like a job. So you need to treat it like a job in order for me to feel okay treating it like a job. You know, that I think is a huge component. If not everybody's on the same page, then I look like a slacker and I look like a terrible person who is here for the wrong reason. So we all need to be on the same page about when it's time for sign out, you are going to leave because then that makes it okay for me to leave at 7 a.m. the next day or whenever the shift ends. So I think that's a huge part of it too, is it needs to be like a collective movement and people recognize that because it doesn't feel good to leave as soon as you're allowed to when the rest of your team stays hard and works late. So maybe that's why we're kind of pushing for that culture is also because we need it ourselves. And I'm not sure. I'm not sure. I've definitely been on the other side of that, though, where I've had experiences where when I was earlier on in my training, I've had seniors say, I'll take care of this, even though, you know, I've offered and I'm like, that's not your shift. You know, let me do it. And then it reminds you, it inspires me. I'm like, gosh, you know, it really is not that big of a deal to work this weekend for someone because they've got all this other stuff going on and I have nothing going on. Or like my co-resident is pregnant and she does not look well and I'm not doing anything. And I kind of enjoy this most days when I don't have to think about all these bad things that they do to us. So why don't I just stay and take care of this? So that, you know, I think we're so easily influenced. And so the culture really does matter, but I don't know who determines what kind of culture exists in a program and where that stems from. I think it really is, people need to feel like everyone is doing what they're doing because medicine very much is a hard working group of people. And so I think it's very difficult for people who are traditionally very hardworking to make decisions to consciously not work as hard. I think that's super hard for people and you don't want to feel judged for that.
And those coming in seem to think that their job, quote unquote, is to get the day team out of the hospital. To the point that some people who may want to stay told me that they feel pressure to either pretend they're leaving or go somewhere else to write their notes. But inevitably, patients get sick during the sign out or they need urgent attention. And I heard that when this happens, it's not uncommon for the night or twilight resident to tell the day person to just go home and that they, the night person, would take care of the patient. So do you think that's a problem for us to be telling trainees to leave if there's something wrong with our patients? Well, I think certain things are okay. So I'll, you know, give you this instance. It was like my first month ever as a second year I am resident. So I'm leading this team. I'm super nervous about it. And I want to be like the mom of the team. But obviously, I want to just also take excellent care of my patients. But I want everyone to feel amazing on my team and to feel supported. So one of my interns, his parents were in town for his birthday and he really didn't tell me. And we're staying there. We're all there after four. Nobody left at four. It was the beginning. It was like July. Nobody's leaving at four. We all were staying there and working on notes. And he happens to kind of like mention that casually, like he's doing something with his parents tomorrow. And then I was like, Oh, when are they getting in? And he was like, Oh, they're actually here right now. And that I was like, this does not really align with mama bear do a team vision, like I've got to let him go. And in that case, I think if it was just notes, you know, which I was so excited to never have to write a note again. But at that moment, I was like, I will write all your notes, like your, you know, your remaining notes, you need to go hang out with your parents. That I think is fine. If it's situations where it's just like, clerical work, or, you know, all this, quote, scut, you know, unquote, it might be Yeah, it probably is different if there's a clinical change, like we need to go together. I would, you know, I, if you had something going on, I think it's case by case. I think it's case by case. But if we're both around and something happens to the patient that we're all taking care of, we will go together and sort that out. That's kind of, you know, what we do, even if it's after our shift, that's kind of been how I've approached that. If it's something that's meaningless and not adding anything to your life and you're still here doing it, I don't think we all have to suffer doing that together. I really don't believe that. The scenario that you mentioned, that is a difficult one. I really don't know that I, I think it would depend. I, you know, I don't know that I would have been like, you go home, I'll take care of this. But also I have done that because again, I feel like I'm the one who's responsible. So you go home, but am I damaging or hurting or taking away a learning opportunity from someone on how to manage like a deteriorating patient or how to do that assessment? I probably was, but I thought I was being a good team leader by doing that and absorbing some of that. So I think that's the difficulty. Yeah, that's a hard scenario. Well, I think that actually helps a lot because I think so much of this is getting all of us back on the same side. So I think when we frame it as do a mama bear, like I love thinking of it like that, which is that like the senior residents are really, they see themselves as taking care of the patients, but they also are trying to take care of the trainees.
And so if we can frame it like that, I think it begins to illuminate some paths forward, like that we need to do a better job making trainees feel cared for. We need to think about how the culture is being passed on. And we need to think about like this hierarchy of care, it sounds like. And also, I think, to do that, I think we have to start to recognize that, you know, as nice as it is to go home, that if we try to compress all the work into this shift that it ends it for, then like by definition, the fun things, which and I would say that like taking care of a sick patient, it's not like normal fun, but it's doctor fun, you know, that gets cut out. And so I think then we get trapped in this cycle where work feels progressively less meaningful. And so I think it actually really helps to like get into the mindset of how trainees are thinking because it makes it very clear that the intentions are still around care. It's just the care is being directed toward the other trainees as opposed to like all of us caring for the patients. And it's all so interwoven. You know, there are certain things where you're like, obviously this is going to be way harder than other jobs. And that's what I signed up for. And I want to do that hard work because I really believe in what I'm doing. But it really comes down to what you believe about what you're doing. So if you really believe this is just a job, nothing you say to me about working hard is going to resonate. I don't actually want to do it. I think you're just manipulating me so I can work harder for you so you can profit and benefit. And so I think it's really because we think of it as like now a corporate thing as opposed to a calling and something that you're just meant to do that requires hard work and sacrifice, which sometimes has been used to manipulate people. So I understand that or improve well-being, we started to lose sight of the importance of some discomfort to our learning and growth. Being a doctor often is uncomfortable. Like you are in situations so often where you're making impossible decisions, where you're tired, like that physical fatigue never goes away, where people are mean to you because humans are human and they're vulnerable and they're sick. And that is inherently uncomfortable. So then the question becomes like how much, how do you set expectations around discomfort as the culture shifts gradually toward a profound intolerance toward discomfort? I think that that's, I don't know how to answer that. And I don't know. And I think people have different levels of tolerance, but I think there is like a baseline certain amount of discomfort that you should be expecting in medicine. And people know that coming in, but then I think things change when you actually experience it because it's uncomfortable. It doesn't feel good. It feels awful. And so why should I be feeling like this if it's just a job? So I really think it comes back to this job calling thing. If this is just a job, I don't need to be dealing with this. But if it's my calling, then there's a lot more discomfort that I'm going to put up with because I feel moved by something much deeper than my paycheck, which is squat and residency. You know what I mean? And so I struggle with that and I don't know where to draw that line. And because it's so personal for everyone, some people are really, really made uncomfortable by something that others might not be. And so it's kind of difficult to say, hey, that's actually not an abusive situation. This happens to everyone, you know, move on from it. I think today you absolutely cannot say that in medicine. Um, it's not seen as, you know, as PC and it's also just not a great practice, right? Cause we're dismissing people, but it's hard. You can't really, again, things are not weighted the same discomfort ways differently for everyone. And that's what I think is so difficult about this.
But it's hard if you are not buying into that or believing that, hey, this actually really was abusive versus just a little discomfort that's associated with training. If you think it's just a little discomfort that's associated with medical training, you feel awful and resentful when you have to change your behavior because someone said, hey, this makes me feel this way. You know, it's just such a weird, touchy, touchy topic. But what you said also about how in general we all just don't want to be uncomfortable anymore. I really find that to be true. And I wonder if it's just because there was such a huge surge in the amount of discomfort that we all felt, just the pandemic, that it kind of used up all of our, you know, discomfort reserves. And now people just absolutely cannot. And I'm, I am one of those people too. I'm like, I just can't deal with this. I'm not going to deal with this one particular aspect anymore. So I don't know. I don't know. It's hard. It's hard because it's so personal. I think lots of trainees and doctors feel like we used up all of our discomfort reserves during the pandemic. And so do workers across many professions. One of the biggest shifts we're seeing in society at large is a growing rejection of the notion that our work should be our primary source of meaning and identity. This shift has pragmatic implications for clinicians that I don't think we've begun to understand. Meaning, if we set firmer boundaries between life and work, how might this impact our patients? But as many of us reevaluate our relationships to work and think about whether it's better to go home, for instance, and let someone else take over or go back to see a sick patient or have a tough conversation. These shifting attitudes also have implications for our well-being and sense of identity. If work becomes less central to our lives, particularly as doctors, does it automatically become less meaningful? And what elements are necessary to make work psychologically satisfying in the first place? We're going to get at some of these questions with David Blustein, a vocational psychologist and professor at Boston College who studies the psychology of working. Blustein has really been a pioneer in understanding work's role in our mental health and sense of identity. When it comes to the working lives of physicians and trainees, what are the key ingredients for being psychologically satisfied at work? I do have a good sense of the work lives of physicians. It's not unlike the work life of a psychologist or a professor. We're folks who have been fortunate. We've had some privileges, psychological, intellectual privileges, as well as, you know, relational and social privileges and economic privileges that have allowed us to pursue a field that we have some passion for and a sense of purpose for. So the psychology of working would basically look at our work lives via the lens of to what extent does our work allow us to meet some fundamental human needs. And I developed a taxonomy of these needs, which were based on other taxonomies within psychology and organizational development. So essentially, there are three clusters of needs. The first one is to meet the need for survival and power, which certainly being a physician would meet those needs. I think of power not so much as a politician having power, but I'm thinking of it in terms of having agency in your life. The second cluster of needs focuses on social contribution and relatedness. So having a career that allows us to make broad contributions to the world, broad and specific contributions to the world, certainly medicine provides that, and it provides it in a variety of very deep and meaningful ways. The third cluster of needs falls under the rubric of self-determination, which comes from a motivational theory called self-determination theory. And the idea there is that if people have access to environments, and in this case, a work environment that provides them with a sense of autonomy, provides them also with the chance to develop competence, and also a sense of relatedness to others, they're more likely to feel authentically engaged in what they're doing. So those are the ways in which we think about work providing people with a sense of well-being.
And I also know, however, that you're married to a pediatrician. So you have a familiar sense of how medicine does or doesn't meet these fundamental psychological needs. And I would love to hear what you've observed in your wife's working life in terms of where medicine seems to meet those critical psychological needs for work and where it's falling short. Okay, yeah. I think, you know, in my position as the husband of a really amazing pediatrician, I could see how the work environment of primary care in particular, but I'm sure other fields of medicine, has become so infused with intense documentation demands and also with business models that no longer provide space and time or rewards for spending time with patients. It seems like the emphasis is on documentation, and often people will document while they're with their patients. I know my wife doesn't do that, which I think is becoming increasingly rare. So my sense is that the business model of the field has shifted as we have moved toward this multi-insurance-based quasi-free market of medicine. And I think that we've lost something along the way, and I could see its impact on my wife and others, her peers. And so when you think about it within the needs that you've laid out to have psychologically satisfying work, in which area particularly are we falling short? And I think it's helpful actually to think about this as rigorously as we can, because we have all these wellbeing efforts in medicine that are like really dumb, honestly, like they don't work. Everybody makes fun of them all the time. And sometimes I like to think that if we could really like hone in on what it is that we're missing, that our efforts to remedy everybody's distress would be better. Yeah, actually psychology of working theory and actually more specifically self-determination theory, that motivational theory that we use, would identify two particular aspects of the working context that I think have been diminishing over the years. One is autonomy. So there's increasingly less autonomy in medicine. There's much more of a push to either see people really quickly or order more tests or order less tests. And this is not necessarily my wife's experience. This is just kind of my own experience being in the world and kind of talking with other physicians as well. So I think the autonomy piece is important. And I think also the relatedness piece is important. And I think that increasingly physicians don't have the time to spend with their patients, getting to know them, and also spend time with their colleagues. So I'm just going to go back in my own life history and think of doctors I've had. I could point to a pediatrician I had when I was a boy who had a profound impact on me through interventions. Basically, there were psychological interventions that really were transformative. And I always remember them. And it took him time to do these, to meet with my family, to spend time getting to know us. Are you comfortable talking about what those interventions are? You don't have to. Yeah, I could talk about it. So I had a period when I was younger where I was overweight. So I know we're in a period where people should be talking about their weight. And it was something that I was aware of. So the intervention, which this happened really in the 1960s, was what I would call a family-based systemic intervention now. So he called in my mom, and my dad wasn't there. It was an aunt who drove us. And he said, Mrs. Blustein, David is overweight, but it's not his fault. You are in charge. I was like 12 years old. You're in charge of the food in the house. You're in charge of what he eats. And the family, the entire family needs to manage this. It's not, doesn't fall on David's shoulders. That was a liberating meeting. I love that. And did it help you? Tremendously. Yes. The really important final end of that intervention is that I never became heavy again. It somehow liberated me from some aspects of my relationship to food that weren't very healthy. And at that point, moving forward, it was really transformative.
He took some time to talk to me and my family, and he did it in a very caring way. It's interesting because there's an analogy within your story to, I think, how we think about well-being in medicine, which is I think a lot of people are feeling like the onus is placed upon them as individuals to fix a problem that is coming more broadly. So in your case, it was your family and your environment. And I think the same is probably true in medicine. But instead of fixing the system so that we have more autonomy, for instance, or more time for relatedness, we get emails, you know, about forest bathing on a Saturday or like doing a sleep module, which just makes everybody crazy. And I think, you know, given your expertise, it would be very helpful to hear you say how ineffective those types of interventions are likely to be. I think you could save the health system millions and millions of dollars because we are paying people, you know, chief wellness officers, offices of well-being. We do these endless surveys. If you could maybe just point out that that probably isn't what is going to solve our emotional distress. Yeah, I think I could say it here with some conviction because there's empirical research in psychology and in organizational psychology where people study the impact of changing organizational structures on the welfare of working people. And the research supports the self-determination theory, which is if you give people more autonomy, enhance their competence, which I think in medicine is where a lot of these trainings come in. And thirdly, allow them and foster relatedness in the workplace. People will feel better. It will require shifting some of the more intrusive aspects of the work environment, you know, mandates and incentives and disincentives for different ways of coding patients. So I want to spend a little time trying to understand the pandemic's role in shifting workplace attitudes. We all know the pandemic changed our society's relationship to work in big and small ways. But what I want to focus on with you, given your expertise, is how COVID changed the psychology of work. Did it change the way we think about meaning and identity and where we ought to find those in our lives? I would say that we probably don't have enough empirical data at this point to give an unequivocal response. But based on trends we're seeing at aggregate data, we certainly did see this great resignation phenomenon toward the tail end of the pandemic, of the intense part of the pandemic, because I don't think the pandemic is completely over. So we did see this great resignation part, and then the quiet quitting phenomenon. Both of these did have some, you know, they were observed in aggregate data reports. I think we have seen, we are seeing a shift. I think it comes from a number of perspectives. One is the existential threat of COVID. I think that one of the adaptive aspects that Freud talked about in terms of defense mechanisms, it's not always adaptive, but somewhat adaptive is denial. Like if we thought all the time about the different ways that we could die, it would be hard for us to go on. So we exercise some denial, you know, like driving on a highway. Like, you know, sometimes when I'm taking a bike ride and I look down at the highway, I think, wow, people saw it from this view. They wouldn't be driving so confidently. So there's this piece about denial. I think the pandemic really broke down our denial about death. I mean, 1.3 million people died in the United States. That's quite a lot. So I think that's one part of it. So it does cause people to question, why am I working so much? I think a second aspect of it is, I feel like it has to do also with other changes that are happening in this decade. And I'm thinking about global climate change. I'm thinking about the sad emergence of really major wars, Ukraine, Russia, and Israel and Gaza. I think these wars are also causing people to rethink things. And I also believe another factor is that the workforce is the baby boomer workforce is aging out. Younger workers are becoming more prevalent.
But I do think that values about work might be related to these generational differences. I think that you raise these questions about existential threats, which I think in the end force us to refocus our priorities, I think, and, you know, war, climate change, spending all of your life, you know, giving to a job that many people feel doesn't love you back, et cetera. And I want to ask you a related question because I think that's led to this like very common assertion that's baked into the zeitgeist right now, which is that we should not center our identity in work. There's a huge backlash to that. And I'm wondering if that's really, truly psychologically bad to center your identity in work, or is it just part of shifting cultural norms that may one day shift again? I think it's part of shifting cultural norms. I think that there's something healthy about people questioning this identification. The reality is it doesn't have to be an either-or phenomenon. Those of us who have been fortunate to be able to really dive into something that we love, like medicine or, in my case, being a psychologist and an academic. Those are, you know, for many of us, like, that's part of our hobbies as well. That's part of how we think of ourselves. I think what's happening, though, is that there's been some research and some really good journalism on this, is that Americans have kind of engaged in a relationship to work that's not always healthy. We have the shortest vacation time of most Western countries. We don't have enough personal time off. And I think, and then there's also a culture, I've heard this from other people within organizations where people have like more personal time off. The culture is often not to take it because it looks like you're not dedicated. So I think the norms in our society that really value work over almost anything else, I think it's an important critique. I think people need to really not take for granted their relationships. Romantic relationships are really special and they take time to nurture. So, you know, one of the thoughts I've had about this is, and this is an adage that a lot of us know, is that when people are dying, they rarely ask if they can kind of talk to their work colleagues. They want to talk to their family and loved ones and close friends. So that's an important piece of data for us. It's an important observation. We're relational creatures. And I think the extent to which over-identifying with our work identity gets in the way of relationships or developing other sorts of meaningful activities. In that case, I think people do need to find more balance. Well, you're right. I mean, I think about the times that I, as a doctor, have gotten to be part of someone's dying process. I've never heard someone say, I wish I had worked more. And I often hear people talk about regrets with family or, you know, lost loves, people they don't speak to anymore. So I think that for me is completely anecdotal, but I think you're probably right. I do want to ask you, though, because, again, medicine plays this unique role in society and that, you know, we're responsible for other people's health. And there's this question about where you draw the line. I think, you know, how you treat your work is a very personal choice. So I feel very strongly it's not my role to say that people should treat medicine like a calling or like a career or like a job. You know, that's up to them. And I also fully recognize that people's limits are necessary in response to the way medicine has changed and the sense that our employers, who largely now health systems, will extract as much work from us as possible. And many people, I think, feel necessarily then that they have to set limits. You know, I'm not going to be spending my entire weekend on my inbox, for instance, or, you know, taking extra call without reimbursement, things like that. But then you did mention quiet quitting, which is sort of an attitudinal shift. And it's not something that we have any data on yet in medicine.
But what the psychology of quiet quitting is like and how it might play out in a job like medicine where not only for our patients do we sometimes need to go above and beyond, but going above and beyond feels good psychologically. Yeah, I think quiet quitting is a form of resistance to work conditions that increasingly encroach on people's lives. So I view it as a form of resistance, as a form of enacting one's feelings that this job has just taken up too much of my time and space. I think in fields like medicine or in fields like psychology, people doing mental health treatments, yeah, I think you don't really want to see quiet quitting in a way that's going to hurt patients. Or in my case, as somebody who also teaches, I don't want to engage in quiet quitting to a point where it will impact negatively on my teaching. So I think when we're serving other people, it is problematic. I think the place where quiet quitting can be really useful is this encroachment on our lives, like the whole culture of people sending emails and answering them on weekends. I have finally changed that behavior for myself, and it feels liberating. The other aspects of quiet quitting are people reformulating their relationship to work and trying to come up with a more balanced view. There's something to be said for a balanced view to work and family. There's a huge literature on work-family interface, work-family integration, and the research tells us that people who can come up with ways of integrating these roles are the ones who have the most satisfying lives. I think David's on to something important. I always find it so valuable to think about how to apply expertise from outside of medicine to our own work environments. I also think it's kind of weird, given how much medicine values certain types of science, that we don't tap into the knowledge of people like David more often. Meanwhile, we spend millions of dollars trying to improve well-being. But although psychological science can give us a framework to think about what makes for satisfying work, it can't force us away from our computers or work rooms to take advantage of all the opportunities for meaning in medicine that remain. And sometimes I worry that if we treat medicine like a job, it becomes one. So I want to do a take of where she landed. So do you think medicine is a job or a calling now? I think where I am right now at this stage in my life and my training, I still do think it's a calling. I think what makes it feel like a job and pushes me to want to treat it like a job is all of the external pressures that take away. And a lot of it is, I think it has to do with capitalism. Everything that takes away from me actually doctoring. So all the charting, all of the appeal paperwork, all of the prior authorizations, seeing a patient in front of me and knowing that I have a medication that can help them not being able to get it, not being able to get patients into clinic, you know, all these things make it feel like a job where, hey, if everyone else is going to not do their best for this patient, it's probably easier for me to also just dissociate and not be so invested because it's eating me up. And the system clearly doesn't want to help me. So I'm just going to clock out and go home. I've never really been able to sustain that, although sometimes I try and talk myself into it, thinking that it'll be better for me. You know, I'll be a lot more mentally healthy if I can just dissociate and just leave work at work. But there are so many instances, you know, throughout clinic where I'm churning, churning, and then I have a conversation with a patient about a new diagnosis for something. And we have a deep talk about it and their eyes well up. And, you know, it's the first time that they've heard X about their diagnosis or even gotten a name for it, and then we hug, and I'm like, this is why. Like, this is why. And, you know, I feel called to do that. It's more than just, like, treating the disease. It's that level of connection that I've always wanted.

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