I think my dad was simping for my mom for a hot second. My mom was really popular. I have a boyfriend. We actually met through the DMs. Yeah, my parents know the story and they hated it. What's going on, everybody? It is a beautiful day in the city. And you know, I was just thinking about how Asian representation in media has been changing over the past few years. And you're seeing more multifaceted Asian characters and Asian artists. I think now is a great time to ask that question about Asians dating in America and how that may have changed over the years. I'm talking about specifically Gen Z. People who are, you know, between the ages of 24 and 18. Those are the people I'm really going to ask today because I want to find out more. Are they still keeping it traditional like their parents who probably are immigrants? Or are they leaning all the way into the American way? Do they want to date more traditional but they're just dating like Americans? Because everybody else is. We need to find out and I want to open that Pandora's box today. This video is in collaboration with EME Hive which is the number one Asian live streaming and dating app with 1.4 million Asian singles and 140,000 happy couples. Guys, it's a great way to just network, meet people, even meet friends or meet the love of your life. EME is a great way to chat with real people via one-on-one video chat. It eliminates catfishing. EME also has advanced matching algorithms and filters such as ethnicity, height, education, interest and even the age that they arrived in the U.S. So increase your response rate from your matches by sending a personalized message. Remember, if you guys are interested, click on that link down below. Now, let's go find out more about how Asians are dating in America. How did your parents date? My parents are Indian and it was an arranged marriage. My parents, they were like an arranged marriage. She told my dad that if you're not getting married then we're not dating. I think my dad was simping for my mom for a hot second. So they met actually working at Korean Air together. My parents were from the Soviet Union but they came to the U.S. in college and they met in college at NYU actually. There was this club and they played this Russian game and they met there and all the Russian people went there. So that's how they met. Hello, how are you? I'm really good, how are you? We are playing this Russian game. I just saw that you also go to NYU. So I figured you're from Russia and go to NYU. So do I. Yeah, I do too. Wow, you're so cute. Yeah, marry? They took things very slow. I think they dated for like 10 years before they got married. They're both art teachers. They met in college.   Are you just like telling me a K drama that you just watched? They met at a Jewish party.  I mean my dad was like in a band in California so they might have done some great, I don't know. Guys in bands, I heard some things. Who knows, maybe. How would you describe how the typical American might date nowadays versus a more typical Asian might date? There's a lot of hook-up culture. Hook-up culture. Hook-up culture. That's kind of where our generation's at right now. If hook-up culture is like a big part, they might like hook up first and then date. Probably gonna play around around.  So they're gonna do whatever they want to do. Dating was always like you have to keep that separate because that's like a no-no in my house. Because I'm from Taiwan. I think people there like take dating more seriously. Just broke up with my long-term boyfriend and we dated for nearly a year and my parents never met him. I think dating apps is like a thing that people do now. They use like dating apps a lot. I have a boyfriend. We actually met through the DMs. I never really tried to look for people in person. Yeah, it's a bit more free right now than how it was before. Who do you think is dated more?  I don't know a lot about their lives, frankly. My mom was really popular. Oh, when I was younger, so many guys lined up outside my house. Like they owned a restaurant.  They brought flowers and chocolate. And my dad was like fighting for her. So do you think you're getting less attention than your mom did? Yeah. What's a typical date for people your age? Probably like a coffee day 100% or a pizza or something. Dating is not actually dating. You don't like nobody's taking you out. It's like you're just gonna meet here, meet at the park, link, smoke, drink. What stage did you guys probably already hook up? I have been here for two weeks. I haven't checked. It's only my third day out here. Damn. It's more like the effort and the gesture that means a lot more than how expensive it is or whatever. Before I get into my takeaways, I want to give a shout out to our collaborator on this video, EME Hive. It is the number one Asian live streaming and dating app. You can use it on your phone. You can use it on your computer. Definitely check it out because it's a great way to meet the love of your life boyfriend girlfriend or just meet a friend. It's not just for dating. It's also for networking, mingling. There's live streams. There's different entertainment. Everything's built in, guys. It is a fully functional app. It's how you use it. And again, when it comes to apps, I just say if your intentions are clear and your heart is good, every app is going to breed results, all right? You just got to put the work in. And that's what I do appreciate about EME Hive. But you can also choose how many years or when did they arrive in the U.S. Because as you know, EME does have a lot of people from Asia who are coming over that are also on the app. So it's a really cool mix of people. You guys should check it out. EME Hive, click on the link down below. Would your parents be at all surprised or mad or appalled at how you date?   Just some chansori.  Yeah, my parents know the story and they hated it. Would your parents be appalled if they found out how you date or how many even people you've messed around with now? Absolutely. Don't watch this, mom or dad. They don't know and that's the way it should stay. Would you guys both agree that the American way of dating, the typical American way of dating is more fun? Yeah, to be honest, yes. Would you engage and see what it's like? If I have a chance, I will probably try it. My friends kind of call me a dog because I only use dating apps. It's kind of gross. It's better with the older tradition than it is now. I did not sign up for this American dating trajectory. I have beef with dating apps. It doesn't work for me because I find that it just creates like, okay, this was fun for this one and I'm never going to see you again and it's just like a pattern and you just kind of end up feeling miserable at the end of it. Do you personally have a preference or are more inclined to seek someone of a similar culture as you? How do you feel? Yeah, I think so. I kind of want to stick with my own culture, like feel more comfortable with that. The only relationships I've been in were interracial relationships. Definitely a lot of judgment, lots of racism. I would say yes and no. I think it's more exciting when it's like somebody different than you. I think from a logistical standpoint, I feel like I'm attracted to also like, you know, Indian people. I like how you said logistically. You're like, yeah, just for kind of how it's going to work and the whole engineering of the structure. But I'm not like specific to only Asian guys. I am attracted to Arab guys, but like... Yeah, no, I mean, that's fair that, yeah. Beards have like dark like... They got, they got to be able to take the vodka. Yeah, that's really important. Vodka is important. So as far as my takeaways from doing all these interviews, I found that even amongst Gen Z Asians who are, you know, under the age of 24, they still have not forgotten how their parents met. They haven't forgot tradition. Now, I don't think they want to be their parents or they don't want to live their parents' lives and they know it's different, but they're more open about it. I also see that a lot of them are communicating with their parents in ways that maybe people of the former generations didn't, you know? Just parents are telling their kids more even if they are more traditional and from Asia. And also, I think it does go to show you that Asian parents from Asia are also changing because the world is changing. So not all culture is lost with the Gen Z. The young people, they still get it, but they still also want to have their fun. So guys, thank you again for watching. Listen, it's 2021. How you date is how you want. My recommendation is just to be clear with people. Don't play people out. Don't break hearts on purpose. Don't forget the human connection. Even if you met them on an app, which it's totally okay. All right, everybody. Thank you so much for watching. That's Andrew from the Fung Brothers here in New York City. Shout out to EME Hive. And until next time, I'm out. Peace.


Thank you so much for the introduction. To actually explain what we have done here in this work, I should explain some basics for all the Trojans. First of all, just consider a circuit that has malicious changes. Actually, this malicious changes means that it has doesn't work. This chip or this IC adds some functionality or removes some functionality of the circuit. Or it can lead to changing or reducing the reliability. It means that you have your design, you have your circuit here, and you give it to the fab and company to produce it for you. And then there are some changes in the design that you are not aware of. And it adds some functionality to the circuit. It leaks information. It gives a key out, for instance, or makes the crypto actually very, very simple or big. But you are not aware of this. This leads to some unpleasant applications for these military applications. Some other applications that may target many more people or even the device that you have in your pocket. If they are totally affected, it means that they have some functionality that you are not aware of. But without the scenarios or, let's say, the potential attack victors, suppose that you just make a design and give it to a factory or foundry. And a malicious foundry or company can introduce a fraud in your design. Or even it can be true that malicious employee during the design process or even during the manufacturing process. Or you as a company just buy an IP core from another company or from another person, which actually fulfills all your requirements that you have. It says the areas, people, whatever. But it has some other functionality that you are not aware of. Or even sometimes can be requested by the government agencies. Or it can be done by the attackers. Let's say by hacker attackers, for instance. You just have a firmware in your system. You want to update the firmware. And then if the partner that provides the firmware is not trusted, it might be trojanized or something that the trojan is introducing to the firmware. Or even it can be during the shipment. You just buy something from the Amazon and then you're in the way, which is shipped to you to the customer. It can be changed or it can be replaced by some other device that it has trojan inside. But actually how the trojans work, usually there are some small changes in the circuit. Particular points of the circuit that they can lead to completely break a broken crypto or a weakened crypto. For instance, it can change the functionality of the system or circuit. And in particular scenarios, just leak the key out or make the circuit very or crypto very simple. For instance, instead of the areas, you have just one round of the areas. Then everything seems random and everything seems encrypted but not necessarily. And then you have one round of the areas that can be easily broken. Or it can be changes in the site and leakage of the circuit. For instance, it leaks about the key in particular scenario, particular fashion, but not easily through a particular site on us. But how do we detect such trojans if you have the functionality testing or even such an evaluation? First of all, what is usually considered in Harvard's community is just comparing the chip with the golden chip. It means that it's a bit hard assumption, a strong assumption that you have a chip and also a golden chip. It means that you have a chip that it might be a trojan infected, another chip that you are definitely sure that there is not a trojan. And then you just compare the characteristics of these two devices. Sometimes it's hard to assume that the golden chip is accessible or you do functional testing. You have your chip and then you just check it with many test vectors to see whether the functionality is correct if the functionality is altered before. Or you do search and evaluations. You go through a set of the art and standard search and evaluations to see whether the circuit is leaking through the search or not. Or you do net list analysis. This means that, again, you have a device. In your hand, you do reverse engineering. Extract all the net list. And then, again, compare with your original design that you set in the factory to see whether it's sent or not. Actually, this is not. It's shown as not enough. In last year's chess, it has been shown that even if the net list appears to be correct, it doesn't mean it not necessarily doesn't have any trojan anxiety. It might be because of the delay of the circuit. The delay is altered. And so, again, it might be trojan infected. What we are doing here in this work is I'm just showing that how to design a circuit that can't pass this search and evaluation means that the device seems completely secure and is secure. But under certain conditions, it starts leaking information through, again, the search. One question is here, whether we are actually helping criminals here by just introducing the new ways of trojans. The answer is that, yeah, it might be, but the detection and design of the trojans are closely related. If we don't know how the trojans can be designed, then we cannot provide protectionists. We cannot provide the efficient detection mechanisms. Particularly in this works, I'm showing that, again, how one search and parametric trojan can be inserted in the system. What does a parametric means? It means that it doesn't leak always, but in particular scenario, in particular condition, it leaks information. In these works, I'm dealing with the high clock frequency. The device is working absolutely fine without the leakage. And then you just increase the clock frequency and it starts leaking. And then you can exploit the leakage. What makes a work different to the other works, instead of the art, search and parametric trojans, is that mostly the other works or previous works either target the PRNG because in search and security, in search and containment measures, we usually need source of randomness internal or ability to the system. I mean, we have seen the last talk about masking and the Boolean masking in some source of randomness are used. And if the attacker or the trojan is targeting the PRNG and changing the distribution of this PRNG and the distribution is not uniform anymore, then the one attack is possible. Either such previous works are targeting the PRNGs or are going to the transistor level manipulation, for instance, changing the dopant of the circuit or particularly separate circuit to just leak particular or certain intermediate values, for instance. The point is that none of these schemes or most of these schemes cannot pass the search and evaluation. It means that if you just have, if you want to get, for instance, a certificate of your design and send it to an evaluation lab, the evaluation lab would just, instead of the art, leakage detection schemes can easily find not done. The lab cannot easily find that the system has trojan or trojan infected. It can detect that the system has a leakage. Whether this leakage is explotable or not, this is another question. But the lab cannot say, definitely, that this device doesn't have a leakage. As I said, our goal here is to say, to see how we can add such a trojan into a system that system stays secure but becomes insecure in particular condition. To explain that, I need to go through masking in hardware a bit. I can explain that after several key risks and add mechanisms that we had for the masking of schemes in hardware. Finally, we had the threshold implementation in short, we call it TI, which can provide toolable security against first-order attacks in hardware particularity. And it's a mixture of boolean masking that we have seen in the last talk and also multi-particle computation. Because we have boolean masking and we have single boolean masking in the last talk, it means that you just have x and represent the x by some shares in the way that if you explore the shares, you get the value x. And if you want to apply one linear function over this mask, easily you just apply the linear function over each share separately and then you are done. This is simple. But the challenge, of course, is the nonlinear functions. If you want to apply nonlinear functions over some shares that they are boolean masking. This is actually the place that TI plays a role and say that I have some requirements how to implement a mask in hardware to be able to provably say that this is our dozen league information through the first order such and other cases. Suppose you have this box that the input is x, output is y, and then you want to represent this box by some other functions that when x is shared in three shares, minimum, and y also, the output of this box is also shared in three shares, and it is a small function. We call it component functions. Each of them provide one output share. One of the requirements is straightforward. Trivial is this the correctness. It means that if you explore this x, all the shares of the x, you get x and gear. If you explore all the y's, you get y. This is the trivial, but non-completeness says that if you have here each of these component functions, each of them should be independent of one share. For instance, you can see a f1 is independent of x1, f2 doesn't receive x2, and f3 doesn't receive x3. But what does it mean? It means that the leakage of f1 will be independent of x1 and then independent of x, and also leakage of f2 and the same for f3, and then it means that an average leakage of this circuit will be independent of x, but an average. This is the meaning of the first or the second. But the third property is the uniformity. To understand the uniformity, I should explain it. As I said, we have a PR range usually, or a source of randomness in the circuit. And then it provides random values to share for instance x. And then it should follow a uniform distribution, I mean the mass. And then uniformity property of the TI says that if the input is a uniform sharing of particular x, for instance, then the old input should be also a uniform sharing of all possible sharing value of the y. It means that actually applying this f1, f2, f3 doesn't change the uniformity or distribution of the masses. Not fulfilling any of these conditions, of course, that non-completeness and uniformity, you cannot guarantee that the system is secure against first order average. Achieving correctness is super easy, even trivial. Non-completeness can be also achieved easily, I would say, explained in the next slide. But the uniformity is a problem. We have to check a lot of things to finally find the trial and error whether the circuit is uniform or not. To explain that, I need to again explain some other one more concept, which is called derachiary. Just to start with an example, suppose that you have this box with forward input and forward output. And I have just a small function here, S1, which gives us the one output width of this box. There are six forward inputs and one with output, E and E, one of the width of the body. And then suppose this is the A and F algebraic normal form of the one bit of this box, this E. And then two linear components and one quadratic component. And then you just replace A with the sharing of the A, A1, XOR, A2, XOR, A3. The same for B, C, and D. Just write the formula and then expand it. And then finally, you have some linear components and quadratic components. And then the idea here with this little sharing is that if you have this, again, circuit, the point here is at which part of this component will go to E1, which one to E2, and which one to E3. And I'm just separating this and to separate this terms in three parts in a way that it fulfills the requirement of the non-completeness. And D. by sharing actually follows a particular format for the indexing. But what is easy and what to say is that the quadratic terms, for instance, B2 and C3, this cannot go to E2 because it has two. It cannot also go to E3 because it's had three. Definitely, it has to go to E1. That means that these components, these quadratic terms, they are clear vertical. We don't have any other terms. But the other components that we have on the terms, either the linear ones or the quadratic ones that they have the same index, they are arbitrary can go to two different functions. For instance, A2 can go to E1 and also to E3. And then they are actually not changing the functionality of the system, but they have effect on the uniformity. It means that if by changing this, by putting A2 into E1 or E3, it changes the uniformity. It means that if the second might be uniform, or if it's uniform, it might be not uniform by after changing. But this is not the end of the story. You can add more terms. Even the terms that they do not exist. For instance, you add B2, add E1, and also E3. It doesn't change the functionality because if all of them, again, B2 is canceled, but again, it changes the uniformity. The same for some other particular quadratic terms that they are actually called correction terms. These are called correction terms. We just add them to achieve the uniformity. Now, suppose that you made your circuit like this. This is the all three-component function. And then one correction terms, which both of them are receiving getting the input from X2. This is the same component function just to achieve the uniformity. Without this C, this circuit is not uniform. Just suppose this. And then what happens if this correction term is the last coming signal. It means that the circuit which is realizing these correction terms is actually the slowest component in this critical path. If you have a register here, there's start and register at the output. The time which happens to this output correction term is ready. If intentionally we make it slow, this just component function, the correction terms, and this will be the result. Suppose that this is the clock, and the clock period or frequency is still slower or the clock period is longer, that the critical pattern lay means that the time is required from all of these values from X1, X2, X3 to generate Y1, Y2, Y3. And then the circuit will be fault-free. No problem at all. The circuit works absolutely fine. But, and also it's uniform. It means that it should be secure against press or objects. You just decrease the clock frequency in a way that the critical path delay of the correction terms are violated means that they are not performing correctly or they are not evaluated correctly. But the circuit becomes unstable. Sometimes it's working correctly. Sometimes not, because you cannot say that how many nanoseconds per second your circuit completely needs. And then if you decrease again the clock frequency means that the delay of these two correction terms are completely violated. They are never, they are ready or correctly evaluated. But the delay of these component functions are not evaluated, are not violated. It means that they are evaluated correctly here. It means that the circuit will be fault-free. The circuit works like this, that these correction terms do not exist in this design. And then what happens? The circuit is still is correct because the X4 of them is actually correct, but it's not uniform anymore. Because the correction terms are not added to the system. And if you again decrease the clock period or increase the clock frequency, then the circuit will not work correctly because the delay of these component functions will be violated. And this is actually the place that we want to inject this rotor. It means that if we intentionally make this circuit, part of the circuit longer or this circuit is slower, then we already inject it or throw it into the system. But how it's complicated? How can we make this part of the circuit slower? As a case of study we have the present, present sulfur in the threshold implementation minimum of three shares. This box is implemented in two steps. Decompose in two parts, G and F, because this box is a cubic function. Now we decompose it into two quadratic functions. And now we target the G function, the first part of the box, and then put the old rotor here by just making the component of the correction terms slower in the whole of the circuit. We target first and when FPGA prototype, this part of six is the Sakura G board, which is also used for such an evaluation in practice. One option in FPGAs to make the delay, to introduce delay is to make particular logic is slow, is to pass the particular routine through switch boxes, because the switch boxes in FPGA are active elements and then just by changing the routine, they go through more active elements and then they become slower. But how can we do this? We have a video here at the moment's place. This is just a full of the view of the FPGA. You just need to select the correction term via here. You just find the correct name of your design and then you see here it's selected. We turn off the other signals and these two lines are the corrections that's actually in the FPGA. And then you just need to select that one that you want and then un-route it. First of all, we get a delay of the signal which is already routed. You see it's 0.8 nanoseconds here, actually it's 0.99 nanosecond. This delay of this and then you just un-route it, just some commands here, un-route. And then just select another area that you can see here. One part of the circuit will be selected here. There's a bit of time. You just select one area which is not used. You will see, for instance here, we select one part which is not used and as the router here to use, definitely one of the wires which are there for the router. For instance, we select this line, you will see now, we select one of the lines here and say the routing should pass through this particular line. And here we get again root. But selecting this, we say again root. You see it's rooted now, we turn off all the other signals that are not necessary. And now you see the circuit now is rooted through this particular line that we want and then coming back. And if you get the delay of this, you get this now 5.2 nanoseconds. You see the 0.9 nanoseconds. And then you are done with just changing the routing. The point here is in the FPGA, it doesn't conceal any resources. I mean resources with respect to the slices, the flip flops and also the loops. Then if you compare the original design with the Trojan infected design, there is no difference in the utilization and the resource utilization. For instance here, the original design has those many flip flops and loops and the slices and then the critical category says that the maximum clock frequency is 219 megahertz. And just by changing the routing through the switch boxes, you see that the utilization stays exactly the same by just changing the routing. And then what the circuit works like this, that the maximum clock frequency will be 196, but in the gray area where the circuit is unstable, 212 megahertz up to 219 megahertz. It means that if we run the circuit at this area in the yellow one, then the circuit should actually leak information in the first order. These are the practical starting results. At 168 megahertz, because we are in the green part, the circuit should be secure, simple power trace. You can see how long does it take from here to here, some microseconds. And there's 100 million traces. And then these are the result of actually the T test, the common leakage protection schemes. Fix versus random. The first order over the number of traces, and also over the time. It doesn't lead to all three components, three orders. Actually, the reason is that we have some non-generator in the system to hide higher order leakage, because the TI that we have is only first order. And now we run the system at the 216 megahertz, which actually we are in the yellow part. Now the circuit, the one simple power trace is the string, it's a shorter, and then 100 million traces. And then it starts leaking after 20 million traces. And then the first order. And then this actually detects the leakage. It means that there is a leakage to exploit. Detectable leakage might be exploitable. We have some attacks also in the paper. And it shows that it's actually proof of concept that these leakages are exploitable. This is my last slide. There might be some rising questions about this work. For instance, how about the ASICs? This is what the FPGA. Whether it's possible on ASIC or not, yeah, it's possible by changing the transistor characteristics. For instance, you can replace the gates of the system by their high threshold variance. Means that the gates are becoming slower. And then again, you can have actually effect on the delay of the particular lines. We already fabricated two chips, 19 nanometer and 65 nanometer chips, with these Trojans infected designs. They are still under evaluation. What are the possible scenarios for this Trojan? You can think about the third IP course and also manufacturers. That the malicious design maximum frequency is 196. I mean, the device is sold by this. Or the IP course is this maximum block frequency is 100. Of course, you don't see the gray and the yellow parts in the specification. And then it will never be evaluated by the solution and lab at a frequency higher than 197 megahertz. And then because the circuit will not function correctly. But the Trojan adversary can run it at higher frequency for instance, 216 megahertz and then explode the leakage. Now this was the point how the scenario of the attack is. The last question or last criticism is that we need to control over the clock. Whether the clock control over the clock is a realistic scenario or not. In FPG, it is because usually it's externally clocked. And then internally it's used a PLL or DCM to increase the frequency multiplied by a particular Trojan value. Usually it's a realistic assumption in FPG. But in ASIC, the clock is commonly generated internally in the embedded systems. And then this cannot be taken into account that the attacker has the control over the clock. But the same effect can be seen by lowering the power supply. It means that you just decrease the power supply voltage and then it gets to start being slower. But as long as the clock frequency is generated internally, it has the same frequency, you have the same gain effect. As a last message, the overclocking actually and then controlling over or monitoring the power supply reduction should be internally done to not detect such a Trojan to just say that if this Trojan is inserted, then we should avoid being it activated. Thank you for your attention. I'm not familiar with hardware design, but I guess that there must be some tools, some optimizer, which can detect that there are some very lengthy and unnecessary problems. So is there any way to obfuscate this kind of problem? Yeah, I can get back to this slide. I don't play the video completely. But the thing is, the whole of this circuit is here. And then not necessarily you select a signal which is not used here, but it's real of the circuit. And then, of course, if you do net list analysis, you will recognize some roots that they are strength in your system. But we are talking about exactly this point, that when you want to buy an IP code from someone else, then what you should look at. With that value, you should look at the long wires that they are unnecessarily long or not. I mean, this is exactly the point that here in this work, we are saying that what we should look at to be able to find such trotons. But if without knowing this, that the troton can be inserted by making your routine long, you would never look at the long wires in your third party IP code. Just a short comment. Your project is basically a kind of fault attack. And manufacturers of smart cards have implemented both overclocking and undervoltage protection on the smart card. And in addition, if the circuit is calculating cryptographic encryption, for example, you can easily avoid the fault attacks by trying to decrypt the result before you send it out. Because if you are overclocking the result of the incorrect and you decrypt it, you see that you need to get the same value if you start with. So that's how good protecting mechanisms are. But the functionality is correct in this case. This is the point. Not that overclocking. Overclocking, it will help you collect. Because it should be correct. This is the point in your design, that the correction terms will be canceled each other. And then, no matter the correction terms on there or not, the functionality of the system is correct because you always receive the correct result if you are in that yellow area. If you are here, the system works correctly. This is the point. If you decrypt it again, you get the same places. OK. I thought that the collection level reaches on the line. Here is correct. There is no problem. Here is the minus table. And here is, again, the result of the function is correct. And here, again, it's just going to be faulty. But here, the result is correct, but the size of the ligament itself. That has been good. Thank you.


So, the title is actually sort of aimed at those of us who live in the northern hemisphere because we're actually going to be entering our winter season. And this is a time when questions about vitamin D are rather important because, as most of you know, in the winter we don't synthesize adequate levels of vitamin D with sun exposure. And for anybody who's coming from the southern hemisphere, you're probably coming out of your winter and you've used up what stores you might have synthesized if you're not supplementing. So this could also be relevant to your situation as well. So what I'll do is I'll, this is an overview of the talk. We'll start out with what is vitamin D and where do we get it. And then move into how does it work and why do we need it. And then how much do we need. And a lot of times this is an area of interest for most people because it's actually been a topic of sort of debate. And finally I'll discuss a bit about how vitamin D can help fight infections since this is my main area of interest, the role of vitamin D in immune function. So start out, what is vitamin D? Well it is a vitamin, at least it's been referred to as a vitamin partly because of its history of its discovery. But and a vitamin is an organic substance that is present in natural foodstuffs. So and we do get vitamin D from our diet but as you'll see from this talk diet is not necessarily the best source. It's more accurately probably should be referred to as a hormone because it's actually something that we synthesize. A hormone is a product of living cells that circulates in body fluids and we and other mammals actually synthesize vitamin D in our skin and it goes into the circulation.  This term secaster steroid just refers to the fact that one of the rings in the structure of vitamin D is cleaved and we'll talk more about this in subsequent slides. It's stored in the liver and fat and so as we synthesize or if we consume this in our diet the excess amounts of vitamin D can be stored. It basically has a really important function in increasing transporter proteins in the small intestine and this is really important for sort of the primary function that most of us know vitamin D for and that's enhancing calcium and phosphorus uptake from in the small intestine. And the primary health benefit is strong bones and preventing rickets. But as we'll discuss there are other health benefits associated with vitamin D. So just before we get started I wanted just to present a brief history of vitamin D and both this sort of cover why it's referred to as a vitamin but also the discovery that it's actually a hormone and something that we synthesize. And so as with most nutrients vitamin D started out as being something identified or the disease from a profound deficiency was actually identified and this actually goes back to the mid 1600s. This is just a picture of the manuscript or book that was written back in the 1650s about the condition of rickets being a common disease in children. But by the early 1800s with the industrial revolution rickets became much more of an epidemic and there were very high levels of rickets occurring in northern Europe and the U.S. And this was primarily in cities large cities where there was a lot of industry and this was associated with a lack or attributed to a lack of sun exposure. And this because of the amount of pollution in cities it was noted that this is that rickets was much more rampant in these areas and they actually noted that if you move children out into the countryside where they could get more sun exposure this could ameliorate the disease. It was also noted that cod liver oil could be used to prevent rickets. So it was obvious that there was an environmental factor as well as a nutritional factor that treat this condition. But it was only about 100 years later when there was sort of a flurry of research in a number of different vitamins when vitamin D was actually identified. And there was a number of vitamins being identified during the early 1900s and they were named based on the discovery, the order of discovery. So vitamin A was the first one. There was B and C and you heard about C in the last webinar. And finally D was the fourth identified. And researcher named Melon B had shown that cod liver oil cured rickets and dogs so they were using animal models of rickets. And he attributed this to vitamin A because cod liver oil is known to contain vitamin A. Following that, McCollum described this anti-racketic factor or anti-ricket factor in cod liver as vitamin D and he did that by destroying the vitamin A in cod liver oil. And the cod liver oil still maintained this activity and he termed this vitamin D. And it was furthermore shown that these anti-racketic properties were found with artificial and natural UV light. And this was demonstrated by Hildensky and Hassan Unger. You could treat individuals with light by heliotherapy and cure rickets. And then at the University of Wisconsin, Steambach irradiated rats that they made deficient and these rats were developing rickets. You could irradiate these rats that would prevent the development of rickets. You could also irradiate their food and this prevented or cured rickets as well. He hypothesized there was an inactive lipid that was involved and somehow the irradiation UV irradiation was activating this lipid. And then sort of in parallel independent work Hassan Wine Stock also showed that they could irradiate different foodstuffs and they would feed these to animals that were deficient and cure rickets. So by the 1930s researchers identified vitamin D. Vitamin D2 was identified from irradiated ergosterol. Ergosterol is a cholesterol like molecule that's in yeast and fungi and was probably responsible for a lot of the vitamin D that was being derived from irradiating various plant materials because of the low levels of fungi associated with those as well as the irradiation of yeast and mushrooms. Wendals and Bach identified vitamin D3 after irradiating 7 to hydrocholesterol and this was vitamin D3. This is the type of vitamin D that we synthesize in our skin from the substrate 7 to hydrocholesterol. And by the 70s Michael Hollick and colleagues and Esvelt and colleagues showed that irradiation of 7 to hydrocholesterol in the skin produced vitamin D3. So it took nearly 400 years for this story to evolve and we're still learning today a lot about vitamin D. So where do we get vitamin D? Many of you are probably aware of some of this but just to get everybody sort of up to speed, an important source is the skin and I've already alluded to this in the prior slide but you have UVB irradiation of the skin and that converts the 7 to hydrocholesterol into vitamin D. This then enters the circulation, goes to the liver and you have a hydroxylation and the addition of a hydroxyl group, this OH, to the vitamin D and at the 25 carbon position and this gives you 25 hydroxy vitamin D. These two forms here are generally considered inactive. They aren't going to mediate the effects of vitamin Ds as we know them but this form here is what is measured when you go to the physician, go to the doctor or if you use one of the in-home kits to test your vitamin D status, this is the form that's being measured. And so when we refer to having adequate levels of vitamin D, this is the form that we're referring to here. The body tightly regulates the production of the active form of the vitamin and that's because too much of the active form can lead to side effects that are not desirable. And the primary synthesis of the active form occurs in the kidney and we refer to this as renal synthesis of the active form of vitamin D and again it's another hydroxylation event and you get 125 vitamin D and this is this active form of vitamin D. This can also occur extra renal-y, not in the kidney but outside the kidney and other cell types and this can be particularly important in immune function and we'll discuss that a bit later on. So this just shows you sort of in a cartoon biochemical cartoon fashion what's going on with vitamin D synthesis in the skin. You have 7-dehydrocholesterol, this is the structure here and the UV light either in sunlight or if you're using artificial UV light cleaves the second ring here and this gives you the vitamin D3 or also it's referred to as cold calciferol and this is the form that's generally sold as a supplement and this is the form that we synthesize and other mammals as well synthesize in their skin. And this gets converted to the biologically active form so this is sort of a repeat of that previous slide but what's going on is you have this vitamin D3 converted by an enzyme in the liver to 25-hydroxy vitamin D3 again these are not the active forms and this form here is what's measured in your blood to determine your status. This form here is what's measured in food items so if people want to know how much vitamin D is in a particular food this is the form that's being measured. And then finally in the kidney it gets converted to the active form this is a very biologically active form that is mediating the effects of vitamin D and again this is regulated quite tightly so that you don't under normal conditions so that you don't have high levels of it but it's generated when it's needed. And so as far as sources of vitamin D again it's generally considered that the sun is your best source and this is just an example of how long you need to be out in the sun to generate a thousand international units of vitamin D and this is generally how we refer to the dose of vitamin D that you need in international units. This website here is actually quite interesting it allows you to enter various parameters such as the time of year, your geographical location and so on and you can determine how long you'll need to be out in the sun and so this is for if you were in Corvallis where this webinar is taking place and you're a darker Caucasian so you'd have darker hair and all you would not be like me I'm fairly fair skinned but at noon if you were outside today in August 27th with clear skies you'd take about eight minutes to synthesize a thousand international units of vitamin D and you can see at other times of the year the time varies but if you'll notice if it was December 27th you could be out and generally it's overcast here in Oregon you could be out for 24 hours and not synthesize anything even if it was a clear day because there's not enough UVB ray in the sunlight and that has to do with the angle of the sun to the earth the light is having to travel through more of the atmosphere and that filters out those rays so there are a number of factors that affect synthesis by the skin and also the serum levels of 25 hydroxy vitamin D so again this is what we measure to know your status and of course I've already sort of alluded to this climate and weather important there's the season what time of year it is as well as your geographical location which be the latitude and so of course in the winter there's very little synthesis north of say 35 or 40 degrees latitude and another factor is skin color and that's because the darker the skin the more melanin is present in the skin and melanin acts as a natural sunscreen so darker skinned individuals need to be out in the sun longer to synthesize the same amount of vitamin D as someone with a lighter skin color clothing and sunscreen are also important factors because they block UVB rays and so these can affect the synthesis age is another factor and that's because the cholesterol content so the seven to hydro cholesterol levels are lower in skin of elderly individuals and so there's less substrate for production of vitamin D also mobility is a factor because people as they get older tend to be outside less and there's less sun exposure and finally diet is important the vitamin D content of foods is important the type of foods you eat and generally most foods don't contain vitamin D and but if you're taking a multi vitamin or vitamin D pills that can affect your levels as well these are not only factors that affect synthesis but they're also they tend to be risk factors for low levels of vitamin D so the darker skin color or if you're fully clothed most of the time or inside these all contribute to low levels of vitamin D and your diet the type of diet you consume can affect the amount of vitamin D in circulation and breastfed babies tend to be a classic sort of population that suffers from low vitamin D levels because in general if the mother does not have high enough levels of vitamin D the babies don't get that milk and if they're breastfed they're not getting much vitamin D so baby babies generally are prescribed it's there are recommended that the pediatrician will recommend that a baby's get a vitamin D drop as a supplement and so you have populations with dark skin colors tend to be vitamin D deficient people living north in the northern or southern very south or very north and during the winter also can tend to be vitamin D deficient and the elderly as well or another vitamin D deficient population population that's susceptible to deficiency so this calendar is a really nice example of what's going or illustration of what's going on with with geography and climate and so what you can see is that the colored dots here the red one is intense UV the orange is less intense and the yellow is low lower intensity and so with the more intense colors here you need shorter times for synthesis with the orange you need longer time and even longer with the yellow the yellow so you can see the months across here and the latitudes so the clear circles are where there's no synthesis of vitamin D during those months and so you can see as you move north that would be during our winter November through February and if you're in the southern hemisphere that would be during their winter from May until August so these are times where you're not going to be synthesizing adequate levels of vitamin D and it's recommended that I mentioned the noon hour in an earlier slide and part of that is that it's found it's it's it's been demonstrated that exposure at the noon hour gives you the maximum UVB and so you synthesize your maximum vitamin D at that time and so you would know when you're synthesizing vitamin D your shadow is shorter than you are tall so that tells you that you're you're at a time of day where synthesis will be maximal so it's diet a good source of vitamin D if you go on the internet you'll see a lot of slides like this with the different vitamins arranged spelled out or written out with various vegetables and fruits and this is somewhat misleading vitamin none of these foods here really have vitamin D in them at all and so actually if you eat a diet like this you're one of those populations that's probably at risk for deficiency and the only real item on here that has that could have vitamin D are the mushrooms in this picture here and this is because of the agar sterol which can lead to the synthesis of vitamin D2 so if you remember there are two forms of vitamin D there's the D2 form from fungal sources that are irradiated and there's the D3 form which is what we synthesize or other animals can synthesize in their skin and this is not lost on food companies so companies like dull and Monterey mushroom have sort of jumped on this as a marketing tool but it also provides a source of vitamin D as well for people who eat vegetarian or vegan type diets and that's by irradiating mushrooms typically mushrooms are grown in the dark they're gonna have very little vitamin D but if they expose them to sunlight or UVB rays they can generate a certain level of vitamin D2 depending on the amount of exposure so these will give you 100% of your vitamin D your RDA with a serving and but you know the idea that it's new is actually sort of misleading because it's really not all that new and I'll show you some evidence of that in some other slides but just to let you know what's going on in this process the agar sterol and you can see it looks very similar to the seven to hydro cholesterol when it's exposed you cleave that second ring there and you do you form vitamin D2 or ergo calciferol this then goes through the the same organs in the body as the D3 and it's hydroxylated in the same positions and you end up with a 125 dihydroxy vitamin D2 as the active form and you can see again it looks very similar to D3 with with a methyl group change that's added here as well as a double bond in the D2 form but otherwise it seems to act very much like D3 so I was saying this this this irradiation of food items and fortification and all is not really new and this was back in the 30s when they American scientists had discovered the process of irradiating items and synthesizing vitamin D2 there were big articles and we see these day today about vitamin D and bottled sunshine and so on and this is just a cover page from one of those articles talking about how you can irradiate and fortify foods now and not suffer vitamin D deficiency during the winter and it's kind of interesting to look at this stuff but the ads were very in your face about the the promise of this and very very much pushing vitamin D fortified items this is cod liver oil that was concentrated and they had nice tasty candy like pills that you could take so the idea was you wouldn't make your kid eat a bunch of wheat for bread why should you make them take cod liver oil and so this is a better way of getting a and D also cocoa malt is like an oval team or chocolate milk mix was also fortified and the idea was feed your kids this in their drink they were also fortifying milk at this time as well and even Fleishman's yeast was irradiating yeast so that it would contain D2 and selling this as a as a something you can mix with water get your D2 and as well as improve your gastrointestinal health and so just so that adults weren't left out even beer companies got into this and Schlitz was selling marketing a sunshine vitamin D beer and they were using yeast that were irradiated to to brew beer and so you could get vitamin D that way you can generally find most of these things in the market today I don't find beer though and I'm not sure if there's rules about that but you can see we still fortify foods and most of these are drinks like milk milk substitutes there's oval team supplements there are other drink mixes that are supplemented orange juice has been supplemented and bread and then of course cereals it tends to be mostly kid cereals so there's a real push still the marketing is really at children partly that is probably because of the rickets but the fortification the sort of the take-home is a fortification is an important source of vitamin D and that's if you look at this table you'll you'll sort of appreciate that because of the natural foods that are on here and this is probably kind of small but what you can see is it really things like mackerel salmon and cod liver oil are really high herring are also very high in vitamin D your radiated mushrooms can be fairly high depending on their exposure time it can be even higher than this but otherwise most of the foods are fairly have fairly low levels of vitamin D in them and so and a lot of these are actually fortified and so if you were restricted just these natural food stuff sources of vitamin D in the diet would be very limited and just to give you an idea I graft these levels and you can see again these these fish and the mushrooms give you fairly high levels these are the inner international units per serving but you can see when you get down into these other natural foods that aren't supplemented they're very low and you would have to consume very large amounts say of eggs or or liver or even sardines to get your RDA of 600 international units and this is just in comparison this is sunlight you can synthesize 2000 international units in about 16 minutes if you were to go outside today so again Sun is a very good source of vitamin D diet tends to be not not as good a source so I've mentioned a couple of different vitamin D's there's the D3 and the D2 and vitamin D3 is actually preferred over D2 so there are a number of times I get questions about which is better D2 or D3 well if you buy over the counter supplements you're generally you're going to get D3 most most of the time unless you seek out a D2 form and the reason it's preferred is that comes from studies like this and this is from Dr. Heaney's group at Creighton and what they found was that if they gave a bolus dose of 50,000 international units of vitamin D either D3 or D2 and then followed the levels in the serum what they found was both of these saturated the the serum quite rapidly within four days or so and the levels were similar but if you followed it over time you could see that the D2 levels were dropping quite a bit faster than D3 in fact D3 was still peaking as you go out and staying in the serum for quite a long time so it seems to be a difference in the way the body handles these two forms and so if you're particularly if you're bolus dosing in other words taking a large dose once say once a week or once a month rather than having to remember to take it each day which is one way of supplementing the D2 may not be the form that you would want to use because the levels could drop to a point where you're not benefiting whereas D3 though does seem to be the form that you could use in this type of dosing however there are people who prefer the D2 form because of lifestyle choices such as a vegan lifestyle and they don't want to consume animal products and D3 technically is an animal product so if you do use D2 it would be recommended that you dose each day with it to keep your levels up so just to summarize this part of the talk best source of vitamin D is sunshine but not in the winter north or south of 35 to 40 degrees latitude another another issue with vitamin sunshine sources is people are concerned about skin damage and we and people want to minimize skin damage because it's clear that UVB damage the skin can lead to forms of skin cancer so it's if you want to get vitamin D through sunshine exposure it's probably best to go out for a few minutes depending on your skin color get your exposure to you know generate one or two thousand IU and if you do that each day that should be adequate if you're out longer you'll make more because the body can actually synthesize anywhere from 10 to 20 thousand international units but you do want to avoid getting sunburned and minimizing skin damage so you can put your sunscreen on after you've gotten your exposure that you want and that one website I pointed I pointed out earlier can give you an idea of the to estimate the amount of time you need to generate what level you're interested in there are some dietary sources but supplements are probably more reliable so a lot of us don't get out in the sun because of our lifestyle we're usually inside like we are right now and this is a good time almost a good time to go out and make vitamin D but we're not doing that we're in an office or we're at work indoors generally and so we're not going to be synthesizing vitamin D and just going out on weekends is probably not going to be sufficient so supplements are a way to maintain those your levels and throughout the year and then vitamin D 3 is a preferred supplement over D2 but D2 can be used but probably it's best to dose each day with it so how does it work and why do we need it I think a lot of you have already heard the number of different health benefits of vitamin D so I'll go over this fairly briefly but before we start talking about why we need it I thought it would be good for people understand how it works many of you may not know how vitamin D actually mediates its effects turns out as I mentioned vitamin D is really a hormone and a number of hormones in our bodies actually use nuclear receptors and these are somewhat different from receptors that sit out on the outside of a cell and get signals from outside the cell these are receptors that are inside the cell and they are something called a transcription factor and that means that they turn on they directly turn on expression of genes so some of these are probably familiar to you there's estrogen there's an estrogen receptor progesterone androgen even vitamin a actually works through a nuclear receptor called the retinoic acid receptor and their styrode hormones so these are all related to the vitamin D receptor or the vitamin D receptors related to those receptors and what they do is a these function as a dimer with a partner usually RXR and so they they form this complex and when the ligand in the case 125 dihydroxy vitamin D the active form binds and this can then this this complex can then bind to the DNA in the cell and turn on gene expression or turn off gene expression this is sort of shown a little more detail on this slide just to remind you you synthesize vitamin D in your skin it gets hydroxylated in the liver it can then go to it can then be hydroxylated again in the kidney this can also occur in some other cell types especially like in immune cells and you have 125 dihydroxy vitamin D this is again that active form it binds to the vitamin D receptor and this complex then goes in turns on gene expression and or turns off gene expression and this is how vitamin D has its classical effects on bone metabolism or bone health and also muscle function and also things that are referred to as non classical which could be the anti cancer effects anti bacterial or immune boosting effects and also anti hypertensive effects and also a number of things that are not even on the slide so just a little more detail on the classic renal activities which are important for normal bone growth and mineralization you have this sort of complex process it occurs and what happens is that in this situation vitamin D is very important for regulating calcium and phosphorus levels and those are important for bone health and so if there's a deficiency of vitamin D you have inadequate levels of circulating calcium that's going to affect bone health because what happens is the the calcium that needs to go into the blood is being taken out of the bones and this is going to weaken the bones but what happens is with low calcium levels you have secretion of parathyroid hormone from the parathyroid glands parathyroid hormone signals the kidney to increase the production of that active form of vitamin D the 125 from this circulating form this 25 which is the inactive form but what we measure in our blood and that increased production of 125 can then go to the small intestine and turn on expression of various proteins so it turns on genes that encode proteins and these proteins are what increase absorption of these things like calcium and phosphorus from the from the gut from the diet and that increases serum calcium and when the levels get back up to where they need to be of course you don't want serum calcium levels too high that can lead to some toxic side effects the body then signals to shut down production of 125 it also suppresses expression of parathyroid hormone and then this stops the increased uptake from the diet also the sequestration from the bone or sorry the removal of it from the bone so if you have deficiency in D this doesn't happen and then all the calcium is being taken primarily from the bone and this leads to weakening and things like rickets as you see in children so this is a slide I borrowed from the vitamin D council I kind of like it because it shows you what it sort of summarizes why we need vitamin D but also it also highlights the fact that vitamin D is important throughout our life starting at pregnancy or even before pregnancy throughout old age and if you take a look at this slide you'll see the various health benefits of vitamin D that have been associated that have been associated with vitamin D clearly know that bone function and muscle function important but then there are things related to the immune system the developing immune system as well as immune responses it seems that vitamin D is quite important for an uncomplicated pregnancy again immune development and along with that resistant to resistance to some certain infections and in adults appears to protect against cancer helps to regulate blood pressure support brain and mental health and as you age it's important balance bone strength and muscle function and there's a supplementation tends to reduce the likelihood of falling and breakage of bones so there's there are these different health benefits that have been attributed to vitamin D and we need these throughout life so question is how much do D do we need and the IOM came out of the Institute of Medicine came came out with their recommendations a few years ago in 2010 and 11 and while they increased the RDA from 400 to 600 a lot of researchers and other other folks believe that this 600 international units is actually still too low and so there's a lot of controversy about how much vitamin D to take and part of that is because there's controversy in what is the adequate level of circulating vitamin D so that 25 hydroxy vitamin D that I mentioned earlier so depending on what level you need circulating in your blood that's going to be determined by how much you either synthesize or consume as a supplement or as a food and so this table is quite dense may be hard to see but basically the recommendation for infants is 400 international units and children that are your older 600 on up through adults up to 70 is 600 adults older than 70 it's recommended 800 and this is males the similar same in females and the recommendation for pregnancy is 600 international units and lactation is 600 international units again this is there's a lot of debate over this this is probably this is considered probably inadequate and there's data to support that this because of the disagreement the endocrine society came out with their clinical guidelines in 2011 and their numbers are shown here and their hire for children is 400 to 1000 or I should say infants for children is 600 to 100 1000 and for adults 19 and older 1500 to 2000 and again similar numbers in females and for pregnancy and lactation the levels are are higher 1500 to 2000 again it's it's possible that even higher numbers are needed here but more research needs to be done to determine what levels in pregnancy and lactation to get adequate levels to to the infant during breastfeeding it's it's there there are pilot studies have been done showing it around 6000 IU or probably what are needed to get about the equivalent of about four three to four hundred IU to the infant and breast milk so that the higher supplementation increases the levels of vitamin D in the breast milk and those appeared at 6000 IU level that appears to be enough to get adequate levels to an infant that would be similar to what the level that is recommended by the IOM one other thing there are some upper levels here and the IOM recommends no more than 4000 IU for adults somewhat less for children and infants and but the endocrine society is recommending 10,000 IU for males and females somewhat less for children younger than 18 and for infants as well and I just one thing to mention that the Linus Pauline Institute is recommendations are in line with the endocrine society clinical guidelines so these recommendations primarily address bone and muscle health so you know the IOM and the endocrine society disagree on intakes or daily allowances they do agree that these are primarily going to address bone health with the higher levels recommended by the endocrine society they're recognizing that there's a lot of biological evidence that higher higher intakes leading to higher serum levels are probably going to provide the other benefits of vitamin D that are not related to bone and muscle and so the recommendations by the endocrine society are to maintain are set to maintain serum levels above 30 nanograms per mil and so this the serum levels also hotly debated as far in vitamin D circles the IOM is basically going with 20 nanograms or mill per mil or higher if you want to convert these to nanomole per liter which is another measurement you would multiply these by 2.5 so there'd be around 75 nanomolar and this would be 50 nanomolar and they this is this 20 and 30 or higher is a point of debate it's also recommended by the endocrine society that patients with malabsorption conditions or obese patients and patients taking certain medications that interfere with metabolism vitamin D take higher levels two to three times higher than these recommendations and obese individuals do tend to have lower circulating levels of vitamin D and are considered vitamin D deficient and it's recommended they take higher doses of vitamin D if they're supplementing so the cut-off the cut-offs of serum 25 hydroxy vitamin D and the optimal levels again like I said are controversial and Institute of Medicine follows these cut-offs deficiencies considered 12 nanograms per mil or lower insufficiency is 12 to 19 and 20 to 50s efficiency the endocrine society is at less than 20 is deficiency 21 to 29 is insufficiency and 30 to 100 is sufficient and these these numbers here are similar to what your physicians probably discussed with you in the years past and what happened when the IOM came out with their new recommendations they actually dropped these cut-offs to these numbers here just point out that there are other organizations that recommend levels that are considered optimal and grassroots health recommends 40 to 60 nanograms per mil and and needy and to reach that you would need to take a higher level of vitamin D than is recommended by either of these groups and this could be anywhere from up to 10,000 international units so this these these sorts of cut-offs are still debated and it won't be surprising if we see changes these and in these in the future by the Institute of Medicine as more and more data comes in but these are generally set for optimal bone and bone health so I just show this slide because it's hard to know how much you need to take to reach the level that you want to reach and that's because everybody's somewhat different and this is from grassroots health and I apologize I guess the link is stuck in the slide there but I'll fix that but what they've done is they've enrolled people into a study where the the individual report their intake that's shown here international units that they're taking and then they get their their vitamin D levels their 25 D levels measured a couple times per year and these are plotted so you can see that for each point is a different person or a different at least a different measurement and you can see that someone taking 2,000 international units can have levels as high as 120 nanograms per mil or as low as 20 and so to know what intake you need and to reach your desired level you probably would have to start with a certain level of intake and then have measurements done and that way you would know how much you need everybody seems to be somewhat different and if you talk to people what their vitamin D levels are and how much they're taking you'll see that some people can take a thousand and reach levels higher than you're getting with say 3,000 so this is this this this slide I think just highlights that difference and a lot of this is probably due to the genetics of individuals so vitamin D deficiency no matter what cutoff you use is still a risk a major health risk for the young and old and middle-aged and it's estimated if you use those cutoffs from the endocrine society probably there are a billion people worldwide that are deficient or insufficient anywhere from 40 to 100% of US and European elderly that are not nursing homes are deficient and 70% of US children are insufficient 10% deficient so people are still not getting enough vitamin D and this could have consequences on health so in taking vitamin D there are a lot of concerns about toxicity and toxicity can lead to hypercalcemia or buildup of calcium in your blood it can also lead to hypercalceria which is buildup of calcium in your urine or elevated levels of calcium in your urine symptoms of toxicity are just listed here there are things like nausea loss of appetite weight loss feeling very thirsty passing urine often muscle and weakness or pain abdominal pain even feeling confused and tired and these these generally only occur with really really high end takes of vitamin D you could you'd might have to take 50,000 IU per day for weeks and months on end or take really high levels hundreds of thousands maybe close to millions of IU's and in a single dose to experiences generally at the levels we're talking about anywhere from 1,000 to 10,000 international units it's really not a symptom these symptoms are not something that you would initially see toxic is not considered to be that much of an issue however the IOM does recommend 4,000 international units or less as their upper level and the endocrine society's 10,000 so what happens though with really high levels of vitamin D which can cause say hypercalcemia this leads to vascular and tissue calcification because you have too much calcium in your blood and so this can lead to subsequent damage to the heart blood vessels and kidney and 25 hydroxy vitamin D levels greater than 150 or say close to 200 nanograms per mill are considered potentially toxic so you want to avoid getting your levels up that high and that's why some doing measurements can be important when you start supplementing and the IOM considers levels greater than 50 nanograms per mill to be dangerous there's also but there's been a recent paper from this group here and it was published in the Mayo Clinic journal from the Mayo Clinic and what they found was they wanted to know with the awareness of vitamin D deficiency or insufficiency and people taking supplements has there been an increase in 25 hydroxy D levels and has this corresponded with increased reports of clinical toxicity and so you can actually look this up on the internet if you're interested but basically what they found was that in looking at see I think it was 20 some thousand individuals yeah 20,000 three-internate individuals that eight percent had measurements that were above 50 point six percent above 80 nanograms per mill and point two percent above a hundred nanograms per mill so there was definitely an increase in serum levels and in the population but they found that even with this increase there was no increase in reported clinical toxicity so that was very rare so that it appears that these increasing levels of serum vitamin D are not leading at least at this point till to increased reports of clinical toxicity and so it's done over a 10-year period from 2002 to 2011 but not necessarily a final word but so far there's an indication that these levels are not that dangerous in that at least with that data also there's a question about increased incidence of kidney stones and there's no there's really a recent paper from grassroots health actually using their data from individuals who are enrolled in their measurement program found there was no significant association with 25 hydroxy should say D levels between 20 to 100 nanograms per mill so they were not finding that the there was no association with kidney stone the development of kidney stones and serum levels of vitamin D and that's actually something that has been borne out by other studies as well so can vitamin B levels be too high not all the data says that vitamin D levels high but vitamin D levels are necessarily safe there are some reports coming out and of course as with any of these clinical studies there they have deficiencies and they have weaknesses that can be said for even studies that promote the benefits of vitamin D but other they are still out there and published and what they're finding and these are retrospective observational cohort studies there's not these are not the best kind of clinical studies they're not like random controlled trials where you're actually setting up an experiment to test a hypothesis but they're reporting things like J-shaped curves that are associated with increased all-cause mortality there's also been increased cardiovascular events and things like that but they're finding this sort of curve where low levels are associated with higher levels of more all-cause mortality but so are high levels and so in their study they suggested that between 20 to 24 was this it was a good of nanograms per mil was sort of the ideal concentration in the serum and in a recent study by Armin Amrin at all they found that 25 hydroxy levels less than 20 nanograms or greater than 60 nanograms per mil in patients before hospitalization was associated with increased odds of 90 day mortality so again it's another retrospective cohort study so these are associations and they definitely the authors have pointed out that this is a causal relationship cannot be inferred but they emphasize maybe a need for caution in using high dose doses of vitamin D so these were patients that came into the hospital had a vitamin D measurement done within a few months before hospitalization so these studies do have their weaknesses but they are there are additional studies that show either these J shaped or U shaped curves and so they they do sound a note of maybe caution but I think what it indicates is that more studies need to be done to really find out our what level at what level is too much there's are too much vitamin D but it's clear a lot of studies have shown that low levels like this are definitely increased or associated with increased mortality or other disease conditions but less is known about how high you need you should go so just to summarize associations with low vitamin D levels and numerous health outcomes are known and a lot of you are probably aware of these it's there's so many that you could fill a slide with it but large numbers of people are not getting enough vitamin D and the optimal level is not known but evidence supports levels higher than 30 nanograms per mil and this is where the endocrine society falls maintain levels higher than that and perhaps even levels higher than 40 it remains to determine what upper levels are safe but 30 to 50 nanograms in my opinion is a conservative range to perhaps aim for and that will give you benefits beyond the bone benefits so really quickly and I'm running low on time short on time how can vitamin D help it fight infections well this just shows it's a complicated slide I put it up there just because it does highlight what vitamin D the impact of vitamin D on the immune system and the immune systems comprised of of innate immune cells and adaptive immune cells the adaptive immune cells are the B and T cells which you're probably familiar with these terms these are important in the immune response to vaccination and they give you that lifelong immunity after an infection and then the innate immune are things like monocytes macrophages and dendritic cells also not on here are neutrophils and some other neutrophil like cells and these are all important for the immediate response to infection so you get a cut your immune system has to respond immediately this arm the innate arm is what responds to the immediate presence of a path immediately to the presence of a pathogen whereas these are more involved in subsequent steps of the immune response but what vitamin D does is it does affect the the activity of these cells and the overall effect is to decrease inflammation which can be caused by T cells and in the innate immune system again to reduce the production of inflammatory cytokines but increase the expression of antimicrobial peptides and so probably vitamin D is important in maintaining a balanced immune response so things don't get out of control too much inflammation is not good enough inflammation is what you're shooting for and then these antimicrobial peptides are important in killing things like bacteria and viruses and these are used primarily by our innate immune cells like the monocyte macrophages and neutrophils these cells in Gulf pathogens they then use these antimicrobial proteins to kill the pathogen and sort of the first evidence are some of the early evidence I should say that vitamin D somehow was fighting infection came from studies on TB these are really interesting if you go back and look at the literature it was known for some time since the late 1800s that exposure to sunlight actually could help treat tuberculosis and this is a bacterial infection of the respiratory system but it can also TB can also infect other organs and this is a skin infection here it's a very disfiguring disease this is lupus vulgaris and so there was then it was known that heliotherapy was useful around 1900 Niels Finsen won the Nobel Prize for showing a heliotherapy with artificial light to cure lupus vulgaris which was this tuberculosis infection or the mycobacterium tuberculosis infection of the skin this is a before and after picture and then in the 40s and 50s after they had they learned how to or they identified vitamin D and could purify it produce it and purify it synthesize it they could give high dose therapy to people and this is using vitamin D2 and again a lupus vulgaris patient and after two weeks of treatment with really pharmacologic doses or therapeutic doses that you would not take if you're supplementing you could get this kind of cure and these are interesting studies to look at but with the advent of macrophage of antibiotics these sort of fell out of favor but what we knew in the 80s was that vitamin D could also and boost the killing activity of macrophages and particularly mycobacterium tuberculosis it was known that deficiency in vitamin D increased susceptibility to mycobacterium infection and if you treated macrophages with 125 you could actually enhance killing also if you activated a macrophage in other words the macrophage senses the presence of a pathogen it would convert 25 hydroxyd to 125 so the macrophage itself was doing this conversion that we see generally in the kidney and the 125 would actually enhance the phagocytosis of the eating of the bacteria and the killing of it and what our group discovered was that vitamin D actually increases a bactericidal protein and this is just a Western blot it's looking at protein and this is before treatment this is after treatment so we can see this really profound induction of this antimicrobial protein that makes a peptide called catholcide antimicrobial peptide okay and so this this was really a quite surprising finding but it then kind of explained what was going on in in the 80s when people were identifying these chain these enhanced killing activities by vitamin D with macrophages so just so this just shows you what happens when a cell encounters a pathogen it has receptors we refer to these as toll-like receptors and when a pathogen or a pathogen associated molecular pattern something from the pathogen is bound by these receptors it activates a whole bunch of pathways in the cell but the ultimate goal is to turn on cytokine expression and other genes that are going to counter the infection they're going to fight the infection and what it turned out was that these antimicrobial peptide we were studying didn't get turned on by this pathway and when we discovered vitamin D was doing this another group at UCLA was looking at this activation of immune cells by pathogens and they found that the binding of the pathogen to the toll-like receptor led to the up regulation of this enzyme that converts 25 hydroxy vitamin D into 125 so the macro and this was known but they pulled together the story that this process led to increase vitamin D and that this turned on the cathol side and along with some other proteins that are important for fighting infection that vitamin D regulates and this enhanced killing of the bacteria and they did they went on to show that if you took syrup from a population that's deficient in vitamin D so African Americans in this case and compared it to serum from Caucasians who tend to have higher levels these are there's 25 D3 levels the deficient serum could not increase expression of this cathol side and antimicrobial peptide in macrophages that were activated but the sufficient serum could this is just showing expression levels here so it's higher in the Caucasian this serum so this suggests that low serum levels of 25 hydroxy vitamin D don't support induction of this antimicrobial peptide and so it's important to have sufficient levels this point it's unclear exactly what levels you need but definitely 30 nanograms per mil or higher would probably suffice so these findings they've spurred a number of studies into protecting against respiratory tract infections using vitamin D sees upper respiratory tract infections initially these were random controlled trials there were a lot of associative studies that showed deficiency correlating with increased susceptibility to infection these studies were actually taking populations putting into arms where you know supplementation or supplementation initially I'll just skim through this but these studies were essentially somewhat negative the study in Japan showed a reduced influenza A infection but overall when they considered all flu infections it was not not it was a negative study this study did show a delay in development of a second pneumonia in these patients when they received a hundred thousand IU bolus but when they tried to replicate this in another study that published in Lancet they couldn't replicate this and part of it was they changed their dosing regimen in the number of doses this was a single dose they switched to a this dose given over every a couple of months for three doses of a hundred thousand IU for over a period of I believe six to twelve months and so they did not see this benefit there have been some additional studies Carlos Carmargo has shown that in Mongolia if they took children who started out with really low levels of serum 25 hydroxyamide here at seven and then they supplemented with milk that had 300 IU they got their levels up to 19 nanograms per mil and this fortified group showed a decreased to a 50% reduction in infection and a similar findings here in some patients that were in an immunodeficiency clinic again they saw a reduction about 23% reduction in disease score so and this is renewed interest in TB yeah okay I'll finish up here in TB they're doing studies with high doses along with traditional therapy with antibiotics the results have been somewhat unexciting but there does seem to be some reduction in inflammation which can be important resolving inflammation during treatment and actually a group that went up to 600,000 IU doses which are similar to what were used back in the 40s and 50s actually found decrease an increase in weight gain and lower residual disease by chest x-ray so sort of the take-home is that there are several RCTs that are indicating a vitamin D supplementation can benefit outcomes of infections maybe reducing rates or improving outcome the design of future experiments that's going to be important so this might explain why some studies are negative it's probably going to be important to enroll people who have very low levels then bring their levels up and also determining the dose the frequency and what serum levels you need to reach are going to be important so I'll stop there take questions and these are some additional sources where you can learn about vitamin D I encourage you to go to the Linus Paulin Institute micro information center but there are some other sources as well we have one question regarding the intake of vitamin D supplementally and whether it makes any difference if it's taken without food or with food or with other substances like vitamin K if you look at the the published literature on taking vitamin D with a with a meal or not just say alone maybe just a glass of water it seems that that's not so critical what's critical is just to take the the dose that you that you need to raise the levels of your serum in other words even though it's a fat soluble vitamin and doesn't appear that taking it with fat has any benefit that's been reported for some other vitamins that are fat soluble like vitamin E but for vitamin D the literature doesn't really support that the it's necessary to do that as far as vitamin K vitamin K and vitamin D interactions are an interesting area it's a little bit out of my field of study but what seems to be important is to have adequate levels of vitamin K in case probably important in just to summarize it reducing the chances of calcification of soft tissues so it seems important in directing the calcium to the bone have another question here you you've mentioned in your presentation nanograms per milliliter and also you have nanomoles per liter you might want to clarify some people are you clear what you mean by either one of those right they're just two different ways of measuring it in the United States we generally use nanograms per mill I think in a lot of the other parts of the world they use nanomoles per liter you can convert between the two by basically multiplying nanograms per mill by point four or believe yeah by point four yeah sorry converting nanomoles per liter to nanograms per mill by multiplying by point four and if you want to convert nanograms to the other you would multiply by 2.5 but they're just two different units of measurement we have another question concerning well maybe yeah maybe regarding units you also see supplementations given as micrograms or as international units and there basically there's a conversion factor one microgram is 40 international units so you can convert back and forth with that sort of conversion factor yeah good we have another question regarding the influence of vitamin D on the bacteria that normally inhabit the gut and whether there's any interaction or whether these interactions have been well characterized it's actually a really interesting it's a very good question it's a very interesting question and it's actually something that our group is quite interested in at this point we've vitamin D is an important I didn't go into this too much but vitamin D is actually very important in barrier function and this could be whether it's the health of the skin or the health of the gut so deficiency leads to problems with gut health of course there's a connection with colon cancer and vitamin D deficiency and part of that's probably due to the fact that you if you have a barrier that's not intact or it's weakened you can get increased inflammation inflammation can contribute to a number of conditions including cancer but the antimicrobial peptide that I mentioned is expressed in the gut and it's important in protecting against infection in the gut and that's been shown in the number of animal experiments and vitamin D itself because it regulates this gene that brings up the question of whether it could play a role in protecting against infection in the gut and whether express regulating the expression this antimicrobial peptide could change the composition the gut microbiota there are some studies in mice that have a knockout of the vitamin D receptor that there are changes in the composition their gut microbiota however in mice this peptide is not regulated by vitamin D however we we think that there may be a connection there so vitamin D could affect expression in the gut and that could affect composition microbiota and that's something we're we're we are hoping to pursue with some funding so the antimicrobial peptide that is induced by vitamin D would recognize pathogenic bacteria in the gut but not helpful back now actually it's it's sort of indiscriminate and it's killing but bacteria different bacteria are have different levels of susceptibility whether you know that's a question we really don't know how how that would how that would sort of enter into it in other words it's fairly indiscriminate tends to kill both grand positive grand negative bacteria it'll also kill viruses and some fungi so all these things can be present in the gut it's possible though that where the the peptide is present in the lining of the gut once a bacteria or a pathogen tries to pass through that lining that layer it's going to encounter this peptide be killed so it's probably acting to keep things away but it's possible it's also secreted and and and depending on the susceptibility of a bacteria particular bacterium to this peptide it may or may not be killed by it and whether some pathogens are more sensitive that definitely some are more resistant but again it's fairly it's fairly unclear how this would work but we once we start looking at composition we can maybe get a better idea we have a question about formulation differences for vitamin D is there any difference in say a micro encapsulated vitamin D or a non micro encapsulated or any other formulations that may exist in the market well that's kind of out of my area of expertise some but I think that most of the formulations out there are taken out once you consume them they do get taken up you mentioned that it's important for the inactive form of vitamin D to be converted to the active form to carry out all these effects in the body and that conversion involves hydroxylation reactions in organs and the question is would vitamin C at all be involved in any of those hydroxylation reactions? I don't know of any evidence for that these are primarily carried out by enzymes and but a cofactor that is important is magnesium because it's magnesium is a mineral that acts as a cofactor for a lot of different enzymes and many of the enzymes involved in the metabolism of vitamin D require magnesium and so there are reports that adequate magnesium is important for vitamin D function and there's been cases there's been case reports of patients who are have rickets they get high doses of vitamin D but doesn't help them and when they provide magnesium to those patients it seems to correct the rickets so there's there's this interaction that goes on with these two factors. A related question to that or at least to the magnesium topic is are there other factors you showed that there's a wide variety or variation in plasma response to taking vitamin D? First question would be which is more important the amount of vitamin D you take or your plasma level and the second is are there other factors like magnesium that have been reported that influence plasma levels of vitamin D? Some interactions with drugs are also asked about. Let's see it's a long question let's see definitely there's like I showed there's a variability in how much what you take and then what your ultimate serum level is and that's probably due to a number of things could be environmental as well as when I say environmental it could be other nutritional factors or compounds that you're consuming and as well as your genetics and so there's definitely there definitely differences in genes we call them polymorphisms that are involved in vitamin D metabolism and function and so these can actually have an impact on on vitamin D and its levels perhaps. There are drugs such as drugs like anti-seizure medications and bile acid sequestration drugs and antibiotics like revampansin and even these compounds that affect fat absorption like orlostat that can also affect vitamin D levels so they may be lowered by by use of these medications or compounds. Let's see and there are medications that can make vitamin D less effective things like a torvastatin or lipotor also calcium channel blockers so there are a number of medications and you can actually go to websites at different say like probably the NIH or the LPI's website or I know the University of Maryland has a nice website on this but about medications that interfere with vitamin D or that you may not want to take we may may want to consider them when you're taking vitamin D supplements. Is vitamin D important for a healthy nervous system? Yeah that's another interesting area of research it does appear that vitamin D there's a number of studies a lot of correlational studies and observational studies of vitamin D deficiency has an effect on on aspects of memory and learning so I'd say yes again there's there with a lot of these health benefits there's probably a lot of research that still needs to be done to understand exactly how vitamin D is is involved in in those those different processes. So you talked about upper limits of dosing recommended by various organizations 4,000 or 10,000 I use a day but doctors often give levels that are 50,000 I use for people that are deficient to take in a week. Is this okay to do in a short period of time? Is there any known toxicity for these high doses for short periods or is it just a long longer doses or continuous doses that are the problem? Generally it's going to be continuous long-term levels like that so taking 50,000 IU for long-term is probably going to be a problem. The physicians not a physician but from what I understand when you go in with a deficiency and a physician wants to get your levels up they'll give you 50,000 IU of prescription vitamin D that's you I believe the vitamin D2 form which is somewhat different from D3 and because of its behavior it may be that 50,000 IU of D2 is less problematic than D3 because it does clear a little more rapidly but again that's just a speculation but they do that for about eight weeks and eight weeks is not generally going to lead to any problems there are there could be conditions that a person has certain disease conditions that could lead to problems and these are fairly rare but there can be they we call them granulomatosis diseases and they the common ones are sarcoidosis and tuberculosis so some others are Crohn's disease and eosinophil granulomas cat scratch disease and these diseases what they have in common is activated macrophages so you have these these macrophages are turned on they're ready to fight infection and like I showed earlier in that slide macrophages are actually very good at converting the 25 to 125 so if you have high levels of 25 these macrophages aren't regulated there's no there's no mechanism to shut down this production and so they'll start cranking out 125 and they're very good at it so they can raise your 125 levels to the point where that could be could lead to toxic conditions so in these rare events where someone has a disease like that it that would need to be considered before you would want to give really high dose vitamin D or you would might even want to monitor things like calcium levels if they're taking vitamin D supplements just to follow up on that briefly so there's no evidence to suggest that levels say 2,000 to 4,000 up the upper limit recommended by the Institute of Medicine have shown any toxicity they're generally safe yeah basically I mean that seems to be the consensus and the evidence for it is it's I have not run across evidence that those those supplementation levels are a problem and just to note humans can synthesize anywhere from 10 to 20,000 internationally it's a day in the sunlight and there's never been a report of people who spend time outside and synthesize prime maximal levels of ever having any sort of toxicity issues so I think it's supplementation levels like you're describing shouldn't be a problem and I'm not aware of any reports of that being again it could depend on your health condition and some of these diseases that could be an issue that I mentioned one last question okay is there anything known about the relationship between vitamin D status and environmental toxicity from things like lead or arsenic or other contaminants well there there are some associations with pollution and smoking leading to their associations of exposure to those things leading to or associations of low vitamin D levels with exposure to those things but actually it's interesting it's an it's a good question because it really hasn't been looked at all that carefully what the impact of exposure to some of these environmental chemicals has on vitamin D metabolism but there are compounds that affect metabolism so it again would be an interesting question to pursue