 Thank you everyone. So vitamin D is of perpetual interest in the ancestral health community because vitamin D is a key example of evolutionary mismatch hypothesis where under the conditions of our evolution, we spent almost, you know, most of our days through most of our lives outside where we had abundant access to the sun and of course we also evolved in a much more equatorial environment and now we're much more spread across the globe where we have more seasonal access to sunlight which provides vitamin D but we also spend most of our modern lives indoors and so regardless of what you think the ancestral vitamin D level might have been it certainly was higher than what most of us would have if we're not supplementing and if we're living indoor lifestyles and aren't careful to specifically go out and get vitamin D. And then of course, COVID-19 is of perpetual interest to anyone who's been alive since January 2020 because all of us just want it to go away and it won't. So therefore the topic of vitamin D and COVID-19 is of interest in any post 2020 ancestral health symposium. Now before the pandemic or at the time that the pandemic was emerging there had already been quite a body of literature suggesting that vitamin D is very protective against respiratory disorders in general and a lot of that research had been done on associations with colds and flu and it had included several randomized controlled trials showing protective effects of vitamin D against the flu. And so when the pandemic emerged it was a reasonable hypothesis for anyone to say well we know that supplementing vitamin D protects against the flu, it seems generally protective against respiratory disorders therefore we should all supplement with more vitamin D to protect ourselves from COVID-19. However, there were also reasonable reasons for caution. And so at the time that the pandemic emerged as I was studying the mechanisms and trying to understand how they might intersect with nutrition I actually had very strong reservations against supplementing with vitamin D. And although I didn't believe that anyone should try to make themselves deficient in vitamin D, I did initially come out and say we should be careful and probably shouldn't be supplementing with vitamin D to try to protect ourselves from COVID-19. And part of the reason for that is that the virus that causes COVID-19 SARS-CoV-2 infects human cells by binding to a protein called angiotensin converting enzyme two or ACE-2. And ACE-2 is from the perspective of human physiology, a an enzyme that is involved in protecting us from high blood pressure and promoting the health of the cardiovascular and respiratory systems. But from the perspective of the virus is just a convenient thing that it can use as a receptor that it can hijack to get into the cell. And so we definitely knew from the beginning that because human ACE-2 has the composition and shape that it has, this is the reason why this virus can get into our cells. And evolutionary mismatch hypothesis is not always necessarily the thing that's going to tell you how to protect yourself from a virus because viruses through their own evolutionary mechanisms evolve to hijack things that are good to do bad things to us. And so the virus evolving to hijack ACE-2 which is a protective enzyme from the perspective of our cardiovascular and respiratory systems is this virus evolved to hijack that and use it against us. And vitamin D as well as some other nutrients including vitamin A were shown in multiple studies prior to the pandemic to increase the amount of ACE-2. So it was reasonable at that time and I did come out and say this that we should be very careful about this because we could actually be increasing our risk of infection. Now some other people pointed out that when you get infected with this virus if you do get severe respiratory problems you actually lose ACE-2 function in the lungs and that's part of the disease process. And so they argued vitamin D might still be protective but there were reasons to wait and be very cautious about it. Now as research started to emerge one of the first things that suggested a protective effect of vitamin D were some correlations with latitude and incidence and severity where it seemed like latitudes with higher UVB exposure which is what is in sunlight and produces vitamin D in your skin had basically being in those latitudes was protective against getting COVID. Now that doesn't really tell you much because there's lots of things that could be confounding that observation but that combined with the known protective effect of vitamin D against respiratory disorders in general were both suggestive of a protective effect of vitamin D. Then when the first observational study came out of South Asia I started to cautiously lean in the direction of thinking vitamin D might be protective and that first three studies that came out all came out of either Indonesia or unspecified countries in South Asia and they showed very strong associations between vitamin D status and lower either incidence or severity or mortality against in the case of COVID-19. However, the first paper has since been retracted from the SSRN website which is a website that publishes preprints that which are basically papers that you can view before they've been peer reviewed. The second study has since been retracted from the SSRN website for reasons that are not specified. And the third study that came out has since been retracted from the SSRN website for reasons that have not been specified. And the authors of the second paper might not exist. So the second paper came out of Indonesia and these authors who wrote this paper also are from Indonesia and they're very familiar with the Indonesian medical system. So they looked for the hospitals that these doctors belong to and they looked for the doctors in every known possible way to search for people who do exist and are professionals in Indonesia. And they could find no evidence for the existence of the authors which may or may not play a role in why this paper has been retracted from the SSRN website. But notice that it says this paper has been removed from the SSRN website at the request of the author which is probably not true if the authors don't exist. Now these authors, they titled their paper, COVID-19 and misinformation, how an infodemic fueled the prominence of vitamin D. And their big complaint was that this paper despite the authors apparently not existing had been shared all over Reddit and all over Twitter. And now there is a pandemic of misbelief that vitamin D is protective against COVID-19. And notice their use of the word infodemic is basically saying, wait a second, you thought the virus was a pandemic? Wait until you see this misinformation that's telling everyone to supplement with vitamin D. Now, despite the first three papers being retracted and despite the authors of the second paper possibly not existing, this concern about an infodemic spreading misinformation about the protective effects of vitamin D in retrospect now seems histrionic and irrelevant because there are now 96 observational studies on vitamin D and COVID-19 from all over the globe by authors who are known to exist studying it in hospitals that have verified existences. And there are six published randomized controlled trials. There are 12 completed randomized controlled trials that have not yet been published. And there are literally dozens more randomized controlled trials that are currently registered at clinicaltrials.gov or by other countries clinical trial registries. So although these overlap in time, I'm gonna start by reviewing the 96 observational studies that cover up until, and there's probably more than that now, but this covers the data up until the end of last week as I was preparing my presentation. Now, if they're in a 30 minute plus 10 minute question talk, if I'm gonna try to cover 96 observational studies, the ideal thing to do would be to show the pool data in meta-analysis. And so, unfortunately, there's a three to six month lag in the publication of meta-analyses. And so I actually found that between the most recent meta-analyses, I read 11 meta-analyses in preparation for this talk, I'm gonna show you the results of the three most recent ones. And I found that there were since 54 new observational studies published between the most recent meta-analysis from the end of July and the end of last week. And so I'm gonna try to summarize those for you as well. But here's a meta-analysis that limited its coverage to peer reviewed papers and didn't include any preprints. And what they found was that there was a 3.3 fold, okay, so 3.3 fold increase in the odds of infection, a 5.1 fold increase in the odds of having a severe case and a 60% increase in the odds of mortality. And unfortunately, the mortality studies were not statistically significant. However, notice that there's an obvious discrepancy here where how do you get a, how do you, if this is a real causal effect, it's basically suggesting that vitamin D gets rid of 80% of the severe cases. How do you get rid of 80% of the severe cases and only have such a small statistically significant 60% effect, relative effect on mortality? That's obviously not representative of what's actually going on. What it's representative of is that there's a lot of infections, there's relatively much fewer severe cases, and then there are far fewer cases of mortality. And there are also fewer studies. So we're going from 13 studies with 2,504 people when we're looking at the odds of a severe case, but there were only seven studies with 1,127 total people that even reported mortality. And so because we have fewer studies and because there are fewer people who died, we are not able to statistically investigate this with as much rigor as we can with the odds of a severe case. Now, another notable thing about this paper is that it only included deficiency, only included studies where they define deficiency as under 20 nanograms per milliliter of 250 HD, which is the key marker of vitamin D status. Now this meta-analysis, from published around the same time, has some benefits and limitations compared to the last one. So this one, as you can see up in this description towards the top, they pooled studies that define deficiency as 20, 12, or 10 nanograms per milliliter. And when you pool those different definitions of deficiency, you do lose some precision, but it also allows you to cover more studies with more people and therefore get a more statistically robust effect. Another fault of this, one limitation of this meta-analysis, though, is that it did include preprints, which are papers that have not yet been peer reviewed, and it included two of the three papers that have since been retracted, including the one whose authors might not exist. And so what you're seeing here is on the left, two panels, you're looking at odds of a severe case, and on the right two panels, you're looking at odds of mortality. In the first example of each panel, you're looking at the total pool data, and in the second case of each panel, you're looking at, after they removed sources of heterogeneity. And what that basically means is, they looked at the data and they said, is it consistent? And they said, our statistical test tells us that this data's kind of all over the map. And then they said, okay, which studies are creating the inconsistency? And then they took them out. Now, that's not what you're supposed to do with heterogeneity when you find it. What you're supposed to do is try to explain it, or say there's too much inconsistency, we're not gonna pool the data. So they're not supposed to do this, but this is what happened when they did. So what they originally found was a 4.6 fold increase in the odds of a severe case. If they removed the sources of heterogeneity, it went down to 2.5 fold, and it stayed statistically significant. There was a 4.9 fold increase in mortality that was almost statistically significant, but wasn't. And then that went down to a 30% increase in mortality that was not even close to statistical significance when they removed the sources of heterogeneity. Now, in the first case of severe cases, they removed the first paper, which had been retracted. I support removing that paper. But they also removed a paper that showed that it was the only single paper in this whole meta-analysis that looked at deficiency as below 10 nanograms per milliliter. Well, of course, that showed different results than the papers that defined it as below 20 nanograms per milliliter. And that's a legitimate source of variation that they should have kept in the data rather than taking it out. On the right, they basically did the same thing. They removed the paper whose authors might not exist. I support that. But they also removed that other paper that was the only one to define it as less than 10 nanograms per milliliter. And so I think basically what, the reason I'm showing you this is because when they looked at mortality, when they had the pool, the total pool data, they did show a five-fold effect in mortality. The fact that it was statistically significant is that, again, just reflecting the fact that we have fewer cases of mortality and fewer studies, so it's less statistically robust, but it seems like it's a real effect there of similar magnitude. Now, this last meta-analysis I wanna show you is I'm showing this basically just to drive home the point that there does seem to be an effect on mortality that's similar in magnitude. So on the left, and they didn't pool these results together, but on the left, they showed the studies that defined it as 20 nanograms per milliliter or lower, which showed a doubling of mortality. And on the right, they showed the studies that defined deficiency as less than 30 nanograms per milliliter, and they showed a three-fold elevation in mortality, and this was statistically significant. So the point is that our ability to show a roughly two to five-fold increase in mortality right now is largely limited by too few studies with too few people. Depending on what angle you cut at it, you do see that it's probably there. Now, in the 54 studies that have came out since the most recent meta-analysis, I am not qualified to do a meta-analysis, so I didn't, but I tried to characterize them over the next two slides by just saying, are these telling us roughly the same story as the previous batch of studies included in the meta-analyses, or do they look different? So the first way I asked that question was, how many of these are suggesting, yes, there's a protective effect, versus no, there's not, versus what I characterized as ambiguous, which meant if they adjust for this, the effect's there, if they adjust for that, it's not. If the results were unclear, I defined it as ambiguous. And what you can see is that it's pretty similar. So although the percentage before, included in the meta-analysis that have a protective effect went from 81% to 74%, that's largely reflected by the fact that there were three, let's see, it's on the bottom. If the percentages had stayed the same, we would have seen 44 protective studies, nine with no association and one ambiguous. So we basically have one more study than we would have expected with no association and three more that are ambiguous. And I ran some stats on this and it's P equals 0.5, so it's not even close to significant. So what that tells us is that the next half of the studies that haven't been included in meta-analyses are basically telling us the same things as the previous batch. And then I also looked at the magnitude of these effects and the details of how I characterized the magnitude, I basically assigned a score to these based on how big was the effect. But I scored them one through six and you can see that for infection it was 2.6 versus 2.5, for severity it was four versus 3.7, for mortality it was 4.7 versus 4.1. That's basically telling us that the magnitude of the effects are pretty much the same in the 54 studies that have been released since those meta-analyses. So my overall conclusions from these observational data are that it looks like there's a two to five fold increase in risk or odds of having a COVID-19 infection or a severe case or mortality. And although the 95% confidence intervals which means 95% probability the effect is somewhere between these two points. Although they go up to 10 for severity and to 30 for mortality. And although mortality's not always statistically significant so far because the results are similar as they continue to come out and because there's so many more studies now I think what we're going to see is that we're gonna converge around this two to five fold increase in infection severity and mortality and that the results are gonna be statistically significant across the board. However it's important to note that the majority of these studies are rated as poor in quality at high risk of bias and none of these studies tell us cause and effect relationships about whether vitamin D is protective or not. In order to answer that question we're gonna need to look at randomized controlled trials and there are six and I'm gonna get to those soon but first I wanna highlight some interesting observations from the observational studies. So right here I'm showing you the set of studies that have tried to say what's the cutoff where we can use 250 HD as a marker to predict someone's risk of having a severe case or in most of these cases dying of COVID. And one of the ways that they look at that is to look at the sensitivity and specificity. Sensitivity is can we find most of the people who are gonna die? Specificity is can we try to avoid predicting someone's gonna die when they're not going to? And so wherever you can try to maximize those two things find everyone who's gonna die. Don't tell people they're gonna die when they're not. Then wherever that optimum balance is you say that's the best cutoff. And so if you look in the third column here for cutoff you see that generally speaking these studies are converging on a point that's somewhere between nine and 25 nanograms per milliliter. That doesn't mean that's the only place you wanna be above. It means somewhere where the severe danger zone is where we can predict yeah you're probably gonna die is somewhere in that range of nine to 25 nanograms per milliliter. This second slide is looking at nine ecological studies. And these are not the best studies because they're looking at population level vitamin D status and they're looking at population level infection severity or mortality rates. And COVID doesn't happen in populations it happens in individuals. However these are interesting from a public health standpoint because if vitamin D status in the population explains 60% of the COVID mortality then from a public health standpoint you probably wanna get your population's vitamin D status up. And what you can see is that these generally come to different explanations of how much of how much of this is explained. But in the top three studies they used the mean 25 OHG of the population which is not the best metric to look at because it doesn't explain the distribution. So for example if there's a lot of people who are below 10 nanograms per milliliter you're probably gonna have a lot of people that are in that danger zone that I just showed you. But if there's a bunch of people who are at 80 nanograms per milliliter they bring the average up but who cares because it's the people under 10 nanograms per milliliter who are all likely to die. So you can see that these estimates are between 12 and 26.7% of the explanation for infection severity or mortality. And they're on the lower end of some of these. Now the only paper that found that vitamin D did not explain this pooled together populations that where deficiency was defined as less than 12 and where deficiency was defined as less than 20. And in my mind they didn't find any association because they were pooling data that was too variable. Every single other study did not do that and every single other study found that vitamin D status in the population predicts infection severity and mortality. Another thing that's interesting here is this paper over here which looked at 24 Asian countries and they found that if they adjusted for age and obesity the explanation level went from 30 to 56% for infection and from 25 to 41% for mortality. And then this study right above it Papa Dimitriou et al. They found that if you control for the life expectancy in that country, then vitamin D status explains 63% of the mortality rate. So I think that generally speaking if you're gonna define deficiency correctly and if you're gonna control for age, obesity and life expectancy, you're looking at vitamin D status at the population level is explaining the vast majority of variation in the mortality rate. Now this study is probably the single most interesting observational study there is. This looked at every single person in the United States who had a quest diagnostics test for COVID and who also had a 250 HD anytime in the preceding year. The sample size for this study is over 190,000 people. The sample studies for the odds of infection that I was showing you before were at a few thousand people. So this is looking at 20 times the number of people that were included in any of those meta-analyses but also people who got serial COVID tests could be included as infected if any of them tested positive. So although it's retrospective they're looking at 250 HD in the year leading up and they're saying okay, you got tested for COVID 10 times because you traveled, you got infected therefore you count. None of the other studies could do that because they're looking at people who were infected at the time of the study and not did any time over this pandemic did you get infected. Now what they found was that when you controlled for age, sex, latitude and seasonality of the measurement of 250 HD and race then 250 HD predicted 96% of the variation in who got infected and who didn't. That suggested vitamin D status was almost the entire explanation of who got infected and who didn't which is way more powerful than any of the other studies had suggested but this is a massively higher sample size with a much better design. Now the other interesting thing is very few studies had more than like seven people or maybe 40 people who had vitamin D status over 40 nanograms per milliliter but here they had 4,000 people between 50 and 59 nanograms per milliliter and they had 8,000 people who were 60 nanograms per milliliter or higher. So they were very much able to say what happens when you go above 30, 40, 50 nanograms per milliliter and what they found here if you look at the graph on the left here the zigzaggy line is like in each category and then they smooth the line so if you just wanna get a sense of what's happening overall you look at the smooth line that goes down here and then it bottoms out at 55 nanograms per milliliter. Now that doesn't mean you don't get infected that means you have a 6% risk of getting infected but it's very interesting because for every one nanogram per milliliter that you go up your infection rate declines 2% until you get to 55 nanograms per milliliter and that explains 96% of whether you got infected or not. A few other things. Okay, let's say you're at 55 nanograms per milliliter so your infection risk is 6% and that's the lowest you can get but it's not zero. What happens? Do you wind up in the hospital or not? And the data on this are way too sparse to form any conclusions but the data I'm showing you are just to show you that just because you have 55 nanograms per milliliter is not gonna stop you from dying of COVID, unfortunately. So in this paper, hospitalized is on the left, non-hospitalized is on the right and what you can see is there's seven people representing these histograms that are over 40 nanograms per milliliter or higher, five of them were hospitalized so being that high does not keep you out of the hospital. This study provided vague low confidence suggestion that being over 40 nanograms per milliliter won't guarantee you stay out of the hospital, why? Because everyone shown in this graph was in the hospital but if you look at over 40 nanograms per milliliter what you see over here is the people who were just hospitalized instead of being in the ICU were basically everyone over this certain point. So all these people at the top here have the highest vitamin D status and none of them are in the ICU. So there's some point right around here where there's a handful of people that were kept out of the ICU. So this study has so few people up there that doesn't really tell you anything but again, it does show you that vitamin D doesn't keep you out of the hospital as a guarantee. So in this study, this was everyone who went to the hospital in New York City to the Mount Sinai Health System during the height of the pandemic when wherever you lived there were ambulances going by your apartment nonstop all day long and there were over 400 people dying of COVID every day. So what they found here is that the only people who had an increased risk of mortality that was statistically significant were the high bar on the left who are less than 10 nanograms per milliliter and nothing to the right of that is statistically significant and although it looks like there's an increased risk of mortality above 30 nanograms per milliliter that's completely inconsistent with almost every single other study so I wouldn't read much into it. However, what this does show you is that, excuse me, is that there were some, in this study there were 65 people who had over 40 nanograms per milliliter and quite a number of them died and so the mortality rate there is about 30%. So having high vitamin D status over 40 to 60 nanograms per milliliter does not stop you from dying of COVID or keep you out of the hospital as a guarantee. Now we saw before it's associated with a decreased risk of severity and mortality but again that doesn't mean, what my point here is just that severity and mortality never goes to zero. That's what I'm saying. So it's reduced, it just never goes to zero. Now there are vague hints of a U-shaped curve with mortality above 100 nanograms per milliliter which is generally defined as a toxicity range from this paper in, where was this, in Iran. And here although the only thing that's statistically significant is that mortality rates highest in less than 10 nanograms per milliliter it still seems to go almost as high over 100 nanograms per milliliter so you probably don't wanna go up that high. Five minutes till the end of the block or till ideal question time. Okay, okay, I'll go kind of fast. Okay, so conclusions with the observational studies are that the lowest risk of infection is around 55 nanograms per milliliter. If you do get infected there's no evidence that being above 40 nanograms per milliliter is associated with a lower risk of severity than being in the 30 to 40 range. Being in the 30 to 60 range doesn't provide you a guarantee against hospitalization or death but being above 30 nanograms per milliliter in general is associated with the least risk of severity and death. Little is known about higher levels than that but there's some suggestions things could get worse above 100 nanograms per milliliter but right now we are not yet looking at causality. Okay, we know that one of the arguments against causality is that infection and inflammation decrease vitamin D status. So maybe you're just looking in most of these cases as people are getting their vitamin D status depleted because they have a severe disease. And we know two studies that showed that your vitamin D status does decline between your last measurement and when you came into the hospital for COVID by 42%. And one study that showed that the prevalence of people with sufficient vitamin D dropped five-fold just over the course of three days of being in the ICU. But the fact that 250 HD is a negative acute phase reactant meaning it goes down in inflammation is not an argument against protective causality because why is it being depleted because your immune system is using it to support immunity. I'm gonna skip over some slides that I had because I don't have time and I wanna head into the randomized controlled trials. So this is a living meta-analysis that will be published every time the Cochrane group will update their conclusions based on new RCTs. And in this meta-analysis there were three RCTs that were included. One was published in Spain that looked at the effect of oral 250 HD. So not vitamin D, but the actual metabolite you measure in your blood. Give that orally, what does it do to 28 day mortality in ICU? The second one was studied in Brazil and it looked at the effect of a single high dose of vitamin D on the length of a hospital stay. Now there were some other studies after and in this meta-analysis that they didn't really pay attention to because it wasn't looking at their key endpoints that I'm gonna ignore. And a few published census meta-analysis that none of them are better than these two. So because of I don't have time I'm gonna ignore those as well. And I just want to show you the two most important trials. So this meta-analysis basically came down to a showdown between these two trials and really the state of the evidence has not changed up until now. So in the Spanish study they had 76 patients that they were treated with other things that were standard at the time. And they randomized the people to give oral 250 HD or to a control. It was blinded to the people who decided whether they went to the ICU but and the doctors and patients weren't told what they were taking. The nurses were giving them their meds which may or may not have included a 250 HD capsule. They probably didn't know whether they were in one group or the other because they're getting a handful of meds. The doctors could have looked it up in the electronical health records. So they did have access to the information even though they weren't told. So this was not a perfectly blinded study but neither the patients nor the doctors were the ones who decided whether they went to the ICU. There was a committee of people who were totally blinded who decided whether they went to the ICU and the statisticians and data analysts were all blinded as well. And this found that 50% of the control group needed the ICU and 2% of the treated group needed ICU which was a 98% reduction in the odds of going to the ICU. And there were two deaths in the control group and zero in the treatment group. On the other hand, the Brazilian paper had people come in to the hospital. They randomized them to 200,000 IU single high dose of vitamin D or placebo. It was very well blinded and there was no effect on the length of hospital stay, ICU admission or mortality. Now because of the imperfect blinding on the left, the Cochrane group did say this has a slightly higher risk of bias than the other study but I wanna highlight more important differences. So in the Spanish study, treatment started on average seven days from symptom onset and on the day of hospital admission. They didn't say if anyone needed respiratory support on the day of admission but it wasn't a criteria for inclusion and they didn't report anyone needing respiratory support. Oral 250 HD takes five hours to maximize your blood 250 HD. So blood 250 HD was maximized at time of hospital admission five hours later on day seven when to our knowledge, no one yet needed respiratory support. In the Brazilian study, treatment was started 10 days from symptom onset. Respiratory needing having respiratory distress was the major inclusion criteria. 90% of the people on the day of admission already needed oxygen support and it takes five days for vitamin D supplements to maximize 250 HD when giving a single high dose when you don't have an inflammatory disorder but because inflammation hurts the 25 hydroxylation of vitamin D it will take some longer time than five days to maximize that. So somewhere between day 15 and day 25 in people who are half dead of COVID a single high dose of vitamin D didn't do anything. But if you look at these two studies it's far more likely that early boosting of 250 HD before you're half dead very quickly leading into this is what decreases your odds of ICU by 98%. It's far more likely than that than that the patient figured out there was an extra capsule in the handful of things that the nurse was giving her and the doctor looked it up in the electronic health record and then somehow convinced the data that went to the blinded ICU committee that these people are on vitamin D therefore they probably don't need to go out to ICU even though they're dying. So it's probably about early treatment and good ways of getting the 250 HD up. So I'm gonna skip ahead to the conclusions. One of the things from this are that while the threat of COVID-19 persists actively maintaining 250 HD in the 30 to 55 nanograms per milliliter range is likely to protect against getting infected. Maintaining in D in this range will also prevent a five or more day delay in the ability to quickly raise your 250 HD with vitamin D supplements if you do get sick. If you take the Spanish paper and convert it into daily oral vitamin D supplements then it's the equivalent of 30,400 IU per day in the first week followed by a maintenance dose of 7,600 IU per day until symptoms resolve. Now in that area in Spain, the average 25 HD is 16 nanograms per milliliter. If you're at 55 when you get COVID you can probably skip the loading dose in the first week. However, I wouldn't be quick to dismiss the value of having a higher loading dose in the first week. And so based on, I actually got COVID last month and it was based largely intuitively I used 20,000 IU of vitamin D during the first per day during the first week and dropped it to 10,000 IU during the second. But I would emphasize that if you're trying to get biological activity as high as you can as soon as you get sick early in the sickness you actually wanna start the loading phase when you sneeze and you say maybe it's COVID because if the next day you're no longer sneezing anymore, who cares? But if the next day all of a sudden you're wheezing and the day after that you have 104 fever then you're gonna wish that you did the loading dose three days earlier. Now I do wanna, the last thing that I do wanna say is as all the other RCTs are published we may revise how we view this but this is the current state of what I believe. And I also would balance vitamin D with other nutrients in the diet especially A and K2 and you certainly don't wanna be deficient in anything in that context but that's what I have for you today. We are officially on break. Chris, would you like to answer questions, five minutes? Yeah, I can answer questions. If the board would allow me, five minutes of questions so if you want to switch between both microphones. So is there any data for those that were within that perceived optimal range if they did get infected? Was there any, what was the outcome for post COVID symptoms? There's almost nothing on post COVID symptoms. The only thing there is is a paper that pooled, actually it's not even worth looking at. The only paper that looked at vitamin D status and post COVID symptoms pooled long hauler symptoms with hospitalized cases and looked at a correlation. And so there's basically nothing. Okay, thank you. Hey Chris, fantastic to the group and to you Chris. Have you heard Dr. Fauci mentioned taking vitamin D at any point? Yeah, I heard Fauci comment on taking vitamin D way before he said he takes vitamin D. And personally, right, but it hasn't been part of whole country taking vitamin D. Well, I mean, he hasn't advocated anything based on these trials, but he did say that he did, someone asked him about taking nutrition in COVID and he was like, well vitamin D seems helpful, but yeah. It was a deficiency and he didn't say anything. So a couple of questions. Does anyone know whether the population of meat eaters versus the population of vegetarians have a dramatic vitamin D level difference? I don't know, but the only observational study that looked at plant-based diets showed that people on plant-based diets did better with COVID. Oh you're right. Really? I mean, not that I would read much into it. The cytokine storm is in fact less active in their immune systems, possibly. Yeah, possibly. Okay, thank you. Possibly. Yeah, would you consider varying a dose if you were somebody who spent a lot of time out in the sun versus, I mean, without knowing what the baseline your blood of. In the context of a theoretical future risk of infection or in the context of getting sick? Maybe both. Well, I mean. Without understanding what your baseline is. In the context of future risk of infection that I don't really think it, you want to think about it like that. You really want to think about it like get a vitamin D test. Did I get it up to the 30 to 55 nanogram per milliliter range and whatever combination of sun and supplements does that. In the context of getting sick, I think there's not even really a hypothetical downside to oh, you added an extra 4,000 IU from your sunbathing today. So I would ignore it and just focus on oral supplements. The chance of getting up towards 100 would be relatively nil. I mean, if your baseline was 50. In the context of an acute dose, during the time of infection, I wouldn't even worry about it. I mean, there's only a vague suggestion from an observational study that above 100 is a risk. But if I were to hypothesize why it would be a risk, I would hypothesize that it was chronic exposure to hypercalcemia and not, oh, it popped up to 100 today, therefore I'm at risk. Okay, thanks. Hey, Chris. Just wondering for 25 hydroxy vitamin D, is there like a proposed mechanism or do we already understand the mechanism of like how that interacts with the immune system and why there seems to be a risk to get that? I had a whole slide on this, but it was I hadn't gotten to the RCT yet and only five minutes left. So I mean, I personally think that probably the main way that it's restricting severity is by restricting IL-6 levels. There's some correlational, like scant correlational stuff in COVID studies, but there are RCTs from other contexts where generally with disorders that have IL-6 that can go very high, vitamin D does reduce it and IL-6 is the main predictor of needing mechanical ventilation in COVID. And vitamin D also increases lymphocytes and high lymphocyte, low neutrophils are one of the best markers of overall better prognosis. But generally speaking, calcitrile, which is the active hormonal form of vitamin D acts on immune cells to stimulate the production of antimicrobial peptides to increase immune activity in a way that favors anti-infective activity and generally modulate immunity in a way that prevents autoimmune type or cytokine storm type activity. Thank you. Hi, you've written at length on the importance of balancing D with other vitamins like A and K and how they synergistically work together. Is there a danger in recommending that people front-load with D supplements in isolation of other things in advance of getting COVID or is this too short? Well, I did mention that at the end very briefly. And actually I have, there's some caveats listed right here in this slide that I didn't get to before. But yeah, I mean, I think that you wanna balance vitamin D and vitamin A and K2 and there's some important interactions as zinc and magnesium. And so I think that's important both on a chronic level but also vitamin A levels are depleted in severe COVID cases. There's almost no research on it but the research that's there suggests vitamin A levels are depleted in severe COVID cases. And there's also a couple of studies that came out of the Netherlands suggesting that vitamin K stat is a blood vessels when it's poor is a predictor of worse outcomes. So I do think that balancing them together is the right thing. I got COVID last month and I matched my vitamin D dose to one to one with vitamin A in terms of IU, not in terms of micrograms. And I supplemented 200 micrograms of K2 and also 40 IU of vitamin E. Thank you so much. Everyone.