Apiery

Why are enveloped respiratory viruses generally seasonal? A few of the potential explanations: Outdoor temperature/humidity Indoor humidity More time spent indoors in winter Adaptation to the seasonality of the host's physiology Outdoor conditions make a lot of sense for wild hosts, but we live climate-controlled 93% indoor lives. Extra time spent indoors in winter can't matter all that much since that's where we spend almost all of our time anyway. Indoor air is significantly drier in the winter thanks to heating. Furthermore infectivity of droplets goes up very sharply as humidity is lowered below 40%. This is at least roughly where it would be expected to. So problem solved. We don't even need to look at that last option do we? Of course we do! No one ever said there was only one option. In fact there almost never is only one. Evolution is messy and it always hill climbs its way up along every dimension of freedom it has. DNA is just big long strings of base pairs, and any of them can be changed. So adapting to seasonal changes in the host must happen. The only questions are how much it matters and whether it contributes or detracts from seasonality. Turns out there are a thousand lines that suggest it favors seasonality and by a respectable amount too. Here's one that is unconfounded by any other reason: "In a double-blind placebo-controlled trial conducted in the Soviet Union during different seasons, nonimmune volunteers were given attenuated live influenza vaccine intranasally. Febrile reactions attributable to vaccine(calculated by subtracting the proportion of participants with reactions in the placebo group from the proportion in the vaccine group) were observed in 6.7% of 360 volunteers inoculated in Leningrad in January, compared with 0.8% of 197 inoculated in June (p = 0.003). Fourfold rises in antibody titer were seen in 31% to 40% in Krasnodar in January, depending on the vaccine strain, compared with 4.3% to 4.8% given the same strains in May and October (all p <0.001). Similar trends with less significant differences were seen in three other cities." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631809/ TLDR: Inoculating soviets in the summer avoided fevers and prevented the adaptive immune system from learning how to recognize the virus quite as well. If we are certain that everyone was infected then the cause must come from within the summertime host and not the wintertime one. Potential mechanisms for how aren't hard to come up with. So instead lets ask, 'Can we find reasons that explain why?' What is the evolutionary purpose of the seasonality of enveloped respiratory viruses? ERVs evolved outdoors and weather conditions result in an evolutionary preference about when to spread and when to simmer. Conditions below room temperature freeze their lipid envelope into a semisolid fatty shell. This is butter-clad armor; it helps them spread. So it is more cost-effective to proliferate in the winter. But what sort of coin pays this cost? Nonimmune hosts are a scarce resource. Hosts come in herds, herds are easy to propogate in until you run out of hosts. A frugal virus conserves hosts until fall when it has the best chance of spreading to new herds. The seasonal change in host immune tactics is the signal it takes advantage of. An upregulated adaptive immune system is easy to taunt into coughing. All it has to do is let the innate immune system keep its numbers in check during the spring and summer. The thinned numbers helps it avoid adaptive detection. This stretches out each host. Infection is asymptomatic, so no coughing and so less propagation. This stretches out each herd. The evolutionary game theoretic analysis has an equilibrium because the host's choice of tactics has a cost to it as well. Boosting innate immunity is like posting a guard at every corner and guards cost food. Stable play in the winter involves the host upregulating costly defenses to honestly signal to the virus whenever it is provoking the immune system too much. The virus prefers to not kill what could be a parent of future hosts. Virus and host come to a compromise. There are quite a few different costly signals that hosts can use. Fevers cost energy. Inflammation costs damage. All of these things are also inherently effective, they actually do things that kill viruses. It isn't just a request. But if a virus wanted you dead, you would be dead. They evolve so much faster. Fortunately the only way I can see this happening is if your species competes with a species they strongly prefer as hosts. Usually though before your kind is completely wiped out a strain of the virus will speciate. They then quickly adapt to play mostly nice and your species gains a symbiotic guardian whose purpose is to keep your immune system capable against its murderous parent. This is a charitable view of viruses as akin to militant warlords competing with one another for host species, ie territory. Like any military, they only have to exist because other militaries exist. What would a 'preferred host' look like? How about one that doesn't aggressively fight off viruses, yet never gets particularly sick from them, hibernates, lives in giant closely bunched herds, flies, lives everywhere, and is more diverse than any other mammal order besides their flightless cousins? Why, it's the goddamn bat's man! Ok yeah, my jokes aren't bat great... Anywho, bats seem like some kind of ecological appendix but for viruses and not bacteria. It's a bit of a mystery how their viruses remain so well-behaved. Bats can't signal to a virus when it is overstepping via fevers because they already get that hot every evening because flight is so demanding. Nocturnal frugivorous bats are completely disconnected from the vitamin D ecology. So no signals there either. Do they just have more effective innate immune responses always at the ready? This next paragraph is very speculative but intriguing. I wouldn't put too much stock in it. COVID-19 made the jump from bats to humans possibly stopping for a bit of pangolin on the way. Pangolins, with their body's perfectly covered in scales and a thriving on a diet of nothing but ants, make me wonder how their vitamin D system works. I wonder if anyone really knows. I also can't seem to quickly find any estimate of how much vitamin D is in a gram of ants. Anyways, if COVID-19 went from bats to pangolins and if pangolins are a bit idiosyncratic w.r.t. vitamin D then this could be expected to result in a virus which has not yet re-tuned itself to live once again in a vitamin D-typical host species. Add to that high levels of human deficiency and you have a recipe for a disease which might respond dramatically to improvement in D status. Let's look at our vitamin D system. Dietary D3, cholecalciferol, seems to immediately predominantly partition itself into our lipid fraction. Thus it is doubtful it has any activity itself. It seems to simply be a buffer storing and smoothing our supply. Calcitriol is thought of as *the* active form, but I think something important may have been overlooked. Calcitriol is indeed the form that activates the vitamin D receptor but I think that it's precursor, calcifediol, may deserve similar recognition. Calcifediol is an inhibitor of VDR. I don't know if it is potent enough to matter but let's assume that it plausibly might be. There are half-lives associated to each of the 3 reservoirs of D and they are nicely spaced out. This suggests to me that there may be two signals. That's when I found out that calcifediol was an inhibitor. The fluctuation of calcitriol level will trail that of calcifediol because it is made from it. The combination of a time-delayed agonist signal and a more immediate inhibitor signal allows our chemistry to derive what is effectively a time-delta of the agonist signal. That is, VDR expression can react to not only the level of calcitriol but also the rate of change of that level. There is a problem though. The signal would be very weak given how closely -triol tracks -diol. Fortunately this is no issue for the ever clever evolution. The VDR actually significantly upregulates its own expression! This is an unusual feature; we expect biochemistry to predominantly favor stability. However such homeostasis would dampen the time-delta signal. Because of this self-upregulation the impact of both agonist and inhibitor are amplified. Is this something that is known to happen elsewhere? About 2 hours ago I realized that this means that you can simulate the signal that winter is becoming spring by administration of the inhibitor. A sudden dose of calcifediol in someone deficient looks like if you went instantly from a winter pallor to a summer sunburn. The significance of this is that if enveloped respiratory viruses are generally attuned to the vitamin D host seasonal status responses then this wouldn't merely just signal to the virus that winter has ended, it would scream it. This is a signal that is impossible for our natural physiology to make. There was a pilot RCT that did exactly this for COVID-19 pre-ICU patients some months ago. Its results were literally too good to be believed. I am writing this today because the medical community has been largely dismissive to the very possibility that the study observed what it claims. No one wants to talk about it. I think it just doesn't smell right to many an epistemic nose. I personally can't see any reasonable way for the study to be anything except either fraud or truth or a 7.7*10^-7 ≈ one-in-a-million fluke or something I personally can't see. Please excuse the tautology. Lately it feels like vitamin D has been vitamin disappointment. Add to that the idea of effectively completely treating an infectious disease with a vitamin. It's no wonder people are so skeptical, and rightly so. Medicine and nutrition are incredibly epistemically noisy fields. However I sincerely believe that diligence is due here. In this case its not just the same old parable of the society who called 'wolf!' one million times too many. This time the cry happens to be a surprisingly detailed description of a wolf. If you agree with me that it should be talked about even if only to make a cogent counter-case, I encourage you to please share this with a peer or maybe a superior and spark a discussion. We are in bystander effect territory. Those who feel the same as I have been trying to figure out how to call the police but there doesn't seem to be anyone who will listen. If you know the right number for me to dial please tell me. I really want to be able to go back to my mathematics. Thank you for your time. Resources: A summary of evidence both pro and con An in depth analysis of the pilot RCT An excellent philosophical treatment of the decision theory

My bones grow best in the season when food is plentiful, how are yours? Fun fact: The same process that grows bones actually goes in reverse if there isn't enough calcium in the diet.

Vitamin D's primary role is to allow gene expression to vary with the season. Do seasonal respiratory viruses make use of this seasonal variation in host tactics? Let's call this hypothesis H. We don't need evolutionary game theory to consider H plausible, but such a model will be sketched below. We know that virus droplet vectors lose effectiveness in warm and wet conditions. It is widely believed that this physical limitation is what accounts for their seasonality. Let's call this hypothesis W. W is in considerable tension with our modern climate-controlled overwhelmingly indoor lifestyles. Why should it depend so strongly on the weather when we are almost all most always indoors? Perhaps then their seasonality really could primarily be caused by the vitamin D status in the host? There are certainly plenty of physiological changes induced by it to potentially entrain to. Let's call this hypothesis D. D is just one pathway in which H might occur. Multiple pathways can occur at once. We should be interested in whether H by means of D is a better explanation than W. The COVID-19 pandemic is a tragic crisis but the wealth of information it provides gives hope. Close examination of the resulting global scale natural 'laboratory' suggests that COVID-19's spread does not depend on weather. Again another tension with W. Is there a convincing W compatible alternative explanation given out there? If not why shouldn't we just suppose D is likely? The biologically active form of vitamin D is calcitriol. It fits like a key into the vitamin D receptor which then tweaks the mix of proteins that are made by the cell. Many changes then happen but the innate immunity is the immediately salient choice for primary channel through which information would flow from host to virus. A test screening for chemicals active against COVID-19 found that calcitriol was active. This is interesting because it is a fairly inert chemical. Does it directly chemically assault the virus? Perhaps by undermining the integrity of the envelope? That's what I had been unthinkingly assuming until thinking about hypothesis D made me realize that another possibility was on the table. Unfortunately I don't have the required background knowledge to even understand what the experimental setup is here. Would someone kindly explain it to me? I would be most appreciative. I am thinking that perhaps it is actually direct laboratory evidence that calcitriol induces changes which effectively signal 'slow down' to the virus. Ok, what's with all of this anthropomorphic talk about signals and such? Well might intuitively think of us hosts as somehow in competition with the virus. But the hosts are really the environment for the virus. Does it even make sense for an environment to be in competition with its organisms? The proper analogy is not one of competition among peers but one of communication between entities which are mathematically *dual*. A host environment is dual to a herd of viruses. By dual here I simply mean that we can swap the roles we choose to see them as. Whatever is filling the role of an environment factor becomes a herd instead and vice versa. But of course we already know this because we normally think of hosts as organisms and organisms come in herds. And it's quite normal to think of a virus as a factor in the fitness environment for a herd of organisms. Herds and their environments must communicate and they do so by changing the fitness landscape of one another. This actually works whether or not the environment is itself entirely biological. Thus ecology arises. Ecology is the fully self-dual perspective on evolving systems. This is all part of the evolutionary game theoretic perspective on viruses. The math is quite beautiful. The real world point is just that we a priori expect to see how the host environment communicates to the virus by seeing how it culls the virus herd either directly or indirectly. The direct channel is the one with the highest bandwidth. I contend that for the above basic (yet deep) reasons that, in this case, it is the change in seasonal fitness landscape of the vitamin D innate immunity vs. adaptive immunity which most efficiently conveys what season it is outside to a virus restricted to looking for cues from the inside. I mean what's your thermostat set to? Seems a might strange that the virus doesn't seem to behave the same all year around when the thermostat hardly moves throughout the year. If the innate immunity keeps numbers in check then the adaptive immunity will accumulate information about the adversary more slowly. This lets the virus conserve hosts in its lean summer times when its droplets spread poorly. In the winter it can spread efficiently to new herds by inducing the host to cough by provoking the adaptive immune system. The fundamental physical temperature and humidity limitation of droplets is what ultimately gives the virus a season dependent preference in tactics. This all works smoothly when infecting a usual host. When crossing between species the tuned balance of the host/virus ecosystem is thrown out the window. The upshot of all of this is that if you can get enough activated vitamin D (Calcitriol) flowing around in a patient early enough then you plausibly would be able to treat COVID-19. There was one such RCT from some months ago which reported exactly this. It has been underappreciated in large part thanks to statistical blinding failings and the usually understandable norm of refusing to take small studies with irregularities and results which are "too good to be true" seriously. I have done my best to analyze it as objectively as a mathematician without prior statistical experience can. By thinking carefully through it at the probability level, one is virtually forced to accept that the study is either true or someone committed fraud. I asked r/statistics if they could find a way in which the ridiculously positive results could be explained without fraud or gross incompetence. I did not get a straight answer. If you will let me speak of game theoretic signals one last time... This is ought to be the maximum signal that a study can send. In a more virtuous world, the researchers would be seen to have bet their careers on the result. Instead we live in a world where epistemic game theory is not yet a practical thing, I guess. It's not hard to get a feel for how it works though. It's really just a form of liar's dice for scientists. A team of scientists describe how to replicate a collection of dice and then they claim to have rolled them a certain way and got a certain set of results. Ultimately its all just paper though. Why believe some scribbles on a pdf? In order for it to not just be a bunch of meaningless cheap talk there must be something wagered. Reputation is what is wagered and the lower the p-value the larger the wager. We really ought to take sharp notice of such astronomically low p-values even if only for the virtue of identifying fraudsters. In light of the above and many other corroborating lines of evidence from distinct avenues I think that hypothesis D is strongly warranted for considerable discussion. It seems to be the most efficient explanation of the observed facts. Furthermore the standard of evidence necessary is proportional to the potential health risk incurred. Very low risk together with even just a moderate probability of benefit implies a lower standard of evidence. I've been at this for a bit and so have others. I am personally at the point where I have almost lost hope that anyone will listen. If you think this warrants professional discussion please bring it up with a peer or maybe a superior. I'm not sure what else I can do or even where to post this. But this is the best explication I can give. Thank you for your time.