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Nov 25, 2021
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Pascal would have made a bad Boy Scout. Always gambling with the other kids and getting hopelessly lost in the woods.

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Nov 26, 2021
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Found a spammer!

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Nov 25, 2021
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I'm not sure it's sufficiently widely appreciated how important the liver is, and how much we stress the shit out of it by asking it to dispose of all the weird things we eat, drink, short, or inject. The more I learn about the liver does, the more I want to take tender care of the beast -- you OK in there? Need more of this, a little less o' that? Anything you want ol' buddy...

I mean, we almost all die of atherosclerosis or cancer, and you wouldn't *think* that has a lot to do with the liver, but...who's to say it does not? All those lipoproteins that people fuss over, where there's a direct connection to CAD, that's traffic to and from the liver. And the immune cells that are supposed to kill off baby cancers, they're trained in the liver. Maybe if you mistreat your liver for a few decades it starts malfunctioning in certain ways that turn up as your arterioles narrowing and your immune system slacking off. Not good.

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CD56 bright NKs are trained in the liver? I mean technically it's the first site of hematopoiesis during development but they're the first cells to pop up after a bone marrow transplant. I def think it's circulating NKs that establish themselves there. Also NK cytotoxicity is based on MHC presentation/T cells are trained in the thymus/B cells either die naively or are selected for by dendritic cells through somatic hypermutation (definitely learn, don't tell the intelligent design people).

You can download Janeway's immunobiology on Libgen*/I'm hoping the pandemic increases public scientific literacy on immunology because my main goal in life is to not have job security. NKs are actually super sensitive to sleep deprivation!/will be depleted and your body will upregulate immunoglobulins across the board.

*It's super readable and fun and once you understand all the inputs into the immune system everyone saying everything makes a difference in everything makes way more sense and also there's a new edition coming out in February. Technically 17β-estradiol helps if you're exposed to COVID, but I'll eat my hat the day Bret Weinstein starts promoting that.

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Thanks. My copy of Janeway got lost during my last move. Now I don't have to buy it again.

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Nov 25, 2021
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I just learned that circulating spike protein can induce inflammation independent of viral infection, even independent of a binding ACE2 receptor (murine). So, I have come to the realization, for the Nth time in my life, that I understand nothing of biology. It will take a while for my self-delusion to wind back up again until I have any opinion about anything biological.

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This is off topic, but in another thread you said you have a very good memory because of a genetic difference... Aha, found the comment:

“...inherited two copies of protein that can only be transcribed as a specific isoform that always stabilizes this kinase involved in presynaptic facilitation so that my memory...”

If this is not too personal of a question, what protein and SNP/allele is that?

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Nov 24, 2021
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Nov 24, 2021
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Is there a name for the effect where if you catch someone going out of their way to stress the qualifications of someone, they're probably a crackpot?

e.g. "John Campbell has written an article about Ivermectin" -- probably not crackpot

"Dr John Campbell has written an article about Ivermectin" -- probably a crackpot

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Nov 25, 2021
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Nov 25, 2021
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He may be DOCTOR WITH A DOT, but he doesn't seem to have heard of isomers.

I got that far in his video then skipped through the rest. If the guy honestly thinks "pooh, dropping a few bonds in this molecule versus this molecule makes no difference, they both are the same molecule and work the same way (and so this proves that Pfizer's new drug and ivermectin are one and the same, and I'm not saying there is a conspiracy to keep a cheap, sure cure hidden while the big drug company creates an expensive 'new' drug, but..... ", then he's about as reliable as a leaky bucket.

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The normal convention is not to mark an abbreviation ending in a lower case letter with a full stop/period if that letter is the last one in the word. So Dr against Prof. would be correct.

And before anyone asks, I have no idea why. But it's been in every academic style guide I've ever read.

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How would it scale with the number of letters?

"Sir Dr. John Campbell, MA, MD, PhD, DPhil, FACP, FRS has writen an article about ivermectin..."

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Credibility probably reaches a minimum at three titles and then starts going up again. I'd actually be interested to hear what this guy with three doctorates and a knighthood has to say.

Nitpick: It would be Dr Sir, not Sir Dr.

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Past three, there would need to be a rule to Google each initialism, lest you find yourself unduly impressed by the medical judgment of a Member of the Association of Accounting Technicians or a Fellow of the Institution of Agricultural Engineers.

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Does a "nurse educator" require good scientific knowledge? In the UK nurses have until recently not prescribed and were expected to follow instructions on drug delivery. It seems unlikely that someone who was presumably a lecturer on nursing from three generations ago would be expected to have any expertise in pharmacology, although clearly it can't be ruled out.

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Nov 25, 2021
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His expertise looks to be physiology, which is a very different field from pharmacology. He may be good at the latter but there's nothing there to necessarily suggest it, and people on this thread are pointing out worrying weaknesses in his arguments. I am thinking there's a high probability he does not have the pharmacological expertise needed to make the claims he's making.

Note in particular his training and career were at institutions (Bolton and Cumbria) focused on training and that don't therefore prioritise staff research. In US terms you're looking at the small state college/well-ranked community college level. I'm not suggesting staff working in these places are not intelligent or competent, but Dr Campbell's career path does not look like one that involved much development of transferrable research skills, as indeed might be suggested the fact his only notable publication (admittedly according to Wikipedia) is a teaching text.

Therefore I don't think the credentials here are particulary relevant, and certainly not enough to shift my opinion of Dr Campbell's likelihood of being correct.

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Are you serious? I watched the Ivermectin video. Claiming that Ivermectin has similar clinical effect to Paxlovid just because they have similar putative MOA does not reflect well on Dr. John Campbell. And, this is assuming that you actually believe the MOA is actually correct, which is pretty bold. It was a couple decades before it was shown that statins don't work (to the extent they do work) by reducing serum cholesterol, even though that was gospel for many years. This is why well run RCTs are so important. It is just not possible to fully predict how a drug will work in a human just by doing a few experiments in cell culture. It's not even possible to predict if the drug will get to the cells, let alone the right compartment in the cell, by looking at stick structures, or even full-on 3d structures. Drug discovery would be infinitely easier if it were so, but it's a real slog because Every. Little. Thing. has to be proved out in humans. Dr. John is not going to prove anything by just looking at a bunch of lab papers. Giving advice to "world leaders" based on in-silico calculations of binding affinities (which are notoriously unreliable) shows a real naivety. He also confuses Fluorine with Fluoride, a sign that he's not a chemist. I recommend Derek Lowe's blog (it's on Scotts blogroll) for the perspective of an honest-to-god, in the trenches, medicinal chemist's view of how much (or little) you can get from these MOA arguments (and in-silico calculations). Dr. John is going to need a bunch more letters after his name before I would give him a second look.

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Nov 25, 2021
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Serious about taking Dr. John seriously. He just goes through a bunch of mechanism papers, which have little relevance. The ironic thing is he actually put up the Pfizer press release (which he thinks is a paper) and then proceeds to ignore the main result, which is that Paxlovid works really well to keep people out of the hospital and alive. So well that they met their significance goal (and FDA agreed) early and could halt the trial. In the face of that, all those in vitro studies don't add or detract from the value of the drug. And if you want to cast aspersions on people's devotion to scientific truth, go back and read Scott's magnum opus on all the Ivermectin papers. He had to throw out half of them because they were so bad you couldn't draw any conclusions from them, or they were just outright fraudulent.

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Nov 25, 2021
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"Now, I don't always follow the details of these statistical analyses" @ 12:10 in the video. He appears to be confused about a very basic statistic from the bayesian analysis in the TOGETHER trial on fluvoxamine. There's a nice graph of it in Figure 2 of the paper. So now I'm convinced he's not well versed enough in either chemistry or math to be explaining the results of a clinical trial. He goes on to the result on the odds ratio of death of treatment vs control (If you're following along at home, this is line 8 of table 3), which is given as 0.68 (17 vs 25 deaths), CI95% [0.36 - 1.27], which he thinks it great because it's a 32% reduction in death! Yea!. Of course he doesn't understand that hi brow statistics stuff, so he completely ignores the p=0.24 (basically meaningless) and the fact that the CI includes a 27% INCREASE in death due to fluvoxamine. He then goes on to emphasize that this is for "very low risk" (i.e. fluvoxamine is known to be a safe drug) right after he just got showing us that the data doesn't rule out an increased risk of death due to fluvoxamine! Now, I don't believe that fluvoxamine has much effect either way, which is what that pathetic p value is saying. But if he's going to put up a bunch of stats to convince you it's safe and worthwhile to take, then he better explain why the numbers aren't agreeing with his commentary.

If you like this guy's style, then by all means watch it as light entertainment, but for God's sake, don't think you're going to get any smarter by listening to him.

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Nov 24, 2021
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Scarcity of any given nutrient causes some specific deficiency disease. Surplus usually causes some mild impact on kidney and/or liver, right? If you ignore small effects, then it looks like avoiding scarcity is better than avoiding surplus. But if you're taking several dozen of these things, then if each one adds a little bit of strain on your liver individually, you might end up with a severe liver issue.

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For poisons that obviously doesn't work, but for nutrients it probably does, since the natural supply of nutrients varies significantly -- which means the body has to have historically had ways to deal with surpluses, up to a point.

I wouldn't take it too far, though. Some substances are harder to get rid of than others, e.g. the fat-soluble vitamins, iron, and some others do ugly things along the way to being dealt with, e.g. ethanol's unfortunate waystation of acetaldehyde.

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Thanks for the (second) shout-out. The thinking behind omura's wager led me to post this thread, which attempted to redesign a large chunk of medicine around it: https://twitter.com/alexandrosM/status/1435565853466972164?t=lOVddQ3v0IxEAv81Rub39g&s=19

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Does the Recovery trial make a small step in the direction that you're suggesting, by incorporating a testing regime into ongoing medical treatment? I believe the people who designed this trial want to extend this sort of testing beyond Covid-19. https://www.recoverytrial.net/

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Thanks for pointing me to that, hadn't seen it

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My new pet-peeve is that Ioannidis paper because it's become an axiom in industry to disregard new findings and protocols.

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Sorry about that!

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Derek Lowe, in his blog, pointed out that that, given the success rate of new candidate drugs, if you're in a drug candidate review and just keep shaking your head saying "that will never work" (said in an Eeyore voice), you will almost certainly be right, and definitely be useless.

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Sime critics od Scotts love for prediction markets told the same story recently: if one is just conservative - not important if its tomorrows weather (most people same like today) or tomorrows universe (most probable like today's) one will be mostly right in it's predictions. That's the nature of doing infinitesimal small steps on the one hand. And the nature of our pretty stable environment: no dangerous changes most of the time. The critic like Take was pointing out that most of us humans are not aware and cannot deal with long-time stable environments interrupted by very rare, extreme events. We now call it black swans after Taleb. And some of us have like a 6th sense of all kinds of black swans which could come upon us. Most others havent. Evolution is so fascinating.

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Eww twitter. Why do "rationalists" keep ignorantly using such a shitty and unethical platform? It boggles the mind.

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When "rationalists" want to use a (presumably) less shitty/more ethical platform, they post on lesswrong.com, but the maximum (and I think also the minimum, mean, and median) number of people who will see your post on lesswrong.com is very small.

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And for good reason most likely. I gave LW a second shot recently and noped out again when I noticed Eloser had insisted that a chicken can't suffer if the GPT3 can't suffer. He then went on to imply anyone who disagreed with him was stupid. Any platform featuring that guy so prominently is pretty objectively worthless.

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Because it's the easiest way to publicly post two sentences and a picture. Just today I was using it as a way of tacking pictures onto ACX comments...

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I've been struggling with this Pascalian *everything* for years for the exact reasons you articulate.

"Struggling" is probably not the right word, but it's always in the back of my mind.

I most don't take 250 supplements or do all the One-Weird-Trick-To-Enhance-Your-Love-Life things because...who has the time to suss out all this shit?

Just doing what Scott tells me is a lot easier.

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Kidney load, cost? Also a lot of those supplements legitimately do have side-effects (though they probably attenuate with usage), I can't imagine what taking 250 would make me feel.

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I wasn't really considering (or not considering!) taking 250 supplements, I was just gesturing towards the whole idea being talked about here. If 250 supplements have probabilistic costs that outweigh the potential probability of benefits, then that course of action is not even on the table for a Pascalian wager.

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It seems that the more stuff you take, the more you expose yourself to a rare Vioxx/Thalidomide-style event.

That 5% chance of something working has to be weighed against a .001% (or whatever) chance it will kill you, or do something else really bad.

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Depending on the condition you’re looking to treat, that kind of 500-to-one difference in chance to work vs. chance to kill might actually be reasonably attractive.

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It depends on what the supplements are and the dosage. We easily take 250 supplements a day in the course of normal living - they are in the food we already eat. Some of them have pretty nasty side effects, too, especially in large doses.

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“Struggling with Pascal’s wager” is the natural state of the world I think! It leads you to very strange places. Now that we have pascalian medicine, it’s time for the more extreme Roko’s Basiliskian medicine. Let’s see what supplements I can get you on by telling you there’s a small probability that not taking them will cause you to be tortured for all eternity.

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Technically, hydrochloric acid

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I feel like the response to this is something we do every day. There are a million things I could be doing to decrease my risk of X or increase my chance of Y, but if I were to actually do all of these things that would result in an enormous cumulative cost, so the sensible thing to do is set a probability threshhold below which the cognitive load of taking everything below that seriously leads to worse outcomes and less focus on things with high confidence than the benefits of caring about all plausible things. This is why I don’t wear a cloth mask anymore

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I always felt the ‘pascals’s wager’ part of this was obvious and a particularly important component in stopping COVID-19 in a world where some people will not take the new vaccines no matter what. Even if these treatments only have a 1% chance of making things better (and it seems higher than that to me), it’s better than the 0% we get in the current hyper-partisan world we inhabit. Not to mention the meta benefit of tamping down the divisive rhetoric. I’ve long felt the ‘vaccine only’ crowd is living in the world they wish existed and not the one that we’re actually inhabiting. Anyway, that’s my obscene, unenlightened $.02.

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You should not overlook the cost and value of information, particularly for the future. One reason we tend to do things carefully and step by step, instead of throw everything against the wall and try to sort out post-facto what sticks, is that this is the *fastest* way to the best quality information about what works and what doesn't. We are doing massive medical experiments on people, and the way to make those experiments give the most definitive answers as fast as possible is to be very careful about the experiment and control arms.

We are, in essence, trading potential present benefit (to the lives and health of those currently alive) for the benefit of acquiring reliable information that the future can use to the lives and health of those alive then. That's the trade-off.

Information, particularly reliable information, is very, very expensive. But also of course very, very valuable. We are the beneficiaries of our forefathers' painful experiments that eventually proved disease is caused by bacteria and not miasmas, that bleeding and cupping don't work, that drinking mercury to cure your intestinal ailments is a Bad Idea, that trephining the skull to let the evil spirits out doesn't cure madness, that "hysterical" women don't have a malfunctioning uterus -- and on and on.

All the insane ideas of the past at one time seemed reasonable to the professionals and amateurs alike, and a well-informed person living in those times would've said they had more than a 5% chance of being correct. But the only way we found out they *didn't* work, at all, and put a stop to centuries of medical butchery, is by insisting on rigorous and well-controlled experiment, which approach rules out a "Why not give it a try?" approach at the social level.

I would say whether you want to try it at the individual level rests on whether you feel like random interverntion in your biochemistry is more likely to do harm than good. As someone who works occasionally with highly-tuned complex machines, like performance car engines, I find the proposition laughable -- if I randomly poke or prod something in an engine it is almost certainly going to make things worse -- but this is just an instinct, not an argument, and others can easily have different instincts for different reasons.

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> As someone who works occasionally with highly-tuned complex machines, like performance car engines

I would expect engines to be very finetuned to operate in one specific way, while living organisms being far more flexible and resistant.

For example human can eat nearly pure fat or nearly pure sugar and survive at least for some time.

Liver can process a lot of problematic chemicals and so on. Though I agree with

> I would say whether you want to try it at the individual level rests on whether you feel like random interverntion in your biochemistry is more likely to do harm than good

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Well, yes and no. For example, engines are designed to operate in a variety of operating temperatures, and under varying loads. That's part of the design spec, so engineers make the engine "flexible" in that it can perform well under varying load, for example. (And if you were making an engine for a different application, like a generator, you wouldn't worry about this.)

And sure arguably evolution has made our biochemistry flexible and able to perform under varying conditions, in exactly the way you describe.

But here's the thing: just as the engineer doesn't think about how to design an engine that can operate in air or under water, because he says what kind of madman would drive his car into a lake and expect it to work? Nature has *not* optimized our biochemistry to work with highly unusual chemical insults that don't occur naturally.

So we're probably indeed pretty flexible with respect to varying amounts of naturally-occuring substances[1] -- a lot or a little vitamin D, curcumin, ethanol -- it's not clear at all to me that we're flexible with respect to substances that *don't* occur naturally in our diets (like ivermectin and HCQ and SSRIs). Why would we be? Like the cars not being driven under water, this hasn't happened in our history and so the Great Designer had no occasion to design for it.

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[1] Of course, it then also logically follows that varying these things isn't likely to have a big effect. If we can maintain homeostasis in the face of widely varying levels of vitamin D, for example, that implies varying the level of vitamin D doesn't do much. So, ironically, if the body can deal easily with it, it probably doesn't do much, and if it does much (e.g. actually effective medicine) it's probably something which you have to use very carefully because the body isn't flexible about it.

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FWIW, I've been told that chronic mild overdoses of vitamin D is positively associated with bone spurs. Of course, that takes a few years to show up. And chronic underdoses of vitamin D is known to cause a multitude of problems, some of which take years to show up. But there's a large area in between those two positions that isn't associated with the relevant problems. (Well, it's enough less associated with them that it can be ignored.)

Note: This is all based on "I've been told". I'm not asserting that it's true, but it sounds plausible to me.

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> Nature has *not* optimized our biochemistry to work with highly unusual chemical insults that don't occur naturally.

Nature managed to produce quite wide-range generic solution which is not ideal but works relatively well.

> it's not clear at all to me that we're flexible with respect to substances that *don't* occur naturally in our diets (like ivermectin and HCQ and SSRIs). Why would we be?

To be more resistant to various novel poisons? Liver is quite amazing at dealing with wide range of chemicals.

Though, obviously, there are many thing that will be too much (try eating random mushroom and you will die).

Truly outside context chemicals like plutonium will be deadly for obvious reasons with few exception of things that evolved to handle it (or even use it!).

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I'm not sure if you're disagreeing or agreeing but in different words.

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This presupposes that we’re capturing detailed and useful data. I’m not convinced but surely it isn’t nothing.

The other aspect is that taking Ivermectin, for example, is nothing like drinking mercury. Billions of doses have been administered over the course of this drug’s existence; it’s as safe as we can possibly make drugs. Combining it with zinc, vitamin D, etc. is super duper low on the risk table and we know it…that’s why it should have been promoted, or at least not ridiculed, mocked and disparaged.

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There's also a similar indirect but persistent cost with promoting stupidity and fantasy.

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> From the Inside View, I have a lot of trouble looking at a bunch of studies apparently supporting a thing, and no contrary evidence against the thing besides my own skepticism, and saying there’s a less than 1% chance that thing is true.

I guess I don't understand why this is the case. In particular, what propertion of things that have at least that much evidence behind them are actually true? In this domain, where low-quality studies are omnipresent, it seems like it should indeed be less than 1%, so there's no problem.

I suppose that it feels intuitively weird to look at a not-exceptionally-bad scientific study and say that there's a >99% chance that it's wrong, but in fact we deal with things like that all the time in all domains. https://www.lesswrong.com/posts/Ap4KfkHyxjYPDiqh2/pascal-s-muggle-infinitesimal-priors-and-strong-evidence seems relevant (not the part about double exponentials, that doesn't apply here, but the part about how decillion-to-one chances crop up all the time).

Maybe the problem is just that a good study and an average study intuitively look similar-ish and like they should have similar-ish effects on our beliefs, even though in fact their Bayes factors differ by orders of magnitude? Maybe a person could cure themself of this intuition by reading enough average studies whose findings were later disconfirmed by good studies?

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I think Scott, of all people, has read enough studies like that that if it were going to work, it already would have. Small probabilities are just hard to think about.

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I mean, yeah, but I still don't feel like I understand *why* it doesn't work.

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Apparently this is pretty common in drugs. If you read med chem blogs, they're stuffed with bitter and cynical people who think even when it looks perfect on paper, rock-solid mechanism fully fleshed out, passed Phase I through III trials with flying colors, the FDA wet itself with enthusiasm, sales are skyrocketing -- it might still end up killing little old ladies in some completely unforeseen way and cause the entire division to be wiped out and everyone fired after the first $1 billion lawsuit is settled. They expect almost nothing to work.

Seems to be relative in some sense to the fact that biochemistry is much more complex than we know about *and* the body is sort of build in a weird Rube Goldberg way in which everything is connected to everything, even when it makes no sense from a design point of view, so you *think* you're just interfering in this pathway over here, but unknown to you some (you thought) unimportant by product plays a critical role in some regulatory pathway way the hell over here, completely different system, and your whole scheme goes up in smoke.

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I work in a field in the physical sciences where there are lots of publications, but most are good quality. If I had to guess, I would say that of the papers that claim that an observation or experiment says that doing/observing A indicates that B is true, I would be 80% to 90% confident that the claim is accurate and reproducible. For top-tier journals in our field, I would raise that to 95% confidence (although I would argue that number drops back down again for Science/Nature/PNAS for complex sociological reasons).

Part of the reason for this high confidence is that we take peer review seriously, and researchers would get a pretty poor reputation if they regularly publish results that fail to reproduce. Also, if I as a referee had low confidence that a paper was reporting reliable results, in the way that Scott suggests, with 5% or 1% or less confidence, I would never recommend publication. I realize that the social and financial incentives can be different in the life sciences, and there is a different journal ecosystem. But at the fundamental level, if the studies have very low reliability, why are the referees and editors allowing them to be published?

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This is Ioannides's general argument in "Most Published Research Findings are False" - if you've got a p-value of 0.05 and a power of 0.8, and you expect that half of the things people would think to study with this sort of method are true, then your posterior for a study's finding to be true should be around 96% (unless I applied Bayes' theorem wrong, which is totally possible). But if your field is such that the vast majority of hypotheses are false, then even a perfectly done study with this good power and p-value should have a posterior less than 1/2 of being true. It may be that your field is one where studies are able to establish things with p value of 0.00000001 (this is common in physical fields where you have little noise and thus don't even bother running a statistical test because the data are blindingly obvious) in which case this doesn't matter. But in noisy fields (usually anything involving humans, especially masses of humans like in macroeconomics or epidemiology) even very high quality studies can't really get better than p value of 0.05 and power of 0.8.

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0020124

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Thanks, that definitely helps clarify these things. That's a better encapsulation of the statistical differences between the fields than I'd seen before.

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I agree with that in general, but look at figure 2 of this paper on the Pfizer vaccine: https://www.nejm.org/doi/full/10.1056/NEJMoa2110345 and tell me that the p for that isn't < 10^(-1000) (each arm of that trial is >20,000 people). A real effect does stand out of the noise in biology, even medicine. A lot of the problem is that lots of papers are published about non-existent effects.

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It's not 10^{-1000} but it is quite low. I think we flipped a coin 1,165 times (total number of covid cases in the trial) and got 1,034 heads (number of those cases that occurred in the placebo group). If I calculated right, this is "only" a p value of 10^-8 against a null that the vaccine has no effect.

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From those numbers, I get about 26 std dev from the mean or p~10^-149. So I was off a bit.

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Perforce. Every single data point in medical research is about 10,000x more expensive to acquire than in a laser spectroscopy experiment. So if you insisted on the kind of statistical power before publication in medical research as you can just casually assume in the realm of physical science research, there'd be no need for journals, because there'd be about 2 papers per decade that were worthy of publication. So in medicine you end up with averaging 10 (ten!) measurements and trying to figure out whether you've got something significant. All the statistical tools are deployed with a vengeance, because your noise level is inherently through the roof and you're trying hard to find a signal. It's understandable, if regrettable.

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I know that this is the reason, but I think it's worth seriously asking if it wouldn't be more useful to have 1-2 papers a year that are 100% rock solid and undeniable rather than however many thousand papers we have now that are functionally worthless because they have 20 patients total?

Or maybe combine the two - have tiny exploratory trials that raise hypotheses for testing, current "big" trials that are like a silver standard and get drugs licenced, and giant, actually huge trials that give you p values in the 5 sigma range and definitively settle issues such that those topics don't need to be dredged up and rehashed over an over again in an interminable replication crisis?

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Well *I* think so, but I'm a smartass in physical science, so I would. No skin off my nose, I don't need to build a career on a bit of research that has to go on for 5 years to have any result at all, and then it turns out not to work for obvious (in hindsight) reasons so we all look like idiots.

There's also the major problem of participant recruitment. People are just very unwilling to coldly roll the dice on their health, regardless of the logical inconsistency this indicates with respect to their daily lifestyle choices. The only trials in which people are generally willing to participate are those in which there is zero potential downside, even if that means there is also near-zero potential upside (which accounts for the vast supplement/neutriceutical market I think).

I mean, the best possible news (for the future) would be if we had a whole series of compounds that each had a 10% chance of extending your lifespan by 100 years and a 90% chance of killing you within 12 hours. Imagine if those trials were done. Presumably one would work out and the future would be amazing. Yay! But who the heck would sign up for the trials *now* in order to acquire the information?

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Someone who expects to die soon anyway? Or, more likely, a nonhuman animal that we don't have to give the option of refusing. :/

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Maybe. I tend to think people aren't especially realistic about death even when it is fast approaching. People who actually have days to live are thinking in terms of weeks. I've seen this a few times in my life and it's often sad, e.g. someone puts off a good-bye visit "until I feel a little better" in a week or two, but in two days it's all over.

The problem with the animal models are that they don't translate as well as we could hope, but yes that would be the best way to start fore sure.

Anyway, I'm just saying that our willingness, as a species, to do the kind of cold empirical experiments that would give us definitive answers to so many important questions -- what diet makes you live longer? what form of child-rearing optimizes the next generations' success/happiness? -- is drastically lower than our willingness to do those experiments in other areas. As soon as a whole human life (or quality of human life) becomes a realistic cost in the process of doing the experiment, we shrink away. "Let's settle this one by argument, shall we? That way nobody has to go into the control arm..."

Understandable, if a bit regrettable, in the sense that if our forefathers had the courage to do these experiments, we'd be much better off, and if *we* had the courage, our descendants would be better off. (But on the other hand, I'm not going to be first in line to volunteer either, so I don't blame anyone else.)

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It seems to me that Algernon's law would not be violated in cases where a person is taking in less of the particular substance than was normal in the evolutionary environment. In other words, in a world where many people are low in Vitamin D, topping up would seem to be a good strategy with an even smaller chance of side effects.

In that case ... which of Kurzweil's 100 supplements do I have a reasonable chance of being deficient in?

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Most vitamins and minerals, probably; some are safer to supplement that others, though - some excesses accrete, whilst others are excreted promptly. The only cost to taking everything in the later category is monetary. My limited understanding is that modern agriculture has lower vitamin and mineral contents in vegetables than was historically the case, do to effectively optimising them for calories per month at the expense of other things.

At a first pass: Vit D unless you work outdoors is almost a no-brainer; B12 has a mutation that hinders absorption in something like 40% of the population, and thus you have decent odds of being deficient (but the 60% with functional metabolisms don't need to bother). Fish Oil (aka EPA/DHA) is also a generally recommended one.

N.B. the primary concern with the supplement market is not a rare side effect of the vitamins you think you're taking, it's the risk that what's actually in the pills is not what's been claimed. The USA in particular has a very lax regulatory environment, though if you live in a more civilised country that's less of a concern.

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IIUC, in at least one study the benefits of fish oil disappeared in a double blinded study. One hypothesis was that the folks who intentionally took fish oil were in other ways more careful about their diet and health. I never encountered a followup study.

Still, it's a greater than 1% chance, at least if you're a male, and thus less able to metabolise the plant derived variant.

(I encountered this in a couple of different articles in Science New over a decade ago, so I can't provide any additional details. But I've combined at least two different studies in my memories. I think one of them was about the sex based metabolism of omega-3s.)

The thing is, there's LOTS of these different choices. My wife siezed on the studies recommending chocolate, until I pointed out that these were unsweetened chocolate. Details matter. I don't think it's really possible to assign reasonable probabilities based on most studies, because they tend to be focused on one set of properties, and ignore other properties. There are probably always tradeoffs, and you won't know most of them. Did that turkey you ate for dinner live on antibiotics? What did that do the the microbes that it carries in its corpse. (Well, they probably didn't survive, but you needed to clean the turkey before cooking it, so they may have survived in you. Or some microbes are remarkably temperature resistant. Usually they don't harm people, but perhaps this time?) And of course if it didn't live on antibiotics, you get the same argument, but with a different selection of microbes. Or people have gotten salmonella from eating raw lettuce, but it could be something worse.

We don't know most of the chances we are taking. Clearly the probabilities of somethign disasterous happening are just about always way less than 1%, but we take thousands of chances every day, and we don't just live one day.

So. You're taking a pill that is labelled as being this chemical you've decided is a good chance. What are the odds that there's something else in that pill too? Something that doesn't appear on the label. Well, actually that's a near certainty, but usually it's nothing harmful, or at least obviously harmful. Isn't titanium dioxide safe? (It won't be on the label.) But I think I read one report on a study that associated titanium dioxide with cancer. How could you figure the odds for everything you don't know about, but could if you researched sufficiently?

Heuristic shortcuts are necessary. They usually work, but in general you can't assign accurate probabilities, and even when you can it usually isn't worth the effort.

So. Pascal's wager. Consider the original Pascal's wager. He didn't consider the chance that the real god was someone else who would be offended by his choice. He didn't even consider that the official Christian god would be offended by his choice (which some theologians think (or thought) he should). The entire argument is based around a falsely constructed set of alternatives consistent with the available evidence. And I feel the same thing is true of Pascal's medicine.

Just consider, there is a common disease of cats that causes those mammals to behave recklessly. And the available evidence indicates that it affects people the same way. This is an existence proof. What are the odds that one of those medicines doesn't have this exact same property? Nobody's even tested, or at least I haven't seen any reports. Did you factor this into your "bad effects estimate"? I doubt it. And there are scores of similar kinds of effects. Say 20% of those drugs have an effect that's at 20% of measurable strength. What happens when you combine those effects? (I'm not assuming the effects are the same. Perhaps one speeds up the reaction for one kind of neuron, and another slows the recovery time for a different kind of neuron, etc. Or, of course, they could directly reinforce [or interfere].)

This *doesn't* mean you shouldn't take the chance. It means you can't calculate the risks (or benefits).

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"Just consider, there is a common disease of cats that causes those mammals to behave recklessly." Never heard of that one, would like to learn more.

I know about the common cat parasite Toxoplasma gondii causing rodents (and maybe humans) to behave recklessly, though.

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Perhaps I phrased that poorly. I was talking about Toxoplasma gondii, and you're right, I don't know that it causes cats to behave recklessly. It's quite possible that all it does is make the smell of cat urine more attractive. But there are other parasites with various known behavioral effects, including things like sacculina, so there may well be others we haven't detected.

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There's a strong argument that Algernon's Law does not apply to Vitamin D. The maintenance dose for the Spanish RCT studying Vitamin D for COVID is around 8000 IU/day. This is about what someone would get from 2 hours in peak direct sunlight shirtless. Hunter-gatherers probably got this or equivalent, but we clearly don't.

(State nutritional guidelines are calibrated for the amount needed to avoid rickets, i.e. severe deficiency, but D does more than just prevent rickets.)

Similar considerations favor vegetarians taking creatine, but not randos taking Ivermectin or SSRIs.

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Agreed that Vitamin D is one of the rare exceptions to this.

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Thinking more about this; humans who left Africa, went to colder/cloudier parts of the world, and put on clothes quickly evolved lighter-coloured skin, despite the added risk of skin cancer. Is there any plausible mechanism for this strong selection pressure apart from Vitamin D absorption?

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At some point: sexual selection, perhaps?

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Melanin is metabolically expensive, it takes a lot of metabolic energy and raw materials to keep your skin dark. It's only worth it if it reliably prevents you from frying in the sun.

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Ancient Dna data suggests that in Europe, there was strong selection to decrease melanin but quite late, about 10 000 -5 000 years ago, well after modern humans came into Europe (about 40 000 years ago). This suggests that melanin became unfavorable in Europe only after the switch to agriculture, which points to vitamin D more than to the cost of melanin synthesis.

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I would've said the reverse. The problem of the Sun being weaker in the winter is immediate on moving to norther latitudes and has nothing to do with agriculture. On the other hand, arguments have been made that the switch to agriculture was driven in part by calorie scarcity -- hunter-gatherers get considerably more calories for a given level of exertion, as long as the population density and climate support the lifestyle at all. As I recall, people got noticeably shorter when they adopted agriculture, which points to poorer average caloric intake. Lower caloric intake would put a lot of pressure on any process that was metabolically expensive.

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"I would've said the reverse. The problem of the Sun being weaker in the winter is immediate on moving to norther latitudes and has nothing to do with agriculture."

The argument was that we can get some Vitamin D from food, but only from animal one, and that transition to a grain based diet forced the early Europeans to rely entirely on the Vitamin D produced in the skin through sunlight.

"As I recall, people got noticeably shorter when they adopted agriculture, which points to poorer average caloric intake. Lower caloric intake would put a lot of pressure on any process that was metabolically expensive." I don't find that likely but it is more a hunch that anything else : it seems to me that pigmentation can not be a very metabolically expensive trait, and that the "saving" coming from producing less melanin has to be small. This does not seem compatible with the very strong selection on the alleles conferring lighter pigmentation in early Europeans ( same magnitude that the selection at the most strongly selected loci in the human genome, like lactase persistence or malaria resistance).

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It wouldn't have occured to me at first either, but I recall coming across arguments along those lines some time ago, and found some of them fairly impressive, e.g.:

https://www.sciencedirect.com/science/article/pii/B9780128026526000190

They mention a few points against the Vit D hypothesis (which they reject), including that evidence for rickets in early skeletal remains is sparse (if it were a general problem, you'd expect that in some areas no matter what there would've been too little), that depigmentation did not occur preferentially in areas more exposed to sun, and that supposedly unpigmented skin does not generate Vit D noticeably faster or more copiously than pigmented skin. The argument is essentially that enough Vit D can be obtained through a typical Paleolithic diet (e.g. with some fish or meat intake) and relatively limited spring/summer sun exposure, and so it would not have been a major force in natural selection.

The argument for the metabolic cost of melanin manufacture is buttressed by the observation that children with protein malnutrition (kwashiorkor) exhibit noticeable depigmentation, meaning the cost of pigment production is sufficiently noticeable to the body that it's minimized in periods of malnutrition, and that in animals somewhat related outcomes seem to point to the importance of conserving energy required for pigment production, e.g. the existence of eyeless animals in dark environments, related possibly to the energy cost for visual pigment production.

I'm not taking a position on which is likely to be true, just pointing out there are alternative hypotheses that seem to be worth considering.

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Better camouflage in grayer (snowy, cloudy, foggy, no foliage) environments at daytime, perhaps? Easier to paint your face with camo (I'm actually not 100% sure, that's the case)?

Camouflage is a good explanation for arctic foxes and ice bears being white (though in their case, it's fur).

So why not humans, too?

Might matter more for hunting/not being hunted by megafauna, which in Africa coevolved to stay away from dangerous humans. And outside of Africa quickly went extinct.

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The Inuit ain't as pale as Scandinavian farmers.

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[iirc from random podcasts, not expert]

The Inuit murder-replaced some older group that didn't have sled dogs. Could be that they were paler?

Also the Inuit have a tendency to store fat in their face as an adaptation to the cold, which... I think might be unique among all people? Maybe you can't be pale and have that kind of adpatation at the same time?

I tried googling "Inuit without clothes", but that just showed me... Inuit clothes. It's kinda hard to get a look at anything but their faces.

So who knows what skin color people have, if they never show skin.

Though probably the same hue, as the rest of the body?

I honestly don't know. But that might be broadly the correct assumption.

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Just jumping in here to say that melatonin definitely, 100 percent works for sleep in at least some people and the fact that studies can't seem to prove it must be down to some weird confounder we haven't figured out yet. I went through a period of severe insomnia that was unresponsive to any of the "proven" drugs and melatonin cured it immediately and I can use it as necessary and get the same overwhelming therapeutic effect, in a way that no other pill even resembles. So there is certainly room in my ontology for effective therapies with idosyncrasies that defy straightforward investigation in RCTs. But there had better be very large signal buried in the overall noise.

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Nov 24, 2021
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There's definitely a hangover of sorts, particularly if you don't give yourself enough time to "sleep it off", as it were. It's not a panacea but it definitely works wonders for some people, myself included.

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After reading Scott's thoughts on the matter, I started taking 300ug Melatonin 7 hours before desired bedtime. Felt weird, but not alarmingly so, for the first couple days, but then something clicked and now I sleep better, at the desired time.

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What's your dose? For me, all doses 1mg-20mg do the same thing, but everybody's different and see SSC: https://slatestarcodex.com/2018/07/10/melatonin-much-more-than-you-wanted-to-know/

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I was actually talking about melatonin for COVID! Some people claim there are a few studies that show it works, though obviously I am skeptical.

Completely unrelatedly, there *are* a few people who claim melatonin doesn't work for sleep, but as far as I know they all work in writing insomnia guidelines - no normal human being is that dumb.

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Well I'm glad to see the world has made progress since I was treated for insomnia, the doctors I saw back then never even mentioned it. I got the standard drugs, not Ambien but several others, and they all did jack. A friend suggested it and it was like flipping a switch. But apparently the clinical evidence is still mixed.

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Interesting. Melatonin works for me, and so do other standard pills. But melatonin is special: the next morning I feel like I got some sleep.

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Something adjacent to the "worms" hypothesis seems even better for melatonin than for ivermectin -- way more people are sleep deprived in North American than have worms in India, and it seems at least as likely that healthy sleep will have a positive effect on immune function as that worm infestation will impair it.

So if melatonin improves sleep in some people, it will probably also reduce the severity of coronavirus infection in those people.

So the Insanity Wolf is right again, I guess.

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Aren’t *multivitamins* arguably a form of Pascalian medicine familiar from many people’s experience? I used to take them every day. I give them to my kids. For any individual vitamin in them, I’d assign a relatively small probability that supplementing it does anything good — but a higher probability that at least one does. So maybe these 30 Pascalian covid treatments could just be bundled into an “anti-covid multivitamin”?

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There was a discussion about this many years ago on LW and I took the exact same stance you have taken and what the Pascalian standpoint would encourage.

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Yes, although there are surprisingly many studies showing that they don't help most of the things you'd expect them to help. Also, manganese is in them and might be slightly bad for you.

The main reason you can't bundle things is 1) the FDA would think of the bundle as a separate medication and you'd have to get it approved, which they would NOT do for something like this, and 2) you can only fit so many milligrams worth of stuff into a pill, and you'd probably need to take so many pills to get the whole bundle that you'd lose a lot of the one-pill advantage from bundling.

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Iron too. It's surprisingly easy to overdose on iron.

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Although men's multivitamins usually exclude iron, for that reason.

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> Yes, although there are surprisingly many studies showing that they don't help most of the things you'd expect them to help.

There are a variety of explanations proposed for this. One of the big ones I'm familiar with is that the form of the minerals in the multivitamin matters for the body's ability to absorb them in the digestive tract. Multivitamin manufacturers tend to strongly favor oxides (e.g. zinc oxide, magnesium oxide, etc) because they're cheap, but the downside is that oxides tend to be much, much less absorbable than other forms (e.g. citrates and amino acid chelations).

Another is that many micronutrients compete with one another for absorption. E.g. if you take zinc, magnesium, and manganese all at once, your body will absorb less of each than if you'd taken the same doses of each spread out hours apart.

> Also, manganese is in them and might be slightly bad for you.

Particularly if you're prone to migraines. My wife and I both have manganese as a major migraine trigger, which we discovered the hard way after trying a new brand of protein shake that consistently triggered nasty migraines for both of us and which turned out to be fortified with large amounts of manganese as its main difference in ingredients that we could find from other brands that neither of us had problems with. Poking around online turns up a bunch of stuff suggesting that manganese is a fairly common migraine trigger.

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I believe Vitamin E supplementation (if you're not deficient) actually causes harm.

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>if I “know” that onion farmers doing studies will convince me that onions have a 5% chance of curing cancer, I should just believe there’s a 5% chance onions cure cancer now.

That doesn't follow, because the fact that people are doing studies about something is itself evidence that should raise your confidence that there's substance to it. It's weak evidence, but it might not be so weak that it can't get you to 5%.

Furthermore, this should depend on the motivation for the studies. Your hypothetical assumes, as a premise, that the studies are motivated purely by a desire to sell onions. But in the scenario "what you think when you see the studies?", you don't know motivation. It may be that if you're fully informed about everything, including the motivation for the studies, you won't think there's even a 5% chance, but being partly informed may falsely lead you to think there's a 5% chance.

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To get specific, onion farmers are currently not doing studies on onions curing cancer, this probably has something to do with them doubting they can convince people onions cure cancer, and this probably has something to do with onions not curing cancer. In a world where they are running the studies, maybe that's because they have some inside information that onions really do cure cancer. After all, the cabbage farmers still aren't running any studies.

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Maybe in Scott's hypothetical scenario it wasn't him that came up with the onion example, he just stumbled upon studies about onions curing cancer. But yeah he didn't clarify that so him picking onions out of a hat is some evidence that the 5% figure is way too high.

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Who’s gonna tell this guy that more people died in the treatment arm of Pfizer’s vaccine trial with significantly more frequent cardiovascular events? Or that only one died of Covid in the control arm vs zero in the vaxx? Or that a Pfizer whistleblower presented very serious accusations of data falsification?

I would love nothing more than to be so innocently credulous towards companies that have paid tens of billions in fines for outright lying in recent years, in an industry whose marketing budget dwarfs any industry in human history, and who are fighting tooth and nail to hide the primary data on which these trials are based from public scrutiny for 55 years.

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My prior is that you're making shit up.

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Nov 24, 2021
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The tenor of your response has strengthened my priors to the point where no link you provide could possibly move it substantially.

For the record, I'm no great fan of the commercial media, but the enemy of my enemy is not automatically a friend, if you take my meaning.

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"Anyone who tells me info I haven't read in the New York Times is making shit up."

Which part? I’ll link you. Witnessing one of the last hyper-credulous media narrative trusters discovering the media has been willfully misleading him for the first time is a very rare these experience days, so I relish the opportunity.

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The NYT is crap almost across the board. That doesn't lend you the slightest shred of credibility.

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Facts: Pfizer vaccine trial data: “Only 3 of the people in the trial died of Covid-related illnesses - 1 who received the vaccine, and 2 who who received the saline shot. “

In terms of overall deaths there were 6 MORE deaths overall in the vaccine group than in the placebo control group.

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