To be clear, all patients received these supplemental drugs, as at the time they were considered the best standard of care. (Also to be clear: they're not anti-virals.)

Of the 75 patients in the trial, 50 people received additionally Vitamin D3 supplementation (in the form of calcifediol), and 25 did not.

Notably, though, diabetes and high blood pressure were substantially more frequent in the control group, which are HUGE risk factors. Also they didn't track BMI or obesity.

Still, check out table 2. Even with these limitations, seems powerful.

Diabetes and high blood pressure are significant risk factors, but I wouldn't go as far as calling them huge, certainly not capital-letter huge.

https://www.nature.com/articles/s41586-020-2521-4

Wow! That link suggests diabetes doubles your risk, but that high blood pressure actually lowers your risk — but turns out to be only for folks over 70. Super weird!

> We similarly investigated the change in the hypertension hazard ratio (from 1.09 (1.05–1.14) adjusted for age and sex, to 0.89 (0.85–0.93) with all covariates included), and found that diabetes and obesity were principally responsible for this reduction (HR 0.97 (0.92–1.01) adjusted for age, sex, diabetes and obesity). Given the strong association between blood pressure and age we then examined the interaction between these variables; this revealed strong evidence of interaction (P < 0.001), with hypertension associated with a higher risk up to the age of 70 years and a lower risk above the age of 70 (adjusted HRs 3.10 (1.69–5.70), 2.73 (1.96–3.81), 2.07 (1.73–2.47), 1.32 (1.17–1.50), 0.94 (0.86–1.02) and 0.73 (0.69–0.78) for ages 18–39, 40–49, 50–59, 60–69, 70–79 and 80 or over, respectively). The reasons for the inverse association between hypertension and mortality in older individuals are unclear and warrant further investigation, including detailed examination of frailty, comorbidity and drug exposures in this age group.

Thanks for sharing this!

> Notably, though, diabetes and high blood pressure were substantially more frequent in the control group

How did this happen? Just bad luck with randomization?

That's the implication from the paper.

ack those could definitely affect this, isn't that why they normally try to select otherwise healthy patients as a baseline? Bring in the unhealthy people for the big studies and they'll most likely be spread much more evenly

Hydroxychloroquine was never the "best standard of care". It's a quack treatment that was pushed by some bad studies.

Reading Hydroxychloroquine mentioned in this study should make one very suspicious.

This is a substantial oversimplification.

Hydroxychloroquine looked promising for a while, and was being studied in an RCT, but that RCT was ended before completion because of the release of an observational study that suggested strongly negative outcomes from Hydroxychloroquine.

Later, that observational study was retracted because it was discovered to be based on falsified data.

So, unfortunately, we don't know very much about Hydroxychloroquine's effectiveness and risks in use -- but we do know that it has become a massive political hot potato, as your comment indicates.

> but we do know that it has become a massive political hot potato

I posted this a few days ago and got an interesting swing of votes on that comment since then:

> So, unfortunately, we don't know very much about Hydroxychloroquine's effectiveness and risks in use

For effectiveness it looks like we actually do, thanks to an experiment Switzerland accidentally ran on their population over May and June [0]. On May 27, they banned use of hydroxychloroquine, and 13 days later the death rate among resolved cases nearly tripled. Just after the spike began, on June 11 they reversed the ban and 13 days later the death rate drops back down. The graph from that article [1] is very stark, comparing the rate from late March through early July.

[0] http://www.francesoir.fr/societe-sante/covid-19-hydroxychlor...

[1] http://www.francesoir.fr/sites/francesoir/files/20200713_fs_...

That is quite a spike! Unfortunately the sharpness of the edge makes it pretty likely that a change in therapy is the cause -- time to death from hospital admission has a median of 10-12 days, but this is not a "wall", it's a median. The actual distribution is probably somewhat normal -- you'd expect a gradual increase and decrease around the intervention. We don't know how or when the Hydroxychloroquine was administered, but the mechanism of action seems to be prevention of infection early in the course of infection, generally before hospitalization.

To me, this seems more likely coincidental or a reporting change.

Ahhh I meant to say "pretty unlikely that a change in therapy is the cause" above.

This was presumably done a while ago, when hospitals were trying all sorts of weird things.

The "HCQ doesn't work"-narrative is entirely political, not scientific.

The original "quack treatment", which is prophylactic zinc+HCQ (as an ionophore) for at-risk groups, has never been shown to be ineffective in an RCT. It is still being studied.

Of course the studies that show it to be effective aren't of the best quality, but they aren't entirely meaningless either.

Logically, the treatment ought to be for exposed people who aren't yet showing symptoms. Prime candidates would be family members of infected people.

Azithromycin is a common antibiotic, not an anti-viral drug. This is an important distinction. Also hydroxychloroquine is an anti-malarial drug, which is also not an anti-viral.

Hydroxychloroquine is a zinc ionophore which helps zinc get into the cells in your lungs and slows the viral replication. It was not designed to be used this way, it just happens to work. This is mostly useful before your viral load is high. Same goes for Quercetin, also a zinc ionophore. They are good proactive measures to slow down the viral transcription before you reach a critical stage. It won't help everyone, especially if given late in their infection and especially if their immune system is compromised or otherwise dysfunctional.

Wiki says that "Hydroxychloroquine is being studied to prevent and treat coronavirus disease 2019 (COVID‑19), but all clinical trials conducted during 2020 found it is ineffective and may cause dangerous side effects."

https://en.wikipedia.org/wiki/Hydroxychloroquine

Here's a good rundown from Science on why hydroxychloroquine has failed large RCTs:

https://www.sciencemag.org/news/2020/06/three-big-studies-di...

That is mostly correct based on the studies I have been following. In most cases, by the time people are admitted to the hospital, the viral load is too high and their immune system has not been able to keep up. There is a whole lot more going on, all the way from interactions with ACE to VWF to clotting, that administering zinc ionophores late in the game may be a bit too late.

In the interest of free speech, here's a PDF with all the positive trials for HCQ:

https://drive.google.com/file/d/1l6y3L_KGb1ilMW0FaP4VZsd7WvX...

I mean, I guess quackery is free speech.

But it's awfully irresponsible to pretend it's good for society to spread it.

Not everyone has the scientific knowledge necessary to understand p-values and what they mean for research like this. It's a lot to ask that everyone know the standard for publishing in medicine is a p-value < 0.05, which corresponds to a 5% chance of the study's results being wrong. It's a lot to ask that everyone be aware that there were 130 different studies on hydroxychloroquine and to do the math from there to determine that we'd expect 6 or 7 of them to be wrong.

It's much better to say "just because it's not illegal doesn't mean it's a good idea" and just not share such thoroughly bad information.

millions of people take HCQ on a daily basis for their lupus. Ask any rheumatologist, the danger of Torsades de Points is only a concern for HCQ if the patient already has a serious heart condition, or if the patient has been taking HCQ for years.

Millions more take HCQ as a malaria treatment. It is generally recognized as safe, if you do not have a heart condition (and even then a short course is unlikely to yield adverse outcomes).

> It is generally recognized as safe

There are no safe drugs for a patient admitted to intensive care. We should not start administering anything in large scale just because most healthy people can tolerate it well.

> Millions more take HCQ as a malaria treatment. It is generally recognized as safe, if you do not have a heart condition (and even then a short course is unlikely to yield adverse outcomes).

COVID-19 can infect the heart and damage it. As safe as HCQ might be on its own, here it's adding extra load to a system that's already under stress.

Covid has severe effects on the cardiovascular system, with myocardial injury being a frequent occurrence of those covid patients admitted to hospital.

The dosages are different (much higher) for Covid-19.

Wikipedia is not a reliable source for anything, let alone medical information or studies

It's pretty good for purely non-political things.

Sadly, this is political.

Wikipedia is pretty reliable for math, old computer hardware, and other dry technical subjects.

This is not one. This is a political subject. Wikipedia is a complete disaster for anything that even remotely touches upon modern politics. There are teams of people paid to impose an opinion on Wikipedia, relentlessly wearing down any neutral editor with 24x7 edits and every kind of bureaucratic fight. The people who edit for free are also pulled from a highly-biased population, with strong overrepresentation by unemployed single people with non-STEM degrees.

Simply put, "ineffective and may cause dangerous side effects" is a purely political attack on the US president.

Last year, the drug was handed out freely, with very little worry, to anybody claiming that they would visit a country with malaria. In many places it is non-prescription. Clearly, the "dangerous side effects" aren't such a big deal. You can get deadly "dangerous side effects" from aspirin (Reye syndrome) and from Tylenol/paracetamol/acetaminophen (complete liver failure).

>"ineffective and may cause dangerous side effects"

Dangerous on an individual level, not really. But at a population level if hundreds of millions of people start taking it, you're going to have high absolute numbers of bad side effects.

> is a purely political attack on the US president.

As for ineffective, there isn't one single national health agency that recommends taking it for covid. Surely the entire globe isn't killing scores of their citizens by preventing the use of an effective treatment just to make the US President look bad.

Since it's ineffective in this case, there's no benefit to outweigh the downsides of "dangerous side effects" like their is with aspirin or Tylenol.

> As for ineffective, there isn't one single national health agency that recommends taking it for covid. Surely the entire globe isn't killing scores of their citizens by preventing the use of an effective treatment just to make the US President look bad.

Not true:

https://www.mohfw.gov.in/pdf/AdvisoryontheuseofHydroxychloro...

Of course, it's controversial because the WHO recommended against it and most health agencies just follow suit.

Also, American politics don't end at the border. There are countries that favor Trump, India being one of them.

> There are countries that favor Trump, India being one of them.

Most countries' health authorities don't take into account public opinion about Important Orange Personages when setting policy, astonishingly.

You'd be surprised.

I’d suspect that where you see other national leaders pushing HCQ, it’s largely not because Trump is doing it, but for similar reasons to why Trump is doing it. HCQ was the most ‘miracle cure’-y of the early proposed treatments. Most treatments being investigated promised modest reductions in the death rate, whereas some of the claims for HCQ were very extravagant (some people were even pushing it as a _prophylactic_). That’s a much more attractive public message than ‘this might reduce your chance of dying by 20%, if you’re on a ventilator’, so if you weren’t overly concerned with whether it was true or not, it might work politically.

I don't see national leaders pushing HCQ because Trump is doing it, I see them pushing against it because Trump is doing it and because they positioned themselves against him.

Trump has poisoned the well. If you bring up HCQ, you are immediately under suspicion of being an anti-science Trump-supporting conspiracy theorist. Guilt by association, reductio ad hitlerum, etc.

As for using HCQ as a prophylactic: That was the whole point right from the beginning. Didier Raoult can be credited with starting the HCQ hype, he has been prescribing HCQ+zinc as a prophylactic for at-risk groups. That's not as outlandish as you make it sound, HCQ has been used as prophylactic for malaria for the longest time and that is considered safe.

The studies that tested HCQ at a late stage (ICU) or without zinc are missing the point. HCQ without zinc doesn't work, zinc without HCQ is at least less effective, because the HCQ works as an ionophore, but if you already have a severe case of COVID, none of it is going to work. It's too late.

There are several studies that suggest that this prophylactic treatment works. There are no big RCTs that show it works, but neither are there big RCTs that disprove that it works.

See also this protocol for prophylaxis of COVID-19:

https://www.evms.edu/media/evms_public/departments/internal_...

It includes zinc and quercetin as an ionophore and is thus politically uncontroversial. However, it's unknown to what extent quercetin really works as an ionophore in vivo.

> Last year, the drug was handed out freely, with very little worry, to anybody claiming that they would visit a country with malaria.

Well, for a start, no it wasn't (many if not most malarial areas mostly have resistant strains, and other drugs are more appropriate there). But anyone who was given it was warned beforehand (or at least should have been). It's not a safe drug. It is, however, safer than getting malaria, so you should probably take it if you're going to an area where it will be effective.

What you should probably not do is take it because a weird French doctor and some people on the internet said to.

Sometimes I feel like I have to remind americans that other countries exist.

How incredibly self centered must it be to think that everything relates to you, your country, your awful president.

Please.

The claim is that those people are among those editing the article, and there's some of the more motivated ones. It's not that everyone else doesn't matter, in fact the problem is exactly that the wider informed opinion of everyone that matters isn't automatically reflected in wikipedia pages.

Any sufficiently intense argument anywhere in the world risks corrupting a wikipedia page.

Other countries may exist, but nobody knows or cares who their head of state is and whether they're any good.

The issue is it stops viral transcription at levels that also happen to be lethal to humans :p

My recollection is that it stops viral replication in vitro in monkey cells but does not stop viral replication in vitro in human cells.

Yes, it just stops replication "within the glass" (that's the meaning of "in vitro") with the cell culture, not in living human patients, and even "within the glass" only when using the "the Vero E6 cell line which is derived from kidney cells of green monkeys."

https://www.infectioncontroltoday.com/view/new-study-hydroxy...

"The mechanism of action of hydroxychloroquine is to block entry of the virus into cells. Viral entry requires a helper enzyme. In the Vero E6 cell line, this enzyme is cathepsin L which hydroxychloroquine blocks. However, in the human lung cell line, the helping enzyme is TMPRSS2. Hydroxychloroquine does not effectively block this enzyme and cellular entry of the virus occurs."

So, inspired by the reports of the experiments with wrong cells a French doctor made some false claims about his success when treating patients, which were then promoted by one person wanting to be reelected, and then the followers... the results can be seen in the comments here.

While neither azithromycin nor hydroxychloroquine are primarily thought of as anti-virals, both are hypothesized by some to have some anti-viral effect, and it's still unclear whether any potential effects they have on Covid-19 are via such anti-viral effects, or other effects.

Just because something helps with issues created by a virus doesn’t make it an anti-viral. For example it seems to be now that steroids are aiding those in the ICU with covid, but I don’t think anyone could plausibly call a steroid an anti-viral, as much as a bandaid can’t be called an antibiotic even if it helps heal a cut and prevent additional bacterial infection.

True, but if you look in the literature, you will find both of these compounds referred to as having some anti-viral effects, and their hypothesized mechanism(s) against Covid-19 may involve those effects.

For example, in <https://www.clinicalmicrobiologyandinfection.com/article/S11..., even though the study concludes other anti-virals are better, we see the footnoted, uncontroversial claim: "The antiviral properties of CQ were first explored against viral hepatitis as far back as 1963 [1]. Since then many observations from in vitro and animal experiments have suggested a beneficial role of HCQ and CQ in viral infections [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]." There are of course hundreds more such authoritative references to observed anti-viral activity.

Or regarding Azithromycin (AZM) in <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290142/>, we see: "It has been shown that AZM has significant antiviral properties. In contrast with CQ or HCQ, its antiviral activity has been shown in vitro and/or in vivo on a large panel of viruses: Ebola, Zika, respiratory syncytial virus, influenzae H1N1 virus, enterovirus, and rhinovirus [4–13]. Its activity against respiratory syncytial virus has been demonstrated in a randomized study in infants [10]. Azithromycin exhibited a synergistic antiviral effect against SARS-CoV-2 when combined with HCQ both in vitro [11] and in a clinical setting [13]."

That HCQ is mainly known as an antimalarial doesn't refute that it has, and is often tried for, antiviral effects. That AZM is mainly known as an antibiotic doesn't refute that it has shown broad antiviral effects as well.

(If you're stuck on 'antiviral' as some binary category, or mutually-exclusive with other categories, you're going to miss all the interesting incremental effects in real chemistry/biology. That sort of "sharply-bounded categories" thinking has killed a lot of people recently, as with those insistent on 'droplets vs aerosols' instead of a continuum including every size/variant of both.)

I always assumed getting sun(in moderation) was good for oneself. As much as I dislike the heat in general, I always have way more energy after spending a few hours in the sun. I assume(perhaps incorrectly) this was due to a Vitamin D bump.

Further, I've known two people in my life who get weird skin issues if they stay out of the sun too long. My wife is one of them! Really weird, considering how damaging the sun is considered.

UV light kills things that might grow on your skin otherwise, might be related to that.

All patients received hydroxychloroquine and azithromycin, i.e. the control group also, meaning the difference in outcome between the intervention and control groups is not due to these drugs.

The American media would have you believe that hydroxychloroquine and Z-packs are completely ineffective. Are we still in the "we don't know" stage? Is there any conclusive data to show that it helps/hurts/or does nothing in the beginning/middle/end stages of infection?

There are other drugs now that both work and have a large effect (20%). Hydroxychloroquine possible 5% increase in survival rate pales in comparsion. Given it's also poisonous I don't see why you would want to use it.

ReflectedImage says>"There are other drugs now that both work and have a large effect (20%). Hydroxychloroquine possible 5% increase in survival rate pales in comparsion. Given it's also poisonous I don't see why you would want to use it."<

Please name the other drugs that "both work and have a large effect (20%)".

Probably referring to Remdesivir.

Does Remdesivir work?

"DESPITE THE HYPE, GILEAD’S REMDESIVIR WILL DO NOTHING TO END THE CORONAVIRUS PANDEMIC"

https://theintercept.com/2020/05/26/coronavirus-gileand-remd...

FTFA:

>While some patients and their families have spent the past few weeks frantically trying to procure remdesivir, another Covid-19 treatment has been quietly been shown to be more effective. Although neither option appears to be the much-needed cure for Covid-19, a three-drug regimen offered a greater reduction in the time it took patients to recover than remdesivir did. People who took the combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin got better in seven days as opposed to 12 days for those who didn’t take it. Critically, the treatment has another leg up on Gilead’s: It clearly reduced the amount of the coronavirus in patients who took it, according to a study published in The Lancet on May 8.<

This experiment compares vitamin D to no vitamin D, and doesn't say anything about those drugs statistically.

Then why introduce two unknown variables into the study?

The point is they are not variables, but rather constants (everyone got them), and they were not introduced, but standard care at the time.

I suspect you have the wrong idea about how the results of the trial are supposed to be interpreted. The point isn't to compare to results outside the study. You should only compare the intervention group to the control group in the same study.

Because it's unethical to leave people who are sick with Covid-19 untreated, so they all got what were considered possibly effective treatments at the time.

No proper trial has shown any positive effect. At this point "don't know but probably not, and it's not risk-free" is probably a reasonable description.

Besides vitamin D, sunlight exposure also stimulates production of nitric oxide and thus lowers blood pressure. We also know that high blood pressure is a risk factor for COVID-19 so it seems plausible that there could be a connection.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593895/

Yes.

This study doesn't show that a non-hospitalized person who is not taking hydroxychloroquine and azithromycin should expect better outcomes from Vitamin D. At best, one could argue that if you get hospitalized, it would be good to have built up some Vitamin D.

I'm still supplementing with Vitamin D, though, but may cut back having been reminded that it's a fat-soluble hormone (and not really a vitamin at all).

Except for all the skin cancer, right?

FWIW, I was told that when the Sun is above 45 degrees over the horizon you will accrue DNA damage, and it stacks up over your entire lifetime. There is no "reset" or "heal", it just adds up.

For that reason I'm doing my darnest best to stay in the shade between 9am and 3pm. Or covering clothing.

> you will accrue DNA damage, and it stacks up over your entire lifetime. There is no "reset" or "heal", it just adds up.

Sort of.

Every time your skin gets 'red' due to sun exposure... that's due to DNA damage.

However, cells have several mechanisms to repair DNA - otherwise we would be in serious trouble after a single radiation burn (which is what UV light does).

They might fully repair an event successfully. Or they might not - in which case the damage may be severe and the cell will either die due to its effects or detect and trigger apoptosis. If the error isn't serious, it might not be detected and be passed on to future cell generations. Those are the ones you need to worry about.

Specifically for the skin, given that skin cells divide quite frequently, they might be caught mid-division, which is a more vulnerable state.

As you get more exposure and more damage, the chances of defects not being properly repaired increase. So you are right that, if you keep letting your skin bake, chances are you will accumulate damage that can't be repaired(over a lifetime, that's a certainty).

Cancer is not the only issue. Have you seen how the skin of people that spent a lifetime working under the sun without adequate protection look like?

I'd be really interested to see a comparison of the relative risks between skin cancer and vitamin D deficiency.

A lot of what I've read lately suggests we're discovering a lot of benefits of vitamin D that were previously unknown, and some evidence that the recommended vitamin D levels should be higher than they are.

For a generation or so we've told people the sun is dangerous because of skin cancer, and obviously skin cancer is really bad. But I wonder if we have a case of need to weight risks that are high cost, low probability (skin cancer) compared with low cost, high probability (low vitamins D complications). What is the overall effect of these two things?

This article gets into that: https://www.outsideonline.com/2380751/sunscreen-sun-exposure...

Short excerpt: People don’t realize this because several different diseases are lumped together under the term “skin cancer.” The most common by far are basal-cell carcinomas and squamous-cell carcinomas, which are almost never fatal. In fact, says Weller, “When I diagnose a basal-cell skin cancer in a patient, the first thing I say is congratulations, because you’re walking out of my office with a longer life expectancy than when you walked in.” That’s probably because people who get carcinomas, which are strongly linked to sun exposure, tend to be healthy types that are outside getting plenty of exercise and sunlight.

> The most common by far are basal-cell carcinomas and squamous-cell carcinomas, which are almost never fatal.

My grandpa died due to complications from a basal-cell skin cancer. He was almost 90 years old. The cancer itself was a few decades old. He served in the Navy during WWII, and likely got it from years of tropical sun exposure with no sunscreen.*

So, yeah, as far as cancers go, that's one you'd rather get if given a choice.

* (Well, and the additional years of fishing and other outdoor activities. Obviously the cause can't be pinpointed like that, but it must have contributed)

This is not strictly true. You have lots of evolved repair mechanisms to fix the damage caused by sunlight. It's only when they get overwhelmed that you accrue permanent damage. It's still a probability game, though.

Note that if we didn't have UV repair mechanisms, we'd blister in a few minutes.

I think the tides have been turning on avoiding all sun exposure. While you obviously want to avoid getting burnt, the benefits of adequate sun exposure seem to outweigh the harms.

Rhee, H. J. van der, E. de Vries, and J. W. Coebergh. “Regular Sun Exposure Benefits Health.” Medical Hypotheses 97 (December 1, 2016): 34–37. https://doi.org/10.1016/j.mehy.2016.10.011.

"Since it was discovered that UV radiation was the main environmental cause of skin cancer, primary prevention programs have been started. These programs advise to avoid exposure to sunlight. However, the question arises whether sun-shunning behaviour might have an effect on general health. During the last decades new favourable associations between sunlight and disease have been discovered. There is growing observational and experimental evidence that regular exposure to sunlight contributes to the prevention of colon-, breast-, prostate cancer, non-Hodgkin lymphoma, multiple sclerosis, hypertension and diabetes. Initially, these beneficial effects were ascribed to vitamin D. Recently it became evident that immunomodulation, the formation of nitric oxide, melatonin, serotonin, and the effect of (sun)light on circadian clocks, are involved as well. In Europe (above 50 degrees north latitude), the risk of skin cancer (particularly melanoma) is mainly caused by an intermittent pattern of exposure, while regular exposure confers a relatively low risk. The available data on the negative and positive effects of sun exposure are discussed. Considering these data we hypothesize that regular sun exposure benefits health."

Hoel, David G., Marianne Berwick, Frank R. de Gruijl, and Michael F. Holick. “The Risks and Benefits of Sun Exposure 2016.” Dermato-Endocrinology 8, no. 1 (October 19, 2016). https://doi.org/10.1080/19381980.2016.1248325.

"This review considers the studies that have shown a wide range health benefits from sun/UV exposure. These benefits include among others various types of cancer, cardiovascular disease, Alzheimer disease/dementia, myopia and macular degeneration, diabetes and multiple sclerosis. The message of sun avoidance must be changed to acceptance of non-burning sun exposure sufficient to achieve serum 25(OH)D concentration of 30 ng/mL or higher in the sunny season and the general benefits of UV exposure beyond those of vitamin D."

This change in thinking has been a long-time coming. There have been results showing studies since the 90s showing lower melanoma mortality from those having more sun exposure, as described in this review:

Egan, Kathleen M., Jeffrey A. Sosman, and William J. Blot. “Sunlight and Reduced Risk of Cancer: Is The Real Story Vitamin D?” JNCI: Journal of the National Cancer Institute 97, no. 3 (February 2, 2005): 161–63. https://doi.org/10.1093/jnci/dji047.

Thanks for taking the time write it all out, much appreciated.

Do you know if the time of day makes a different? I avoid the Sun between 9am-3pm as that seems relatively easy to get sunburned during that time, but I wonder if the alleged benefits are tied to the same time window?

Yes, time of day actually matters greatly since it depends on UVB exposure. Here's some classic research from 1988 discussing the topic:

Webb, A. R., L. Kline, and M. F. Holick. “Influence of Season and Latitude on the Cutaneous Synthesis of Vitamin D3: Exposure to Winter Sunlight in Boston and Edmonton Will Not Promote Vitamin D3 Synthesis in Human Skin.” The Journal of Clinical Endocrinology and Metabolism 67, no. 2 (August 1988): 373–78. https://doi.org/10.1210/jcem-67-2-373.

Also, here's a web calculator that can help you calculate UV exposure required to get a desired amount of Vitamin D (and to avoid a sunburn) based on location, time of year and day: https://fastrt.nilu.no/VitD_quartMEDandMED_v2.html