blithedale

Truvada is PREP. PRE exposure prophylaxis.

PEP =/= PREP. PEP is after the fact treatment, there's more than just Truvada in that protocol.

PEP is typically much harder on the body than PREP.

Most every gay man I know takes PREP with few or no side effects.

Findings: In this double-blind, randomized, placebo-controlled trial involving 240 hospitalized patients with severe COVID-19, a single dose of 200,000 IU of vitamin D3 supplementation was safe and effective in increasing 25-hydroxyvitamin D levels, but did not significantly reduce hospital length of stay (hazard ratio, 1.12) or any other clinically-relevant outcomes compared with placebo.

Thanks for clarifying comments here, much appreciated.

I have to think my initial comment was overly harsh as well, given Supplement 3.

I think all I can say is that it may be possible for this issue to affect their data once they have OS stats accumulated in five years, but it was unlikely to do anything to yield differences in adherence with these kinds of patients over this kind of follow-up length.

I'm not convinced the 2/3 dropout rate of the FMD didn't simply select for people with less aggressive tumors, given that the Intention-To-Treat analysis found no difference in response rate, and that this paper is telling a nice story that actually happens to reverse cause and effect.

Basically, this?

   HAS AGGRESSIVE TUMOR ---> CANNOT DO THE FMD

   HAS SLOW-GROWING TUMOR ---> ABLE TO MAINTAIN FMD

Good stuff.

Also of note is tumor heterogenity. Not only are cancers different between cell origin and across different patients, cancer is not one uniform genetic entity even inside a single person.

Why? The cancer's ability to repair DNA mutations is crap, so different chunks of tumor can rapidly evolve different mutations.

You might be able to drug one portion of the tumor based on a fancy receptor/biomarker, but that tumor chunk will get outcompeted by a different cancer blob that doesn't express that.

Their "better response rate" touted at the top ignores the 2/3 of women who couldn't carry out the assigned FMD.

When you fold back in those 2/3 of people on that arm, the response rate is the same:

   "The overall pCR rate was 11.7% and did not differ between the two groups (10.8% in FMD group versus 12.7% in control group; OR 0.830, 95% CI 0.282–2.442, P = 0.735)."

This is like making people with cancer do an Ironman triathalon.

People about to enter hospice and pass on in a few weeks are gonna be way less able to complete it than someone who has months left to live.

But all you've done is stratify your patients.

The triathalon doesn't make anyone live longer.

A lot of people might think "Ah, well, fasting is clearly effective for the 1/3 that are able to carry it out, just gotta make sure you have the willpower to be the 1/3."

But hold on. Slow down. There's a good chance the "women who fasted had better chemo responses" story completely REVERSES cause and effect. Here's how:

    WOMEN 1 - Has indolent biology, slower growing tumor than your average breast cancer at this stage.
 - Symptoms: Less pain, neuropathy, less swelling, tumors not affecting distant organs as much

    WOMEN 2 - Has aggressive biology, faster growing tumor than your average breast cancer at this stage.
 - Symptoms: More pain, neuropathy, more swelling, tumors begin to affect distant organs

Clearly WOMEN 1.

ARGH. ARGH ARGH ARGH.

Almost no one reads these papers when stuff like this gets posted on HN.

And there is shameful statistical fuckery afoot in this paper. People are only repeating the hype statistics at the top of the paper.

Their "pathological response" rates touted at the top of paper only come from the 1/3 of women able to actually carry out the diet. This is the "per-protocol" language in the abstract. An honest evaluation here would be "intention to treat" and analyze chemo responses in every assigned to each arm.

And they do that evaulation, but bury it later in their paper. Turns out when you account for the 2/3 of women who can't do that fasting, there's NO DIFFERENCE in response rate:

   "The overall pCR rate was 11.7% and did not differ between the two groups (10.8% in FMD group versus 12.7% in control group; OR 0.830, 95% CI 0.282–2.442, P = 0.735."

Except the dosing in this study is a massive supra-physiological bolus that's something like 50x the daily RDV.

Welcome to every Vitamin D study done ever. I follow some PHD/RD combination researchers on Twitter and they all get together each time one of these studies is done and bang their heads against a wall.

Thank you thank you thank you. There is a craze for popping Vitamin D related to the raft of observational studies, here... so many of which never find a causal link.

Take my own particular condition: an inherited vascular dysplasia which causes frequent nose and GI bleeds. People with low Vitamin D seem to have a worse time of it in OBSERVATIONAL studies.

But people with GI bleeds so bad they have daily diarrhea from hemorrhages and anemia that disables them to the point they can't work aren't going to be out in the sun, and aren't going to be able to absorb as many vitamins in their gut due to the havoc the hemorrhaging is yielding.

Thinking really hard about the direction the arrow of causality runs here is massively important. Is it:

LOW VITAMIN D ---> BAD BLEEDING?

Or:

BAD BLEEDING ---> LOW VITAMIN D

And as the consequences of overdosing show, this isn't like popping an extra Metamucil cracker a day or something - dire stuff can happen.

There are seven results for American trials found on clinicaltrials.gov for Condition= "COIVD19" and Drug = "VitaminD" run by institutions like Harvard/MGH, Brigham, UNC, Arizona State University, etc.

https://clinicaltrials.gov/ct2/results?term=vitamin+d&cond=C...

The worst case scenario isn't 'healthier bones'.

It's kidney failure - https://www.cmaj.ca/content/191/14/E390

Or fatal hypercalcemia - https://link.springer.com/article/10.1007/s12098-016-2109-z

And so on.

I frankly think its irresponsible and facile for anyone to suggest there are no downsides to high doses of Vitamin D. This stuff is available OTC and a lot of folks are just gonna dose themselves ad libitum here.

I suggest folks read the cited research. It's eye-opening here, in a way that's very irritiating. This does not seem like particularly good science journalism.

Because of the road rage story in the lede, a whole lot of people are going to walk away from that piece thinking Statins -> Aggression.

The author even repeats it in a troubling way by linking to Golomb's research (their main source for this article I imagine) on statins and aggression:

"Since then, more direct evidence has emerged. Several studies have supported a potential link between irritability and statins, including a randomised controlled trial – the gold-standard of scientific research – that Golomb led, involving more than 1,000 people. It found that the drug increased aggression in post-menopausal women though, oddly, not in men."

You can see right there - it's plain as day. Randomised controlled trial, gold standard. The really astute scientists now know statins make people aggressive!

Except, EXCEPT... the study that Golomb DID found that statins overall lowered aggression... in men, and did not raise it in pre-menopausal women.

Again, the paper the journalist linked to shows the OPPOSITE of what the BBC piece claims it does.

The only reason the author found a subset of people that statins increase aggression in: they sliced and dice their data a bajillion different ways. They looked at age strata, baseline aggression, sleep-status, serotonin status, until they found a group -- post meno-pausal women -- in which the statin appeared to increase aggression. And that was only significant when they excluded one participant who had medically induced menopause!

"Among (postmenopausal) women, a borderline aggression-increase on statins became significant with exclusion of one younger, surgically-menopausal woman (N=310) β=0.70(SE=0.34)P=0.039"

When you adjust for multiple comparisons done (otherwise pretty sure you're just p-hacking) the result for women becomes statistically insignificant --which, given the number of ways they sliced the data, is not at all surprising!

"The sample size for women is half that for men, calculations did not power separately for women, and significance of findings for women would not be sustained under multiple comparison adjustment."

The overall thrust of 'Be a medical conservative, it's easy to cause treatment related harms you're not aware of' is a good one - there are many pharma companies pushing product on iffy claims. And a lot of research that shows how pharma trials minimize side effects and maximize results by surreptitiously excluding unhealthy trial participants.

The research in this piece is neither brilliant, nor awful... but given that the author appears to happily be quoted in a way that takes their research out of context, and seems to be the main source in an article that makes claims that their research does not support, really concerns me that they have their own flawed biases on statins ...

You're a cardiology fellow, so you're likely much better versed in this than me, but take a look at the paper cited here:

Sure looks like they were doing multiple comparisons until they found a happenstance significant subgroup. : |

"Several studies have supported a potential link between irritability and statins, including a randomised controlled trial – the gold-standard of scientific research – that Golomb led, involving more than 1,000 people. It found that the drug increased aggression in post-menopausal women though, oddly, not in men."

https://journals.plos.org/plosone/article?id=10.1371/journal...

They adjusted for multiple comparisons, and after that even the post menopausal group wasn't significant. The bit about how that doesn't matter because testosterone mechanisms and independent chance seems very hand-wavey to me.

(Moved my broader comment on this from a reply here to it's own reply to the thread.)