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Friday, June 19, 2020 - 23:06 SGT
Posted By: Gilbert

Of Logic, Looting, Twitter & Disinformation (Part 2.75)

This should be it on coronavirus cures for awhile, and so, first the good news: the RECOVERY trial has concluded that Dexamethasone can reduce deaths by a third to a fifth, in severely-ill hospitalized patients; the caveat, of course, is that by the time it's useful, the mortality rate is at least about 20%. Some badly-bitten scientists have seen fit to reserve judgment until more details are forthcoming (note no preprint yet, as far as is known), but that hasn't stopped the WHO and other mainstream outlets from hailing it as a "breakthrough lifesaver", with the U.K. already endorsing it as an authorized NHS treatment. As hoped for in the previous post, Dexamethasone is indeed cheap, though former users have hastened to warn of potential adverse effects. But more on this in particular later on.

The mainstream media has meanwhile finally seen fit to commentate on #Lancetgate, with articles from our State's Times and The New York Times coming out within a day of each other. Both agreed that the fraud was unacceptable, before devoting most of their column space to pinning the fault on the sloppiness/difficulty of the peer-review process, and the NYT did at least mention possible politicization... in the final paragraph; readers who followed the saga through the last few blog posts here might consider some quick discourse analysis, as to what perspectives were not raised, despite their significance. On this, I'd recommend the curious to occasionally peruse sites like AllSides to receive different points of view, even if only to prepare improved counterarguments for one's stand (was actually planning a side-project about this, but eh)

The battle over HCQ has continued in the alternative media, despite some poor monkeys and hamsters biting it (the same group are saying Remdesivir works, by the way), with various reports on pre-exposure efficacy still going nowhere fast. Giuliani, Zelenko and Him in the White House have quite rightly torn into the relevant journals and media on this deception. Nevertheless, the FDA has revoked the Emergency Use Authorization for HCQ (though this paradoxically makes its prescription more accessible, so it seems), apparently based at least in part on the RECOVERY trial's largely data-and-analysis-free headlines. We'll have quite a bit to discuss about that, but one can't help but imagine some ready parallels between this and the sorry WHO/#Lancetgate affair (on which Internet investigators have kept on prying into possible links)...

But before that, more quick go-overs of other preventive measures. Our local DSO has come up with a number of antibodies, but most of the talk has probably been swirling around vaccines, with Italy, Germany and France having already signed up with AstraZeneca/Oxford. There may be some very cautious optimism to be had here, with experts warning that the first vaccine candidates might not actually protect fully against the coronavirus, and instead settle for a partial prophylactic effect. Hmm. And then there's the joint China-U.S. study suggesting that humans aren't producing long-lasting antibodies against the coronavirus, which has clear negative implications for vaccines, but that's enough bad news for today.

Returning to face masks, Dr. Fauci has now openly admitted that the advice against them was due to shortages for medical staff, which really doesn't do much for trust in authorities, their interpretation of science (with recent research now somehow all pointing the way of masking up), and their future advisories - as the Governor of New York, among others, might be belatedly discovering. The ever-quotable Taleb has chipped in on just how all of the world's top bureaucrats and medical minds combined managed to come up with reasoning that is so blatantly wrong, which seems to boil down into poor intuition on probabilities, once again. For some historical context, consider that folks had advanced breathable mask designs (a tad creepy, fine) during the 1918 Spanish flu pandemic, more than a century ago; nothing new under the sun, indeed.

1918 or 2020?
(Original source: auburnpub.com, colorized by deepai.org)

Prosecution & Defence

And now the main course - #Recoverygate, yea or nay? But first, a pretty comprehensive timeline of the happenings involved, some of which have not been covered here (note that Surgisphere's HCQ paper in The Lancet was so egregious, that multiple observers were calling foul within a day of its publication). Now, to pick up where we left off, the France-Soir interview with RECOVERY trial co-head Prof. Landray seems entirely genuine, with the French online newspaper releasing raw audio of Landray's very Brit pronouncements, with further confirmation of his assertions reportedly sought (wouldn't be a proper -gate without audio evidence, would it?)

Given that another RECOVERY trial head has tried to clear the air on another French site, instead of outright denying the charge, one has to suppose that the event did take place. Prof. Horby would describe the initial 2400mg loading dose as having low associated risks, an angle also explored by Dr. Watson, whom recall was behind the open letters that carried #Lancetgate (and that were, ironically, probably at least partly instigated by Oxford researchers unhappy at The Lancet's HCQ paper putting a stop to their RECOVERY trial)

Now batting for the other side, Watson would offer a paper from 1949 that describes the treatment of hepatic amebiasis with chloroquine (HCQ had barely been invented then), while also mentioning "quite a few other papers from the 50s-70s". He went on to describe the 1949 dosings as a loading dose of 600mg for the first two days, and then 300mg for two to three weeks, which seems curiously similar to modern-day recommendations. Watson then says that RECOVERY was giving these 600mg/300mg doses, but just twice daily (and actually, closer to 2.5 times than twice), for the same peak concentration by the end of treatment (10 days versus up to three weeks)

This largely repeats the more-detailed reasoning provided in the official trial protocol, although one suspects that at least some curious reviewers would find the correlation drawn with amoebic liver abscess seemingly coming out of the blue, and moreover at increased dosages. The argument appears to run as follows:
  • The WHO has recommended a treatment regimen for amoebic liver abscess [ALA] (fair enough?)
  • Our loading doses are the same as the regimen for ALA (wait, how does suitable dosages for the coronavirus relate to those for ALA in the first place?)
  • Only, we double these dosages again (okay...)
  • This is such that the total dose over 10 days is the same as standard treatment for ALA over 20 days (clearly, the risks aren't automatically going to be "standard" here...)
  • The seriousness of COVID-19 (~20% in-hospital mortality) justifies testing these higher doses

On that final point, it certainly hardly seems immediately evident that relatively high mortalities necessarily imply that (unprecedentedly) high doses are appropriate. Obviously, there has to be some trade-off between expected detriment to patient health directly from the high dosage of HCQ applied, and the expected benefit gained. Notably, while the trial heads have repeatedly made references to "careful pharmacokinetic modelling" and the like, the exact details on just this risk-benefit modelling appear to be exactly what's missing (and what a proper reviewer would ask for). In particular, statements like "ensure the necessary blood concentrations are achieved rapidly" should be qualified - for example, what would be the delay were a more common regime (e.g. 600mg/day) to be applied? If it is a matter of a few days, is the rush actually imperative, especially given that a recent study in Brazil has already suggested danger for such high doses? And if no happy middle ground could be found for a safe yet effective dosing regime, why go ahead with the trial only to vacillate between calling it toxic and not?

One hopes that the Oxford dons eventually engage in an open dissection of the full reasoning behind the dosage calculations, as befits the university's storied history, instead of rehashing explanations of the following forms (some as seen on Twitter), none of which are actual scientific explanations:
  • Look at our shiny ISO certifications!
  • It's similar to the WHO's SOLIDARITY trial (which may turn out to be a circular argument; also, there is talk that Singapore had been hesitant to participate in the SOLIDARITY trial for HCQ due to the dosages involved, which if true, makes me proud of our health system)
  • Any disagreement suggests that the U.K.'s regulatory processes are inadequate
  • Our ethics committee would have blocked the trial if there were any real concerns
  • Hundreds of Very Important People have been involved in the trial design, and tens of thousands of patients have been recruited for this big national project

As one wise statistician has it, with #Lancetgate, the fraud was perhaps the least of it. Instead, the real scandal was that the prestigious journal (or ethics committee, or governing body, etc) "aids and abets in poor research practices by serving as a kind of shield for the authors of a questionable paper, by acting as if secret pre-publication review has more validity than open post-publication review".

Sure, all this worry could be over nothing - the trial investigators might eventually release sufficient evidence supporting their choice of dosages. However, it might also be noted that policies have already shifted without the public release of data & analysis (note that the WHO at least waited for The Lancet to publish). I don't expect this to be over yet, what with many critics emboldened by #Lancetgate (which didn't directly involve real patients in treatment, remember), and spurred on by AstraZeneca - in collaboration with Oxford on their vaccine - apparently seeking to merge with Gilead. As it is, France-Soir has just alleged that the very pharmacokinetic analysis of interest had been cut from the trial's HCQ info sheet, leaving it a mere three pages for version 3, down from 25 in version 2 (which appears to have been entirely disappeared). Much more drama ahead, then?

Kengan Omega Singapore Represent!

Distant relative of you-know-which-clan?
[N.B. Belle Delphine also back for the simps, after a long layoff following her kidnapped hamster rescue!]
(Source: r/singapore)

I was pleasantly surprised when Thursday's scheduled instalment of Kengan Omega revealed the first known Singaporean fighter in that comicverse; not so much when he turned out to be a massive weeb (then again, Singapore does have our fair share of those...). Can't lie, he was fairly cool in his initial appearance, only to turn out to be the cringiest Sasuke-cosplaying banana magic poseur spouting phrases like "have at thee!". In my estimation, the only way to salvage this would be to go the whole hog with the Merlion green mist. Oh, and his favourite dish is chicken rice. Did the Tourism Board slip the mangaka a couple of bucks under the table here?

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Next: Through Glasses Darkly

Related Posts:
Of Logic, Looting, Twitter & Disinformation (Part II)
Of Logic, Looting, Twitter & Disinformation (Part 2.5)
"Science" & Facts
Of Logic, Looting, Twitter & Disinformation (Part I)
Politics & Fixes

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