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Sunday, June 07, 2020 - 02:31 SGT
Posted By: Gilbert

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

The relevance of this shall become apparent later in this blog post
(Source: dilbert.com)

At least it took only about twelve days, and not twelve years, this time around; the Lancet has retracted their super-shady HCQ BAD paper, as have the NEJM for their paper by much the same authors, on cardiovascular disease.

I had originally been planning to get to the next part of this series - on the American domestic situation - but there's been just too much coming in on the #Lancetgate scandal front. But before diving deep into that, we might note yet another retraction, this one from the Annals of Internal Medicine, often seen as comparable to the Big Four medical journals in prestige. This relates to an April paper on the effectiveness of face masks against the coronavirus, that demonstrated on four [!] patients that both surgical and cotton masks were ineffective. On this, one can only muse that it might be rather easier to publish in high places, if you're spouting the same "wisdom" as the establishment...

Anyway, it appears that this retraction was to make way for the latest establishment (i.e. WHO) stand, as newly canonized in... The Lancet: that face masks actually were effective (along with physical distancing & eye protection). Not a few unimpressed souls would thank Mr. Obvious there, with observations that medical staff weren't striking for the right to wear them for fun, and that perhaps it just makes sense that exhalations would be impeded by a mask, or why did the powers that be recommend coughing into a crooked arm? By the way, the WHO has also resumed HCQ trials based on the Lancet retraction, since that was their original justification - but I won't be expecting any positive results, for reasons that shall soon be clear.

Consequences Of Fraud (i.e. Next To None)

As it should, to all good doctors
(Source: twitter.com)

The previous post has, I hope, explained just how serious this #Lancetgate fraud was - on the back of unverifiable data from an unknown company, the WHO made it global health policy to discontinue investigations into one of the most accessible potential treatments on the reputation of The Lancet (The WHO chief scientist admitted to simply trusting the authors, in pulling the plug within days). It might also be noted that none of the very well-credentialed Harvard-laundering clinicians that "authored" the paper apparently ever had any access to the underlying data (wow); I guess the science fiction writer under their employ had been very busy.

Of course, retractions - even those rightly described as "one of the biggest... in modern history" seldom tend to make nearly as much of a splash as the original scoop. Notably, none of the NYT, CNN or WaPo thought fit to even mention HCQ in their headlines on the scandal, although one would think this hugely more newsworthy than the initial declaration. No indication of the scandal's significance, or analysis as to what might have caused the unthinkable, was forthcoming from these doyens of the mainstream media either, and it was left to the Wall Street Journal, National Review and The Hill to diagnose the malady: that medicine has regrettably become politicized.

It should be emphasized here that the relevant journals and the WHO deserve very little credit for the retractions - the legwork and necessary evidence had been tirelessly compiled by various amateur sleuths, who turned out to be far more competent peer-reviewers, than the actual ones. In other words, were it not for their investigations, the potential of HCQ for treating similar conditions - whether ultimately tenable or not - would have been almost entirely shut down, and those reponsible would have been happily mucking about collecting fat paycheques (with a couple of top-tier publications to boot)

Some of these doughty hero sleuths have been pressing for information on any of the "data" behind the Lancet paper, all the more after their esteemed editor expressed hope for only "lessons, not consequences". I wouldn't hold out too much hope on this, since I fully expect Surgisphere's CEO (who seems the only one on Earth to have ever had access to it) to soon disappear from public life (and perhaps re-emerge some months later with a new name and nip-and-tucked face). Still, Dr. Horton shouldn't worry overmuch, since as one Twitter wit has it: "China has the iron rice bowl; academia's got tenure, but what I really want in terms of job security is to edit The Lancet!"

More Incoming HCQ Research!

As it is, the blatant political hit job has done quite some damage, with recruitment for HCQ trials already impacted in Australia. Here, I will attempt to summarize the most relevant recent releases on HCQ efficacy, that I know of. Before we begin, it might be helpful to note that HCQ can be considered to have four possible broad areas of application:
  • Pre-exposure of coronavirus
  • Post-exposure of coronavirus
  • Early community treatment
  • Hospitalized patients

It seems mostly accepted that there are very few really high-quality results for any of the above (a notable exception being the retracted Lancet paper, for how large and diverse its surveyed population was touted to be). I'll survey the prominent ones supporting HCQ use first, since it seems that the media somehow doesn't cover them: there's the NYU Langone study by Carlucci et al., which suggests that HCQ+AZ+Zinc resulted in a 1.5 times greater likelihood of recovering enough to be discharged, and being 44% less likely to die, with the understanding that HCQ was best applied to early-stage patients.

Internationally, Didier Raoult - the French infectious diseases specialist who arguably kicked the whole HCQ fad off - has just put out a preprint claiming that "early diagnosis, early isolation and early treatment with at least 3 days of HCQ-AZ result in a significantly better clinical outcome and contagiosity in patients with COVID-19 than other treatments"; the Indian Council of Medical Research has published in the Indian Journal of Medicine, proclaiming that six weeks of HCQ prophylaxis - yes, early treatment again, since this makes the most sense with anti-virals like HCQ - reduced infection likelihood by 80% amongst symptomatic health care workers (with PPE)

In the interests of some objectivity, I shall try to provide some critique of these studies. None of them follow the "gold standard" randomized controlled trial (RCT) format, that every public health head honcho is insisting upon as proof (well, it has to be said that the retracted Lancet study wasn't one either, but it was big, so...); Raoult for one is philosophically opposed to RCTs, as he explains with the parachute paradigm: we tend to accept the claim that parachutes reduce injury among people who leap from airplanes, but this effect has never been proved in a randomized study that compares an experimental parachute group to an unlucky parachuteless control. In other words, he doesn't like to sacrifice a control group, for purposes of research (of course, the counter is that there would probably be subjects who are against the intended treatment in any large trial)

The not-being-a-RCT was one of the main objections in an open statistical review of Raoult's original HCQ paper from March, along with lack of covariate-adjusted analysis, the dropping out of six patients, and choice of outcome (viral load); Raoult has also apparently come under some criticism, in particular that he churns out "an extraordinary number of publications but few of great quality" (as to this, it's kinda hard to argue with a h-index of 179, for those that care about this sort of thing). It should also be said that Raoult is at least an actual infectious disease researcher with a track record in successfully applying HCQ to new diseases such as Q Fever, unlike the three cardiologists who somehow became viral experts (likely on their NEJM high)

First Do No Harm

And we come to the "HCQ is rat poison" new publications, two of which have exploded across the corporate mainstream media these few days, right as #Lancetgate broke. First up, fresh from the NEJM, there's a trial from the University of Minnesota, that claims no benefit for HCQ post-exposure, from 821 enrolled subjects; the relief immediately expressed by a collection of big names supposedly dedicated to healing felt... oddly off. This was swiftly followed by a tweet from the United Kingdom's much-awaited RECOVERY trial: no clinical benefit from HCQ in hospitalized patients. I'll quote our own State's Times on this: "This is not a treatment for Covid-19. It doesn't work." Martin Landray, an Oxford University professor who is co-leading the Recovery trial, told reporters. "This result should change medical practice worldwide. We can now stop using a drug that is useless."; he further added that HCQ was "quite toxic", so halting the trials would be of benefit to patients.

Now, these are some pretty definitive proclamations for a scientist, and given the world's experience with various supposed-authoritative medical journals and organizations of late, I hope that readers will indulge in a bit of ad-hoc review of the above papers/claims here. For the Minnesota trial, it was noted that 85% of participants didn't even test for coronavirus, and the trial somehow tested for symptoms (instead of, say, PCR) from assumed existing infections despite that saying little about viral load (comment: "Please tell me this is a joke. So a study on a treatment for covid-19 didn't test for covid-19???"). Not only that, patients self-reported data, and one-fifth didn't even take their assigned doses. But well, this seems good enough for the NEJM, so what can we say?

An even more interesting observation would be made in the discussion on Science Translational Medicine's post on the paper, which was that the Minnesota study was powered to detect a 50% difference in symptoms (which it failed). This meant that despite an actual observed improvement with HCQ (11.8% with symptoms) versus placebo (14.3%), the authors (correctly) claimed that HCQ could not statistically be claimed to have worked (or not worked), because it didn't hit the (kinda optimistic?) bar set initially, essentially due to not having enough subjects. Here, it might also be possible to add that Surgisphere had initially claimed a partnership with researchers from Minnesota on their website, now scrubbed, and that the first author Boulware receives funding from Gilead.

The Oxford study is even more intriguing, despite the above. First off, it might be noted that unfortunately, about 25% of the patients died (25.7% with HCQ, 23.5% usual care), from which it might be reasonably surmised that these were largely ICU-level patients, or close to that. As stated in a previous blog post, HCQ - or indeed most anything else, as far as known - is kind of a toss-up by this point. Indeed, I am inclined to agree that for moderately-to-very sick hospitalized patients, HCQ is unlikely to do much if anything, from many previous retrospective studies.

From the U.S. CDC advisory on HCQ

This is a good time to take a small detour. Recall that the #Lancetgate fraud had kicked off not because the investigators checked out their LinkedIn page and found a camgirl, but from the data - and, in particular, that "...the big finding is that when controlling for age, sex, race, co-morbidities and disease severity, the mortality is double in the HCQ/CQ groups (16-24% versus 9% in controls). This is a huge effect size! Not many drugs are that good at killing people." Of course, this is exactly the sort of outcome you'd want, if you wanted to sell "HCQ is arsenic/bleach/cyanide combined!" (which the editor of a certain journal might have liked), but critical thinking and some sanity checks should come in here: can this be true?

The problem with this message was that, as with face masks, the claim of HCQ being dangerous didn't have much face validity to begin with. As various common folks all over the Internet noted, HCQ is, like, amongst the boringest of boring medications. It's been around for so long, that it's outlived many great-grandfathers; while we're on authority, the CDC has it generally safe for pregnant women and nursing mothers; it's on the WHO's Model List of Essential Medicines, that are considered the "most effective and safe". It's a customary long-term malaria prophylaxis in many tropical countries, been prescribed in the millions of doses for various chronic diseases - surely some indication that it was terribly unsafe, would have rung the bell after over 65 years? And suddenly, just because a certain political leader mentioned it and went on a course, you have a Fox News host screaming that it'll kill you?

Of course, it's not untrue that HCQ can kill; but so can Panadol, or cough syrup, or heck, plain water. As the National Review clarifies, the dose makes the poison. Let's consider the example of aspirin. Most everyone's taken it before, it's not very exciting, but most people should also recognize the dangers of an overdose from low-budget drama serials - the kind where a heartbroken silly girl cups a handful of pills, swallows them all, and either achieves a fairytale ending through reconcilling with her lover in the hospital, or gets written out of the show. Some guidelines have 300mg per kg of bodyweight of aspirin as a mildly toxic amount, with 500mg/kg as potentially fatal.

Now consider a scenario where aspirin has become a candidate drug for treating sharp head pains. Somehow, you have researchers gathering emergency room patients with severe head injuries from car crashes, and feeding them inordinately-high doses of aspirin - say, sixteen pills a day. It doesn't seem to help, and some of these patients (expectedly) suffer the side effects such as nausea and ulcers. A reasonable person might figure that this might not prove much. No problem, more researchers continue running similar studies on severely-injured patients from bicycle/bus/Roomba crashes instead. The same reasonable person might say, fine, we get it, aspirin doesn't help when it's come to this. But what about preventing headaches?

Instead, all the mainstream media sites propagate the same headlines: "Aspirin very dangerous. Do not use for headache."


Another little detail not explored by the mainstream media
(Source: twitter.com)

This seems suspiciously like what may be happening with HCQ. It might be noted that Oxford's RECOVERY trial had its HCQ results spread by the mainstream news despite the lack of even a preprint, but fortunately, there are some details about their study protocol. In particular, the HCQ dosage used over ten days was revealed on Page 9: 800mg initial, another 800mg after 6 hours, 400mg after 12 & 24 hours, and 400mg every 12 hours thereafter. Understandably, not a few observers were shocked at the 2400mg dose within the first 24 hours (and 800mg/day afterwards), which appears rather... excessive, to say the least.

To put it into perspective: common HCQ dosing guidelines for malaria prophylaxis is 400mg weekly; acute treatment is admittedly up to 1600mg in the first 24 hours, but with no indication of continued application for long. Treatment for chronic conditions involves 200-600mg/day. For coronavirus application, Raoult's protocol involves 600mg/day (which does seem the maximum limit recommended by French guidelines); Zelenko, if you've heard of him, advocated for just 200mg twice a day (with Azithromycin & Zinc). The Indian ICMR advisory calls for 800mg for the first 24 hours, and then a 400mg maintenance dose weekly. In summary, the maximum first-day dosage of the major HCQ proponents appears barely a third of what was used in the RECOVERY trial; it is quite difficult to imagine what inspired these Oxford investigators to begin with such an exceptional dose, although it might be mentioned that the university is developing a vaccine, that might be somewhat less critically-needed were a good prophylaxis to be discovered.

Like, "first do no harm", right?

Astoundingly, this doesn't even appear to be the beginning of it. A Redditor claimed to be one of the principal investigators of the RECOVERY trial on the Medicine subreddit (his comment history appears at least plausible as to that), and said that "We didn't suspend our HCQ arm, partly because the doses we used were lower than some of the other trials' protocols."

What in the absolute fuck is this?!

Let's return to the investigators that exposed the #Lancetgate fraud: one of them mentions FDA guidelines of 800mg on the first day, and then 400mg/day for up to a week. I really, really hope to stumble upon a good explanation for these trial dosage decisions in the coming days, or my faith in the medical profession will be extremely severely shaken. I mean, you might expect this sort of hanky-panky with casino money laundering, or oil/gas bunkering, or drug/gun/avocado smuggling, but medicine?! Say it ain't so, Joe!

The outcomes have been determined;
Trial investigator: *applies toxic dose of drug*
Trial investigator: "This drug is quite toxic"
World: *pikachu face*

(Source: twitter.com)

Unfortunately, the way I'm seeing it, there's no way out now. I don't think that the rational response of, well, HCQ doesn't work with severely-ill patients, but maybe it can help all of us to an extent in prevention (like with face masks), is gonna fly here. Above and beyond the billions and billions of dollars that are at stake for Big Pharma and their allies in medical journals and the WHO, and possibly American pride in wanting a home-grown drug, it's gotten too up close and personal for a lot of bigwigs. Do you know what it means, if it is shown that HCQ kind-of-works prophylactically? Yes, a lot of people would be saved, but I don't think that's at the top of certain fellas' minds now. This would mean that, after defeating first the entire Republican establishment, and then the entire Democratic establishment, a certain slightly-orange former reality TV star would demonstrate his Ultra Instinct on epidemiology, to be superior to essentially the entire (Anglo-American) medical establishment.

Now, if I know anything at all about the type of guy that's managed to claw themselves up the establishment, they are gonna pull in every favour they can, and pull out every dirty trick in the book, to destroy HCQ now. Like, how did it come to this?! The early TRUMP mention of HCQ was more or less in passing, and moreover with a request to defer to one's physician! Somehow, you have the greatest and goodest of America's health professionals now basically forced to hammer down a prospective solution, because the reaction if it actually comes to pass that HCQ could actually have helped - which really isn't that far-fetched - would be disastrous to them?

They can't buy stuff quite like he can, after all

[N.B. For those getting depressed at the flood of negativity and/in politics, may I recommend... r/PoliticalCompassMemes! All sides of the political spectrum take the mickey out of each other there, and one might learn some new stuff too!]

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Next: Of Logic, Looting, Twitter & Disinformation (Part 2.5)

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Of Logic, Looting, Twitter & Disinformation (Part 2.5)
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