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Friday, June 11, 2021 - 02:02 SGT
Posted By: Gilbert

Communications Of The Social Media Gang

Informal missives have played quite the role in the ongoing coronavirus saga locally, the earliest such of which was probably the advice by four doctors to wear a mask if possible, from last February; this would be dismissed by a medical chief, but well, we know what happened. After a long lull, unofficial channels would be called back into action with a Dr. Lye from the NCID calling on Singaporeans to "do much more beyond what government dictates" - including forming and sticking to small social bubbles - in the middle of May, right before the latest wave. Fearmongering or otherwise, we remain in all-but-lockdown, so I suppose it was not too far off credibility.

Not all such open letters have been home runs, though; a few days after Dr. Lye's plea, a group of twelve doctors would appeal to MOH to approve a (particular?) "killed-virus vaccine" with an accompanying host of reasons, mainly a focus on balancing the relative harmlessness of the coronavirus for children, with the unknown long-term effects of mRNA vaccines. For their pains, the dissenting dozen would have their arguments trashed by a Senior Minister of State for Health, the local expert committee and further an expert on emerging infectious diseases at Duke-NUS. This has led to eleven of the doctors retracting their opinion; well, to be frank, I can admire those who stand by their convictions, and it might be noted that the points on short and unknown potential long-term effects of mRNA vaccines had been addressed by one expert telling The State's Times that "...we should not worry about what happens 10 to 20 years later. We will deal with future problems if and when they arise". That's one way to think about the issue, I suppose.

These doctors' advocacy for killed-virus vaccines would be interpreted as a drive to get Sinovac approved by some - which it has, just last week, under the Special Access Route (i.e. not as part of the official national vaccine programme). Some have identified an undercurrent of "pro-[China], anti-vax propaganda" among middle-aged boomers in recent years (which I have observed personally), for which the Manglish grammar (example message) has been suggested to act as a filter of sorts (as with email scams), and/or foster relatability. On this, Dr. Lye of WhatsApp warning fame has (been prodded to?) call out the inaccurate science on Sinovac viz-a-viz mRNA vaccines, in particular emphasizing that there remains hardly any data on Sinovac's efficacy, which I suppose is true. Notably, even the Moderna option appears not especially popular locally, so limited expected uptake for a vaccine with only 60+% self-claimed efficacy is hardly unthinkable.

Dr. Lye's latest message will be referenced several more times in the following exposition - as it just has by Dr. Danny Soon in the local news on drug safety (which includes an observation on Viagra's unexpected off-label uses resulting in happy endings, har har) - but now, the more-specific analyses:

Have A Cold One Two

"Straightforward Trade War doesn't sound so bad now, eh?"
"Now that you put it this way..."

(Source: scmp.com)

Beneath the "scientific" figures for efficacy and transmissibility and whatnot, however, it can hardly be denied that a deeper and more ominous battle has been brewing under the prim and proper facade. Regrettably, the millions of excess dead from the coronavirus will probably be regarded as an appendix to what will very probably be recognized as Cold War II. Personally, I had been hoping for a sensible, restrained, businesslike, honourable approach to the likely-unavoidable conflict, as pursued by the previous U.S. administration, where demands and transactions were laid out clearly; instead, it's sadly shaping up to be another dirty affair involving copious mindf**kery, as the first edition was. The new admin has only doubled down on the hostility, expanding the previous more-circumspect list of China-based companies banned from investing in America, while fanning military assets across the Pacific and not-so-subtly assembling an anti-China coalition.

A fuller discussion on geopolitical developments would really warrant a post of its own, so we'll restrict ourselves to the role that the coronavirus, the vaccines and other related therapies are playing in The Greatest Game at present. This topic had been raised this March too, of course, and I would have to put it as a draw tilting America's way, for now. In China's favour, they have managed to keep a tight lid on virus spread - officially, at least - through methods incompatible with democratic governance. This twofold achievement - both in on-the-ground pandemic management results and internal narrative control - stands in stark contrast to the self-sabotage brought about to a large extent by competing political parties jostling for advantage at all costs, and amplified by the mainstream FAKE NEWS, in America. Simultaneously, China has also been pretty overtly flaunting their scitech capabilities, most prominently their unmanned Moon and Mars landings over the last half a year.

Left largely unsaid, though, is that these accomplishments are literally fifty years behind the state-of-the-art, and in the natural head-to-head contest of scientific ability that everybody cares about - i.e. vaccine development - China remains some distance off the best of the West. Their Sinovac/Sinopharm offerings based on traditional killed-virus tech have achieved efficacies of just 51% to 79%, as compared to the roughly 95% claimed by the spanking-new mRNA vaccines, before delving into the ancillary signal of them being unable to even come up with any numerical estimates against the coronavirus variants. One downside of officially claiming to have all but eradicated the virus domestically, whatever the degree of truth, is that one can then hardly present research based on nonexistent local cases. Of course, it doesn't seem that complicated to liaise with hard-hit foreign nations to obtain such data... just that China has, for whatever reasons, been unable to do it. I'm not saying that this sort of hamstringing is good in a humanitarian sense, but it does suggest that China may not have all that many firm friends willing to defy the current world order for them, out there.

One could, then, view the soft rejection of Sinovac versus Pfizer/Moderna (and wise diversification of sources in inviting Sanofi etc. for the future) as a hint towards a country's leanings, though to again clarify, I maintain no preferences where it comes to the purer pursuit of science and medicine; I simply call it as I see it. Well, a mutual (probably one-sided) vaccine passport might take the sting out of it somewhat, and there might be a delicious irony in handing off the excess Sinovacs to Taiwan (okay, or neighbouring countries), after the apparent collapse of their Pfizer/BioNTech deal over an unseen technicality. This comes as the formerly tinfoil-hatter Wuhan lab leak "conspiracy theory" turns out to be a distinct possibility after all (but more on that next time), which has China's state media now warning about preparing for nuclear war, as America sets up for a deeper probe into the theory. Ah, for firm, logical, optimistic, professional international diplomacy again...

The Early Treatment Cures The Worm

Was there really *nothing* that could be done for early cases?
(Source: c19legacy.com)

The previous two blog posts have already been centered about the potential of early treatment, which I do sincerely believe is the biggest story not being told right now, as described by a NY Times bestselling author, whose actual formerly-prize-winning investigative journalism would somehow be blanket-rejected by the mainstream media to the extent that he had to publish it in a local Pennsylvanian magazine that his wife is the editor of (shades of Dr. Tambyah, the MS-IHU HCQ study and the IJID, methinks). Being in Singapore, it is easy to forget that access to vaccines - and moreover having the luxury to quibble about Pfizer vs. Moderna vs. Sinovac - is actually a rare privilege, with barely 12% of the global population having received at least one dose of any vaccine as of today, despite over 2 billion doses supposedly administered. While the current POTUS is pushing to vaccinate the world, he appears unlikely to even reach his domestic goals despite some more-progressive states going as far as to offer weed for jabs, and India for one may have some choice words about grand vaccine supply pronouncements; in any case, more-realistic timelines expect vaccinations in less-developed countries to drag well into 2023, at best.

Against this backdrop, it is easy to understand why many of these up-and-coming nations would be eager for anything at all that might help - and on the cheap - and on this, one would sadly have to admit that global health authorities have perhaps been worse than useless thus far. With bullshit, one can at least use it as fertilizer to grow crops (if not, please, as coronavirus treatment), and it doesn't draw large salaries to stomp potential remedies. We have probably said more than enough about HCQ since the previous year's #Lancetgate, and if that were too politically-compromised, there were always options as benign as Vitamin D and even sunlight exposure, the former of which increasingly seems to have an association with coronavirus severity and mortality. Now, one doesn't want to oversell such results, certainly, even if you'd be really hard-pressed to overdose on Vitamin D; at some point, I think it reasonable to say that, look, one can kill oneself with anything if stupid enough, it's not really a valid excuse to shut stuff down.

HCQ for one appears to be enjoying a minor renaissance of sorts, with a number of new studies finding that, well, if you aren't an idiot with the dosages and apply it early enough, there's likely some benefit to be had. Please note, however, that I am hardly being picky in promoting potential early treatments here - if povidone-iodine throat spray or Vitamin C+Zinc gets you 20+% absolute risk reduction over the baseline of Vitamin C alone, with Vitamin C by itself not unlikely to have some minor protective effect, excellent - recommend it by all means! Instead, the powers that be appear more interested in insisting that the evidence is not good enough by stating that there is no evidence (note the shift in implication), while demonstrating a distressing lack of interest in verifying the impact of all but any of these inexpensive and accessible mitigations.

There are, one supposes, a number of very good reasons for finding such early treatments, in addition to (not replacing, mind) vaccines. Firstly, as just mentioned, vaccines are and remain unavailable to large swathes of the global population, and it must border on the criminal to deny these people improved odds upon infection through some common medication, if it were available and efficacious. Secondly, the efficacy of the non-mRNA vaccines that many of those in less-resourced countries will likely have to rely on, has never been particularly high; from 50% to 80% has been reported for the likes of AstraZeneca, J&J, Sinovac etc. on the original strain, with reduced efficacy probable for variants - and given that new (and future) variants seem to crowd out the old, one might expect the practical efficacy to be towards the lower end. Thirdly, it is becoming increasingly accepted that the coronavirus is here to stay in some form or other anyway, so one would expect a continuing need for early treatment - and, as a bonus, there are indications that being infected may have a similar protective effect as vaccination, which seems to imply that if a patient is treated early and recovers, he's safe too.

Well, among the many contenders for salvator mundi from the coronavirus, one candidate has stood out from the pack in recent months: Ivermectin.

The Case For & Against IVM

What constitutes "reliable evidence"?
(Source: wikipedia.org)
[N.B. For convenience, the cited sources [16],[17] & [18]]

In many ways, the story of Ivermectin (IVM) has paralleled that of HCQ; huge excitement amongst some front-line practitioners at a potential easy, cheap sorta-fix to the pandemic, and then silence, derision and outright animosity from major health agencies and organizations. IVM's story has been well-recounted by Capuzzo and others, with much of its initial advocacy coming from Drs. Paul Marik and Pierre Kory in the States. Notably, the latter's earlier support for steroid usage in hospitalized patients has contributed to it becoming current standard of care (with Dexamethasone; though observe how even that has been spun on Wikipedia, against the word of a single critic), so it can hardly be claimed that they are entirely unqualified to speak on the matter. They, along with a number of other doctors, have since formed the Front Line COVID-19 Critical Care Alliance (FLCCC) to promote their I-MASK+ prevention and early treatment protocol, which includes IVM, Vitamins C and D3, Zinc and a number of other common medications, in what by all means appear to be entirely unremarkable doses.

So the story goes, largely vindicated by the acceptance of steroid treatment in late-stage patients, Dr. Kory went before the U.S. Senate pushing for Ivermectin to be considered by the NIH, only to be boycotted by eleven of the fourteen Senators on the committee (many of whom, one might note, have been amply funded by Big Pharma) - and to rub it in, the testimony and later podcasts on the subject would be entirely censored on YouTube (since rehosted elsewhere or restored). Now, one wonders - the doctor might not be entirely correct, perhaps he might be exaggerating somewhat, but is he not allowed to say his piece? Mind, if spreading inaccurate information warrants a ban, the channels of the WHO, NIH, CDC etc. would probably have to be set on fire and dumped into a pit, long ago.

Anyway, the months since Dr. Kory's December testimony have seen the FLCCC and other proponents apparently manage to convince a number of local authorities throughout the world to give IVM a shot, and given that one can hardly expect the actually-infected to be content with sitting on their arses and waiting to know whether they're part of the unlucky bunch, take-up appears to have been pretty broad. Mexico City appears one of the early success stories, for one, and it is hardly a stretch that places such as India, South Africa, Argentina and Peru, where anti-malaria drugs such as HCQ and IVM might have already been widely used, would be willing to give it a go. The impact in these places have been reported to be astonishing - a dizzying plunge in the number of coronavirus cases and deaths. Of course, correlation is not causation, something else might have been responsible, and I'm not a huge fan of relying on trends as evidence for, say, the utility of face masks either. So, let's move on to the actual trials on Ivermectin.

Now, recall when IVM was being derided as HCQ v2.0, in some quarters? This is hardly a baseless comparison, given that they are both common, cheap and slandered by supposed health authorities; however, if initial indications hold up, IVM is distinguished by one characteristic, that furthers its claim to be an improved Version Two: it really, really works.

Is this a vaccine?
(Source: ivmmeta.com)

It's not too hard to kill a treatment with a weak-to-moderate effect (to be explored later), but according to the evidence put forth by the FLCCC and other IVM supporters, the efficacy of IVM is so obvious as to be undeniable. Perhaps cognizant of the issue over RCTs and having the bulk of the evidence base outright denied for HCQ, there have been a relatively-large number of RCTs run for IVM at this point - about twenty - and they apparently almost all point, and strongly at that, in the same direction: IVM very good against the coronavirus. Moreover, it has been observed that the general effect has hardly changed with additional RCTs over time, further suggesting that the experiments are relatively unbiased.

Now, the opposition. There is, to begin with, the usual argument that the above evidence is insufficient (oft further twisted into "there is no evidence" in the mass media) and that more trials are needed. To this, the counter has been that there have already been over 50 trials involving over 18,000 patients, about all pointing the same way, and that (more expensive) drugs have been approved with far fewer trial participants, and while showing far weaker effects, and with many accompanying claims not actually backed by RCTs. As for IVM being applied in various combinations, my perspective remains that the findings should remain largely valid if IVM is the common factor there, further following the machine learning intuition on the strength of combining multiple heterogeneous/weak learners.

There is an interesting connection with Dr. Lye's message here, in which he warns that Ivermectin had not been proven effective, and that "evidence cited for Ivermectin in COVID included the faked database company called Surgisphere which led to two journal retractions from the prestigious NEJM and Lancet in 2020" (i.e. #Lancetgate), and that "...a large trial on ivermectin conducted at a dormitory by National University Hospital doctors including Dr Paul Ananth Tambyah was not effective in preventing Covid-19". To this, it should be evident to my longtime readers that #Lancetgate had been crafted to discredit HCQ as its main objective, and no direct reference to IVM could be found in the retracted fake Lancet paper, in the first place. On the second point, the NUS/NUH Seet et al. paper purporting the efficacy of HCQ (notably unmentioned by Dr. Lye) appears to actually indicate a significant reduction of acute respiratory symptoms and symptomatic coronavirus by IVM, just that it was hidden in a data table. This 50% reduction in progression to severe symptoms (moreover with relatively low 12mg total doses compared to the other RCTs) was then what was included in the ivmmeta.com meta-analysis, congruent with their practice of pooling analysis on the most serious outcome reported, which one supposes is not entirely unreasonable.

The FDA's current stand, for posterity
(Source: fda.gov)

That clarified, other objections to early treatment with IVM include its danger, which one supposes cannot be much greater than any plausible medication, given how IVM had been considered by the WHO and various (formerly?) prestigious medical journals for mass administration even for young children, against malaria. And then there are jibes at IVM being "horse/dog medicine", but frankly it is unsurprising that anti-parasitics can work on both humans and other animals - and if we were going by this logic, many perfectly-good antibiotics would have to be forsworn. And next there are the objections that Merck - the original patent holder of IVM - has not supported its use against the coronavirus, but it might be observed that their patent has since expired and IVM is being produced as a generic drug in many countries, that Merck has been developing its own new experimental therapeutics (for which they have just signed a US$1.2 billion deal with the U.S. government), and that an actual discoverer of IVM - the Japanese Nobel Prize winner Satoshi Omura - appears actually supportive of its possible application against the virus.

The battle rages on in academia too, and while there have been a number of complementary meta-analyses - hardly unexpected given the published evidence, unless there is some hidden trove of negative studies in addition to the contested Colombian study that made it to JAMA - there has hardly been a lack of opposition in that sphere. A commentary in BMJ Evidence-Based Medicine, for example, claims improper collation of evidence in other meta-analyses (though it may be telling that they did not simply conduct their own proper such analysis as a refutation, instead of just stating an opinion), and the argument that in vitro experiments suggest that unsafe dosages are required for impact - on this, one might shrug and figure that maybe it doesn't work in (simulated) theory, but if it works in practice (as measured by the various RCTs), what is the complaint here?

One other group did write up their own meta-analysis against IVM, which was so hilarious that it deserves special mention. The initial preprint included ten RCTs, with the primary thesis that IVM did not reduce all-cause mortality versus the controls (RR=1.11), along with a host of other claims that IVM bad. Those following the IVM situation would unavoidably be puzzled at how they managed to come up with that finding by combining any ten of the existing RCTs - almost all strongly positive, mind - and quickly found that the authors had swopped the IVM and control results for a key component study, and that when corrected, the relevant RR is about 0.34 (i.e. 66% reduction in fatalities, broadly in line with other meta-analyses). Now, I don't like to slam researchers too hard for such mistakes, we have probably all made them, and the authors did go on to correct the transposition in the second version... while seemingly nudging the study weights around to leave the effect marginally non-statistically significant (RR=0.37, 95% C.I.: 0.12-1.13). Well, I'll be watching out as to which mainstream media outlets cite this paper in their articles, if it somehow gets published, to argue that yes, 63% fewer deaths, but why should you care?

CCP propaganda, or a despairing cry at an uncaring, mad world?
(Source: twitter.com)

The Trial By Fire (And Worse, Politics)

In any case, the momentum for IVM seems to have reached something of a critical mass of late; at least one British doctor has resigned his practice over the IVM/HCQ cover-up, even as the British Ivermectin Recommendation Development Group (BiRD) gets their summit kicked off YouTube, and guest editors step down from the Frontiers in Pharmacology journal over what they viewed as unwarranted suppression of papers suggesting positive results for IVM in early treatment. If it's any consolation at all, social media platforms appear to be wavering on the censorship and misdirection, likewise belatedly in the scientific community. Notwithstanding Gavi, the Vaccine Alliance going as far as to pay for Google Adwords to advertise against IVM (when the FLCCC/BiRD etc. have always maintained the necessity of vaccines in the first place), IVM has been going places.

While application in the West appears still limited, with a prominent convert in Germany, adoption in less-developed (and vaccine-short) regions of the world seems to only be increasing. India and Brazil aside (the latter for which BBC News continues to smear IVM as a "bogus remedy" by stating that "according to several leading health authorities, there's no evidence to back up those claims"), ASEAN appears to be getting very interested as well, as foreshadowed in the previous blog post. Indonesia is beginning IVM distribution in Kudus after an encouraging meta-analysis by researchers from Pelita Harapan University, and Malaysia's Ministry of Health has started a 500-person I-TECH study on IVM in high-risk patients, apparently after popular lobbying and with underground prescription already taking place. Much the same is happening in the Philippines, with the University of Philippines set to hold trials, alongside a newly-submitted bill to enable emergency use of IVM in Japan (its homeland, after all), and more encouraging results from Israel.

The counterstrikes have begun, so it seems, with the Directorate General of Health Services in India suddenly removing IVM (together with multivitamins and Zinc) from their guidelines, though it appears that their reach is limited to only three hospitals, and competing guidelines continue to support IVM (and HCQ, etc.), only several weeks after indications that they were ramping up IVM (and other protocol drug) production. However, Goa - one of the first states to defy the WHO's utter incompetency - seems to have made a sudden U-turn. Concurrently, the U.S. medical establishment has arranged several trials on IVM and related early treatments, among of which the most prominent are probably the ongoing TOGETHER trial (which dismissed HCQ after finding a hazard ratio of 0.76, 95% C.I.: 0.30-1.88 for preventing hospitalization), a forthcoming 1,100-person trial from the UMinn group that had provided the NEJM study oft pointed to as proof of HCQ's inefficacy (and which some have already observed to be rigged against IVM in its recruitment), and a huge 15,000-person ACTIV-6 trial by the NIH that has already drawn US$155 million in funding, and is only scheduled to finish up by 2023.

Well, one might expect three broad scenarios, for these forthcoming American and non-American trials:
  • Both the American & non-American trials find that IVM works: This is what would be expected from the RCTs thus far and, like, great for the world, and everyone can get on with their lives to a far greater extent... right? Very strangely, I somehow feel that a number of health professionals would not exactly be pleased at this outcome, but I really don't want to think too much about why that could even be the case.

  • Both the American & non-American trials find that IVM doesn't work: Yeah, this sucks, and one would have to puzzle about how results can seemingly flip overnight. But we'll see.

  • The American trials find that IVM doesn't work, and the non-American trials find it works: The most interesting outcome. What will the WHO recommend, then? Perhaps more trials on why cheap drugs seem to work elsewhere, but once imported into the U.S. - with arguably the best physicians and the most-advanced medical apparatus in the world - they somehow fail? Myself, if it works for some people, just let them have it, please.
[N.B. I am aware that there is a fourth combination, but I can't see how it's going to turn out that way, and am ready to make a fat donation to charity if that is indeed the case.]

The Reputation & Future Of Medicine

In his missive, Dr. Lye claimed that "[Medical] Doctors are well respected in our society". One can hardly disagree with that. Physicians do heal the sick, after all, and while lawyers for example also (sometimes) exonerate the innocent, the habitual difference in the level of vitriol from jokes directed at these two honoured professions might indicate a gap in their public image (not intended as a knock on lawyers, I know a few, they're nice fellas really). It would, therefore, be a real shame if the good name of medicine were to be dragged into the gutter, for being a Big Pharma-Big Government complex accessory to unnecessarily denying plausible and accessible treatments for early-stage patients, against its primary calling. Singapore appears to have avoided the worst of the U.S. Sickcare system's excesses thus far, as from last month's tangle between the SMA and insurers towards keeping the sector honest, at least.

Before continuing, I must clarify that I have nothing against the business side of medicine, or even the pharmaceutical industry in principle. Developing new drugs and cures takes resources, after all, and one can hardly expect the scientists and doctors to work for free. One believes there a lot of people with noble intentions in medicine and pharma. Say that the current standard of care for some disease is a US$10/month drug that is 70% effective. If a pharma firm invents an improved drug that is 90% effective, well, they should be able to charge what they want for it (even if much of the basic research had been done at universities with public money, fine); one hopes that they are sensible and not outright maliciously profiteering (which sadly, does not always seem the case), but one can hardly deny that the firms have the right to set their price.

Ethics in medicine is not always a simple affair, and it can be hard to insist on where the line is to be drawn (e.g. on the Right to Try), but purposefully sabotaging existing medications in a manner that does not maximize their efficacy, must certainly violate it. And, to be entirely honest, one senses that the public trust in doctors and medical experts is not as high as it was or could be, and not exactly trending higher. Errors are entirely forgivable if committed in good faith (though possibly irritating if common sense would have suggested otherwise, as with the initial recommendations on masks and border closures). There may be no coming back for a long while if the deception is thought to be intentional, however, which the Ivermectin/HCQ saga is threatening to blow the lid off on. One can scarcely imagine the blow to the profession's prestige were it found to work adequately in some countries, only to be clamped down by the medical establishment and a cabal of "top journals" in others. Eventually, despite the best efforts of the corrupt FAKE NEWS, the dissonance is likely to become too great to maintain.

More than enough has been said about the different-seeming standards of evidence for cheap remedies against vaccines (which have by the way minted nine new billionaires) and expensive novel drugs - note the grousing over the FDA approval for Biogen's Aducanumab for Alzheimer's a few days back (when one supposes that plenty of protein would do much the same), and of course the persistent media shilling for US$3,000+ a course Remdesivir, when the WHO's own supposed-authoritative SOLIDARITY trial couldn't even eke out any significant effect (not that I'm against anyone trying it, if they think it may help). One popular explanation has been that alternative treatments had to be blocked for the (non-approved) vaccines to get emergency use authorizations (EUA), which does seem the kindest possible explanation for what has happened, if those involved sincerely believed that mass vaccination was the best way out. Not saying I agree with the logic, just saying that it at least sounds within the bounds of probity and sanity.

Still, if this were the case, perhaps a better way might be to, you know, just tell the truth? Something like, "there are a number of promising early interventions, but we believe vaccines to be the more reliable solution, so let us withdraw the EUA requirement for there not to be any alternatives, so no possible mitigations are overlooked"? And then just get POTUS or the head of the NIH or Congress or whoever you need to overwrite the EUA, because it's not like any of these currently seem very interested in upholding even the Constitution, nowadays? Maybe... maybe humanity is NGMI, after all.

With language exchange included in the making!
[N.B. Original version/tempo]
[N.N.B. Note Tesla, "Superme", etc. as signifiers]
[N.N.N.B. Can't deny that the unity that money can buy (as at the end of the video), does seem tempting at times...]

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