academic freedom agit-prop, opinion manipulation and well-poisoning games Defending our Civilization Economics and policy issues Epistemology (the study of knowledge and its conditions) Geo-strategic issues Medicine

Dr Thomas Frieden, formerly Director of the US CDC, 2017 in NEJM, on the need to go beyond placebo-controlled studies as “gold standard”

Spread the love

One of the key steps in dismissing evidence of efficacy of hydroxychloroquine-based cocktails in treating early stageCovid-19 for patients in vulnerable groups on an outpatient basis is the use of the premise that such evidence is of low quality as it does not match the “gold standard” of placebo-controlled, randomised tests (often. RCT’s). However, observations are observations, natural regularities are often observable from the first few trials, evidence is evidence, ethical and practical considerations are real, and valid scientific methods do not reduce to applied statistics.

It is in that context that we should attend carefully to remarks by Dr Thomas Frieden, writing in NEJM 3 1/2 years ago, in terms that uncannily anticipate our current woes:

Despite their strengths, RCTs have substantial limitations. Although they can have strong internal validity, RCTs sometimes lack external validity; generalizations of findings outside the study population may be invalid.2,4,6 RCTs usually do not have sufficient study periods or population sizes to assess duration of treatment effect (e.g., waning immunity of vaccines) or to identify rare but serious adverse effects of treatment, which often become evident during postmarketing surveillance and long-term follow-up but could not be practically assessed in an RCT. The increasingly high costs and time constraints of RCTs can also lead to reliance on surrogate markers that may not correlate well with the outcome of interest. Selection of high-risk groups increases the likelihood of having adequate numbers of end points, but these groups may not be relevant to the broader target populations. These limitations and the fact that RCTs often take years to plan, implement, and analyze reduce the ability of RCTs to keep pace with clinical innovations; new products and standards of care are often developed before earlier models complete evaluation. These limitations also affect the use of RCTs for urgent health issues, such as infectious disease outbreaks, for which public health decisions must be made quickly on the basis of limited and often imperfect available data. RCTs are also limited in their ability to assess the individualized effect of treatment, as can result from differences in surgical techniques, and are generally impractical for rare diseases.

Many other data sources can provide valid evidence for clinical and public health action. Observational studies, including assessments of results from the implementation of new programs and policies, remain the foremost source, but other examples include analysis of aggregate clinical or epidemiologic data . . .

He also presents a table of options with strengths and weaknesses, which we now sample:

Dr Thomas Friedman on strengths and limitations of Placebo controlled testing

Later in the same article, as he concludes, he also notes:

There is no single, best approach to the study of health interventions; clinical and public health decisions are almost always made with imperfect data (Table 1). Promoting transparency in study methods, ensuring standardized data collection for key outcomes, and using new approaches to improve data synthesis are critical steps in the interpretation of findings and in the identification of data for action, and it must be recognized that conclusions may change over time. There will always be an argument for more research and for better data, but waiting for more data is often an implicit decision not to act or to act on the basis of past practice rather than best available evidence. The goal must be actionable data — data that are sufficient for clinical and public health action that have been derived openly and objectively and that enable us to say, “Here’s what we recommend and why.”

In that context, it is appropriate for me to again highlight a diagram on sustainability oriented decision making, adapted from the Bariloche Foundation of Argentina:

Where, BAU is in fact a natural baseline of reference. We seek a more satisfactory alternative, ALT. It must be credible enough incrementally to justify onward exploration and that first requires becoming a candidate for more costly investigation that shifts epistemic probabilities. Where, of arguments by/among clever people there is no end, so empirical demonstration at various levels is pivotal.

Here, epistemology of empirically based knowledge does not allow for gold standards that impose selective hyperskepticism against otherwise reasonable evidence. Evidence is evidence (and various uncertainties, risks and potential for errors cannot be wholly eliminated). So, we must recognise that BAU is a baseline/ benchmark/ control, and there is no strict necessity to construct an artificial, no effective treatment baseline; call it 0TB.

After all, the point is really to improve outcomes from BAU, and gap analysis ALT vs BAU has no inherent reference to 0TB. Algebraically, on credible or observed outcomes, we see this from

(ALT – 0TB) – (BAU – 0TB) = ALT – BAU

Where, with people as test subjects, if 0TB is based on deception — e.g. sugar pills deliberately mislabelled and presented under false colours and ceremonies of medicine and research in the face of significant risk of harm to vulnerable patients — and has potential for significant harm, it becomes ethically questionable. We know of extreme cases of concentration camp experimentation, the Tuskegee syphilis atrocity and more. However in more recent times, people have been subjected to fake surgeries under general anesthesia etc. The placebo effect has covered a multitude of sins.

In the face of pandemic, urgency is another issue. What yields results in a timeframe relevant to taming the surge of cases becomes a highly relevant criterion. As does the tradeoff of lives lost under various treatment, public health [e.g. quarantines vs general lockdown] and policy options. Where, relevantly, economic dislocation carries a toll in health and lives too. (It is suggested by some that deaths of despair and from postponed medical procedures may/do exceed those attributed to the epidemic.) This means BTW that the dismal science, Economics, has a seat at the decision makers’ table as of right.

It is time for mindset change. END

PS/UD Aug 15: I have found at Bit Chute, a July 28 Frontline Doctors seminar which describes several mechanisms of action. Accordingly, I take liberty to annotate a screenshot, summarising several mechanisms of action described by these Doctors [cf. here for their references], but which are hard to find because of now almost pervasive censorship:

I note, this first answers a puzzle on the mode of action, shape-shift of ACE2: the shift is INTERNAL to the cell by hindering “glycation” of the final AA (thus prior to exposure to buffering of blood etc), altering the shape enough to hamper S-protein reception. This reduces fusion with bilipid layer and RNA injection.

Other direct mechanisms as noted, reduce intracellular acidity thus action of organelles. They highlight stalling of assembly of new viri in the Golgi bodies, with implication of blocking export of fresh viri, thus hampering the multiplication chain. The by now well known indirect activity is that as a lipophilic molecule, HCQ enters the cell bilipid layer membrane, acting as a Zn ionophore, i.e. it “shoots” Zn into the cell. Zn in turn hinders a key viral enzyme, RdRP.

Thus, we see a plausible picture of causal action, involving multiple, synergistic effects. This lends credibility to the use of HCQ-based cosctails in treating the early viral phases of CV19.

PPS: Given tendencies to be dismissive, I here reproduce two key illustrations/charts from Dr Raoult’s work on now over 3,000 patients at IHU in Marseilles France.

First, his statistical summary on difference made with vulnerable groups through HCQ-Azithromycin treatment, by May:

We note that expected death rates for vulnerable groups are as high as 15%.

Next, here is a chart from his early, about 80 patient stage, illustrating rapid reduction of viral load . . . for which we now have specific, scientifically plausible causal mechanisms on the table:

I add, just for stirring the pot, a Frontline Doctors chart on CV19 case fatality rates vs accessibility of HCQ:

Thus, we see good reason to accept that HCQ-based cocktails (which were available from the outset of the pandemic) are credibly effective and should not have been treated with the extreme skepticism, hostility and suppression we have instead seen. Note, the leader of the Frontline Doctors, Dr Simone Gold, was fired immediately on leading a public protest. Frankly, that smacks of whistleblower retaliation.

It is appropriate to raise pointed questions, through the voice of the doctors writing an open letter to Dr Fauci:

>>There is currently no recommended pharmacologic early outpatient treatment for individuals in the flu stage of the illness, correct?
It is true that COVID-19 is much more lethal than the flu for high-risk individuals such as older patients and those with significant comorbidities, correct?
Individuals with signs of early COVID-19 infection typically have a runny nose, fever, cough, shortness of breath, loss of smell, etc., and physicians send them home to rest, eat chicken soup etc., but offer no specific, targeted medications, correct?
These high-risk individuals are at high risk of death, on the order of 15% or higher, correct?
So just so we are clear—the current standard of care now is to send clinically stable symptomatic patients home, “with a wait and see” approach?
Are you aware that physicians are successfully using Hydroxychloroquine combined with Zinc and Azithromycin as a “cocktail” for early outpatient treatment of symptomatic, high-risk, individuals?
Have you heard of the “Zelenko Protocol,” for treating high-risk patients with COVID 19 as an outpatient?
Have you read Dr. Risch’s article in the American Journal of Epidemiology of the early outpatient treatment of COVID-19?
Are you aware that physicians using the medication combination or “cocktail” recommend use within the first 5 to 7 days of the onset of symptoms, before the illness impacts the lungs, or cytokine storm evolves?
Again, to be clear, your recommendation is no pharmacologic treatment as an outpatient for the flu—like symptoms in patients that are stable, regardless of their risk factors, correct?
Would you advocate for early pharmacologic outpatient treatment of symptomatic COVID-19 patients if you were confident that it was beneficial?
Are you aware that there are hundreds of physicians in the United States and thousands across the globe who have had dramatic success treating high-risk individuals as outpatients with this “cocktail?”
Are you aware that there are at least 10 studies demonstrating the efficacy of early outpatient treatment with the Hydroxychloroquine cocktail for high-risk patients — so this is beyond anecdotal, correct?
If one of your loved ones had diabetes or asthma, or any potentially complicating comorbidity, and tested positive for COVID-19, would you recommend “wait and see how they do” and go to the hospital if symptoms progress?
Even with multiple studies documenting remarkable outpatient efficacy and safety of the Hydroxychloroquine “cocktail,” you believe the risks of the medication combination outweigh the benefits?
Is it true that with regard to Hydroxychloroquine and treatment of COVID-19 infection, you have said repeatedly that “The Overwhelming Evidence of Properly Conducted Randomized Clinical Trials Indicate No Therapeutic Efficacy of Hydroxychloroquine (HCQ)?”
But NONE of the randomized controlled trials to which you refer were done in the first 5 to 7 days after the onset of symptoms- correct?
All of the randomized controlled trials to which you refer were done on hospitalized patients, correct?
Hospitalized patients are typically sicker that outpatients, correct?
None of the randomized controlled trials to which you refer used the full cocktail consisting of Hydroxychloroquine, Zinc, and Azithromycin, correct?

While the University of Minnesota study is referred to as disproving the cocktail, the meds were not given within the first 5 to 7 days of illness, the test group was not high risk (death rates were 3%), and no zinc was given, correct?
Again, for clarity, the trials upon which you base your opinion regarding the efficacy of Hydroxychloroquine, assessed neither the full cocktail (to include Zinc + Azithromycin or doxycycline) nor administered treatment within the first 5 to 7 days of symptoms, nor focused on the high-risk group, correct?
Therefore, you have no basis to conclude that the Hydroxychloroquine cocktail when used early in the outpatient setting, within the first 5 to 7 days of symptoms, in high risk patients, is not effective, correct?
It is thus false and misleading to say that the effective and safe use of Hydroxychloroquine, Zinc, and Azithromycin has been “debunked,” correct? How could it be “debunked” if there is not a single study that contradicts its use?

Should it not be an absolute priority for the NIH and CDC to look at ways to treat Americans with symptomatic COVID-19 infections early to prevent disease progression?
The SARS-CoV-2/COVID-19 virus is an RNA virus. It is well-established that Zinc interferes with RNA viral replication, correct?
Moreover, is it not true that hydroxychloroquine facilitates the entry of zinc into the cell, is a “ionophore,” correct?
Isn’t also it true that Azithromycin has established anti-viral properties?
Are you aware of the paper from Baylor by Dr. McCullough et. al. describing established mechanisms by which the components of the “HCQ cocktail” exert anti-viral effects?

So- the use of hydroxychloroquine, azithromycin (or doxycycline) and zinc, the “HCQ cocktail,” is based on science, correct?>>

123 Replies to “Dr Thomas Frieden, formerly Director of the US CDC, 2017 in NEJM, on the need to go beyond placebo-controlled studies as “gold standard”

  1. 1
    kairosfocus says:

    Dr Thomas Frieden, formerly Director of the US CDC, 2017 in NEJM, on the need to go beyond placebo-controlled studies as “gold standard”

  2. 2
    jerry says:

    Kf,

    Good luck with this. The logic is impeccable. Brings back graduate school with internal and external validity.

    My guess is they will not address the obvious but divert.

  3. 3
    Bob O'H says:

    As kf hasn’t provided it, here’s the link to the full article. I’m amused that kf didn’t quote this sentence:

    Determining when data are sufficient for action is difficult, but the bar should be much higher when recommending that millions of persons with no disease take medications.

    FWIW, I’ve never argued that retrospective studies can’t be used as evidence, rather that they have weaknesses that can make the inferences invalid. Frieden acknowledges this problem in the table. What this means is that retrospective studies have to be done carefully to make sure any potential confounders are identified and controlled for in the analysis. The studies that have mainly been pushed here (i.e. by Raoult and Zelenko) fail to do this.

  4. 4
    jerry says:

    The studies that have mainly been pushed here (i.e. by Raoult and Zelenko) fail to do this.

    Nonsense. Each has large numbers. Each indicates a degree of effectiveness that is high. The drugs are safe. The drugs are extremely inexpensive. It is sadistic not to allow their use.

    Now if someone doesn’t want to take them, so be it. But they should be made available and most definitely not disparaged.

    The most egregious disparagement was by Fauci of the Henry Ford study where deaths were cut in half and his comment was there was confounding issues. He didn’t say we see something that cut deaths in half. He dismissed the study. Revealing something not very pretty about himself.

    It turns out the study was re-evaluated and the conclusions were the same. And a near identical study in Italy showed the same thing.

    My guess is they will not address the obvious but divert.

    Didn’t take long. More to come I’m sure.

  5. 5
    kairosfocus says:

    BO’H: I thought I had, thanks, now provided, it is sitting in the next tab on my browser. KF

  6. 6
    kairosfocus says:

    Jerry, you are of course quite correct, and predictably the gold standard fallacy has led to selectively hyperskeptical dismissal. KF

    PS: For introductory reference on Decision Theory, try here.

  7. 7
    ET says:

    I’m amused that Bob is amused by an irrelevant sentence. OTC’s aren’t medications. For the most part they are essential vitamins and minerals.

    Again, that is why I choose quercetin over HCQ

  8. 8
    kairosfocus says:

    BO’H:

    >>FWIW, I’ve never argued that retrospective studies can’t be used as evidence, rather that they have weaknesses that can make the inferences invalid.>>

    1: ANY form of study has limitations that can invalidate its consequences.

    2: If possibility of error disqualifies or marginalises an approach, you have just disqualified human, error-prone, rationality.

    >> Frieden acknowledges this problem in the table. >>

    3: Cherry picking. As the excerpt of Table I in the OP illustrates, EVERY approach has strengths and limitations. Including, placebo based studies.

    >>What this means is that retrospective studies have to be done carefully to make sure any potential confounders are identified and controlled for in the analysis.>>

    4: Cherry picking again. EVERY approach including general reasoning, faces this challenge.

    >>The studies that have mainly been pushed here (i.e. by Raoult and Zelenko) fail to do this.>>

    5: In this, you are wrong, and your cherry picking, selective hyperskepticism and gold standard fallacies reinforce your error. See Jerry at 4.

    KF

  9. 9
    Bob O'H says:

    Jerry @ 4 – at least make an attempt to answer my criticism. I didn’t say that they were under-powered, so that they needed bigger numbers.

    Now, read what I wrote. If you don’t understand something, then ask. I appreciate you probably don’t get to think about these issues as part of your work, so you might be missing something, or I might be writing something that isn’t clear.

  10. 10
    Bob O'H says:

    ET – I was thinking about HCQ. Sorry if that wasn’t clear.

  11. 11
    kairosfocus says:

    ET, that may well work for prophylaxis. The cost-risk-benefit-uncertainties issues balance says that a low cost fairly safe “treatment” with enough reason to be plausibly effective is worth exploring. KF

    PS: $36 for 240, some suppliers are out of stock on Amazon. Sounds like my emergency resort to 70% alc by volume hi wine from Guyana which is 7 points above the mamby pamby limits they have put on Jamaica overproof rum; I don’t like a faint fruitiness, I don’t know what esters they are adding or if they are actually using fruit; for sure the odd pale tan colour is food colouring . Subsequently, I am buying sanitiser from Antigua’s main Rum Distillery which is 70% and smells suspiciously like white rum. Of course, isopropyl alcohol, 91% — my usual general purpose disinfectant, first resort solvent etc — is not on the cards for now and I cannot talk shop-keepers here into getting Everclear. I am also using cotton fabric face masks, trusting in the London intermolecular force, despite serious discomfort. Glasses are low risk standby for goggles, which I have waiting just in case. I am eyeing face shields. I wish guavas were running hot, and trust Mangoes as high vitamins etc superfruit. The trees in the garden are running a second crop in rapid succession. All of these pass a first tier cost-benefit-uncertainty assessment.

  12. 12
    Bob O'H says:

    kf @ 8 – it would be helpful for your case if you actually explained why poor control of confounders isn’t an important problem in the retrospective studies of Raoult and Zelenko, rather than just try to dismiss any criticisms.

    Yes, every methods has its weaknesses. But when discussing the weaknesses of one particular type of study, it’s not cherry-picking to mention the weaknesses of that particular type of study.

  13. 13
    kairosfocus says:

    BO’H, there is more than adequate evidence to hold HCQ-based cocktails as reliably effective and some is emerging that adding or substituting ivermectin will work. Also that this may be effective later in the disease course. FYI, the crucial point for me is rapid response to the course of medication, often in 1 – 2 days. That does not happen by accident. And it is cherry picking to fail to recognise that an in common possibility of error is being taxed against one alternative. Also, possibility of error and need for due care are across the board. I repeat, the downfall of so many critiques is rapid, reliable strong response to treatment. It works. KF

  14. 14
    jerry says:

    Now, read what I wrote.

    Now, read what I wrote. Is anything I wrote not true? No. Confounding is not an issue. It is a diversion as Fauci used it in a reprehensible way. Why pick two practicing doctors of C19 patients who had success saving lives? Who gives a rat’s rear end if the data is not 100% perfect? There is no downside to using their approach. Absolutely none. An incredible up side. Hundreds of thousands of lives might have been saved.

    The question has always been is why such a large number of successes repeated by many doctors around the world? Have all these doctors been duped?

    Why the suppression and obfuscation. That should generate outrage. But no, we get nitpicking.

  15. 15
    kairosfocus says:

    A reminder from Frieden:

    >>RCTs often take years to plan, implement, and analyze reduce the ability of RCTs to keep pace with clinical innovations; new products and standards of care are often developed before earlier models complete evaluation. These limitations also affect the use of RCTs for urgent health issues, such as infectious disease outbreaks, for which public health decisions must be made quickly on the basis of limited and often imperfect available data . . . .

    Many other data sources can provide valid evidence for clinical and public health action. Observational studies, including assessments of results from the implementation of new programs and policies, remain the foremost source, but other examples include analysis of aggregate clinical or epidemiologic data . . . >>

    KF

    PS: I adjusted highlighting in the OP.

  16. 16
    RHolt says:

    KF

    Of course, isopropyl alcohol, 91% — my usual general purpose disinfectant, first resort solvent etc — is not on the cards for now and I cannot talk shop-keepers here into getting Everclear.

    For your own, and others safety, high concentration alcohols are not an effective disinfectant. The high percent alcohols act to dehydrate and preserve, but not denature, viral proteins and this renders them ineffective. you need some water present to denature the proteins. Alcohols in disinfectant should be no less than 70% with 75% being more effective. High proof alcohols also evaporate too fast and reduce contact time. There is a great deal of literature on this and if you are interested I can dig them up and link them although they aren’t too difficult to find w/google.

    If higher alcohols, e.g., everclear, are available I suggest using The Who recipe. This recipe contains some glycerol to reduce evaporation and increase contact time as well as some peroxide which acts to kill any mold or fungi in the mix (the peroxide is relatively ineffective as an antiviral). The recipe is for 10-L but is easily scaled down for smaller volumes. One last point if ethanol and isopropyl alcohol is unavailable 1-propyl alcohol is equally effective (at the 75%) as a disinfectant. Below 70% is also ineffective. A 75% alcohol concentration will effectively denature and scramble viral proteins with a contact time of 30 seconds or so.

    Be safe out there. When this pandemic first started I also thought that higher percent alcohols would be better. I only discovered this to be not true after researching how alcohols act as a disinfectant and how to prepare a hand sanitizing solution since the store shelves were rendered bare. I was able to order some 99% isopropyl and ethyl alcohols, however. Surprised me but after reading the literature the chemistry behind the 75% solution(s) made sense. The Who recipe also produces a disinfectant that is suitable for surgeries in locales where clean water is scarce and hand washing is difficult, obviously poorer third world countries are the target for this option.

  17. 17
    RHolt says:

    ps sorry for the off-topic post I thought it was important info to help us all protect ourselves and loved ones during these trying times!

  18. 18
    kairosfocus says:

    RHolt, of course, I control my own dilution, why pay for the water at drug price rates? And yes I know the 70% debate. I want the option of all the way to get other effects, up to and including use as less toxic fuel than alternatives for spirit burners. It’s cheaper to add my own water. Oh yes, eyeglasses cleaner is a use mixed with soapy solution. I also use Chlorox 5.25% for certain things. And of course, I firmly believe in soap at 20 sec dwell time. KF

  19. 19
    Bob O'H says:

    kf @ 13 – OK, so you’re ignoring my critique. If you can’t provide any answer at all to these problems, then perhaps the studies aren’t as good as you think they are.
    Jerry @ 14 – Why is confounding not an issue?

  20. 20
    RHolt says:

    KF

    It’s cheaper to add my own water.

    Not to derail your thread too far but there is a breaking point with cost. Alcohol purity of 91% can be obtained with distillation. After that to get a higher percent alcohol, e.g., 95 and 99%, the producers have house chemical dehydration methods and this adds considerable to the cost. Sometimes you just have to bite the bullet and pay the higher price is high-percent reagent grade is all that is available.

    What is a ‘spirit burner’?

  21. 21
    ET says:

    And there is still a $200,000 reward for anyone who can show Dr. Z’s protocol is ineffective.

    What are Bob, RHolt and RHampton waiting for?

  22. 22
    daveS says:

    ET,

    Do you have a link to this reward? I don’t have any of the background required, but I wouldn’t mind reading the terms of the challenge.

  23. 23
    jerry says:

    Why is confounding not an issue?

    Because knowing exactly which variable contributed what is not the immediate issue. What is the immediate issue is that there is a result that is saving lives. What caused it exactly is certainly of interest but in the mean time moving forward with the protocol which is saving lives is the only consideration.

    There is no downside!

    There is a huge potential upside!

    Dithering over exactly which variable contributed what is for the future not while people are dying. That Fauci dismissed a treatment that reduced deaths by 50% is one of the most incredibly bad decisions of all time. As I said it reveals more about him than anything.

    Dismissing Raoult and Zelenko and thousands of other doctors because of possible confounding variables is right up there with that.

    Are the objections to HCQ and its subsequent suppression based on power, money or ego? Pick one or for some all three. Ignorance is not a choice.

  24. 24
    ET says:

    Jerry has been providing that, for weeks, now.

  25. 25
    Bob O'H says:

    Jerry @ 23 –

    Why is confounding not an issue?

    Because knowing exactly which variable contributed what is not the immediate issue.

    No, that is precisely the issue. If differences between the groups are due to HCQ, then great. But if they are due to (say) age, or initial severity of the disease, then you’re making the wrong inference.

    What is the immediate issue is that there is a result that is saving lives.

    But is it? How do we know? To be precise, how do we know that in the studies that have shown a difference between groups, it’s because of the treatment and not a confounder?

  26. 26
    daveS says:

    Oh well, probably best if I don’t find the link anyway. What with all the chores I have lined up for today.

  27. 27
    kairosfocus says:

    RHolt, a spirit burner would be familiar from Chemistry set days, a glass, shallow, metal topped bottle with a cotton wick that burns alcohol fuels. Useful for certain crafts, especially for softening lignin to bend wood. My current one is from a small Maraschino Cherry bottle. 90% is fine for that and for most solvent work. Mix down to dilute, the water here is spring water. I do not need reagent grade. KF

  28. 28
    kairosfocus says:

    DS, if you mean the Frieden paper, the link was added to the OP: https://www.nejm.org/doi/full/10.1056/NEJMra1614394 KF

  29. 29
    daveS says:

    Thanks, KF, I was actually referring to details about the $200,000 reward ET mentioned (nevermind, though, there really is no point in me reading about it).

  30. 30
    Mac McTavish says:

    RHolt

    What is a ‘spirit burner’?

    A Ghostbusters’ proton pack? 🙂

    Actually, alcohol burners are common in microbiology labs for sterilizing loops or tweezers between use. Dip the loop in alcohol, then place it in the flame of an alcohol burner.
    https://en.wikipedia.org/wiki/Alcohol_burner

  31. 31
    kairosfocus says:

    BO’H: We already know that key effects are plausibly coming from synergies so no one component is responsible for the effect. This is brought out in the string of questions in the open letter to Dr Fauci, here: https://www.thedesertreview.com/opinion/columnists/open-letter-to-dr-anthony-fauci-regarding-the-use-of-hydroxychloroquine-for-treating-covid-19/article_31d37842-dd8f-11ea-80b5-bf80983bc072.html and has been highlighted any number of times over months. For example a main antiviral action is from Zn ions, with HCQ serving as ionophore transporting across the bilipid layer. Azithromycin is a typical antibiotic targetting secondary infection and is known to have some antiviral activity. Zn, vits C and D are supplements in a context where dietary deficiencies are common. In addition, we know from 40 years of successful use as a fish tank cleaner using reasonably comparable concentrations that the CQ family attack across kingdoms so would target core molecular cellular functions, complex animals stand it better than unicellular organisms and the like, so delicate fish thrive, crud, marine ick etc die. The issue is that this is background to see how it works reasonably well in cases, with effective action for vulnerable groups. Where, safety is clearly manageable, never mind gross exaggerations that were trumpeted. In the face of a pressing emergency that should be enough. Later, go find a handy animal analogue and experiment to heart’s content on relative contributions, synergies and the like. The proper priority is to blunt a pandemic capable of killing 15% of vulnerable groups, without so crashing the global economy that dislocation, despair, bankruptcies, famine etc cause more losses than the pandemic. Where, it is seriously arguable that gold standard fallacies significantly contributed to needless losses on a material scale. History, for cause, will judge us harshly. KF

  32. 32
    kairosfocus says:

    MMT, Spirit burner is what I know it as, with direct parallel to Bunsen burner. I saw Wiki, I have a 4 inch flame burner depending on wick level; my wick is extra wide. Another one using a small Altoids can gives a linear flame with about 2 inch height. Beyond are chafing cans and gas hot plates etc. KF

    PS, are they still selling Heet yellow and red?

  33. 33
    RHolt says:

    i first thought of an alcohol lamp when KF mentioned ‘spirit burner’ then I began to think it might be a type of kitchen stove burner like a coleman-brand stove or, more applicable a MSR-type backpacking stove which can burn pretty much any fuel, i.e., gas, kerosene, or diesel, you have on hand. I see now he meant an alcohol burner/lamp.

  34. 34
    Mac McTavish says:

    KF

    my wick is extra wide.

    I was told that size didn’t matter. 🙂

  35. 35
    ET says:

    Mac:

    I was told that size didn’t matter.

    Yes, Mac, I am sure that you get that all of the time. 😛

  36. 36
  37. 37
    Mac McTavish says:

    RHolt@33, I only know about alcohol burners because in a past life I spent endless hours per day for a few years standing over one while filtering water samples and using flamed tweezers to transfer the filters to an agar plate. Making sure water is safe to drink and/or swim in can be very tedious.

  38. 38
    ET says:

    Holy crap, Mac. You sound as if you had/ have the same job as one Acartia Eddie George.

  39. 39
    Mac McTavish says:

    ET

    Holy crap, Mac. You sound as if you had/ have the same job as one Acartia Eddie George.

    Was he a microbiologist as well? But I haven’t done that for a little over thirty years. I’m sure they do it much differently now.

  40. 40
    ET says:

    He claims to be a marine biologist. However he was ignorant of the fact that a whale has a tail.

  41. 41
    Mac McTavish says:

    It has been over 30 years so I am sure that I am now ignorant of much of microbiology. KF’s mention of the alcohol burner just brought back some memories.

  42. 42
    ET says:

    And your memories sparked a deja vu. The timing of your arrival here, along with the fact that you had/ have the same job as a person who just left, I’m sure is just a coincidence.

  43. 43
    Mac McTavish says:

    Sorry, but I can’t be responsible for your imagination. What did this other guy do? I was a water treatment operator For three years. Collect samples from the distribution system, test them for chlorine, turbidity and pH using hand-held instruments, then bring some back to the plant for Colifirm testing by membrane filtration. Not exactly what I was expecting after a degree in microbiology. But I don’t imagine that I am unique in having unreasonable expectations after graduating.

  44. 44
    ET says:

    I am just making an observation.

  45. 45
    Mac McTavish says:

    Fair enough.

  46. 46
    jerry says:

    No, that is precisely the issue. If differences between the groups are due to HCQ, then great. But if they are due to (say) age, or initial severity of the disease, then you’re making the wrong inference.

    What could possibly be a cofounding variable? You indicate that you have not read any of the links provided you since the beginning or else you would have not made this statement.

    Age and severity of the disease are certainly not cofounding variables because they have been controlled for since the beginning. No other medicines have been given other than palliative care treatments such as Tylenol. This palliative care given is similar to that given to all the C19 patients in the US. So that is not a cofounding variable. If there is something else causing the almost universal success for these high risk patients to get better it would be an amazing medical discovery.

    For example, Zelenko only included those who had the virus and were high risk in his study, over 60 or those under 60 with comorbidities. All were treated with the first couple days of showing symptoms. You were pointed to this information over 4 months ago.

    How do we know? To be precise, how do we know that in the studies that have shown a difference between groups, it’s because of the treatment and not a confounder?

    As I said if there is a cofounder that is causing almost 100% success that would be the most amazing discovery of the entire virus scenario, probably one of the top 10 in medical history. Any suggestions for what could be this cofounder? If you find one you will make medical history and you are not even a medical doctor.

    So we have extremely high success with treating high risk patients early in the virus and no plausible competing explanation other than the treatment. I would go with the treatment and if there is a mystery factor, look for it. But the treatment has no down side and potentially an extremely high upside. And many other doctors also reporting similar results.

  47. 47
    rhampton7 says:

    Racey Muchilwa, head of Sub-Sahara Africa, Novartis, a multinational pharmaceutical company, sheds light on its Covid-19 programmes targeted at low and middle-income people of Nigeria and 78 other countries. The Interview was conducted by Taiwo Alimi.

    Note: Novartis is a manufacturer of HCQ

    Another drug, hydroxychloroquine (HCQ), has come into the picture thanks to the US president, Donald Trump. How do you think Nigerians should relate to this?

    It should be noted that the US FDA recently withdrew its emergency-use registration for hydroxychloroquine (HCQ) to be used in Covid-19 and several trials in mild and severe Covid-19 have not shown any benefit. However, there are still several trials ongoing researching its effectiveness to treat Covid-19. There is no current evidence to suggest that HCQ should be taken to prevent disease and if symptoms appear, people should seek advice from a healthcare provider.

    How much of R&D has been done and ongoing on Covid-19 pandemic in relation to Sub Saharan Africa?

    The Novartis HCQ trial was cancelled due to difficult recruitment and also based upon latest evidence emerging to show lack of benefit in COVID-19. That trial had a number of sites in South Africa. We are also aware of some trials being carried out in Sub Sahara Africa by independent organizations such as the DNDi. There are no Novartis clinical trials ongoing in SSA specifically relating to Covid-19; however we have a number of clinical trials ongoing in malaria and sickle cell disease in East and West Africa, with our efforts also being focused on clinical trials in other disease areas such as cardiovascular, eye disease and oncology. Our aim is to improve patient access and outcomes and to this end, expanding our clinical trial footprint in SSA allows us to build R&D capabilities and to diversify the body of evidence that exists from developed parts of the world.

    https://thenationonlineng.net/how-were-helping-low-income-nigerians-mitigate-covid-19-impact/

  48. 48
    rhampton7 says:

    Novartis’ Sandoz division, which had previously donated 30 million doses of HCQ tablets to the U.S. government for use in controlled clinical studies, announced in June that it had discontinued its own sponsored HCQ clinical trial for COVID-19, due to “acute enrollment challenges.”

    Immediately after this decision, Novartis CEO Vas Narasimhan, in an interview with Wired magazine, was asked what he felt the drugmaker’s responsibility was in clarifying that HCQ is not the miracle cure people had hoped it would be.

    “Right now, unfortunately, the words ‘study, results, scientific evidence’ in the media are not actually reflecting what scientists know is high-quality evidence,” Narasimhan told Wired.

    “There are studies that are very poor quality, or conjecture. And then we have appropriately powered randomized control blinded clinical studies, which is what regulators expect of us, and that is the only way to really know if a drug has an impact or not,” Narasimhan said.

    https://www.pharmamanufacturing.com/articles/2020/making-hydroxychloroquine-great-again/

  49. 49
    kairosfocus says:

    RH7, do you know who Dr Thomas Frieden is? Not that that adds to the intrinsic force of his point, but one hopes it would give pause. KF

  50. 50
    Bob O'H says:

    Jerry –

    What could possibly be a cofounding variable? You indicate that you have not read any of the links provided you since the beginning or else you would have not made this statement.

    I have read many, but perhaps not all of the links. I’ve read several of the papers that have been touted (but again, not all).

    Age and severity of the disease are certainly not cofounding variables because they have been controlled for since the beginning.

    Not in Zelenko’s study – the authors admitted that they didn’t know these for the control group. Raoult, of course, went one further by not even having a control group for some of his studies.

    No other medicines have been given other than palliative care treatments such as Tylenol.

    In any of the studies? Not according to this paper (l141-5): “We found that in several studies, patients used several molecules with established or potential antiviral properties. For instance, in China and Iran, almost all patients used multiple antivirals: lopinavir/ritonavir, oseltamivir, entecavir, ribavirin, umifenovir and nebulisation of interferon aerosol.”

    As I said if there is a cofounder that is causing almost 100% success that would be the most amazing discovery of the entire virus scenario, probably one of the top 10 in medical history. Any suggestions for what could be this cofounder?

    We know age and co-morbidities are confounders. We don’t know if the distribution of these was the same in the control group.

    So we have extremely high success with treating high risk patients early in the virus and no plausible competing explanation other than the treatment.

    We also have extremely high success with patients that are not treated with HCQ, because most patients recover anyway. I’m surprised you weren’t aware of this already.

  51. 51
    kairosfocus says:

    BO’H:

    again, you are setting aside evidence to speculate on marginal issues to cast a pall on something that is not too hard to see. At this stage, it is fairly obvious that the issues raised by Dr Frieden nearly four years ago and by others since simply have not registered.

    Meanwhile, if one takes up a pebble and drops it, it reliably falls.

    Beyond a certain point, issues of accidents/coincidence, possible interfering factors etc fade out and we begin to recognise that we face a reliable natural regularity. That is the level of the underlying problem: basic inductive reasoning is being unduly frustrated.

    And BTW, this is — unsurprisingly — the same challenge that is shown by common linguistic and technology patterns so that when we see say alphanumeric, string data structure algorithmic codes with molecular nanotech execution machinery, there is a strong, ideological polarisation backed refusal to acknowledge that there is a highly consistent cause of language, algorithms and execution machinery, intelligent design.

    The implication is, until the ideology is decisively broken, there will never be an acknowledgement of the balance of the matter.

    In the case at focus for this thread, the sort of evidence that — as Dr Frieden noted and many doctors from Raoult and Zelenko to Lozano and Simone Gold et al point out (sometimes, in the face of censorship, slander and dismissal) — reasonably can be expected under prevailing circumstances will be rejected on one excuse or another. Where, specifically, you have just brushed off a sharp and highly obvious change in death rates of vulnerable groups once early treatment has been given, a death rate which has been up to 15%, about one in 6 patients. Which is what business as usual has been facing.

    Where, let’s bring it down to algebra as the OP summarises:

    (ALT – 0TB) – (BAU – 0TB) = ALT – BAU

    The no effective treatment baseline does not make a material difference to identifying a credible change in outcome on shifting to a reasonable alternative. Your underlying reasoning seems rather similar to insisting on buying vehicles from a source with a high incidence of lemons because those who have bought the alternative just possibly might — absent duly complex, expensive and time consuming studies — be the result of coincidence or potential interfering factors.

    So, your “surprise” is about as rhetorical as Hume’s was when he set out to create a mystery on where moral government arises, shunting aside the obvious to obfuscate the self-evident.

    Just as, we see massive selective hyperskepticism with the design inference in cases where by the very nature of the past we cannot see the remote past of origins.

    Duly noted.

    KF

    PS: Some further questions from the open letter to Dr Fauci, seem appropriate:

    Is it not misleading for you to repeatedly state to the American public that randomized clinical trials are the sole source of information to confirm the efficacy of a treatment?
    Was it not misinformation when on CNN you cited the Lancet study based on false data from Surgisphere as evidence of the lack of efficacy of hydroxychloroquine?
    Is it not misinformation as is repeated in the MSM as a result of your comments that a randomized clinical trial is required by the FDA for a drug approval?
    Don’t you realize how much damage this falsehood perpetuates?
    How is it not misinformation for you and the FDA to keep telling the American public that hydroxychloroquine is dangerous when you know that there is nothing more than anecdotal evidence of that?

    PPS: Some of the earlier questions need to be faced again:

    While some doctors may not want to use the drug, should not doctors who believe that it is indicated be able to offer it to their patients?
    Are you aware that doctors who are publicly advocating for such a strategy with the early use of the HCQ cocktail are being silenced with removal of content on the internet and even censorship in the medical community?
    You are aware of the 20 or so physicians who came to the Supreme Court steps advocating for the early use of the hydroxychloroquine cocktail. In fact, you said these were “a bunch of people spouting out something that isn’t true.” Dr. Fauci, these are not just “people,” these are doctors who actually treat patients, unlike you, correct?
    Do you know that the video they made went viral with 17 million views in just a few hours, and was then removed from the internet?
    Are you aware that their website, American Frontline Doctors, was taken down the next day?
    Did you see the way that Nigerian [–> I think, actually Cameroun] immigrant physician, Dr. Stella Immanuel, was mocked in the media for her religious views and called a “witch doctor?” [–> incubus/ succubus is a notoriously longstanding, global phenomenon; describing it in colourful terms commonly used in W Africa is not relevant to observable result of treating 350+ patients, to me it seems that incubus/succubus is now driving entire billion dollar industries, national policy and a consequent policy that has destroyed 800+ million unborn over the past 40+ years . . . maybe we need to read the White Rose Martyrs pamphlet IV again]
    Are you aware that Dr. Simone Gold, the leader of the group, was fired from her job as an Emergency Room physician the following day?
    Are you aware that physicians advocating for this treatment that has by now probably saved millions of lives around the globe are harassed by local health departments, state agencies and medical boards, and even at their own hospitals? Are you aware of that?
    Don’t you think doctors should have the right to speak out on behalf of their patients without the threat of retribution?
    Are you aware that videos and other educational information are removed off the internet and labeled, in the words of Mark Zuckerberg, as “misinformation?”
    Is it not misinformation to characterize hydroxychloroquine, in the doses used for early outpatient treatment of COVID-19 infections, as a dangerous drug?
    Is it not misleading for you to repeatedly state to the American public that randomized clinical trials are the sole source of information to confirm the efficacy of a treatment?
    Was it not misinformation when on CNN you cited the Lancet study based on false data from Surgisphere as evidence of the lack of efficacy of hydroxychloroquine?
    Is it not misinformation as is repeated in the MSM as a result of your comments that a randomized clinical trial is required by the FDA for a drug approval?
    Don’t you realize how much damage this falsehood perpetuates?

    Also:

    In regards to the use of hydroxychloroquine, you have repeatedly made the same statement: “The Overwhelming Evidence from Properly Conducted Randomized Clinical Trials Indicate no Therapeutic Efficacy of Hydroxychloroquine.” Is that correct?
    In Dr. Risch’s article regarding the early use of hydroxychloroquine, he disputes your opinion. He scientifically evaluated the data from the studies to support his opinions. Have you published any articles to support your opinions?
    You repeatedly state that randomized clinical trials are needed to make conclusions regarding treatments, correct?
    The FDA has approved many medications (especially in the area of cancer treatment) without randomized clinical trials, correct?
    Are you aware that Dr. Thomas Frieden, the previous head of the CDC wrote an article in the New England Journal of Medicine in 2017 called “Evidence for Health Decision Making — Beyond Randomized Clinical Trials (RCT)?” Have you read that article?
    In it Dr. Frieden states that “many data sources can provide valid evidence for clinical and public health action, including analysis of aggregate clinical or epidemiological data.” Do you disagree with that?
    Frieden discusses “practiced-based evidence” as being essential in many discoveries, such SIDS (Sudden Infant Death Syndrome). Do you disagree with that?
    Frieden writes the following: “Current evidence-grading systems are biased toward randomized clinical trials, which may lead to inadequate consideration of non-RCT data.” Dr. Fauci, have you considered all the non-RCT data in coming to your opinions?
    Risch, who is a leading world authority in the analysis of aggregate clinical data, has done a rigorous analysis that he published regarding the early treatment of COVID-19 with hydroxychloroquine, zinc, and azithromycin. He cites five or six studies, and in an updated article there are five or six more, a total of 10 to 12 clinical studies with formally collected data specifically regarding the early treatment of COVID. Have you analyzed the aggregate data regarding early treatment of high-risk patients with hydroxychloroquine, zinc, and azithromycin?
    Is there any document that you can produce for the American people of your analysis of the aggregate data that would rebut Dr. Risch’s analysis?
    Yet, despite what Dr. Risch believes is overwhelming evidence in support of the early use of hydroxychloroquine, you dismiss the treatment insisting on randomized controlled trials even in the midst of a pandemic?
    Would you want a loved one with high-risk comorbidities placed in the control group of a randomized clinical trial when a number of studies demonstrate safety and dramatic efficacy of the early use of the hydroxychloroquine “cocktail?”
    Are you aware that the FDA approved a number of cancer chemotherapy drugs without randomized control trials based solely on epidemiological evidence? The trials came later as confirmation. Are you aware of that?
    You are well aware that there were no randomized clinical trials in the case of penicillin that saved thousands of lives in World War II? Was not this in the best interest of our soldiers?
    You would agree that many lives were saved with the use of cancer drugs and penicillin that were used before any randomized clinical trials, correct?
    You have referred to evidence for hydroxychloroquine as “anecdotal,” which is defined as “evidence collected in a casual or informal manner and relying heavily or entirely on personal testimony,” correct?
    But there are many studies supporting the use of hydroxychloroquine in which evidence was collected formally and not on personal testimony, has there not been?
    So, it would be false to conclude that the evidence supporting the early use of hydroxychloroquine is anecdotal, correct?

    with:

    There is currently no recommended pharmacologic early outpatient treatment for individuals in the flu stage of the illness, correct?
    It is true that COVID-19 is much more lethal than the flu for high-risk individuals such as older patients and those with significant comorbidities, correct?
    Individuals with signs of early COVID-19 infection typically have a runny nose, fever, cough, shortness of breath, loss of smell, etc., and physicians send them home to rest, eat chicken soup etc., but offer no specific, targeted medications, correct?
    These high-risk individuals are at high risk of death, on the order of 15% or higher, correct?
    So just so we are clear—the current standard of care now is to send clinically stable symptomatic patients home, “with a wait and see” approach?
    Are you aware that physicians are successfully using Hydroxychloroquine combined with Zinc and Azithromycin as a “cocktail” for early outpatient treatment of symptomatic, high-risk, individuals?
    Have you heard of the “Zelenko Protocol,” for treating high-risk patients with COVID 19 as an outpatient?
    Have you read Dr. Risch’s article in the American Journal of Epidemiology of the early outpatient treatment of COVID-19?
    Are you aware that physicians using the medication combination or “cocktail” recommend use within the first 5 to 7 days of the onset of symptoms, before the illness impacts the lungs, or cytokine storm evolves? [–> see the chart of CV19 disease phases in the OP; duly note, it could not be found with Google, I have had to revise my opinion of the utility of Yandex]
    Again, to be clear, your recommendation is no pharmacologic treatment as an outpatient for the flu—like symptoms in patients that are stable, regardless of their risk factors, correct?
    Would you advocate for early pharmacologic outpatient treatment of symptomatic COVID-19 patients if you were confident that it was beneficial?
    Are you aware that there are hundreds of physicians in the United States and thousands across the globe who have had dramatic success treating high-risk individuals as outpatients with this “cocktail?”
    Are you aware that there are at least 10 studies demonstrating the efficacy of early outpatient treatment with the Hydroxychloroquine cocktail for high-risk patients — so this is beyond anecdotal, correct?
    If one of your loved ones had diabetes or asthma, or any potentially complicating comorbidity, and tested positive for COVID-19, would you recommend “wait and see how they do” and go to the hospital if symptoms progress?
    Even with multiple studies documenting remarkable outpatient efficacy and safety of the Hydroxychloroquine “cocktail,” you believe the risks of the medication combination outweigh the benefits?
    Is it true that with regard to Hydroxychloroquine and treatment of COVID-19 infection, you have said repeatedly that “The Overwhelming Evidence of Properly Conducted Randomized Clinical Trials Indicate No Therapeutic Efficacy of Hydroxychloroquine (HCQ)?”
    But NONE of the randomized controlled trials to which you refer were done in the first 5 to 7 days after the onset of symptoms- correct?
    All of the randomized controlled trials to which you refer were done on hospitalized patients, correct?
    Hospitalized patients are typically sicker that outpatients, correct?
    None of the randomized controlled trials to which you refer used the full cocktail consisting of Hydroxychloroquine, Zinc, and Azithromycin, correct?
    While the University of Minnesota study is referred to as disproving the cocktail, the meds were not given within the first 5 to 7 days of illness, the test group was not high risk (death rates were 3%), and no zinc was given, correct?
    Again, for clarity, the trials upon which you base your opinion regarding the efficacy of Hydroxychloroquine, assessed neither the full cocktail (to include Zinc + Azithromycin or doxycycline) nor administered treatment within the first 5 to 7 days of symptoms, nor focused on the high-risk group, correct?
    Therefore, you have no basis to conclude that the Hydroxychloroquine cocktail when used early in the outpatient setting, within the first 5 to 7 days of symptoms, in high risk patients, is not effective, correct?
    It is thus false and misleading to say that the effective and safe use of Hydroxychloroquine, Zinc, and Azithromycin has been “debunked,” correct? How could it be “debunked” if there is not a single study that contradicts its use?
    Should it not be an absolute priority for the NIH and CDC to look at ways to treat Americans with symptomatic COVID-19 infections early to prevent disease progression?
    The SARS-CoV-2/COVID-19 virus is an RNA virus. It is well-established that Zinc interferes with RNA viral replication, correct?
    Moreover, is it not true that hydroxychloroquine facilitates the entry of zinc into the cell, is a “ionophore,” correct?
    Isn’t also it true that Azithromycin has established anti-viral properties?
    Are you aware of the paper from Baylor by Dr. McCullough et. al. describing established mechanisms by which the components of the “HCQ cocktail” exert anti-viral effects?

    From later in their letter: >>As clearly presented in the McCullough article from Baylor, and described by Dr. Vladimir Zelenko, the efficacy of the HCQ cocktail is based on the pharmacology of the hydroxychloroquine ionophore acting as the “gun” and zinc as the “bullet,” while azithromycin potentiates the anti-viral effect. Undeniably, the hydroxychloroquine combination treatment is supported by science. Yet, you continue to ignore the “science” behind the disease. Viral replication occurs rapidly in the first 5 to 7 days of symptoms and can be treated at that point with the HCQ cocktail.>>

    So- the use of hydroxychloroquine, azithromycin (or doxycycline) and zinc, the “HCQ cocktail,” is based on science, correct?

    We have needlessly wasted months, leading to avoidable deaths in large numbers, people left with permanent debilitation, massive economic dislocation and linked socio-psychological consequences of despair.

  52. 52
  53. 53
    jerry says:

    We also have extremely high success with patients that are not treated with HCQ, because most patients recover anyway. I’m surprised you weren’t aware of this already.

    You obviously never watched or read Zelenko. He constantly discusses this. When one has nearly 100% success with a large number of the population that is high risk it eliminates the possibility that all would have recovered naturally. Why his high risk population? This has been pointed out about a hundred times. Something called statistics is used to Verify this.

    As I said it was pointed out to you 4 months ago.

  54. 54
    kairosfocus says:

    F/N: I have found a Frontline Doctors seminar at BitChute (that’s a testimony to censorship . . .), and have updated the OP to include a summary of direct and indirect/synergistic activity of HCQ. Links are there. The causal mechanisms tied to common natural regularities and the known key-lock patterns of cell activity lend credibility to the observed rapid effectiveness of HCQ which has been observed in thousands of cases as reported. The overall effect of the annotated chart is that we now have a framework for discussing mechanisms in fair detail, which in turn shifts the context of our plausibility structures, a key element in scientific thought. KF

  55. 55
    kairosfocus says:

    RHolt, kindly notice the new information on the table regarding mechanisms. It seems the ACE2 shape shifts are in the assembly stage prior to going to the membrane. In addition, several mechanisms are on the table going forward, as summarised. KF

  56. 56
    kairosfocus says:

    Jerry, yup. High risk patients do mostly recover but up to 15% die. That is sharply reduced through the Zelenko etc protocols. Sufficiently so that we are in the h’mm, clearly stones drop when released territory. See the summary on mechanisms, which clears up a puzzle on ACE2 shape shifting and gives us cell biology reasons to be confident in the cocktail. KF

  57. 57
    Bob O'H says:

    Jerry @ 53 –

    When one has nearly 100% success with a large number of the population that is high risk it eliminates the possibility that all would have recovered naturally.

    I’m not sure what you were trying to say, but not what you actually said.

    Why his high risk population? This has been pointed out about a hundred times. Something called statistics is used to Verify this.

    To verify what?

  58. 58
    johnnyb says:

    The gold standard of disagreement with holding up RCTs as the absolute standard is this famous parody paper that was published by the British Medical Journal titled “Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials”.

    https://pubmed.ncbi.nlm.nih.gov/14684649/

    I used to work in Evidence-based Medicine a little bit, and saw both sides of the fence. In any case, it is definitely true that medicine is a practical discipline that has to work prior to having all the facts you might want.

  59. 59
    kairosfocus says:

    JB, money shot clip:

    Conclusions: As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.

    KF

  60. 60
    kairosfocus says:

    JB, First runner up:

    https://pubmed.ncbi.nlm.nih.gov/26769034/

    >>

    Randomized Controlled Trial
    Eur Spine J

    . 2016 May;25(5):1349-1354.
    doi: 10.1007/s00586-016-4381-z. Epub 2016 Jan 14.
    Does usage of a parachute in contrast to free fall prevent major trauma?: a prospective randomised-controlled trial in rag dolls
    Patrick Czorlich 1 , Till Burkhardt 1 , Jan Hendrik Buhk 2 , Jakob Matschke 3 , Marc Dreimann 4 , Nils Ole Schmidt 1 , Sven Oliver Eicker 5
    Affiliations

    PMID: 26769034 DOI: 10.1007/s00586-016-4381-z

    Abstract

    Purpose: It is undisputed for more than 200 years that the use of a parachute prevents major trauma when falling from a great height. Nevertheless up to date no prospective randomised controlled trial has proven the superiority in preventing trauma when falling from a great height instead of a free fall. The aim of this prospective randomised controlled trial was to prove the effectiveness of a parachute when falling from great height.

    Methods: In this prospective randomised-controlled trial a commercially acquirable rag doll was prepared for the purposes of the study design as in accordance to the Declaration of Helsinki, the participation of human beings in this trial was impossible. Twenty-five falls were performed with a parachute compatible to the height and weight of the doll. In the control group, another 25 falls were realised without a parachute. The main outcome measures were the rate of head injury; cervical, thoracic, lumbar, and pelvic fractures; and pneumothoraxes, hepatic, spleen, and bladder injuries in the control and parachute groups. An interdisciplinary team consisting of a specialised trauma surgeon, two neurosurgeons, and a coroner examined the rag doll for injuries. Additionally, whole-body computed tomography scans were performed to identify the injuries.

    Results: All 50 falls-25 with the use of a parachute, 25 without a parachute-were successfully performed. Head injuries (right hemisphere p = 0.008, left hemisphere p = 0.004), cervical trauma (p < 0.001), thoracic trauma (p < 0.001), lumbar trauma (p < 0.001), pelvic trauma (p < 0.001), and hepatic, spleen, and bladder injures (p GT 0.001) occurred more often in the control group. Only the pneumothoraxes showed no statistically significant difference between the control and parachute groups.

    Conclusions: A parachute is an effective tool to prevent major trauma when falling from a great height.

    Keywords: Evidence-based medicine; Fall; Parachute; Prevention; Trauma.

    Silver medal.

    KF

  61. 61
    Bob O'H says:

    kf @ 56 –

    Jerry, yup. High risk patients do mostly recover but up to 15% die. That is sharply reduced through the Zelenko etc protocols.

    And for Zelenko specifically, your evidence that it is the Zelenko protocol that is responsible for any differences is what? Please be specific, and give the evidence, i.e. a comparison to an equivalent control group, where any differences in major confounders are identified and controlled for.

  62. 62
    RHolt says:

    KF

    kindly notice the new information on the table regarding mechanisms. It seems the ACE2 shape shifts are in the assembly stage prior to going to the membrane.

    I’ve previously have mentioned the proposed mechanism of inhibition of terminal glycosylation of the ACE receptor several times. I can only assume from your comment that you missed it each of those times.

    The question is what is the rate of turnover of the ACE receptor? If it is slow (likely) than, obviously, this proposed mechanisms does not have any impact on the very large number of ACE receptors already present on the cell surface which are not modified and open to viral binding and subsequent transport into the cell. In other words this is likely a mechanism of HCQ activity but inadequate to affect viral entry into the cell given it does not affect ACE receptors already present on the cell surface.

    We also have ET’s citation which mentions the very slow onset of action for HCQ, via endoscope/lysosome pH modification, as well as citations documenting how de-acidification of these vesicles can have a positive impact on RNA virus replication, i.e., it increases the viral replication.

  63. 63
    daveS says:

    KF,

    OT, but there apparently has been some exciting progress on Erdős’ most famous conjecture.

  64. 64
    kairosfocus says:

    RHolt, put up to duly note. KF

  65. 65
    kairosfocus says:

    BO’H, you full well know that proof is not in the gift of inductive logic. Warrant per best explanation is. Here, we have a cluster of plausible mechanisms that lead to highly significant differences in outcomes, including a key case of squeezing through cracks in the biased to fail methods. In that context we can safely set aside a quasi-infinite multiverse with no causal connexions. We can accept cause and filter on means. In that context, best explanation across thousands of cases is that the mechanisms are working as advertised. Your good reason to reject that are? ______ And why should we take such seriously? ____ KF

  66. 66
    RHolt says:

    KF

    put up to duly note

    Sure it is prudent to have all the info on the table which is why I mentioned it in previous posts. The important thing is to put such information into the perspective of phsyiological feasibility and what can be accomplished from an acute intervention. For example cell culture research has demonstrated that ACE2 receptors can be ‘stripped’ from the cell surface within 4 hrs by flooding the culture with angiotensin. Might work effectively to prevent COVID infection of the cell albeit with dire consequences for a living organism so while it is a quasi-feasable mechanism it is physiologically not a viable treatment given the obvious consequences of ACE2 elimination from the cell surface.

  67. 67
    Mac McTavish says:

    On the bright side, it looks like the actions being taken to prevent the spread and deaths by COVID might have a significant impact on the spread and deaths caused by the flu.

    influenza and influenza-like illness (ILI) activity are lower than average across all systems for this time of year.”
    Australia had just 36 laboratory-confirmed flu deaths from January to July 26, 2020, the report said. Over the same period a year earlier, there were 383 confirmed deaths.

    https://www1.health.gov.au/internet/main/publishing.nsf/Content/cda-surveil-ozflu-flucurr.htm/$File/flu-09-2020.pdf

  68. 68
    jerry says:

    The politicization of HCQ https://www.tabletmag.com/sections/science/articles/hydroxychloroquine-morality-tale

    Hydroxychloroquine: A Morality Tale

    We live in a culture that has uncritically accepted that every domain of life is political, and that even things we think are not political are so, that all human enterprises are merely power struggles, that even the idea of “truth” is a fantasy, and really a matter of imposing one’s view on others. For a while, some held out hope that science remained an exception to this. That scientists would not bring their personal political biases into their science, and they would not be mobbed if what they said was unwelcome to one faction or another. But the sordid 2020 drama of hydroxychloroquine—which saw scientists routinely attacked for critically evaluating evidence and coming to politically inconvenient conclusions—has, for many, killed those hopes.

    The world plays out in miniature on UD. Even people dying makes no difference to them. Winning a political battle or just a rhetorical battle trumps human lives.

  69. 69
    Bob O'H says:

    kf @ 65 – you can wave your (metaphorical. Or perhaps literal – I don’t know how you type) arms as much as you want, but you really need to be able to address the issue of confounders in these observational studies. If you can’t do that (and it might be possible with some of them – I wouldn’t expect to see perfection), you’re pretty much admitting that the results are worthless.

  70. 70
    kairosfocus says:

    BO’H: the mere abstract possibility does not overturn a strong pattern. So strong, that PaV is highlighting the enthusiasm gap on actual practitioners. Above, we can see an interesting correlation between death rate and attitude to HCQ+. You are also implying that a leading, world class researcher responsible for the results now again shown above is grossly incompetent without good specific reason apart from things that pivot on appeals to gold standard fallacies. If there is a credible candidate “confounding” agent, what is it, do, let us know. That might be a pretty strong candidate treatment. An agent in use all around the world where HCQ cocktails are in use. Or is it that the confounding agent suspect is the obvious: the cocktail itself? KF

  71. 71
    kairosfocus says:

    Jerry,

    Further down:

    in the midst of a pandemic, thousands started earnestly hoping—before the science was really in—that a drug, one that might save lives at a comparatively low cost, would not actually do so. Reasonably good studies were depicted as sloppy work, fatally flawed. Many have excelled in making counterfeit bills that look real, but few have excelled at making real bills look counterfeit. As such, as we sort this out, we shall observe not only some “tricks” about how to make bad studies look like good ones, but also how to make good studies look like bad ones. And why should anyone facing a pandemic wish to discredit potentially lifesaving medications? Well, in fact, this ability can come in very handy in this midst of a plague, when many medications and vaccines are competing to Save the World—and for the billions of dollars that will go along with that.

    So this story is twofold. It’s about the discussion that unfolded (and is still unfolding) around hydroxychloroquine, but if you’re here for a definitive answer to a narrow question about one specific drug (“does hydroxychloroquine work?”), you will be disappointed. Because what our tale is really concerned with is the perilous state of vulnerability of our scientific discourse, models, and institutions—which is arguably a much bigger, and more urgent problem, since there are other drugs that must be tested for safety and effectiveness (most complex illnesses like COVID-19 often require a group of medications) as well as vaccines, which would be slated to be given to billions of people. “This misbegotten episode regarding hydroxychloroquine will be studied by sociologists of medicine as a classic example of how extra-scientific factors overrode clear-cut medical evidence,” Yale professor of epidemiology Harvey A. Risch recently argued . . .

    To us design inference advocates (not to mention those with questions on some of the claims in the dominant climate trends narrative), that’s an old story. It seems the bad habits are metastising.

    It looks like things will have to crash hard enough and burn enough for there to be serious rethinking.

    KF

  72. 72
    kairosfocus says:

    Jerry, at last I see a somewhat sympathetic portrayal of one of our mavericks, Dr Raoult. KF

  73. 73
    Mac McTavish says:

    Jerry

    The world plays out in miniature on UD. Even people dying makes no difference to them. Winning a political battle or just a rhetorical battle trumps human lives.

    Do you seriously think that the people here who disagree with you and KF with respect to the efficacy of HCQ, or the vast majority in the medical field who have examined the evidence and don’t see efficacy, were not hoping that HCQ would be the miracle that some are touting it to be? I suspect that most who have serious doubts about its efficacy are either in a high risk category, or have loved ones who are in a high risk category.

  74. 74
    jerry says:

    Do you seriously think that the people here who disagree with you and KF with respect to the efficacy of HCQ,

    Yes, it’s possible to disagree on the amount of efficacy but not on any efficacy at all. It’s not possible for those who do not recommend it at all to come down on wanting to save lives. They are allowing people to die for no valid reason.

    The drug is safe, inexpensive and there are thousands of reasons to believe it has some positive effect, probably significant positive effect. To block it is immoral.

  75. 75
    jerry says:

    at last I see a somewhat sympathetic portrayal of one of our mavericks, Dr Raoult

    Yes, interesting facts about Raoult and his studies. Halfway through. Very long. No mention of Zelenko or zinc. Will read rest later. Have to go out.

  76. 76
    rhampton7 says:

    KF, I don’t understand your appeals to authority when it’s obviously of no concern to you when it works against your argument. Entire nations, like Israel, have consulted with their medical experts and concluded otherwise.

    You do know how many Nobel Prize winning scientists and docrors come from Israel, yes? And that’s but one glaringly obvious example. Yet for you, it is inconsequential.

  77. 77
    rhampton7 says:

    The first study on the possible effectiveness of HCQ on Covid-19 was done by a group of French doctors who used HCQ plus an antibiotic Azithromycin to treat patients and reported that the patients had a very low mortality rate.

    The problem is that this study only observed 80 patients, and there was no comparison group. We don’t know what the mortality rate of patients would be if HCQ was not used.

    This group of French doctors published a report on 1061 patients in May and continued to claim that the patients had a very low mortality rate, but there was still no comparison group.

    In July, another report of observation of more than 3,000 patients was published . This time there are groups, but not RCTs. Their study design and conclusions are very strange, saying that HCQ plus antibiotic Azithromycin is helpful for patients, but the number of groups is very uneven. 3119 patients received treatment, only 162 patients did not receive HCQ or Azithromycin, and the others received different courses of treatment.

    Comparing the group with no treatment at all and the group with HCQ plus antibiotic Azithromycin, “Poor Clinical Outcome” (death or requiring intensive treatment) was 6.2% and 4.9%, respectively. It is statistically significant (p=0.02). But the difference between the two groups is too big. Only 5.9% of the treatment group had heart disease; 15% of the treatment group had heart disease, 11.1% of the untreated group had heart disease, and 19.1% had high blood pressure. Therefore, it is normal to have higher malignant clinical results, and it is difficult to get treatment Valid conclusion.

    https://www.thestandnews.com/society/%E7%BE%A5%E6%B0%AF%E5%96%B9-hydroxychloroquine-hcq-%E7%9A%84%E9%99%B0%E8%AC%80%E8%AB%96/

  78. 78
    rhampton7 says:

    Thomas Frieden, March 22:

    Roberts also asked Frieden for his thoughts on President Trump’s frequent touting of anti-malarial drug hydroxychloroquine as a potential treatment for the virus, despite lack of FDA approval for that use.

    “We all hope there’ll be good treatment for people with severe infection for this virus because that would make a big difference,” Frieden said, adding “things seem promising but until you really study them, until you really figure out does it work, we don’t know.”

    https://thehill.com/homenews/sunday-talk-shows/488859-former-cdc-head-i-would-feel-a-lot-safer-if-it-were-clear-that-the

    Thomas Frieden May 24:

    ‘Very unlikely’ hydroxychloroquine will be dramatically effective against COVID-19

    https://www.fullcourtgreta.com/video/2020/05/24/dr-frieden-very-unlikely-hydroxychloroquine-will-be-dramatically-effective-against-covid-/

  79. 79
    rhampton7 says:

    Thomas Frieden August 7:

    Dr. Thomas Frieden said that the CDC had been sidelined early on in the pandemic and described Trump’s contradictory messages as “chaotic leadership,” which has led to partisanship, confusion and increased spread of the virus.

    “It’s unbelievable that six months into the pandemic, it’s not clear who’s in charge, federally,” Frieden said during a roundtable hosted by ABC News Live.

    “There’s no plan. There’s no common data that we’re looking at to see what’s happening with the virus and what’s happening with our response.”

    Dr. Jeffrey Koplan said that “every one of those falsehoods” damages the nation’s mitigation efforts against the virus.

    Frieden added that Americans want information from the CDC. “Americans are voting with their clicks. There have been 1.6 billion clicks on the CDC website,” said Frieden. “The more we learn, the more we know, the better we can control it.”

    https://www.cnn.com/world/live-news/coronavirus-pandemic-08-07-20-intl/index.html

  80. 80
    kairosfocus says:

    RH7, Really. I cited Dr Thomas Frieden as an example of someone of indubitably world class standard — former head of the US CDC — who is also acknowledging the force of relevant decision theory points I have made since March, precisely because I am familiar with it and its power. At no point have I suggested the fallacy of blind acquiescence in the face of authority. Obviously, that is not inclining you to attend to that force of fact and logic. And if you mean to dismiss the Frontline Doctors, simply provide good reason to dismiss the cluster of identified plausible attack modes. For example, is it false that HCQ is a weak base? [Not likely!] Or, that it is able to access cells and would shift internal pH? Would that not hinder organelles? Especially, Golgi? Likewise, would it not serve as ionophore and would Zn not hinder viral replication? I think we can take it instead that plausible mechanisms provide cumulative support to the reported success, where it is obvious that viral replication dominant phases are different from onward infections and cytokine storms. In short, there are good reasons to have some confidence that HCQ based cocktails will work as suggested. KF

  81. 81
    Mac McTavish says:

    Jerry

    Yes, it’s possible to disagree on the amount of efficacy but not on any efficacy at all.

    There are hundreds, if not thousands, of medical professionals and epidemiologists who would disagree with you. Every drug has some risk associated with it, and HCQ is no different. The benefits must significantly outweigh the risks before it should be recommended, especially on an outpatient basis. Based on current knowledge, that simply hasn’t been demonstrated to be the case for HCQ.

    It’s not possible for those who do not recommend it at all to come down on wanting to save lives.

    That is simply not true. Based on what I have read so far about HCQ, I would not recommend it unless it was under a hospital setting, or if a full medical work up has been performed, including a medical and family history.

    I say this with the caveat that I am not a medical professional, and I do not even play one on TV. As such, I will rely on the consensus of the medical profession.

  82. 82
    rhampton7 says:

    Thomas Frieden July 21:

    “We have a real vacuum of leadership at the national level,” said Dr. Thomas R. Frieden, the former C.D.C. director, who now runs Resolve to Save Lives, a nonprofit health advocacy initiative.

    “Absent a national strategy, our best hope is to get all 50 states on the same page, so we know where we are,” he said.

    Dr. Frieden’s organization concluded that states are reporting only 40 percent of the data needed to fight the pandemic. Some states disclose less useful information than the government of Uganda, which Resolve to Save Lives also advises on its coronavirus response, he said.

    The report laid out 15 indicators that every state should report daily on a public “dashboard” that anyone can view.

    They included not just basic elements like cases, hospitalizations and deaths, but sophisticated metrics such as what percentage of infections came from clusters of people who know one another, how many health care workers get infected on the job, how long it takes to get a diagnostic test result, and what percentage of any city’s or county’s residents are wearing masks.

    https://www.nytimes.com/2020/07/21/health/coronavirus-data-states-cdc.html

  83. 83
    rhampton7 says:

    Thomas Frieden August 8:

    “Right now, we’re flying blind,” said Thomas Frieden, a former director of the Centers for Disease Control and Prevention. “Public health is not getting in the way of economic recovery and schools reopening. Public health is the means to economic recovery and schools reopening. You don’t have to believe me. Look all over the world. The U.S. is a laggard.”

    https://www.washingtonpost.com/politics/trump-struggled-summer-coronavirus/2020/08/08/e12ceace-d80a-11ea-aff6-220dd3a14741_story.html

  84. 84
    rhampton7 says:

    And here is the killer quote

    March 20:

    Former CDC director Dr. Tom Frieden said chloroquine “urgently needs to be further tested in more patients in a randomized fashion so we can know if these and other medications are helpful to people with COVID-19.”

    https://www.bostonherald.com/2020/03/19/fda-fast-tracks-2-coronavirus-treatments-boston-hospital-already-using-malaria-drug-on-patients/

  85. 85
    rhampton7 says:

    Good reasons in a Petri dish do not necessarily mean it will work in reality. That’s why you do RCTs. You know this.

  86. 86
    rhampton7 says:

    Killer quote 2

    Thomas Frieden March 27:

    There are close to 70 different medicines that are being studied.

    The first really rigorous study was of two of the most promising drugs that together kill viruses.

    And it didn’t work.

    So it’s one thing to have a promising substance or anecdotal evidence, and it’s quite another to show that it works.
    We all hope there’ll be effective treatment.

    http://www.pbs.org/wnet/firing.....en-vwz2xa/

  87. 87
    kairosfocus says:

    RH7, BTW, the mechanisms would fit in well with how HCQ and/or CQ have worked as fish tank cleaner for some 40 years. Fish, as complex organisms, live but the crud across kingdoms of life, dies. The effects given boil down to systematic but obviously manageable toxicity that attacks the various functions in the cell. Multicellular complex animals will have more “give” but for unicellular organisms or viruses as cell hijackers, it all depends on one cell. In short, we have convergent evidence and mutual reinforcement. KF

  88. 88
    kairosfocus says:

    MMT, we have mechanisms, we have thousands of cases once we avoid biased to fail errors, we have the independent cross-check of working as a fish tank cleaner so fish thrive but crud across kingdoms dies; it must have attack modes that affect core, cross kingdom cell functions . . . and that is what is plausibly on the table, cf OP as augmented. There is good reason to accept HCQ based cocktails as credible. At this point, it is very hard to overturn the questions put on the table in the open letter to Dr Fauci. KF

  89. 89
    GCS says:

    Article in my local newspaper (remember that – ink and newsprint!) concerning questions about why so few deaths from Covid in Africa.

    The usual speculations – not one word that they may be a malaria area that uses HCQ.

    The refusal to treat immediately when any risk factor is present is no longer just a poor decision – it is criminal. No other disease is not treated as early as possible.

  90. 90
    rhampton7 says:

    GCS, several large African countries have stopped using HCQ (South Africa, Kenya, Nigeria) after determining it wasn’t effective or have never approved it outside of clinical trials. I posted those reports in the previous thread.

    Also, Brazil is this worst hit nation despite using HCQ. In fact, a recent RCT was a trial in Brazil that “ found that hydroxychloroquine — given either alone or in combination with the antibiotic azithromycin — did not improve the conditions of hospitalized patients with mild-to-moderate Covid-19.”

  91. 91
    rhampton7 says:

    Presumed attack modes does not necessarily mean actual attack modes. Again, that’s why you do RCTs.

    This is a novel virus, after all.

  92. 92
    rhampton7 says:

    More on Africa:

    Africa CDC director John Nkengasong said estimating the true number of cases on the continent is “very tricky.” Some 70% of infections are asymptomatic, he has said. Africa’s young population also might be a factor. Without a dramatic increase in testing, “there’s much we don’t know.”

    Reflecting the pandemic’s diverse nature across Africa, just five countries account for 75% of confirmed cases: South Africa, Egypt, Nigeria, Ghana and Algeria. Nigeria alone could have had close to 1 million cases by now if Africa’s most populous country hadn’t acted quickly, the Africa CDC’s Nkengasong said.

    Africa’s most developed country, South Africa, has strained to cope as hospital beds fill up and confirmed cases are over a half-million, ranking fifth in the world. The country has Africa’s most extensive testing and data collection, and yet a South African Medical Research Council report last week showed many COVID-19 deaths were going uncounted. Other deaths were attributed to other diseases as people avoid health centers and resources are diverted to the pandemic.

    https://www.khon2.com/international/africa-passes-1m-confirmed-virus-cases-true-number-far-more/

  93. 93
    Mac McTavish says:

    Executive Director of the National COVID-19 Clinical Evidence Taskforce [Austrakia], said the evidence indicates hydroxychloroquine is potentially harmful and no more effective than standard care in treating patients with COVID-19.

    ‘We have reviewed all the scientific data around hydroxychloroquine and we can now say, definitively, that hydroxychloroquine should not be used as a treatment for anyone with COVID-19,’

    ‘There is now sufficient data for us to make a very clear and strong recommendation. In this instance, that is based on data from randomised controlled trials that enrolled nearly 6000 patients.

    ‘This is a substantial amount of very high-quality scientific data upon which we’ve based the recommendation.

    ‘The pooled results show the drug does not reduce mortality, or shorten the amount of time a sick person spends in hospital. It also exposes them to side effects including cardiac toxicity.’

    Of note is the fact that they have seen a ten-fold reduction in influenza deaths during the current flu season. If the lockdown/distancing/mask measures being taken To combat COVID-19 are having this impact on flu deaths, is it not reasonable to assume that they are having a similar impact on COVID deaths?

  94. 94
    rhampton7 says:

    An editorial published in The Lancet Infectious Diseases warned of the dangers of the COVID-19 “infodemic” and noted that the circulation of medical information beyond expert circles before it has been reviewed can be particularly dangerous.

    “Fake news, misinformation and conspiracy theories have become prevalent in the age of social media and have skyrocketed since the beginning of the COVID-19 pandemic,” the authors wrote. “This situation is extremely concerning because it undermines trust in health institutions and programs.”

    Aaron E. Glatt, MD, chairman of the department of medicine and chief of infectious diseases at Mount Sinai South Nassau in Oceanside, New York, told Healio that physicians can help patients by discussing their concerns and reviewing how they receive medical information.

    He cited the conversation about hydroxychloroquine’s use as a COVID-19 treatment as a recent example of the rapid spread of COVID-19 misinformation.

    “The only good way to get medical information is to see the data published — I can assess it, and I can tell you ‘this is good’ or ‘this is garbage,’” Glatt said. “On social media, a person can videotape [himself or herself] and say, ‘I have the cure for everything under the sun — just take this,’ but they don’t present any data. It excites tremendous amounts of interest in both the public and the lay press, but nobody is assessing it.”

    https://www.healio.com/news/infectious-disease/20200814/covid19-infodemic-persists-could-worsen

  95. 95
    kairosfocus says:

    RH7, actually, it seems the Frontline Doctors are following models such as the one for W Nile Virus discussed here in a follow up OP: https://uncommondescent.com/medicine/the-frontline-doctors-put-some-plausible-mechanisms-for-hydroxychloroquine-on-the-table/ Instead of dismissively sweeping off the table, you would be well advised to ponder that context. In that light, I suggest to you that you also seem to be simply refusing to recognise that placebo controlled studies have weaknesses and limitations and should not be used as a pivot to selectively hyperskeptically dismiss other relevant evidence. KF

  96. 96
    RHolt says:

    RH7

    Presumed attack modes does not necessarily mean actual attack modes

    This has been repeatedly pointed out to KF. You will never find chloroquine used, or recommended, to treat viral diseases in fish which might cause some to ask why that is? Often chloroquine, and other anti-parasitic agents (formalin, malachite green, and salt) are recommended to treat sick fish, even if the agent is suspected as being viral in nature, simply because the diagnosis might be wrong and there is an the outside chance the etiology of the disease is parasitic and not viral. Perhaps the lack, actually the complete absence, of cholorquine use in aquaria and aquaculture treatment is a lack of efficacy in its use for treating viral disease but OK for protozoa infestations which have a known mechanism of action.

  97. 97
    RHolt says:

    KF

    simply refusing to recognise that placebo controlled studies have weaknesses and limitations and should not be used as a pivot to selectively hyperskeptically dismiss other relevant evidence.

    The other evidence, discarding anecdotes, are the retrospective studies which have an even greater number of weaknesses inherent in their basic design. It could also be considered to be selective hyperskepticism to discount RCT in favor of retrospective trials. Each trial needs to be assessed and evaluated on the design study and data analysis. Larger numbers don’t mean much if the basic design is poor.

  98. 98
    kairosfocus says:

    RHolt, where did I argue that HCQ is used to target viral diseases in fish? Nowhere. I pointed out that cross-kingdom attacks on microorganisms points to attacks on core cell processes. Of course, viruses hijack those processes so something that reduces effectiveness of hijack may well buy time for in-control immune response to do the actual work of destroying the infection. However, I am sure you are aware that there is a general problem of need for antivirals, so the strawman is even more outrageous. What is on the table is a summary from work, on virus attack modes and on how HCQ may counter such. In turn, this fits with the pattern that early intervention with the cocktail, for the vulnerable leads to improved likelihood of a good outcome. People not in those groups don’t have a lot of room for improvement compared to case fatality rates for the vulnerable on order of up to 15%. KF

  99. 99
    kairosfocus says:

    PS: Let me again draw attention to what Dr Frieden put on the table nearly four years ago, clipping from the OP cite of his paper in NEJM:

    Despite their strengths, RCTs have substantial limitations. Although they can have strong internal validity, RCTs sometimes lack external validity; generalizations of findings outside the study population may be invalid.2,4,6 RCTs usually do not have sufficient study periods or population sizes to assess duration of treatment effect (e.g., waning immunity of vaccines) or to identify rare but serious adverse effects of treatment, which often become evident during postmarketing surveillance and long-term follow-up but could not be practically assessed in an RCT. The increasingly high costs and time constraints of RCTs can also lead to reliance on surrogate markers that may not correlate well with the outcome of interest. Selection of high-risk groups increases the likelihood of having adequate numbers of end points, but these groups may not be relevant to the broader target populations. These limitations and the fact that RCTs often take years to plan, implement, and analyze reduce the ability of RCTs to keep pace with clinical innovations; new products and standards of care are often developed before earlier models complete evaluation. These limitations also affect the use of RCTs for urgent health issues, such as infectious disease outbreaks, for which public health decisions must be made quickly on the basis of limited and often imperfect available data. RCTs are also limited in their ability to assess the individualized effect of treatment, as can result from differences in surgical techniques, and are generally impractical for rare diseases.

    Many other data sources can provide valid evidence for clinical and public health action. Observational studies, including assessments of results from the implementation of new programs and policies, remain the foremost source, but other examples include analysis of aggregate clinical or epidemiologic data . . .

    That is what you first need to face, then learn to refrain from the gold standard fallacy serving as pivot for undue dismissiveness. For example, Dr Raoult’s results (tabulated in OP) are not a collection of unrelated anecdotes — [fairy/fiction/one that got away] stories, in good Anglo Saxon words.

  100. 100
    RHolt says:

    KF

    where did I argue that HCQ is used to target viral diseases in fish?

    You didn’t and I never meant to imply that you did. My point is that you keep touting this ‘multi level’ effect and I was pointing out that the chloroquine treatment in fish has no anti-viral effects.

    KF

    Of course, viruses hijack those processes so something that reduces effectiveness of hijack may well buy time for in-control immune response to do the actual work of destroying the infection.

    I am not aware of any direct action of chloroquine or hydroxychloroquine on any of the cellular processes that a virus utilizes for replication. Feel free to point me to this info I’d appreciate reading it!

    KF

    However, I am sure you are aware that there is a general problem of need for antivirals

    Yes, anti virals for most viral diseases are lacking. It is a difficult nut to crack. The most successful cases are with HIV and HepC. While not for COVID there is promise in the development of a universal flu vaccine that has merit and bears watching.

    KF

    so the strawman is even more outrageous

    You misinterpreted my comment or more likely I did not make myself clear enough. There was no attempt made to mischaracterize your position. If you read it that way I apologize for not being expressing myself clearer.

  101. 101
    GCS says:

    Rhampton
    Thank you for your comments.

    @90 – The comment quoted on Brazil is for hospitalized patients. That is not my recommendation or the recommendation of the Doctors asking that this be considered – Immediate treatment on an out patient basis, especially for any high risk patient.

    @92 – My original comment is about why there is no curiosity at all about HCQ. They can speculate about everything else. (I observed a similar problem in an article where Fauci was willing to talk about all the possible sociological reasons why Blacks might be more affected but there was no mention any possibility of underlying genetic issues. They can not even be talked about because they are not P.C.)

    Again, Thank you.

  102. 102
    kairosfocus says:

    RHolt, this is what you stated:

    RHolt, 96: >>You will never find chloroquine used, or recommended, to treat viral diseases in fish which might cause some to ask why that is?>>

    I rightly objected that I never argued such. In short, you directly implied a strawman. I pointed it out and responded, you suggest misinterpretation on my part. But in fact, what I discussed shouldn’t even be controversial.

    For, it is known that cell based life has many processes in common. Further, we know that specific, minor mutations etc can and do blunt diseases that target particular species; sickle cell anemia is a classic example. But if something is hitting microorganisms at cross kingdom level, it is attacking life processes that are common. For instance, many disinfectants or fire do that. Illustrating, Chlorine bleach attacks fats and bonds in general through aggressive chemical action. So, for some time I have raised that question on HCQ.

    Linked, we know that viruses attack cells and hijack their processes, so agents that affect those processes in ways that slow down or stop replication will reduce intensity of a viral infection and will buy time for proper immune response. The fish tank cleaner effect leaves fish (notoriously delicate organisms) thriving, but kills crud across kingdoms. That points to manageable toxicity. And that in an agent known to work as a drug otherwise.

    In that context, the direct action modes tied to being a weak base make some sense. Which, are summarised in the OP and are explained (with pointers to underlying documentation in the linked). So, I “answered” your request early this morning, a matter that came up in discussion already.

    I infer that what you mean is you reject the described modes, which you will see come from the literature that is in play already. In an onward OP, I have added a comparative, the process for another RNA virus, W Nile. You will note the pH levels shown, which with one exception are somewhat acidic. So, the concept of pushing pH up is plausible, and that would affect activity.

    The indirect action of promoting Zn, with onward effects of Zn, should not be in serious dispute.

    I put it to you that there are good reasons to see why HCQ based cocktails should work, and when appropriately targetted, there is strong evidence from actual cases by hundreds and thousands that they do work and are responsibly safe enough to be manageable. More than enough that physicians should be able to prescribe off label use without fear or intimidation.

    That is all that was asked for, going back to March.

    What has happened instead is a sorry tale and history will not look kindly on us.

    KF

  103. 103
    RHolt says:

    KF

    I rightly objected that I never argued such.

    I disagree that you ‘rightly’objected. No where in that quote is it directed at you. When I state that ‘which might cause some to ask why the target was a general audience. further down your post you make this statement:

    I infer that what you mean is you reject the described modes

    which I could interpret as you making a straw man characterization of my position. However, I don’t because I know you know that I am familiar with the invitro literature from which you are pulling much of your data. I might outright reject, or question plausibility in extending the in vitro findings to the in vitro situation but that is far from rejecting proposed mechanisms. there is the documentation in the literature and the question is ‘can this be extrapolated to the intact organisms’ and in many cases the answer is no, sometimes it is maybe, and occasionally it is yes! While I can appreciate your passion I suggest.a more charitable reading might be in order for our discussions.

    KF

    For, it is known that cell based life has many processes in common.

    sure nothing to disagree with there but how many of those processes are involved in viral replication. With that answer the field gets dramatically narrower.

    KF

    So, the concept of pushing pH up is plausible, and that would affect activity.

    this is not even in question. I’ve pointed to ET’s reference on RA numerous times where the increase in pH in the lysosome, is the associated mechanism for its efficacy in treatment. However, this is a slow onset to action for this process as ET’s reference highlights.

    KF

    The indirect action of promoting Zn, with onward effects of Zn, should not be in serious dispute.

    It certainly can be questioned. There is an abundance of zinc in cells already and while we see in vitro ionophore activity this has not been documented in vitro. then comes the next most obvious question of ‘how much zinc is necessary?’ to elicit an anti-viral response in vivo. There is literature references for taking zinc supplements, typically lozenges preferred, within the first 48 hrs of the onset of sore throat or potential cold but this affect diminishes dramatically after the 48 hr window. It is thought it is a ‘surface effect’ more than anything else. There is a knowledge gap here and it would be prudent to recognize the limitations of the claims.

    KF

    More than enough that physicians should be able to prescribe off label use without fear or intimidation.

    off label prescribing is ongoing with doctors even publicly proclaiming they are doing so. I am not aware of any action being taken against these doctors.

    KF

    I put it to you that there are good reasons to see why HCQ based cocktails should work

    And I and many many others think there is adequate evidence to question this premise….even the CEO of a company that produces HCQ is in this camp!

  104. 104
    kairosfocus says:

    RH&, there is adequate evidence and the correlation opf mechanisms and successful treatments speaks. KF

  105. 105
    RHolt says:

    KF

    there is adequate evidence and the correlation opf mechanisms and successful treatments speaks

    As I pointed out others believe differently based on adequate evidence and demonstrated lack of efficacy.

    You reference zika and HCQ as a potential treatment. However, another virus, dengue, in the same family of virus and also a single-stranded RNA virus treatment with hydroxychloroquine has very limited benefit in treating this disease. In vitro data showed strong viral inhibition. However, HCQ-treated dengue patients showed no shortening duration of viremia, i.e., no anti-viral effect, but some benefit was observed on patient symptoms. However, upon cessation of HCQ symptoms rapidly returned in infected patients. This data, to me, suggests a different mode of action than anti-viral. This only demonstrates how imperative it is to use care and caution when speculating on what HCQ does and doesn’t do as far as anti viral properties.

    here is one reference:

    A Randomized Controlled Trial of Chloroquine for the Treatment of Dengue in Vietnamese Adults

    There is no available drug or vaccine against dengue, an acute viral disease that affects ?50 million people annually in tropical and sub-tropical countries. Chloroquine (CQ), a cheap and well-tolerated drug, inhibits the growth of dengue viruses in the laboratory with concentrations achievable in the body. To measure the antiviral efficacy of CQ in dengue, we conducted a study involving 307 adults with suspected dengue. Patients received a 3-day oral dosage of placebo or CQ early in their illness. Unfortunately, we did not see an effect of CQ on the duration of viral infection. We did, however, observe that CQ had a modest anti-fever effect. In patients treated with CQ, we observed a trend towards a lower incidence of dengue hemorrhagic fever, a severe form of dengue. We did not find any differences in the immune response that can explain this trend. We also found more adverse events, primarily vomiting, with CQ. This trial provides valuable new information on how to perform trials of antiviral drugs for dengue.

  106. 106
    jerry says:

    Another study showing HCQ has a positive effect. This makes about 50.

    Reduces death by 30% in hospitalized patients in Italy based on almost 3500 cases of C19. https://bit.ly/2PYoNF8

    Q: What were the mortality rates in the hydroxychloroquine and control groups?

    A: The mortality rate of patients receiving hydroxychloroquine was 8.9 / 1000 patients / day, the mortality rate of those not receiving hydroxychloroquine was 15.7 / 1000 patients / day.

    Treatment was started on the first day of admission in most clinical centers, at a dose of 400 mg once a day, for an average duration of 10 days. 76% of patients were on HCQ treatment .

    Of course they could have put many of those on HCQ on placebos to equal the numbers and killed more. It seems unfair that those who got HCQ had a better chance of living.

  107. 107
    rhampton7 says:

    GCS, “ My original comment is about why there is no curiosity at all about HCQ. ”

    Not true. The reason there are RCTs on HCQ therapy is precisely because of curiosity. Doctors and scientists want to learn more about the virus and possible treatments.

    It’s people like KF who decided sometime in March or early April that HCQ was “proven” to be effective and thus no further was study required, and All the RCTs after that date must simply be wrong.

  108. 108
    rhampton7 says:

    And more clinical studies on RCT are ongoing. Again, the need to know more continues, but not with Raoult and certainty not with KF. Plausible effects count as fact to him.

  109. 109
    RHolt says:

    Jerry’s recent citation to a news interview doesn’t have much present to evaluate the research but the publication might be out soon.

    I did note this comment that was made:

    We believe that HCQ acts on this very component of the disease rather than inhibiting viral replication.

    He doesn’t say why his team believe this is so but perhaps that is fleshed out in the manuscript. We’ll have to wait and see.

  110. 110
    kairosfocus says:

    RHolt, all you are doing is manifesting the crooked yardstick principle. Once a crooked yardstick somehow becomes the accepted standard of straight, upright, accurate, then whatever does not conform will be dismissed. Where the kicker is, what genuinely is straight, accurate, upright cannot conform to crookedness. That too often includes denying the message of a plumb line, which is naturally straight and upright. You have dismissed actual facts [cf. OP, from Dr Raoult, regarding 3,000+ cases], you have disregarded the point that all evidence matters, you effectively disregard reasonable mechanisms on the table, you have refused to engage the questions being posed in the open letter. We now draw our own conclusions, in all prudence. KF

  111. 111
    ET says:

    Mac @ 93- Good point about the flu. As for social distancing- In Massachusetts the rural areas have very few cases whereas the big cities and their suburbs have the bulk. The problem occurs when someone brings it home. BUT there have been instances when one family member didn’t infect others in their household: Covid-19 pandemic: Not everyone in coronavirus-hit family prone to disease. It would be nice if they can find out why people are naturally immune.

  112. 112
    Mac McTavish says:

    ET@111, it wasn’t clear from that article if the family members weren’t infected or if they just never showed symptoms.

    For example, I can’t remember ever having the flu (knock on wood), even though family members have and I assume that I have been exposed to others who have. Does this mean that I have a natural immunity or just that when I have been infected my symptoms were so minor that it never registered to me that I had the flu?

  113. 113
    kairosfocus says:

    ET & MMT, it seems that for some (many?), there is significant transfer of immunity from the common cold; likely depending on strains you have caught. We are also in a fuzzy zone between, injection of an agent, early replication, initial immune response, a-symptomatic, mild cases and stronger cases. Being infectious seems to be associated with symptomatic cases. Also, as was highlighted here in MNI, the polymerase tests amplify remnants that may persist for some time. That is part of why an argument was made to use a much cheaper, readily administered at home test [daily, pre-school/work tests in a few minutes to results] that picks up about an order of magnitude higher viral concentration, a more reasonable threshold, see here: https://uncommondescent.com/medicine/on-the-trajectory-of-covid-19-and-similar-diseases/ KF

  114. 114
    Mac McTavish says:

    KF@113, the polymerase process acts my multiplying DNA (or RNA) so that it is in concentrations high enough to be detected. But you are correct in that it can’t detect whether or not a person is infectious, only that they are infected. I’m not sure that the less sensitive test is more appropriate as the polymerase test has a high false negative rate due to the inconsistency in sampling.

    This being said, I think the test you mention may be better simply because it is quick.

  115. 115
    Bob O'H says:

    ET @ 111 –

    BUT there have been instances when one family member didn’t infect others in their household: Covid-19 pandemic: Not everyone in coronavirus-hit family prone to disease. It would be nice if they can find out why people are naturally immune.

    Are they naturally immune or just lucky?

  116. 116
    jerry says:

    It would be nice if they can find out why people are naturally immune.

    There is evidence that a substantial percentage of the population may have T-cells that inhibit the virus and have had them for years.

    Comment from a couple days ago https://uncommondescent.com/philosophy/covid-19-and-the-need-for-skeptics-in-science/#comment-709640

    The latest on Tcells from MedCram 101 https://bit.ly/31LjUVl

    As always MedCram is highly informative. Is inherent Tcell immunity what has been called the dark matter of the population that explains infections or infections that don’t progress very far? See interview with Karl Friston in early June. https://bit.ly/31FLiUK

    This would explain why some in a family would not appear to get the virus. To be specific, they get the virus but it doesn’t progress very far before being killed by the immune system.

    We tend to forget that the final elimination process is the immune system and not drugs such as HCQ and zinc or Ivermectin. However, if HCQ and Ivermectin prevent entry into the cell when used on a prophylactic basis, then technically these people do not ever get the virus.

    The Been video on the other thread has been very helpful.

  117. 117
    ET says:

    Thanks, Jerry

  118. 118
    ET says:

    Bob O’H- If they’re just lucky then there are many millions of lucky people. Maybe doctors should be handing out 4-leaf clovers instead of medicine.

  119. 119
    Bob O'H says:

    ET – well, yes. I think that’s the pattern that’s generally observed, e.g. with ‘flu epidemics. You could turn it around and say that people who catch SARS-Cov-2 are unlucky. So doctors should warn people to beware of braking mirrors and walking under ladders.

  120. 120
    ET says:

    Or it could be that some people are just healthier than others.

    Nearly all disease can be traced back to a nutritional deficiency. – Linus Pauling

  121. 121
    jerry says:

    I believe they are seeing in the blood of those exposed to C19 and who have recovered that certain T-cells are present. They also examined blood donated from 2-3 years ago and found these same T-cells present in a high percentage of the samples. It may be these people who have the quick immutability to the virus. It is also apparently higher in some Asian countries that have low infection rates.

    One of the benefits from all this is that about 20 years ago all I heard was they know a lot about how to treat diseases that originate from a bacterium like substance but almost nothing about how to treat viruses except by palliative care. That may now be changing.

  122. 122
    rhampton7 says:

    Researchers at Case Western Reserve University have added to the growing body of understanding about how hydroxychloroquine (HCQ) is not a possible defense against COVID-19.

    Specifically, they found that HCQ is not effective in preventing COVID-19 in patients with lupus and rheumatoid arthritis (RA), suggesting a broader interpretation of HCQ as ineffective preventive medicine for the general population. Their findings were recently published in the Annals of the Rheumatic Diseases.

    “ Our study shows, with a large degree of confidence, that HCQ is ineffective as a preventive antiviral in people with SLE and/or RA taking drugs that suppress their immune system, putting them at greater risk. Given how the study was structured, one can make an educated extension that it is not effective in preventing COVID-19 in people without those conditions. It is not uncommon for something to show promise in the lab, and then prove ineffective in the more complex biological landscape of humans.”

    Mendel Singer, PhD, MPH, lead author and associate professor and vice chair for education in the Department of Population & Quantitative Health Sciences at the Case Western Reserve School of Medicine

    https://www.news-medical.net/news/20200817/Hydroxychloroquine-is-not-a-possible-defense-against-COVID-19-study-shows.aspx

  123. 123
    rhampton7 says:

    Dr Tom Frieden:

    Where does the epidemic go from here? This modeling site has performed better than most, using solely deaths and machine learning. Nationally, Youyang Gu estimates there are 4.8 million people with Covid today—1 of every 78 people. The same site projects 211,500 deaths in the US by the end of October.

    Better care and newer treatment can decrease death rates (maybe: plasma and remdesivir early, steroids for some patients late). Even with a vaccine, the virus is here to stay. We need a comprehensive response that will minimize deaths and get to the new normal soon and as safely as possible.

    https://www.drtomfrieden.net/blog

Leave a Reply