Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Why the Ivermectin Evidence is Pathetic

In a pandemic, which has killed almost a million Americans, you might expect that people would try to figure out the most effective treatment, rather than scam their fellow Americans, but you would be wrong.

There are some doctors, who do not understand the difference between good research and garbage, and are promoting bad research because they really really believe – and they were right lucky about steroids before the evidence was clear. Therefore they must be right about everything.

Except, reality does not care what you believe.

They believed in steroids before there was good evidence that steroids work, but their belief was based on wishful thinking and willful ignorance, not on good science. That they were right was purely coincidence. We have seen doctors kill tens of thousands of patients with antiarrhythmic drugs, because the drugs were widely prescribed without high quality evidence of safety and efficacy.

CAST – The Cardiac Arrhythmia Suppression Trial (the high quality evidence that was agreed to in order to prove which drug saved more lives) showed that the doctors fooled themselves, and killed their patients, by believing in something that only appeared to be an improvement in outcomes. Tens of thousands of deaths were not an improvement in outcomes.

If we have a story that seems to make sense, it is much easier to convince ourselves that we are not killing patients. After all, we mean well. At least some of us do. This is an example of misleading ourselves with a narrative fallacy. C A S T and Narrative Fallacy. Rudyard Kipling called these Just So Stories.

Dr. Pierre Kory (president of the Frontline COVID-19 Critical Care Alliance – FLCCC, which is different from the extreme quackery of America’s Frontline Doctors) may be a true believer, but if Dr. Kory really believes ivermectin works, he should be demanding large scale randomized double blinded placebo controlled research, rather than making excuses for low quality research.

Dr. Kory’s claims are so bad that even PolitiFact can’t find any truth in Dr. Kory’s claim – and PolitiFact tries to be as fair to every claim as possible.

What about the science? The promoters of ivermectin have claimed that the odds are over 2 trillion to 1 that the results of the latest meta-analysis are due to chance low quality research methods. Their research methods are almost as bad as their math.

Dr. David Gorski has written a long article that goes into detail about the problems with this latest paper. Ivermectin is the new hydroxychloroquine, take 2. Read the whole article, but here is a sample:

In fairness, the authors don’t actually say that meta-analyses of crappy studies do make good evidence, at least not in the paper. However, ivermectin advocates touting the study fans are certainly making that claim, and Dr. Kory sure did seem to me to imply the same in his interview with Bret Weinstein. In any event, one large, well-designed rigorous double-blind clinical trial for prevention, along with one large, well-designed rigorous clinical trial for treatment, could trump this entire meta-analysis.

Indeed, Gideon Meyerowitz-Katz did a reanalysis of the studies analyzed by the BIRD Group that shows that if you leave out the two studies that are as yet only preprints, are very small, and actually appear to have been miscategorized as higher quality than they are, the results are very different:

This basically shows that without those two studies, the analysis demonstrates no benefit for ivermectin at all compared to placebo, with a confidence interval that includes everything from a big benefit to a large harm from the drug.

If the study really had a 2 trillion to 1 chance of the results being by chance alone, it would not rely of such low quality research (preprints, tiny studies, studies without placebos, studies that are not double blinded, . . .).

There is no good reason to look at any research on treatment for COVID-19 that is not randomized placebo controlled and double blinded.

There are millions of patients to study, so the only reasons to avoid using the highest quality of research is a lack of confidence in the treatment.

As with promoters of alternative medicine, the actions of the promoters of ivermectin do not demonstrate confidence that what they are selling will survive high quality research.

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What Treatments Will the Anti-Science President Use?

Now that President Trump’s attempts to prevent himself from developing COVID-19 have failed, for the president and for many of those around him, will the president continue to reject science, when it comes to treatment?

President Trump promoted hydroxychloroquine[1], [2], [3], which is a useful treatment for several medical conditions, but not effective against COVID-19. Should President Trump expose himself to the side effects, when there is no expectation of any benefit?

A reasonable person would not take hydroxychloroquine. A superstitious person might. This is a version of Pascal’s wager.[4] You have everything to gain, but nothing to lose. Except that Pascal’s wager ignores the more probable harms that comes from the preferred choice and assumes that all harm comes from not making the preferred choice. Therefore, Pascal’s wager is actually, You have everything to lose, but only a ridiculously long shot at any gain. Being unreasonable, Pascal’s is a losing wager.

President Trump promoted oleandrin[5], which is not a useful treatment for anything, unless you are trying for suicide or murder. Should President Trump take poison, when there is no expectation of any benefit? I suspect that many of the people who have been harmed by President Trump would say, Yes, but that is not the way medicine works.

The role of medicine is to provide the most effective treatment, taking into consideration the potential harm, in order to improve the outcome for the patient. Killing people, other than as part of medically assisted suicide (where the goal is to end the suffering of the patient at the request of the patient), is for other professions.

President Trump promoted convalescent plasma[6], which is only supported by low quality evidence and no completed high quality research. Maybe convalescent plasma works, but we may not know for a long time, because the high quality research will have trouble continuing. The EUA (Emergency Use Authorization) makes convalescent plasma available to patients outside of controlled research.

Since doctors have trouble understanding science, how do we expect patients to understand?

I was involved in a discussion with one experienced emergency physician who claimed that he should be able to give hydroxychloroquine to patients outside of controlled trials, because he would be giving hope. I asked how this is any different from what alternative medicine does? He responded just as an alternative medicine promoter would – with logical fallacies about What if . . . ? We should actually hope for better from doctors, who are supposed to understand medicine. This willful ignorance is probably the most deadly medicine doctors prescribe.

Will President Trump be as smart as British Prime Minister Boris Johnson and leave the science to the scientists? President Trump has not provided any evidence to expect reasonable decisions, yet.

What does work? If given early, remdesivir might be effective.[7] On the other hand, remdesivir might not be that effective.[8] If oxygen is used to treat low oxygen saturation, dexamethasone[9], [10] is the most effective treatment.

If you want to minimize your chances of having to make these choices, wear a mask and eye protection, stay physically away from other people, and wash your hands.

Footnotes:

Some of the footnotes are to what I have previously written about these treatments. They contain links to the research on the proposed treatments, rather than add footnotes for all of links to research and other evidence.

[1] Hydroxychloroquine – The More You Know, The Worse It Looks

Rogue Medic

May 22, 2020

Article

[2] What’s the Good News on Hydroxychloroquine?

Rogue Medic

June 6, 2020

Article

[3] Is Hydroxychloroquine Effective Against COVID-19?

Rogue Medic

July 31, 2020

Article

[4] Pascal’s wager

Wikipedia

Article

Criticism of Pascal’s Wager began in his own day, and came from both atheists, who questioned the “benefits” of a deity whose “realm” is beyond reason, and the religiously orthodox, who primarily took issue with the wager’s deistic and agnostic language. It is criticized for not proving God’s existence, the encouragement of false belief, and the problem of which religion and which God should be worshipped.[4][15]

[5] The Oleandrin Scam Exposes Incompetent Doctors

Rogue Medic

August 23, 2020

Article

[6] Is convalescent plasma safe and effective? We answer the major questions about the Covid-19 treatment

STAT

Lev Facher

August 23, 2020

Article

[7] Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial

Christoph D Spinner 1, Robert L Gottlieb 2, Gerard J Criner 3, José Ramón Arribas López 4, Anna Maria Cattelan 5, Alex Soriano Viladomiu 6, Onyema Ogbuagu 7, Prashant Malhotra 8, Kathleen M Mullane 9, Antonella Castagna 10, Louis Yi Ann Chai 11, Meta Roestenberg 12, Owen Tak Yin Tsang 13, Enos Bernasconi 14, Paul Le Turnier 15, Shan-Chwen Chang 16, Devi SenGupta 17, Robert H Hyland 17, Anu O Osinusi 17, Huyen Cao 17, Christiana Blair 17, Hongyuan Wang 17, Anuj Gaggar 17, Diana M Brainard 17, Mark J McPhail 18, Sanjay Bhagani 19, Mi Young Ahn 20, Arun J Sanyal 21, Gregory Huhn 22, Francisco M Marty 23, GS-US-540-5774 Investigators

JAMA. 2020 Sep 15;324(11):1048-1057. doi: 10.1001/jama.2020.16349.

PMID: 32821939 PMCID: PMC7442954 DOI: 10.1001/jama.2020.16349

Free Full Text from JAMA

[8] Remdesivir and COVID-19

The Lancet

October 3, 2020 (Yes, that is tomorrow’s date.)

DOI: https://doi.org/10.1016/S0140-6736(20)32021-3

Article

[9] Dexamethasone in Hospitalized Patients with Covid-19 – Preliminary Report

RECOVERY Collaborative Group; Peter Horby 1, Wei Shen Lim 1, Jonathan R Emberson 1, Marion Mafham 1, Jennifer L Bell 1, Louise Linsell 1, Natalie Staplin 1, Christopher Brightling 1, Andrew Ustianowski 1, Einas Elmahi 1, Benjamin Prudon 1, Christopher Green 1, Timothy Felton 1, David Chadwick 1, Kanchan Rege 1, Christopher Fegan 1, Lucy C Chappell 1, Saul N Faust 1, Thomas Jaki 1, Katie Jeffery 1, Alan Montgomery 1, Kathryn Rowan 1, Edmund Juszczak 1, J Kenneth Baillie 1, Richard Haynes 1, Martin J Landray 1

July 17, 2020

N Engl J Med. 2020 Jul 17; NEJMoa2021436. doi: 10.1056/NEJMoa2021436. Online ahead of print.

PMID: 32678530 PMCID: PMC7383595 DOI: 10.1056/NEJMoa2021436

Free Full Text from NEJM

[10] The RECOVERY Trial: Dexamethasone for COVID-19?

REBEL EM

June 23, 2020

Article

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Mask vs. Vaccine – Which is More Effective?

Currently, mask vs. vaccine is an easy answer. Masks are 100% more effective than something that is not available. Eventually, mask plus vaccine may be the best answer.

According to the evidence, the the masks decrease the amount of virus that is able to be detected on the other side of the mask, regardless of whether the mask is being worn by an infectious person trying to avoid infecting others or the mask is being worn by a healthy person trying to avoid becoming infected.

The dose of virus does seem to matter in transmission of disease.

This does not mean that vaccines will not help, assuming that a safe and effective vaccine is eventually available. The stated cut off level to be applied for approval of a vaccine is currently at least 50% effective. Masks are already more than 50% effective.

“I might even go so far as to say that this face mask is more guaranteed to protect me against COVID than when I take a COVID vaccine, because the immunogenicity may be 70%,” Redfield said in testimony before a Senate appropriations committee. “And if I don’t get an immune response, the vaccine is not going to protect me. This face mask will.”[1]

That statement was later contradicted by President Trump, but that statement was not contradicted by any credible scientist and was not contradicted by any credible physician. Oddly, the article title suggests that Dr. Redfield walked back his statement, although the article never states that. This may be because the headline is often not written by the person writing the article, but by an editor, looking to get more clicks.

Masks work.

Vaccines are not available and probably will not be available until sometime next year.

If we want the economy to recover, we need to be aggressive about wearing masks to protect others and to protect ourselves.

This is from a paper written in 2009 about influenza, which is transmitted the same way SARS-CoV 2 is transmitted. These were people with influenza, wearing masks, and coughing. The results with an N95 mask and a surgical mask show that both decreased the amount of virus, that would be spread by a cough, to the undetectable level.[2]

Masks do not protect your eyes, so you should consider wearing eye protection. Masks also do not protect your hands, so wash your hands. Typhoid Mary might not have killed anyone if she had washed her hands.

**********************

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Footnotes:

.

[1] CDC Chief Walks Back Masks v. Vaccine Comments
By Ralph Ellis
WebMD
Article

.

[2] A Quantitative Assessment of the Efficacy of Surgical and N95 Masks to Filter Influenza Virus in Patients with Acute Influenza Infection
D. F. Johnson, J. D. Druce, C. Birch, M. L. Grayson
Clinical Infectious Diseases, Volume 49, Issue 2, 15 July 2009, Pages 275–277, 
https://doi.org/10.1086/600041 Published: 15 July 2009

.

What Does the Approval of a Russian Vaccine Mean?



Today, after testing on a grand total of 76 people, President Putin announced the approval of a vaccine in Russia, Sputnik-V, to prevent COVID-19.

We knew another pandemic was coming, because we understand evolution. We should have been prepared. We were prepared under the Bush administration. We were prepared under the Obama administration. The current administration chose to stop wasting money on being prepared.

There are three human phases of testing generally required before the approval of a vaccine or drug, after testing in other animals. Phase I is testing in humans for common adverse effects, dosing ranges, and to generally learn how the body reacts. For the most discussed vaccine trial, Moderna had 45 people (three groups of 15 people each receiving different doses of vaccine) in their Phase I trial.

Phase II expands the use to people who are not as healthy as the people in Phase I and to a more people. Phase III is refining this, based on the results of the earlier trials. Phase I and II are being combined in some vaccine trials. Phase II and II are being combined in others.

The Moderna Phase III trial of mRNA-1273 (mRNA is messenger RiboNucleic Acid – the stock ticker for Moderna, Inc. is also MRNA) is expected to enroll 30,000 people who have no evidence of previous COVID-19 infection.[1] Half will get mRNA-1273 and half will get a meningitis vaccine as a placeboish control. While a placebo often means inert, a saline solution injection would not produce the temporary fever, soreness, and/or redness to the site at the same rate as an actual vaccine. This is expected to keep the volunteers from being able to tell which they have received and it provides a benefit to those in the placebo group.

Russia has enrolled 76 people in Phase I and President Putin has announced that Phase III will happen at the same time as the mass vaccination of the people most likely to be exposed to infection. This is Phase IV – post approval study.

Russia has not announced any challenge testing, which might have been a more ethical approach than skipping Phase III. Challenge testing has not being announced anywhere for COVID-19 vaccine testing, because of the ethical concerns. With an expected 1/2% to 1% fatality rate, a much higher rate of serious complications, and an unknown rate of long term complications that appear to be related to COVID-19, it is difficult to justify intentionally exposing people to infection with a vaccine of unknown ability to protect the people being exposed. Thousands of people dying each day, thousands more developing serious complications each day, and thousands more developing long term complications each day. Where is the line drawn between approving challenge testing and not approving it? Where is the line drawn between challenge testing and skipping Phase III trials?

When will the Russian vaccine be given to people? Some time in October.

What could go wrong?

Meanwhile the Moscow-based Association of Clinical Trials Organizations (Acto), which represents the world’s top drug companies in Russia, urged the health ministry to postpone approval until after phase-three trials.

Acto executive director Svetlana Zavidova told the Russian MedPortal site that a decision on mass vaccination had been carried out after a combined first- and second-phase tests on 76 people, and that it was impossible to confirm the efficacy of a drug on this basis.[2]

Will this be just another political intervention, like hydroxychloroquine? Only time will tell.

What would indicate that the United States has a safe and effective vaccine?

I want to see recommendation of a vaccine by the people who know the most about vaccines – Paul Offit, Michael Osterholm, Peter Hotez, and Anthony Fauci. They need to be able to see all of the evidence. The only reasonable conclusion about a refusal to share the evidence with any of them is that there is something bad being hidden. These are not politicians. None of these medical experts have shown signs of being influenced by political pressure.

The pandemic was not at all a surprise. The conspiracy theorists will misrepresent this video, because of their lack of understanding of what they are hearing. If it doesn’t support their prejudices, they don’t seem to hear anything at all, as if they have been programmed to ignore valid evidence and logic.

Pandemic Preparedness in the Next Administration: Keynote Address by Anthony S. Fauci – Feb. 14, 2017 – Almost 3 years before COVID-19, but the medically competent audience understood that this was a reasonable prediction to make in 2017. If you don’t understand that, watch the whole video.



Every reasonable person should have known there would be another pandemic, but we have media that discourage understanding, especially about science.


Late addition – 10:55 – 8/12/2020 – For further information, Carl Zimmer has an article in The New York Times going into more detail. A couple of important quotes from the article are below.

‘This Is All Beyond Stupid.’ Experts Worry About Russia’s Rushed Vaccine
August 11, 2020
by Carl Zimmer. Andrew Kramer and Katherine J. Wu contributed reporting.
The New York Times
Article

“This is all beyond stupid,” said John Moore, a virologist at Weill Cornell Medical College in New York City. “Putin doesn’t have a vaccine, he’s just making a political statement.”

Dr. Nicole Lurie, a former assistant secretary for preparedness and response at the U.S. Department of Health and Human Services and currently an adviser at the Coalition for Epidemic Preparedness Innovations, said the lesson that the U.S. government should draw from Mr. Putin’s announcement is clear.

“This is exactly the situation that Americans expect our government to avoid,” she said.

Footnotes:

[1] Phase 3 clinical trial of investigational vaccine for COVID-19 begins – Multi-site trial to test candidate developed by Moderna and NIH.
Monday, July 27, 2020
NIH (National Institutes of Health)
News Release

[2] Coronavirus: Putin says vaccine has been approved for use
Analysis by Fergus Walsh, Medical correspondent
BBC
Article

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Is Hydroxychloroquine Effective Against COVID-19?

     
As with any popular treatment, there are plenty of people who want us to ignore the research, or to focus on giving people hope. That is not a reasonable, or ethical, approach to medicine. That is not even a medical approach to medicine. If we lower our standards enough, we can claim that everything works, but that would kill a lot more people than only using treatments based on EBM (Evidence Based Medicine). Should we make excuses for lowering our standards, and killing people, or should we insist on raising our standards?

There is currently a pandemic, so there is a bit of a rush to find something that works, which some people mistake for a need to provide hope. If you want hope, you can pray and there should not be any harmful effects of praying. However knowing that you were being prayed for by others has been associated with a significantly higher incidence of complications. In other words, praying for yourself or others is fine, but telling others that you are going to pray for them is probably harmful, even though your intent is to help.[1]

The reasonable way to look at taking medicine is take only those treatments that have been demonstrated to improve outcomes for people with the studied diagnosis, when you have that diagnosis. Everything else is a crap shoot, where you don’t even know the risks – and there probably is no benefit.

Why do I state that the risks to the person taking the treatment are unlimited, but the benefits probably do not exist?

That is the history of the study of treatments. Almost everything proposed as a treatment has been more harmful than beneficial. It would be nice if this were not true, but reality doesn’t care about being nice. All of alternative medicine falls into the category of probably more harmful than safe and unlikely to be of any benefit, other than a benefit to the finances of the person selling the alt med.

Is hydroxychloroquine alternative medicine? Hydroxychloroquine is approved as real medicine for malaria, lupus erythematosus, and rheumatoid arthritis.[2] For these diagnoses, hydroxychloroquine is not alternative medicine. For everything else, the use is off-label, which is a legal way of saying alternative medicine, as far as the FDA (Food and Drug Administration) is concerned. Sometimes off-label use can be supported by good evidence, but the treatment has not been submitted to the FDA for approval for that diagnosis, but that is not the case with hydroxychloroquine. The FDA issued an EUA (Emergency Use Authorization) for hydroxychloroquine limited to adults and adolescents who weigh 50 kg (approximately 110 pounds) or more, who were hospitalized with COVID-19, and for whom participation in a clinical trial was not available, or participation was not feasible.[3]

Why are those limitations important?

1. If a treatment is effective, diverting patients from clinical trials will delay learning that the treatment is effective, which will significantly decrease the number of lives saved.

2. If a treatment is not effective, diverting patients from clinical trials will delay learning that the treatment is not effective, which will significantly decrease the number of lives saved, because patients are receiving a useless distraction from effective treatment.

3. If a treatment is harmful, which is much worse than just being not effective, diverting patients from clinical trials will delay learning that the treatment is harmful, which will significantly increase the number of patients killed.

All of those results – and those are the possibilities – are ignored by those who reject research. No treatment, however good, will be purely beneficial. All treatments have adverse effects. however, the reverse of that is not true. A treatment that is harmful often does not provide any benefit.

The odds are always against the patient. Any doctor trying to just do something is endangering patients. Kitchen sink medicine (throwing everything at the patient, just in case) has always been bad medicine.

There is a good discussion of the evidence in two podcasts:

15. Covid-19: Is There a Case for Hydroxychloroquine?
Stimulus with Rob Orman, MD (who also hosts the ERCast)
July 30, 2020
Podcast page

Dr. Orman does not specifically mention the Arshad study, which claims to show a benefit in patients treated with HCQ (HydroxyChloroQuine), AZM (AZithroMycin), and HCQ+AZM (HydroxyChloroQuine + AZithroMycin), but that does not change the conclusion of an examination of the evidence.[4]


COVID-19 Treatment Update: Can We Just Stop Wasting Time on Hydroxychloroquine
Written by Salim Rezaie
July 6, 2020
Podcast page

Here is the most important point from Salim Rezaie about the outcomes from the Arshad study:

As most patients in this trial receiving HCQ or HCQ + AZM received steroids and the patients receiving AZM alone or neither therapy had far fewer patients receiving steroids, the likely mortality benefit of this trial is due to the steroids and not the HCQ or HCQ + AZM


Dr. Rezaie concludes: This study should not change clinical practice of not prescribing these medications.

The Arshad study is being used by proponents of hydroxychloroquine alternative medicine to try to contradicting higher quality research, which is the reason it is not real medicine. When there is only low quality evidence, we should be cautious in recommending any treatment. When the high quality evidence shows that the low quality evidence is misleading, we should ignore the low quality evidence until there is high quality evidence to support the findings of the low quality evidence. Don’t expect that to happen.

The reason most medical research is overturned is the reliance on low quality evidence.[5], [6], [7], [8]


Footnotes:

[1] Study of the Therapeutic Effects of Intercessory Prayer (STEP) in cardiac bypass patients: a multicenter randomized trial of uncertainty and certainty of receiving intercessory prayer
Herbert Benson 1, Jeffery A Dusek, Jane B Sherwood, Peter Lam, Charles F Bethea, William Carpenter, Sidney Levitsky, Peter C Hill, Donald W Clem Jr, Manoj K Jain, David Drumel, Stephen L Kopecky, Paul S Mueller, Dean Marek, Sue Rollins, Patricia L Hibberd
Am Heart J. 2006 Apr;151(4):934-42. doi: 10.1016/j.ahj.2005.05.028.
PMID: 16569567

Our study had 2 main findings. First, intercessory prayer itself had no effect on whether complications occurred after CABG. Second, patients who were certain that intercessors would pray for them had a higher rate of complications than patients who were uncertain but did receive intercessory prayer.



[2] Hydroxychloroquine Sulfate tablet
INDICATIONS AND USAGE
Daily Med
FDA Label


[3] Frequently Asked Questions on the Revocation of the Emergency Use Authorization for Hydroxychloroquine Sulfate and Chloroquine Phosphate
FDA
Page as PDF download

Q. Why did FDA grant the EUA for hydroxychloroquine sulfate (HCQ) and chloroquine phosphate (CQ) for the treatment of COVID-19 initially?
A. On March 28, 2020, BARDA requested and FDA issued an Emergency Use Authorization (EUA) for emergency use of oral formulations of chloroquine phosphate (CQ) and hydroxychloroquine sulfate (HCQ) for the treatment of COVID-19. Based on the scientific information available to FDA as of that date, the Agency determined that CQ and HCQ may be effective in treating COVID-19 and that the known and potential benefits of CQ and HCQ outweighed the known and potential risks for this use. The agency limited the use of authorized products to adults and adolescents who weigh 50 kg (approximately 110 pounds) or more, who were hospitalized with COVID-19, and for whom participation in a clinical trial was not available, or participation was not feasible.



[4] Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19
Samia Arshad,a Paul Kilgore,b,c Zohra S. Chaudhry,a Gordon Jacobsen,e Dee Dee Wang,d Kylie Huitsing,a Indira Brar,a George J. Alangaden,a,c Mayur S. Ramesh,a John E. McKinnon,a William O’Neill,d Marcus Zervos,a,c,⁎ and Henry Ford COVID-19 Task Force1
Int J Infect Dis. 2020 Aug; 97: 396–403.
Published online 2020 Jul 2. doi: 10.1016/j.ijid.2020.06.099
PMID: 32623082

PMCID: PMC7330574 (Free Full Text from PubMed Central)


[5] Why Most Published Research Findings Are False
John P. A. Ioannidis
PLoS Med. 2005 Aug; 2(8): e124.
Published online 2005 Aug 30. doi: 10.1371/journal.pmed.0020124
PMID: 16060722

PMCID: PMC1182327 (Free Full Text from PubMed Central)

The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance.



[6] Evidence-based de-implementation for contradicted, unproven, and aspiring healthcare practices
Vinay Prasad and John PA Ioannidis
Implement Sci. 2014; 9: 1.
Published online 2014 Jan 8. doi: 10.1186/1748-5908-9-1
PMID: 24398253

PMCID: PMC3892018 (Free Full Text from PubMed Central)

Abandoning ineffective medical practices and mitigating the risks of untested practices are important for improving patient health and containing healthcare costs. Historically, this process has relied on the evidence base, societal values, cultural tensions, and political sway, but not necessarily in that order. We propose a conceptual framework to guide and prioritize this process, shifting emphasis toward the principles of evidence-based medicine, acknowledging that evidence may still be misinterpreted or distorted by recalcitrant proponents of entrenched practices and other biases.


[7] Observational studies often make clinical practice recommendations: an empirical evaluation of authors’ attitudes
Vinay Prasad 1, Joel Jorgenson, John P A Ioannidis, Adam Cifu
J Clin Epidemiol.
2013 Apr;66(4):361-366.e4.
PMID: 23384591   DOI: 10.1016/j.jclinepi.2012.11.005

It is common to see new studies contradict previous adopted standards of care [25,26]. Even the results of highly cited studies can be refuted [7], and the replication rate tends to be low for claims made from observational designs [7]. We have previously noted that the most common correlate for reversal of standards of care was the original adoption of a practice based on nonrandomized evidence alone [27]. The studies examined here offer many recommendations that may be precarious or erroneous. If adopted, such practices may need to be reversed in the future after having been detrimental to health, health finances, and the reputation of medical science.



[8] Contradicted and initially stronger effects in highly cited clinical research
John P A Ioannidis
JAMA. 2005 Jul 13;294(2):218-28. doi: 10.1001/jama.294.2.218.
PMID: 16014596   DOI: 10.1001/jama.294.2.218

Free Full Text from JAMA

Of the 45 eligible highly cited studies with efficacy claims (Table 2), 7 (16%) were contradicted by subsequent research, and another 7 (16%) were found to have initially stronger effects. In all these 14 cases (BOX 1), subsequent studies were either larger or better controlled (randomized vs a nonrandomized original study). The findings of 20 highly cited articles (44%) were replicated (also with a larger sample size in subsequent research compared with the original highly cited study) and 11 (24%) had remained largely unchallenged.58-78



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Happy Darwin and Lincoln Day 2020


Happy Lincoln-Darwin Day!
 
Today is the birthday of two people considered enemies by the American slavery belt – Charles Darwin and Abraham Lincoln. The slavery belt was so afraid of Lincoln that most of the slave states seceded before Lincoln took office as president.

Charles Darwin wrote a book that exposed the slavery of human beings as immoral. The slaves were just as human as every slave owner. Bible quotations in defense of slavery were regularly provided by slave owners to justify their immorality, but it was not working as well as it used to. To be fair, many of the Founding Fathers opposed slavery, but this was a compromise that will always stain the Constitution. There was even an agreement in the Constitution to allow the importation of slaves at least until 1808.
 

The Migration or Importation of such Persons as any of the States now existing shall think proper to admit, shall not be prohibited by the Congress prior to the Year one thousand eight hundred and eight, but a tax or duty may be imposed on such Importation, not exceeding ten dollars for each Person.[1]

 

There was enough opposition to the importation of slaves that a law prohibiting importation went into effect the first day possible – January 1, 1808.

Opponents of Lincoln continue to make excuses for the treason of the slave states that seceded and made war on the United States of America.

Opponents of Darwin continue to make excuses for rejection of biology, even though genetics and evolution are essential for the understanding of biology. Denial of science has become a tenet of Creationist sects.

Currently the most popular method of denying science is the one made notorious by the exposure of private documents of the cigarette industry. Create the appearance of scientific doubt and scientific controversy, even though the only doubt and controversy is about minor details, rather than the broad conclusions.
 

The most important type of story is that which casts doubt in the cause and effect theory of disease and smoking. Eye-grabbing headlines should strongly call out the point[2]

 

 

Doubt is our product next hit since it is the best means of competing with the “body of fact” that exists in the mind of the general public. It is also the means of establishing a controversy. Within the business we recognize that a controversy exists. However, with the general public the consensus is that cigarettes are in some way harmful to the health. If we are successful in establishing a controversy at the public level, then there is an opportunity to put across the real facts about smoking and health. previous hit Doubt is also the limit of our ” product.” Unfortunately, we cannot take a position directly opposing the anti-cigarette forces and say that cigarettes are a contributor to good health. No information that we have supports such a claim .

Truth is our message because of its power to withstand a conflict and sustain a controversy. If in our pro-cigarette efforts we stick to well documented fact , we can dominate a controversy and operate with the confidence of justifiable self-interest [italic emphasis added]. {2111.01, pp. 4, 5}[3]

 

The point was to create the appearance of honesty, without the substance. This method is used by a lot of other science denialists – anti-vaxers, climate change deniers (both those who deny that climate change is real and those who claim that human activity is not responsible for the dramatic acceleration of global warming), flat earthers, alternative medicine promoters, anti-GMO activists, anti-abortion activists, anti-equality activists, geocentrists, et cetera.

Reality is their enemy.

Reality will always be their enemy.

Footnotes:

[1] Article 1 Section 9
U.S. Constitution
Link to Article 1 Section 9 at constitution.net

[2] Tobacco Explained – The truth about the tobacco industry …in its own words
World Health Organization
Page 11/79 on the pdf counter, but marked as page 7 on the page
Free Full Text in PDF format from WHO
 

Carl Thompson from Hill and Knowlton writes a letter on the best angles for the
industry magazine, Tobacco and Health Research:
“The most important type of story is that which casts
doubt in the cause and effect theory of disease and
smoking. Eye-grabbing headlines were needed and
“should strongly call out the point – Controversy! Contradiction! Other Factors! Unknowns!” 31 (Hill and
Knowlton, 1968)

 

[3] Using Cigarette Ads to Counter Health Information
The Cigarette Papers
Chapter 5 Public Relations in the “Safe” Cigarette Era
Resisting Government Regulation: Advertising Campaigns
Pages 190-191
University of California Press
Link to book with search for “Doubt is our product”

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How Effective Is Epinephrine for Improving Survival Among Patients in Cardiac Arrest?

   

There have been two studies comparing epinephrine with placebo to treat out of hospital cardiac arrest. The Jacobs study was stopped early, because of interference by those who do not want to know if their medicine actually works.[1] The purpose of research is to determine, as objectively as possible, if a treatment is better than placebo nothing.  

Click on the image to make it larger.  

Even the small sample size shows a impressive p values of <0.001 for both ROSC (Return Of Spontaneous Circulation) and being admitted to the hospital. Unfortunately, that does not lead to outcomes that are better than placebo.

The Perkins study (PARAMEDIC2) did not find a significant difference between adrenaline (epinephrine in non-Commonwealth countries) and placebo.[2] The Jacobs study also did not find a difference, but the numbers were small, due to the interference by the less than knowledgeable. Following the Jacobs study, some intervention proponents have suggested that the problem is not a lack of evidence of benefit, but need to look at the evidence from the right perspective. The inadequate evidence is not “inadequate”, but really just misunderstood. All we need to do is use a method of analysis that compensates for the tiny sample size. A Bayesian approach will produce the positive outcome that is not justified by so few patients.[3]

What happens when the numbers are combined, so that the sample size is large enough to eliminate the need for statistical chicanery to come up with something positive?

The outcomes do not improve.  

Neither standard dose adrenaline, high-dose adrenaline,vasopressin nor a combination of adrenaline and vasopressin improved survival with a favourable neurological outcome.[4]
 

If the Bayesian approach were appropriate, then the much larger sample size would have provided more than enough patients to confirm the optimism of the epinephrine advocates. The result is still not statistically significant. Maybe a much, much larger study will show a statistically significant, but tiny, improvement in outcomes with epinephrine, but don’t hold your breath for that. It took half a century to produce the first study, then seven more years for the second. With the cost of research and the problems coordinating such a large study, it is more likely that the guidelines will continue to recommend spending a lot of time and money giving a drug that diverts attention from the interventions that do improve outcomes.

There is still no evidence that adrenaline provides better outcomes than placebo in human cardiac arrest patients.

  –  

Footnotes:

  –  

[1] Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Resuscitation. 2011 Sep;82(9):1138-43. doi: 10.1016/j.resuscitation.2011.06.029. Epub 2011 Jul 2. PMID: 21745533

Free Full Text PDF Download from semanticscholar.org  

This study was designed as a multicentre trial involving five ambulance services in Australia and New Zealand and was accordingly powered to detect clinically important treatment effects. Despite having obtained approvals for the study from Institutional Ethics Committees, Crown Law and Guardianship Boards, the concerns of being involved in a trial in which the unproven “standard of care” was being withheld prevented four of the five ambulance services from participating.

In addition adverse press reports questioning the ethics of conducting this trial, which subsequently led to the involvement of politicians, further heightened these concerns. Despite the clearly demonstrated existence of clinical equipoise for adrenaline in cardiac arrest it remained impossible to change the decision not to participate.

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[2] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators. N Engl J Med. 2018 Aug 23;379(8):711-721. doi: 10.1056/NEJMoa1806842. Epub 2018 Jul 18. PMID: 30021076

Free Full Text from N Engl J Med.

  –  

[3] Regarding “Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial”. Youngquist ST, Niemann JT. Resuscitation. 2012 Apr;83(4):e105; author reply e107. doi: 10.1016/j.resuscitation.2011.09.035. Epub 2012 Jan 18. No abstract available. PMID: 22266068

Free Full Text from Resuscitation.

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[4] Adrenaline and vasopressin for cardiac arrest. Finn J, Jacobs I, Williams TA, Gates S, Perkins GD. Cochrane Database Syst Rev. 2019 Jan 17;1:CD003179. doi: 10.1002/14651858.CD003179.pub2. PMID: 30653257    

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Vaccines are probably the safest and most effective medical intervention available, so why do anti-vaxers lie about them

 

Why does anyone lie?

Anti-vaxers lie for the same reason as other people – for personal benefit.

Many anti-vaxers claim that there is an international conspiracy of doctors and researchers, as if all of the doctors and researchers, or even the pediatric doctors and researchers, in the world could agree on much of anything. When you realize how ridiculously large this conspiracy would be, how much a doctor or researcher would gain from providing valid information to expose such a conspiracy, and how aggressively law enforcement would punish those behind such a conspiracy, you understand the use of ridiculous is appropriate as a description of the conspiracy theory.

This is just another example of some people thinking they know more than everyone else, based on a lack of understanding. This feeds the over-inflated egos of anti-vaxers.

The smallpox vaccine has saved hundreds of millions of lives. Anti-vaxers opposed the smallpox vaccine and delayed the eradication of smallpox. Anti-vaxers helped smallpox kill people..

Our children are no longer vaccinated against smallpox, because smallpox has been wiped out by vaccines. Millions of children’s lives, and adult lives, are saved every year by the smallpox vaccine, without even giving it to children, because enough people rejected the lies of anti-vaxers.

Vaccines continue to save millions of lives every year, in spite of opposition by anti-vaxers.

There is plenty of research showing that vaccines are effective and safe, but to give the single clearest example of the benefit of vaccines, look at the following paper from JAMA. The Journal of the American Medical Association is one of the most respected medical publications in the world. Use any search engine to find a list of the most respected medical journals and you will find JAMA near the top.

Look at the decrease in the rates of illness and the rates of death for each vaccine-preventable illness after the introduction of the vaccine for that illness. Click on the image for a larger, easier to read version.
 


 

Table 1. Historical Comparison of Morbidity and Mortality for Vaccine-Preventable Diseases With Vaccines Licensed or Recommended Before 1980: Diphtheria, Measles, Mumps, Pertussis, Poliomyelitis, Rubella, Smallpox, Tetanusa [1]

 

This information has been simplified for those not comfortable with scientific research (I do not know the source of the image, it was not part of the paper in JAMA):
 


 

As you can see, these diseases are almost never a problem in America, where vaccination rates are still pretty high, although anti-vaxers are causing more and more outbreaks of diseases we had not seen in decades.

Some anti-vaxers will claim that the vaccines didn’t get rid of these diseases. These anti-vaxers claim that improved sanitation, improved hygiene, and improved diet got rid of these diseases. While these improvements are helpful, here is why that is just another anti-vax lie.

We have outbreaks of vaccine-preventable illnesses in America, when the rate of vaccination drops, even though sanitation, hygiene, and diet did not deteriorate. Yes, many of our diets are getting worse, but that is not what is causing outbreaks of whooping cough, measles, and other vaccine-preventable illnesses.

The rates of illness and death only have a dramatic change for each of the vaccine-preventable illnesses after the introduction of each vaccine. If sanitation, hygiene, and diet were the reasons, the illnesses would all start to go away at the same time, although not necessarily at the same rate. If that were the case, the decreases in these diseases could easily be shown to be due to improvements in sanitation, hygiene, and diet, but that is not the case.

Anti-vaxers cannot explain that, but anti-vaxers are not reasonable.
 

Why has the polio vaccine been so effective in India, when India has widespread problems with sanitation, hygiene, and diet?

Here is what the authors wrote:
 

India, a vastly diverse country with a 27 million birth cohort, undertook the largest vaccination drive against WPV (Wild Polio Virus) in the world. With high population density, poor civic infrastructure, poor sanitation, an almost nonexistent public health system, rampant malnutrition and diarrhea, difficult-to-reach locales, high population mobility, and extremely high force of WPV transmission in few states,3 the interruption of WPV transmission was extremely difficult and demanding. The interplay of these challenging factors provided a perfect milieu for the WPV to circulate, and the prospect of achieving zero-polio status seemed insurmountable.[2]

 

India completed a full 5 years as a “polio-free nation” on January 13, 2016.1 It was a remarkable feat considering the odds against achieving this status. [2]

Anti-vaxers will make excuses, but this clearly exposes the anti-vax lie that disease elimination being due to improved sanitation, hygiene, and diet, rather than due to vaccines.
 

The reason smallpox vaccine is no longer given to children, is the worldwide eradication of smallpox by vaccination.

Anti-vaers delayed the worldwide eradication of smallpox.

Anti-vaxers have prevented the worldwide eradication of polio.

Anti-vaxers continue to try to protect polio from eradication.

Children would no longer need polio vaccination, if it weren’t for anti-vaxers.

If you don’t like giving the polio vaccine to your child, blame the anti-vaxers.

Footnotes:

[1] Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States.
Roush SW, Murphy TV; Vaccine-Preventable Disease Table Working Group.
JAMA. 2007 Nov 14;298(18):2155-63.
PMID: 18000199

You can also read the full text of the article for free at JAMA at the link below, if you want to understand more of the details that the anti-vaxers don’t want you to understand.

Historical Comparisons of Morbidity and Mortality for Vaccine-Preventable Diseases in the United States

[2] Polio Eradication in India: The Lessons Learned.
Thacker N, Vashishtha VM, Thacker D.
Pediatrics. 2016 Oct;138(4). pii: e20160461. Epub 2016 Sep 2. Review. No abstract available.
PMID: 27590898

You can also read the full text of the article for free at Pediatrics at the link below, if you want to understand more of the details that the anti-vaxers don’t want you to understand. Pediatrics is one of the most respected pediatric medical publications in the world. Use any search engine to find what pediatric medical journals are the most respected and you will find Pediatrics near the top.

Polio Eradication in India: The Lessons Learned

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