Last updated by The POOG on August 01, 2021.
Apart from hydroxychloroquine, there are a number other therapeutics that have come to prominence, some effective and some not. In this article, we discuss some of them. The result of 600 studies using various neutraceuticals and generic pharmaceuticals for treatment of COVID-19 is presented here: COVID-19 early treatment: real-time analysis of 771 studies.
With a goal of repurposing of existing drugs, a study of 530 lysosomotropic compounds identified 36 with potential anti-viral properties. Of these, 14 of them showing evidence of broad-spectrum antiviral activity are already under study or in use.
The action of alkalinizing lysosomotropic drugs has been studied extensively]. Drugs studied include chloroquine, hydroxychloroquine, amodiaquine, azithromycin, bafilomycin A1, fluoxetine and chlorpromazine.
Video deleted by YouTube.
The following presentation by Dr. Ryan Cole, his segment runs from 00:40 to 28:50 minutes, covers both Vitamin D and Ivermectin. One statement that he makes is that if your Vitamin D levels are in the mid range, you cannot suffer the cytokine storm that is particularly harmful or lethal in advanced COVID-19 cases. It supports everything presented below. You will see that these two drugs together are more effective than the vaccines and render them unnecessary.
Over recent years, Vitamin D has been found to have an efficacy in preventing or treating a wide range of diseases and disorders. We will not explore the topic here since our focus is on COVID-19. For a general discussion of Vitamin D which is quite extensive but readable and cites original research, read the article by Adda Bjarnadotti or the book by Dr. MF Holick.
Garvin et al (2020) list vitamin D as a potential therapeutic in treating COVID-19 patients. Israel et al (2020) in a study observed “a highly significant correlation between prevalence of vitamin D deficiency and Covid-19 incidence“.
A stronger analog of vitamin D, calcifediol, was used in a clinical trial. The r
pilot study demonstrated that administration of calcifediol may improve the clinical outcome of subjects requiring hospitalization for COVID-19.Castillo (2020)
Calcifediol does have side effects.
Gene studies by Glinsky found that
… vitamin D and quercetin have been identified as putative 2019 coronavirus disease (COVID-19) mitigation agents. Quercetin has been identified as one of top-scoring candidate therapeutics in the supercomputer SUMMIT drug-docking screen and Gene Set Enrichment Analyses.
There are several other studies that demonstrate the efficacy of Vitamin D both as a prophylactic and for reducing the severity of infections.
Dr. Chris Martenson gave a good discussion on vitamin D in a September video:
In an October video he discussed recent findings that Vitamin D reduces mortality risk by 89%.
Next is a chart showing the relationship between Vitamin D levels and disease severity:
Here’s another doctor’s assessment:
The following video gives the best explanation of what Vitamin D3 is, how it works, and its correlation with COVID-19 infection and mortality. It discussess a number of important papers on Vitamin D3 and particularly how low serum levels of 25(OH)D, the metabolized form of D3 correlates to increased infection rates and mortality.
This is a very professional analysis of the efficacy of Vitamin D3 based on scientific studies. I take 5000IU daily. You should too, more if your BMI is high. Consult your doctor but only if he/she has done their homework on the topic.
Dosage and Side Effects
The Mayo Clinic describes a rare side effect of too high Vitamin D level:
Vitamin D toxicity, also called hypervitaminosis D, is a rare but potentially serious condition that occurs when you have excessive amounts of vitamin D in your body.
Vitamin D toxicity is usually caused by large doses of vitamin D supplements — not by diet or sun exposure.
The main consequence of vitamin D toxicity is a buildup of calcium in your blood (hypercalcemia)Source: Mayo Clinic
They cite a study using 60,000 IU a day over several months as causing the severe response. The RDA, according to them is 600 IU.
The problem with recommended dosages is that they are general. Every individual absorbs and process all vitamins differently. With vitamin D where there is natural bodily generation due to sun exposure, the individual’s blood serum levels will vary. It is this latter number that is important. Bjarnadotti gives the recommended ranges as:
- Sufficient: 20–30 ng/ml, or 50–75 nmol/L.
- Safe upper limit: 60 ng/ml, or 150 nmol/L.
- Toxic: Above 150 ng/mL, or 375 nmol/L.
In one individual, 5000 IU daily produced a serum level of 46 ng/ml a month after the winter solstice. This is midway between the sufficient and safe upper levels. The calculator in the following section may be helpful to you.
There is not a lot of data on a recommended prophylactic dose for COVID-19 and sources vary considerably from around 2000 IU per day an up. COVID.US.org cites studies that recommend 5000 IU as a maintenance dose.
Optimal vitamin D serum blood levels, attained through sunlight or supplementation, dramatically reduce the risk of many diseases other than bone maladies. Most people in the northern hemisphere, by raising blood serum levels of 25-hydroxyvitamin D [25(OH)D] to an optimal value, can cut their risks from most major diseases by 50 to 80 percent. Diseases and conditions positively affected by adequate D include:
- bone density,
- cardiovascular disease,
- type 1 diabetes,
- type 2 diabetes (to a lesser extent),
- rheumatoid arthritis,
- peripheral vascular disease,
- multiple sclerosis,
- autoimmune diseases, and
- viral diseases such as H1N1 and AIDS.
Vitamin D Links
A Contrarian Study
Butler-Laporte et al. (2021) have published in PLOS Medicine, a statistical analysis of a large database of subjects to which they applied genetic-factor distributions to arrive at this conclusion:
In this 2-sample MR study, we did not observe evidence to support an association between and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.Butler-Laporte et al. (2021)
In other words, their critique of the extensive body of clinical studies and research is based on a statistical genetic analysis. They state that:
Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal.ibid.
The most troubling aspect of this paper is that they appear to be using a genetic factor analysis to determine a person’s natural 25OHD level. They correlate that to test subjects statistically – not actually. In fact I could find no reference that they looked at real level data. Their dismissive remark about “many confounding variables” might be paraphrased as “we couldn’t be bothered in reviewing any of the studies that we are trying to invalidate so we’ll say it is too complicated”.
The general claim for efficacy of vitamin D involves much higher serum levels than they are looking at. Their conclusion is therefore specious. Further, to insert a policy recommendation in a “scientific” paper suggests an unstated agenda.
The paper comes out of McGill University in Montreal. McGill has been one of the strongest influences on health policy in Canada and is closely aligned with the government. The government’s vaccine implementation has been an embarrassment from the start. To save face, the Prime Minister has stated his goal is 100% vaccination.
To achieve this, the government must remove any alternative strategies that might be as, or even more effective than vaccination. Hence, a hit piece on Vitamin D would seem a logical response.
Also, PLOS Medicine is a journal that states that it “publishes articles of general interest on biomedical, environmental, social and political determinants of health“. Not quite a front-line journal but a place to get published otherwise.
What has become the best drug for prophylaxis and treatment of COVID-19 is the drug Ivermetin. There are a number of good, short descriptions of Ivermectin, its properties and uses.
Chris Martenson discusses an Egyptian study of its efficacy starting at about the 11:10 minute mark. His original video was censored on both YouTube and Vimeo but he has it on his site at https://www.peakprosperity.com/censored-most-recent-covid-video-banned-by-youtube/. Both videos are about the same length but the one on his website that I can’t embed here is better.
The paper by Elgazzar et al (2020) that Martenson references tested the effect of Ivermectin and hydroxychloroquin on two groups each of mild-moderate and severe cases. Table 4 in their report shows a much better improvement with Ivermectin than HCQ alone, 99% to74% and 94% to 50%.
Next is an impassioned plea for Ivermectin from a hugely qualified medical specialist, Dr. Pierre Kory. It acts as a prophylactic and at all stages of an infection. As a note, this interview goes against the interests of Big Pharma and the official narrative of public health authorities. YouTube censors remove it as soon as it appears. It may still be on C-SPAN: Dr. Pierre Kory US Senate hearing – Ivermectin is 100% cure for COVID-19.
Studies and Clinical Trials
In this section we review a few of the studies and references that we have come across concerning the use of Ivermectin to fight SARS-CoV-2.
The first is a reference to an in vitrio (cell culture) trial that “reduces the number of cell-associated viral RNA by 99.8 % in 24 hours“. This is the first stage of drug testing and is done before human trials. This is an extremely encouraging result.
A study by Behera et al (2020) found that (emphasis added):
Two-dose ivermectin prophylaxis at a dose of 300 μg/kg with a gap of 72 hours was associated 73% reduction of COVID-19 infection among healthcare workers for the following one-month.Source: Beheraa et al (2020)
A meta study by Covid Analysis (2020) of 24 single studies found that:
•Ivermectin is effective for COVID-19. 100% of studies report positive effects. The probability that an ineffective treatment generated results as positive as the 24 studies to date is estimated to be 1 in 17 million (p = 0.00000006).
•Early treatment is most successful, with an estimated reduction of 87% in the effect measured using a random effects meta-analysis, RR 0.13 [0.04-0.51].
•100% of the 10 Randomized Controlled Trials (RCTs) report positive effects, with an estimated reduction of 74% in the effect measured using a random effects meta-analysis, RR 0.26 [0.12-0.56].Source: Covid Analysis (2020)
A meta study by Kory et al (2020) concluded:
the FLCCC recommends that ivermectin should be used in both the prophylaxis and treatment of COVID-19.51 In the presence of a global COVID-19 surge, the widespread use of this safe, inexpensive, and effective intervention could lead to a drastic reduction in transmission rates as well as the morbidity and mortality in mild, moderate, and even severe disease phases.Condensed Summary of the Emerging Evidence Supporting the Use of Ivermectin in the Prophylaxis and Treatment of COVID-19.
In a more recent meta study (June 2021), Bryant et al concluded:
Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.
Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%–91%). … Low-certainty evidence suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” clearly favored ivermectin use.Bryant et al (2021)
In the following video, Dr. Mobeen Syed explains the data in a number of studies on Ivermectin:
Heidary and Gharebaghi (2020) review the literature for the antiviral properties of Ivermectin and find it is widely efficacious.
Dr. Mark Skidmore did an assessment of Ivermectin and hydroxychloroquin and discusses the implications with Greg Hunter. The results from all studies covered assign a high efficacy to Ivermectin for all stages of SARS-CoV-2 infections as well as prophylaxis. More studies can be found at the US NIH. Also reports of its efficacy continue to appear in the literature.
The US NIH has provided new treatment guidelines for Ivermectin.
Dosage is based on body weight. It has thirty years or more of use in the field as an anti-parastitic drug similar to hydroxychloroquin.
All reported side effects experienced are mild not requiring medical attention. A single more serious but not life-threatening effect has been noted in the treatment of river blindness (onchocerciasis) only. This effect is due to the body’s elimination of dead parasites.
The Campaign Against Ivermectin and Hydroxychloroquine
In some countries, there have been active campaigns to suppress information about the efficacy of Ivermectin and HCQ which threaten vaccine programs and sales. India is an example.
This is on my research list. Start with this video:
Dexamethasone is a corticosteroid that prevents the release of substances in the body that cause inflammation. Inflationary of the alveoli in the lungs by the SARS-CoV-2 virus is responsible for hypoxia and damage done in severe cases. Corticosteroids have proven to be an effective treatment for severe and late stage COVID-19 infections.
Convalescent Plasma Antibody
Using antibodies extracted from the plasma of recovered victims has some degree of efficacy in treating SARS-CoV-2 infections. One study of patients not on ventilators found that higher rather than lower antibody levels in plasma lowered the risk of death.
They have some efficacy in treating SARS-CoV-2 infections.
A study by the World Health Organization has found that Remdesivir is ineffective in treating late-stage SARS-CoV-2 infections. Despite this, the FDA in the US has approved its use. In the following video the claim is made that Remdesivir is highly toxic. I haven’t looked at the cited studies.
This is a red flag against Dr. Fauci that needs to be followed up.
Fasting has been known to strengthen the immune system and promote autophagy for cleaning up cellular debris. Animal trials indicate that it promotes longevity. Hannan et al (2020) are suggesting that fasting, although not a therapeutic agent, may be a form of prophylaxis that can be used against a SARS-CoV-2 infection.
As a healthy practice, calorie restriction in the form of intermittent fasting (IF) in several clinical settings has been reported to promote several health benefits, including priming of the immune response. This dietary restriction also activates autophagy, a cell surveillance system that boosts up immunity. With these prevailing significance in priming host defense, IF could be a potential strategy amid this outbreak to fighting off SARS-CoV-2 infection.Hannan et al (2020)
Other benefits including neuological benefits and longer lifetimes of intermittent fasting have also been observer.
Recommended Protocols Using Generic Pharmaceuticals
The following are recommended protocols for use of these pharmaceuticals for preventing or treating SARS-CoV-2 infections. Hannan et al are proposing that
The FLCCC Alliance has a pair of protocols, I-MASK+: Prophylaxis & early outpatient treatment for COVID-19 and MATH+ Protocol: Hospital Treatment Protocol for COVID-19. Their analysis of other studies published to date has lead them to recommend Ivermectin for all stages of infection plus prophylaxis.
The Eastern Virginia Medical School has a treatment protocol called the Critical Care COVID-19 Management [Marik] Protocol. In the following video, Dr. Marik discusses the application, action and benefit of a number of the established pharmaceuticals in the treatment of the various stages of the SARS-CoV-2 infection:
Australia has released a Triple Therapy Protocol for COVID-19 using Ivermectin + zinc + an antibiotic. This is similar to the triple therapy for HCQ.
Swiss Policy Research (SPR) Collaboration has a COVID-19 treatment protocol using a variety of common pharmaceuticals and supplements.
A Canadian Doctor prescribes for his patients in treating COVID-19, the following, along with HCQ and azythromycin:
- Garvin, M.R., Alvarez, C., Miller, J.I., et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. Elife. 2020 Jul 7;9:e59177. doi: 10.7554/eLife.59177.
- Ariel Israel, Assi Albert Cicurel, Ilan Feldhamer, et al. (2020). The link between vitamin D deficiency and Covid-19 in a large population. medRxiv preprint, doi: https://doi.org/10.1101/2020.09.04.20188268.
- Castillo, M.E. , Costa, L.M.E., Barrios, J.M.V., et al.Effect of Calcifediol Treatment and best Available Therapy versus best Available Therapy on Intensive Care Unit Admission and Mortality Among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical study. J Steroid Biochem Mol Biol. 2020 Aug 29;105751. doi: 10.1016/j.jsbmb.2020.105751.
- Calcifediol Side Effects. Medically reviewed by Drugs.com. Last updated on Jul 15, 2020.
- Calcifediol (Oral Route). Mayo Clinic.
- William B Grant, Henry Lahore, Sharon L McDonnell, et al. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 2020 Apr 2;12(4):988. DOI: 10.3390/nu12040988.
- Patrick Zemb, Peter Bergman, Carlos A Camargo Jr, et al. Vitamin D deficiency and the COVID-19 pandemic. J Glob Antimicrob Resist. 2020 Sep;22:133-134. doi: 10.1016/j.jgar.2020.05.006.
- Nurshad Ali. Role of vitamin D in preventing of COVID-19 infection, progression and severity. J Infect Public Health. 2020 Jun 20;13(10):1373-1380. doi: 10.1016/j.jiph.2020.06.021.
- Solidarity Therapeutics Trial produces conclusive evidence on the effectiveness of repurposed drugs for COVID-19 in record time. WHO, 15 October 2020.
- Hongchao Pan, Richard Peto, Quarraisha Abdool Karim, et al. Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results. medRxiv, October 15, 2020; doi: https://doi.org/10.1101/2020.10.15.20209817.
- FDA Approves Gilead’s Remdesivir To Treat COVID-19 Despite Data Showing Drug Doesn’t Work. Zero Hedge, October 22, 2020.
- Katherine Zeratsky. What is vitamin D toxicity? Should I be worried about taking supplements? Mayo Clinic, as of November 24, 2020.
- Adda Bjarnadotti. How Much Vitamin D is Too Much? The Surprising Truth. Healthline, June 4, 2017.
- Prophylaxis for Covid-19 (prevention protocols). COVID.US.org, September 10, 2020.
- Doctors cure 6,000 patients with Covid-19 with Ivermectin. DominicanToday, December 10, 2020.
- Ivermectin Side Effects. Drugs.com, updated on May 5, 2020.
- Melisa Puckey. Can Ivermectin be used to treat COVID-19 (coronavirus)? Drugs.com, updated Apr 04, 2020.
- Philip Thornton. Ivermectin. Drugs.com, updated Apr 08, 2020.
- Ivermectin Tablets. Drugs.com, updated Feb 20, 2020.
- Ivermectin. WebMD, as of December 12, 2020.
- Ivermectin (Oral Route). Mayo Clinic, as of December 12, 2020.
- Behera, P., Patro, B.K., Singh, A.K., et al. Role of ivermectin in the prevention of COVID-19 infection among healthcare workers in India: A matched case-control study. medRxiv, 2020.10.29.20222661; doi: https://doi.org/10.1101/2020.10.29.20222661.
- Ivermectin is effective for COVID-19: meta analysis of 24 studies. Covid Analysis, November 26, 2020 (Version 4, December 12, 2020).
- Doctor explains 99.3% of COVID-19 patients treated with Ivermectin recovered in five days. DominicanToday, November 30, 2020.
- Kory, P., Meduri, U., Iglesias, J. et al. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. FLCCC Alliance; updated December 7, 2020.
- Paul Marik. An overview of the MATH+ and I-MASK+ Protocols: A Guide to the Management of COVID-19. FLCCC Alliance, December 03, 2020.
- Ivermectin Triple Therapy Protocol for COVID-19 Released to Australian GPs for Infected Elderly and Frontline Workers. ACN Newswire, August 20, 2020.
- On the Treatment of Covid-19. SPR, updated December 10, 2020.
- Ivermectin. NIH Clinical Trials, as of December 16, 2020.
- Heidary, F., Gharebaghi, R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot 73, 593–602 (2020). https://doi.org/10.1038/s41429-020-0336-z.
- Glinsky GV. Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells. Biomedicines. 2020 May 21;8(5):129. doi: 10.3390/biomedicines8050129.
- Elgazzar A, Hany B, Youssef SA, et al. Efficacy and Safety of Ivermectin for Treatment and prophylaxis of COVID-19 Pandemic. Research Square. November 13, 220. DOI: 10.21203/rs.3.rs-100956/v2.
- Hannan A, Rahman A, Rahman S, et al. Intermittent fasting, a possible priming tool for host defense against SARS-CoV-2 infection: Crosstalk among calorie restriction, autophagy and immune response. Immunol Lett. Oct;226:38-45. doi: 10.1016/j.imlet.2020.07.001. Epub 2020 Jul.
- Melatonin.WebMD. As of December 31, 2020.
- Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. NEJM. January 13, 2021; DOI: 10.1056/NEJMoa2031893.
- NIH Revises Treatment Guidelines for Ivermectin for the Treatment of COVID-19. FLCCC. January 15, 2021.
- The COVID-19 Treatment Guidelines Panel’s Statement on the Use of Ivermectin for the Treatment of COVID-19. NIH. January 14, 2021.
- Pisonero-Vaquero S, Diego Luis DL. MedinaLysosomotropic Drugs: Pharmacological Tools to Study Lysosomal Function. Curr Drug Metab. 2017;18(12):1147-1158. doi: 10.2174/1389200218666170925125940.
- Villamil Giraldo AM, Appelqvist H, Ederth T, and Öllinger K. Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death. Biochem Soc Trans. 2014 Oct;42(5):1460-4. doi: 10.1042/BST20140145.
- Lübow C, Bockstiegel J, Weindl G. Lysosomotropic drugs enhance pro-inflammatory responses to IL-1β in macrophages by inhibiting internalization of the IL-1 receptor. Biochem Pharm. Volume 175, May 2020, 113864/. https://doi.org/10.1016/j.bcp.2020.113864.
- Basque J, Martel M, Leduc R, and Cantin AM. Lysosomotropic drugs inhibit maturation of transforming growth factor-β. Canadian Journal of Physiology and Pharmacology. V. olume 86, Number 9, September 2008.
- Grant WB, Lahore H, McDonnell SL, et al. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. April 2020, 12, 988; doi:10.3390/nu12040988.
- Staff. Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. NIH. January 22, 2021.
- Canadian Doctors Speak out against corona virus nonsense. Odysee. Vjdeo. March 8th, 2021.
- Cox P. The Best Low-Cost, High-Benefit Life Extension Technique Available Today. Mauldin Economics. March 25, 2014.
- Holick MF. The Vitamin D Solution: A 3-Step Strategy to Cure Our Most Common Health Problem. Penguin. April 1, 2010. PDF.
- Skidmore M. Covid Lies cost 100,000 Lives – Mark Skidmore. USAWatchdog. April 27, 2021.
- Mercola J, Grant WB, andWagner CL. Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity. Nutrients. October 31, 2020.
- Dias GP, Murphy T, Stangl D, et al. Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho. Mol Psychiatry (2021). May, 2021. https://doi.org/10.1038/s41380-021-01102-4.
- Hope JR. Is Ivermectin the New Penicillin? Desert Review. May 25, 2021.
- Corbishley N. “I Don’t Know of a Bigger Story in the World” Right Now Than Ivermectin: NY Times Best-Selling Author. Naked Capitalism. May 25, 2021.
- Kory P, Meduri GU, Varon J, et al. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. Am J Ther. 2021 May-Jun; 28(3): e299–e318. April 22, 2021. doi: 10.1097/MJT.0000000000001377.
- Todhunter C. The Campaign against Ivermectin: WHO’s Chief Scientist Served with Legal Notice for Disinformation and Suppression of Evidence. Global Research. June 03, 2021.
- COVID, Ivermectin and the Crime of the Century. Global Research
- Ivermectin Could Have Saved ‘Millions’ of Lives — But Doctors Were Told Not to Use It
- Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. Am J Ther. 2021 June 17. doi: 10.1097/MJT.0000000000001402. PDF.
- Butler-Laporte G, Nakanishi T, Mooser V, et al. Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study. PLoS Med. 2021 Jun 1;18(6):e1003605. doi: 10.1371/journal.pmed.1003605. PMID: 34061844; PMCID: PMC8168855.