10 Mar 2019

Purported miracle medicines have always been with us. In the 1800s, traveling salesmen hawked cure-all elixirs. Nowadays, companies peddle myriad supplements on the internet, often with spurious claims that they are “scientifically” proven to treat this or that chronic ailment. Some promise to boost cognition, lower the risk of dementia, and even treat Alzheimer’s disease. However, these substances are not approved by the Food and Drug Administration for these indications, and data to support their claims are lacking. Researchers who spoke with Alzforum believe such supplements offer false hope while shrinking the wallets of people worried about cognitive decline and dementia.

The FDA warned 17 companies to stop advertising their dietary supplements as treatments for AD.
All but one quickly complied.
The move is part of an FDA initiative to better regulate the supplement industry.

It appears the FDA has had enough. On February 11, the agency mailed letters to 17 companies it accused of illegally marketing dietary supplements as dementia treatments (see FDA press release). In response, most companies removed the language in question. The supplements included vitamins, minerals, and herbal products. They also include compounds that were previously investigated as AD treatments but showed no efficacy against dementia in large trials. Lindsay Haake at the FDA press office told Alzforum that the agency’s goal is to “help consumers easily differentiate high-quality, compliant supplements from those that have not been manufactured or distributed in accordance with the law.”

Across the board, Alzheimer’s researchers and clinicians applauded the move. “The actions by the FDA are necessary and long overdue,” Jose Luchsinger at Columbia University, New York, wrote to Alzforum (see full comment below). Caleb (Tuck) Finch at the University of Southern California, Los Angeles, agreed, “As a basic researcher, I fully agree with the FDA initiatives.” In a statement, the Alzheimer’s Association wrote, “It is vital that federal agencies charged with consumer protection act quickly and decisively against dishonest businesses preying on individuals affected by this devastating disease.”

However, these FDA warnings by themselves may do little to stem the tide of deceptive advertising. With internet vendors and sites multiplying, new products and false claims continue to crop up faster than the agency can find them. In a February 12 JAMA editorial, Joanna Hellmuth at the University of California, San Francisco, wrote “More needs to be done on a national level to limit the claims of benefit for interventions that lack proven efficacy.”

The FDA agrees. Also on February 11, commissioner Scott Gottlieb outlined a number of steps the agency will take to improve regulation of dietary supplements. “We are announcing a new plan for policy advancements with the goal of implementing one of the most significant modernizations of dietary supplement regulation and oversight in more than 25 years,” Gottlieb wrote. This includes more efficient enforcement, alerting the public more quickly to unsafe or ineffective products, and working with industry to improve the safety of supplements. It is unclear what effect Gottlieb’s resignation, announced March 5, will have on this initiative.

Internet Hosts Modern-Day Traveling Medicine Show
The dietary supplement market has exploded with the commercialization of the internet and global marketing. The FDA estimates that supplement sales have expanded 10-fold in the last 25 years, and amount to a $40 billion industry in the U.S. alone, with as many as 80,000 products. Worldwide, the market has ballooned to $160 billion. Brain health supplements make up more than $3 billion of the global market, and are predicted to reach $5.8 billion by 2023 (see industry forecast). The surge in sales is driven by fear of cognitive decline and dementia, as well as a desire to enhance cognitive performance at work and school.

The supplement market expanded because regulations for these products are much looser than for drugs. Under the 1994 Dietary Supplement Health and Education Act (DSHEA), products are reasonably expected to be safe and labels to be truthful and not misleading, but unlike drugs, companies are not required to test either the safety or efficacy of dietary supplements. This is because according to DSHEA and the FDA, they are considered foods, not drugs. Most supplements are naturally occurring compounds that can be found in plants, animals, or the human body. This does not mean they are healthy. Socrates, if he came back from the dead, would likely say he was killed by a cup of hemlock—an extract from a flowering herb. Furthermore, the FDA does not regulate the purity of supplements, which means they can harbor harmful ingredients or active pharmaceuticals that are not disclosed on the label, Haake wrote.

Compounding this free-for-all, companies have leeway in what they are allowed to say on labels. They can claim that dietary supplements reduce the risk of a disease or condition, or that they improve an aspect of human health, such as the immune system, without having to prove it. This is known as a structure/function claim. They may not state that supplements prevent, treat, or cure a specific disease, and product labels must include a disclaimer to that effect. Thus, a supplement could say that it improves memory or concentration, but not that it treats Alzheimer’s disease.

The regulations mean companies must walk a fine line in their advertising. Some step out of bounds. For example, Nutrition Coalition in Moorhead, Minnesota, boasted that its coenzyme Q formulation “fights off degenerative brain diseases like Alzheimer’s.” Even when companies follow the rules, their language may mislead consumers into believing the product has more efficacy than it does, such as the claim by Earth Turns LLC in Chesterfield, Missouri, that a green tea supplement “supports healthy cognitive function.” The same can be said of many foods. How is the public to distinguish between “supports healthy cognitive function” and “treats Alzheimer’s?” In an email to Alzforum, Hellmuth wrote, “You can see how it could be confusing for patients and caregivers to distinguish between these two kinds of claims, particularly considering most people with Alzheimer's disease want to improve memory and concentration.”

Ads bend the rules to their advantage in other ways, too. Absent scientific proof to back up claims, they lean on personal testimonials and anecdotes, and cite research in animal or cellular models as though it proved relevance for human disease. For example, Nutrition Coalition noted the ability of curcumin to inhibit amyloid aggregation in vitro, and concluded that the spice “helps fight off that horrible disease.” Ads exaggerate findings, and neglect to mention study limitations. Rachelle Doody at Roche in Basel, Switzerland, told Alzforum that when she was in clinical practice, patients would often bring in newspaper ads or printouts from the internet asking about the touted benefits of some supplement for cognitive function. “If the ad mentioned patients or research in any way, or referenced the comments of an M.D. or Ph.D., patients often did not realize that it was an advertisement and not a news item,” Doody wrote to Alzforum. Conversations to debunk a supplement claim then take up visit time that could be spend discussing more helpful measures, or available drug trials. Eric Siemers at Siemers Integration, who was formerly with Eli Lilly, noted, “People are very worried about AD, and companies play on those fears.”

All of this creates a hall of mirrors, where consumers struggle to distinguish supplements that might be helpful from those that are a waste of money, or harmful. As one example, Hellmuth noted that high doses of Vitamin E increase the risk of stroke and death (Miller et al., 2005; Schürks et al., 2010). Neuroscientists contacted by Alzforum believe most brain health supplements are ineffective. “It is very likely that all such remedies are useless, and some are potentially hazardous,” Paul Aisen at the University of Southern California, San Diego wrote (full comment below). The Alzheimer’s Association notes that even if a supplement is safe to take on its own, it may interact with prescription medicines or other supplements in unpredictable ways.

The financial damage can be considerable. “Many consumers of these supplements are on fixed incomes. Retired elderly may be spending an important portion of their income on these unproven therapies,” Luchsinger said. Belief in the efficacy of a supplement could dissuade people from pursuing approved AD treatments. “It would be a shame if somebody took fish oil for their Alzheimer’s and not Aricept,” Siemers said. Aricept is a cholinesterase inhibitor approved by the FDA to treat AD.

The Sheriff Rides In
The situation spurred the FDA to step up enforcement, Haake wrote to Alzforum. First, the agency scoured product pages, newsletters, and blogs to identify companies claiming, illegally, that their products treated dementia. On February 5, the FDA issued 12 warning letters jointly with the Federal Trade Commission, which polices deceptive or fraudulent advertising. Such letters give companies 15 days to correct regulatory violations, after which the FDA may enact penalties. Previously, in November 2018, the agency had issued five advisory letters to separate companies selling putative AD treatments. Advisory letters flag less serious violations and ask companies to voluntarily comply with regulations, but do not threaten action. Both types of letter are posted online to alert consumers to the issue.

Fourteen of the companies are in the U.S., one in Canada, one in India, and one in Malaysia. The FDA flagged multiple products from each company (see table). They span a wide range, from vitamins (particularly B, C, D, and E) and minerals such as selenium, to various herbal extracts such as echinacea root and milk thistle. The list also includes physiological compounds like melatonin and colostrum, antioxidants like glutathione, and non-essential amino acids such as L-carnitine and L-theanine, which is found in plants. Some of the products have been investigated in AD studies, including curcumin, green tea, ginkgo biloba, omega-3 fatty acids, and coenzyme Q (CoQ10). A number of companies market mixtures of these ingredients with suggestive names like Cognispark, Mind Ignite, and Memory Revitalizer.

The warning letters spell out illegal statements the FDA found on each website, including claims to treat cancer, infection, diabetes, arthritis, etc. The brain health advertising can be blatant. Sovereign Laboratories LLC in Sedona, Arizona, claimed: “Studies have shown proline-rich polypeptides [in colostrum] improve the cognitive functioning of patients with mild to moderate Alzheimer’s disease.” This statement appears to be based on a few small, short trials from Poland (Leszek et al., 1999; Leszek et al., 2002; Bilikiewicz and Gaus, 2004). The Canadian company BR Naturals, Innisfil, Ontario, asserted that, “A new study in the … Journal of Alzheimer’s Disease supports existing evidence that coconut oil may help alleviate the neurodegenerative effects of Alzheimer’s disease and Parkinson’s.” In actuality, the study reported that coconut oil helped preserve the health of cultured neurons exposed to Aβ (Nafar and Mearow, 2014). TEK Naturals in Mount Pleasant, South Carolina, claimed “Mind Ignite is a safe and highly effective alternative to Adderall. … Clinically shown to help diseases of the brain such as Alzheimer’s and even dementia,” while Gold Crown Natural Products in Miami went further when it wrote: “It is proved that melatonin supplements are used to cure Alzheimer’s disease.”

Alzheimer’s researchers and advocates are angered by the level of deception. “My take is that the extent of false claims made by many supplement or memory-enhancing drug manufacturers is criminal,” wrote David Knopman at the Mayo Clinic in Rochester, Minnesota.

How effective is the FDA intervention? In this instance, it seems to have sparked quick action to clean up product advertising by all but one of the companies. “The site has removed the links and commentary that offended the FDA. That was never a selling feature of the products,” Dennis Butts at Peak Nootropics LLC in Houston wrote to Alzforum. Alzforum requested comment from all the companies warned by the FDA bar two, for which no contact information could be found. Save for Peak Nootropics, none responded. However, their websites, accessed between February 25 and March 7, were scrubbed of the language the FDA had called out. Some websites appeared to have deleted newsletters, articles, and blog posts discussing purported medical benefits; in a few cases, the products themselves were no longer for sale. For example, The Alzheimer’s Store, which sells household items to aid caregivers of people with dementia, received an advisory letter admonishing it for advertising aromatherapy as a means to boost cognition and alertness in AD patients. No aromatherapy products now appear on the site. As of March 8, one company appears to have ignored the FDA censure. This Wonderful Life New Age Shop, based in Malaysia, continues to offer products such as Dementia/Alzheimer’s (Day) Synergy Oil, which claims to be “an effective non-pharmacological therapy for dementia.” The company received an advisory letter.

Another recent FDA action drew a similar response. On February 19, the FDA cautioned consumers and health care providers not to use plasma from young donors to treat diseases of aging. “Such treatments have no proven clinical benefits … and are potentially harmful,” the agency wrote, warning of “bad actors charging thousands of dollars for infusions.” Although the letter threatened no action, one such clinic, Ambrosia Health in Monterey, California, immediately stopped treating patients. They had been charging $8,000 for one liter of young plasma.

If past regulatory actions are any guide, advertising changes prompted by official warnings do no damage to companies’ bottom lines. In January 2016, the FTC fined Lumos Labs $2 million dollars for deceptive advertising of its Lumosity brain-training software, which claimed to protect against cognitive decline (Jan 2016 news). The company paid up, and the FTC doled out the money in the form of refunds to Lumos customers. Since then, Lumos Labs has changed its marketing to make more modest claims, but continues to maintain a customer base and offer new products (see 2016 Fortune article).

What Does the Science Say?
Could any of these brain health products actually help Alzheimer’s patients? Gregory Cole at the University of California, Los Angeles, noted that some supplements, such as resveratrol, curcumin, and vitamin D, have demonstrated efficacy against AD-like pathology in preclinical studies and small clinical trials. However, no supplement has ever produced a clear benefit for AD patients in pivotal trials. Ginkgo biloba, the omega-3 fatty acid docosahexanoic acid, B vitamins, vitamin E, selenium, and resveratrol have all fallen short (Nov 2008 news; Nov 2010 news; Nov 2014 news; Mar 2017 news; Zhu et al., 2018).

Some companies abandoned clinical development when trials failed, only to market the compounds as “medical foods” (Oct 2009 series). Medical foods contain ingredients shown to benefit a particular disease or condition, and usually require a prescription, but they do not undergo FDA efficacy review (Morgan and Baggott, 2006). “CoQ10 is a good example of a nutraceutical with lots of interesting biochemistry in vitro, but it’s been studied in Parkinson’s and Huntington’s and does not have clinical effects, even at doses that would cost ~$100/month at the health food store,” Siemers wrote to Alzforum (Mar 2014 news).

“There is zero evidence from any reasonably rigorous study that any supplement or dietary aid has any benefit on cognitive function or decline in late life,” Knopman noted. Other clinicians agreed, noting that the only time they prescribe supplements is when patients have a documented deficiency, such as for vitamin B12. A recent meta-analysis of vitamin and mineral supplements supports this position, finding no consistent cognitive benefit of supplementation for healthy adults across 28 studies (Rutjes et al., 2018).

In general, the researchers Alzforum contacted believe that the purported benefits of dietary supplements should be investigated more rigorously than current regulations demand. “Personally, I think that we owe it to the public to hold such potential treatments to the same standards of evidence that we do for pharmaceuticals when they advertise to the public directly,” Doody wrote.

Philip Scheltens at VU University, Amsterdam, cited clinical trials of the nutraceutical drink Souvenaid, which he has helped run, as an example of how this should be done. In a two-year study of 311 people with prodromal AD, Souvenaid missed its primary endpoint, but met two secondary endpoints (Nov 2017 news). “I do think this is the way to test all these products, exactly as we do with pharma products, to avoid unfounded claims,” he wrote (full comment below). Tobias Hartmann at Saarland University in Homburg, Germany, agreed. “Any health claim related to any intervention should be derived from an informative prospective clinical trial,” he said.

One drawback is patents. Cole noted that because most supplements are not patented, they are unlikely to attract enough funding for rigorous clinical evaluation. “We need another mechanism to evaluate supplements … I believe the government should set up an internet-based, curated, evidence-reporting system that patients and their doctors can submit data to,” he wrote to Alzforum (full comment below).

Bringing Order to the Wild West
What does the FDA think? While the agency has not proposed holding dietary supplements to the same standards as drugs, its recent statement outlines several steps it will take to modernize the regulation of this market. Gottlieb set up a Dietary Supplement Working Group that will develop better ways to enforce regulations, and will also create a “rapid-response tool” to inform consumers about deceptive advertising. The FDA established a public-private partnership, the Botanical Safety Consortium, to determine how best to evaluate the safety of dietary supplements. The agency plans to hold a public meeting this spring to discuss ways to foster innovation in the supplement field while maintaining safety. Finally, the FDA expressed openness to updating the DSHEA.

“It is appropriate for the FDA to continue to evolve its regulatory framework to best serve both consumers and a rapidly changing industry,” Haake wrote. The agency would not make Gottlieb or other administrators available for an interview with Alzforum.

Some researchers believe revising the DSHEA is imperative. “I question the realistic impact these FDA actions can have when the DSHEA continues to allow manufacturers to make ambiguous claims of efficacy without supportive evidence … Stronger federal legislation is needed around supplements,” Hellmuth wrote to Alzforum.

One example of how the DSHEA opens the door to potential harm is the burgeoning market for nootropics, so-called “smart drugs” that are purported to enhance cognition. Under DSHEA regulations for “structure/function claims,” such supplements can be legally marketed as cognitive enhancers without clinical proof. One popular type is piracetam, a GABA derivative, and related racetam compounds. Others include plant extracts like forskolin, L-theanine, and bacopa monnieri. Under the DSHEA rules, even some prescription drugs fall into the nootropic category. These include modafinil and Adderall, which are prescribed for attention-deficit disorder. Websites and YouTube testimonials filmed by self-proclaimed “biohackers” promote the cognitive benefits of these supplements. In a June 2016 press release, the American Medical Association cautioned that the use of prescription stimulants to achieve a cognitive boost “is associated with a variety of adverse mental health conditions and patterns of substance misuse” while the benefits are “limited or modest at best in healthy individuals.” Moreover, safety and efficacy for non-prescription herbal nootropics are unknown, the association added.

Does the FDA have sufficient resources to police the growing supplement market? While the companies that were warned have cleaned up their acts while the FDA is looking at them, similar peddlers are likely to pop up in a game of regulatory whack-a-mole. The FDA has limited staff and funding to comb through websites. “I remain concerned that the FDA lacks the authority and resources to protect patients from entities promoting pseudomedicine for dementia and brain health,” Hellmuth noted. In a February 11 statement, the Council for Responsible Nutrition, the main trade association for the dietary supplement industry, based in Washington, D.C., called on Congress to appropriate more money to allow the FDA to regulate dietary supplements and “root out bad actors.”—Madolyn Bowman Rogers

Comments

- Jose Luchsinger
  Columbia University
- Posted: 11 Mar 2019
In general, I only recommend supplements in documented states of deficiency (for example, vitamin B12 deficiency). There is no strong support for taking vitamin or nutrient supplements in the absence of documented deficiencies for the prevention or treatment of cognitive impairment. In addition, supplements are often taken under the assumption that they are not harmful, which may not be the case. Lastly, many of the consumers of these supplements are persons on fixed incomes, such as retired elderly, who may be spending an important portion of their income on these unproven therapies. I believe that the actions by the FDA are necessary and long overdue, and I applaud its actions.

View all comments by Jose Luchsinger

- Paul Aisen
  USC Alzheimer’s Therapeutic Research Institute
- Posted: 11 Mar 2019
The FDA action is most welcome. Alzheimer’s disease may be the single most feared disease in the aging population, and approved therapies, while modestly effective, are inadequate. So naturally millions of people seek alternative therapies, creating an enormously lucrative market for companies and practitioners to sell unproven remedies. Many people decide to spend money to try such therapies, believing that the touted benefits justify the cost and risks. In my opinion, it is very likely that virtually all such remedies are useless and some are potentially hazardous. (An exception would be the treatment of an individual with a documented deficiency, for example B12 deficiency, known to be associated with cognitive impairment.) In my view, the FDA and other regulatory bodies should move toward requirements that marketing claims for supplements be backed by rigorous clinical studies similar to those required for prescription drugs.

View all comments by Paul Aisen

- Philip Scheltens
  Alzheimer Center Amsterdam; Head EQT Life Sciences Dementia Fund
- Posted: 11 Mar 2019
I think that anything that is unproven/not investigated for Alzheimer’s disease should not be used! I never prescribe supplements, but do advise that people follow a healthy lifestyle, including meals that contain all the necessary vitamins. If deficiencies are present, for instance vitamin B12, we correct that of course. Of all the non-pharma products that I know for AD, only Souvenaid has been properly investigated in four clinical trials and in the LipiDiDiet study, but I am not the one to comment on these since I was involved as author and principal investigator of some of the studies. I do think this is the way to test all these products, exactly as we do with pharma products, to avoid unfounded claims.

View all comments by Philip Scheltens

- Gregory Cole
  UCLA/VA
- Posted: 11 Mar 2019
In a nutshell, supplement manufacturers frequently make claims, either directly or through leaflets and media campaigns, that wildly overstate the evidence for efficacy. The most egregiously successful advertise about the benefits of orally delivered jellyfish peptides, but there are a host of less successful firms with misleading advertising. The FDA should crack down on those making false and very poorly substantiated claims. However, there are other types of supplements with substantial preclinical and mechanistic support and some clinical trial support that put them in a different class that I would call plausible but unproven. These include B vitamins to prevent deficiency, ketone-related supplements like Accera and immunomodulatory vitamin D, polyunsaturated fatty acids that give rise to resolvins, maresins, and protectins, and some plant-derived polyphenols and flavonoids.

One big problem is that like conventional drugs, many of the supplements work as interventions at early stages in animal models, which adequately model selected early stage events, but only get tested in humans in symptomatic patients. So they might work for prevention but not for treatment, and the barriers to getting FDA approval for prevention are huge. For example, resveratrol has a strong rationale, preclinical efficacy, and favorably moved CSF biomarkers for neuroinflammation in an Alzheimer’s Disease Cooperative Study trial but it did not meet primary cognitive endpoints in AD patients. It appears to have beneficial activity but because it is a supplement without strong patent protection, it is not likely to ever get FDA approval. Similarly, curcumin is immunomodulatory and protective in many animal models for AD and related conditions and now in primates, and there is some limited evidence for bioavailable formulations in small clinical trials but failures with other formulations in AD patients. Because it can promote amyloid removal via the innate immune system and target oligomers, mechanisms it shares with many anti-Aβ antibodies that have target engagement in AD, this type of less-expensive immunomodulatory supplement has an intriguing mechanism-based rationale. Like other supplements, it is very difficult to get the funds to properly evaluate curcumin, but because it is a supplement, some patients and caregivers are testing it on themselves in the absence of satisfactory FDA-approved agents. There are anecdotes of remarkable symptomatic improvements with curcumin and some other supplements that encourage proper clinical trials, but even if they are done they are highly likely to be underpowered unless they can advance to proper trials in early stage AD patients via an NIA-funded cooperative consortium.

We need another mechanism to evaluate supplements. Because supplements are generally inadequately tested but available to patients, I believe the government should set up an internet-based, curated, evidence-reporting system that patients and their doctors can submit data to, and in return get an unbiased professional summary of the evidence for consideration that is better than Yelp- or Amazon-level feedback.

Supplements that can be marketed as medical foods, including omega-3 fatty acids, Fortasyn Connect/Souvenaid, and products under development by major food manufacturers, are receiving adequate trial support. As medical foods the FDA will have enough power to regulate them.

View all comments by Gregory Cole

- Lei Feng
  National University of Singapore
- Posted: 11 Mar 2019
Definitely we need more randomize controlled trial evidence to back up any claims that any supplements / nutraceuticals / medical foods may improve cognitive symptoms in dementia or delay cognitive decline among individuals with normal cognition or mild cognitive impairment.

Trial results on all endpoints should be reported, regardless of them being positive or negative. And results should be interpreted objectively without biases.

Good examples in this field include the GEM study and the LipiDiDiet project.

With emerging new compounds and new formulations, clearly we need more such trials.

View all comments by Lei Feng

- Takaomi Saido
  RIKEN Center for Brain Science
- Posted: 11 Mar 2019
There is a Chinese saying well-known in Japan: "Medicines and foods come from the same sources." Indeed, hundreds of effective Chinese medications are being prescribed in Japan under health care, although the essential ingredients remain elusive in many cases. Chinese medicines are said to have survived 2,000 years of real-life "clinical trials." It is therefore possible that some diet-derived supplements may be effective.

There are, however, some problems: the ingredients of the Chinese medicines may differ depending on the site and timing of harvesting the source materials despite improvements in quality control.

Both for Chinese medicines and for commercial supplements to become relevant remedies, we need statistically significant evidence in experimental paradigms that correspond to such conditions as preclinical AD, subjective cognitive decline, pre-AD MCI, and AD. Obviously, use of pertinent animal models and recruitment of appropriate human populations must be practiced.

In addition, plasma biomarker(s) that can be used for presymptomatic diagnosis and for prognosis will accelerate our quest for answers.

View all comments by Takaomi Saido

- Timothy Daly
  Sorbonne Université
- Stéphane Epelbaum
  Paris Brain Institute and Neurology department, AP-HP
- Posted: 29 Jan 2021
The history of Alzheimer’s Disease research demonstrates that getting a validated drug to market is incredibly difficult. So it is not surprising that all sorts of claims are made about alternatives, the “supplement hype” described here being one of them. Ethical guidelines for currently incurable diseases remind us that while there is room for innovation with new treatments in the absence of alternatives for patients, this should be done responsibly, rigorously, and with measured language, since claiming to have a treatment without strong data to back it up can create false hope, cause financial harm, undermine informed consent, and frustrate the production of generalizable knowledge necessary to find and validate a treatment for Alzheimer’s.

In a recent article, we tackle the case of so-called “metabolic enhancement protocols” for Alzheimer’s disease. We argue that their authors have overstated the evidence in favor of these interventions within the scientific and lay press, failing to communicate weaknesses in their data and uncertainty about their conclusions. We therefore offer more stringent guidelines for innovation in the Alzheimer’s field.

References:

Daly T, Mastroleo I, Gorski D, Epelbaum S. The ethics of innovation for Alzheimer's disease: the risk of overstating evidence for metabolic enhancement protocols. Theor Med Bioeth. 2020 Dec;41(5-6):223-237. Epub 2021 Jan 18 PubMed.

View all comments by Timothy Daly View all comments by Stéphane Epelbaum