Drug recently shown to reduce coronavirus death risk could run out, experts warn

Injectable dexamethasone is more difficult to manufacture than tablets, because production needs to take place under sterile conditions. SOUMYABRATA ROY/NURPHOTO VIA AP

By Eli Cahan Jun. 21, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.

This week’s report that dexamethasone, a commonly used corticosteroid, reduces death rates of COVID-19 by up to one-third was greeted with enthusiasm around the globe.#

It also raised a question: Will there be enough of the medication? So far, doctors are not reporting problems getting dexamethasone for their patients. And as many news stories have pointed out, dexamethasone is off-patent, cheap, and relatively abundant.

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But that doesn’t mean there won’t be shortages, says Stephen Schondelmeyer, director of the Pharmaceutical Research in Management and Economics Institute at the University of Minnesota, Twin Cities. “Even though this is an old drug that’s been around a long time, I think people saying that it’s commonly available … spoke too soon, without looking at the data,” he says. Since the trial findings came out, there has been “a degree of irrational exuberance,” about dexamethasone, Schondelmeyer says. “We are already seeing hoarding behaviors and lack of availability of the product because of it,” he adds.

“Hoarding and speculative procurement appear to have already started,” confirms Emer Cooke, head of regulation of medicines and other health technologies at the World Health Organization (WHO). But she says it’s “probably too early to say if there will be a global shortage.”

The situation could become especially dire for the injectable version of the drug, which some physicians say is the preferred formulation and is more complicated to produce than oral dexamethasone. One major Indian manufacturer of intravenous dexamethasone, Cadila Healthcare, has repeatedly gotten in trouble with the U.S. Food and Drug Administration (FDA) for serious problems in its production process. According to a letter from the agency, the company said in October 2019 that it would stop producing injectable drugs for the United States.

The trial that identified dexamethasone’s potential benefit, named Recovery, included more than 6400 patients in the United Kingdom, 2104 of whom received the medication. Its outcome “offers miraculous hope that a dose of a commonplace medication might do what we all want it to do: Help people survive,” says Lewis Kaplan, a surgeon at the University of Pennsylvania’s Perelman School of Medicine and president of the Society of Critical Care Medicine (SCCM). WHO Director-General Tedros Adhanom Ghebreyesus praised the findings as a “lifesaving scientific breakthrough.” The U.K. National Health Service has already incorporated the drug into its standard of care for COVID-19 and the country issued restrictions on exports of dexamethasone. Demand appears to be surging worldwide.
How the drug is given makes a difference

But dexamethasone can be administered in several ways. According to the trial’s protocol, patients received the medication either orally or by intravenous injection. In many cases, the distinction may be trivial. But for the sickest patients, administering oral medications is “rolling the dice to some degree,” says Clifford Deutschman, an intensivist at the Feinstein Institutes for Medical Research and former SCCM president. Gastrointestinal problems in these patients can cause “inconsistencies in uptake of the medication,” leading to blood levels that are too low or too high, Deutschman says. And for patients on ventilators, administering the medication orally means grinding the pills up by hand and delivering them through fluids or a feeding tube. Both for safety and effectiveness, “Hands down, if you’ve got the intravenous stuff, you give the intravenous stuff,” he says.

The sickest patients are the ones most likely to benefit from the drug. In the study, dexamethasone reduced the death risk for patients on a ventilator by one-third, and for those requiring oxygen by one-fifth. Patients with milder disease did not benefit.

Intravenous dexamethasone was already in short supply in the United States before the Recovery results came out, according to an independent shortage tracking tool run by the American Society of Health-System Pharmacists. FDA lists the drug as “in shortage” as well. Dexamethasone is not in the U.S. Strategic National Stockpile.


Hoarding and speculative procurement appear to have already started.Emer Cooke, World Health Organization

The question is whether production of the intravenous form of dexamethasone can be ramped up quickly. Whereas oral dexamethasone is “relatively straightforward to make,” the intravenous form is harder to manufacture, says former FDA Commissioner Mark McClellan, because it needs to be done under sterile conditions to prevent microbes from reducing efficacy or sickening patients. (In 2012, a fungal meningitis outbreak linked to contaminated steroid injectables killed more than 100 people.)
Issues with quality control up the supply chain

Most of the drug is produced by two Indian companies, Wockhardt and Cadila Healthcare. Wockhardt has a “very limited” supply presently available for export, but has “enormous capacity” to produce both oral and intravenous dexamethasone and is able to ramp up further, its CEO said in a 17 June news report.

But Schondelmeyer, whose center recently launched a partnership with the U.S. Biomedical Advanced Research and Development Authority and the Department of Homeland Security to enhance the resilience of the United States’s pharmaceutical supply chain, is skeptical. “There aren’t a lot of [unused] plants that can make sterile injectables of anything, let alone dexamethasone, so I’m not sure how much capacity they really have,” he says. Ramping up supply “takes a lot of time, even if the world was normal and sane, let alone during COVID.”

FDA has turned away Cadila’s products at the U.S. border 83 times since 2004 because of quality concerns. Since 2015, the agency has sent the company three warning letters related to its production process. FDA inspectors found myriad inadequacies at Cadila’s facilities, including noncompliance with sterile procedures, evidence of Pseudomonas bacteria in the water system, and “several plastic bags filled with paperwork in the scrapyard“ including “a torn notebook of deficiencies.”

In the most recent of the three letters, dated 29 October 2019, FDA writes that Cadila Healthcare has informed the agency that it will “permanently cease production of injectable drug products for the United States.” This history “makes me very nervous, as to whether they can ramp up in the first place, and if they can, if that’s a product anyone should use,” Schondelmeyer says. (The company did not respond to requests for comment.)

Cooke stresses the importance of buying dexamethasone from quality-assured suppliers. There’s a “high risk that rogue manufacturers will offer substandard or falsified options,” she says. Trusted producers should be able to meet the rising demand, Cooke adds, but if hoarding and speculative procurement continue, “it will create chaotic demand signals and put scale up plans at risk. This is especially true for injectable products,” whose production is harder to scale up.

Potential for shortages at the bedside

McClellan does not see major problems ahead. “If there’s a reasonable response to this news, with clinicians using the drug appropriately and no disruptions related to stockpiling … I think this is a manageable development,” he says. Based on the study, the drug should only be used in severe cases, a small subset of the total number of COVID-19 patients. And physicians could use other corticosteroids—such as methylprednisolone, hydrocortisone, or prednisone—that may work as well.

Kaplan isn’t so sure: Dexamethasone has “unique properties” in the ways it interacts with the cells and proteins that produce the body’s immune response, he says. And demand may increase because doctors will prescribe the drug for less severe cases as well, Deutschman says. He is “worried” this might accelerate shortages.

“When you’re standing at the bedside watching somebody die as the family stands outside, asking yourself, is there anything else I could have done, it’s difficult to be rational,” Deutschman says. “There’s always a temptation to take the results of a trial and overextend them.”

*Correction, 22 June, 3:15 p.m.: An error in the description of FDA’s October 2019 warning letter to Cadila Healthcare has been corrected.

*Correction, 24 June, 8:05 a.m.: An incorrect statement about back orders of injectable dexamethasone at U.S. drug suppliers has been removed from this story.
Posted in:
Health
Coronavirus

doi:10.1126/science.abd4447

Eli Cahan
Eli is an intern on the News staff of Science. He is pursuing a master’s degree in health policy as a Knight-Hennessy Scholar at the Stanford School of Medicine and his MD at the New York University (NYU) School of Medicine. Twitter

A cheap steroid is the first drug shown to reduce death in COVID-19 patients


The steroid dexamethasone may quickly be added to the global standard of care for severe COVID-19 patients. REUTERS/YVES HERMAN

By Kai Kupferschmidt Jun. 16, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.
After months of dire news about the spread of the novel coronavirus and a mounting global death toll, a glimmer of hope arrived today: Researchers announced that dexamethasone, a cheap, widely available corticosteroid, significantly reduced deaths of severely sick COVID-19 patients in a major clinical trial. Although full trial data have not yet been released, several outside commentators hailed the result as a “breakthrough.”

“These are really surprising, but really very convincing results,” says Martin Landray of the University of Oxford, one of the principal investigators of the Recovery trial in the United Kingdom that evaluated the steroid. If they hold up, adds Devi Sridhar, an expert on global public health at the University of Edinburgh, they could be a game-changer for critical patients, as the drugs are accessible even in lower-income countries.
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The Recovery trial, one of the biggest efforts to evaluate whether existing drugs can treat COVID-19, included 2104 patients given a relatively low dose of 6 milligrams of dexamethasone for 10 days. When their outcomes were compared with those of 4321 patients receiving standard care, the steroid reduced deaths by one-third in patients already on ventilators and by one-fifth in patients receiving supplemental oxygen in other ways, Recovery researchers announced in a press release. They did not find any benefit in patients not receiving respiratory support.

Dexamethasone’s effect is seemingly much stronger than that of remdesivir, the only other drug so far shown to help COVID-19 patients in a randomized clinical trial. That antiviral reduced the number of days critical patients were hospitalized, but it did not clearly reduce deaths.

Tedros Adhanom Ghebreyesus, director-general of the World Health Organization (WHO), hailed the dexamethasone results as “great news” given it’s the first COVID-19 drug that has clearly proved to reduce mortality. “The results are pretty remarkable for severely ill patients,” adds Nahid Bhadelia, a physician at Boston Medical Center. “I can see ICU [intensive care unit] physicians being more likely to provide steroids in the critically ill who are mechanically ventilated and who are not improving from other interventions based on these results.”

But she and others expressed disappointment that the Recovery team did not release additional information. “More detailed data would help us identify which subset of COVID-19 patients would benefit from steroids,” Bhadelia says.

Landray acknowledges the criticism. “I fully understand why scientists want to see the details. I’m a scientist, I want to see the details.” But with thousands of people dying of COVID-19 every day, it was important to get the basic message out first, he says. “There is this tension between having the final details and the final decimal points nailed down, and having what is actually a clear-cut and practical message in the public domain.”

Recovery is evaluating several experimental COVID-19 therapies, including the HIV drug combination Kaletra, convalescent plasma, and the controversial antimalarial drug hydroxychloroquine. When researchers found 2 weeks ago that hydroxychloroquine did not improve patient outcomes, they stopped that arm of the trial. In the other arms, Landray says, they stuck to their plan to wait until 2000 patients had received a treatment and 4000 patients had enrolled in a control arm, because that would provide a 90% chance of picking up a reduction in deaths of about 18%. Dexamethasone was the first drug to reach the milestone, so the researchers stopped its arm on 8 June and began to look at the data.

“The decimal points might change a bit when we tidy things up, but we’ve got to a point where the message will not change,” Landray says, adding that Recovery hopes to make public the full data within about 10 days. If the findings hold up under scrutiny, it would mean that treating eight ventilated patients with dexamethasone would save one life. “That is a big effect,” says Ashish Jha, a global health expert at Harvard University’s T.H. Chan School of Public Health who is eager to see the data.

The United Kingdom’s National Health Service has already announced its standard care for COVID-19 patients will now include dexamethasone. “It’s very, very rare that you announce results at lunchtime, and it becomes policy and practice by tea time, and probably starts to save lives by the weekend,” Landray says.

Although much of the early hope for COVID-19 treatment focused on drugs that might directly attack the virus (like remdesivir and hydroxychloroquine), there has also been considerable debate about medicines that dampen the immune system, like dexamethasone. In its fight against the virus, the body’s defenses can overreact, eventually breaking down the thin barrier between the insides of the lungs and the surrounding tissue. That causes the lungs to fill up with liquid and triggers acute respiratory distress syndrome (ARDS) in which patients can end up essentially drowning in their own liquid.

But reducing the immune response through steroids could also hobble the body’s fight against the new coronavirus or secondary infections, Bhadelia says. For this reason, the guidelines of WHO and the U.S. National Institutes of Health have so far recommended against using steroids in COVID-19 patients, she points out.

Doctors have used steroids to treat viral pneumonias in the past, including those caused by the severe acute respiratory syndrome virus or H1N1 influenza, says Wei Shen Lim, a respiratory physician at Nottingham University Hospital. But there were no randomized clinical trials with those viruses and available data were hard to interpret.

A Cochrane review looking at the data from H1N1 patients, co-written by Lim, found that patients treated with corticosteroids had a higher risk of dying. But that might be explained by the fact that sicker patients were more likely to receive steroids, Lim says. “Before the Recovery trial, I was neither an advocate for or an opponent of steroids,” he says. “You couldn’t be sure.” To get a clearer answer, Lim designed a trial to evaluate steroids in viral pneumonias in the case of another pandemic. When COVID-19 emerged, that was integrated into the Recovery trial as one arm, using dexamethasone.

In places like Spain, dexamethasone has already been widely used against COVID-19. Carlos Ferrando, an anesthesiologist at the Hospital Clinic of Barcelona, was one of the authors on a paper published in Lancet Respiratory Medicine on 7 February that showed the steroid reduced mortality in non–COVID-19 patients with ARDS. When COVID-19 patients started to show up in Spanish hospitals, Ferrando started a randomized clinical trial to test dexamethasone, but recruitment into the placebo group was slow because most patients were given the steroid, he says. Ferrando is now analyzing data from thousands of patients in Spanish ICUs, about 80% of whom received steroids, he says. “It seems like we have a signal that those corticoids decrease mortality, but we need to finalize the analysis.”

Sridhar says the positive result of the Recovery trial also holds an important lesson for the debate about how best to initially respond to a pandemic like this: that delaying the spread of a pathogen, through temporary stay at home orders or other measures, can give people infected later in a pandemic a better chance of surviving. “It shows the value of buying time for science to deliver, and indicates that with time, more and more findings will come to light that help doctors manage COVID-19 patients with better clinical outcomes.”

But even if steroids reduce mortality, they do not solve the problem of COVID-19 patients potentially overwhelming a health care system, Sridhar cautions. That’s because the drug can help treat patients who are already sick, but not prevent the illness in the first place. “The real game-changer will be a drug that prevents people going from mild symptoms to a severe state, and a vaccine.”
Posted in:
Health
Coronavirus

doi:10.1126/science.abd3683

Kai Kupferschmidt
Kai is a contributing correspondent for Science magazine based in Berlin, Germany. He is the author of a book about the color blue, published in 2019.Twitter

Researchers around the world prepared to #ShutDownSTEM and ‘Strike For Black Lives’

WWW.SHUTDOWNSTEM.COM; WWW.PARTICLESFORJUSTICE.ORG

By Sophia Chen Jun. 9, 2020

Thousands of researchers around the world have pledged to pause their work on Wednesday to support the ongoing Black Lives Matter movement and efforts against racism in the scientific community and society at large.

Responding to calls from an array of organizers operating under banners including the Strike For Black Lives, #ShutDownSTEM, and #ShutDownAcademia, numerous university laboratories, scientific societies, technical journals, and others have pledged to spend 10 June focused on issues of racial equality and inclusiveness.

“In the wake of the most recent murders of Black people in the U.S., it is clear that white and other non-Black people have to step up and do the work to eradicate anti-Black racism. As members of the global academic and STEM [science, technology, engineering, and math] communities, we have an enormous ethical obligation to stop doing ‘business as usual,’” the organizers of #ShutDownSTEM state on its website.

Those who participate should “stop all usual academic work for the day, including teaching, research, and service responsibilities,” the organizers of Strike For Black Lives write on their website. Black strikers should spend the day doing “whatever nourishes their hearts,” it states, whereas non-Black strikers should “take actions that center Black lives and agitate for change in our communities.”

Organizers are urging scientists to participate in local protests and learn about the history of anti-Black violence and racism; various groups have amassed online resources for participants to use.

Astrophysicist Brian Nord of Fermilab, an organizer of both the Strike For Black Lives and #ShutDownStem, who is black, is urging all strikers to emerge from tomorrow’s activities with plans for making real change at institutions involved in science. “I don’t want more diversity and inclusion seminars,” Nord says. “Those activities are used to provide a shield to institutions so that they can do the bare minimum.”

The movement began with two different groups: a network of mostly particle physicists organizing under the hashtag #Strike4BlackLives; and a multidisciplinary group of largely astronomers and biologists operating under #ShutDownSTEM. (One #ShutDownSTEM organizer, Casey Newlin, works in the music industry. Newlin, who is white, contributed what she learned from participating in that industry’s Blackout Tuesday on 2 June.) The groups coordinated with a third entity, #VanguardSTEM, an online platform that promotes women of color working in STEM, to announce their plans in unison on 5 June.

Brittany Kamai, a physicist at the University of California (UC), Santa Cruz, who started #ShutDownSTEM, says the idea originated, in part, from thinking about how scientists who are stuck at home because of the COVID-19 pandemic could make an attention-getting statement like those made by protesters who block a busy road. “This was my way of answering the question: ‘How do we shut down our digital streets of academia?’” says Kamai, who is Native Hawaiian.

The strike has gotten extensive support. Senior scientists have taken to social media to announce they are backing the effort, as have science facilities, organizations, and journals (including AAAS, which publishes Science). At many academic laboratories, “people have committed to stop group meetings,” Kamai says. Her own research group, the Laser Interferometer Gravitational-Wave Observatory, is participating in the strike by canceling a planned leadership meeting and postponing a test of its public alert system.

Elsewhere, researchers are planning an array of actions—or inactions.

At the online preprint repository arXiv—the backbone of physicists’ information highway—staff say they will participate in the strike by not announcing new submissions on Tuesday night. Many journals, such as the American Physical Society’s Physical Review Letters, have also pledged not to release papers tomorrow.

At UC Irvine, physics department chair Timothy Tait, who helped organize #Strike4BlackLives, says his department will hold a virtual educational event with an invited speaker and a town hall–style meeting with hired moderators. One goal of the events is “to inform ourselves what the black experience in academia is like,” says Tait, who is white.

At the University of New Hampshire (UNH), Durham, Karsten Pohl, a white physicist who signed the strike pledge and chairs the physics department, plans to hold a free-form discussion for his department on Zoom. Pohl especially wants feedback from undergraduate students and staff “who we usually don’t hear from,” he says.

At the University of Chicago and the Woods Hole Oceanographic Institution, scientists plan to march on their campuses.

Nord emphasizes that his group is specifically asking nonblack academics to step up tomorrow, to make up for what it sees as years of inaction. By giving black scientists the option to abstain from doing racial justice work for one day, the group says, nonblack strikers can acknowledge the disproportionate effort to improve diversity and mentor students from underrepresented groups that black scientists are often asked to perform without compensation.

For example, UNH physicist Chanda Prescod-Weinstein, an organizer of the Strike For Black Lives who is black, says that because she frequently speaks out about racism in science, many students from underrepresented backgrounds—and sometimes even their parents—contact her for advice about race-related conflicts in their education. Black students have told her of assailants throwing objects at them on campus, or people threatening to call the police on them when they are leaving the lab. Providing such advice “is a lot of work,” she says. “I also believe it has to be done, and I also believe it is unfair that it has to be done.” (Prescod-Weinstein has spent so much time supporting students of color, she says, that she asked for that work to be explicitly put in her job description when she was hired as a tenure-track professor at her university.)

Nord hopes tomorrow will help catalyze change. “I imagine a future where there is representation, retention, and recruitment of black physicists in academia,” he says. “Representation means there are lots of us around. I’m not just talking about black men. I’m talking about genderqueer, trans, women—all of us, we’re there. I imagine a future where we stay there, and we also work in leadership levels.”

Posted in:
Scientific Community

doi:10.1126/science.abd2504

Who’s to blame? These three scientists are at the heart of the Surgisphere COVID-19 scandal


E. PETERSEN/SCIENCE

By Charles Piller Jun. 8, 2020
Science’s COVID-19 reporting is supported by the Pulitzer Center.

Three unlikely collaborators are at the heart of the fast-moving COVID-19 research scandal, which led to retractions last week by The Lancet and The New England Journal of Medicine (NEJM), and the withdrawal of an online preprint, after the trove of patient data they all relied on was challenged. The three physician-scientists never were at the same institution nor had they ever before written together, but they are the only authors in common on the disputed papers, and the other co-authors all have ties to at least one of them. Their partnership, which seized a high-impact role during a global public health crisis, has now ended disastrously.

The first author for both retracted papers was cardiac surgeon Mandeep Mehra, an eminent Harvard University professor who works at Brigham and Women’s Hospital (BWH) and is known internationally for cardiovascular medicine and heart transplants. He provided the kind of gravitas that can fast-track papers to leading journals. In a statement provided by BWH, Mehra said he had met another of the trio, cardiac surgeon Amit Patel, in “academic and medical circles,” and that Patel had introduced him to Sapan Desai, a vascular surgeon and founder of Surgisphere, the tiny company that supplied the data. Journal disclosures, however, also indicate Mehra received compensation from Triple-Gene, a gene therapy company Patel co-founded to develop cardiovascular treatments.
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Desai publicly aspired to combine big data and artificial intelligence (AI) in ways that he said can replace randomized controlled clinical trials. For a brief moment, it seemed that Surgisphere’s enticing data set, said to include nearly 100,000 detailed patient records from about 700 hospitals on six continents, would settle questions about the possible benefits of various drugs—including the controversial antimalarial hydroxychloroquine—for COVID-19 patients.

Patel once apparently headed cardiac surgery at the University of Miami Miller School of Medicine. A university press release announcing his arrival in 2016 is no longer posted on the university website, however, and the school has not confirmed his job duties there. More recently, he has been a volunteer adjunct professor at the University of Utah. But, as STAT first reported yesterday, Patel tweeted on Friday that he had severed his relationship with the university, which a school spokesperson confirmed. In recent years Patel has developed and commercialized experimental stem cell therapies purported to cure heart problems, reverse aging, or treat sexual dysfunction. He is also part of a network of physicians that just launched a trial to use stem cells from umbilical cord blood to treat COVID-19 patients.

Normally co-authors of high-profile papers share subject area expertise or have clear professional ties, says Jerome Kassirer, chief editor of NEJM during the 1990s. He calls the collaboration of the apparently disparate individuals “completely bizarre,” and a red flag that the studies warranted intensive scrutiny that the journals failed to provide.

None of the three co-authors responded to requests for comment. Patel spoke with a Science reporter initially but said he wanted to wait for audits of the Surgisphere data to comment, and Desai’s spokesperson stopped communicating after the retractions. Still, interviews with former colleagues and a long paper trail shed some light on each of them.
Sapan Desai

Desai had a history of convincing respected researchers of his skill and integrity. One of them, Gilbert Upchurch, department of surgery chair at the University of Florida, wrote last year in a journal commentary that he had only brief encounters with Desai but had nonetheless mentored him remotely and developed an online friendship with him. Upchurch placed the scientist in a group of “amazing and talented young vascular surgeons.”




Sapan Desai SOUTHERN ILLINOIS UNIVERSITY SCHOOL OF MEDICINE

Illinois court records show Desai is facing two medical malpractice lawsuits filed last year. He told The Scientist that he “deems any lawsuit naming him to be unfounded.”

Desai has a history of big aspirations and entrepreneurial ventures—some short-lived. His science-fiction blog, corewardfront.com, was meant “to find the most parsimonious route for mankind to establish a meaningful presence in space.” In 2009, he wrote that the site would publish fiction “grounded in facts and reality,” adding, “the scientific method must be followed … religiously.” The blog is no longer published.

As a student, Desai won several small National Institutes of Health (NIH) grants for studies of the vestibular system. He started Surgisphere in 2007, when he was a medical resident at Duke University. Surgisphere’s initial products were medical guides and textbooks, although Desai has said he was working on big data projects for the company from its birth. In 2010, under the firm’s auspices, he founded the Journal of Surgical Radiology—whose editors included researchers with well-established publishing records. It folded in January 2013. Articles from the journal were cited only 29 times in its history, according to Scimago, a journal rating service. Yet an undated Surgisphere web page, no longer accessible online, said the online-only publication had 50,000 subscribers and nearly 1 million page views monthly—which would have placed it in elite company in academic publishing.

Surgisphere appears over time to have shifted its efforts into developing a database of hospital records that could be used for research. When the pandemic erupted, Desai declared that his data set could answer key questions about the efficacy and safety of treatments. Speaking about the finding that hydroxychloroquine increases mortality in COVID-19 patients, the main finding from the now retracted Lancet paper, he told a Turkish TV reporter, “with data like this, do we even need a randomized controlled trial?” Soon after, the World Health Organization temporarily suspended enrolling patients for its COVID-19 trial of the drug.

Immediately after the Lancet and NEJM studies appeared, however, critics identified anomalies in the data. And they doubted that a tiny firm—with a scant public track record in AI, few employees, and no publicly named scientific board—could convince hundreds of unidentified hospitals in dozens of nations to share complex, protected, and legally fraught patient data. Ultimately, despite Desai promising repeatedly to allow an independent audit of Surgisphere, the firm refused to release the raw patient data and agreements with hospitals for an audit, so no one could validate the authenticity of its database.

No hospitals have come forward to acknowledge working with Surgisphere. Indeed, NHS Scotland, which is mentioned as a case study on the company’s website, says none of its hospitals worked with Surgisphere and that it would ask the firm to remove an image of a Glasgow hospital from its website.

Science contacted several of Desai’s current or former employees or colleagues. Most would not comment. But Fred Rahimi, an Illinois podiatrist and co-author of a paper with Desai, praises the surgeon as highly capable for salvaging limbs, and easy to work with. Through his publicist, Desai cited Mark Melin, a University of Minnesota, Twin Cities, vascular surgeon, as a supporter. Before the retractions, Melin called Desai “a gentleman of the highest integrity” who has “nothing to cover up.”

But one physician-scientist who worked closely with Desai several years ago, says, “Just about everyone who knew him would say: ‘I just didn’t have a good feeling about him.’ … After they’d been with him, most people dissociated themselves from him,” the scientist says, declining to be named to avoid personal and institutional embarrassment.

In the decade since completing his medical residency, Desai moved from job to job—at Duke, the University of Texas, Southern Illinois University, and two private Illinois hospitals, according to his LinkedIn profile. “You might say we should have stopped him, which now seems obvious,” Desai’s former colleague says. “We should have found a way to get together and say, ‘What’s going on here?’ rather than allowing him to move from place to place. We should have done better as a medical community. We looked the other way.”
Amit Patel

Before and after his stint at the University of Miami, which appears to have started in late 2016 or early 2017, Patel’s academic home was the University of Utah. He started as a full-time faculty member at Utah in 2008 and kept that position until he left for Miami. The website for Foldax, a heart valve company that he serves as medical adviser, describes him as a “Tenured Professor of Surgery in the Division of Cardiothoracic Surgery at the University of Utah School of Medicine and Director of Clinical Regenerative Medicine and Tissue Engineering at the University of Utah.”




Amit Patel LAURA SEITZ/DESERET NEWS

The university confirmed Patel had tenure there, but says the directorship was an “unofficial title.” And among more than 100 publications listed on his University of Utah profile, nearly two-thirds were actually co-authored by other scientists who share the same surname. The page was removed from the university website after inquiries from Science. A university spokesperson said the timing, late Friday last week, was when Patel and the school agreed to separate.

According to the NIH database, Patel has never received funding from the agency. Before the recent COVID-19 papers, one of his most notable publications was a 2016 paper in The Lancet, which reported that extracting stem cells from the bone marrow of a person with end-stage heart failure and then reinjecting them could reduce the number of cardiac events that produced deaths or hospital admissions by 37%. The 126 patient, 31-site, phase II trial was billed in a press release, now not available on the University of Utah website but stored elsewhere, as “the largest cell therapy trial for heart failure to date.” Despite the apparent positive results, the sponsoring company Vericel no longer is developing stem cells for heart disease and, according to its webpage, is focused on “advanced cell therapies for the sports medicine and severe burn care markets.”

Patel left Miami under unclear circumstances, but has retained ties with Camillo Ricordi, an influential stem cell researcher at the University of Miami School of Medicine who is also the founder of a nonprofit called the Cure Alliance. The alliance previously focused on testing whether stem cells derived from umbilical cord blood could treat diabetes or Alzheimer’s, but has now pivoted to “fighting COVID-19,” according to its website. Ricordi is the principal investigator on a multisite trial to see whether the stem cells can treat lung inflammation in severe COVID-19 patients and Patel is listed in various references to the trial as a “key contributor” or “co–principal investigator.” Ricordi says Patel is an upaid collaborater on the trial and praises Patel's work in regenerative medicine.

Patel recently tweeted that he is “related to Dr. Desai by marriage” but called that “old news” and added, “Despite this I still do not have the information of what happened at Surgisphere.” In addition to apparently connecting Mehra and Desai, Patel had prior connections with other authors of the NEJM paper and the preprint. David Grainger, co-author of the preprint, is a professor of biomedical engineering at the University of Utah and also works with Foldax. Grainger declined to comment.

Timothy Henry, a cardiovascular clinician and scientist at the Christ Hospital in Cincinnati and a co-author on the NEJM article, has written several scholarly articles with Patel, including the 2016 Lancet paper. Henry, who also declined to comment, advises Patel’s Triple-Gene, which develops cardiovascular gene therapy treatments. Henry and Patel advise—and Patel is a board member of—Creative Medical Technology Holdings, a Phoenix company that develops and markets stem cell therapies, including treatments purported to reverse aging and cure sexual disfunction.

Creative Medical’s CaverStem and FemCelz kits are distributed to physicians who use them to extract stem cells from a patient’s bone marrow, then inject the cells into the penis or clitoral area to stimulate blood flow, according to a statement filed with the U.S. Securities and Exchange Commission. (As of the market close Friday, the publicly traded firm’s shares were valued at one-third of 1 cent.) The CaverStem treatments are advertised by the company as successful in more than 80% of patients, based on a 40-person phase I clinical trial that was not randomized or controlled, and on observations of 100 other patients. Phase I trials typically measure safety, not health benefits of a potential treatment.

Science contacted multiple colleagues or co-authors of Patel. None would comment. Before the retractions, two high-profile researchers—Deepak Bhatt, who directs interventional cardiovascular programs at BWH; and Peter Gruber, a pediatric cardiothoracic surgeon at Yale University—endorsed Patel on his LinkedIn page. Bhatt says he doesn’t know Patel and attempted to remove his endorsement after being contacted by Science. Gruber says he overlapped with Patel at the University of Utah about a decade ago, but doesn’t know his work in detail.
Mandeep Mehra

In contrast, Mehra—author of more than 200 scholarly articles, editor of The Journal of Heart and Lung Transplantation, and head of the cardiology division of the University of Maryland before moving to BWH in 2012—enjoys considerable support even after the unraveling of the recent studies. “Obviously, you don’t rise to the position he’s risen to without being ambitious, but I’ve never had any indication whatsoever that he would do anything unethical,” says Keith Aaronson, a cardiologist at the University of Michigan, Ann Arbor, who collaborated with Mehra on several studies, including a clinical trial of a mechanical pump for heart failure patients.




Mandeep Mehra © STU ROSNER

Mehra, the first author on both retracted papers, was the only one to issue a personal statement of apology, for failing “to ensure that the data source was appropriate for this use.” BWH and Harvard declined to say whether further investigation of Mehra’s roles in the papers would occur. (Mehra has written papers recently with another co-author of the Lancet paper, Frank Ruschitzka of University Hospital Zürich.)

“I think he just fell into this—perhaps a little naïvely,” says another former collaborator, cardiothoracic surgeon Daniel Goldstein of the Albert Einstein College of Medicine. “Given the amount of data that was in the [Surgisphere] database, it’s just hard to believe someone would [fabricate] something like this.”

Kassirer offers a harsher view: “If you’re a scientist and you’re going to sign on to a project, by God you should know what the data are.”

With reporting by Kelly Servick and John Travis.

This story was supported by the Science Fund for Investigative Reporting.
Posted in:
Health
Scientific Community
Coronavirus
Science Fund for Investigative Reporting

doi:10.1126/science.abd2252

Charles Piller
Charles is a contributing correspondent based in Oakland, California.

U.S. science groups wary of new Senate bills to curb foreign influences

U.S. science groups wary of new Senate bills to curb foreign influences

LOOKING FOR REDS UNDER THE BED
Senator Rob Portman (R–OH) has assembled a bipartisan coalition for his bill targeting foreign influences. SENATE TELEVISION VIA AP

By Jeffery Mervis Jun. 18, 2020

A bipartisan group of U.S. senators today proposed sweeping—and controversial—changes in how the federal government manages academic research in the face of threats from other countries.

The authors of the legislation, more than 1 year in the making, tout it as a way to stop China and other countries from stealing the fruits of federally funded research and using the information to damage U.S. economic and national security. But research advocates worry that if enacted, the bill could damage the U.S. academic research enterprise by restricting the flow of talent and ideas.

The legislation, which was drafted by Senators Rob Portman (R–OH) and Tom Carper (D–DE) and has eight Republican and five Democratic co-sponsors, is the latest, and most substantive, attempt in Congress to reconcile these competing interests. It would make a number of subtle but potentially significant changes in how the U.S. government keeps tabs on those who receive federal grants, who gets to enter the country to carry out research deemed sensitive to national interests, and how U.S. scientists interact with foreign partners.

One contentious provision would give the Department of State grounds to reject a visa application from anyone with ties to a foreign government seen as hostile to the United States. Other sections of the bill would expose scientists who fail to disclose ties to a foreign government to criminal penalties including jail time, require international partners to embrace U.S. scientific norms, and give the White House budget office new powers to oversee research security.

The legislators backing the bill say they recognize the need to strike a balance. But their rhetoric is anything but subtle. “For nearly 2 decades, the federal government has been asleep at the wheel while foreign governments have exploited the lack of transparency in our education system and bought access and influence on our school campuses,” says Portman, who leads the homeland security committee’s Permanent Subcommittee on Investigations (PSI), which has sharply criticized current federal efforts to tackle the problem.

Nor do the lawmakers hide their intended target. “America’s research enterprise is the best in the world and the Chinese Communist Party knows it,” says Senator Josh Hawley (R–MO). “That’s why they’ve spent the last 20 years stealing American taxpayer-funded intellectual property.”

Carper, the top Democrat on the panel, is a bit more judicious in his language, describing “the ways in which the Chinese government has worked to exploit the open and collaborative nature of the U.S. research community to advance their businesses and military interests.” He calls the bill a “common sense [approach] to protect American intellectual property and better leverage our international research partnerships.”

Unease among science groups

Science advocates acknowledge the need to protect U.S. interests, but they believe Portman’s bill goes too far in how it would police the research enterprise. “I don’t think the higher education community is going to like any of this,” says one science lobbyist, who like many advocates requested anonymity because they were not authorized to speak for their organization.

The Association of American Universities, a 66-member coalition of leading research institutions, said in a statement that it “shares Senators Portman and Carper’s goal of securing research conducted on our campuses, and universities are taking specific steps to address security concerns,” but “key provisions in the bill are overly broad and will only serve to harm American science without improving national security. … We appreciate that Sens. Portman and Carper have changed language in certain sections of the bill in response to concerns raised by our universities, but the breadth of the current bill language could still block talented students and scholars from coming to the U.S., where they advance our science and economic interests.”

One big sticking point is language giving the State Department the ability to reject a visa application from anyone based on their “cooperation with … military organizations adversarial to the United States, foreign institutions involved in the theft of United States research [or] a government that seeks to undermine the integrity and security of the United States research community.” Although the bill doesn’t name China, Portman and many other legislators believe its growth as a scientific superpower has been fueled by the widespread use of such tactics.

Lobbyists worry that, depending on how it is interpreted, the language has the potential to slam the door on the thousands of Chinese graduate students and postdocs who seek to study in the United States each year. The provision puts “no guard rails” on the State Department’s power, one lobbyist worries. “Every Chinese student has a direct connection to the government” and so could be viewed as persona non grata. The State Department already has criteria in place to exclude high-risk foreign applicants, the critics add, so it’s not clear why it needs broader powers.

PSI staffers say those fears are not warranted. They say the legislation gives the State Department authority it now lacks and has requested, to consider such factors as a visa applicant’s ties to military groups. Such ties are currently insufficient to exclude an applicant, they say. Instead, the bill would direct the State Department to “weigh the proportionality of risk” before deciding whether to issue a visa.

“The focus of the bill is on bad actors,” a staffer notes. “The vast majority of foreign researchers [asking to come to the United States] are benign, and we need their talents.”

The bill would also empower the State Department to reject or restrict the activities of a visa applicant if officials decide it would harm the country to give them access to “goods, technologies, or sensitive information.” The United States already has extensive rules governing the sharing and export of research products deemed sensitive. But lobbyists worry government officials could use the new provision to require universities to impose arbitrary restrictions on who could attend an open lecture, for example, or who could visit a laboratory that is doing unclassified research. “It violates the culture of openness that is fundamental to academic research,” one says.

PSI staffers believe the community is overreacting to what is simply a common-sense approach to research security in today’s globally competitive environment. “We’re not locking down campuses,” one says. But universities and other federally funded institutions “don’t need to give everyone access to everything.”

Using the budget hammer

The legislation would also lower the profile of an existing high-level intergovernmental panel that is tackling many of these issues. That panel, the Joint Committee on Research Environment (JCORE), was created last year by Kelvin Droegemeier, director of the White House Office of Science and Technology Policy (OSTP), to examine issues ranging from foreign influences to sexual harassment.

Its first product, expected out later this summer, is expected to be a proposed common federal policy relating to disclosing foreign sources of support. Nearly a score of research agencies has been working on the document. (Portman’s bill would criminalize the failure to disclose such ties, and would ban violators from receiving a federal grant for 5 years.)

The bill would make JCORE a working group of a new body, called the Federal Research Security Council, which would be led by the White House Office of Management and Budget (OMB). Lobbyists question giving that role to OMB. They say OMB has neither OSTP’s understanding of the research enterprise nor its strong connections to the scientific community. And they worry OMB’s purview is so broad that research could get lost among its many priorities.

PSI staffers say OMB’s clout is exactly why it was put in the driver’s seat. “We think that OSTP has been doing a great job. And giving OMB these powers is a good way to supercharge that effort,” one staffer says. As one example, staffer cite the role OMB could play in implementing the bill’s requirement that research agencies use a common grant application. “If one agency argues that it has unique needs, then OMB has the ability to step in and insist that it make concessions to reach an agreement.” OSTP, they suggest, couldn’t knock heads in the same way.
Gifts in the spotlight

Higher education organizations are also unhappy with a provision that lowers the requirement for reporting gifts, including grants, from another government or any foreign entity. The current standard is $250,000, and in the past year, the Department of Education has conducted investigations of several major universities that it says have ignored the rule. Universities say the government has never spelled out what it expects from institutions.

Portman’s bill throws gasoline on the simmering dispute by reducing the threshold to $50,000. University officials say the smaller amount negates the original purpose of the rule, which was designed to monitor attempts by foreign governments to influence such core academic activities as course offerings or the direction of faculty research.

“$50,000 is not enough to influence anything,” one official says. “And the additional reporting that would be required represents a significant administrative burden.”

Portman dismisses that criticism and doesn’t see the need to compromise. “There’s some in the university community that don’t love our legislation,” he said last month in a floor speech that outlined his pending bill. “I would just ask them, given what we know is happening in terms of the theft of U.S. research, are you really going to stand in the way of legislation that just says you have to report when you receive more than $50,000 from a foreign government? Is that too much to ask? I don’t think so.”

Whose values?

Another potential bone of contention for researchers is a provision that would require all U.S. international agreements to contain language requiring foreign partners “to adhere to U.S. scientific values.” On the surface, those values appear noncontroversial; they include “transparency, reciprocity, integrity, and merit-based competition.”

“If we expect U.S. federally funded researchers to be transparent, ensure the integrity of their work, make their work available to others to confirm, compete based on the merit of their work and not their seniority or rank, and share information with the scientific community, then we should hold U.S. federally funded projects involving foreign counterparts to the same standard,” a PSI staffer says.

But those principles are more nuanced than they appear, one lobbyist notes. For example, not every U.S agency uses “merit-based competition” for all grantmaking. Beyond that detail, the lobbyist notes, the attempt to require another country to follow U.S. “values” before partnering with U.S. scientists could be problematic for researchers overseas.

This and other sections of the original bill relating to international agreements were removed at the last minute and introduced as separate legislation. The move was taken to align the bills with the oversight authority of individual Senate committees. The main bill will be taken up by the homeland security panel that Portman chairs. The second piece goes before the Senate Committee on Foreign Relations.

So far there is no companion bill in the House of Representatives, although some members have introduced narrower measures aimed at curbing foreign influences on federally funded research. Congress watchers say such sweeping legislation would be harder to pass in the House because of jurisdictional issues as well as greater skepticism among its Democratic leaders that the problem warrants wholesale changes in federal oversight of research.

doi:10.1126/science.abd3887

‘Has it peaked? I don’t know.’ NIH official details foreign influence probe

The National Institutes of Health (main campus shown here) can take months to vet an allegation of undisclosed foreign ties. NATIONAL INSTITUTES OF HEALTH

By Jeffrey Mervis Jun. 22, 2020

Four years after the National Institutes of Health (NIH) began to investigate grantees who it believed had failed to disclose their ties to foreign governments, officials still don’t know the full extent of the problem.

“We’ve learned of 150 cases in the past 12 months,” says the head of NIH’s extramural research program, Michael Lauer, who oversees an ongoing probe that has swept up 399 scientists since NIH received the first allegation in June 2016. “But has it peaked, and will we have the same number of new cases over the next 12 months? I just don’t know.”

On 12 June, Lauer offered the fullest analysis to date of the pool of scientists NIH has been investigating and the nature of their offenses. But the data left many questions unanswered. Last week, Lauer fleshed out that analysis during an interview with ScienceInsider, offering new details on the scope of NIH’s investigation and how it fits into the larger debate now roiling Congress over how to prevent other countries from acquiring federally funded research in ways that threaten U.S. economic and national security.

Since July 2018, Lauer says, NIH has sent letters to 87 institutions raising questions about the behavior of 189 scientists. That group is a subset of the 399 grantees who have so far come to NIH’s attention, Lauer explained. Of those 399 scientists, he says, NIH determined that 251 warranted further scrutiny. NIH has since exonerated 76 scientists; 72 cases are still pending.
Lost jobs

Within the group of 189, 54 have subsequently lost their jobs. (NIH has declined to make their names public, although media reports have described and identified roughly two dozen scientists who appear to fall into that category.)

Asked why they were fired or dismissed, Lauer says the decisions were made by their institutions, not by NIH. “We do not render an opinion on HR [human resources] matters,” he says.

He notes that 70 of the 189 scientists were found to have violated rules at their institution, most notably a ban on receiving outside support for their research without prior approval from their employer. (In 93% of the 189 cases, the funding came from China, and the vast majority of the scientists under scrutiny are Asian men in their 50s.)

Lauer emphasized that NIH is examining only a narrow slice of the broader issue of inappropriate or illegal activity involving foreign sources of funding. “We focus on grant noncompliance,” he says, referring to a long-standing NIH policy that grantees must disclose material support for their research from any outside source.

The data Lauer presented are in line with that explanation. Of the 189 scientists flagged in its letters to institutions, 133 of them (70%) failed to disclose a grant from a foreign entity, and 102 failed to disclose their participation in a foreign talent recruitment program, such as China’s Thousand Talents Program.


Michael Lauer oversees the National Institute of Health’s review. NATIONAL INSTITUTES OF HEALTH

Cases involving the alleged theft of intellectual property or economic espionage, he says, are referred to either the inspector general for NIH’s parent body, the Department of Health and Human Services, or to the Department of Justice (DOJ). DOJ’s China Initiative, launched in November 2018, has led to the arrests of several scientists, including biochemist Charles Lieber of Harvard University.

Although the U.S. government asserts that many of them have helped the Chinese government illegally acquire U.S. technology, they are typically charged with other offenses, such as lying to the Federal Bureau of Investiation (FBI). Lauer’s data show a relative handful of the 189 scientists tagged appeared to be active in commercializing their research: Only 17 had hidden their involvement with a foreign company, for example, and seven had failed to tell NIH about a foreign patent.
Few mistakes claimed

Investigating alleged nondisclosure by an NIH grantee is a very labor-intensive process that can take “as long as several months,” Lauer says. It encompasses looking for mentions of foreign ties and grants in published papers, press releases, and other public descriptions of their research activities. Although NIH’s own sleuthing accounts for the majority of the workload, FBI did the initial legwork in some 30% of the 399 cases, according to Lauer’s data. In 11% of the cases, the scientist’s own institution contacted NIH with concerns.

Lauer says NIH is rarely wrong once it decides an NIH-funded scientist is likely to have violated its policies on disclosure. The data he presented on 12 June show 71% of the 87 institutions that received letters “acknowledged noncompliance.” He says there are additional cases in which an institution took action without admitting liability. He cited, for example, a December 2019 settlement between DOJ and the Van Andel Research Institute, in which the institute agreed to repay NIH $5.5 million in a case involving two scientists that had received funding from the Chinese government.

“They claimed that because the [Chinese] research did not overlap with what we were funding, they had no obligation to report it to us,” Lauer says. “But that is false,” he asserts.

“Of course, an institution has the right to disagree with us,” Lauer says. But he estimates that there are “fewer than 10 cases” in which institutions persuaded NIH that it had erred in claiming a grant recipient had violated the agency’s policy on disclosure.
Posted in:
Science and Policy
Scientific Community

doi:10.1126/science.abd4593

Fifty-four scientists have lost their jobs as a result of NIH probe into foreign ties


The National Institutes of Health has been investigating grantees suspected of not disclosing their links to foreign institutions, notably in China. NATIONAL INSTITUTES OF HEALTH

By Jeffrey Mervis Jun. 12, 2020

Some 54 scientists have resigned or been fired as a result of an ongoing investigation by the National Institutes of Health into the failure of NIH grantees to disclose financial ties to foreign governments. For 93% of the 189 scientists whom NIH has investigated to date, China was the source of their undisclosed support.

The new numbers come from Michael Lauer, NIH’s head of extramural research. Lauer had previously provided some information on the scope of NIH’s investigation, which had targeted 189 scientists at 87 institutions. But his presentation today to a senior advisory panel offered by far the most detailed breakout of an effort NIH launched in August 2018 that has roiled the U.S. biomedical community, and resulted in criminal charges against some prominent researchers, including Charles Lieber, chair of Harvard University’s department of chemistry and chemical biology.

“It’s not what we had hoped, and it’s not a fun task,” NIH Director Francis Collins said in characterizing the ongoing investigation. He called the data “sobering.”

In the vast majority of cases, Lauer reported, the person being investigated has been an Asian man in his 50s. Some three-quarters of those under investigation had active NIH grants, and nearly half had at least two grants. The 285 active grants totaled $164 million.

Lauer also presented data on the nature of the violations that NIH has uncovered. Some 70% (133) of the researchers had failed to disclose to NIH the receipt of a foreign grant, and 54% had failed to disclose participation in a foreign talent program. In contrast, Lauer said, only 9% hid ties to a foreign company, and only 4% had an undisclosed foreign patent. Some 5% of cases involved a violation of NIH’s peer-review system.

Lauer said the fact that 82% of those being investigated are Asian “is not surprising” because “that’s who the Chinese target” in their foreign talent recruitment programs. Some 82% are men, and their median age is 56, with the youngest being 48 and the oldest 59. Slightly more than one-half had been an NIH peer reviewer in the past 2 years, and 41% of those under investigation (77 scientists) have been barred by their institutions from submitting a grant proposal to NIH or serving as a principal investigator on an NIH award.

NIH has been in the forefront of federal efforts to identify and block behavior that many U.S. government officials say poses a significant threat to the country’s economic well-being and to national security. Several bills pending in Congress seek to limit that threat in various ways, including by limiting the flow of scientific talent from China to the United States, and by restricting access to federally funded research that provides a foundation for cutting-edge technologies and new industries.

Lauer’s presentation also provided a glimpse into the scope of that broader investigation. There are 399 scientists “of possible concern” to NIH, he told the advisory council, and the Federal Bureau of Investigation has fingered 30% (121) of them. An additional 44 have been flagged by their own institutions. Of that pool, Lauer said, investigations into 63%, or 256 scientists, came out “positive.” Investigations into some 19% came up “negative,” he noted, whereas the status of the remaining 18% is “pending.”

*Correction, 19 June, 1:15 p.m.: This story has been revised to clarify the pool of scientists who have failed to disclose financial support from foreign sources and the actions that their institutions have taken.
Posted in:
Scientific Community

doi:10.1126/science.abd308

‘It’s a nightmare.’ How Brazilian scientists became ensnared in chloroquine politics


The Nossa Senhora Aparecida cemetery in Manaus, Brazil, where many COVID-19 victims are buried. The city’s clinical trial with chloroquine started in late March, when cases had begun to explode. MICHAEL DANTAS/AFP VIA GETTY IMAGES

‘It’s a nightmare.’ How Brazilian scientists became ensnared in chloroquine politics

By Lindzi Wessel Jun. 22, 2020

Science’s COVID-19 reporting is supported by the Pulitzer Center.

Now that several big trials have shown disappointing results, hope has faded that chloroquine or hydroxychloroquine might be miracle drugs against COVID-19. But for one group of researchers in Brazil, the story is far from over.

In April, a team led by Marcus Lacerda, a clinical researcher at the Heitor Vieira Dourado Tropical Medicine Foundation in Manaus, Brazil, published a study showing chloroquine can increase mortality in COVID-19 patients. Since then, they have been accused of poisoning their patients with a high dose of chloroquine just to give the drug—praised by U.S. President Donald Trump and his Brazilian counterpart Jair Bolsonaro—a bad name. Social media attacks, defamatory articles, death threats, and even a legal inquiry into the group’s work have left Lacerda and his team stressed and exhausted.
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Other scientists have watched the public spectacle with dismay. But some agree that about half of the patients in the trial received such a high dose that severe side effects, or even deaths, were not unexpected. Lacerda’s trial was one of several using doses that were “dangerous and definitely too high,” says Peter Kremsner of the University of Tübingen in Germany, who is using far lower doses in two trials of hydroxychloroquine. Others say Lacerda and his colleagues took a calculated risk at a time when the optimal dose for SARS-CoV-2, the virus that causes COVID-19, was still under debate. “It’s clearer now that you wouldn’t have gone for that dose,” says Nicholas White, a veteran malaria researcher at Mahidol University in Bangkok who helped design the Recovery trial in the United Kingdom, which included a hydroxychloroquine arm. “But at that time, I think it was a legitimate choice.”
‘Left-wing medical activists’

Lacerda started the trial in late March, at a time when coronavirus cases in Manaus were growing explosively and scientists had promising results from chloroquine and hydroxycholoroquine in test tube studies and small, nonrandomized clinical studies. (Lacerda chose chloroquine because it’s widely available as a malaria treatment in Brazil.) The plan was to recruit 440 patients and give half of them 600 milligrams (mg) of chloroquine twice a day over a 10-day period—a total of 12 grams. The other half received 900 mg for 1 day followed by 450 mg for 4 days, a total of 2.7 grams.

When the trial’s independent data safety monitoring team saw the number of deaths in the high-dose group rise rapidly, they alerted the researchers and asked for that arm to be stopped. Of 81 patients enrolled at the time, seven in the high-dose group had died, versus four in the low-dose group. By the times the results were published, those numbers had risen to 16 and six, respectively. Two patients from the high-dose group developed dangerous cardiac arrhythmias before death, a known side effect from chloroquine, and warning signs for future heart trouble were more common in the high-dose group. An 11 April preprint about the results was covered by international media outlets, including The New York Times.

On 14 April, Michael James Coudrey, CEO of a U.S. marketing company whose website says he offers “social media and ‘digital information warfare’ services to political candidates,” tweeted accusations that the researchers had overdosed their patients and used them as “guinea pigs” in a study conducted “so irresponsibility I can’t even believe it.” Three days later, Eduardo Bolsonaro, the Brazilian president’s son, tweeted out a similar message, including an article that called the researchers “left-wing medical activists” and included their past social media posts in support of certain political candidates and sporting rainbow flag profile frames as proof. The article framed the study, which was later published in JAMA Network Open, as an attempt to “disparage the drug that the Bolsonaro government approved as effective for treating COVID-19.” Soon, death threats against the researchers and their families started to come in.

Then came the inquiry from the federal prosecutor’s office—the first such investigation of a medical study approved by an ethical review board, according to the research team’s lawyers. A Brazilian official announced the investigation on Twitter and posted a nine-page document that asked Lacerda’s team to justify everything from their choice of chloroquine to why the study didn’t focus on patients in earlier stages of COVID-19. Many of the questions centered on how the dose was determined and whether patients in the study experienced cardiac problems. The investigation is ongoing.

Brazilian researchers worry the legal inquiry from a federal prosecutor’s office could set a dangerous precedent in a nation already beset by attacks on science. “Today it’s [Lacerda], tomorrow it’s anyone else,” says Mauro Schechter, an infectious disease researcher at the Federal University of Rio de Janeiro, Rio de Janeiro. “It was quite outrageous the way things developed,” adds Adauto Castelo, an infectious disease researcher at the Federal University of São Paulo, São Paulo.
Tricky position

But there has been a real scientific debate about what an appropriate dose might be. Chloroquine is highly effective against malaria—unless resistance emerges—but test tube studies suggest much higher levels may be needed for the drug to block viruses. Both chloroquine and hydroxychloroquine are known to be toxic at high doses, but most information on toxicity comes from studies on suicides and accidental poisonings, where the dose was often not precisely known.

That put clinical researchers in a tricky position, White says. Go too low and you might miss the lifesaving activity of the drug. Go too high and you might endanger your patients.

Lacerda went very high. The 12 grams given to participants in his high-dose arm approached two times what was used in Recovery trial, which didn’t show a benefit from hydroxychloroquine, and in the World Health Organization’s Solidarity trial, which didn’t see a benefit either and ended its hydroxychloroquine arm on Wednesday. At least two hydroxychloroquine trials—one of 150 patients in Shanghai and a study at the University of Pennsylvania—went slightly over Lacerda’s total, but most studies used far less.

The participants in Lacerda’s trial were also given two to three other medications, including azithromycin, which shares chloroquine’s propensity to cause heart problems. It’s hard to evaluate just how harmful the high-chloroquine doses may have been, says James Watson of Mahidol University, who has attempted to model the toxicity of various dosing regimens.

“I’m sure that it’s going to be a very nice scientific discussion,” Lacerda says, adding that the criticisms of the high dose didn’t start until politics got involved. “Some people will be against that dose, some people will be in favor of that dose, and, unfortunately, I was the one who had the bad luck to be the first one to try the high dose. I probably will have to pay the price for that forever.”

White maintains Lacerda and his team made a reasonable choice at the time of their trial. But Kremsner says both Recovery and Lacerda’s trial were “a dangerous undertaking.” Two trials in Germany he leads—one in hospitalized patients and one in milder cases at home—use 3.3 grams over 7 days as the maximum dose . David Boulware of the University of Minnesota, Twin Cities, who led a study of hydroxychloroquine as a prophylactic drug in people exposed to the virus, says he wouldn’t be comfortable with Lacerda’s high dose either, but says the decision was “not crazy,” particularly given the “desperate times” of a pandemic without alternative treatment. (Boulware’s own study, which came up empty-handed, gave subjects 2.9 grams over 3 days.) “I think it would be reckless if they had no monitoring plan,” Boulware says. “There was a monitoring plan, they did stop the trial early, and they didn’t hide their results—they published them to try to warn others.”
Intense strain

Part of Lacerda’s problem is that he appeared unaware that the dose was very high. In the preprint, the team justified the high dose in part by pointing to an expert consensus coming from Guangdong province in China that recommended using 500 mg of chloroquine phosphate twice daily—seemingly in the same ballpark as the 600 mg the Brazilian team used. Lacerda also discussed the consensus in the New York Times story and again in a 20 April written statement defending his study.

But the comparison was off. A dose of chloroquine base, the nomenclature used by Lacerda, is 67% more potent than an equal dose of cloroquine phosphate, which the Chinese authors used. Lacerda said the mistake came when writing the preprint, after the trial was completed. He says the team did a wide literature review before making its dose decision and that the Guangdong dose was just one factor in their choice. Lacerda is still under intense strain from the fallout. “It’s a nightmare,” he told Science in a video call. For weeks he hasn’t been able to stop worrying that “my whole career is gone” or agonizing over the death threats against his family. “The day someone tells in your social media, that they’re going to kill your children to make you suffer the way you made other people suffer, you will understand what I’ve been through,” he says.

With reporting by Kai Kupferschmidt.
Posted in:
Health
Coronavirus

doi:10.1126/science.abd4620

Lindzi Wessel  is a writer based in Santiago, Chile.

ANIMAL EXPERIMENTATION

This shrimp has some of the fastest eyes on the planet


KINGSTON ET AL., BIOLOGY LETTERS

By Elizabeth PennisiJun. 23, 2020

Though not much bigger than a wooden match stick, snapping shrimp (Alpheus heterochaelis, pictured) are already famous for their loud, quick closing claws, the sound of which stuns their prey and rivals. Now, researchers have discovered these marine crustaceans have the eyesight to match this speed.

In the new study, scientists stuck a thin conducting wire into the eye of a chilled, live shrimp and recorded electrical impulses from the eye in response to flickering light. The crustaceans refresh their view 160 times a second, the team reports today in Biology Letters.
That’s one of the highest refresh rates of any animal on Earth. Pigeons come close, being able to sample their field of view 143 times per second, whereas humans top out at a relatively measly 60 times a second. Only some day-flying insects beat the snapping shrimp, the researchers report. As a result, what people—perhaps even Superman—and all other vertebrates see as a blur, the shrimp detects as discrete images moving across its field of vision.

Until a few years ago, most researchers assumed snapping shrimp didn’t see very well because they have a hard hood called a carapace that extends over their eyes. Although the hood seems transparent, with some coloration, it wasn’t clear how well it transmitted light. But it appears to be no impediment to the shrimp detecting fast moving prey or even predators whipping by. This might be important because the shrimp tend to live in cloudy water, so they don’t have much notice when another critter is approaching them.

Posted in:
Plants & Animals

doi:10.1126/science.abd4752

Lawsuit alleges scientific misconduct at U.S. nuclear weapons lab

Peter Williams claims tweaks to a program for modeling a bomb’s explosive trigger make its predictions unreliable. CLAUDIA WILLIAMS

By Adrian ChoJun. 24, 2020 ,

An unusual lawsuit alleges scientific misconduct at Lawrence Livermore National Laboratory in California, one of the United States’s three nuclear weapons labs. Peter Williams, a 50-year-old physicist, worked at Livermore from January 2016 until May 2017, when he says he was fired in retaliation for complaining that his superiors were mishandling a computer program that simulates the detonation of high explosives, undermining their ability to predict how a particular nuclear weapon would perform if used. Williams, who now works at a private research lab, has sued Livermore and seven individuals for reinstatement and $600,000 in damages.

Researchers familiar with the labs say Williams’s allegations should be taken seriously. “If there’s been a cover-up, that’s something that ought to be looked into,” says Raymond Jeanloz, a geophysicist at the University of California, Berkeley, who has been involved with the weapons labs. But he also says the labs implement internal reviews and other measures to ensure the integrity of their work and head off the kind of problem Williams alleges. “This is exactly the kind of thing the people at the lab worry about,” Jeanloz says. Livermore declined to comment on the suit, but in a statement said: “Rigorous debate is a part of the scientific process—the Laboratory does not retaliate against individuals for holding differing opinions.”

The suit, which Williams filed on 22 May, seems quixotic. He is representing himself; to make his case, he needs documents that only the lab can provide; and his complaint centers on a differential equation. Williams spent only a short time at Livermore before he was fired. (In a 12-month performance review Williams included in his suit, his superiors state he wasn’t keeping up with assignments.) Before joining the lab he did two postdocs, taught at City College of San Francisco and Sonoma State University, and worked for 8 years at Agilent Technologies. But Williams is a talented scientist, says Craig Wheeler, an astrophysicist at the University of Texas, Austin, who was his graduate adviser and has subsequently published with him. “He’s a deep, independent thinker,” Wheeler says. “He’s definitely not a crackpot.”

At Livermore, Williams was given the unclassified task of modeling the behavior of a high explosive. Called PBX 9502, the polymer-bonded explosive is intended to be used in refurbishing a 40-year-old thermonuclear warhead called the W80, which is about the size of a garbage can and fits on a cruise missile. The explosive, when detonated, would compress the warhead’s plutonium pit to set off a nuclear fission explosion, which in turn would trigger an even more powerful fusion explosion. Modeling a high explosive is difficult, researchers say, because its behavior depends on its density, which can vary from batch to batch and within a single piece. But such modeling is crucial to be sure that stored weapons will work as intended because the United States gave up nuclear testing in 1992 under the still unratified Comprehensive Nuclear-Test–Ban Treaty.

PBX 9502 is especially tricky because it’s an insensitive explosive, meaning it won’t go up if smacked or set on fire. But that also means that as the detonation front moves through the material, the chemical reactions behind it progress more slowly than in older explosives, Williams says. So instead of assuming the reactions are instantaneous, researchers must model their evolution, too.

To make sure they can do so correctly, researchers detonate samples of the stuff in different geometries, observe the explosions with ultra–high-speed cameras and other tools, and compare the results with simulations. For example, in one test, the sample resembles a mallet, with a thin cylindrical handle that leads to a fatter cylindrical head. Because the detonation front cannot instantly turn the corner where skinny cylinder meets fat, the explosion doesn’t consume the entire sample, but leaves a ring of material whose thickness reveals the speed of the detonation front and chemical reactions.

Livermore used such test explosions to refine a modeling program called ARES-CHEETAH. But Williams says he became aware that one of his supervisors was essentially changing parameters in the program after the fact to make sure the simulation fit the data from each experimental setup. That’s “pseudoscience,” Williams charges, as it guarantees the model will look accurate, even if it isn’t. He says he repeatedly asked the researcher to explain the rationale for the tweaking. “It became clear that he didn’t have a rationale, he had a motive,” Williams says. “And the motive was to keep money flowing to help develop and improve CHEETAH.”

Such “curve fitting” renders the program incapable of making meaningful predictions, he says. If CHEETAH can’t properly model the bench tests of PBX 9502, larger, far more expensive integrated test explosions of the weapon’s nonnuclear components could fail, he says. And modelers may not be able to correctly calculate the yield of the refurbished weapon, he says.

That would be a big problem, says Robert Rosner, a theoretical astrophysicist at the University of Chicago and former director of Argonne National Laboratory who is on Livermore’s advisory board. The uncertainty in the yields of various weapons directly affects calculations of how big the U.S. nuclear arsenal should be and could determine the course of future arms control negotiations, Rosner says. “The extent to which we can decrease [the stockpile] is completely related to the ability to be certain about the yield.”

But Rosner says he’s neither surprised nor alarmed to hear researchers had to adjust the high-explosives models to fit different experiments. What Williams sees as unacceptable tweaking is an inevitable part of the empirical modeling of any complex system, such as the climate or a star, Rosner says. “The idea that the model has to be tuned, I find that unsurprising,” he says. “I would be stunned if it didn’t.”

Both Rosner and Jeanloz say they suspect Williams may not know the whole story behind ARES-CHEETAH, as the lab dismissed him before he obtained a clearance to work on classified material. The weapons program also takes explicit measures to ensure that researchers adhere to scientific standards, Jeanloz says, such as running its own classified peer-reviewed journals and encouraging researchers to keep a hand in unclassified research. The rivalry between Livermore and Los Alamos National Laboratory in New Mexico provides a particularly valuable check, scientists say.

Yet Jeanloz and Rosner agree that models like CHEETAH need careful scrutiny. That’s because some policymakers may view uncertainties in modeling as a reason to resume nuclear testing. In fact, Jeanloz says, some arms control experts argue that to discourage calls for new tests, the United States should make no changes to its existing nuclear arms—even ones that make them safer, such as switching to insensitive explosives.

Williams does not yet have a court date. He’s suing, he says, not out of anger, but out of a sense of scientific duty: “I couldn’t look myself in the mirror if I didn’t do it.”
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doi:10.1126/science.abd4839