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As Top Scientists Say Concussions Can Cause C.T.E., These Sports Doctors Dig In

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As Top Scientists Say Concussions Can Cause C.T.E., These Sports Doctors Dig In

AMSTERDAM — For the primary time since 2016, one of the influential teams guiding docs, trainers and sports activities leagues on concussions met final month to resolve, amongst different issues, if it was time to acknowledge the causal relationship between repeated head hits and the degenerative mind illness referred to as C.T.E.

Regardless of mounting proof and a extremely regarded U.S. authorities company not too long ago acknowledging the hyperlink, the group all however determined it was not. Leaders of the Worldwide Consensus Convention on Concussion in Sport, assembly in Amsterdam, signaled that it will proceed its lengthy apply of casting doubt on the connection between the ravages of head trauma and sports activities.

C.T.E., or continual traumatic encephalopathy, was first recognized in boxers in 1928 and burst into prominence in 2005, when scientists revealed their posthumous analysis of the illness within the N.F.L. Corridor of Fame middle Mike Webster, creating an existential disaster for sports activities comparable to soccer and rugby that contain gamers hitting their heads 1000’s of occasions a 12 months.

Scientists have spent the previous decade analyzing lots of of brains from athletes and army veterans, and the variable evident in practically each case of C.T.E. has been their publicity to repeated head trauma. Researchers have additionally established what they name a dose response between the severity of the C.T.E. and the variety of years taking part in collision sports activities.

After taking part in down an affiliation between head accidents and mind injury for years, the N.F.L. in 2016 acknowledged that there was a hyperlink between soccer and degenerative mind problems comparable to C.T.E. Simply days earlier than the convention in Amsterdam, the Nationwide Institutes of Well being, the most important funder of mind analysis in america, mentioned that C.T.E. “is prompted partly by repeated traumatic mind accidents.”

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However in one of many closing classes of the three-day convention, one of many leaders of the convention, a neuropsychologist who has acquired $1.5 million in analysis funding from the N.F.L., dismissed the work of scientists who’ve documented C.T.E. in lots of of athletes and troopers as a result of he mentioned their research so far didn’t account for different well being variables, together with coronary heart illness, diabetes and substance abuse.

“To assume that there’s one issue that’s contributing to their present issues and that issue you may see below a microscope after dying is a very naïve place when you consider the human situation,” mentioned Dr. Grant Iverson, a neuropsychologist at Harvard who ran the session and was a lead author of the convention’s assertion on long-term impacts of repeated head trauma.

A recording of that session obtained by The New York Occasions, in addition to interviews with individuals who attended, supplied a uncommon glimpse of the fissures among the many scientists who set concussion coverage in sport, and it revealed causes for his or her continued refusal to think about of just about the entire new analysis on long-term impacts of head trauma as they put together to launch steering for sports activities leagues around the globe.

On the coronary heart of the group’s goal is its consensus assertion, periodically issued concussions steering agreed upon by most of group’s a number of dozen members. It’s foundational to the protocols of most of the world’s high pro-sports leagues. Medical advisers to lots of these leagues, together with the chief medical officers for the N.C.A.A. and World Rugby, helped craft that assertion in Amsterdam. The latest iteration was anticipated to be launched in 2023.

However the make-up of the group itself poses obvious conflicts of curiosity that decision into query their delay on accepting new analysis on concussions. FIFA; the I.O.C.; the F.I.A., which governs vehicle racing leagues together with Method One; World Rugby; and different governing organizations in sports activities sponsor the convention and have working relationships with most of the leaders of the convention or present them with analysis funding.

“This group has been led by individuals who don’t actually have a full understanding of the pathology of head damage at that degree,” mentioned Willie Stewart, a neuropathologist in Glasgow who has identified C.T.E. in lots of athletes. He mentioned the convention leaders ought to have their phrases restricted. “There needs to be a rotation of individuals so that they don’t have any concern of what they mentioned 4 years in the past.”

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Earlier consensus statements claimed that the science was not settled on C.T.E., and that language has been adopted by sports activities leagues together with the N.H.L., the N.C.A.A. and New Zealand Rugby, a stamp of approval from scientists that has helped a few of these organizations fend off lawsuits accusing them of hiding the risks of concussions from athletes.

Nonetheless, researchers pushing for a recognition of a cause-and-effect relationship between head trauma and C.T.E. have been initially optimistic that the group’s leaders is perhaps swayed by new analysis. In March, Paul McCrory, a longtime chief of the group and a vocal skeptic of the hyperlinks between head hits and C.T.E., resigned after he was caught plagiarizing.

However in conversations earlier than and throughout the convention, leaders of the group centered their discussions on what was unknown about C.T.E., noting that it was unclear why some athletes bought the illness and others who performed the identical sport didn’t. Nobody can say how a lot head trauma is required to get C.T.E. A dependable check for diagnosing the illness within the residing is no less than 5 years off, consultants mentioned.

Then, in one of many convention’s closing classes, titled “Lengthy Time period Sequellae and Standards for Retirement,” Iverson started the hourlong confab by discussing the factors the group would use to overview concussions analysis.

Of the practically 7,500 papers on concussions that the group recognized, the writers of the consensus assertion thought of simply 26, which didn’t embody any of the most important analysis papers on C.T.E. Dr. Ann McKee, a neuropathologist at Boston College who’s the world’s main C.T.E. knowledgeable, pulled out of the convention as a result of she was advised her work wouldn’t be totally built-in into the assertion.

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Jon Patricios, Bob Cantu, Mike McNamee and Kathryn Schneider, the leaders of the convention, mentioned in an e mail that some analysis on C.T.E. that was excluded from the formal overview was nonetheless introduced on the session in order that “a spectrum of views” may very well be heard. They added that they have been unable to share specifics on which have been included.

Iverson described the constraints of the present analysis and why a lot of it was excluded from consideration. Most C.T.E. analysis, he defined, thought of just one or two variables, like age and intercourse, however not others, like coronary heart illness, diabetes and alcohol abuse.

As a result of the illness can solely be identified posthumously, scientists haven’t but created long-term research which observe residing topics via their lives as some are uncovered to mind trauma and others should not. In that state of affairs, scientists would want to solicit brains from individuals who didn’t compete in collision sports activities and wouldn’t know the outcomes of the examine till after the contributors had died.

“If we take into consideration the significance of later-in-life mind well being, these are some variables which might be vital to think about,” Iverson mentioned.

Some who attended the session have been unconvinced that the shortage of such analysis mitigated the avalanche of research that set up a causal relationship between mind trauma and C.T.E.

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“To do the kinds of research they need to embody on this means will take many years,” mentioned Michael Gray, who teaches rehabilitation neuroscience on the College of East Anglia in England. “Are we supposed to attend many years and have tens of 1000’s of individuals undergo from neurodegeneration once we may very well be doing one thing about it now?”

A convention rule permits simply 7 of the 29 writers to dam language within the assertion, doubtlessly creating one other barrier to the group agreeing to phrasing that hyperlinks head trauma to C.T.E. The consensus-statement writers embody many docs who don’t specialise in degenerative mind illness but advise the N.H.L., Australian Soccer League and different leagues.

Cantu, one of many foremost researchers on C.T.E., adopted Iverson with a 15-minute presentation by which he advised the group that it had “kicked down the street” the problem of C.T.E. of their final two consensus statements, revealed in 2013 and 2017. He mentioned that the cognitive, behavioral and temper points related to C.T.E. overlap with many different illnesses, which make it exhausting to diagnose clinically.

However since 2016, he mentioned there have been greater than 100 papers a 12 months revealed on C.T.E., together with one he co-wrote this 12 months with Chris Nowinski, a Ph.D. in behavioral neuroscience who co-founded the nonprofit Concussion Legacy Basis, and different researchers. In it, they detailed their findings that there existed a excessive chance that repeated head trauma causes C.T.E. Their paper, he mentioned, helped persuade the N.I.H. to vary its stance.

Nowinski and his colleague from the Concussion Legacy Basis, Adam White, taunted the leaders of the convention by holding satirical drawings as they arrived.

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Credit score…Adam White

Their posters featured smiling docs in lab coats holding cigarettes, with “Get pleasure from repetitive head impacts” and “Don’t fear about CTE!” a parody of promoting within the Forties and Fifties by which docs promoted smoking.

“I’m there to remind them that in the event that they don’t acknowledge a cause-and-effect relationship, much more persons are going to get harm and it’s going to break their reputations,” Nowinski mentioned. “The issue is, if they are saying cause-and-effect is established, it can value the organizers of the convention some huge cash in lawsuits.”

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Opinion: Wait times go down. Patient satisfaction goes up. What's the matter with letting apps and AI run the ER?

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Opinion: Wait times go down. Patient satisfaction goes up. What's the matter with letting apps and AI run the ER?

My resident describes our next emergency room patient — a 32-year-old female with severe, crampy mid-abdominal pain, vomiting and occasional loose stools. The symptoms have been present for nearly a week, and there is tenderness to both sides of the upper abdomen. It could be a gallbladder problem, the resident says, hepatitis, pancreatitis, diverticulitis or an atypical appendicitis. She proposes routine blood tests along with an ultrasound and an abdominal CT scan.

This is the time-honored approach to an undifferentiated patient complaint: Generate a list of possible diagnoses, decide which represent a “reasonable” concern and use the results from further testing to conclude what’s going on. Yet increasingly the second phase of this process — evaluating which diagnoses represent a reasonable concern — is getting short shrift. It is the heavy lift of any patient encounter — weighing disease probabilities, probing for details. It’s often simpler, and faster, to cast a wide net, click the standard order for blood work and imaging, and wait for the results to pop up.

The issue of the “busy doctor ordering too many tests” has plagued medicine for decades. Now, as hospitals inject algorithms and technology into their workflow, it’s much worse. Medicine is moving inexorably away from the deductive arts, becoming more technology- and test-dependent and less patient-centric.

Go to an emergency room today and you will likely be met within minutes by a doctor whose sole role is to perform a “rapid medical evaluation.” The provider asks a few questions, ticks boxes on a computer screen and, shazam, you are in line for the most likely series of tests and scans, all based on typically a less than 60-second encounter.

This strategy seems obvious. When workups are initiated as soon as the patient arrives, wait times go down, patient satisfaction goes up, and fewer patients leave out of frustration before even being seen. These are the metrics that put smiles on administrators’ faces and give hospitals high marks in national surveys.

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But is it good doctoring? Without the luxury of time, these gateway providers typically lump patients into broad, generic categories: the middle-aged person with chest pain, the short-of-breath asthmatic, the vomiting pregnant patient, the septuagenarian with cough and fever, and so forth. The diagnosis is then reverse-engineered with tests to cover all possible bases for that particular complaint.

In essence this is flipping the script on traditional doctoring while incentivizing doctors to use testing as a surrogate for critical thinking, dumbing down the practice of medicine and throwing gasoline on the problem of over-testing.

Since rapid evaluation became the norm, use of laboratory, CT and ultrasound services at my hospital has increased nearly 20%. Just the other day, a pregnant woman in my ER went through a full battery of time-consuming, expensive and invasive tests even though she’d been through all of them at another hospital the day before. As far as I can tell, the only reason we did that was because that’s what an algorithm told us to do.

This has real effects on patients. Contrary to popular perception, more tests may not supply more answers. That’s because the accuracy of any test depends on the likelihood that the patient has the disease in question before the test is performed. Testing performed without the appropriate indication or context can produce incidental or even spurious results that may have your doctor looking in entirely the wrong direction.

The basic problem with hospitals’ growing obsession with efficiency is this: Algorithmic systems treat all patients the same, expecting precise, like-for-like responses to every question with just the right amount of detail. Except every patient is unique. And they tend to give up their stories at their own pace, in broken, non-linear fits and starts, sometimes conflating truth and fiction in ways that can be counterproductive and frustrating, but also uniquely human. I am often reminded of Jack Webb in the old TV series “Dragnet” imploring a witness to offer “just the facts, ma’am, just the facts.” In real life, whether from situational stress, self-delusion, superstition, health illiteracy, mental illness, drugs or alcohol, my patients’ initial version of their complaint is rarely “just the facts” or the final word on the subject.

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A colleague recently described her role in a clinical encounter as 9 parts translator to 1 part doctor. One question leads to another, and then another, and another until she successfully translates the patient’s lived experience into a language modern medicine and its algorithms might begin to understand. My experience is similar. Properly choreographed, the doctor-patient interaction becomes a pas de deux — two people in sync, jointly trying to solve a puzzle with each sharing their perspective and expertise. In the transition to front-loaded care, I worry health decisions will be made with information that may be incomplete or, at times, totally unreliable.

Algorithmic medicine also seems tailor-made for an AI takeover. The logic is obvious. Use “big data” to assist doctors and nurses struggling to keep up with the demands of modern medicine. AI can ensure a level, consistent floor of care that avoids errors of omission by considering a deliberately broad list of diagnostic possibilities. In an ideal world, a synergy of human and machine intelligence could amplify the patient-doctor encounter. As likely, AI will lead doctors to abdicate judgment and responsibility to the automated response of the machine.

And so, I complimented my resident on her list of concerns but suggested that we spend a little more time with the patient. The story of her symptoms didn’t feel complete. I recommended my resident grab a chair and simply ask the patient about her life. What emerged was the chaotic picture of an exhausted part-time student by day, working two evening waitressing jobs and surviving on pizza, pasta and energy drinks. She had always had a “fragile stomach.”

Our list of reasonable diagnoses was expanding and contracting, replaced with irritable bowel syndrome, food intolerances, gut motility issues, all overlying a stressed individual barely keeping it together. The labs, ultrasound or CT scan initially proposed now seemed irrelevant.

The result: The patient got out of the hospital faster. She received helpful suggestions about stress reduction, diet and sleep habits. She got an appointment with a primary care physician and avoided thousands of dollars in tests. Had we just relied on tests instead of asking a few more questions, there is a good chance we would have missed the best approach to her problem entirely.

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ER waiting rooms and wards are bursting at the seams, and the streamlining of care has never felt more essential. But this is not an excuse for doctors to relinquish their humanity or their “method.” We should tweak the process: Allow more time for doctors to get the story right, do less testing until we have weighed the risks and rewards, prioritize asking questions rather than merely looking for answers.

Sociologists coined the term “pre-automation” to describe the transitional phase in which humans lay the groundwork for automation, often by acting in increasingly machine-like ways. As providers, we must not fall in line.

Put another way, with AI primed to take on a substantial role in how doctors deliver care, we should remind ourselves: If we behave like machines, we certainly won’t be missed when machines replace us.

Eric Snoey is an ER doctor at Alameda Health System-Highland Hospital in Oakland.

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Column: Democrats show that they're no better than Trump in allowing politics to interfere with science

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Column: Democrats show that they're no better than Trump in allowing politics to interfere with science

Anyone who cares about the importance of science in the making of government policy had to be deeply dispirited by the hearing into the origins of COVID-19 staged by a Republican-led House subcommittee on May 1.

The sole witness at the hearing, and its target, was Peter Daszak, the head of EcoHealth Alliance, a nongovernmental organization tasked with overseeing international virus research funded by federal agencies.

It wasn’t just that the GOP majority used the occasion to promote the ignorant, imbecilic and 100% evidence-free notion that SARS-CoV-2, the virus that caused the COVID pandemic, originated in a Chinese laboratory, through work funded by the U.S. government, and overseen by EcoHealth.

Science is a myth-buster…Because of this, science has become a nuisance, even an enemy to some industries and many of the most powerful actors in the new attention economy.

— Science blogger Philipp Markolin

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It was that the Democratic minority showed itself to be complicit with the GOP attack on EcoHealth.

As I wrote at the time, the Democrats threw Daszak and by extension science itself under the bus: “Perhaps they hoped that by allowing Daszak to be drawn and quartered, they might persuade the Republicans to climb down from their evidence-free claims about government complicity in the pandemic’s origins.”

The Democrats’ craven and shameful performance hinted that EcoHealth’s government funding, which had been blocked by the Trump administration and restored, though delayed, under Biden, was pretty much doomed.

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On Wednesday, the bell tolled. EcoHealth received a notice from the Department of Health and Human Services, the parent agency of the NIH, that it was immediately suspending all funding to the organization and moving to “debar” it from federal funding going forward.

It’s impossible to overstate what a serious blow this is for EcoHealth and research into the origins of pathogens that could cause illness and death on a global scale — the central purpose of EcoHealth’s work.

The organization, which has operated with a budget of about $16 million, cannot receive a contract from any federal agency or even serve as a subcontractor of another awardee. All organizations with federal contracts that have affiliated with EcoHealth will be “carefully examined.”

EcoHealth says it will appeal the proposed debarment, as is its right. But that process could take years. In the meantime, the organization will be effectively out of money, and very likely out of business. The HHS action effectively turns one of the leading organizations in the quest to protect humankind from the next pandemic into a pariah, completely unjustifiably.

The debarment threat “will mean the demise of EcoHealth, one of the most scientifically productive and internationally respected groups conducting field surveillance for potential pandemic viruses,” says Gerald T. Keusch, a former associate director of international research at the NIH. “And that means our national security will be compromised.”

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Let’s be clear about what has happened here. EcoHealth has been made a scapegoat for the pandemic for partisan reasons. The process started with President Trump. At a news conference on April 17, 2020, a reporter from a right-wing organization mentioned that the NIH had given a $3.7-million grant to the Wuhan Institute of Virology. (Actually, the WIV grant, which was channeled from a larger EcoHealth grant, was only $600,000.)

Trump, sensing an opportunity to show a strong hand against China and advance his effort to blame the Chinese for the pandemic, responded: “We will end that grant very quickly.” The NIH terminated the grant one week later, prompting a backlash from the scientific community, including an open letter signed by 77 Nobel laureates who saw the action as a flagrantly partisan interference in government funding of scientific research.

The HHS inspector general found the termination to be “improper.” The NIH reinstated the grant, but immediately suspended it until EcoHealth met several conditions that were manifestly beyond its capability, as they involved its demanding information from the Chinese government that it had no right to receive. The grant was reinstated last year under Biden, but NIH bureaucrats, perhaps worried about their careers in a new Trump administration, continued to put administrative obstacles in the way of EcoHealth’s work.

The attacks on Daszak and his organization are simply instruments of the GOP project to pin blame for the pandemic on Anthony Fauci, one of the world’s most respected public health figures.

The context is a battle for the minds of uninformed and misinformed Americans over the origin of COVID-19. The hypothesis favored by most qualified virologists and epidemiologists is that the virus reached humans the way most viruses do — as spillovers from wildlife. The alternative hypothesis, for which absolutely not a speck of evidence has ever been presented, is that the virus emerged from a laboratory—specifically the Wuhan Institute of Virology in China, whether deliberately or through sloppy lab practices.

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The latter hypothesis was initially promoted by an anti-China cabal in the Trump-era State Department. Although they never produced any grounds for the conspiracy theory, it remains favored by anti-vaccine agitators and in the Republican anti-science camp. It has a certain appeal for uninformed people susceptible to sinister explanations of complicated, troubling events; but it’s not science.

Daszak calls the government actions “fundamentally unfair” and “based on a set of false assumptions about COVID-19 origins and on persistent mischaracterizations and misunderstandings of our research…Our work has been at the forefront of understanding pandemic risk for over two decades, and it’s a very cruel irony that because we knew that China was a potential hotspot for the next coronavirus pandemic, we’re now being targeted in a political backlash caused by exactly the type of pandemic we were concerned about preventing.”

An outgrowth of the lab-leak fantasy is the asinine claim that as head of the National Institute of Allergy and Infectious Diseases, Fauci funded research in China that created the pandemic virus and let it loose on the world, and then concealed his complicity. This is a favorite meme among lab-leak fanatics. Among the research bodies that received NIAID funding to conduct field work in China was EcoHealth. (Fauci retired last year as director of NIAID, which is part of the National Institutes of Health.)

On May 1, the GOP-led Select Subcommittee on the Coronavirus Pandemic brought things to a head with its grilling of Daszak. It was a circus featuring posturing politicians intent on smearing Daszak and EcoHealth on the pretext of getting to the bottom of the pandemic’s cause. The committee Democrats participated fully, hammering Daszak as a “poor steward of the taxpayers’ dollars,” based on transparent trivialities.

During a follow-up subcommittee hearing Thursday, ranking member Raul Ruiz (D-Indio) alluded to the dishonestly of the GOP attack on Fauci. But, perhaps inadvertently, he also exposed the dishonesty of his caucus’ attack on Daszak.

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The committee Republicans, Ruiz said, “still have not succeeded in substantiating their allegations that NIH and NIAID through a grant to EcoHealth Alliance created SARS-CoV-2 and conspired to cover it up. … No evidence demonstrates that work performed under the EcoHealth grants, including at the Wuhan Institute of Virology, led to the creation of SARS-CoV-2.”

Does Ruiz ever listen to the words coming out of his mouth? The very goal of the GOP’s dragging Daszak and EcoHealth into this controversy was to fabricate a link in the chain between Fauci and COVID-19; by rejecting the GOP position, Ruiz demolished the case against EcoHealth.

Yet Ruiz didn’t walk the last mile. “EcoHealth has defied its obligations to be a transparent steward of taxpayer dollars,” he said, repeated the lame case against the organization that he first aired, in connivance with the Republicans, during the public interrogation of Daszak on May 1.

Legitimate scientists, such as virology experts uninfected by the conspiratorial fantasy that the virus originated in the lab, are aghast at the suspension of EcoHealth’s funding and the organization’s likely debarment, as well as the Democrats’ supine behavior.

The Democrats, as Stuart Neil, a professor of virology at Kings College London, wrote on X, “have made some shoddy back room deal to allow them to look tough to the conspiracy theorists.” Neil is right. There is no rational explanation for the Democrats’ behavior than some sort of deal with the Republican majority to give them cover to challenge the lab leak theory.

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Put it all together, and it looks like HHS started with a politically driven impulse to cut off EcoHealth’s funding, followed by an effort to assemble every justification for doing so, no matter how trivial. The absurdity of its action drips from the closing words of the notice issued by H. Katrina Brisbon, an HHS “suspension and debarment official.” She wrote that “the immediate suspension of EHA is necessary to protect the public interest and due to a cause of so serious or compelling a nature that it affects EHA’s present responsibility.”

The notice was accompanied by an 11-page bill of particulars, but they all boil down to two key purported offenses — that EcoHealth had missed a 2019 deadline for an annual report of its activities to NIH, and that work EcoHealth had funded in China had produced a recombinant version of a virus that grew fast enough to trigger a safety halt in the work.

The first was tantamount to a traffic violation. EcoHealth maintained that it hadn’t been able to file the report on time because it had been locked out of NIH’s onlline reporting portal, which NIH denies. On the second, there were legitimate disagreements over whether the subject virus’ growth actually did trigger the halt requirement; in any case, the virus wasn’t a threat to human health. The work at issue took place in 2018.

HHS cited several other supposed offenses, including EcoHealth’s failure to submit lab notebooks from the Wuhan institute that NIH has requested in November 2021. But since NIH had ordered EcoHealth to stop funding the institute as of April 2020, those notebooks were plainly out of its reach.

Daszak says EcoHealth will respond to the HHS and the subcommittee “with documentary evidence…refuting every single allegation that’s been levied against us.”

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The roots of anti-science slant of Trump and others on the far right isn’t hard to discern. It’s aimed at protecting the economic establishment from new ideas and realities such as global warming, while providing financial and personal opportunities for grifters and charlatans.

Swiss scientist and science blogger Philipp Markolin has put his finger on this phenomenon.

“Science is a myth-buster,” he writes. “Its debunking activity reduces the value of information products that too many media manipulators rely on for their business. Because of this, science has become a nuisance, even an enemy to some industries and many of the most powerful actors in the new attention economy.”

Why did the Democrats agree to participate in this charade? In joining the Daszak smear, they have shredded their credibility as of scientific truth, at the very moment when science is most in need of their protection.

The time has come to ask this question of Ruiz, his Democratic colleagues on the coronavirus subcommittee — Debbie Dingell of Michigan, Kwesi Mfume of Maryland, Deborah Ross of North Carolina, Robert Garcia of Long Beach, Ami Bera of Sacramento and Jill Tokuda of Hawaii — along with Health and Human Services Secretary Xavier Becerra: How can you live with yourselves?

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Star USC scientist faces scrutiny — retracted papers and a paused drug trial

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Star USC scientist faces scrutiny — retracted papers and a paused drug trial

Late last year, a group of whistleblowers submitted a report to the National Institutes of Health that questioned the integrity of a celebrated USC neuroscientist’s research and the safety of an experimental stroke treatment his company was developing.

NIH has since paused clinical trials for 3K3A-APC, a stroke drug sponsored by ZZ Biotech, a Houston-based company co-founded by Berislav V. Zlokovic, professor and chair of the department of physiology and neuroscience at the Keck School of Medicine of USC.

Three of Zlokovic’s research papers have been retracted by the journal that published them because of problems with their data or images. Journals have issued corrections for seven more papers in which Zlokovic is the only common author, with one receiving a second correction after the new supplied data were found to have problems as well.

For an 11th paper co-authored by Zlokovic the journal Nature Medicine issued an expression of concern, a note journals append to articles when they have reason to believe there may be a problem with the paper but have not conclusively proven so. Since Zlokovic and his co-authors no longer had the original data for one of the questioned figures, the editors wrote, “[r]eaders are therefore alerted to interpret these results with caution.”

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“It’s quite unusual to see this volume of retractions, corrections and expressions of concern, especially in high-tier influential papers,” said Dr. Matthew Schrag, an assistant professor of neurology at Vanderbilt who co-authored the whistleblower report independently of his work at the university.

Both Zlokovic and representatives for USC declined to comment, citing an ongoing review initiated in the wake of the allegations, which were first reported in the journal Science.

“USC takes any allegations of research integrity very seriously,” the university said in a statement. “Consistent with federal regulations and USC policies, this review must be kept confidential.”

Zlokovic “remains committed to cooperating with and respecting that process, although it is unfortunately required due to allegations that are based on incorrect information and faulty premises,” his attorney Alfredo X. Jarrin wrote in an email.

Regarding the articles, “corrections and retractions are a normal and necessary part of the scientific post-publication process,” Jarrin wrote.

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Authors of the whistleblower report and academic integrity experts challenged that assertion.

“If these are honest errors, then the authors should be able to show the actual original data,” said Elisabeth Bik, a microbiologist and scientific integrity consultant who co-wrote the whistleblower report. “It is totally human to make errors, but there are a lot of errors found in these papers. And some of the findings are suggestive of image manipulation.”

Given the staid pace of academic publishing, publishing this many corrections and retractions only a few months after the initial concerns were raised “is, bizarrely, pretty quick,” said Ivan Oransky, co-founder of Retraction Watch.

The whistleblower report submitted to NIH identified allegedly doctored images and data in 35 research papers in which Zlokovic was the sole common author.

“There had been rumblings about things not being reproducible [in Zlokovic’s research] for quite some time,” Schrag said. “The real motivation to speak publicly is that some of his work reached a stage where it was being used to justify clinical trials. And I think that when you have data that may be unreliable as the foundation for that kind of an experiment, the stakes are just so much higher. You’re talking about patients who are often at the most vulnerable medical moment of their life.”

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Over the years, Zlokovic has created several biotech companies aimed at commercializing his scientific work. In 2007, he co-founded ZZ Biotech, which has been working to gain federal approval of 3K3A-APC.

The drug is intended to minimize the bleeding and subsequent brain damage that can occur after an ischemic stroke, in which a blood clot forms in an artery leading to the brain.

In 2022, USC’s Keck School of Medicine received from NIH the first $4 million of a planned $30-million grant to conduct Phase III trials of the experimental stroke treatment on 1,400 people.

In Phase II of the trial, which was published in 2018 and called Rhapsody, six of the 66 patients who received 3K3A-APC died in the first week after their stroke, compared to one person among the 44 patients who got a placebo. Patients who received the drug also tended to report more disability 90 days after their stroke than those who got the placebo. The differences between the two groups were not statistically significant and could have been due to chance, and the death rate for patients in both groups evened out one month after the initial stroke.

“The statements that there is a risk in this trial is false,” said Patrick Lyden, a USC neurologist and stroke expert who was employed by Cedars-Sinai at the time of the trial. Zlokovic worked with Lyden as a co-investigator on the study.

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One correction has been issued to the paper describing the Phase II results, fixing an extra line in a data table that shifted some numbers to the wrong columns. “This mistake is mine. It’s not anybody else’s. I didn’t catch it in multiple readings,” Lyden said, adding that he noticed the error and was already working on the correction when the journal contacted him about it.

He disputed that the trial represented any undue risk to patients.

“I believe it’s safe, especially when you consider that the purpose of Rhapsody was to find a dose — the maximum dose — that was tolerated by the patients without risk, and the Rhapsody trial succeeded in doing that. We did not find any dose that was too high to limit proceeding to Phase III. It’s time to proceed with Phase III.”

Schrag stressed that the whistleblowers did not find evidence of manipulated data in the report from the Phase II trial. But given the errors and alleged data manipulation in Zlokovic’s earlier work, he said, it’s appropriate to scrutinize a clinical trial that would administer the product of his research to people in life-threatening situations.

In the Phase II data, “there’s a coherent pattern of [patient] outcomes trending in the wrong direction. There’s a signal in early mortality … there’s a trend toward worse disability numbers” for patients who received the drug instead of a placebo, he said.

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None are “conclusive proof of harm,” he said. But “when you’re seeing a red flag or a trend in the clinical trial, I would tend to give that more weight in the setting of serious ethical concerns around the pre-clinical data.”

The NIH paused the clinical trial in November, and it remains on hold, said Dr. Pooja Khatr, principal investigator of the NIH StrokeNet National Coordinating Center. Khatr declined to comment on the pause or the trial’s future, referring further questions to USC and NIH.

The NIH Office of Extramural Research declined to discuss Rhapsody or Zlokovic, citing confidentiality regarding grant deliberations.

ZZ Biotech Chief Executive Kent Pryor, who in 2022 called the drug “a potential game-changer,” said he had no comment or information on the halted trial.

Zlokovic is a leading researcher on the blood-brain barrier, with particular interest in its role in stroke and dementia. He received his medical degree and doctorate in physiology at the University of Belgrade and joined the faculty at USC’s Keck School of Medicine after several fellowships in London. A polyglot and amateur opera singer, Zlokovic left USC and spent 11 years at the University of Rochester before returning in 2011. He was appointed director of USC’s Zilkha Neurogenetic Institute the following year.

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A USC spokesperson confirmed that Zlokovic has retained his titles as department chair and director of the Zilkha institute.

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