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USC neuroscientist faces scrutiny following allegations of data manipulation

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USC neuroscientist faces scrutiny following allegations of data manipulation

A star neuroscientist at USC is facing allegations of misconduct after whistleblowers submitted a report to the National Institutes of Health that accused the professor of manipulating data in dozens of research papers and sounded alarms about an experimental stroke medication his company is developing.

The accusations against Berislav V. Zlokovic, professor and chair of the department of physiology and neuroscience at the Keck School of Medicine of USC, were made by a small group of independent researchers and reported in the journal Science.

The report identifies allegedly doctored images and data in 35 research papers in which Zlokovic is the sole common author. It also raised questions about findings in Phase II clinical trials of a drug called 3K3A-APC, an experimental stroke treatment sponsored by ZZ Biotech, the Houston-based company Zlokovic co-founded.

Preclinical data appeared to have been manipulated, the report authors allege. In addition, the Phase II results appear to contain errors that would skew interpretation of the data in favor of the drug.

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An attorney for Zlokovic said the neuroscientist takes the accusations “extremely seriously” and was “committed to fully cooperating” with a USC inquiry into the matter. However, he said his client could not comment on the allegations while the review was pending.

“Professor Zlokovic would normally welcome addressing every question raised, insofar as allegations are based on information and premises Professor Zlokovic knows to be completely incorrect,” attorney Alfredo X. Jarrin wrote in an email. “And other questions address work not performed at his lab or papers where he was not the senior author or contact author and his role was limited.”

The university also issued a statement saying it takes allegations of research integrity seriously. “Consistent with federal regulations and USC policies, the university forwards any such allegations to its Office of Research Integrity for careful review,” the university said in a statement. “Under USC policy, this review is required to be confidential. As a result, we are unable to provide any further information.”

Last year, 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.

Given the serious issues outlined in their report, the whistleblowers say those trials should be stopped immediately.

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“It should certainly be paused in my opinion,” said Matthew Schrag, an assistant professor of neurology at Vanderbilt and co-author of the whistleblower report. “There are red flags about the safety of that treatment.”

He said that evidence from the USC-led phase II trial of the drug, which was published in 2018 and called RHAPSODY, raised questions of patient safety. Patients in that trial were more likely to die in the week after treatment, and more likely to be disabled 90 days later than those who were given a placebo.

In addition, Schrag said, some patients given the placebo had to wait longer for the standard stroke treatment of the drug tPA or surgery to dissolve the blood clot.

“The faster you’re able to intervene to either restore blood flow with the drug or restore blood flow by removing the clot, the more brain cells survive,” he said.

He added that he did not believe the delay was intentional but that it had the effect of “skewing the results in favor of the drug.”

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Schrag previously raised questions about the integrity of other neurological research, work he said was separate from his employment at Vanderbilt.

Scientists have questioned Zlokovic’s research anonymously for years, Schrag said. Many of these concerns were published on PubPeer, a website on which anonymous contributors can examine scientific papers and highlight potential flaws.

Yet scientists working with Zlokovic did not complain publicly, he said, allowing the studies to continue for years and succeed at attracting tens of millions of dollars in taxpayer funding.

“I think people are concerned about the potential for backlash for harm to their own careers,” Schrag said. “And so I think that motivates people to just go along.”

In its report, the journal Science interviewed four former employees of Zlokovic’s lab who said that Zlokovic routinely pressured them to manipulate data. Two said they were told to discard notebooks with results that didn’t fit preferred conclusions he hoped to reach.

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“There were clear examples of him instructing people to manipulate data to fit the hypothesis,” one former employee told the journal.

The severity of the data manipulation charges merits a thorough investigation of Zlokovic’s data, said Elisabeth Bik, a microbiologist and scientific integrity consultant who co-wrote the whistleblower report.

“Appropriate steps would be for USC to ask Zlokovic to give them the lab’s notebooks and data,” Bik said. “For example, for images where it appears that certain parts might have been duplicated or erased, the original images as they came off a scanner or microscope need to be compared to the published figure panels.”

Bik is among a subset of the report’s authors who are considering filing a federal whistleblower lawsuit. Should the NIH deem that any federal grant money was used improperly, a successful suit would entitle the plaintiffs to a portion of the money the government can claw back.

Zlokovic has received roughly $93 million in NIH funding, according to Science. A spokesperson for NIH’s Office of Extramural Research would not comment on the specifics of the case.

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“We take concerns related to research integrity very seriously, and this may include allegations of research misconduct,” the office said in a statement.

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.

Last year, Kent Pryor, ZZ Biotech’s chief executive, called the drug “a potential game-changer.”

“I believe, based on the positive clinical results to date, our 3K3A-APC will potentially create the first new drug class to treat ischemic stroke since 2003,” Pryor said.

On Tuesday, Pryor declined to comment on the details in the whistleblowers’ report. “I don’t want to get into particular explanations right now because of the ongoing investigations,” he said.

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He said the Phase III clinical trial had not yet begun.

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.

“My role will be to enhance an already very strong neuroscience base and try to make USC the No. 1 place in the neurosciences in the country and the world,” Zlokovic said upon rejoining the USC faculty. “It’s a big goal, but I think, with what’s going on right now, it’s actually moving in that direction. I think that could be my greatest contribution.”

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California effort to confront implicit bias among doctors faces 1st Amendment challenge

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California effort to confront implicit bias among doctors faces 1st Amendment challenge

Los Angeles anesthesiologist Dr. Marilyn Singleton was outraged about a California requirement that every continuing medical education course include training in implicit bias — the ways in which physicians’ unconscious attitudes might contribute to racial and ethnic disparities in healthcare.

Singleton, who is Black and has practiced for 50 years, sees calling doctors out for implicit bias as divisive, and argues that the state cannot legally require her to teach the idea in her continuing education classes. She has sued the Medical Board of California, asserting a constitutional right not to teach something she doesn’t believe.

The way to address healthcare disparities is to target low-income people for better access to care, rather than “shaking your finger” at white doctors and crying “racist,” she said. “I find it an insult to my colleagues to imply that they won’t be a good doctor if a racially divergent patient is in front of them.”

The litigation is part of a national crusade by right-leaning advocacy and legal groups against diversity, equity and inclusion, or DEI, initiatives in healthcare. The resistance is inspired in part by last year’s U.S. Supreme Court ruling barring affirmative action in higher education.

The California lawsuit does not dispute the state’s authority to require implicit-bias training. It questions only whether the state can require all teachers to discuss implicit bias in their continuing medical education courses. The suit’s outcome, however, could influence obligatory implicit-bias training for all licensed professionals.

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Leading the charge is the Pacific Legal Foundation, a Sacramento-based organization that describes itself as a “national public interest law firm that defends Americans from government overreach and abuse.” Its clients include the activist group Do No Harm, founded in 2022 to fight affirmative action in medicine. The two groups have also joined forces to sue the Louisiana medical board and the Tennessee podiatry board for reserving board seats exclusively for racial minorities.

In their complaint against the California Medical Board, Singleton and Do No Harm, along with Los Angeles ophthalmologist Dr. Azadeh Khatibi, argue that the implicit-bias training requirement violates the 1st Amendment rights of doctors who teach continuing medical education courses by requiring them to discuss how unconscious bias based on race, ethnicity, gender identity, sexual orientation, age, socioeconomic status or disability can alter treatment.

“It’s the government saying doctors must say things, and that’s not what our free nation stands for,” said Khatibi, who immigrated to the U.S. from Iran as a child. Unlike Singleton, Khatibi does believe implicit bias can unintentionally result in substandard care. But, she said, “on principle, I don’t believe in the government compelling speech.”

The lawsuit challenges the evidence of implicit bias in healthcare, saying there is no proof that efforts to reduce bias are effective. Interventions have thus far not demonstrated lasting effects, studies have found.

In December, U.S. District Judge Dale S. Fischer dismissed the suit but allowed the Pacific Legal Foundation to file an amended complaint. A hearing is scheduled for March 11 in federal court in Los Angeles.

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In enacting the training requirement, the California Legislature found that physicians’ biased attitudes unconsciously contribute to healthcare disparities. It also found that racial and ethnic disparities in healthcare outcomes are “remarkably consistent” across a range of illnesses and persist even after adjusting for socioeconomic differences, whether patients are insured and other factors influencing care.

Black women are three to four times as likely as white women to die of pregnancy-related causes, are often prescribed less pain medication than white patients with the same complaints, and are referred less frequently for advanced cardiovascular procedures, the Legislature found.

It also noted that women treated by female doctors were more likely to survive heart attacks than those treated by men. This month, the Legislature’s Black Caucus unveiled a bill requiring implicit-bias training for all maternal care providers in the state.

Dr. Khama Ennis, who teaches an implicit-bias class for Massachusetts doctors, sees only the best intentions in her fellow physicians. “But we’re also human,” she said in an interview. “And to not acknowledge that we are just as susceptible to bias as anybody else in any other field is unfair to patients.”

Ennis offered an example of her own bias in a training session. Preparing to treat a patient in a hospital emergency room, she noticed a Confederate flag tattoo on his forearm.

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“As a Black woman, I had to have a quick chat with myself,” she said. “I needed to ensure that I provided the same standard of care for him that I would for anyone else.”

Ennis’ class meets the requirements of a Massachusetts law that physicians earn two hours of instruction in implicit bias to obtain or renew their licenses, as of 2022.

That same year, California began requiring that all accredited continuing medical education courses involving direct patient care include discussion of implicit bias. The state mandates 50 hours of continuing education every two years for doctors to maintain their licenses. Private institutions offer courses on an array of topics, and physicians generally teach them.

Teachers may tell students they do not believe implicit bias drives healthcare disparities, Fischer wrote in her December ruling. But the state, which licenses doctors, has the right to decide what must be included in the classes, the judge wrote.

Professionals who elect to teach courses “must communicate the information that the legislature requires medical practitioners to have,” the judge wrote. “When they do so, they do not speak for themselves, but for the state.”

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Whether they speak for themselves or for the state is a pivotal question. While the 1st Amendment protects private citizens’ right to free speech, that protection does not extend to government speech. The content of public school curricula, for example, is the speech of state government, not the speech of teachers, parents or students, courts have said.

The Pacific Legal Foundation’s amended complaint aims to convince the judge that its clients teach as private citizens with 1st Amendment rights. If the judge again rules otherwise, lead attorney Caleb Trotter said, he plans to appeal the decision to the U.S. Court of Appeals for the 9th Circuit, and, if necessary, the Supreme Court.

“This is not government speech at all,” he said. “It’s private speech, and the 1st Amendment should apply.”

“Plaintiffs are plainly wrong,” lawyers for Rob Bonta, the state attorney general, responded in court papers. “There can be no dispute that the State shapes or controls the content of continuing medical education courses.”

The medical board declined to comment on the pending litigation.

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From 2019 through July 2022, in addition to California and Massachusetts, four states enacted legislation requiring healthcare providers to be trained in implicit bias.

A landmark 2003 Institute of Medicine report, “Unequal Treatment,” found that limited access to care and other socioeconomic differences explain only part of racial and ethnic disparities in treatment outcomes. The expert panel concluded that clinicians’ prejudices could also contribute.

In the two decades since the report’s release, studies have documented that bias does influence clinical care and contribute to racial disparities, a 2022 report said.

But implicit-bias training might have no impact and might even worsen discriminatory care, the report found.

“There’s not really evidence that it works,” Khatibi said. “To me, addressing healthcare disparities is really important because lives are at stake. The question is, how do you want to achieve these ends?”

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KFF Health News, formerly known as Kaiser Health News, is a national newsroom that produces in-depth journalism about health issues.

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'What is this, “The Handmaid’s Tale”?' Exploring moral questions posed by controversial IVF ruling

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'What is this, “The Handmaid’s Tale”?' Exploring moral questions posed by controversial IVF ruling

Is a frozen embryo a child?

The Alabama Supreme Court says yes. In ruling this month that three couples who lost frozen embryos in a storage facility accident could sue for wrongful death of a minor child, the court wrote that the “natural, ordinary, commonly understood meaning” of the word “child” includes an “unborn child” — whether that’s a fetus in a womb or an embryo in a freezer.

Hospitals and clinics across the conservative state have since paused in vitro fertilization services as they scramble to figure out the legal and ethical ramifications of the decision. Transport companies are also on hold as they assess the risks of carrying embryos out of state.

To better understand the ethics of IVF and what this ruling means for clinics, families and the more than a million embryos stored in freezers across the country, we spoke with Vardit Ravitsky, a professor of bioethics at the University of Montreal and president of the Hastings Center, an independent bioethics research institute in New York. The interview has been edited for clarity and length.

You became interested in the ethical issues of IVF as a college student, when a friend asked if you would consider donating an egg.

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I was almost 20. I was absolutely fascinated by the notion of carrying a fetus that is not genetically related to you. What does that mean to be the biological mother of a fetus that is genetically not your child? On the flip side, what happens when you give your egg to another woman and you have a genetically related child that is not yours?

The notion of genetic relatedness — IVF kind of broke that. You can now carry a fetus that is not yours; you can give your genetics to another person. That blew my mind, because it took the notion of motherhood that was the same for all of human history and broke it down into two components.

So technology can change our fundamental concept of human beings. And that’s what’s happening here. We’re talking about a batch of cells on ice, and we call it a child. That just wasn’t possible before.

Do people have a common understanding of what an embryo is?

Embryo, fetus and newborn baby are, first and foremost, medical biological terms. An embryo is the name we use in the beginning of the development, up to about 11 weeks pregnancy or nine weeks in embryonic development. Then, when it’s more developed, we call it a fetus. When it breathes on its own, outside of a female body, we call it a baby.

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The separate issue is when do we accord these entities moral status? We can call them whatever we want; we can call them cells or we can call them children. That’s a value-based, societal decision.

Do we treat embryos outside of the body morally in the same way that we treat them inside of the body? In most jurisdictions, we treat them differently.

For years, anti-abortion advocates in red states have pushed “fetal personhood” — the idea that life begins at conception and fetuses are children entitled to legal rights. Now Alabama’s Supreme Court has ruled that frozen embryos should be considered children. What ethical questions does this pose?

To imply or say explicitly that [frozen embryos] are children, in the same sense that fetuses are seen as children, to me, that’s a very dangerous development.

Think about it logically: If you have a pregnancy and you do nothing, and there’s no miscarriage, a baby will be born. If you have an embryo in a dish in a freezer and you do nothing, there will not be a baby.

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I would like women to have access to abortion because I care about their health and autonomy and their freedom to choose. When it comes to frozen embryos, it has nothing to do with a woman and with her body.

The potential of these embryos to become babies or children depends on so many steps: They have to be thawed, they have to continue to develop, they have to be implanted in the uterus, the uterus has to accept them, pregnancy has to develop. These are all steps that can still go wrong. To think of them as children in the same way that we think about newborns or fetuses is just, to me, going so far in how we understand the concept of a child.

In a concurring opinion, Alabama Chief Justice Tom Parker wrote that the people of the state adopted the “theologically based view” that “human life cannot be wrongfully destroyed without incurring the wrath of a holy God, who views the destruction of His image as an affront to Himself.” What does this mean for the future of IVF in conservative states?

Even if you say life begins at conception — for religious reasons or for any other values that you hold — you could still assign different moral values to the two scenarios of conception: outside of the body or inside of the body.

But if you take the view that life starts at conception and you apply that to in vitro, you are potentially shutting down IVF facility care. For clinics, as we’ve already seen beginning to happen, there are risks of handling human embryos that are very fragile biological entities. If the law treats them as children, then clinics rightly freak out about all that could happen to them during fertility treatments.

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Unfortunately, accidents happen in clinics: freezers malfunction, embryos get destroyed by accident. Sometimes they have to be tested, and the testing harms them.

Does treating embryos as children necessarily call into question clinics’ ability to provide IVF?

Even if there’s technically the possibility of continuing to provide IVF, under this framework of “embryos are children” … if you’re actually convinced that you’re treating children under the microscope, the risks are so huge that I don’t see how clinics will continue to function long-term.

What ethical and legal dilemmas do clinics face?

What is the extent and the nature of their liability if something happens to an embryo? Is it criminal liability? What part of the law would they be liable for?

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Now, in the current reality, couples can agree to the destruction of their embryos, they can donate them for research, they can allow genetic testing of those embryos. If this is a child that deserves independent protection, then what the couple wants becomes irrelevant.

If I owned a fertility clinic, I’d be very scared right now. If you treat embryos seriously as children, you cannot justify any level of risk. You cannot justify using them for training, for research. If we don’t allow genetic testing, we’re slowing down the quality of facility care, entire programs of research that are critical to biomedicine. The ripple effects are huge.

Could clinics be required to maintain all the frozen embryos they have in perpetuity?

Absolutely. If you don’t know what to do with them, other than implant in the uterus and start a pregnancy, then the obvious alternative under this ruling is to keep them frozen indefinitely, which costs hundreds of dollars a year. Currently, if parents abandon their embryos and stop paying the storage fee, clinics can destroy them after five years. But if that’s no longer an option, they will just accumulate and accumulate.

There are over a million frozen embryos in the U.S. today. And that number is growing all the time, because every time a woman undergoes a cycle, most often not all the embryos are used. So every cycle of IVF potentially leaves a few behind in a freezer. For clinics to carry that cost is a significant burden; IVF is already exceptionally expensive.

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If a frozen embryo is viewed as a child, could it be interpreted as having a right to be implanted and born?

Absolutely yes. Celine Dion famously said that her frozen embryos in New York are children waiting to be born. You know Sofia Vergara from “Modern Family”? Her ex named their frozen embryos and sued in their name — they were the plaintiffs — that they have a right to be born. He argued he can make that happen because he has created a trust in their name, he has a surrogate, he will father them, he will take responsibility; they will want for nothing. He said leaving them on ice is like murdering them.

The court in Louisiana dismissed the case on a technicality that the embryos were created in California. They didn’t say, “You’re being ridiculous!” So that line of thinking — that frozen embryos have a right to be implanted in order to be born — has already been tried in the U.S., and it wasn’t even refuted fully.

What is this, “The Handmaid’s Tale”? Catch women and impregnate them because [embryos] have a right to be born? Where do we stop?

So what’s the fate of the more than a million embryos stored in freezers?

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If state after state adopts this approach, then in those states, you will not be able to discard embryos or donate them for research or literally do anything with them, except seize them for reproduction. Will you be allowed to ship them to another state becomes the big question.

What does this ruling mean for patients in Alabama and other states with fetal personhood laws?

If I were in the middle of a cycle, and my eggs have not been retrieved yet, and I haven’t gone through fertilization, I’d be questioning whether I want to continue in Alabama. Because I wouldn’t know what I would be allowed to do with the embryos. If I had frozen embryos in Alabama, I would definitely look into shipping them to another state.

We have to remember that people going through IVF are very vulnerable. It’s a high-stress situation anyway, without the added layers of complexity and fear. At a medical level, such stress when you’re going through such an intricate process is definitely not in the best interest of patients.

As IVF clinics will shut down and move to other states, we’ll start seeing reproductive tourism within the U.S., just like we’re seeing with abortion. But the ethical problem with that is equity. Poor couples without resources will just not have access to IVF anymore.

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It’s been more than 45 years since the world’s first baby conceived by IVF was born in the U.K. What was the significance of that technological development, and what were the key discussions when IVF was developed?

At the time, they were called test-tube babies. That’s a term that we’ve luckily abandoned, because it implied that they’re artificial children. Some people saw the actual methods of fertilizing the egg outside the body as violating the sacred nature of the creation of life. The Catholic Church was and still is against this, because of the method of conception.

The other concern was, “Oh, these children will be stigmatized. They will not be like other children.” Beyond medical risks that we didn’t know about at the time, how will they be viewed by society? Now it’s so normalized. In some countries, 1 in 6 children is born from assisted reproduction.

Do you think this is a real turning point?

If you think globally, Catholic countries have grappled with the status of embryos for years. Germany, for example, does not allow the destruction of embryos, because the embryos are defined as a person in the Constitution. And that’s for the historical reason that they reject any kind of selection associated to life and will do anything to protect the dignity of human life. So this is new to the U.S., but it’s not new in the world.

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The shift has been from worrying about the technique, in itself, to worrying about who’s using it: gay couples using it, lesbian couples using it, single people using it with egg or sperm donation.

A married heterosexual couple using it to overcome infertility has become a nonissue. It became just medical care, no moral issues associated, other than: What do you do with your leftover frozen embryos that still remain?

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6 Great Space Images From February

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6 Great Space Images From February

Last fall, the Osiris-Rex spacecraft dropped off bits of an asteroid to scientists on Earth. After struggling to open the lid on the spacecraft’s container, scientists found that the mission had recovered more than a quarter pound of pristine space rock — the largest sample to date.

Erika Blumenfeld and Joseph Aebersold/NASA

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