As shots roll out to growing numbers of Americans, the political picture is getting more chaotic.Antonio de Luca/The New York TimesPresident Biden today called for governors to open coronavirus vaccinations to all adults within the next two weeks, speeding up a target he had previously set for May 1.But recent polls and political tides, particularly in red states, suggest that if the country is to reach herd immunity, simply making the vaccine available may not be enough. A sizable minority of skeptics remain wary of being vaccinated, polls suggest, with questions about the vaccine’s safety lying at the heart of their doubt.Dr. Anthony Fauci, the nation’s top infectious disease expert, has said the country shouldn’t expect to reach herd immunity — whereby a disease effectively stops traveling freely between infected people — until at least 75 percent of Americans are vaccinated.Some states and businesses are starting to treat proof of vaccination as a kind of passport. Many cruise ships, for instance, are requiring proof of vaccination for passengers, and Gov. Andrew Cuomo of New York last month announced the creation of Excelsior Pass, a way for state residents to easily show proof of vaccination using a smartphone. Proof of a shot is now required for entry into some large venues under New York’s current reopening guidelines.But the political picture is different elsewhere. Yesterday, Greg Abbott of Texas became the second Republican governor, after Ron DeSantis of Florida, to sign an executive order preventing companies from requiring their employees to be vaccinated.Fauci made it clear yesterday that he and the Biden administration were likely to stay out of it. “I doubt that the federal government will be the main mover of a vaccine passport concept,” he told the “Politico Dispatch” podcast. “They may be involved in making sure things are done fairly and equitably, but I doubt if the federal government is going to be the leading element of that.”But without a nudge, polls suggest that it could take a while to get the full country vaccinated.Nearly half of American adults reported that they gotten at least one dose of the vaccine, according to an Axios/Ipsos poll released today, but there is reason to believe that the rise in vaccinations may taper off soon. Among those who had not gotten a shot, people were more likely to say they would wait a year or longer (25 percent) than to say they’d get the vaccine within a few weeks of it being available (19 percent). Thirty-one percent of Republicans said they were not at all likely to get the shot. Partly driving that is deep-seated wariness among white evangelical Christians, a core part of the Republican base, whom polls have shown to be among the most vaccine-averse populations.A separate poll released today by the Kaiser Family Foundation and The Washington Post revealed that more than one-third of the country has little confidence that the Covid-19 vaccines have been “properly tested for safety and effectiveness.” Health care workers tracked evenly with the rest of the population in terms of vaccine skepticism: Thirty-six percent of them were not confident.When it comes to confidence, there’s no stronger measure than whether you’d give something to your child. Fauci has made clear that herd immunity won’t be possible without widespread vaccinations for young people, so any target for the country must include them as well. But nearly half of all parents polled by Axios/Ipsos said they probably wouldn’t be first in line to get their children a vaccine when it became available.Fifty-two percent of respondents with a child under 18 in the home said they would probably take advantage of the vaccine as soon as their kid’s age group was eligible, but 48 percent said they wouldn’t.But even as some vaccine skepticism lingers, Americans are reporting convening in far higher numbers. Fifty-five percent of the country said they had been in the company of family or friends in the past week, more than at any point in the past year. Forty-five percent said they had recently gone out to eat.Thirty-six percent said they hadn’t been practicing social distancing at all over the past week.New York Times PodcastsThe Ezra Klein Show: Did the boomers ruin America?On today’s episode, Ezra spoke with the conservative writer Helen Andrews and the liberal journalist Jill Filipovic about why millennials are so mad at their parents’ generation.Filipovic and Andrews, both of whom are millennials (as is Ezra), agree that the boomers left their generation worse off; but they disagree on just about everything else. They discussed the value of generational analysis, the legacy of the sexual revolution, the impact of boomer economic policies, the decline of the nuclear family, the so-called millennial sex recession, the millennial affordability crisis, the impact of pornography, how much the critique of the boomers is really a critique of technological change and much more.You can listen here, and read the transcript here.On Politics is also available as a newsletter. Sign up here to get it delivered to your inbox.Is there anything you think we’re missing? Anything you want to see more of? We’d love to hear from you. Email us at onpolitics@nytimes.com.

A devastating itching of the skin driven by severe liver disease turns out to have a surprising cause. Its discovery points toward possible new therapies for itching, and shows that the outer layer of the skin is so much more than insulation.
The finding, which appears April 2 in Gastroenterology, indicates that the keratinocyte cells of the skin surface are acting as what lead researcher Wolfgang Liedtke, MD PhD, calls ‘pre-neurons.’
“The skin cells themselves are sensory under certain conditions, specifically the outermost layer of cells, the keratinocytes,” said Liedtke, who is a professor of neurology at Duke School of Medicine.
This study on liver disease itching, done with colleagues in Mexico, Poland, Germany and Wake Forest University, is a continuation of Liedtke’s pursuit of understanding a calcium-permeable ion channel on the cell surface called TRPV4, which he discovered 20 years ago at Rockefeller University.
The TRPV4 channel plays a crucial role in many tissues, including the sensation of pain. It was known to exist in skin cells, but nobody knew why.
“The initial ideas were that it plays a role in how the skin is layered, and in skin barrier function,” Liedtke said. “But this current research is getting us into a more exciting territory of the skin actually moonlighting as a sensory organ.” Once a chemical signal of itching is received, keratinocytes relay the signal to nerve endings in the skin that belong to itch-sensing nerve cells in the dorsal root ganglion next to the spine.

A team led by scientists at the UNC School of Medicine identified a molecule called microRNA-29 as a powerful controller of brain maturation in mammals. Deleting microRNA-29 in mice caused problems very similar to those seen in autism, epilepsy, and other neurodevelopmental conditions.
The results, published in Cell Reports, illuminate an important process in the normal maturation of the brain and point to the possibility that disrupting this process could contribute to multiple human brain diseases.
“We think abnormalities in microRNA-29 activity are likely to be a common theme in neurodevelopmental disorders and even in ordinary behavioral differences in individuals,” said senior author Mohanish Deshmukh, PhD, professor in the UNC Department of Cell Biology & Physiology and member of the UNC Neuroscience Center. “Our work suggests that boosting levels of miR-29, perhaps even by delivering it directly, could lead to a therapeutic strategy for neurodevelopmental disorders such as autism.”
miR-29 and brain maturation
MicroRNAs are short stretches of ribonucleic acid inside cells that regulate gene expression. Each microRNA, or miR, can bind directly to an RNA transcript from certain other genes, preventing it from being translated into a protein. MiRNAs thus effectively serve as inhibitors of gene activity, and the typical microRNA regulates multiple genes in this way so that genetic information is not overexpressed. These essential regulators have been intensively researched only in the past two decades. Therefore, much remains to be discovered about their roles in health and disease.
Deshmukh and colleagues set out to find microRNAs involved in the maturation of the brain after birth, a phase that in humans includes approximately the first 20 years of life. When the scientists looked for microRNAs with more activity in the adult mouse brain than the young mouse brain, one set of miRNA stuck way out from the rest. Levels of the miR-29 family were 50 to 70 times higher in the adult mouse brains than in young mouse brains.

In a recent study published by the Journal of Pain, co-authored by Elizabeth Losin, assistant professor of psychology and director of the Social and Cultural Neuroscience lab at the University of Miami, researchers found that a patient’s pain responses may be perceived differently by others based on their gender.
According to “Gender biases in estimation of others’ pain,” when male and female patients expressed the same amount of pain, observers viewed female patients’ pain as less intense and more likely to benefit from psychotherapy versus medication as compared to men’s pain, exposing a significant patient gender bias that could lead to disparities in treatments.
The study consisted of two experiments. In the first, 50 participants were asked to view various videos of male and female patients who suffered from shoulder pain performing a series of range of motion exercises using their injured and uninjured shoulders. Researchers pulled the videos from a database that contains videos of actual shoulder injury patients, each experiencing a range of different degrees of pain. The database included patients’ self-reported level of discomfort when moving their shoulders.
According to Losin, the study likely provides results more applicable to patients in clinical settings compared to previous studies that used posed actors in their stimuli videos.
“One of the advantages of using these videos of patients who are actually experiencing pain from an injury is that we have the patients’ ratings of their own pain,” she explained. “We had a ground truth to work with, which we can’t have if it’s a stimulus with an actor pretending to be in pain.”
The patients’ facial expressions were also analyzed through the Facial Action Coding System (FACS) — a comprehensive, anatomically based system for describing all visually discernible facial movements. The researchers used these FACS values in a formula to provide an objective score of the intensity of the patients’ pain facial expressions. This provided a second ground truth for the researchers to use when analyzing the data.

Businesses and universities want fast, easy ways to see if students and customers are vaccinated, but conservative politicians have turned “vaccine passports” into a cultural flash point.WASHINGTON — Cathay Pacific airlines, convinced that digital proof of coronavirus vaccination will bring about the return of safe international travel, asked its pilots and crew to try out a new mobile app that showed their vaccination status on a recent flight from Hong Kong to Los Angeles.New York has rolled out “Excelsior Pass,” billed by the state as “a free, fast and secure way to present digital proof of Covid-19 vaccination” in case reopening sports and entertainment venues require proof of attendees’ status.And Walmart, the nation’s largest private employer, is offering electronic verification apps to patients vaccinated in its stores so they “can easily access their vaccine status as needed,” the company says.Around the country, businesses, schools and politicians are considering “vaccine passports” — digital proof of vaccination against the coronavirus — as a path to reviving the economy and getting Americans back to work and play. Businesses especially fear that too many customers will stay away unless they can be assured that the other patrons have been inoculated.But the idea is raising charged legal and ethical questions: Can businesses require employees or customers to provide proof — digital or otherwise — that they have been vaccinated when the coronavirus vaccine is ostensibly voluntary?Can schools require that students prove they have been injected with what is still officially an experimental prophylaxis the same way they require long-approved vaccines for measles and polio? And finally, can governments mandate vaccinations — or stand in the way of businesses or educational institutions that demand proof?Legal experts say the answer to all of these questions is generally yes, though in a society so divided, politicians are already girding for a fight. Government entities like school boards and the Army can require vaccinations for entry, service and travel — practices that flow from a 1905 Supreme Court ruling that said states could require residents to be vaccinated against smallpox or pay a fine.“A community has the right to protect itself against an epidemic of disease which threatens the safety of its members,” Justice John Marshal Harlan wrote in Jacobson v. Massachusetts, the 1905 case.Private companies, moreover, are free to refuse to employ or do business with whomever they want, subject to only a few exceptions, ones that do not include vaccination status. And states can probably override that freedom by enacting a law barring discrimination based on vaccination status.But as the nation struggles to emerge from the worst public health crisis in a century, the arrival of digital vaccine verification apps — a modern version of the World Health Organization’s “yellow card” that provides international proof of yellow fever vaccination — has generated intense debate over whether proof of vaccination can be required at all.On Tuesday, Gov. Greg Abbott of Texas became the latest Republican governor to issue an executive order barring state agencies and private entities receiving funds from the state from requiring proof of vaccination. The World Health Organization, citing equity concerns, also said on Tuesday that it currently did not support mandatory proof of vaccination for international travel.Others are moving forward. Universities like Rutgers, Brown and Cornell have already said they will require proof of vaccination for students this fall. The Miami Heat this week became the first team in the N.B.A. to open special “vaccinated only” sections.And though businesses have yet to announce outright bans on unvaccinated clientele, some states and technology firms are preparing: At least 17 companies or nonprofits are developing websites or apps that might be used by sporting venues, restaurants and other businesses seeking to keep their customers and employees safe, according to Joel White, the executive director of the Health Innovation Alliance, a broad coalition of health providers, tech companies, employers and insurers.Airlines including JetBlue and United are also testing the “CommonPass” app, developed by The Commons Project, a nonprofit trust dedicated to using technology to help people control their personal information. Airlines for America, the trade group for the nation’s major carriers, opposes making proof of vaccination mandatory for air travel but would like a clean, easy way for travelers to show their status. Other countries may require proof of vaccination, and the apps can also be used to prove negative coronavirus test results, which the United States requires for international travelers.“On the face of things, requiring proof of vaccination seems a lot like, ‘No shoes, no shirt, no service,’” said Mark Tushnet, a law professor at Harvard.The Centers for Disease Control and Prevention already provides everyone who is vaccinated a card that can serve as proof, and people can always carry paper records of negative coronavirus tests. But industry leaders liken digital vaccination apps to security screening services like TSA PreCheck; it is not required, but it might make the travel experience smoother.In Israel, a “Green Pass” is already in place that allows vaccinated citizens to go to restaurants, concerts and sporting events.Backers of digital vaccination cards are pressing the Biden administration to become involved, at least by setting standards for privacy and for verifying the accuracy of the records.The White House is clearly skittish.“The government is not now nor will we be supporting a system that requires Americans to carry a credential,” Jen Psaki, the White House press secretary, said on Tuesday. “There will be no federal vaccinations database and no federal mandate requiring everyone to obtain a single vaccination credential.”She promised that the administration would provide some form of guidance — most likely in the form of questions and answers — about privacy, security, discrimination and concerns.Last week, the chief technology officer of the Department of Health and Human Services held a conference call with state and local health officials, who are mystified by the administration’s reticence.“It’s going to be necessary to have this, and there is going to have to be some kind of system where it’s verified,” said Dr. Marcus Plescia, the chief medical officer of the Association of State and Territorial Health Officials. “I think everybody in our network is a little bit perplexed by the way the federal government seems to be at arm’s-length with this.”A man presenting his “Green Pass” vaccination certificate before entering a coffee shop last month in Tel Aviv.Amir Levy/Getty ImagesOne arm of the government has offered some help: The Equal Employment Opportunity Commission has told employers that they can mandate coronavirus vaccination because public health comes first. But if an employee cannot get vaccinated because of a disability or a sincerely held religious belief, and the company cannot make an accommodation, the agency said, “then it would be lawful for the employer to exclude the employee from the workplace.”Conservatives and libertarians, though, are resisting such mandates. Gov. Ron DeSantis of Florida on Friday signed an executive order barring businesses from requiring patrons or customers to show vaccine documentation, under penalty of losing state contracts. Mississippi’s Republican governor, Tate Reeves, said on Sunday that he too opposed the idea.That has left technology executives like Stanley Campbell in the lurch. His firm, EagleForce, which specializes in health records, has created “myVax,” a digital platform that, he said, might even be used by farmers to screen their workers. Mr. Campbell, a Florida native, pitched the idea to Florida’s agriculture commissioner last week — a day before Mr. DeSantis issued his ban.“It’s not really a political football, which is what they keep using this thing as,” said Mr. Campbell, whose wife, Cheryl Campbell, who is also a health care technology expert and who recently joined the Biden administration. “It’s sad because Florida could lead the nation in this if we just took a minute to talk and think it through.”Mr. DeSantis’s order has already altered the back-to-school plans for Nova Southeastern University, based in Fort Lauderdale, which had announced a policy for returning students to be vaccinated. The university’s president and chief executive officer, George Hanbury, said the university was reviewing the order and planned to follow it.“We’re not trying to do anything but protect our students,” he said.Republican critics say vaccine passports raise the specter of centralized databases of vaccinated people, which they view as a government intrusion on privacy.“A vaccine passport—a unified, centralized system for providing or denying access to everyday activities like shopping and dining—would be a nightmare for civil liberties and privacy,” Justin Amash, a former Republican congressman who is now a libertarian, wrote on Twitter last week.But, in fact, every state already has a database, or an “immunization registry.” And under “data use agreements,” the states are required to share their registries with the C.D.C., though the agency de-identifies the information and not all states have agreed to provide it.And digital vaccine cards are not new. STChealth, an Arizona-based health care technology company, created an app called MyIR — my immunization record — about five years ago with the idea of helping parents who need their children’s vaccination records for school or camp. The app, which is free, connects with the immunization registries of five states and can verify vaccination data for those states’ residents.“We never built it as a digital passport kind of thing because that wasn’t an issue at the time,” the company’s chief executive officer, Mike Popovich, said in an interview. “But here in Arizona, I got my Covid shot and four hours later, I could use that to take a look at my record that had been reported to the state information system — and there it was.”With apps already proliferating, the Health Innovation Alliance sent a letter last month to Jeffrey D. Zients, the White House coronavirus response coordinator, calling on the administration to set standards. Mr. White, the organization’s executive director, said the group had not gotten an answer.He said he understood his fellow Republicans’ concerns, but disagreed.“We live in a free society where people are free to work or not, to go to concerts or not, to go to restaurants or not,” Mr. White said. “And when you are dealing with a highly infectious disease that is transmissible particularly in closed spaces — and that can kill you — it is not unreasonable for businesses in a free society to protect their employees and protect their patrons by asking people if they have been vaccinated.”

Cells from individuals with Major Depressive Disorder (MDD) were found to have higher than expected rates of methylation at specific sites on their DNA, when compared to cells from healthy individuals without MDD, according to a study by a multidisciplinary team of UC San Francisco scientists, in collaboration with others. Methylation is a process by which DNA is chemically modified at specific sites, resulting in changes in the expression of certain genes. Methylation of particular sets of genes, called “DNA methylation clocks,” typically change in predictable ways as people age, but the rate of these changes varies between people. Methylation patterns in individuals with MDD suggested that their cellular age was, on average, accelerated relative to matched healthy controls.
In the study, published April 6, 2021 in Translational Psychiatry, blood samples from individuals with MDD were analyzed for methylation patterns using the ‘GrimAge’ clock — a mathematical algorithm designed to predict an individual’s remaining lifespan based on cellular methylation patterns. Individuals with MDD showed a significantly higher GrimAge score, suggesting increased mortality risk, compared to healthy individuals of the same chronological age — an average of approximately two years on the GrimAge clock.
The individuals with MDD showed no outward signs of age-related pathology, as they and the healthy controls were screened for physical health before entry into the study. The methylation patterns associated with mortality risk persisted even after accounting for lifestyle factors like smoking and BMI. These findings provide new insight into the increased mortality and morbidity associated with the condition, suggesting that there is an underlying biological mechanism accelerating cellular aging in some MDD sufferers.
“This is shifting the way we understand depression, from a purely mental or psychiatric disease, limited to processes in the brain, to a whole-body disease,” said Katerina Protsenko, a medical student at UCSF and lead author of the study. “This should fundamentally alter the way we approach depression and how we think about it — as a part of overall health.”
MDD is one of the most prevalent health concerns globally. According to the World health Organization, some 300 million people (4.4% of the population) suffer from some form of depression. MDD is associated with higher incidence and mortality related to increased rates of cardiovascular disease, diabetes, and Alzheimer’s disease among sufferers.
“One of the things that’s remarkable about depression is that sufferers have unexpectedly higher rates of age-related physical illnesses and early mortality, even after accounting for things like suicide and lifestyle habits,” said Owen Wolkowitz, MD, professor of psychiatry and a member of UCSF’s Weill Institute for Neurosciences, co-senior author of the study. “That’s always been a mystery, and that’s what led us to look for signs of aging at the cellular level.”
The researchers collected blood samples from 49 individuals with MDD who were unmedicated prior to the study and 60 healthy control subjects of the same chronological age. They analyzed the methylation rates of both groups using the GrimAge clock. While there are numerous methylation-based longevity algorithms, GrimAge is the only one based specifically on methylation patterns associated with mortality.
The researchers say that they don’t yet know if depression causes altered methylation in certain individuals, or if depression and methylation are both related to another underlying factor. It is possible that some individuals may have a genetic predisposition to produce specific methylation patterns in response to stressors, but this has not been well-studied. Alterations in methylation patterns have previously been observed in individuals with Post-Traumatic Stress Disorder.
Moving forward, the researchers hope to determine whether pharmacological treatments or therapy may mitigate some methylation changes related to MDD in hopes of normalizing the cellular aging process in affected individuals before it advances. Although the GrimAge methylation clock has been associated with mortality in other populations, no studies have yet determined whether this methylation pattern also predicts mortality in MDD.
“As we continue our studies, we hope to find out whether addressing the MDD with anti-depressants or other treatments alters the methylation patterns, which would give us some indication that these patterns are dynamic and can be changed,” said Synthia Mellon, PhD, professor in the Department of Ob/Gyn & Reproductive Sciences at UCSF and co-senior author of the study.
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Materials provided by University of California – San Francisco. Original written by Alan Toth. Note: Content may be edited for style and length.

The Baltimore plant that recently had to scrap up to 15 million ruined doses had flouted rules and downplayed errors, according to internal audits, ex-employees and clients. Other doses had to be scrapped last year.WASHINGTON — More than eight years ago, the federal government invested in an insurance policy against vaccine shortages during a pandemic. It paid Emergent BioSolutions, a Maryland biotech firm known for producing anthrax vaccines, to have a factory in Baltimore always at the ready.When the coronavirus pandemic arrived, the factory became the main U.S. location for manufacturing Covid-19 vaccines developed by Johnson & Johnson and AstraZeneca, churning out about 150 million doses as of last week.But so far not a single dose has been usable because regulators have not yet certified the factory to allow the vaccines to be distributed to the public. Last week, Emergent said it would destroy up to 15 million doses’ worth of the Johnson & Johnson vaccine after contamination with the AstraZeneca vaccine was discovered.Emergent and government health officials have long touted their partnership as a success, but an examination by The New York Times of manufacturing practices at the Baltimore facility found serious problems, including a corporate culture that often ignored or deflected missteps and a government sponsor, the Biomedical Advanced Research and Development Authority, that acted more as a partner than a policeman. Previously undisclosed internal documents and interviews with current and former federal officials and former company employees depict a factory operation that was ill-equipped to take on such a mammoth manufacturing task, despite Emergent’s having received a $163 million federal contract to improve the facility and prepare it for high-volume production.The loss of the Johnson & Johnson doses was not the first time the company threw out coronavirus vaccine for fear of contamination. Between early October and January, Emergent discarded five lots of AstraZeneca vaccine — each the equivalent of two million to three million doses — because of contamination or suspected contamination, according to internal logs, a government official and a former company supervisor.Audits and investigations — including ones conducted in 2020 by Johnson & Johnson, AstraZeneca, two federal agencies and Emergent’s own quality evaluators — found that Emergent had not followed some basic industry standards at the Baltimore plant, and identified repeated shortcomings in efforts to disinfect and prevent contamination.While audits always find problems, federal officials and outside experts said that the pattern of lapses suggested deeper quality issues.“These are the fundamental steps,” said Dr. Ajaz Hussain, a pharmaceutical quality expert who oversaw efforts by the Food and Drug Administration to ensure quality in drug development and manufacturing from 2000 to 2005. “If you are making mistakes or errors in the fundamentals, what else is wrong with your system? That would be my question.”An audit conducted for AstraZeneca specifically highlighted the risks of viral cross-contamination, which experts believe was responsible for tainting the millions of Johnson & Johnson doses, according to a review of the confidential document by The Times. The audits and investigations also flagged a persistent problem with mold in areas required to be kept clean, poor disinfection of some plant equipment leading to growth of bacteria, the repeated approval of raw materials that had not been fully tested, and inadequate training of some employees. A lab at the Baltimore facility, where both internal and external audits have identified problems.Jerry Jackson/Baltimore Sun MediaIn their own audit last July, Emergent’s auditors said errors “are not investigated to determine root cause, or are not investigated adequately,” a report stated. “Investigations are terminated without sufficient cause.”In one example, the Emergent auditors said mold had been repeatedly discovered in the room where cell cultures were grown. Mold can be serious if airborne spores contaminate the vaccine substance. Emergent workers conducted “essentially no investigation” beyond checking the wheels of one cart for mold, and wrongly classified the incident as minor, the audit said.While the Baltimore plant remains under scrutiny, another 62 million doses of the Johnson & Johnson vaccine made there are in jeopardy until it can be determined whether they were also contaminated. Over the weekend, Johnson & Johnson assumed responsibility for the manufacturing at the direction of the Biden administration, which also limited future production to only the Johnson & Johnson vaccine.Because other manufacturers are now churning out so many Covid-19 vaccine doses, it does not appear that the disruptions in Baltimore will upend the Biden administration’s expedited timetable for vaccine supplies and availability. But health experts worry the revelations could heighten safety concerns and make some people more wary about getting shots.Emergent is a longtime government contractor that has spent much of the last two decades cornering a lucrative market in federal spending on biodefense. The Times reported last month that sales of its anthrax vaccines to the Strategic National Stockpile accounted for nearly half of the stockpile’s half-billion-dollar annual budget throughout most of the last decade, leaving the federal government with less money to buy supplies needed in a pandemic.In response to questions about the Baltimore plant, an Emergent spokesman, Matt Hartwig, said in a statement that the company had been cooperating with the federal government “to address issues” and “resolve them in support of the federal Covid response.” He said the company had “a proven track record as a world-class provider of both bulk drug substances and sterile injectable drug products” and that it had “rigorous safety, quality and compliance programs, which include programs, policies, and processes that allow early identification of issues and means to address them.”He added, “Any allegation that our safety, quality and compliance systems are not working or that we do not take these responsibilities seriously is false.”But four former company officials, speaking on the condition of anonymity because they had signed nondisclosure agreements or feared retaliation, described an environment where top Emergent leadership tolerated and even encouraged the flouting of federal standards for manufacturing and marketing products.One of the former officials said that as the company scrambled to meet the heavy demands of vaccine production, a senior manufacturing supervisor often responded to reports of quality errors by asking: “Do you want me to make drugs or fix issues? I don’t have time to do both.”Even before the Covid-19 vaccine production began, there were concerns about Emergent’s ability to deliver on its contract with the government, The Times found. As a test of Emergent’s readiness, the original contract required the company to demonstrate that it could rapidly produce 50 million doses of a pandemic influenza vaccine, but Emergent hadn’t done so by the original deadline last June.“This was the way that you demonstrate you’re surge-ready,” said Dr. Nicole Lurie, who until 2017 oversaw the office that awarded Emergent the 2012 contract. Not meeting that requirement after eight years, she said, “would have been of huge concern to me.”In the end, as the coronavirus swept across the country, federal officials said they had little choice but to turn to Emergent because few companies based in the United States were able to make the type of vaccines developed by Johnson & Johnson and AstraZeneca.Dr. Robert Kadlec, who was with the Department of Health and Human Services under the Trump administration, appearing last March with members of the coronavirus task force.Anna Moneymaker/The New York Times“There weren’t a lot of alternatives,” said Dr. Robert Kadlec, who oversaw the agency that awarded the manufacturing contract under the Trump administration. “We even looked at veterinary vaccine facilities around the country. We couldn’t find the capacity.”Most large pharmaceutical companies have spurned this work because of the relatively small payouts and the hassle of government contracting. Emergent, by contrast, has deployed a well-funded lobbying apparatus and a web of Washington connections to build its business around preparations for potential bioweapon attacks and infectious disease outbreaks.Emergent’s stock has suffered in the last week, closing Monday just under $79, down from $94 before news broke that the doses had been ruined. Still, the Covid-19 work has been lucrative for the company.In all, Emergent’s Covid-19 manufacturing deals are worth up to $1.5 billion, according to company presentations and calls with investors. Profitability for 2020 was “off-the-chart successful,” the company’s chief executive, Robert Kramer, boasted to investors in March.The Last One StandingThe government’s investment in Emergent’s Baltimore facility was rooted in a lesson from the last pandemic, the 2009 H1N1 influenza outbreak that claimed an estimated 12,000 lives in the United States.A government report the next year noted that the nation had developed vaccines for the novel pathogen “in record time,” but that “the vaccines were not broadly available before the virus had spread widely among the U.S. population.”To ensure that didn’t happen again, the report determined, the federal government should partner with companies and universities to expand and sustain domestic manufacturing sites.Barda/Department of Health and Human ServicesIn 2012, the Department of Health and Human Services awarded three contracts, including one to Emergent to retrofit and expand its Baltimore site. And between 2015 and 2019, the government placed a handful of relatively small orders for doses of treatments and vaccines being developed for use against viruses including Ebola and Zika.The contract also required Emergent to stand ready to produce up to 50 million doses of vaccine within four months in the event of an influenza pandemic. To show that it was up to the task, Emergent was supposed to work with a company developing a flu vaccine candidate and seek F.D.A. approval to manufacture it by June 2020.As the deadline neared, however, Emergent still had not met the requirement. The vaccine candidate of its chosen partner company had failed in clinical trials, and Emergent had not found a replacement. “Emergent does not have a candidate, strategy or plan for fulfilling the flu requirement,” according to a government document in June 2019. “Emergent needs to make this a priority so they are not in default.”By then, the government had scaled back its partnership with Emergent, shortening its maximum possible duration to 15 years from 25 years.Dr. Kadlec, who ran the office overseeing the contract, said he commissioned a review of the government partnerships, including the one with Emergent, that concluded in 2019 that their ability to deliver in a pandemic remained largely unproven.“What I perceived is that we did not pressure-test those systems on a regular basis to see what they could do,” said Dr. Kadlec, who had previously worked as a consultant for Emergent. “The military term is ‘live fire.’”When the June 2020 deadline arrived, Emergent hadn’t met the flu requirement, but the government nevertheless awarded it a $628 million contract to manufacture Covid-19 vaccines.By then, only two of the three government-funded centers remained, and Emergent’s was the only one with the ability to make the type of vaccines being developed by Johnson & Johnson and AstraZeneca. Justifying an exception to normal contracting requirements, the government said it needed to act fast.“Discussions with Emergent have revealed that they are in discussions with multiple vaccine developers interested in reserving the capacity” at the Baltimore plant, according to a government contracting document. Should that happen, it added, the government “would not be in a position to manufacture vaccines in a relevant time frame” to meet the Trump administration’s goal of 300 million vaccine doses.Dr. Kadlec said he knew it was a risky decision.“It’s like trying to take the finest champagne in France and recreate it in parts of the United States,” he said. “You could bring the grapes over, but it’s a science and an art.”A majority of the contract — more than a half-billion dollars — was allocated for monthly fees to reserve manufacturing space at Emergent’s facilities. Emergent’s chief financial officer acknowledged during a July call with Wall Street analysts that for the company, there were “minimal costs associated with the reservation piece itself,” and executives have since cited the reservation fees during investor calls as one reason for an increase in Emergent’s gross profit margins.Emergent’s C.E.O., Robert Kramer, told investors that profitability for 2020 was “off-the-chart successful.”AWNewYork/Shutterstock Mr. Hartwig, the Emergent spokesman, said the government funding “reserved manufacturing capacity and allowed Emergent to acquire the equipment and hire the work force necessary to support vaccine production on a scale of one billion doses annually.”The government later extended the flu vaccine deadline under the original contract. A spokeswoman for the agency administering the deal, the Biomedical Advanced Research and Development Authority, or BARDA, said Emergent’s Covid-19 work “is meeting” the original contract’s “intent.”Meanwhile, the company struck separate deals with Johnson & Johnson and AstraZeneca worth roughly another $875 million. In a July conference call with investors, Emergent announced that it was tripling its projected contract manufacturing revenue for the year.“Emergent is uniquely prepared to answer the call for Covid-19 pandemic,” Mr. Kramer told investors.A Pattern of LapsesIn the days that followed, investors flocked to Emergent’s stock, pushing it to a record high. But out of public view, internal monitors and auditors from the company’s new partners, Johnson & Johnson and AstraZeneca, were finding the Baltimore factory’s procedures deficient, especially in disinfecting the plant and preventing contamination.Internal logs show that Emergent had to toss out one batch of AstraZeneca’s vaccine in early October because of suspected contamination, and four more in December. Those four were spoiled by bacterial contamination of equipment, a former company official said.In November, production of a batch of Johnson & Johnson vaccine was discarded after workers “hooked up” the wrong gas line and accidentally “suffocated” the cells where the virus for the vaccine is grown, the logs show. The next month, the records indicate, workers making AstraZeneca’s vaccine deviated from manufacturing standards on average more than three times a day. About one-fifth of the deviations were classified as major.Because of the pandemic, most of the auditors drew their conclusions from documents and video tours, during which Emergent workers controlled the camera angles, one former company official said.Johnson & Johnson’s auditors said monitoring reports for bacteria or other contaminants were filed four to six months late. AstraZeneca’s said that Emergent repeatedly loosened monitoring criteria so it appeared to meet them, resorting to measures like “historical averages.” But even then it failed the tests, the report said.In another audit, BARDA officials documented similar concerns, classifying some of them, including the risks of microbiological contamination, as “critical.” That designation is reserved for the most serious problems that pose an immediate and significant risk.Emergent’s own internal audit in July also said the flow of workers and materials through the plant was not adequately controlled “to prevent mix-ups or contamination.” The reports echoed quality-control shortcomings documented in an April inspection by the F.D.A., reported earlier by The Associated Press, that concluded the facility was “not ready for commercial operations.” Multiple audits underscore how poorly the company was prepared for the huge workload it accepted. The Covid-19 projects required significantly more testing to ensure materials remained stable, but Emergent had just one employee coordinating it all, the BARDA audit found. Emergent acknowledged at the time that its testing system was “not ideal” and pledged to train at least one more Emergent worker and hire a third. BARDA did not respond to requests for comment on its audit or any of the others, beyond saying that it had “worked with Emergent to resolve the issues” raised during the F.D.A. inspection.Another internal investigation in August found that Emergent approved four raw materials used to produce AstraZeneca’s vaccine without first fully testing them. That type of shortcut, called a conditional release of material, occurred on average twice a week in October, internal logs show. The measure was deemed necessary because the company was working with shortened production times, testing backlogs and the needs of Operation Warp Speed, the Trump administration’s crash vaccine development program. And while a manager “knowingly deviated” from standards, the report said, the batches of vaccine would be not released without quality and safety tests.Mr. Kramer, right, giving a tour at the lab in Baltimore where Emergent makes Covid-19 vaccines.Joe Andrucyk/Office of Governor Larry HoganPlant supervisors often cited pressures from Operation Warp Speed as a justification for glossing over violations of manufacturing guidelines, according to one former company official. But even before Emergent launched into Covid-19 vaccine production, a major client charged that the firm was too complacent about mistakes.A New Jersey-based company called Soligenix had hired Emergent to produce its experimental vaccine against ricin, a toxin, for use in clinical trials. But shortly after the trial began in December 2019, Emergent informed Soligenix that it had failed to properly test the vaccine before releasing it, according to Soligenix’s filing with the Securities and Exchange Commission, which was reported earlier by The Washington Post.By then, two volunteers had already received doses, the filing stated.Forced to suspend the trial, Soligenix is now seeking $19 million in damages from Emergent, which has denied negligence or deliberate wrongdoing.In a follow-up audit in February 2020, Soligenix auditors said “the primary driver” of the mistake was that Emergent had fostered “a culture where written instructions are regularly not followed with no consequences.”62 Million Doses in the BalanceShortly before 6:20 p.m. on March 25, an urgent email landed in the inboxes of top officials at the Department of Health and Human Services. “Developing Situation _ Emergent Bayview,” the subject line read.What followed was even more alarming: “Viral cross-contamination confirmed in the control cells for JANSSEN GMP Lot #8.”The message, referring to the Johnson & Johnson vaccine production at Emergent’s Baltimore factory, set off a series of hurried nighttime telephone calls, according to officials familiar with the situation.The Johnson & Johnson and AstraZeneca vaccines use the same technology: A harmless version of a virus — known as a viral vector — is transmitted into cells to make a protein that stimulates the immune system to produce antibodies.Sometime in February, Emergent workers had unknowingly contaminated Johnson & Johnson’s viral vector with AstraZeneca’s. The error was not discovered for weeks, until, in one of the final checks before release, Johnson & Johnson sampled a batch of 13 million to 15 million doses’ worth of vaccine for purity.In short order, top Biden administration health officials directed a hold on shipments from the Baltimore facility and instructed Johnson & Johnson executives to take charge of its operations. Days later, they quietly told AstraZeneca officials their vaccine would no longer be made at the Baltimore plant, to avoid a repeat of that error.At a Monday morning staff meeting at the plant, Emergent officials claimed the mistake was an isolated incident and the media had exaggerated its significance, according to a person briefed on the meeting. They urged workers to be proud of what the plant had accomplished in such a short time.But quality-control managers are now required to test anew every lot of Johnson & Johnson vaccine made at the plant — 62 million doses in all — to make sure they weren’t also contaminated. Another roughly 70 million doses of AstraZeneca’s may also need to be tested.F.D.A. inspectors are expected to intensely scrutinize the plant before certifying it to release doses to the public. It remains uncertain whether that would occur in time for Johnson & Johnson to deliver the 24 million doses it has promised to ship to the federal government this month.In the meantime, the Emergent factory faces a complex and costly makeover to devote itself solely to producing the Johnson & Johnson vaccine. Experts said it could take weeks to phase out production of AstraZeneca’s vaccine at the 112,000-square-foot plant and restart it somewhere else. Emergent announced on Monday that the government had awarded it another $23 million to help expand Johnson & Johnson’s production lines.The plant remains a risky bet for the government. While Johnson & Johnson is expected to roughly double the number of supervisors on-site, to about 12, the work force of hundreds is still Emergent’s. Some federal officials are privately concerned that the government is stuck in an unhappy marriage with Emergent and that Johnson & Johnson, whose manufacturing expertise is largely overseas, may not be able to salvage it.For President Biden, who has vowed to “always level with the American people,” the factory’s error — which was not known publicly until The Times reported it last week — is as much a public-relations problem as a supply problem.Emergent said last week that it would destroy millions of doses’ worth of the Johnson & Johnson vaccine after contamination with the AstraZeneca vaccine was discovered.Bryan Anselm for The New York TimesEven without any doses made by Emergent, administration officials say they will have enough vaccine by the end of May to cover as many as 240 million of the roughly 260 million American adults. That puts them on track to meet Mr. Biden’s goal of having enough for everyone who wants to be vaccinated.But the story of the ruined doses is also unfolding against the backdrop of a highly politicized public health crisis, just as the administration is trying to convince skeptics that Covid-19 vaccines are safe.“I want to emphasize the issue at the Baltimore plant did not impact any J&J doses that had been distributed, as all J&J finished doses to date were produced in a different, F.D.A.-approved facility,” Jeffrey D. Zients, the White House coronavirus response coordinator, told reporters last week.The Biden administration must also figure out how to rein in a company accustomed to getting its way with the government.After the administration announced Saturday that Johnson & Johnson would take control of the Covid-19 manufacturing from Emergent, the company issued its own statement Sunday night noting that it “continues to own and operate” the plant while also suggesting it welcomed “the additional oversight and support.”The Biden team was apparently displeased. Hours later, sometime past midnight, the statement was amended to acknowledge that Johnson & Johnson now has “final signoff of manufacturing” its vaccine at the Baltimore plant.Kitty Bennett

The founding chair of the Biomedical Engineering Department at the University of Houston is reporting a new deep neural network architecture that provides early diagnosis of systemic sclerosis (SSc), a rare autoimmune disease marked by hardened or fibrous skin and internal organs. The proposed network, implemented using a standard laptop computer (2.5 GHz Intel Core i7), can immediately differentiate between images of healthy skin and skin with systemic sclerosis.
“Our preliminary study, intended to show the efficacy of the proposed network architecture, holds promise in the characterization of SSc,” reports Metin Akay, John S. Dunn Endowed Chair Professor of biomedical engineering. The work is published in the IEEE Open Journal of Engineering in Medicine and Biology.
“We believe that the proposed network architecture could easily be implemented in a clinical setting, providing a simple, inexpensive and accurate screening tool for SSc.”
For patients with SSc, early diagnosis is critical, but often elusive. Several studies have shown that organ involvement could occur far earlier than expected in the early phase of the disease, but early diagnosis and determining the extent of disease progression pose significant challenge for physicians, even at expert centers, resulting in delays in therapy and management.
In artificial intelligence, deep learning organizes algorithms into layers (the artificial neural network) that can make its own intelligent decisions. To speed up the learning process, the new network was trained using the parameters of MobileNetV2, a mobile vision application, pre-trained on the ImageNet dataset with 1.4M images.
“By scanning the images, the network learns from the existing images and decides which new image is normal or in an early or late stage of disease,” said Akay.
Among several deep learning networks, Convolutional Neural Networks (CNNs) are most commonly used in engineering, medicine and biology, but their success in biomedical applications has been limited due to the size of the available training sets and networks.
To overcome these difficulties, Akay and partner Yasemin Akay combined the UNet, a modified CNN architecture, with added layers, and they developed a mobile training module. The results showed that the proposed deep learning architecture is superior and better than CNNs for classification of SSc images.
“After fine tuning, our results showed the proposed network reached 100% accuracy on the training image set, 96.8% accuracy on the validation image set, and 95.2% on the testing image set,” said Yasmin Akay, UH instructional associate professor of biomedical engineering.
The training time was less than five hours.
Joining Metin Akay and Yasemin Akay, the paper was co-authored by Yong Du, Cheryl Shersen, Ting Chen and Chandra Mohan, all of University of Houston; and Minghua Wu and Shervin Assassi of the University of Texas Health Science Center (UT Health).
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Materials provided by University of Houston. Original written by Laurie Fickman. Note: Content may be edited for style and length.

Since the discovery of leptin in the 1990s, researchers have wondered, how does leptin, a hormone made by body fat, suppress appetite? Despite tremendous gains in the intervening three decades, many questions still remain. Now, a new study in mice describes novel neurocircuitry between midbrain structures that control feeding behaviors that are under modulatory control by leptin.
John Krystal, MD, Editor of Biological Psychiatry, said of the findings, “Omrani and colleagues shed light on how, in non-obese animals, leptin puts the brakes on overeating.”
Leptin acts as a critical link between the body and the brain, providing information about metabolic state and exerting control over energy balance. The importance of leptin is illustrated by the finding that animals deficient for leptin rapidly become obese without its regulatory stop on feeding behavior.
Roger Adan, PhD, of the Department of Translational Neuroscience, University Medical Center Utrecht and University Utrecht, the Netherlands, who led the study, said, “This process is shaped by communication between bodily fat storages (via a hormone called leptin) and the brain’s dopamine reward system. This leptin-dopamine axis is critically important for body weight control, but its modes of action were not well understood.”
Leptin suppresses eating by signaling to brain regions that control eating behaviors, but it also decreases the reward value inherent in foods, engaging the brain’s dopamine (DA) reward system. That food-reward pathway was known to involve dopaminergic neurons of the ventral tegmental area (VTA) signaling to the nucleus accumbens (NAc), but most of those DA neurons do not contain receptors for leptin.
The work used a combination of powerful technologies, including optogenetics, chemogenetics and electrophysiology to map the new microcircuitry.
“Although leptin receptors are present on [some] dopamine neurons that signal food reward,” said Professor Adan, also of the Department of Translational Neuroscience, University Medical Center Utrecht and University Utrecht, “we discovered that leptin receptors are also present on inhibitory neurons that more strongly regulate the activity of dopamine neurons. Some of these inhibitory neurons suppressed food seeking when [animals were] hungry, whereas others [did so] only when [animals were] in a sated state.”
Dr. Krystal said of the study, “It turns out that leptin plays key modulatory roles in an elegant circuit that unites midbrain and limbic reward circuitry. By inhibiting hypothalamic neurons and ultimately suppressing the activity of dopamine neurons in the midbrain that signal reward and promote feeding, leptin reduces food intake in animals under conditions when caloric intake has exceeded energy use.”
Ultimately, Professor Adan said, “Targeting these neurons may provide a new avenue for the treatment of anorexia nervosa and to support dieting in people with obesity.”
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Materials provided by Elsevier. Note: Content may be edited for style and length.

Researchers have uncovered pathways involved in the body’s response to glucocorticoid treatments and identified a novel biomarker that could be used to monitor how these drugs work in patients, according to a clinical study published today in eLife.
A more reliable indicator of an individual’s response to glucocorticoid drugs could be used to develop a clinically applicable test that could help tailor treatments and potentially minimise side-effects.
Glucocorticoids, such as cortisol, are a type of hormone with key roles in the body’s response to stress. Glucocorticoid drugs are one of the most commonly prescribed treatments for a range of conditions, including for patients whose adrenal glands are unable to produce enough cortisol. The effects of glucocorticoids are complex, meaning the level of cortisol in the blood does not reliably reflect what is happening in the tissues. This makes it hard for medical professionals to know how to tailor treatments.
“Side effects of glucocorticoid treatments are common in patients, indicating that current methods to monitor their action, which typically focus on clinical response or disease activity, are inadequate,” explains first author Dimitrios Chantzichristos, Head Physician at the Section for Endocrinology-Diabetes-Metabolism, Sahlgrenska University Hospital, Sweden. “We wanted to find some kind of biomarker that could be measured to monitor the action of glucocorticoids in individuals, with the hopes this will help clinicians understand how best to treat patients.”
The team studied patients with Addison’s disease who lack the ability to produce their own cortisol. This allowed them to compare the activity in the tissues of the same patient both when their cortisol levels were low and when they were being restored by glucocorticoid treatments, helping account for variations between individuals.
Rather than focusing only on the metabolic products associated with glucocorticoid exposure, they also looked at gene expression and microRNAs in the patients using new computational approaches developed in collaboration with Dr Adam Stevens at the University of Manchester, UK. MicroRNAs are short strands of ribonucleic acid (RNA) that can regulate the expression of genes by interfering with protein production. The team analysed these different factors in blood cells and body fat, an important metabolic tissue, as the patients’ cortisol levels were changed, revealing close relationships between different elements involved in glucocorticoid action.
Among the elements they identified, a microRNA called miR-122-5p closely correlated with genes and metabolites that are regulated by the glucocorticoid treatments. To test this correlation, the team looked at miR-122-5p levels in blood from patients exposed to different levels of glucocorticoids from three independent studies and found the same pattern, supporting the idea that this microRNA could be a useful biomarker of glucocorticoid action.
“This potential biomarker can now be investigated in larger groups of patients with the aim to develop a clinically applicable test,” concludes senior author Gudmundur Johannsson, Professor at the Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Sweden. “Our work has also increased our understanding of the action of glucocorticoids, which may help uncover their role in many common diseases such as diabetes, obesity and cardiovascular diseases.”
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Materials provided by eLife. Note: Content may be edited for style and length.