Research has found that obesity and mental disorders such as depression and anxiety seem to often go hand in hand. Researchers at Baylor College of Medicine and collaborating institutions are providing new insights into this association by identifying and characterizing a novel neural circuit that mediates the reciprocal control of feeding and psychological states in mouse models.
Similar to human patients, mice that consumed a high-fat diet not only became obese, but also anxious and depressed, a condition mediated by a defective brain circuit. When the researchers genetically or pharmacologically corrected specific disruptions they had observed within this circuit, the mice became less anxious and depressed and later lost excess body weight.
Interestingly, weight loss was not the result of lack of appetite, but of the animals’ change of food preference. Before the treatment, the mice naturally preferred to eat a high-fat diet, but after the treatment they turned their preference toward a healthier diet with reduced fat and abundant protein and carbohydrates. The findings, published in the journal Molecular Psychiatry, for the first time, not only reveal a key regulatory mechanism for coinciding obesity and mental disorders, but also suggest the possibility of a pharmacological treatment.
“Reports indicate that 43% of adults with depression are obese and that adults with mental illness are more likely to develop obesity than those who are mentally healthy,” said corresponding author Dr. Qi Wu, a Pew Scholar for Biomedical Sciences, Kavli Scholar and assistant professor in pediatrics-nutrition at Baylor’s Children’s Nutrition Research Center. “Factors such as hormonal dysregulation, genetic deficiency and inflammation have been proposed to be involved in the connection between obesity and mental disorders. Here we provide evidence that supports the involvement of a neural component.” To investigate the neuronal circuits that could be involved in reciprocally regulating weight gain and depression or anxiety, the researchers provided mice with a high-fat diet. As expected, the animals became obese. They also developed anxiety and depression. In these mice, the team studied the function of neuronal circuits.
“We discovered in normal mice that two groups of brain cells, dBNST and AgRP neurons located in separate brain areas, form a circuit or connection to each other by extending cellular projections,” said co-first author Dr. Guobin Xia, postdoctoral associate in the Wu lab. “This newly discovered circuit was malfunctioning in mice that were both obese and depressed.”
“Using genetic approaches, we identified specific genes and other mediators that were altered and mediated the circuit’s malfunction in the obese and depressed mice,” said co-first author Dr. Yong Han, postdoctoral associate in the Wu lab.
“Importantly, genetically restoring the neural defects to normal eliminated the high fat diet-induced anxiety and depression and also reduced body weight,” Xia said. “We were surprised to see that the animals lost weight, not because they lost their appetite, but because genetically-aided readjustment of the mental states changed their feeding preference from high-fat to low-fat food.”
“Keeping in mind translational applications of our findings to the clinic, we investigated the possibility of restoring the novel circuit pharmacologically,” Wu said. “We discovered that the combination of two clinically-approved drugs, zonisamide and granisetron, profoundly reduced anxiety and depression in mice and promoted weight loss by synergistically acting upon two different molecular targets within our newly identified brain circuit. We consider that our results provide convincing support for further studies and future clinical trials testing the value of a cocktail therapy combining zonisamide and granisetron (or a selection of their derivatives) to treat metabolic-psychiatric diseases.”
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Materials provided by Baylor College of Medicine. Original written by Homa Shalchi. Note: Content may be edited for style and length.

When Laura Drager contracted Covid-19 in July, it was as though someone had suddenly muted her olfactory system.One morning she was sipping her favorite Gatorade (the yellow one), and two hours later the drink was completely flavorless. She immediately lit a candle and blew it out, but she couldn’t smell the smoke.Her sense of smell had disappeared. Now, she said, “everything either tastes like bleach or tastes like nothing.”Over the past few months she has lost 19 pounds. “I don’t have that ‘I’m hungry’ feeling,” said Ms. Drager, 41, who lives in Sevierville, Tenn., about 45 minutes from Knoxville. “I think you forget how much smell and taste is a part of your life until it goes away.”As the coronavirus continues to spread, there are increasing numbers of people who have either lost their senses of smell after contracting Covid or are struggling with parosmia, a disturbing disorder that causes previously normal odors to develop a new, often unpleasant aroma.One meta-analysis published in September found that as many as 77 percent of those who had Covid were estimated to have some form of smell loss as a result of their infections.The recommended treatment for these conditions is smell training. But how exactly do you do it, and why should you bother?We spoke with several experts to demystify the process.What is smell training?First, let’s talk about what smell training is not. If the words conjure up images of a “Rocky” training montage — as they did for Tejal Rao, a New York Times restaurant critic who lost her sense of smell after contracting Covid last year — the reality is very different. Smell training is more akin to physical therapy for your nose: tedious and repetitive. It involves sniffing several potent scents twice a day, sometimes for months, to stimulate and restore the olfactory system — or at the very least to help it function better.“It’s not a quick fix,” said Chrissi Kelly, a member of the Global Consortium for Chemosensory Research and the founder of AbScent, a nonprofit based in England and Wales that offers support and education to people around the world who have smell disorders. “You have to keep up with it.”If it has been a couple of weeks since you lost your sense of smell and it hasn’t started to come back, then it makes sense to start smell training. When your smell starts to come back, it might happen gradually rather than all at once. At first, scents might seem distorted or foul.Scientists are still learning about all of the mechanisms by which the coronavirus affects the olfactory system, but they believe parosmia occurs because the neural pathways from the nose to the brain have been disrupted, “kind of like a telephone operator from the 1950s connecting the wrong party to another line,” said Pamela Dalton, a faculty member at the Monell Chemical Senses Center, a nonprofit research institute in Philadelphia.For most people, parosmia is a symptom of recovery, and that’s why experts believe smell training can be beneficial as you continue to heal.Patricia Voulgaris for The New York TimesWhy smell training?Even if you’re devastated over having lost your sense of smell, you might be thinking: Do I really need to add smell training to my to-do list? Won’t my sense of smell return eventually all by itself?For many people, it appears to come back within weeks of being infected.A study published in January that recruited patients from 18 European hospitals found that among 1,363 coronavirus patients with olfactory dysfunction, most recovered their senses of smell within two months and 40 percent saw their ability to smell return within two weeks. All patients were encouraged to follow two daily sessions of smell training at home, said Dr. Jerome R. Lechien, a professor of otolaryngology at the University Hospital of Brussels and one of the authors of the study. Though it’s unclear how many patients did the training, nearly one-quarter were still experiencing smell dysfunction 60 days after the onset of their symptoms. By the six-month mark, 95 percent of the patients had recovered their senses of smell.Robust studies examining the efficacy of olfactory training among Covid survivors have not yet been published. Several studies, however, have demonstrated that smell training can help people who have lost some or all of their senses of smell to other viral illnesses like sinus infections — that’s why it is widely considered the best option for those who can no longer smell properly after contracting Covid.“It has no risk — except boredom,” Dr. Dalton said wryly.Before you begin, however, it is wise to rule out other conditions that could be affecting your sense of smell.“I saw somebody recently who had smell dysfunction following Covid-19, and it turned out they had inflammatory nasal polyps,” said Dr. Sunthosh K. Sivam, an ear, nose and throat specialist and an assistant professor at the Baylor College of Medicine in Houston. Once he removed the polyps, which were unrelated to Covid, his patient’s sense of smell improved greatly.“Seeing an E.N.T. is a good way to make sure nothing else is missed,” he added.How do you choose your scents?To start, decide on four scents that are familiar to you and that evoke strong memories, the experts said. These are the fragrances that you will stick with throughout the initial phase of your training. Maybe one of them is a scented shampoo, a favorite cologne or lemons from the tree in your backyard. An avid home cook, for example, might use certain spices from his pantry.Alternatively, “some people have had a lot of success with things that smell bad,” Dr. Dalton said.At one point during her smell training, Ms. Rao, the restaurant critic, used spoiled milk. Ms. Drager, who had Covid-19 over the summer, extinguishes a candle every day and tries to smell the smoke.If that doesn’t sound appealing, you can choose to buy a smell kit that contains essential oils: the classic scents are rose, eucalyptus, clove and lemon. The kits usually retail for under $50.Or you can purchase these oils yourself at a place like Whole Foods. Ms. Kelly includes instructions on how to make your own scent kit on the AbScent website.If you buy your own oils and you want to smell them directly from the open container, first ask someone who isn’t smell impaired to try it. Then ask whether the person can easily smell the fragrance when the scent is a few inches below his or her nose. (Some containers have such small openings that it might be difficult to get a good whiff.) In the process, avoid getting any of the oils on your skin because they are highly concentrated.How does smell training work?There is not one uniform, universal way of undergoing smell training, but the experts we spoke with offered similar advice.They recommend keeping your scents in an easily accessible location — such as by your bedside — and smelling each scent for about 20 seconds so that the entire smell-training session lasts approximately one minute.While you’re doing this, take short sniffs rather than deep inhales, recommended Ms. Kelly of AbScent as she demonstrated a series of repetitive whiffs that she referred to as “bunny sniffs.”While you’re smelling the fragrances, it often helps to look at a picture of the thing that you’re smelling, said Dr. Nicholas R. Rowan, an assistant professor of otolaryngology-head and neck surgery at the Johns Hopkins University School of Medicine in Baltimore.Then, try to imagine what the item used to smell or taste like to you.“It’s not simply the act of smelling something, but it’s also this sort of mindful imagining of what that smelled like when you were eating it or when you put it on your skin — if it was a lotion, for example,” Dr. Dalton said. “It just makes it more enjoyable to continue with the process.”Smelling something that is connected to a memory or emotion is ideal, she said, because the brain plays such a big role in how we perceive smell.How long do you need to do it?Generally, doctors advise their patients to do smell training twice a day for three months.“Keep on training for a year if you have to,” said Dr. Thomas Hummel, a researcher at the Smell and Taste Clinic of the otorhinolaryngology department at the Technical University of Dresden in Germany, whose work has informed the odor training methods now used around the world.The success of your training depends on a variety of factors, including your age. In general, younger people recover their sense of smell after a viral illness at a higher rate than older people, Dr. Hummel added. This is partly because older people tend to have fewer olfactory receptor neurons — the cells that detect and transmit information about smells to the central nervous system — and their receptor neurons do not regenerate as quickly.“When you’re older, everything is slower,” he said.How do you stay motivated?As with any process that doesn’t yield immediate results, you may find it difficult to stick with the plan.“It’s very frustrating for patients,” Dr. Rowan said. “They seek out this care because they can’t smell and want it fixed and then we say, ‘Hey, use this sensory function that you don’t have.’” But, he added, “this is the best thing out there.”He suggested using a calendar to record each scent training session in order to build the habit.Keeping a diary can also be helpful, Ms. Kelly said, so that you can take notes on what you’re experiencing during each session. For further motivation, the AbScent website offers an app called Snif that can help you track your progress.Finally, if you don’t know many people who have a smell dysfunction, consider joining an online community for support and inspiration. The AbScent Facebook group for people with Covid has grown to more than 25,000 people, Ms. Kelly said.As for Ms. Drager, although she is still working to heal her olfactory system, she did smell a lemon scent this year for the first time since her sense of smell disappeared.She cried with relief.“I’m making slow progress,” she said.

When the brain suffers injury or infection, glial cells surrounding the affected site act to preserve the brain’s sensitive nerve cells and prevent excessive damage. A team of researchers from Charité — Universitätsmedizin Berlin have been able to demonstrate the important role played by the reorganization of the structural and membrane elements of glial cells. The researchers’ findings, which have been published in Nature Communications, shed light on a new neuroprotective mechanism which the brain could use to actively control damage following neurological injury or disease.
The nervous system lacks the ability to regenerate nerve cells and is therefore particularly vulnerable to injury. Following brain injury or infection, various cells have to work together in a coordinated manner in order to limit damage and enable recovery. ‘Astrocytes’, the most common type of glial cell found in the central nervous system, play a key role in the protection of surrounding tissues. They form part of a defense mechanism known as ‘reactive astrogliosis’, which facilitates scar formation, thereby helping to contain inflammation and control tissue damage. Astrocytes can also ensure the survival of nerve cells located immediately adjacent to a site of tissue injury, thereby preserving the function of neuronal networks. The researchers were able to elucidate a new mechanism which explains what processes happen inside the astrocytes and how these are coordinated.
“We were able to show for the first time that the protein ‘drebrin’ controls astrogliosis,” says study lead Prof. Dr. Britta Eickholt, Director of Charité’s Institute of Biochemistry and Molecular Biology. “Astrocytes need drebrin in order to form scars and protect the surrounding tissue.” By switching off the production of drebrin inside astrocytes, the researchers were able to study its role in brain injury in an animal model. They used electron microscopy and high-resolution light microscopy to investigate cellular changes in the brain, in addition to undertaking real-time investigations using isolated astrocytes in cell culture. “Loss of drebrin results in the suppression of normal astrocyte activation,” explains Prof. Eickholt. She adds: “Instead of engaging in defensive reactions, these astrocytes suffer complete loss of function and abandon their cellular identity.” Without protective scar formation, normally harmless injuries will spread, and more and more nerve cells will die.
To enable scar formation, drebrin controls the reorganization of the actin cytoskeleton, an internal scaffold responsible for maintaining astrocyte mechanical stability. By doing so, drebrin also induces the formation of long cylindrical membrane structures known as tubular endosomes, which are used in the uptake, sorting and redistribution of surface receptors and are needed for the defensive measures of astrocytes. Summing up the researchers’ findings, Prof. Eickholt says: “Our findings also show how drebrin uses the dynamic and versatile cytoskeleton as well as membrane structures to control astrocyte functions which are fundamental to the defense mechanism against injury.” She continues: “In particular, the membrane tubules which are formed during this process have not previously been described in this manner, neither in cultured astrocytes nor in the brain.”
“Drebrin’s role as a cytoskeletal regulator suggests that it may be a risk factor for severe outcomes in both neurological and other disorders, because loss of the protein can produce similar changes in astrocytes,” says Prof. Eickholt. She adds: “It is also possible that individuals with defects in the drebrin gene — comparable to those in the animal model — might remain without symptoms until triggers like cellular stresses, environmental toxins or diseases occur.” It is hoped that investigations involving patient samples will elucidate the extent to which drebrin also plays a role in degenerative brain disorders, such as Alzheimer’s disease.
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Materials provided by Charité – Universitätsmedizin Berlin. Note: Content may be edited for style and length.

Scientists at the Institute for Integrated Cell-Material Sciences (iCeMS) and colleagues in Japan have revealed molecular mechanisms involved in eliminating unwanted cells in the body. A nuclear protein fragment released into the cytoplasm activates a plasma membrane protein to display a lipid on the cell surface, signalling other cells to get rid of it. The findings were published in the journal Molecular Cell.
“Every day, ten billion cells die and are engulfed by blood cells called phagocytes. If this didn’t happen, dead cells would burst, triggering an auto-immune reaction,” explains iCeMS biochemist Jun Suzuki, who led the study. “It is important to understand how dead cells are eliminated as part of our body’s maintenance.”
Scientists already know that dead cells display an ‘eat me’ signal on their surface that is recognized by phagocytes. During this process, lipids are flipped between the inner and outer parts of the cell membrane via a variety of proteins called scramblases. Suzuki and his team have already identified several of these lipid-scrambling proteins, but some of their activation mechanisms have been unclear.
To solve this, the team used an array of screening approaches to study the scrambling protein called Xkr4. The broad aim was to single out the genes that are active during cell death and to specifically zoom in on Xkr4 and its associated proteins to understand how they interact.
“We found that a nuclear protein fragment activates Xkr4 to display the ‘eat me’ signal to phagocytes,” says iCeMS cell biologist Masahiro Maruoka, the first author of the study.
Specifically, the scientists found that cell death signals lead to a nuclear protein, called XRCC4, getting cut by an enzyme. A fragment of XRCC4 leaves the nucleus, activating Xkr4, which forms a dimer: the linking of identical pieces into configurations. Both XRCC4 binding and dimer formation are necessary for Xkr4 to ultimately transfer lipids on the cell surface to alert phagocytes.
Xkr4 is only one of the scrambling proteins. Others are activated much faster during cell death. The team now wants to understand when and why the Xkr4 pathway is specifically activated. Since it is strongly expressed in the brain, it is likely important for brain function. “We are now studying the elimination of unwanted cells or compartments in the brain to understand this process further,” says Maruoka.
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Materials provided by Kyoto University. Note: Content may be edited for style and length.

International genomics research led by the University of Leicester has used artificial intelligence (AI) to study an aggressive form of cancer, which could improve patient outcomes.
Mesothelioma is caused by breathing asbestos particles and most commonly occurs in the linings of the lungs or abdomen. Currently, only seven per cent of people survive five years after diagnosis, with a prognosis averaging 12 to 18 months.
New research undertaken by the Leicester Mesothelioma Research Programme has now revealed, using AI analysis of DNA-sequenced mesotheliomas, that they evolve along similar or repeated paths between individuals. These paths predict the aggressiveness and possible therapy of this otherwise incurable cancer.
Professor Dean Fennell, Chair of Thoracic Medical Oncology at the University of Leicester and Director of the Leicester Mesothelioma Research Programme, said:
“It has long been appreciated that asbestos causes mesothelioma, however how this occurs remains a mystery.
“Using AI to interrogate genomic ‘big data’, this initial work shows us that mesotheliomas follow ordered paths of mutations during development, and that these so-called trajectories predict not only how long a patient may survive, but also how to better treat the cancer — something Leicester aims to lead on internationally through clinical trial initiatives.”
While use of asbestos is now outlawed — and stringent regulations in place on its removal — each year around 25 people are diagnosed with mesothelioma in Leicestershire and 190 are diagnosed in the East Midlands. Cases of mesothelioma in the UK have increased by 61% since the early 1990s.
Until very recently, chemotherapy was the only licenced choice for patients with mesothelioma. However, treatment options start to become limited once people stop responding to their treatment.
Professor Fennell in collaboration with the University of Southampton recently made a major breakthrough in treating the disease by demonstrating that use of an immunotherapy drug called nivolumab increased survival and stabilised the disease for patients. This was the first-ever trial to demonstrate improved survival in patients with relapsed mesothelioma.
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Materials provided by University of Leicester. Note: Content may be edited for style and length.

Medical privacy has become the latest casualty of vaccination efforts, as friends, co-workers and even total strangers ask intrusive questions about personal health conditions.Peter GamlenWhen Helena Jenkins, 23, recently asked to leave work early for a vaccination appointment, her boss at a Nashville retail store was incredulous.“Well how did you get that?” he asked.Ms. Jenkins was embarrassed, but answered truthfully. “Um, my weight,” she stammered, referring to the fact that, in Tennessee, a body mass index of 30 qualified her for vaccination in early March. “I had a moment of ‘ugh,’” she said later. “It made me so uncomfortable, but it didn’t click until afterward that I definitely didn’t have to answer that.”As public health officials push to get more at-risk people vaccinated, many of the newly qualified are discovering an unwelcome side effect of vaccination: Intrusive questions about their personal health.The majority of states now have expanded vaccine eligibility to include people with underlying health conditions that put them at risk for complications from Covid-19, such as high blood pressure, a compromised immune system or obesity. As a result, the demographics of the vaccine waiting lines have shifted from mostly older people and now include many seemingly healthy people in their 20s, 30s and 40s. Young vaccine recipients say their friends and co-workers are intensely curious about the appointment process, and as a result, often ignore boundaries about personal health that they never would have crossed in the past. Some of them ask directly: “What health problem allowed you to qualify?”When Amy Coody, 43, a mental health worker in Montgomery, Ala., told her friends and colleagues she had a vaccine appointment, she was shocked when it felt like people were judging her and assuming she had taken another person’s spot in line. Ms. Coody knows that she looks young and healthy, but she qualifies for two reasons — her work takes her into hospital settings, and she also has an underlying health condition that puts her at high risk.“The hostility was definitely there,” she said. “They’d be like, ‘Wait, how did you get an appointment?’ I wasn’t prepared for that kind of reaction. It took me off guard so I eventually stopped telling people I planned to get the vaccine.”Vaccine supply issues resulted in the cancellation of two of her appointments, and the shaming even made her debate rescheduling. “I would never want to step in front of somebody who needed it,” said Ms. Coody. “Then I realized, I do need it. There are a lot of patients in hospitals waiting for care. I thought, it’s about them. It’s not about me and my shame or anybody else who doesn’t understand the situation.”Getting policed about a hidden health issue isn’t new to Ms. Coody, who has a condition called dysautonomia, a disorder of the autonomic nervous system that can cause her to suddenly pass out. She said the vaccine shaming she has experienced was similar to when she’s been confronted after parking in a handicapped space, even though she has a tag that allows her to park there.“People come up to me and say, ‘You’re young and you obviously don’t have an illness so why are you taking a handicap spot?’” Ms. Coody said. “Even though it’s none of their business, I feel the need to defend myself. If more people realized there are invisible illnesses out there, maybe they might be a little more respectful about it.”Even total strangers waiting in vaccine lines have felt justified in interrogating someone who looks young and healthy. Those on the receiving end of the questions say the implication is that they must have cheated and jumped the line.Joanna Hua, 23 and a graduate student at Georgetown University, was standing in line for her second dose recently when an older woman she’d never met confronted her. “She looked at me and said, ‘You look very young to be getting the vaccine,’” Ms. Hua recounted. “She asked me, ‘How did you end up being able to qualify for one?’”Ms. Hua said she was taken aback by the question. She told the woman truthfully that she qualified because she worked in a grocery store, but she didn’t mention that she also qualified based on her weight. She said another young woman in line near her also nervously explained her reasons for qualifying.“I felt an instinctive need to justify myself,” said Ms. Hua. “It felt almost accusatory and invasive to ask about it. I think there is some sort of idea going around that people are just taking advantage and trying to get a vaccine whenever possible. I don’t doubt that some people do that. But to have a stranger come up and ask you?”Tanmoy Lala Das, a medical and doctoral student in New York City, has been helping with vaccination efforts in Manhattan, giving shots to patients and helping as a patient navigator. He said overall the experience at vaccination centers has been upbeat, and everyone is collegial and happy to be there. But he has, on occasion, heard people asking others about personal health issues while waiting in line for their shots.“I’ve overheard people ask, ‘So what brings you in today?’” Mr. Das said. “The less stigmatized conditions people are open to talking about. They’d laugh and say, “Oh, you know, diabetes.’ I think the ones who are more sensitive, they say, ‘Oh, I just got a spot.’”It doesn’t help that many people know someone who has jumped the line by claiming to be a teacher or a smoker or lying about a health condition. In New York a fitness instructor got vaccinated by claiming to be an educator, and in Florida two women even “dressed up as grannies” to get the vaccine.“I think in New York, people are trying to figure out these dynamics of are you getting the dose because it was left over, or a condition that qualifies you or did you lie about something,” said Mr. Das. “The honest reality is I know people who have cut the line and lied about things — 29-year-old people who have gotten vaccines who don’t have pre-existing conditions. But I think most people are not lying. The goal is to vaccinate everyone.”Rhonda Wolfson, who lives in Toronto, said that in places where the vaccination process still is age-restricted, it has created a different privacy problem, casting light on the fact that a person is above a certain age. Ms. Wolfson qualified for a pilot vaccination program in Ontario for people aged 60 to 64, and she realized that talking about her vaccination would reveal her as a sexagenarian to people who thought she was younger.“I have one friend in her 40s, and she knows I’m older, but she doesn’t know my exact age,” said Ms. Wolfson. “She’s never asked, and I’ve never offered. I spoke to her last week and in my excitement I mentioned, ‘OMG, I got vaccinated.’ I could almost hear her pause, ‘Oh, you’re that age.’”In some circles, the stigma of early vaccination is even more concerning because it could dissuade at-risk people from getting the shot. In the gay community, for instance, a young person who gets vaccinated in the early group might be seen to be immunocompromised.“In the gay community there is this assumption that if you are getting the vaccine right now you must be secretly H.I.V. positive,” said Mr. Das, who is gay. “It has become an assumption in the community that if you’re a gay and you post a picture of the vaccine card, you’re positive and haven’t told us. I always talk to my friends and tell them, ‘Don’t assume things.’”Mr. Das said he is hopeful that any stigma or medical privacy issues associated with early vaccination will disappear once vaccine appointments are open to everyone. President Biden has urged all states to expand medical eligibility to the general population by May 1, and many states, including Alaska, Arizona, Georgia and Mississippi, have already made the change.“The sooner we get to vaccinating everyone, I think this question of ‘Oh, what qualified you?’ will stop,” Mr. Das said. “Once that goes away hopefully these barriers will break down, and people won’t keep asking these very personal questions.”

As U.S. manufacturers hit their stride, vaccine scarcity will soon turn to plenty as much of the world goes begging. And vaccine makers need answers now about what to do with the coming surplus.WASHINGTON — Biden administration officials are anticipating the supply of coronavirus vaccine to outstrip U.S. demand by mid-May if not sooner, and are grappling with what to do with looming surpluses when vaccine scarcity turns to glut.President Biden has promised enough doses by the end of May to immunize all of the nation’s roughly 260 million adults who are eligible for shots. But between then and the end of July, the government has locked in commitments from manufacturers for enough vaccine to cover another 100 million people — or about 70 million more than the nation’s entire population.Whether to keep, modify or redirect those orders is a question with significant implications, not just for the nation’s efforts to contain the virus but also for how soon the pandemic can be brought to an end. Of the vaccine doses given globally, about three-quarters have gone to only 10 countries. At least 30 countries have not yet injected a single person.And global scarcity threatens to grow more acute as nations and regions clamp down on vaccine exports. With infections soaring, India, which had been a major vaccine distributor, is now holding back nearly all of the 2.4 million doses manufactured daily by a private company there. That action follows the European Union’s decision this week to move emergency legislation that would curb vaccine exports for the next six weeks.Biden administration officials who are inclined to hold on to the coming U.S. surplus point to unmet need and rising uncertainty: Children and adolescents are still unvaccinated, and no one is certain if or when immunity could wear off, which could require scores of millions of booster shots.“We want to, largely, be a part of the global solution here,” Jen Psaki, the White House press secretary, said this week. But she added, “There are still a number of factors that are unpredictable that we need to plan for to the best of our ability, including the variants and the impact and what will be most effective, as well as what will work best with children.”Vaccine manufacturers and some top federal officials say decisions about what to do with extra orders must be made within weeks, or the uncertainty could slow production lines. The manufacturing process can take up to 10 weeks, and changes for a foreign market need time. The regulatory rules that govern vaccine shipments present another hurdle, as does the limited storage life of the drug substances that make the vaccine.Vials in the nation’s bottling plants in Michigan and Indiana are being labeled for use at home. If their destination is unclear, either the production line must pause or vials directed for overseas may need to be relabeled.Once the doses are shipped out to states, federal regulations prohibit recalling them even if they are not needed domestically. And vials cannot sit in storage forever: While vaccine itself can last up to a year in a frozen state, once bottled it must be used within four to six months.All these variables threaten to complicate what so far has been relatively smooth sailing for the Biden administration. Thanks in part to the federal government’s determined assistance over many months, vaccine manufacturers have been steadily increasing their output, and states have snapped up new doses as fast as the government could deliver them.Where to go from here is a matter of intense debate.Clinical trials to determine which vaccines work for the nation’s adolescents and children are continuing and most likely will not neatly wind up at the same time. By the end of spring, for example, Moderna and Pfizer are hoping for interim results on how their vaccines would work for the nation’s 30-some-million adolescents. But Moderna, at least, does not expect results for children under 12 until after the school year starts next fall.The administration could hang on to doses from those two manufacturers while it awaits findings, only to discover later that another vaccine whose trials began later — say Johnson & Johnson’s — is a better option.If one or more of the three authorized vaccines turn out to provide only brief protection against Covid-19, scores of millions of more doses could be required for booster shots. But when that answer will come is also uncertain.A woman received one of New Jersey’s first Johnson & Johnson vaccine doses this month. Of all the vaccine doses given globally, about three-quarters have gone to only 10 countries.Bryan Anselm for The New York TimesFederal health officials have also discussed canceling or reducing some orders from Moderna and Pfizer in return for the promise of a fresh supply this fall of either pediatric doses or shots of a new vaccine that has been reconfigured to work against the fast-spreading variants.There is some push for that from the manufacturers, whose vaccines are coveted by other high-income countries. But it would also deprive federal officials of the power to decide which nations get the surplus doses, as well as the humanitarian and diplomatic credit it would reap from sending the vaccine to countries in greater need.For all these reasons, senior officials say, the administration is leaning toward keeping the doses it has ordered then at some point directing the excess to other nations in bilateral deals or giving it to Covax, an international nonprofit organization backed by the World Health Organization that is trying to coordinate equitable distribution of vaccine. The Biden administration has already donated $4 billion to that international effort.Mr. Biden has stressed that his top priority is to protect Americans, but pressure is growing to share the U.S. stock. The United States has ordered a billion doses from the three federally authorized manufacturers and AstraZeneca, whose vaccine is not yet cleared for emergency use in the States but has been authorized by more than 70 countries. It recently announced that it was negotiating a deal with Johnson & Johnson for enough doses to cover another 100 million.Taken together, the supply would be enough to vaccinate 650 million people — nearly twice the U.S. population. With the world’s highest death toll from Covid-19, the United States has fully vaccinated 14 percent of its population.Last week, the White House announced that it would share four million doses of AstraZeneca’s vaccine with Mexico and Canada, but emphasized that no Americans would lose out because the vaccine has not been deployed here yet.That is a trickle compared with the 300 million AstraZeneca doses the federal government has ordered, enough to cover 150 million people with the two-dose regimen. Senior administration officials say tens of millions of those doses can be released now or imminently, and tens of millions of unbottled doses possibly could also be given away.Brazil is particularly eager for help. With more than 300,000 lives lost, the country has the second-highest death toll and has fully vaccinated less than 2 percent of its population.“After we do take care of the really difficult situation we’ve had in our own country with over 535,000 deaths, we will obviously, in the future, have surplus vaccine, and there certainly is a consideration for making that vaccine available to countries that need it,” Dr. Anthony S. Fauci, the government’s top infectious disease expert, said at a White House news conference on Wednesday.He has cast early May, when the Biden administration wants states to open up vaccinations to all adults, as a turning point. In an interview this week, he said it was likely that anyone who wants a vaccine would be able get one then.Some will not want to be vaccinated, although their numbers appear to be dwindling. According to a Pew Research Center poll this month, 69 percent of the public intends to get inoculated or already has.In the summer, the U.S. production outlook brightens further. Pfizer and Moderna together have promised enough doses to cover another 100 million people by the end of July.Pfizer continues to beef up its production lines. And Moderna is hoping to win regulatory approval to increase the number of doses in each vial by at least 40 percent, although shortages of specialized syringes might hinder that plan.A shipment of the AstraZeneca vaccine arriving in Ethiopia this month, as part of the United Nations-led Covax program.Amanuel Sileshi/Agence France-Presse — Getty ImagesJohnson & Johnson has been slower to scale up its manufacturing in the United States and is now racing to deliver as many as 24 million doses manufactured at its Dutch plant by the end of the month, according to federal officials. The Food and Drug Administration just certified its new bottling operation in Indiana and is expected any day to approve its vaccine production lines at a Baltimore plant.But while Johnson & Johnson has lagged behind the other manufacturers, its technology carries enormous promise for mass production because it can deliver many more doses per lot.Later this year, when Merck & Company is expected to begin producing Johnson & Johnson’s vaccine, it could churn out 100 million doses a month — or as much as Pfizer and Moderna together deliver monthly. The White House hailed the deal between Johnson & Johnson and Merck, but by the time production gets up to speed, those doses may be bound for a growing surplus or for export.One option is to ship the frozen vaccine that will be manufactured in Merck’s plant overseas, where it can be bottled much more cheaply. Of the $10 that the federal government has agreed to pay for a dose of Johnson & Johnson’s vaccine, the drug substance itself accounts for only about 30 cents, federal officials said. The rest is the so-called fill-and-finish cost.If AstraZeneca wins emergency use authorization from U.S. regulators, that will throw still more shots into the mix. Officials expect about 50 million doses to be ready for delivery in May.But Biden administration officials are skittish about AstraZeneca’s vaccine. It appears to be roughly as effective as Johnson & Johnson’s but requires an additional shot, meaning a more complicated rollout. Some health officials worry that if there are already enough doses in the pipeline to cover every adult who wants a shot, introducing a fourth vaccine will just confuse people.On the other hand, if the administration decides to donate the AstraZeneca doses without offering any to its own citizens, other countries might conclude that the United States lacks confidence in the vaccine’s safety or effectiveness.“As we gain more confidence in the doses that we have and the ability or the need or not to be boosting, then we can make a more definitive statement about what the role of the AZ product is going to be in the United States” should it gain clearance, Dr. Fauci said in an interview this week, “but right now I think it’s too premature to say anything.”Sheryl Gay Stolberg

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While Europe faces a shortage of vaccines and governments argue about who gets what, one company in north Wales is producing jabs solely for the UK population.Almost all of the UK’s AstraZeneca supply comes through here; it’s where the vaccine’s filled into sterile vials, inspected dozens of times, and sent out for distribution.The Prime Minister Boris Johnson called it a “saviour of humanity” and it’s fair to say the staff inside are feeling immense pressure – and pride – from their role in the vaccination programme.BBC Breakfast was given world-first access to the production line.Camera/Edit: Brijesh PatelProducer: Josh ParryReporter: Jayne McCubbin

Scientists can now sequence an entire genome overnight. This technology has been the key tool in identifying and tracking Covid […]