Culture

A gene linked to unusually long lifespans in humans protects brain stem cells from the harmful effects of stress, according to a new study by Weill Cornell Medicine investigators.

Studies of humans who live longer than 100 years have shown that many share an unusual version of a gene called Forkhead box protein O3 (FOXO3). That discovery led Dr. Jihye Paik, associate professor of pathology and laboratory medicine at Weill Cornell Medicine, and her colleagues to investigate how this gene contributes to brain health during aging.

In 2018, Dr. Paik and her team showed that mice who lack the FOXO3 gene in their brain are unable to cope with stressful conditions in the brain, which leads to the progressive death of brain cells. Their new study, published Jan. 28 in Nature Communications, reveals that FOXO3 preserves the brain's ability to regenerate by preventing stem cells from dividing until the environment will support the new cells' survival.

"Stem cells produce new brain cells, which are essential for learning and memory throughout our adult lives," said Dr. Paik, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "If stem cells divide without control, they get depleted. The FOXO3 gene appears to do its job by stopping the stem cells from dividing until after the stress has passed."

Many challenges like inflammation, radiation or a lack of adequate nutrients can stress the brain. But Dr. Paik and her colleagues looked specifically what happens when brain stem cells are exposed to oxidative stress, which occurs when harmful types of oxygen build up in the body.

"We learned that the FOXO3 protein is directly modified by oxidative stress," she said. This modification sends the protein into the nucleus of the stem cell where it turns on stress response genes.

The resulting stress response leads to the depletion of a nutrient called s-adenosylmethionine (SAM). This nutrient is needed to help a protein called lamin form a protective envelope around the DNA in the nucleus of the stem cell.

"Without SAM, lamin can't form this strong barrier and DNA starts leaking out," she said.

The cell mistakes this DNA for a virus infection, which triggers an immune response called the type-I interferon response. This causes the stem cell to go dormant and stop producing new neurons.

"This response is actually very good for the stem cells because the outside environment is not ideal for newly born neurons," Dr. Paik explained. "If new cells were made in such stressful conditions they would be killed. It's better for stem cells to remain dormant and wait until the stress is gone to produce neurons."

The study may help explain why certain versions of the FOXO3 are linked to extraordinarily long and healthy lives--they may help people keep a good reserve of brain stem cells. It may also help explain why regular exercise, which boosts FOXO3 helps preserve mental sharpness. But Dr. Paik cautioned it is too early to know whether this new information could be used to create new therapies for brain diseases.

"It could be a double-edged sword," Dr. Paik explained. "Over activating FOXO3 could be very harmful. We don't want to keep this on all the time."

To better understand the processes involved, she and her colleagues will continue to study how FOXO3 is regulated and whether briefly turning it on or off would be beneficial for health.

Scientists have discovered the first evidence of protein folding driven by liquid-liquid phase separation, a phenomenon in which fluids form into microscopic droplets and separate inside cells -- like drops of oil in water.

In a study published in the journal Chemical Science, researchers at the University of Notre Dame found that elevated concentrations of proteins within the droplets triggered a folding event, increasing the potential for protein aggregation -- or misfolding -- which has been linked to neurological diseases including Alzheimer's disease and amyotrophic lateral sclerosis (ALS).

"These particular proteins are intrinsically disordered -- they have no well-defined structure -- but when forced together by these droplets, we see evidence of folding," said Arnaldo Serrano, assistant professor in the Department of Chemistry and Biochemistry at Notre Dame and principal investigator of the study. Proteins are naturally shapeless, like pieces of cooked spaghetti -- and only function when folded into specific, three dimensional structures. "Imagine you're in a crowd, and everyone in the crowd has their arms stretched out. You're not going to fit together very well. You pull your arms in, and maybe pull your hands together. When it gets crowded, these proteins condense down into a folded structure."

Over the years, researchers have studied how the microscopic droplets, forming naturally and spontaneously within cellular structures, serve multiple functions. Cells can direct and contain dangerous biomaterial within the fluid compartments to protect the cell from harm. There's also evidence that they can drive various chemical reactions such as protein aggregation.

In their study, Serrano and his team used infrared spectroscopy to measure the folding of a specific protein associated with ALS. The infrared lasers create pulses of light, generating vibrational frequencies that act as an identifier similar to a fingerprint. The frequency uniquely and accurately identifies a protein's structure as folded or unfolded.

While the research did not test for evidence of aggregation of the proteins, Serrano explained protein folding and aggregation are intimately linked.

"You can think of aggregation as a second-order folding event," he said. "Proteins often fold into intermediate structures along the way towards aggregation. We've validated this idea that proteins in the droplet don't have a lot of room and are forced to fold -- the next logical step is they're forced to aggregate."

Serrano said he and his team are currently conducting a follow-up study to determine whether such a folding event could in fact serve as a first step for misfolding in other proteins.

In African Americans, the genetic risk landscape for inflammatory bowel disease (IBD) is very different from that of people with European ancestry, according to results of the first whole-genome study of IBD in African Americans. The authors say that future clinical research on IBD needs to take ancestry into account.

Findings of the multi-center study, which analyzed the whole genomes of more than 1,700 affected individuals with Crohn's disease and ulcerative colitis and more than 1,600 controls, were published on February 17 in the American Journal of Human Genetics.

As part of their analysis, the researchers developed an algorithm that corrects for ancestry when calculating an IBD polygenic risk score. Polygenic risk scores are tools for calculating gene-based risk for a disease, which are used for IBD as well as other complex conditions such as coronary artery disease.

"Even though the disease destination looks the same, the populations look very different, in terms of what specific genes contribute to risk for IBD," says lead author Subra Kugathasan, MD. "It shows that you can't develop a polygenic risk score based on one population and apply it to another."

Kugathasan is scientific director of the pediatric IBD program and director of the Children's Center for Transplantation and Immune-mediated Disorders at Children's Healthcare of Atlanta,
as well as Marcus professor of pediatrics and human genetics at Emory University School of Medicine.

The first author of the paper is geneticist Hari Somineni, PhD, who earned his doctorate working with Kugathasan at Emory, and is now working at Goldfinch Bio in Massachusetts.

The primary sites to recruit study participants were Emory, Cedars-Sinai and Rutgers, along with Johns Hopkins and Washington University at Saint Louis. Along with Kugathasan, the co-senior authors and co-organizers of the study were Steven Brant, MD from Rutgers and Dermot McGovern, MD, PhD from Cedars-Sinai.

"One of our goals in treating IBD is to move toward a more personalized approach," says McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics at Cedars-Sinai. "Deciphering the genetic architecture is an important part of this effort. Studies such as this one are vital to ensure that diverse populations, including African-Americans, benefit from the tremendous advances promised by genomic medicine."

Having a first-degree relative with a form of IBD confers a greater risk than any known environmental factor. African-Americans are conventionally thought to be less at risk for IBD, but Kugathasan says that view may reflect disparities in diagnosis and access to healthcare.

The study showed that the most important genetic risk locus for IBD in African Americans -- PTGER4 - is relatively minor in European ancestry populations, Kugathasan says. In contrast, two gene loci that are major in Europeans - NOD2 and IL23R - play smaller roles in African Americans.

There is some overlap in genetic risk factors based on the African-American population historically having about 20 percent European genetic background, with known IBD risk factors such as IL23R coming from the European side.

In 2016, the research team published the first genome-wide association study of IBD in African Americans, identifying regions of the genome associated with ulcerative colitis only in people of African descent.

Future clinical studies of IBD treatments need to take the genetic background of specific populations into account, Kugathasan says. Several therapies are being developed for IBD targeting the IL23 receptor pathway, partly because IL23R is a major genetic risk factor, with little focus on PTGER4. That needs to change, he says.

The current study also identified rare genetic variants conferring IBD risk that are specific to African Americans, which had not been observed in previous studies. The variants are connected to the gene encoding calbindin 2 (CALB2), a protein involved in nervous system signaling.

What the study did not find - disappointing the researchers - were a host of rare genetic variants that explain the "missing heritability" in IBD among African-Americans. In genome-wide association studies, missing heritability refers to disease risk that is not accounted for by common gene variants.

For the future of the IBD field, Kugathasan says studies of gene-environment interactions - examining factors such as diet, microbiome, or toxic exposures -- may yield insights that genome-wide association studies have not.

Exploratory analyses including 17,178 participants find that higher vaccine efficacy is obtained with a longer interval between the first and second standard dose (81% for 3-month interval vs 55% for up to 6-week interval). In addition, a single dose of vaccine is highly efficacious in the first 3 months (76% efficacy from 22 days after vaccination onwards).

The study also includes updated estimates of overall vaccine efficacy against symptomatic disease for two standard doses, which confirm that the vaccine is effective. There were no hospitalisations or deaths among those receiving the COVID-19 vaccine from 22 days after the first dose, compared with 15 instances in the control group.

Authors say this provides further support for current policy of extended intervals between doses in the UK and is consistent with the WHO's new policy advice.

A 3-month interval between doses of the Oxford COVID-19 vaccine results in higher vaccine efficacy than a 6-week interval, with the first dose offering 76% protection in the 3 months between doses. These results, from post-hoc exploratory analyses from a phase 3 randomised controlled trial published in The Lancet, suggest that the interval between doses can be safely extended to 3 months given the protection a single dose offers, which may allow countries to vaccinate a larger proportion of the population more rapidly.

The authors note that this regimen may be beneficial while vaccine supplies are initially limited.

Study lead author Professor Andrew Pollard, University of Oxford, UK, says: "Vaccine supply is likely to be limited, at least in the short term, and so policy-makers must decide how best to deliver doses to achieve the greatest public health benefit. Where there is a limited supply, policies of initially vaccinating more people with a single dose may provide greater immediate population protection than vaccinating half the number of people with 2 doses. In the long term, a second dose should ensure long-lived immunity, and so we encourage everyone who has had their first vaccine to ensure they receive both doses." [1]

Other vaccines, such as for flu, Ebola and malaria, also give greater protection and stronger immune responses after a longer interval between doses.

Following the regulatory approval of a vaccine, it is important to understand the best dose interval to ensure optimal roll-out of the vaccine. Factors associated with this include the effect of different intervals on protection after the second dose, and the risk of infection between doses either due to lower efficacy of a single dose or rapid waning of efficacy while waiting for the second dose.

To understand these factors, the authors combined data from randomised controlled trials in the UK, Brazil, and South Africa, including 8,948, 6,753, and 1,477 people, respectively (totalling 17,178 people). Participants were aged 18 years and over (see appendix table S1 for more detail), and either received two standard doses of the Oxford COVID-19 vaccine (8,597 participants) or a control vaccine/saline placebo (8,581). In the UK trial, a subset of participants (1,396 people) received a lower dose of the vaccine as their first dose.

The primary outcome of the trial was the number of symptomatic COVID-19 cases (confirmed by positive COVID-19 test, and having fever, cough, shortness of breath, loss of smell or loss of taste) in the control and COVID-19 vaccine groups occurring more than 14 days after the second dose.

The exploratory analyses in the new study (of the efficacy of an extended interval between vaccine doses and of a single dose) were requested by regulators and policy makers, and the authors also conducted an analysis to establish the impact of one or two doses of the vaccine on reducing all COVID-19 cases (including symptomatic cases, cases with less common COVID-19 symptoms, asymptomatic cases, and those with unknown symptoms) as an indicator of how the vaccine might help to reduce transmission in the community. The authors note that these were not pre-specified analyses and should be considered as supportive analyses to the overall vaccine efficacy analyses.

The single-dose analysis included participants who chose not to receive a second dose (the trial was originally set up as a single-dose vaccine trial, and so some chose not to participate further), and people who had COVID-19 before they received their second dose. To establish the efficacy of a single dose, the authors analysed participants who had had their first standard dose who tested positive for COVID-19 more than 21 days afterwards.

Looking at the interval between two standard doses and its impact on efficacy, participants who were given their doses 12 or more weeks apart had greater protection (81%, based on 8/1,293 cases in the COVID-19 vaccine group vs 45/1,356 cases in the control group), than people given their two doses less than 6 weeks apart (55%, based on 35/3,890 cases in the COVID-19 vaccine group vs 76/3,856 cases in the control group). Efficacy results were supported by immune response results in 18-55 year olds, which found that binding antibody responses were more than two-fold higher in the group having their two vaccines with a longer delay.

Following a single standard vaccine dose, vaccine efficacy from 22 days to 3 months after vaccination was 76% (based on 17/9,257 cases in the COVID-19 vaccine group vs 71/9,237 cases in the control group), and modelling indicated that this protection did not reduce over the 3 months. In addition, antibody levels against the SARS-CoV-2 spike protein remained at similar levels for 3 months.

The authors note that it is not yet clear how long protection with a single dose of the vaccine might last, as the trial results are limited to the 3 months maximum. For this reason, a second dose of vaccine is still recommended.

Following an additional month of data from the interim efficacy results (which were based on 131 COVID-19 cases), there were 332 cases amongst the trial participants. Based on these cases, the study finds that two doses of the vaccine protect against symptomatic disease in 67% of cases (based on 84/8,597 cases in the COVID-19 vaccine groups vs 248/8,581 cases in the control group) - with a vaccine efficacy of 63% for people given two standard doses (74/7,201 cases in the COVID-19 vaccine group vs 197/7,179 in the control group), and of 81% for those given a low dose then a standard dose vaccine (10/1,396 cases in the COVID-19 vaccine group vs 51/1,402 in the control group).

In addition, counting from 22 days after participants had received their first dose, there were no hospitalisations in the COVID-19 vaccine group and there were 15 in the control group.

Study author, Dr Merryn Voysey, University of Oxford, UK, says: "This latest analysis confirms our previous findings of the higher efficacy of a low- then standard-dose regimen. However, with additional data available, we have found that the enhanced efficacy and immunity may be partly driven by the longer interval between doses that was common in this trial group. This further supports the relationship we have found between vaccine interval and efficacy in those receiving two standard doses, which is the preferred regimen because there are more data to support its use, and because it is simpler to deliver a vaccine programme when the same vaccine is given for both doses." [1]

Lastly, looking at how the vaccine might help to reduce transmission in the community, the authors estimate that a single dose of the vaccine may lead to a 64% reduction, and that two doses may reduce cases by 50% (the effect of two doses appears less than a single dose because there are more asymptomatic cases included in this part of the analysis, and vaccine efficacy against asymptomatic cases is lower). They suggest that these data may mean that using the vaccine as outlined by regulators could have a substantial impact on transmission by reducing the number of infected individuals in the population.

Professor Pollard says: "It is important to understand whether vaccines can reduce COVID-19 transmission. While specific transmission studies were not included in our analysis, UK trial participants were tested for COVID-19 each week regardless of symptoms, and we combined this with other positive COVID-19 cases in the trial to help determine the overall impact of the vaccine on risk of infection. If the vaccine had no impact on transmission, we would expect that the number of positive tests in our trial would be the same in vaccine and control groups. This is because the vaccine would convert severe cases to mild cases, and mild cases to asymptomatic cases. However, we saw a reduction in the overall number of positive cases, which indicates that the vaccines may reduce infections. Real-world assessments of how the vaccine is working in the population will be needed to confirm this preliminary result." [1]

The authors note some limitations to their study, including that there is limited follow-up after the second dose of the vaccine currently and more research is needed to determine duration of protection.

The trials were not designed to establish whether vaccine efficacy differed by dose interval and the varying intervals between doses were a result of the complex logistics of running large-scale clinical trials in a pandemic. These results in the study are therefore post-hoc exploratory analyses only, and have potential for multiple sources of bias. However, the authors say that these analyses provide a peer-reviewed assessment of the approach that is currently being used to deploy their vaccine during the pandemic.

The results, recently published in the journal Communications Biology, have important applications in the field of coevolutionary biology

The physical movement of species determines their potential scope to leave their primary ecosystem behind in the quest for new niches in which to survive or reproduce--a decisive factor for the processes that determine their genomic characteristics.

Researchers from the University of Granada (UGR) and the University of Illinois (UI) have, for the first time, analysed the relationship between this potential for movement in different species of parasites--their dispersal capacity--and their levels of genetic introgression. Introgression--the gradual movement of genes from one species into the gene pool of another--affects the proportion of regions of the genome of a given species that comes from different species via hybridisation.

This new study on this phenomenon was led by Jorge Doña Reguera, a Marie Curie postdoctoral researcher from the Department of Zoology at the University of Granada and a member of the University of Illinois at Urbana-Champaign. Its results were recently published in the journal Communications Biology.

The team of scientists demonstrated that differences in the dispersal capacities of different species can modulate levels of genomic introgression--that is, the parasite species with the greatest ability to reach different host species presented higher levels of introgression.

Doña Reguera, together with Drs Andrew Sweet and Kevin Johnson, began this study in 2018, focusing on the relationship between dispersal capabilities and genomic introgression levels in the case of bird lice. Currently, the research is expanding its focus within the Marie Curie "INTROSYM" project in which, together with Drs Juan Gabriel Martínez Suarez from the UGR and Kevin Johnson, introgression processes in symbionts is being investigated. This project will analyse the incidence of this phenomenon and its impact on the ecology, evolution, and conservation of symbiont species (for more information, visit https://cordis.europa.eu/project/id/886532/en).

Returning to the bird lice study, the ecological replicate system of wing and body lice of pigeons and doves was used. That is, this replicate system (which is ecologically similar, but phylogenetically independent), was used to study both the louse group with the highest dispersal capacities (wing lice) and the group with the lowest dispersal capacity (body lice).

First, the authors found a higher proportion of introgressed regions and, subsequently, a greater number of reticulated phylogenetic networks in the genus of wing lice. Therefore, the results indicated that species with higher dispersal abilities present increased genomic signatures of introgression (due to hybridisation events).

"The fact that dispersal capacities are linked to introgression rates could enable us to get closer to predicting the introgression rate of a given species of parasite, which could have very important implications for understanding parasite-host dynamics," explains the UGR researcher.

For example, this knowledge could be of great value in the case of co-adaptation processes between species (that is, the adaptation of a species in response to interaction with another) or modulating the speciation processes of parasites by modifying the opportunities for colonisation of new hosts, "something that may be important for understanding the emergence of infectious diseases."

Doña notes the warm reception the publication has received in the scientific community, although much remains to be done, due to the novelty of the subject. Matter. "One very important aspect of this work is that the study system that we used, bird lice, was the same as that of numerous foundational studies in coevolutionary biology and reference books such as Coevolution of Life on Hosts," he says. "The fact that we have found evidence of introgression in this system opens up many questions, such as how does this new process/result fit into everything we knew before?" As the INTROSYM project continues to evolve, he expects new answers to be uncovered.

A new study, in which the Andalusian Earth Sciences Institute (IACT) (CSIC-UGR) participated, has described for the first time a key stage in the beginning of the great glaciations and indicates that it can happen to our planet in the future. The findings were recently published in the scientific journal Nature

The study claims to have found a new connection that could explain the beginning of the ice ages on Earth

Antarctic iceberg melt could hold the key to the activation of a series of mechanisms that cause the Earth to suffer prolonged periods of global cooling, according to Francisco J. Jiménez-Espejo, a researcher at the Andalusian Earth Sciences Institute (CSIC-UGR), whose discoveries were recently published in the prestigious journal Nature.

It has long been known that changes in the Earth's orbit, as it moves around the Sun, trigger the beginning or end of glacial periods by affecting the amount of solar radiation that reaches the planet's surface. However, until now, the question of how small variations in the solar energy that reaches us can lead to such dramatic shifts in the planet's climate has remained a mystery.

In this new study, a multinational group of researchers proposes that, when the Earth's orbit around the sun is just right, the Antarctic icebergs begin to melt further and further away from the continent, moving huge volumes of freshwater from the Antarctic Ocean into the Atlantic.

This process causes the Antarctic Ocean to become increasingly salty, while the Atlantic Ocean becomes fresher, affecting overall ocean circulation patterns, drawing CO2 from the atmosphere and reducing the so-called greenhouse effect. These are the initial stages that mark the beginning of an ice age on the planet.

Within this study, the scientists used several techniques to reconstruct oceanic conditions in the past, including by identifying tiny fragments of rock that had broken away from Antarctic icebergs as they melted into the ocean. These deposits were obtained from marine sediment cores recovered by the International Ocean Discovery Program (IODP) during Expedition 361 off the sea-margins of South Africa. These sediment cores enabled the scientists to reconstruct the history of the icebergs that reached these latitudes in the last million and a half years, this being one of the most continuous records known.

Climate simulations

The study describes how these rocky deposits appear to be consistently associated with variations in deep ocean circulation, which was reconstructed from chemical variations in minute deep-sea fossils known as foraminifera. The team also used new climate simulations to test the proposed hypotheses, finding that huge volumes of fresh water are carried northward by icebergs.

The first author of the article, PhD student Aidan Starr from the University of Cardiff, notes that the researchers are "surprised to have discovered that this teleconnection is present in each of the different ice ages of the last 1.6 million years. This indicates that the Antarctic Ocean plays a major role in the global climate, something that scientists have long sensed, but that we have now clearly demonstrated."

Francisco J. Jiménez Espejo, a researcher with the IACT, participated in his capacity as a specialist in inorganic geochemistry and physical properties during the IODP 361 expedition aboard the JOIDES Resolution research vessel. For two months, between January and March 2016, the research team sailed between Mauritius and Cape Town, collecting deep-sea sediment cores.

Jiménez Espejo's main contribution to the study focused on identifying the geochemical variations associated with glacial and interglacial periods, which has made it possible to estimate with greater accuracy the age of the sediment and its sensitivity to the different environmental changes associated with those periods.

Over the course of the last 3 million years, the Earth began to experience periodic glacial cooling. During the most recent episode, about 20,000 years ago, icebergs continuously reached the Atlantic coasts of the Iberian Peninsula from the Arctic. Currently, the Earth is in a warm interglacial period known as the Holocene.

However, the progressive increase in global temperature associated with CO2 emissions from industrial activities could affect the natural rhythm of glacial cycles. Ultimately, the Antarctic Ocean could become too warm for Antarctic icebergs to be able to carry freshwater north, and therefore a fundamental stage in the beginning of the ice ages--the variations in thermohaline circulation--would not take place.

Ian Hall, also of Cardiff University, who co-directed the scientific expedition, indicates that the results may contribute to understanding how the Earth's climate may respond to anthropic changes. Similarly, Jiménez Espejo, notes that "last year, during an expedition aboard Hespérides, the Spanish Navy research vessel, we were able to observe the immense A-68 iceberg that had just broken into several pieces next to the islands of South Georgia. Ocean warming may cause the trajectories and the melt patterns of these large icebergs to alter in the future, affecting the currents and, therefore, our climate and the validity of the models that scientists use to predict it."

Several University of Illinois Chicago faculty members have addressed the issue of how to ethically conduct research with Black populations.

In their paper "Ethics of Research at the Intersection of COVID-19 and Black Lives Matter: A Call to Action," authors Natasha Crooks, an assistant professor, Phoenix Matthews, a professor, both of the UIC College of Nursing, and Geri Donenberg, director of the Center for Dissemination and Implementation Science at the UIC College of Medicine, highlight the historical issues that impact research involving Black populations. They also provide recommendations for researchers to ethically engage Black populations in research. The article is published online in the Journal of Medical Ethics.

"Our recommendations include understanding the impact of ongoing trauma, acknowledging historical context, ensuring diverse research teams and engaging in open and honest conversations with Black populations to better address their needs," they said.

The authors call for new standards to engage continued research with Black communities, fully understanding the need for strategies that avoid "re-traumatizing or perpetuating violence of Black lives as disposable at every point of the research process."

"It will also require research institutions to change how we engage Black populations, commit resources to diversify our workforce and enact antiracist programs and policies to foster greater sensitivity to these issues," the paper states.

The paper includes three areas targeting change: ensuring research settings are emotionally and physically safe; sharing research findings with communities to facilitate trust and encourage feedback into interpreting results; and having honest conversations with Black participants about how they feel about participating in research, including the risks, strengths and barriers.

Each recommendation includes examples to help implement changes including asking research participants pointed questions regarding safety, concentrating on the participants' experience, using mixed method approaches like open-ended questions and interviews, and sharing research findings transparently.

"Researchers must engage in open and honest conversations with Black participants about how they feel participating in research during the COVID-19 pandemic, including the risks, strengths and barriers," the paper states. "Then, researchers must listen, adjust timelines, protocols and objectives based on the information provided."

Crooks, who conducts research in Black communities frequently, said she has found ways to engage with potential research subjects by adding a personal perspective.

"The most useful thing for me has been going to Black organizations and introducing myself, putting a face to the research. I spend time telling them my story about becoming a Black doctor and how I became interested in this area of research. I give them the space to ask me any questions to help build trust," Crooks said. "It's critical to get groups exposed to participating in research and making them feel comfortable with the research process."

Biotechnologists from RUDN University in collaboration with Lomonosov MSU and Kurchatov institute made an important contribution to the technology of phosphate and nitrate biocapture from wastewater using Lobosphaera algae fixed on the filters.The biomass obtained in the course of this process can be used as a fertilizer. The results of the study were published in the Journal of Water Process Engineering.

Phosphates and nitrates get to the wastewater together with industrial and household waste, especially detergents. Both substances are parts of phosphorus and nitrogen chemical cycles. However, these cycles are disturbed by human activity, as the growing amounts of phosphates and nitrates cannot be processed by water ecosystems. As a result, these substances turn from useful nutrients to pollutants. Wastewater is treated with special equipment and microorganisms, including microalgae that consume phosphates and nitrates. A team of biotechnologists from RUDN University together with their colleagues from MSU and the Kurchatov Institute developed a biopolymer filter on which useful microalgae can be placed. The polymer is chitosan-based, safe for the algae, biodegradable, and captures chemical elements from wastewater more effectively than its existing analogs.

"Our team was the first to successfully use cross-linked chitosan polymers to immobilize unicellular algae and make them effectively consume nutrients while at the same time not preventing them from growing and photosynthesizing," said Alexei Solovchenko, a PhD in Biology from the Department of Agrobiotechnology, RUDN University.

Chitosan is a polysaccharide with amino groups and its chemical composition is similar to that of chitin that can be found in shellfish crusts and mushroom cell walls. Chitosan is not water-soluble and therefore can be used to grow algae. However, it is biodegradable. Using an original methodology developed in the Kurchatov Institute, it was cross-linked with glutaraldehyde molecules and thus turned into a strong biocompatible polymer. Then, the team grew the IPPAS C-2047 strain of the Lobosphaera incisa algae on it for seven days.

Based on the results of the seven-day long experiment, the team concluded that a complex of microalgae cells and chitosan-based polymer with a total molecular mass of 600 kDa was more effective than that with a molecular mass of 250 kDa. The algae on the filter captured the nutrients more efficiently than those suspended in the wastewater: specifically, they consumed phosphates 16.7 times and nitrates 1.3 times faster.

Used chitosan biofilters could be repurposed as fertilizers. With time, chitosan would degrade without causing any harm to the environment, while the algae would act as a source of accumulated phosphates and nitrates for the plants.

"Our team has demonstrated that cross-linked chitosan polymers are safe for the environment and effectively support the biocapture of nutrients from wastewater by unicellular algae. When added to a non-toxic medium, the algae biomass could be used as a fertilizer that would gradually release the accumulated nutrients into the soil," added Alexei Solovchenko from RUDN University.

New Orleans, LA - A retrospective study conducted by LSU Health New Orleans reports that contrary to previous research, most patients who drop out of peritoneal dialysis may do so for psychosocial reasons. The findings are published in The American Journal of the Medical Sciences, available here. The paper inspired a companion editorial, available here.

The research team evaluated the reasons that 27 of the 83 patients enrolled in the peritoneal dialysis program withdrew between 2016 and 2018. Twenty-four or 86% were African American. They found that psychosocial factors, including mental health illness such as anxiety and depression, loss of support networks, or inability to tolerate the number of treatment sessions required by peritoneal dialysis, accounted for 63% of the dropout rate due to controllable factors.

According to the National Institutes of Health, peritoneal dialysis is a treatment for kidney failure that uses the lining of the abdomen to filter blood inside the body. The dialysis solution flows into the belly through a catheter, where it absorbs wastes before draining. The process must be done four to six times a day. Patients can perform peritoneal dialysis at home, work or when traveling.

Patients with end-stage renal disease must undergo either peritoneal dialysis or hemodialysis - a method of filtering waste from the blood through a filter outside the body called a dialyzer.

The researchers note that the United States accounts for the largest percentage of end-stage renal disease patients in the world but significantly underutilizes peritoneal dialysis despite its lower costs and a lower first-year risk of death. Peritoneal dialysis can also be more accessible because patients don't have to travel to treatment centers. Other advantages include greater flexibility in treatment schedules, potentially fewer dietary restrictions and fewer side effects like nausea, vomiting and cramping.

The National Institutes of Health estimates that more than 661,000 Americans have kidney failure, and that of these, 468,000 are on dialysis. Compared to Caucasians, end-stage renal disease prevalence is about 3.7 times greater in African Americans, 1.4 times greater in Native Americans, and 1.5 times greater in Asian Americans. Each year, kidney disease kills more people than breast or prostate cancer. In 2013, more than 47,000 Americans died from kidney disease.

"Early intervention or identification of these problems will allow for physicians and care teams to improve not only patient outcomes but also improve the patient's quality of life," notes Hayden Torres, a third-year medical student at LSU Health New Orleans School of Medicine and also first author of the paper.

The research team concludes that both patients and caregivers may benefit from both counseling and assisted dialysis programs. Future research should focus on ways to improve pre-PD training depending on the type of patient beginning treatment, improving interventions for psychosocial factors that lead to dropout, and developing ways to identify sources of psychosocial problems before they impact patients.

Biruh T. Workeneh and Sreedhar Mandayam from the Department of Nephrology at the University of Texas at MD Anderson Cancer Center wrote in their editorial, "As Torres et al. have expertly illustrated, examining the reasons for technique failure is critical particularly in special populations because they have to reveal factors that may not be apparent and point to areas to focus further research and policy prescriptions. As the manuscript shows, psychosocial factors are a significant factor that has not received enough attention. Not surprisingly, their investigation found that when technique failure results from psychosocial factors, it does so in the first year, which is consistent with other reports. Torres et al. have effectively and poignantly highlighted a need for further research about how to retain racial minorities more effectively, who may not have robust social and emotional
support."

A survey by a Boston University researcher of nearly 33,000 college students across the country reveals the prevalence of depression and anxiety in young people continues to increase, now reaching its highest levels, a sign of the mounting stress factors due to the coronavirus pandemic, political unrest, and systemic racism and inequality.

"Half of students in fall 2020 screened positive for depression and/or anxiety," says Sarah Ketchen Lipson, a Boston University mental health researcher and a co-principal investigator of the nationwide survey published on Februray 11, 2021, which was administered online during the fall 2020 semester through the Healthy Minds Network. The survey further reveals that 83 percent of students said their mental health had negatively impacted their academic performance within the past month, and that two-thirds of college students are struggling with loneliness and feeling isolated—an all-time high prevalence that reflects the toll of the pandemic and the social distancing necessary to control it.

Lipson, a BU School of Public Health assistant professor of health law, policy, and management, says the survey's findings underscore the need for university teaching staff and faculty to put mechanisms in place that can accommodate students' mental health needs.

"Faculty need to be flexible with deadlines and remind students that their talent is not solely demonstrated by their ability to get a top grade during one challenging semester," Lipson says.

She adds that instructors can protect students' mental health by having class assignments due at 5 pm, rather than midnight or 9 am, times that Lipson says can encourage students to go to bed later and lose valuable sleep to meet those deadlines.

Especially in smaller classroom settings, where a student's absence may be more noticeable than in larger lectures, instructors who notice someone missing classes should reach out to that student directly to ask how they are doing.

"Even in larger classes, where 1:1 outreach is more difficult, instructors can send classwide emails reinforcing the idea that they care about their students not just as learners but as people, and circulating information about campus resources for mental health and wellness," Lipson says.

And, crucially, she says, instructors must bear in mind that the burden of mental health is not the same across all student demographics. "Students of color and low-income students are more likely to be grieving the loss of a loved one due to COVID," Lipson says. They are also "more likely to be facing financial stress." All of these factors can negatively impact mental health and academic performance in "profound ways," she says.

At a higher level within colleges and universities, Lipson says, administrators should focus on providing students with mental health services that emphasize prevention, coping, and resilience. The fall 2020 survey data revealed a significant "treatment gap," meaning that many students who screen positive for depression or anxiety are not receiving mental health services.

"Often students will only seek help when they find themselves in a mental health crisis, requiring more urgent resources," Lipson says. "But how can we create systems to foster wellness before they reach that point?" She has a suggestion: "All students should receive mental health education, ideally as part of the required curriculum."

It's also important to note, she says, that rising mental health challenges are not unique to the college setting—instead, the survey findings are consistent with a broader trend of declining mental health in adolescents and young adults. "I think mental health is getting worse [across the US population], and on top of that we are now gathering more data on these trends than ever before," Lipson says. "We know mental health stigma is going down, and that's one of the biggest reasons we are able to collect better data. People are being more open, having more dialogue about it, and we're able to better identify that people are struggling."

The worsening mental health of Americans, more broadly, Lipson says, could be due to a confluence of factors: the pandemic, the impact of social media, and shifting societal values that are becoming more extrinsically motivated (a successful career, making more money, getting more followers and likes), rather than intrinsically motivated (being a good member of the community).

The crushing weight of historic financial pressures is an added burden. "Student debt is so stressful," Lipson says. "You're more predisposed to experiencing anxiety the more debt you have. And research indicates that suicidality is directly connected to financial well-being."

With more than 22 million young people enrolled in US colleges and universities, "and with the traditional college years of life coinciding with the age of onset for lifetime mental illnesses," Lipson stresses that higher education is a crucial setting where prevention and treatment can make a difference.

One potential bright spot from the survey was that the stigma around mental health continues to fade. The results reveal that 94 percent of students say that they wouldn't judge someone for seeking out help for mental health, which Lipson says is an indicator that also correlates with those students being likely to seek out help themselves during a personal crisis (although, paradoxically, almost half of students say they perceive that others may think more poorly of them if they did seek help).

"We're harsher on ourselves and more critical of ourselves than we are with other people—we call that perceived versus personal stigma," Lipson says. "Students need to realize, your peers are not judging you."

Cancer researcher Rita Fior uses zebrafish to study human cancer. Though this may seem like an unlikely match, her work shows great promise with forthcoming applications in personalised medicine.

The basic principle of Fior's approach relies on transplanting human cancer cells into dozens of zebrafish larvae. The fish then serve as "living test tubes" where various treatments, such as different chemotherapy drugs, can be tested to reveal which works best. The assay is rapid, producing an answer within four short days.

Some years ago, when Fior was developing this assay, she noticed something curious. "The majority of human tumour cells successfully engrafted in the fish, but some tumours didn't. They would just disappear within a day or two. However, when I treated the transplanted fish with chemotherapy, these tumors would not disappear anymore. They engrafted much more", she recalls.

This seemingly paradoxical observation triggered a new working hypothesis. "Chemotherapy suppresses the immune system", Fior explains. "If the tumour is rejected under normal conditions, but thrives in immuno-suppressed animals, then this points towards a new explanation: the fish's immune system is actively destroying the cancer cells. Whereas in the ones that implant well, the tumor is able to suppress the fish's immune system."

Soon after, Fior, together with Vanda Povoa, a doctoral student in her lab at the Champalimaud Centre for the Unknown in Portugal, set off on a new research project. It's main conclusions, published today (February 19th) in the journal Nature Communications, advance our understanding of how cancer-immune interactions may lead to immunotherapy resistance and tumour growth. In the long run, these results may contribute to the development of new treatments and diagnostics.

Good Cop

Following this serendipitous observation, the researchers began systematically investigating why certain tumours are eliminated while others survive.

They focused on a pair of human colorectal cancer cells that were derived from the same patient but showed these contrasting behaviours. One was derived from the primary tumor and was constantly rejected from the fish; whereas the other was derived from a lymph node metastasis but implanted very efficiently.

They started by characterising the immune cells that were summoned to the tumor site. Specifically, they zoomed-in on cells of a subsystem called innate immunity.

"Contrary to mature zebrafish, the larvae only have innate immunity, which is the body's first line of defence. This offers a vantage point to study the role of innate immune cells in cancer, which is not very well understood", Fior explains.

The team proceeded to quantify the number and type of innate immune cells in the tumor microenvironment. The primary tumor [which gets rejected] was swarming with innate immune cells. But in contrast, the metastatic tumor that implants well, showed very sparse numbers of innate immune cells.

This result indicated that the researchers' hunch was correct. But to be sure, they had to artificially reduce the number of innate immune cells in the fish using selective genetic and chemical approaches. As expected, this manipulation "saved" the cells from being rejected.

Together, these results show a clear role for the innate immune system in eliminating tumour cells. But then, if the immune system is so good at getting rid of "fresh" cancer cells from the primary tumour, why would metastasis happen?

Bad Cop

"The reason is that the relationship between cancer and the immune system is far from static", says Fior. "At the beginning, cancer cells may simply try to hide from the immune system. But with time, they learn how to confuse and finally corrupt immune cells. This evolution happens through a dynamic process called 'Immunoediting'. If the process is successful, the corrupted cells begin supporting the tumour in many ways, including sending away other immune cells that could vanquish the tumour."

Is the innate immune system per se able to do cancer immunoediting? "Our results show that yes, it does indeed. This is the second study, to our knowledge, that shows this phenomenon", adds Povoa.

The researchers observed that tumor cells not only recruit different numbers of innate immune cells but can also change their function. Instead of fighting the tumour, macrophages began supporting and protecting it. Alarmingly, the researchers demonstrated that this transformation happens very quickly.

"Even though most cells from the primary tumour are rejected within a day or two, some survive. When we transplanted this small group of survivors back into the fish, we discovered that they had already acquired immune-editing capabilities! In fact, they engrafted almost as well as cells from metastatic tumours", Povoa points out.

The researchers also compared the genetic profile of metastatic and primary tumour cells and identified several interesting features. "We now have a list of candidate genes and molecules that we plan to study. We hope that by pinpointing the mechanism by which cancer cells suppress and corrupt the innate immune system we will be able to find ways of blocking this process", Fior adds.

Giving immunotherapy a boost

Fueled by this exciting set of results, Fior and Povoa are full of plans for the future. "There are so many things we can do", says Fior. "For instance, we now know that our zebrafish assay can tell if the tumour environment is immunosuppressive in just a few days. Immunotherapy is less likely to be effective in these cases. Therefore, our assay may become useful to help determine which patients will benefit mostly from immunotherapy ."

Another angle the team is thinking about is the development of new immunotherapy approaches. "The majority of immunotherapy drugs do not rely on innate immunity. They boost other immune subsystems. But as we saw, innate immunity has a great capacity for fighting cancer. Therefore, identifying the mechanisms that amplify this effect will allow us to devise new potential therapies, which could be combined with existing ones to increase their efficacy.", she concludes.

University of Warwick scientists model movements of nearly 300 protein structures in Covid-19

Scientists can use the simulations to identify potential targets to test with existing drugs, and even check effectiveness with future Covid variants

Simulation of virus spike protein, part of the virus's 'corona', shows promising mechanism that could potentially be blocked

Researchers have publicly released data on all protein structures to aid efforts to find potential drug targets: https://warwick.ac.uk/flex-covid19-data

Researchers have detailed a mechanism in the distinctive corona of Covid-19 that could help scientists to rapidly find new treatments for the virus, and quickly test whether existing treatments are likely to work with mutated versions as they develop.

The team, led by the University of Warwick as part of the EUTOPIA community of European universities, have simulated movements in nearly 300 protein structures of the Covid-19 virus spike protein by using computational modelling techniques, in an effort to help identify promising drug targets for the virus.

In a new paper published today (19 February) in the journal Scientific Reports, the team of physicists and life scientists detail the methods they used to model the flexibility and dynamics of all 287 protein structures for the Covid-19 virus, also known as SARS-CoV-2, identified so far. Just like organisms, viruses are composed of proteins, large biomolecules that perform a variety of functions. The scientists believe that one method for treating the virus could be interfering with the mobility of those proteins.

They have made their data, movies and structural information, detailing how the proteins move and how they deform, for all 287 protein structures for Covid-19 that were available at the time of the study, publicly accessible to allow others to investigate potential avenues for treatments.

The researchers focused particular efforts on a part of the virus known as the spike protein, also called the Covid-19 echo domain structure, which forms the extended corona that gives coronaviruses their name. This spike is what allows the virus to attach itself to the ACE2 enzyme in human cell membranes, through which it causes the symptoms of Covid-19.

The spike protein is in fact a homotrimer, or three of the same type of protein combined. By modelling the movements of the proteins in the spike, the researchers identified a 'hinge' mechanism that allows the spike to hook onto a cell, and also opens up a tunnel in the virus that is a likely means of delivering the infection to the hooked cell. The scientists suggest that by finding a suitable molecule to block the mechanism - literally, by inserting a suitably sized and shaped molecule - pharmaceutical scientists will be able to quickly identify existing drugs that could be effective against the virus.

Lead author Professor Rudolf Roemer from the Department of Physics at the University of Warwick, who conducted the work while on a sabbatical at CY Cergy-Paris Université, said: "Knowing how this mechanism works is one way in which you can stop the virus, and in our study we are the first to see the detailed movement of opening. Now that you know what the range of this movement is, you can figure out what can block it.

"All those people who are interested in checking whether the protein structures in the virus could be drug targets should be able to examine this and see if the dynamics that we compute are useful to them.

"We couldn't look closely at all the 287 proteins though in the time available. People should use the motion that we observe as a starting point for their own development of drug targets. If you find an interesting motion for a particular protein structure in our data, you can use that as the basis for further modelling or experimental studies."

To investigate the proteins' movements, the scientists used a protein flexibility modelling approach. This involves recreating the protein structure as a computer model then simulating how that structure would move by treating the protein as a material consisting of solid and elastic subunits, with possible movement of these subunits defined by chemical bonds. The method has been shown to be particularly efficient and accurate when applied to large proteins such as the coronavirus's spike protein. This can allow scientists to swiftly identify promising targets for drugs for further investigation.

The protein structures that the researchers based their modelling on are all contained in the Protein Data Bank. Anyone who publishes a biological structure has to submit it to the protein databank so that it is freely available in a standard format for others to download and study further. Since the start of the Covid-19 pandemic, scientists all over the world have already submitted thousands of protein structures of Covid-19-related proteins onto the Protein Data Bank.

Professor Roemer adds: "The gold standard in modelling protein dynamics computationally is a method called molecular dynamics. Unfortunately, this method can become very time consuming particularly for large proteins such as the Covid-19 spike, which has nearly 3000 residues - the basic building blocks of all proteins. Our method is much quicker, but naturally we have to make more stringent simplifying assumptions. Nevertheless, we can rapidly simulate structures that are much larger than what alternative methods can do.

"At the moment, no-one has published experiments that identify protein crystal structures for the new variants of Covid-19. If new structures come out for the mutations in the virus then scientists could quickly test existing treatments and see if the new mechanics have an impact on their effectiveness using our method."

Genetic mutations which occur naturally during the earliest stages of an embryo's development can cause the severe birth defect spina bifida, finds a new experimental study in mice led by UCL scientists.

The research, published in Nature Communications, explains for the first time how a 'mosaic mutation' - a mutation which is not inherited from either parent (either via sperm or egg cell) but occurs randomly during cell divisions in the developing embryo - causes spina bifida.

Specifically the scientists, based at UCL Great Ormond Street Institute of Child Health, found that when a mutation in the gene Vangl2 (which contains information needed to create spinal cord tissue) was present in 16% of developing spinal cord cells of mouse embryos, this was sufficient to produce spina bifida.

Researchers say the findings add to scientists' understanding of how and why mosaic mutations can affect and disrupt cell function, including those of neighbouring cells, helping cause birth defects.

For parents, the findings may help reduce the burden felt by those who believe their child inherited spina bifida from them via genes, and believe future children could also inherit the condition. This is often discussed during genetic counselling.

Spina bifida and current knowledge

Spina bifida is one of a group of birth defects called neural tube defects, affecting the brain or spinal cord. They happen in the first month of pregnancy, often before a woman even knows that she is pregnant. People born with this condition suffer nerve damage because part of their spinal cord remains exposed while in the womb. Advances in recent years now allow surgeons in a few centres around the world, including at Great Ormond Street Hospital and University College London Hospital, to perform surgery on foetuses in the womb to reduce the neurological consequences of their condition*.

Some neural tube defects can be prevented by taking folic acid supplements before and during early pregnancy, yet these conditions continue to affect around one in every thousand pregnancies globally. Researchers say they do not fully understand why mosaic mutations occur - though environmental factors may be involved - and cannot yet draw a link with taking (or not) folic acid during pregnancy. Notwithstanding this they say folic acid is known to help embryonic cells make DNA and encourage all expectant mothers to add folic acid to their diets from before conception.

Commenting on the potential causes, Principle Investigator, Dr Gabriel Galea (UCL Great Ormond Street Institute of Child Health), said: "Some environmental factors are known to increase the risk of these conditions occurring and very few affected individuals or their parents receive a meaningful genetic diagnosis. The discovery that mosaic mutations, which cause spina bifida, may not be inherited from either parent, and are not necessarily present in blood or saliva commonly used for genetic testing, may explain why."

Genetic mutations

Genetic mutations happen in every cell throughout development. In order to grow from a fertilised egg cell into a foetus, each of our cells must replicate and divide in order to increase in number and grow. Cells must copy their DNA every time they divide, but mistakes can happen which change the DNA sequence in the daughter cells. These DNA code mistakes, called mutations, are then inherited by all cells derived from that cell. If these mutations happen in germ cells - the egg and sperm cells - they are inherited from parent to offspring. Many mutations do not happen in germ cells, but rather in cells which give rise to specific tissue types. These are known as mosaic mutations.

Experimental study approach

In humans with spina bifida a number of gene mutations have been identified, but in many cases it had not been known whether they could cause spina bifida.

In this experimental study, researchers caused a specific mutation, which inactivates a single gene called Vangl2 in mouse embryos. This gene is part of a cellular signalling pathway which tells cells which way they are facing within a tissue. Mutations in this pathway had been identified in people who have neural tube defects, and recent reports from the USA and China previously found mosaic Vangl2¬-pathway mutations in 15% of human foetuses with spina bifida. For the cellular signalling pathway to function normally, cells must interact with their neighbours in order to communicate directional information.

For the study, researchers induced this mutation of Vangl2 in a small proportion of cells which form the developing spinal cord of mice. This was done in a number of mouse embryos. Researchers then counted the proportion of spinal cells which harboured this mutation in those which had successfully covered their spinal cord with skin (ie had developed normally), versus those which had an exposed spinal cord (had spina bifida).

Researchers found that when the mutated Vangl2 gene was present in just 16% of developing spinal cord cells, spina bifida occurred.

They say, these results show that the cellular signalling process is surprisingly vulnerable to the uninheritable mosaic mutations. Each mutant cell stops each of its neighbouring cells from functioning to promote spinal cord development. And each cell has six neighbouring cells on average, massively amplifying the effects of each mutant cell.

Explaining the findings, Dr Gabriel Galea said: "We found that the requirement for cells to talk to each other makes them exquisitely vulnerable to mutations in the signalling pathway that Vangl2 acts in. We now need to understand whether this vulnerability extends to other genes which could cause spina bifida. Detecting these mosaic mutations in living people will require technological advances and careful analysis of tissues resected during surgery."

What The Study Did: This is a diagnostic study that examines the accuracy and acceptability of a 3-dimensionally printed swab for identifying SARS-CoV-2.

Authors: David M. Allen, M.D., of the National University of Singapore, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamaoto.2020.5680)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Peer-reviewed | Observational | People

Study based on 26.5 million Medicare records finds significant racial and ethnic disparities in uptake of seasonal flu vaccine in people living in the USA aged 65 years and older during the 2015-2016 flu season.

Inequities persist among those who were vaccinated, with racial and ethnic minority groups 26-32% less likely to receive the High Dose Vaccine, which is more effective in older people, compared with white older adults.

Authors note that while these results are from the 2015-2016 flu season, the findings point to systemic failings that may hamper efforts to vaccinate against COVID-19, which disproportionately affects minority populations.

A new study published today in The Lancet Healthy Longevity journal has found significant racial and ethnic disparities in uptake of the seasonal influenza vaccine among people aged 65 years and over in the USA.

The findings, based on records from 26.5 million Medicare beneficiaries during the 2015-2016 flu season, revealed that Hispanics (29.1%), Blacks (32.6%) and Asians (47.6%) were less likely to receive a seasonal flu vaccine than whites (49.4%).

Among those who received a vaccine, there were also inequities in those who were given the High Dose Vaccine (HDV), a more effective influenza vaccine in people aged 65 and older. More than half of vaccinated white people received the HDV (53.8%) compared with 37.8% Hispanics, 41.1% Blacks and 40.3% Asians.

These inequities persisted after accounting for region, income, chronic conditions, and patterns of health care use, revealing that among the vaccinated group, minorities were 26-32% less likely to receive the HDV relative to whites.

Taken together, the researchers say their findings point to systemic failings that must be addressed to increase vaccine uptake. The findings may also be relevant for other vaccines, including COVID-19, which has disproportionately affected Blacks and other minorities.

Dr Salah Mahmud, Canada Research Chair and Professor of Community Health Sciences and Pharmacy at the University of Manitoba (Winnipeg, Canada) said: "Our finding that racial and ethnic disparities persist even among people who received a flu vaccine rules out the often-cited justifications for inequities in vaccine uptake, such as higher levels of vaccine hesitancy and distrust of public institutions among minority groups. Rather, our study points to deeply rooted structural deficits that systematically hamper access to influenza vaccination, which may be have serious implications for our ability to effectively roll out the COVID-19 vaccination programme." [1]

In the USA, seasonal flu vaccines are recommended for all adults aged 65 years and older. The High Dose flu vaccine, also known as Fluzone® High-Dose, was licensed in 2009 as an alternative to the standard-dose vaccines and has been shown to be more effective in older adults aged 65 and older because it elicits a stronger immune response. Although it is widely used in the USA, HDV is not preferentially recommended and the choice of whether to have HDV or a standard dose vaccine is left to the individual and their healthcare provider. For Medicare beneficiaries, there are no additional out-of-pocket expenses for receipt of either standard- or high-dose influenza vaccines.

A recent review has shown that flu vaccine uptake among Black and Hispanic older adults living in the community is consistently lower than white older adults. The studies included in this review, however, had significant limitations, including reliance on self-reported vaccination history, which may give a biased view.

In the latest study, researchers analysed anonymised data from the health care records of people in receipt of Medicare benefits between 1 July 2015 and 30 June 2016. The researchers focused on beneficiaries who were older than 65 years at the study start date and who were living in the community rather than in a care home, which amounted to some 26.5 million people.

Across the entire group, slightly less than half of participants received any form of flu vaccine during the 2015-2016 season (47.5%). Women were more likely to be vaccinated than men (49.5% women vs 44.8% men) but were slightly less likely to receive the HDV (52.1% women vs 53.6% men).

When the team looked at the breakdown of HDV versus standard dose among the vaccinated group, all minorities were 30-48% less likely than whites to have received the superior HDV, even after adjusting for age and gender (odds ratios [95% CI]: Black, 0.59 [0.59-0.60]; Asian, 0.58 [0.58-0.59]; Hispanic, 0.52 [0.52-0.53]; Other, 0.70 [0.70-0.71]). The gap narrowed to 26-32% after accounting for region, income, chronic conditions, and patterns of healthcare use, suggesting that these factors may mediate some, but not all of the effect of race on HDV uptake (odds ratios [95% CI]: Black, 0.68 [0.68-0.69]; Asian, 0.71 [0.71-0.72], Hispanic, 0.74 [0.73-0.74]; Other, 0.73 [0.72-0.74]).

Overall, the findings reveal stark disparities in vaccine uptake even among people who received, and presumably wanted, a flu vaccination. This suggests the differences in vaccination rates are not due to higher levels of vaccine hesitancy among minority groups and points to systemic challenges.

Dr Laura Lee Hall, President of the National Minority Quality Forum's Center for Sustainable Health Care Quality and Equity, said: "These findings are alarming because they point to a level of disparity that can hamper efforts to reduce the burden not just of flu, but for other vaccine-preventable diseases. While people of colour may face more challenges in terms of accessing health care due to lack of providers, costs, health literacy issues, and other social determinants, these factors are themselves the results of deeply ingrained discrimination and implicit bias in the health system and broader society. These failings must urgently be addressed if we are to increase uptake of vaccines among minority groups." [1]

The authors note several limitations to their study. Notably, the study only included data from the Medicare database, which may underestimate overall levels of vaccine uptake because it may not include those administered during mass vaccination campaigns. Some groups may be more likely to get vaccinated through such mass vaccination campaigns, which may skew the results between racial and ethnic groups. However, there is no reason to suspect that the extent of under-ascertainment of HDV uptake among those captured in the database varies with race or ethnicity.

Additionally, the authors caution that their findings may not be generalisable to other flu seasons. However, the pattern of inequities observed in this study is consistent with previous studies from at least the late 1990s. There is also little indication that the economic and social drivers of inequities have diminished in the last few years, as highlighted by poorer outcomes among minorities during the COVID-19 pandemic.

Writing in a linked Comment article, Dr Maria Sundaram, from the University of Toronto, and Dr John R. Pamplin II, from New York University, who were not involved in the study, said: "The study by Mahmud and colleagues highlights the reality that public health programmes that are implemented without explicit consideration of racial equity frequently produce inequities downstream. In some cases, the magnitude of these disparities might eclipse the effectiveness of the programme itself. Interventions to resolve these disparities should therefore be a primary focus among influenza epidemiology research, lest we forget a core tenet of vaccine epidemiology: vaccines do not save lives-- vaccinations do."